The tumor microenvironment (TME) surrounding tumor cells is a complex and highly dynamic system that promotes tumorigenesis. Cancer-associated fibroblasts (CAFs) are key elements in TME playing a pivotal role in cancer cells’ proliferation and metastatic spreading. Considering the high expression of the fibroblast activation protein (FAP) on cell membrane, CAFs emerged as appealing TME targets, namely for molecular imaging, leading to a pan-tumoral approach. Therefore, FAP inhibitors (FAPis) have been recently developed for PET imaging and radioligand therapy, exploring the clinical application in different tumor sub-types. The present review aimed to describe recent developments on radiolabeled FAP inhibitors and evaluate the possible translation of this pan-tumoral approach in clinical practice. At present, the application of FAPi-PET has been explored mainly in single-center studies, generally performed in small and heterogeneous cohorts of oncological patients. However, preliminary results were promising, in particular in low FDG-avid tumors such as primary liver and gastro-entero-pancreatic cancer, or in regions with unfavorable tumor-to-background ratio at FDG-PET/CT (i.e. brain), as well as in radiotherapy planning of head and neck tumors. Further promising results have been obtained in the detection of peritoneal carcinomatosis, especially in ovarian and gastric cancer. Data regarding the theranostics approach are still limited at presents, and definitive conclusion about its efficacy cannot be drawn at present. Nevertheless, the use of FAPi-based radio-ligand to treat the TME has been evaluated in first-in-human studies and appears feasible. Although the pan-tumoral approach in molecular imaging showed promising results, its real impact in day-to-day clinical practice has yet to be confirmed, and multi-center, prospective studies powered for efficacy are needed.

Podoplanin (PDPN) is a cell-surface mucin-like glycoprotein that plays a critical role in tumor development and normal development of the lung, kidney, and lymphatic vascular systems. PDPN is overexpressed in several tumors and is involved in their malignancy. PDPN induces platelet aggregation through binding to platelet receptor C-type lectin-like receptor 2. Furthermore, PDPN modulates signal transductions that regulate cell proliferation, differentiation, migration, invasion, epithelial to mesenchymal transition, and stemness, all of which are crucial for the malignant progression of tumor. In the tumor microenvironment (TME), PDPN expression is up-regulated in the tumor stroma, including cancer-associated fibroblasts (CAFs) and immune cells. CAFs play significant roles in the extracellular matrix remodeling and the development of immunosuppressive TME. Additionally, PDPN functions as a co-inhibitory molecule on T cells, indicating the involvement with immune evasion. In this review, we describe the mechanistic basis and diverse roles of PDPN in malignant progression of tumor and discuss the possibility of the clinical application of PDPN-targeted cancer therapy, including cancer-specific monoclonal antibodies, and chimeric antigen receptor T technologies.

Importance: p53 is an unequivocal tumor suppressor altered in half cancers. The immune system produces systemic p53 autoantibodies (p53 Abs) in many cancer patients. Objective: The focus of this systemic review and meta-analysis is on the prognostic value of p53 Abs expressed in the serum of patients with solid tumors. Data Sources: All the clinical investigations were searched on PubMed, MBase and Cochrane from 1993 reporting the first study until May 2021. Study Selection: Studies were included that met the following criteria: 1) participants with cancer; 2) outcome results expressed in relation to the presence of a p53 antibody; 3) a primary outcome (disease free survival, overall survival or progression free survival) expressed as hazard ratio (HR). The following exclusion criteria were used: 1) insufficient data available to evaluate outcomes; 2) animal studies; 3) studies with less than 10 participants. 1333 potentially relevant articles; studies as duplicates, non-patients studies or reviews were excluded. After viewing the titles and abstracts of the 52 remaining studies, the full texts of 34 studies were retrieved and 12 studies were included in the analysis. Data Extraction and Synthesis: PRISMA guidelines were used for abstracting and assessing data quality and validity by three independent observers. The summary estimates were generated using a fixed-effect model (Mantel–Haenszel method) or a random-effect model (DerSimonian–Laird-method) depending on the absence or presence of heterogeneity (I2). Main Outcome(s) and Measure(s): The primary study outcome was to determine the prognostic value of p53 Abs from a large population size of patients with solid tumors, as determined before data collection. Results: In total 12 clinical studies and of which 2094 patients were included and it was determined that p53-wt Abs expression in the serum significantly correlated with a worse survival of cancer patients (95% CI 1.48 [1.24, 1.77]; p<0.00001). On the contrary, data from literature indicated that there was a potential association between p53-mut Abs antibodies with better survival. Conclusions and Relevance: This is the first meta-analysis proving the diagnostic utility of p53-Abs for cancer patients, predicting a worse outcome. The serum-p53 value (s-p53-value) could be useful for future theranostics.

Background: transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, samples’ heterogeneity and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicate the interpretation of bulk transcriptomic profiles. Methods: we collected 48 microarray datasets of laser capture microdissected breast tumors, and performed a meta-analysis to identify robust lists of genes differentially expressed in these tumors. We created a database with carefully harmonized metadata to be used as a resource for the research community. Results: combining the results of multiple datasets improved the statistical power, and the analysis of stroma and epithelium separately allows identifying genes with different contribution in each compartment. Conclusions: our database can profitably help biomarkers’ discovery and is readily accessible through a user-friendly web interface (https://aurorasavino.shinyapps.io/metalcm/).

Introduction: The aim of the study was to test and validate the performance of the 2012 Briganti nomogram as a predictor for pelvic lymph node invasion (LNI) in men who underwent radical prostatectomy (RP) with extended pelvic lymph node dissection (PLND), to examine their performance and to analyse the therapeutic impact of using different nomogram cut-off . Material and methods: The study group consisted of 222 men with clinically localized prostate cancer (PCa) who underwent RP with ePLND between 01/2012 and 10/2018. Measurements included: preoperative PSA, clinical stage (CS), primary and secondary biopsy Gleason pattern and percentage of positive cores. The area under curve (AUC) of the receiver operator characteristic analysis was appointed to quantify accuracy of the primary nomogram model to predict LNI. The extent of estimation associated with the use of this model was graphically depicted using calibration plots. Results: The median number of removed lymph nodes was 16 (IQR 12-21). A total of 53 of 222 patients (23,9%) had LNI. Preoperative clinical and biopsy characteristics differed significantly (all p&lt;0.005) between men with and without LNI. A nomogram-derived cut-off of 7% could lead to a reduction of 43% (95/222) of lymph node dissection, while missing 19% (10/53) of patients with LNI. The sensitivity, specificity, and negative predictive value associated with the 7% cut-off were 81.1%, 50.3%, and 96.3%, respectively. Conclusions: Analysed nomogram demonstrated high accuracy for LNI prediction. A nomogram-derived cutoff of 7% confirmed good performance characteristics within a first external validation cohort from Poland.

Cervical cancer is the fourth most common malignancy in women worldwide, although it is preventable with prophylactic HPV vaccination. HPV transmission-dynamic models can predict the potential for global elimination of cervical cancer. The random network model is a new approach that allows individuals to be followed, and to implement a given vaccination policy according to their clinical records. We developed an HPV transmission dynamics model on a lifetime sexual partners network based on individual contacts, also accounting for the sexual behavior of men who have sex with men (MSM). We analyzed the decline in the prevalence of HPV infection in a scenario of 75% and 90% coverage for both sexes. An important herd immunity effect for men and women was observed in the heterosexual network, even with 75% coverage. However, HPV in-fections are persistent in the MSM population, with sustained circulation of the virus among un-vaccinated individuals. Coverage around 75% of both sexes would be necessary to eradicate HPV-related conditions in women within five decades. Nevertheless, the variation in the decline in infection in the long term between vaccination coverage of 75% and 90% is relatively small, suggesting that reaching coverage of around 70-75% in the heterosexual network may be enough to confer high protection. Nevertheless, HPV eradication maybe achieved if men’s coverage is strictly controlled. This accurate representation of HPV transmission demonstrates the need to maintain high HPV vaccination coverage, especially in men, for whom the cost-effectiveness of vaccination is questioned.

Background: Metastatic cancer is associated with an invariably fatal outcome. However, DeltaRex-G, a tumor- targeted retrovector encoding a CCNG1 inhibitor gene, has induced long term (>10 years) survival of patients with chemo-resistant metastatic pancreatic adenocarcinoma, MPNST, osteosarcoma, B-cell lymphoma, and breast carcinoma. Objective: To evaluate the level of CCNG1 expression in tumors as a potential biomarker for CCNG1 inhibitor therapy. Methods: CCNG1 RNA expression levels were measured in tumors (TCGA, N=9161), adjacent “tissues” (TCGA, N=678) and GTEx normal tissues (N=7187) across 22 organ sites. Differential expression of CCNG1 and Ki-67 in primary (N= 9161) vs metastatic (N= 393) tumors were also compared and particularly in primary (N=103) vs. metastatic (N=367) skin cancer (i.e., melanoma). Results: Enhanced CCNG1 RNA and protein expression were noted in tumors compared to normal analogous counterparts, and CCNG1 expression correlated significantly with that of Ki-67. Further, CCNG1 expression tended to be higher than that of Ki-67 in metastatic vs primary tumors, particularly in skin cancer (melanoma). Conclusions: Taken together, these data indicate that (1) CCNG1 expression is frequently enhanced in tumors when compared to their normal analogous counterparts, (2) CCNG1 and Ki-67 expressions are higher in metastatic vs primary tumors, (3) CCNG1 expression is significantly correlated with that of Ki-67, and (4) CCNG1 may be a stronger marker of metastasis than Ki-67. Phase 2 studies are planned to identify patients who are likely to respond favorably to CCNG1 inhibitor therapy by correlating treatment outcome parameters with CCNG1 expression levels in various cancer types.

Cancers overexpressing the ERBB2 oncogene are aggressive and associated with a poor prognosis. Trastuzumab is a ERBB2 specific recombinant antibody employed for the treatment of these diseases since it blocks ERBB2 signaling causing growth arrest and survival inhibition. While the effects of Trastuzumab on ERBB2 cancer cells are well known, those on the extracellular vesicles released from these cells are scarce. This study focused on ERBB2+ breast cancer cells and aimed to establish what type of EVs they release and whether Trastuzumab affects their morphology and molecular composition. To these aims, we performed immunoelectron microscopy, immunoblot, and high-resolution mass spectrometry analyses on EVs purified by differential centrifugation of culture supernatant. Here we show that EVs released from ERBB2+ breast cancer cells are polymorphic in size and appearance, and that ERBB2 is preferentially associated with large (120 nm) EVs. Moreover, we report that Tz induces the expression of a specific glycosylated 50 kDa isoform of the CD63 tetraspanin and modulates the expression of 51 EVs proteins, including TOP1. As these proteins are functionally associated with organelle organization, cytokinesis, and response to lipids, we suggest that Tz may influence these cellular processes in target cells at distant sites via modified EVs.

A sufficient amount of tissue sample is required to perform next-generation sequencing (NGS) with a high success rate, but the majority of patients with advanced non-small-cell lung cancer (NSCLC) are diagnosed with small biopsy specimens. Biopsy samples were collected from 184 patients with bronchoscopically diagnosed NSCLC. The tissue surface area, tumor cell count, and tumor content rate of each biopsy sample were evaluated. The impact of the cut-off criteria for the tissue surface area (≥ 1 mm2) and tumor content rate (≥ 30%) on the success rate of Oncomine Dx Target Test (ODxTT) was evaluated. The mean tissue surface area of the transbronchial biopsies was 1.23 ± 0.85 mm2 when small endobronchial ultrasonography with a guide sheath (EBUS-GS) was used, 2.16 ± 1.49 mm2 with large EBUS-GS, and 1.81 ± 0.75 mm2 with endobronchial biopsy (EBB). The proportion of samples with a tissue surface area of ≥ 1 mm2 was 48.8% for small EBUS-GS, 79.2% for large EBUS-GS, and 78.6% for EBB. Sixty-nine patients underwent ODxTT. The success rate of DNA sequencing was 84.1% and that of RNA sequencing was 92.7% over all patients. The success rate of DNA (RNA) sequencing was 57.1% (71.4%) for small EBUS-GS (n = 14), 93.4% (96.9%) for large EBUS-GS (n = 32), 62.5% (100%) for EBB (n = 8), and 100% (100%) for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (n = 15). Regardless of the device used, a tissue surface area of ≥ 1 mm2 is adequate for samples to be tested with NGS.

Background. This study aims to estimate the rate of death by cancer, according to Radio Base Stations (RBS) radiofrequency exposure, especially for the types of breast, cervix, lung and esophagus cancer. Methods. We collected information about the number of deaths by cancer, gender, age group, Gross Domestic Product per capita, death year and the amount of exposure over the lifetime. We investigated all cancer types and some specific types (breast, cervix, lung and esophagus cancers). Results. In capitals where RBS radiofrequency exposure was higher than 2,000/antennas-year, the average mortality rate was 112/100,000 for all cancers. The adjusted analysis showed that the higher the exposure to RBS radiofrequency, the higher cancer mortality. The highest adjusted risk was observed for cervix cancer (Rate Ratio = 2.18). The spatial analysis showed that the highest RBS radiofrequency exposure was observed in a city in southern Brazil, which also showed the highest mortality rate for all types of cancer and specifically for lung and breast cancer. Conclusion. The balance of our results indicates that the exposure to radiofrequency electromagnetic fields from RBS increases the rate of death by all types of cancer.

Background: Comorbidities have been frequently reported in COVID-19 patients, which often lead to more severe outcomes. The underlying molecular mechanisms behind these clinical observations have not yet been explained. Herein, we investigated the disease-specific gene expression signatures that may induce susceptibility to SARS-CoV-2 infection. Methods: We studied 30 frequently occurring acute, chronic, or infectious diseases of recent times that have shown comorbidity in one or another respiratory disease(s) caused by pathogenic human infecting coronaviruses, especially SARS-CoV-2. We retrieved array-based gene expression data for each disease and control from relevant datasets. Subsequently, all the datasets were quantile normalized, and log-2 transformed data was used for analysis. Results The expression of ACE2 receptor and host proteases, namely FURIN and TMPRSS2 that are essential for cellular entry of SARS-CoV-2, was upregulated in all six studied subtypes of leukemia (hereafter, referred as leukemia). The expression of ACE2 was also increased in psoriasis, lung cancer, Non-alcoholic fatty liver disease (NAFLD), breast cancer, and pulmonary arterial hypertension patients. The expression of FURIN was higher in psoriasis, NAFLD, lung cancer, and in type II diabetic liver, whereas it was lowered in breast cancer. Similarly, the expression of TMPRSS2 was increased during lung cancer and type II diabetes; it was decreased during psoriasis, NAFLD, lung cancer, breast cancer, and cervical cancer.Furthermore, a heightened expression of genes that are involved in immune response was observed in leukemia patients, as shown by the higher expression of IFNA2, IFNA8, IFNA10, IFNA14, IFNA16, IFNA21, IFNB1, CXCL10, and IL6. The expression of JAK1, STAT1, IL6, and CXCL10 was higher in NAFLD. Besides, JAK1 and STAT1 were upregulated in type II diabetic muscles. In addition, most of the upregulated genes in COVID-19 patients showed a similar trend in leukemia, NAFLD, and psoriasis. Furthermore, SARS-CoV-2, SARS-CoV and MERS CoV, were found to commonly alter two genes, namely, CARBONIC ANHYDRASE 11 and CLUSTERIN.Conclusions: The genes that may confer susceptibility to SARS-CoV-2 infection are mostly upregulated in leukemia patients; hence, leukemia patients are relatively more susceptible to develop COVID-19, followed by other chronic disorders, such as, NAFLD, type II diabetes, psoriasis, and hypertension. This study identifies key genes that are altered in the studied diseases types, which may aid in the infection of SARS-CoV-2 and underlie COVID-19 associated comorbidities.

Background: Bladder cancer (BC) development is highly related to immune cell infiltration and inflammation. This study aimed to construct a new classification of bladder cancer (BC) molecular subtypes based on immune cells-associated CpG sites. Methods: The genes of 28 types of immune cells were obtained from previous studies. Then methylation sites corresponding to immune cells-associated genes were acquired. Differentially methylation sites (DMSs) were identified between normal samples and bladder cancer samples. Unsupervised clustering analysis of differentially methylation sites was performed to divide into several subtypes. Then the potential mechanism of different subtypes was exploded. Result: Bladder cancer patients were divided into three groups. Cluster 3 (methylation-L) subtype had the best prognosis. Cluster 1 (methylation-M) had the worst prognosis. The distribution of immune cells, level expression of checkpoints, stromal score, immune score, ESTIMATEScore, tumor purity, APC_co_inhibition, APC_co_stimulation, HLA, MHC_class_I, Type_I_IFN_Reponse, and Type_II_IFN_Reponse were significant difference among three subgroups. The distribution of genomic alterations was different among them. Conclusion: The classification was accurate and stable. BC patients could be divided into three subtypes based on the immune cells-associated CpG sites. Specific biological signaling pathways, immune mechanisms, and genomic alterations were various among three subgroups. High level immune infiltration was a correlation with high level methylation. The lower RNAss score was associated with higher immune infiltration and higher level expression of CD274.

Over the last two months, as oncology specialists, we have frequently been contacted for estimating prognosis for cancer patients affected by COVID-19 infection. Until now, there have been no clear markers to guide decision making regarding the appropriateness of invasive ventilation in cancer patients affected by COVID-19 infection. Therefore, we developed a practical tool encompassing a prognostic score. We aimed at identifying a subgroup of patients likely to have a better outcome and therefore may be potential candidates for invasive ventilation, "The Milano Policlinico ONCOVID-ICU score". The score is composed by three groups of variables: patient’s characteristics such as sex, age, BMI and comorbidities; oncological variables (treatment intent, life expectancy, on or off-treatment status) and clinical parameters in association with laboratory values (SOFA score and D-dimer). The SOFA score includes six different clinical parameters and during the first few days of ICU admissions has an important prognostic role. The oncological history should never represent, per se, a contraindication to intensive care and must be considered together with other variables, such as laboratory values, clinical parameters and patient characteristics, in order to make the hardest but best possible choice. The Milano Policlinico ONCOVID-ICU score, to our knowledge, is the first prognostic score proposed in this setting of patients and may be a useful tool to assess the prognosis of cancer patients being in this critical condition.

Objective: Application of ERA methods to investigate the atmospheric pollution and built environment factors influencing lung cancer incidence rate in Chinese women. Methods: Lung cancer incidence rate among Chinese women at 339 cancer registries were obtained from the China Cancer Registry Annual Report 2017, air quality and built environment data were obtained from the Greenpeace and China Construction Yearbook. After multiple covariates variables were eliminated, an exploratory regression analysis was performed using the world standardized population incidence rate as the dependent variable. Air quality and built environment factors as the independent variable. Results: Shandong Peninsula, Hebei and Liaoning are high incidence rate areas of female lung cancer in China, with significant regional aggregation. In addition to air quality factors such as industrial smoke emission data, the association between built environmental factors such as urbanization rate, development LUI, population density and greening coverage of built-up areas and female lung cancer incidence rate is statistically significant. Conclusion: In addition to air quality factors, urban spatial factors can also significantly affect respiratory health. The LUI is positively while urbanization rates and population density are negatively correlated with the incidence rate of lung cancer. The role of green space for respiratory health has not been proven. In addition, there is little relationship between income and health, and similar findings are found for indicators such as the public transportation and roads network.

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance, culminating in relapse and metastatic disease continue to be associated with fatal disease. Cancer stem cells (CSCs) are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterised in many cancers with data illustrating that CSCs display great abilities to self-renew, withstand therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ABC membrane transporters, activation of several survival signaling pathways and increased immune evasion DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we re-visit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

Targeted radioisotope-guided sentinel lymph node dissection (sLND) has shown high diagnostic accuracy in prostate cancer (PCa). To overcome the downsides of the radioactive tracers, magnetometer-guided sLND using superparamagnetic iron oxide nanoparticles (SPIONs) was successfully applied in PCa. This prospective study (SentiMag Pro II, DRKS00007671) determined the diagnostic accuracy of magnetometer-guided sLND in intermediate- and high-risk PCa. Fifty intermediate- or high-risk PCa patients (PSA≥10 ng/ml and/or Gleason score ≥7; median PSA 10.8 ng/ml, IQR 7.4–19.2 ng/ml) were enrolled. After intraprostatic SPIONs injection a day earlier, patients underwent magnetometer-guided sLND and eLND, followed by radical prostatectomy. SLNs were detected in vivo and in ex vivo samples. Diagnostic accuracy of sLND was assessed using eLND as the reference. SLNs were detected in all patients (detection rate 100%), with 447 SLNs (median 9, IQR 6–12) being identified and 966 LNs (median 18, IQR 15-23) being removed. Thirty-six percent (18/50) of patients had LN metastases (median 2, IQR 1–3). Magnetometer-guided sLND had 100% sensitivity, 97.0% specificity, 94.4% positive predictive value, 100% negative predictive value, 0.0% false negative rate, and 3.0% additional diagnostic value (LN metastases only in SLNs outside the eLND template). In vivo, one positive SLN/LN-positive patient was missed, resulting in a sensitivity of 94.4%. In conclusion, this new magnetic sentinel procedure has high accuracy for nodal staging in intermediate- and high-risk PCa. The reliability of intraoperative SLN detection using this magnetometer system requires verification in further multicentric studies.

Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity; however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16–18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms’ tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.

Triploidy in cancer is associated with poor prognosis but its origins remain unclear. Here, we attempted to differentiate between random chromosomal and whole-genome origins of cancer triploidy. In silico meta-analysis was performed on 15 male malignant and 5 benign tumour cohorts (2928 karyotypes) extracted from the Mitelman Database, comparing their ploidy and combinations of sex chromosomes. A distinct near-triploid fraction was observed in all malignant tumour types, being especially high in seminoma. For all tumour types, X-chromosome doubling, predominantly observed as XXY, correlated strongly with the near-triploid state (r≈0.9, p<0.001), negatively correlated with near-diploidy, and did not correlate with near-tetraploidy. A smaller near-triploid component with a doubled X-chromosome was also present in 3 of 5 benign tumour types, especially notable in colon adenoma. Principal Component Analysis revealed a non-random correlation structure shaping the X-chromosome disomy distribution across all tumour types. We suggest that doubling of the maternal genome followed by pedogamic fusion with a paternal genome (a possible mimic of the fertilization aberration, 69, XXY digyny) associated with meiotic reprogramming may be responsible for the observed rearrangements of genome complements leading to cancer triploidy. The relatively frequent loss of the Y-chromosome results secondary from chromosome instability.

Background: Improving patients’ quality of life (QoL) is a principal objective of all treatment in any clinical setting, including oncology practice. Cancer-associated inflammation is implicated in disease progression and worsening of patients’ QoL. Conventional anticancer therapeutics while selectively eliminating cancerous cells, are evaded by stem cell-like cells, and associated with varying degrees of adverse effects, thus reducing patients’ QoL. This necessitates novel therapeutic approaches with enhanced efficacy, minimal or no treatment-related adverse effects, and improved QoL in patients with cancer, especially those with metastatic/advance stage disease. Methods: Sequel to our team’s previous publication, the present study explores probable effects of Astragalus polysaccharides (PG2) on cancer-related inflammatory landscape and known determinants of QoL, as well as the probable link between the two to provide mechanistic insight. In exploratory double blind randomized controlled trial using patients with metastatic disease (n=23), we comparatively evaluated the therapeutic efficacy of high (500mg) or low (250mg) dose PG2 administered intravenously (i.v.), with particular focus on its suggested anti-inflammatory function and the probable effect of same on QoL indices at baseline, then at weeks 4 and 8 post-PG2 treatment. Results: All 23 patients with metastatic disease treated with either low or high PG2 experienced reduced pain, nausea, vomiting and fatigue, as well as better appetite and sleep, culminating in improved global QoL. This was most apparent in the high dose group, with significant co-suppression of pro-inflammatory interleukin (IL)-1β, IL-4, IL-6, IL-13, IL-17, monocytes chemotactic protein (MCP)1, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), tumor growth factor (TGF)-β1, interferon (IFN)-γ, and immune suppressors IL-10, and IL-12. Univariate and multivariate analyses revealed that IL-1β, IL-13 and GM-CSF are independent prognosticators of improved QoL. Conclusion: This proof-of-concept study provides premier evidence of functional association between PG2 anti-inflammatory effects and improved QoL in patients with advanced stage cancers, laying the groundwork for future larger cohort blinded controlled trials to establish the efficacy of PG2 as adjuvant anticancer therapy in metastatic or advanced stage clinical settings.

Doxorubicin (DOX) is a frequently used chemotherapeutic drug for breast cancer, but its site specificity and local internalization into tumor cells is rather low. In this paper we conjugated magnetic nanoparticles (MNPs) with DOX and/or a pseudopeptide NucAnt (N6L) as modality to enhance DOX-induced antitumor effects in breast cancer cells (BT474). In this context, we determined cellular uptake of MNP formulations, analyzed cell viability and expression of apoptotic and cell cycle proteins after magnetic hyperthermia (43°C, 1 h) in vivo and in vitro. We have shown that i) the presence of N6L on the surface of DOX-functionalized MNPs increases their internalization into a target cells and potentiates the cytotoxic potential of the anticancer drug, ii) in combination with hyperthermia, DOX functionalized MNPs influence the expression of apoptotic and cell cycle proteins, and also favors tumor regression in vivo. Our data show that intratumoral application of DOX coupled MNPs is able to overcome biological barriers to chemotherapeutic drugs, enabling them to penetrate into the target cells. Combined with hyperthermia these MNPs can be an effective method in enhancing the localised delivery and penetration of DOX into breast cancer cells.

The search for improved therapeutic approaches to breast cancer are still on going. Breast tumor kinase (BRK, also known as PTK6) is one of the targets, it is highly expressed in breast carcinomas while displaying low or no expression in the normal mammary gland, which hints at the oncogenic role of this enzyme in breast cancer. In these twenty years, an increasing number of studies have focused on understanding the cellular roles of BRK in breast cancers. This review outlines the advances made towards understanding the cellular and physiological role of BRK, the molecular and chemical inhibitors and its therapeutic significance in breast cancer.

Sea anemones are a remarkable source of active principles due to a decentralized venom system. Blood vessel formation or angiogenesis is a very promising target against cancer, but the few available anti-angiogenic compounds have a limited efficacy. In this study, a protein fraction was purified from tentacles of Anemonia viridis able to limit endothelial cells proliferation and vessel network formation or angiogenesis at low concentration (14 nM). The sequences in this protein fraction were determined with Edman degradation and Mass Spectrometry In Source Decay and revealed homologies with BDS sea anemones. The presence of a two turn alpha helix observed with Circular Dichroism and a trypsin activity inhibition suggested that the active principle could be a Kunitz-type inhibitor, which may interact with an integrin due to a RGD motif well exposed to the solvent as revealed by Molecular Modeling. This active principle could improve antiangiogenic therapy from existing antiangiogenic compounds binding on the VEGF.

Some of the most promising small molecule toxins used to generate antibody drug conjugates (ADCs) include anti-mitotic agents (e.g auristatin and its derivatives) which are designed to attack cancerous cells at their most vulnerable state during mitosis. We were interested to identify a human cystostatic protein eventually showing comparable activities and allowing the generation of corresponding targeted fully human cytolytic fusion proteins. Recently, we identified the human microtubule associated protein tau (MAP tau) which binds specifically to tubulin and modulates the stability of microtubules thereby blocking mitosis and presumably vesicular transport. By binding and stabilizing polymerized microtubule filaments, MAP tau-based fusion proteins skew microtubule dynamics towards cell cycle arrest and apoptosis. This biological activity makes rapidly proliferating cells (e.g cancer and inflammatory cells) an excellent target for MAP tau-based targeted treatments. Their superior selectivity for proliferating cells confers additional selectivity towards upregulated tumor-associated antigens at their surface, thereby preventing off-target related toxicity against normal cells bearing tumor-associated antigens at physiologically normal to low levels. In this review, we highlight recent findings on MAP tau-based targeted cytolytic fusion proteins reported in preclinical immunotherapeutic studies.

Maintenance of integrity and function of the gastric mucosa (GM) requires a high regeneration rate of epithelial cells during the whole life span. The health of the gastric epithelium highly depends on redox homeostasis, antioxidant defense and activity of detoxifying systems within the cells as well as robustness of blood supply. Bioactive products of lipid peroxidation, in particular second messengers of free radicals, the bellwether of which is 4-hydroxynonenal (HNE), are important mediators in physiological adaptive reactions and signaling but they are also thought to be implicated in the pathogenesis of numerous gastric diseases. Molecular mechanisms and consequences of increased production of HNE and its protein adducts in response to stressors during acute and chronic gastric injury are well studied. However, several important issues related to the role of HNE in gastric carcinogenesis, tumor growth and progression, the condition of GM after eradication of Helicobacter pylori, or the relevance of antioxidants for HNE-related redox homeostasis in GM still need more studies and new comprehensive approaches. In this regard, preclinical studies and clinical intervention trials are required, which should also include the use of state-of-the-art analytical techniques such as HNE determination by immunohistochemistry and ELISA as well as modern mass-spectroscopy methods.

The Golgi apparatus (GA) dysfunctions in Parkinson’s Disease (PD), neurodevelopmental disorders (NDDs), cancer, and organelle structural biology (OSB) can provide insights into therapeutic targets, gene therapy, and drug design. Primary defects and fragmentation within the GA are implicated in a wide range of neurodegenerative diseases. GA defects typically result in mislocation of proteins, accumulation of undegraded proteins, and impaired glycosylation of proteins. Inhibition of vesicular trafficking by α-synuclein (aSyn) may affect the dopamine-producing neurons and neuromodulators. GA regulates apoptosis during pathological mechanisms of neurological diseases and could provide new avenues in treatments through translation research. PD patients bearing the hereditary E46K disease mutation manifest the clinical picture of parkinsonism. How do we provide high resolution nanoimages of the GA during disease to capture dysfunction? Could we visualize the aSyn traffic jam between vesicles in the organelles ER and GA? OSB is emerging as a field as more technology advances and is more accessible. Structural studies of the GA will advance the field of neurological disease forward with an in depth understanding of dysfunction, fragmentation, and defects. Discoveries of the GA in PD, NDDs, and cancer would break new ground and provide translational medicine data of these diseases. Future research could be visualizing high angle annular dark field-STEM (HAADF-STEM) tomograms, cryogenic electron tomography (cryo-ET), multiplex correlative light and electron microscopy (cryo-CLEM), nanobody-assisted tissue immunostaining for volumetric EM (NATIVE) and using soft X-ray tomography (SXT) and computational reconstruction of the GA.

Introduction: Identifying the complexity of palliative care needs is a key aspect of referral to specialised multidisciplinary early palliative care (EPC) teams. The PALCOM scale is an instrument consisting of five multidimensional assessment domains, developed in 2018 and validated in 2023, to identify the level of complexity in patients with advanced cancer. Objectives: The main objective of this study was to determine the degree of instability (likelihood of level change or death), health resource consumption and survival of patients according to the level of palliative complexity assigned at the baseline visit during a 6-month follow-up. Method: An observational, prospective, multicentre study was conducted using pooled data from the development and validation cohort of the PALCOM scale. The main outcome variables were: a) instability ratio (IR), defined as the probability of level change or death; b) emergency department visits; c) days of hospitalisation; d) hospital death; e) survival. All variables were analysed monthly according to the level of complexity assigned at the baseline visit. Results: A total of 607 patients with advanced cancer were enrolled. According to the PALCOM scale, 20% of patients were classified as low complexity, 50% as medium and 30% as high complexity. The overall IR was 45% in the low complexity group, 68% in the medium complexity group and 78% in the high complexity group (p

Matrix metalloproteinase 3 (MMP3) plays multiple roles in pro-tumorigenic proteolysis and in intracellular transcription. These include inducing connective tissue growth factor [CTGF, also known as cellular communication network factor 2 (CCN2)] and prompting a new definition of MMP3 as a moonlighting metalloproteinase. Members of the MMP family have been found within tumor-derived extracellular vesicles (EVs) such as oncosomes or exosomes. We here investigated the roles of MMP3-rich oncosomes in tumor progression, molecular transmission, and gene regulation. MMP3 and CCN2/CTGF were significantly co-expressed in tumor samples derived from patients suffering from colorectal adenocarcinoma. We found that oncosomes derived from a rapidly metastatic colon cancer cells (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich oncosomes were highly transmissive into recipient cells and were pro-tumorigenic in an allograft mouse model. Oncosome-derived MMP3 was transmissive into recipient cell nuclei, trans-activated CCN2/CTGF promoter, and induced CCN2/CTGF production at 1 to 6 hours after the addition of oncosomes to culture media. In addition, CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects, including inhibition of migration and invasion of LuM1 cells in vitro, inhibition of tumor growth in vivo, and reduction of CCN2/CTGF and its promoter activity in vitro. These data newly demonstrate that the oncosome-derived moonlighting metalloproteinase promotes metastasis and is pro-tumorigenic at distant sites as well as a transmissive trans-activator for the cellular communication network gene.

A distinctive feature of the SARS-CoV-2 spike protein is its ability to efficiently fuse cells, thus producing syncytia found in COVID-19 patients. This commentary proposes how this ability enables spike to cause COVID-19 complications as well as side effects of COVID-19 vaccines, and suggests how these effects can be prevented..

Neutrophils are the principal trouper of innate immune system. Activated neutrophils undergo a noble cell death termed NETosis and release a mesh-like structure called neutrophil extracellular traps (NETs) as a part of their defensive strategy against microbial pathogen attack. This web-like architecture includes a DNA backbone embedded with antimicrobial proteins like myeloperoxidase (MPO), neutrophil elastase (NE), histones etc. and deploys in the entrapment and clearance of encountered pathogens. Thus NETs play an inevitable beneficial role in the host's protection. However, recent accumulated evidence shows that dysregulated and enhanced NET formation has various pathological aspects including promotion of sepsis, pulmonary, cardiovascular, hepatic, nephrological, thrombotic, autoimmune, pregnancy, cancer diseases etc. and the list is increasing gradually. In this review, we summarize NETs mediated pathophysiology of different diseases, focus on some updated potential therapeutic approaches against NETs and share our future perspectives.

The fresh bulbs of Stenomesson miniatum, a plant belonging to Amaryllidaceae family with a poorly investigated phytochemical profile, were traditionally employed by Andean healers to treat tumors and abscesses. The aims of this study were to characterize the alkaloid extract from the bulbs of S. miniatum and test its cytotoxic and antibacterial potential. The alkaloid extract was characterized by dereplication using various techniques (CPC, NMR, UPLC-HRMS) and referring to in-home or online databases for spectroscopic data matching. Cytotoxic activities were evaluated on A431 human epidermoid carcinoma cells through a metabolic assay, and on Jurkat human acute T-leukemia cells through a cell-impermeant fluorescent nuclear probe. Antibacterial assays were carried out against Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pyogenes by using a standardized microdilution broth method 96-well plate. Eleven known Amaryllidaceae alkaloids were identified together with another compound determined as being an extraction artefact. The alkaloid extract showed good cytotoxic activity against both the tumor cell lines, reaching an IC50 of 3.3 µg/mL against A431 cells and of 10.9 µg/mL against Jurkat cells. The analysis of the fractions allowed the activity to be attributed to the presence of pretazettine and haemathamine. Conversely, no antibacterial activities were recorded for any of the samples.

Colonization of distant organs by tumor cells is a critical step of cancer progression. The initial avascular stage of this process (micrometastasis) remains almost inaccessible to study due to the lack of relevant experimental approaches. Here, we introduce an in vitro/in vivo model of organ-specific micrometastases of triple-negative breast cancer (TNBC) that is fully implemented in a cost-efficient chick embryo (CE) experimental platform. The model is built as three-dimensional (3D) tissue engineering constructs (TECs) combining human MDA-MB-231 cells and decellular-ized CE organ-specific scaffolds. TNBC cells colonized CE organ-specific scaffolds in 2-3 weeks, forming tissue-like structures. The feasibility of this methodology for basic cancer research, drug development and nanomedicine was demonstrated on a model of hepatic micrometastasis of TNBC. We revealed that MDA-MB-231 differentially colonize parenchymal and stromal com-partments of the liver-specific extracellular matrix (LS-ECM) and become more resistant to the treatment with molecular Doxorubicin (Dox) and Dox-loaded mesoporous silica nanoparticles than in monolayer cultures. When grafted on CE chorioallantoic membrane, LS-ECM-based TECs induced angiogenic switch. These findings may have important implications for the diag-nosis and treatment of TNBC. The methodology established here is scalable and adaptable for pharmacological testing and cancer biology research of various metastatic and primary tumors.

The delineation of the clinical target volumes (CTVs) for radiation therapy is time-consuming, requires intensive training and shows high inter-observer variability. Supervised deep learning methods depend heavily on consistent training data, thus state-of-the-art research focuses on making CTV labels more homogeneous and strictly bounding them to current standards. International consensus expert guidelines standardize CTV delineation by conditioning the extension of the clinical target volume on surrounding anatomical structures. Training strategies that directly following the construction rules given in the expert guidelines or the possibility to quantify the conformance of manually drawn contours with the guidelines are still missing. 71 anatomical structures that are relevant for CTV delineation in head and neck cancer patients according to the expert guidelines were segmented on 104 CT scans to assess the possibility to automate their segmentation by state-of-the-art deep learning methods. nnU-Net models were trained to automatically segment those 71 structures on planning CT scans. We report the DICE, HD and sDICE for 71 + 5 anatomical structures for most of which no previous segmentation accuracies have been reported. For those structures, for that prediction values have been reported, our segmentation accuracy matched or exceeded the reported values. The predictions from our models were always better than those predicted by the TotalSegmentator. The sDICE with 2mm margin was larger than 80% for almost all structures. Individual structures with decreased segmentation accuracy are analyzed and discussed with respect to their impact on the CTV delineation following the expert guidelines. No deviation is expected to affect the rule-based automation of the CTV delineation.

Drp1 is considered the master regulator of mitochondrial fission and affects the proper segregation during mitosis. Here, we identified two clusters on mitochondria, including Drp1-Ser-616/Mff/Mid51 and-Drp1-Ser637/Fis1/Mid49 for midzone fission (division) and peripheral fission signatures, respectively. This study revealed that phospho-Drp1-Ser637 is involved in mitigating mitochondrial oxidative stress, resolving a long-standing localization issue. Additionally, we demonstrated that Mid49 and Mid51 exhibit distinct functions in recruiting Drp1 for mitochondrial fission. It also confirmed the essential role of the Fis1 and Mid49 adaptors contributed into mitochondrial fission within the phospho-Drp1-Ser637/Fis1/Mid49 cluster during M-phase. Moreover, it suggested that there is mutual exclusivity between two clusters of phospho-Drp1 with four adaptors on mitochondria, as well as varied responses to specific anti-cancer drugs during mitotic arrest. Remarkably, the upregulation of the spindle assembly checkpoint (SAC) was also observed, ensuring the prolongation of M-phase with the formation of multipolar spindles. Collectively, the phospho-Drp1-637/Fis1/Mid49 cluster may not only function in peripheral fission (mitophagy) but also serve as a key SAC coordinator for the regulation of spindle assembly during mitotic arrest. These findings appear to be mutually exclusive of phospho-Drp1 with four adaptors on mitochondria and vary in response to specific anti-cancer drugs.

Background: Patients with locally advanced/metastatic urothelial cancer have been conventionally treated with platinum-based chemotherapy. Recently, numerous new treatments have been proposed to improve overall survival (OS) and reduce adverse effects, but no head-to-head direct comparison is available. Methods: We considered: a) monotherapy with immune checkpoint inhibitors (ICI); b) combinations of an ICI with chemotherapy; c) combinations of an ICI with other drugs. An indirect comparison was performed to identify the regimens most effective in prolonging OS compared to each other and to chemotherapy. Results: A total of 6 articles were included. In our final analysis, nivolumab plus chemotherapy showed better OS compared to chemotherapy (HR= 0.70, 95%CI: .59-0.82); while durvalumab plus tremelimumab showed no OS benefit (HR=0.95, 95%CI 0.82-1.11). More interestingly, enfortumab vedotin plus pembrolizumab significantly prolonged OS compared to both chemotherapy alone (HR=0.53, 95%CI 0.45-0.63) and nivolumab plus chemotherapy (HR= 0.76, 95%CI 0.60-0.97). Discussion and conclusion: Among new treatments for locally advanced and metastatic urothelial cancer, enfortumab vedotin + pembrolizumab showed the best efficacy in terms of OS. Our results support the use of this combination as first-line treatment in this setting.

Background: Fine-needle aspiration cytology (FNAC) is widely used to diagnose and monitor thyroid nodules. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is the standard for interpreting FNAC specimens. The risk of malignancy in Bethesda III nodules also known as Atypia of Undetermined Significance (AUS) varies significantly throughout several studies published worldwide. This retrospective study examines the risk of cancer in thyroid FNAC categorized as Bethesda III, as identified in the final histopathology of thyroidectomy specimens at a single endocrine surgery center. Methods: This retrospective cohort analysis included 1038 consecutive patients who underwent elective thyroid surgery with complete follow up data between January 2020 and March 2024. Preoperative data on clinical and pathological characteristics have been collected. The final histopathology report from the thyroidectomy specimen was compared to the results of the preoperative FNAC on nodules that were judged to be Bethesda category III. Statistical methods were performed using SPSS version 29. Results: A total of 670 ultrasound-guided FNACs (64.5%) performed during the study period were included in the final analysis. The study population was predominantly female, represented by 79.6% of patients with a mean age of 42.5 (SD 12.1), while 20.4% were male and significantly older with mean age 45.13 years (p = 0.02). The FNAC inadequacy rate was 5.1%, which was associated with a high risk of malignancy (6 out of 34, 17.6%). Out of the total sample size of 170 patients classified as group III, 57 were found to have malignancies in final surgical histopathology, representing 33.5% of the cases within this category. The secondary gender-related outcome analysis showed that female patients classified under the Bethesda II category had a significantly higher risk of malignancy, with a rate of 21.2%, compared to males who had a malignancy rate of 3.4% in the same Bethesda category (p = 0.001, chi square test). However, female had more better prognostic non-invasive tumors than male (p = 0.02, chi square test). Conclusion: The study's results indicate that Bethesda categories II and III are associated with a higher risk of malignancy in comparison to the reports of the first and third editions of the TBSRTC, particularly for female patients classified under category II.

Non-Small Cell Lung Cancer (NSCLC) is the most common pulmonary malignancy, most frequently diagnosed at an advanced stage (III/IV). Patients in the Locally-Advanced Stage Subgroup (IIIA) are relatively few, yet compose of heterogenic phenotypes posing a diagnostic and treating challenge, leading to lack of clinical guidelines regarding the optimal standard of care. Several approaches exist, with a general agreement that a combined oncological and surgical modality approach is required. In this current retrospective descriptive study, operable Stage IIIA NSCLC patients who underwent surgery between 2013-2020 were evaluated on several aspects, including initial diagnosis, neoadjuvant regimens, outcomes of surgical intervention, overall survival at 2-years and 5-years following treatment. A total of 35 patients had neoadjuvant oncological treatment (mostly chemoradiation therapy) prior to surgery, out of which 28 patients were diagnosed with Stage IIIA NSCLC. In post-operative assessment of pathological staging, downstaging was reported in 20 patients, of which 7 (25%) cases were defined as complete pathological response. The 2-years overall survival rate was 65% and the 5-years overall survival rate was 60%. The main pattern of disease recurrence was distant metastasis.

Reactive oxygen species (ROS) play an important role in biological processes and offer hope for the development of effective treatments for ROS-dependent diseases, including cancer. The interaction of hydrogen peroxide with proteins stimulates the creation of chemical molecules that can weaken or stop the pathological process in cancer. However, reliable drugs have not yet been described. To understand the reason for the failure, we studied the behavior of ROS-containing compounds in cancer cells. The epidermal growth factor receptor (EGFR) is activated by interaction with a ligand protein, as well as by binding the chemical structure of hydrogen peroxide to the catalytic cysteine in the intracellular domain. Both mechanisms trigger signaling pathways in cells. The EGFR can be inactivated by protein tyrosinase phosphatase PTP-1B, which itself is activated by hydrogen peroxide. A simple in-gel fluorescence technique was used to demonstrate the rapid binding of hydrogen peroxide to a large number of proteins, including both activating and inactivating target proteins. Natural defense systems take longer to action and apparently cannot prevent hydrogen peroxide from binding to protect cells from exposure to unwanted proteins. Therefore, superoxide dismutase, which produces hydrogen peroxide, is not a suitable target for disease therapy.

This study delves into the realm of potential therapeutics for breast cancer by conducting a comprehensive docking simulation and virtual screening analysis using Autodock Vina Algorithm. The focus based on the human epidermal growth factor receptor 2 (HER2), a key protein associated with various cancers, particularly in the context of breast cancer.The results reveal compelling insights into the binding interactions of several natural compounds and drugs with HER2. Notably, Acebilustat, Bemcentinib, and Amentoflavone exhibit outstanding binding energies, averaging around -10 kcal/mol, suggesting strong and favorable interactions with the HER2 target.These encouraging findings not only emphasize the potential biological significance of these compounds but also hint at their potential usefulness in fighting breast cancer.Their promising binding affinities with HER2 position them as potential candidates for further investigation and development as therapeutic agents against breast cancer.

Bacteriophages are viruses obligately infecting bacteria. They constitute the most numerous categories of biological forms populating our biosphere and are highly diverse and capable of infecting almost all bacteria. Phages make use of their host cell molecular machinery to express their own genes as they lack the ability to independently reproduce themselves. The inimitable characteristics of bacteriophages have enabled them to become propitious tools in biotechnology and genetic engineering. Phages show no tropism for mammalian cells but however, can be easily modified to present targeting ligands on their surface as coat protein fusions without any negative impacts on phage structure. These displayed ligands thereupon guide the recognition, interaction, and internalization of the phage into cells wherein efficiency of transfection is directly influenced by the copy number of the ligands used for targeting. Engineered phages are more efficacious for transgene delivery and gene expression in cancer cells when compared to other non-viral gene transfer strategies and are therefore being employed in developing cancer vaccines. The high level of stability as well as resistance of bacteriophages to various environmental conditions have enabled the development of virus-like particles (VLPs) capable of successful deliverance of several therapeutic drug cargos into tumors by selective targeting. Phage display technology has been used in therapy of Alzheimer’s disease and drug delivery into the brain. Exogenous peptides fused into the coat protein of phages enables the display of these peptides on the phage surface to generate combinatorial phage that facilitates their rapid separation using their ability to bind to a specific molecular target. Phage therapy has been shown to be safe in clinical settings when compared to antibiotics as it shows no adverse anaphylaxis nor adverse effects such as the emergence of multi-drug resistant bacteria. This review provides intriguing details of the use of natural and engineered phages in the therapy of diseases such as cancer, bacterial infections, bovine mastitis and dementia in addition to the use of CRISPR-Cas9 technology in generating genetically engineered phages. Further, the use of phage display technology in generating monoclonal antibodies against various human diseases is elucidated.

As breast cancer continues to take a devasting public health toll, most primary prevention approaches are targeted at individual actions. We have proposed, instead, developing systemic, population approaches to preventing the disease. We used a combined qualitative-quantitative methodology, Group Concept Mapping (GCM), to identify Importance and Feasibility ratings of systemic interventions across a wide spectrum of approaches and stakeholders. Participants (n=351) from across the state of California sorted 84 potential interventions into topical piles, and then rated each intervention on perceived Importance and Feasibility. Multidimensional scaling and cluster analysis identified eleven clusters or themes of interventions. Participants rated interventions on Importance and Feasibility differently depending on the region of the state in which they lived. The results of this study underscore the importance of sharing health information with and seeking public health solutions from community partners in general and from beyond the urban areas usually studied.

Obesity is one of the most prevalent chronic diseases and has become a global epidemic. Obesity leads to a greater risk of breast cancer (BC), metastases, recurrence, and decreased survival. For sustained weight loss, bariatric surgery is effective as a long-term solution. Bariatric surgery is associated with improved outcomes of several cancers including BC, although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Indeed, patients with greater expression of the bile acid receptor FXR displayed improved survival in specific BC subtypes. Patients with tumors that are estrogen receptor negative (ER-) displayed significantly elevated survival with higher FXR (NR1H4) expression compared to lower expression. FXR is a nuclear hormone receptor activated by bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would display anticancer effects. Indeed, FXR agonism by the bile acid mimetic known commercially as OCALIVA (“OCA”), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor (GPBAR1, TGR5) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. Findings suggest that FXR is a tumor suppressor gene with high potential for personalized therapeutic strategies for individuals with BC.

Resistance to therapy and disease progression are the main causes of mortality in most cancers. In particular, the development of resistance is an important limitation affecting the efficacy of therapeutic alternatives for cancer, including chemotherapy, radiotherapy, and immunotherapy. Signaling pathways are largely responsible for the mechanisms of resistance to cancer treatment and progression, and multiple myeloma is no exception. p38 mitogen-activated protein kinase (p38) is downstream of several signaling pathways specific to treatment resistance and progression. Therefore, in recent years, developing therapeutic alternatives directed at p38 MAPK has been of great interest, in order to reverse chemotherapy resistance and prevent progression. In this review, we discuss recent findings on the role of p38, including recent advances in our understanding of its expression and activity as well as its isoforms, and its possible clinical role based on the mechanisms of resistance and progression in multiple myeloma.

Аnalysis of small RNA sequencing data across a range of biofluids is a significant research area, given the diversity of RNA types that holds potential diagnostic, prognostic, and predictive value. The intricate task of segregating the complex mixture of small RNAs from both human and other species, including bacteria, fungi, and viruses, poses one of the most formidable challenges in the analysis of small RNA sequencing data, currently lacking satisfactory solutions. This study introduces sRNAflow, a user-friendly bioinformatic tool with a web interface designed for the analysis of small RNAs obtained from biological fluids. Tailored to the unique requirements of such samples, the proposed pipeline addresses various challenges, including filtering potential RNAs from reagents and environment, classifying small RNA types, managing small RNA annotation overlap, conducting differential expression assays, analysing isomiRs, and presenting an approach to identify the sources of small RNAs within samples. sRNAflow also encompasses an alternative alignment-free analysis of RNA-seq data, featuring clustering and initial RNA source identification using BLAST. This comprehensive approach facilitates meaningful comparisons of results between different analytical methods. The source code can be accessed at https://github.com/zajakin/sRNAflow under the GPL3 licence.

Background: One of the most astounding discoveries of recent times is the recognition that cancer embodies a transition from a higher level of metazoan cell organization to a more foundational pre-metazoic state. This shift is steered by genes housed within the ancestral genome compartment, pervasive across all metazoan genomes, encompassing humans, and governed by a pre-metazoic gene regulatory mechanism (aGRN). This work aims to highlight the emerging field of evolutionary cancer cell biology (ECCB), which points to the deep homology between cancer and protist life cycles tracing back to the common ancestor of amoebozoans, metazoans, and fungi (AMF). The ECCB analysis reveals the essence of the non-gametogenic germline of the AMF ancestor, which serves as a blueprint for all metazoan germlines and stem cell lineages and controls the life cycle of cancer. Every germ and stem cell lineage of humans and metazoans traces its lineage back to this Urgermline, transmitting crucial processes such as asymmetric cell cycling, differentiation, stemness, and phenomena like GST and SGT (aka EMT and MET) to their subsequent evolutionary descendants. Oxygen-sensitive germline and stem cells suffer DNA-DSB due to stress and oxygen ranges reminiscent of ancestral hyperoxia, leading to cell senescence. Cells that can overcome senescence can proliferate as DSCD cells with defective symmetric cell division, paving the way for malignancy and PGCC cancers. Conclusions: Understanding cancer from its evolutionary origins may help break some of the logjams in cancer prevention and open up new therapeutic pathways.

Protein-drug interactions are crucial for understanding drug delivery and cell functions. Jacalin is a suitable molecule for such targeting, as it specifically recognizes the tu-mor-associated Thomsen-Friedenreich antigen that is expressed on the glycosylated proteins in cancer cells. The present paper describes the interaction of curcumin and jacalin, a possible carrier molecule for the delivery of antitumor drugs due to its ability to recognize tumor cells. Our results have shown that both steady state fluorescence and fluorescent label-ling of jacalin are two reliable methods to determine jacalin-curcumin interactions. The affinity of jacalin for curcumin is consistently within the micromolar range (using flu-orescence and microscale thermophoresis) showing high-affinity binding of the com-plex. In vitro experiments on the triple negative breast cancer MDA-MB-231 cells indi-cated inhibition of cell growth after treating with the jacalin-curcumin complex for 48 h. The cell survival fraction was significantly reduced to 50% after combined treatment. In this paper, we report for the first time about the jacalin-curcumin interaction. We quantified this unique biomolecular interaction and gathered additional information on the binding event. We observed that the jacalin-curcumin complex inhibits the proliferation of the triple negative breast cancer MDA-MB-231 cells.

Different prognostic scores have been applied to identify patients with non-small cell lung cancer who have a higher probability of poor outcome. In this study we evaluated whether Naples Prognostic Score, a novel index which considers both inflammatory and nutritional values, was associated with long-term survival. The study is a retrospective propensity score matching analysis of patients who underwent curative surgery for non-small cell lung cancer from January 2016 to December 2021. The score considered four pre-operative parameters: neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio, serum albumin and total cholesterol. Kaplan-Meier method and Cox regression analysis were performed to evaluate the relation between the score and disease-free survival, overall survival and cancer-related survival. A total of 260 patients were selected for the study, reduced to 154 after propensity score matching. Post-propensity Kaplan-Meier analysis showed a significant correlation between Naples Prognostic Score and overall survival (p=0.018) and cancer-related survival (p=0.007). Multivariate Cox regression analysis further validated the score as an independent prognostic indicator for both these survivals (p=0.007 and p=0.010 respectively). Naples Prognostic Score proved to be an easily achievable prognostic factor of long-term survival in patients with non-small cell lung cancer after surgical treatment.

Machine learning (ML) techniques can help predict survival among cancer patients and might help with a timely integration in palliative care. We aim to explore the importance of subjective variables self-reported and collected via electronic patient reported outcome measure (ePROM) for survival prediction. A total of 256 advanced cancer patients met the eligible criteria. We analyzed objective variables collected from electronic health records, subjective variables collected via ePROM and all clinical variables combined. We used logistic regression (LR), decision trees, and random forests to predict 1-year mortality. Receiver operating characteristic (ROC) curve - area under the curve (AUC) and the ML models feature importance were analyzed. The performance of all variables for predictions (LR reaches 0.80 [ROC AUC] and 0.72 [F1 Score]) does not improve over the performance of only clinical non-patient reported outcome (non-PRO) variables (LR reaches 0.81 [ROC AUC] and 0.72 [F1 Score]). Our study indicates that patient-reported outcome (PRO) variables, which measure subjective burden, cannot be reliably used to predict survival. Further research in this area is needed to clarify the role of self-reported patient's burden and mortality prediction via ML.

Simple cysts (SCs) within the testes are rare in adults. The testicular SC lining comprises mesothelial cells. This report presents a case involving the accidental discovery of a castration-worthy SC in the right testis of a Japanese man in his 90s who was diagnosed with prostatic adenocarcinoma. Microscopic analysis revealed that the cystic wall was covered with flat to cuboidal mesothelial cells. Immunohistochemistry demonstrated mesothelial cell positivity for calretinin, Wilms tumor 1 (WT-1), Hector Battifora mesothelial epitope-1 (HBME-1), and cyclin-dependent kinase inhibitor p16 (p16INK4a). Notably, no human papillomavirus (HPV) in situ hybridization was detected. This report outlines an exceptionally rare instance of a simple cyst within the testis, suggesting the possibility of its origin from ectopic rete testis epithelium. This marks the inaugural documentation in the English literature of an SC within the testis found incidentally during castration for prostatic cancer.

Extreme cytoreductive surgery (eCRS) may sometimes be required to achieve complete cytoreduction, which is one of the most important prognostic factors. This study investigated the impact of eCRS on survival and peri-postoperative outcomes. Malignant peritoneal mesothelioma (MPM) patients who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) were retrospectively examined. Patients who underwent CRS-HIPEC were divided into eCRS and less extensive CRS (leCRS) groups. Resection of ≥5 organs or ≥3 small bowel anastomoses was defined as eCRS. Survival and perioperative outcomes of both groups were compared.In the study including 31 patients, eCRS-HIPEC was used in 15 patients. Complete cytore-duction (CC score 0/1) was achieved in all 31 patients. Compared with LeCRS, mean length of stay, length of stay in the intensive care unit, mean peritoneal cancer index (PCI), and intraoperative blood loss were higher in the eCRS group. Additionally, the risk of developing complications was observed to be more frequent and the duration of surgery was longer. Rates of serious complications and morbidity were similar in patients undergoing eCRS compared with leCRS. In patients with high PCI and multiple organ involvement, complete cytoreduction can be achieved by performing eCRS and equivalent survival results can be achieved with low PCI..

BACKGROUND: Few studies have examined the use of immunoassay urine drug testing of cancer patients in palliative care clinics. OBJECTIVES: We examined the frequency of immunoassay urine drug test (UDT) abnormalities and the factors associated with aberrancy at a safety-net hospital palliative medicine clinic. METHODS: A retrospective review of the electronic medical records of consecutive eligible patients seen at the outpatient palliative medicine clinic in a resource-limited safety net hospital system was conducted between September 1, 2015 and December 31, 2020. We collected longitudinal data on patient demographics, UDT findings, and potential predictors of aberrant results. RESULTS: Of the 913 patients in the study, 500 (55%) underwent UDT testing, with 455 (50%) having the testing within the first three visits. Among those tested within the first three visits, 125 (27%) had aberrant UDT results; 44 (35%) of these 125 patients were positive for cocaine. In a multivariable regression model analysis of predictors for aberrant UDT within the first 3 visits, non-Hispanic White race (odds ratio [OR]=2.13; 95% confidence interval [CI]: 1.03-4.38; p=0.04), history of illicit drug use (OR=3.57; CI: 1.78-7.13; p< 0.001), and history of marijuana use (OR=7.05; CI: 3.85-12.91; p< 0.001) were independent predictors of an aberrant UDT finding. CONCLUSION: Despite limitations of immunoassay UDT, it was able to detect aberrant drug taking behaviors in a significant number of patients seen at a safety net hospital palliative care clinic, including cocaine use. These findings support universal UDT monitoring and utility of immunoassay-based UDT in resource limited settings.

Urothelial cell carcinoma (UCC, bladder cancer) remains a difficult to treat malignancy with rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those &gt;55 years of age, ~four times more commonly observed in men than women. The most important risk factor for developing bladder cancer is tobacco smoking, which accounts for ∼50% of cases followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC is highly aggressive and remains generally incurable since these cancers are associated with intrinsic and acquired drug resistance. UCC is highly lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss the novel therapies to improve the management of mUCC.

There exists a variety of studies about tumor-infiltrating lymphocytes (TILs) in cervical cancer, but their prognostic value in correlation to the histopathological subtype was never investigated. Therefore, the aim of this study was to quantify TILs in a panel of 250 sporadic cervical cancers and investigate the correlation with cervical cancer subtype and patient survival. TIL levels were significantly increased in the subgroup of squamous cell carcinomas in comparison to adenocarcinomas. In squamous cell carcinomas, TIL infiltration shows a negative correlation to age, FIGO stage and to the histone protein modification H3K4me3. Moreover, in adenocarcinomas, it was positively correlated to p16 and to the glucocorticoid receptor and inversely correlated to the MDM2 protein and to H3K4me3. Interestingly, immune infiltration was an independent positive prognosticator for disease free survival (DFS) in patients with squamous cell carcinomas, those bearing tumors with the strongest TIL infiltration showing the better DFS. Altogether, the present study provides a differentiated overview of the relations between TIL levels and prognosis in patients with cervix squamous cell carcinomas vs patients with cervix adenocarcinomas.

Background and purpose: Dynamic 18F-FDG PET-CT scanning can accurately quantify 18F-FDG uptake and has been successfully applied in diagnosing and evaluating therapeutic effects in various malignant tumors. There is no conclusion as to whether it can accurately distinguish benign and malignant lymph nodes in nasopharyngeal cancer. The main purpose of this study is to reveal the diagnostic value of dynamic PET-CT in cervical lymph node metastasis of nasopharyngeal cancer through analysis. Method: We first searched for cervical lymph nodes interested in static PET-CT, measured their SUV-Max values, and found the corresponding lymph nodes in magnetic resonance images before and after treatment. The valid or invalid groups were included according to the changes in lymph node size before and after treatment. Their Ki values were measured on dynamic PET-CT and compared under different conditions. Then, we conducted a correlation analysis between different factors and Ki values. Finally, diagnostic tests were conducted to compare the sensitivity and specificity of Ki and SUV-Max. Result: We included 67 cervical lymph nodes from different regions of 51 nasopharyngeal cancer patients and divided them into valid and invalid groups based on changes before treatment. The valid group includes 50 lymph nodes, while the invalid group includes 17. Significant differences (P<0.001) between the two groups in SUV-Max, Ki-Mean, and Ki-Max values. When the SUV-Max≤4.5, there was no significant difference in the Ki-Mean and Ki-Max between the two groups (P>0.05). When SUV-Max≤4.5 and pre-treatment lymph nodes<1.0cm, the valid group had significantly higher Ki-Mean (0.00910) and Ki-Maximum (0.01004) values than the invalid group (Ki-Mean=0.00716, Ki -Max=0.00767) (P<0.05). When SUV-Max≤4.5, pre-treatment lymph nodes<1.0cm, and EBV DNA replication was normal, Ki-Mean (0.01060) and Ki-Max (0.01149) in the valid group were still significantly higher than the invalid group (Ki-Mean=0.00670, Ki-Max=0.00719) (P<0.05). The correlation analysis between different factors (SUV-Max, T-stage, normal EB virus DNA replication, age, pre-treatment lymph node<1.0cm) and Ki value showed that SUV-Max and pre-treatment lymph node<1.0cm were related to Ki-Mean and Ki-Max. Diagnostic testing was conducted, the AUC value of the SUV-Max value was 0.8259 (95% confidence interval: 0.7296-0.9222), the AUC value of the Ki-Mean was 0.8759 (95% confidence interval: 0.7950-0.9567), and the AUC value of the Ki-Max was 0.8859 (95% confidence interval: 0.8089-0.9629). It was found that the sensitivity of SUV-Max was 88%, the specificity was 76%, the sensitivity of Ki-Mean was 88%, the specificity was 80%, the sensitivity of Ki-Max was 94%, the specificity was 76%, the specificity of Ki-Mean was better than SUV-Max, the sensitivity of Ki-Max was better than SUV-Max. Conclusion: Dynamic PET-CT has shown significant diagnostic value in diagnosing cervical lymph node metastasis of nasopharyngeal cancer, especially for the small SUV value, and lymph nodes do not meet the metastasis criteria before treatment, and EBV DNA replication is normal. Moreover, its sensitivity and accuracy are superior to static PET-CT.

Two monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2), trastuzumab and pertuzumab, were clinically approved. We previously developed a highly sensitive and specific anti-HER2 mAb, H2Mab-139 (mouse IgG1, kappa). In this study, we produced a defucosylated IgG2a version of anti‑HER2 mAb (H2Mab-139-mG2a-f) to enhance ADCC-mediated antitumor activity. H2Mab-139-mG2a-f exhibits a high binding affinity in flow cytometry with the dissociation constant (KD) determined to be 3.9 × 10‑9 M and 7.7 × 10‑9 M against HER2‑overexpressed Chinese hamster ovary (CHO)-K1 (CHO/HER2) and HER2-positive BT-474 cells, respectively. Moreover, we showed that H2Mab-139-mG2a-f exerted ADCC and complement-dependent cytotoxicity against CHO/HER2 and BT-474 cells in vitro and exhibited potent antitumor activities in the xenograft models. These results indicated that H2Mab-139-mG2a-f exerts antitumor effects against HER2-positive human breast cancers and could be useful for an antibody treatment regimen for HER2-positive human cancers.

Background The purpose of this study was to clarify the relationship structure of quality of life (QOL) in survivors of breast cancer, including difficulty in daily life and negative experience as health-related indicators. Methods Participants were survivors of breast cancer for more than 2 years after primary breast cancer surgery and belonged to self-help groups. The assessment used FACT-B (QOL), HADS (anxiety and depression), SOC (sense of coherence), WHODAS 2.0 (difficulties in daily life), and CAOD (negative experiences). Bayesian structural equation modeling (BSEM) was performed to analyze the hypothesized model. If the causal model was significant, multiplication of the path coefficient from anxiety and depression to QOL, and from SOC to anxiety and depression, was considered a direct effect on QOL, and from SOC to difficulty in daily life, from difficulty in daily life to negative experiences, and from negative experiences to anxiety and depression were considered indirect effects on QOL. Results Goodness of fit of the model in the BSEM was satisfactory. The direct effect was 0.274, and indirect effect was 0.163. Conclusions These direct and indirect approaches to difficulties in daily life are very significant because they can provide a basis for development of support strategies to increase QOL.

Aim: This study aimed to investigate whether baseline 18F-FDG PET-derived semiquantitative parameters could predict disease-free survival in patients with grade III breast cancer of different molecular subtypes undergoing neoadjuvant chemotherapy (NAC). Materials and Methods: Patients were retrospectively retrieved from the databases of two Italian hospitals (University of Padua and University Hospital of Ferrara). Inclusion criteria were: 1) histologically proven diagnosis of grade III breast cancer; 2) history of NAC; 3) execution of a baseline 18F-FDG PET/CT scan before the start of NAC; 4) adequate follow-up time to compute the 3Y-DFS. For each 18F-FDG-PET/CT scan, the following parameters were calculated in the primary tumor (SUVmax, SUVmean, MTV, TLG) and whole-body (WB_SUVmax, WB_MTV, and WB_TLG). Receiver operating characteristic (ROC) analysis was used for each parameter to assess the prediction capability for 3Y-DFS. DFS differences between groups were assessed using Kaplan-Meier curves and compared by log-rank test. Results: Ninety-five grade III breast cancer patients with different molecular types were retrieved (luminal A: 5; luminal B: 34; luminal B-HER2: 22; HER2-enriched: 7; triple-negative: 27). In the whole group of patients, WB_SUVmax was the best predictor of recurrence (AUC: 0.66; best cut-off: WB_SUVmax>9.43; SS: 96%; SP: 38.1%; p<0.008). Patients with luminal A and Her-2-enriched breast cancer types were excluded from the molecular subgroup analysis due to the small study samples (5 and 7, respectively). In luminal B patients (n=34), WB_MTV (AUC: 0.75; best cut-off: WB_MTV>195.33; SS: 55.56%, SP: 100%; p=0.002) and WB_TLG (AUC: 0.73; best cut-off: WB_TLG>1066.21; SS: 55.56%, SP: 100%; p=0.05) were the best predictors of 3Y-DFS. Patients had a higher probability of DFS in case of a WB_MTV≤195.33 (3429±210 vs. 446±144 days; p<0.001) or WB_TLG≤ 1066.33 (937.35±19 vs. 496±131 days; p<0.001). In luminal B-HER2 patients (n=22), WB_SUVmax was the only predictor of 3Y-DFS (AUC: 0.857; best cut-off: WB_SUVmax>13.12; SS: 100%; SP: 71.43%; p<0.001); patients with WB_SUVmax≤13.12 had a significantly longer DFS (3857 days) than patients with a WB_SUVmax >13.12 (1693±430 days; p<0.004). No parameter resulted significant in the prediction of 3Y-DFS in patients with grade III triple-negative cancer. Conclusion: Volume-based parameters, extracted from baseline 18F-FDG PET, seem to be promising tools in the prediction of recurrence within 3 years in patients with grade III luminal B and luminal B- HER2 breast cancer undergoing NAC. Larger study samples are needed to confirm these preliminary findings.

Ribosome profiling and mass spectroscopy have identified canonical and noncanonical translation initiation codons (TICs) that are upstream of the main translation initiation site and used to translate oncogenic proteins. Here, we use a Kozak Similarity Score algorithm to find that nearly all of these TICs have flanking nucleotides closely matching the Kozak sequence. Remarkably, the nucleotides flanking alternative noncanonical TICs are frequently closer to the Kozak sequence than the nucleotides flanking TICs used to translate the gene’s main protein. Of note, the 5’ untranslated region (5‘UTR) of cancer-associated genes with an upstream TIC tend to be significantly longer than the same region in genes not associated with cancer. The presence of a longer than typical 5’UTR increases the likelihood of ribosome binding to upstream noncanonical TICs, and may be a distinguishing feature of a number of genes overexpressed in cancer. Noncanonical TICs that are located in the 5’UTR, although thought disadvantageous and suppressed by evolution, may translate oncogenic proteins because of their flanking nucleotides

In epithelia, breakdown of tensional homeostasis is closely associated with E-cadherin dysfunction and disruption of tissue function and integrity. In this study, we investigated the effect of E-cadherin mutations affecting distinct protein domains on tensional homeostasis of gastric cancer cells. We used micropattern traction microscopy to measure temporal fluctuations of cellular traction forces in AGS cells transfected with the wild-type E-cadherin or with variants affecting the extracellular, the juxtamembrane, and the intracellular domains of the protein. We focused on the dynamic aspect of tensional homeostasis, namely the ability of cells to maintain a consistent level of tension, with low temporal variability around a set point. Cells were cultured on hydrogels micropatterned with different extracellular matrix (ECM) proteins to test whether the ECM adhesion impacts cell behavior. A combination of Fibronectin and Vitronectin was used as a substrate that promotes the adhesive ability of E-cadherin dysfunctional cells, whereas Collagen VI was used to test an unfavorable ECM condition. Our results showed that mutations affecting distinct E-cadherin domains influenced differently cell tensional homeostasis, and pinpointed the juxtamembrane and intracellular regions of E-cadherin as the key players in this process. Furthermore, Fibronectin and Vitronectin might modulate cancer cell behavior towards tensional homeostasis.

Biofouling is the unwanted adsorption of cells, proteins, or intracellular and extracellular bio-molecules that can spontaneously occur on the surface of metal nanocomplexes. It represents a major issue in bioinorganic chemistry because it leads to the creation of a protein corona, which can destabilize a colloidal solution and result in undesired macrophage-driven clearance, consequently causing failed delivery of a targeted drug-cargo. Hyaluronic acid (HA) is a bioactive, natural mucopolysaccharide with excellent antifouling properties, arising from its hydrophilic and polyanionic characteristics in physiological environments which prevent opsonization. In this study, hyaluronate-thiol (HA-SH) (MW 10 kDa) was used to surface-passivate gold nanoparticles (GNPs) synthesized using a citrate reduction method. HA functionalized GNP complexes (HA-GNPs) were characterized using absorption spectroscopy, scanning electron microscopy, zeta potential, and dynamic light scattering. GNP cellular uptake and potential dose-dependent cytotoxic effects due to treatment were evaluated in vitro in HeLa cells using ICP-OES and Trypan blue and MTT assays. Further, we quantified the in vivo biodistribution of intratumorally injected HA functionalized GNPs in Lewis Lung carcinoma (LLC) solid tumors grown on the flank of C57BL/6 mice and compared localization and retention with nascent particles. Our results reveal that HA-GNPs show overall greater peritumoral distribution (**p<0.005, 3 days post-intratumoral injection) than citrate-GNPs with reduced biodistribution in off-target organs. This property represents an advantageous step forward in localized delivery of metal nano-complexes to the infiltrative region of a tumor, which may improve the application of nanomedicine in the diagnosis and treatment of cancer.

Cervical cancer is the fourth common cancer amongst women worldwide. Environmental factors such as smoking and obesity, and recurrent infection by high-risk human papillomavirus subtypes are known to promote progression towards invasive cervical disease. Infection by high-risk HPV is necessary in most cases but not sufficient to develop invasive cervical cancer. Despite a predicted genetic heritability of between 27-36%, known genetic susceptibility loci that may be tumorigenic or influence host response to infection, only account for a small fraction of heritable risk factors so far. Various biobank-driven population based studies and meta-analyses have found corroborative evidence for several risk variants at the 6p21.3 locus (HLA), while many reports of variants outside the HLA region remain to be validated in other cohorts. Here, we review cervical cancer susceptibility variants arising from recent genome-wide association studies and meta-analysis in large cohorts and propose 2q14 (PAX8), 17q12 (GSDMB), and 5p15.33 (CLPTM1L) as consistently replicated non-HLA cervical cancer susceptibility loci. We further discuss the available evidence for these loci, knowledge gaps, future perspectives, and the potential impact of these findings on precision medicine strategies to combat cervical cancer.

Interferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogramme the tumour microenvironment. However, the antitumour immunomodulatory properties of IFNg still need to be validated due to variable therapeutic outcomes in preclinical and clinical studies. We developed a replication-deficient Semliki Forest virus vector expressing IFNg (SFV/IFNg) and evaluated its immunomodulatory antitumour potential in vitro in a model of 3D spheroids and in vivo in immunocompetent 4T1 mouse breast cancer model. We demonstrated that SFV-derived IFN-g stimulated bone marrow macrophages to acquire the tumoricidal M1 phenotype in 3D nonattached conditions. Coculturing SFV/IFNg-infected 4T1 spheroids with BMDMs inhibited spheroid growth. In the orthotopic 4T1 mouse model, intratumoural administration of SFV/IFNg virus particles alone or in combination with the Pam3CSK4 TLR2/1 ligand led to significant inhibition of tumour growth compared to the administration of the control SFV/Luc virus particles. Analysis of the composition of intra-tumoural lymphoid cells isolated from tumours after SFV/IFNg treatment revealed an increase in CD4+ and CD8+ and a decrease in T-reg (CD4+/CD25+/FoxP3+) cell populations. Furthermore, a significant decrease in the populations of cells bearing myeloid cell markers CD11b, CD38 and CD206 was observed. In conclusion, the SFV/IFNg vector induces a therapeutic antitumour T-cell response and inhibits myeloid cell infiltration in treated tumours.

The idea of using the lytic power of viruses against the malignant cells has been entertained for many decades. However, oncolytic viruses (OV) gained broad attention as an emerging anti-cancer therapy only recently with the successful implementation of the oncolytic herpesvirus to treat advanced melanoma. OVs offer an attractive therapeutic combination of tumor-specific cell lysis together with immune stimulation, yet the latter effect is less well studied. Nevertheless, OVs can be envisaged as potential in situ tumor vaccines. The therapeutic potential of OVs can be instigated further by using the molecular biological and biotechnological tools to modify the existing viruses for their optimal tumor selectivity and enhanced immune stimulation. Furthermore, OVs can be readily combined with other therapeutic agents to increase the efficacy of the existing therapeutic schemes. In this review, we discuss biotechnological advances in the development of therapeutic applications of OVs in Russia. Particular emphasis is made on the OV-mediated treatment of glioblastoma. In addition, we highlight the challenges of oncolytic virotherapy, and describe the strategies to optimize current approaches to improve clinical outcomes.

Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). CAFs exhibit a pro-tumor effect in vitro and have been implicated in tumor cell proliferation, metastasis, and treatment resistance. Our objective is to analyze the geospatial distribution of CAFs with proliferating and apoptotic tumor cells in the ccRCC tumor microenvironment and determine associations with survival and systemic treatment. Pre-treatment primary tumor samples were collected from 96 patients with metastatic ccRCC. Three adjacent slices were obtained from 2 tumor-core regions of interest (ROI) per patient, and immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, and caspase-3 to detect CAFs, proliferating cells, and apoptotic cells, respectively. H-scores and cellular density were generated for each marker. ROIs were aligned, and spatial point-patterns were generated, which were then used to perform spatial analyses using a normalized Ripley's K function at a radius of 25μm (nK(25)). The survival analyses used an optimal cut-point method, maximizing the log-rank statistic, to stratify the IHC-derived metrics into high and low groups, and multivariable Cox regression analyses were performed accounting for age and International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall survival (OS) from the date of diagnosis, OS from the date of immunotherapy initiation (OS-IT), and OS from the date of targeted therapy initiation (OS-TT). Therapy resistance was defined as progression-free survival (PFS) <6 months, and therapy response was defined as PFS >9 months. CAFs exhibited higher cellular clustering with Ki-67+ cells than with caspase-3+ cells (nK(25): Ki-67 1.19; caspase-3 1.05; P = .04). The median nearest neighbor (NN) distance from CAFs to Ki-67+ cells was shorter compared to caspase-3+ cells (15 μm vs 37μm, respectively; P < .001). Multivariable Cox regression analyses demonstrated that both high Ki-67+ density and H-score were associated with worse OS, OS-IT, and OS-TT. Regarding CAFs, only a high H-score was associated with worse OS, OS-IT, and OS-TT. For caspase-3+, high H-score and density were associated with worse OS and OS-TT. Patients whose tumors were resistant to targeted therapy (TT) had higher Ki-67 density and H-scores than those who had TT response. Overall, this ex vivo geospatial analysis of CAF distribution suggests that close proximity clustering of tumor cells and CAFs potentiates tumor cell proliferation, resulting in worse OS and resistance to TT in metastatic ccRCC.

The clinical significance of carbon-ion radiotherapy (CIRT) for adenocarcinoma (AC) of the uterine cervix has been assessed in several single-institutional studies. To validate the significance, we conducted a multi-institutional survey of CIRT for locally advanced AC (LAAC) of the uterine cervix. We retrospectively analyzed the clinical outcomes of patients with stage IIB–IVA LAAC of the uterine cervix who underwent chemo-CIRT or CIRT alone between April 2010 and April 2016. Patients received 74.4 Gy (relative biological effectiveness [RBE]) in 20 fractions of CIRT or 55.2 Gy (RBE) in 16 fractions of CIRT plus 3 sessions of brachytherapy. Patients aged ≤70 years with adequate bone marrow and organ function were administered cisplatin weekly (40 mg/m2 per week for up to 5 weeks). Fifty-five patients were enrolled in this study. The median follow-up period was 67.5 months. The 5-year overall survival (OS) and local control (LC) rates were 68.6% and 65.2%, respectively. Multivariate analysis showed that the initial tumor response within 6 months was significantly associated with LC and OS. The present study represents promising outcomes of CIRT or chemo-CIRT for LAAC of the uterine cervix, especially in the cases showing initial rapid regression of the tumor.

Abstract: Oncogenic RAS mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. So far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase independent functions in apoptosis, cell cycle progression and cell migration.

Cancer immunotherapy reaches a remarkable achievement in various cancer types and brings new possibilities to improve cancer patients’ long-term survival. However, outcomes vary from case to case, and the present protocol benefits a small fraction of patients. One notable factor is the tumor microenvironment, especially the immune cell components, that may reflect the immune response's status quo on site. Thus, understanding the content of infiltrating immune cells in tumors is not only for research interesting but also a crucial subject toward precision medicine. We implement an algorithm for resolving relative proportions of twenty-one immune cell subclasses from a human tissue profiled transcriptome by microarray technology to reach the goal above. By selecting gene features and then adopting ?-Support Vector Regression, we can construct a deconvolution model and resolve the immune cell context. The excellent consistency between the estimated values and the correct immune-cell composition further demonstrates this approach provides a more natural alternative to revealing samples' immune cell content and reliable results like recent single-cell technologies. Based on this algorithm, the web-based deconvolution tool implemented named mySORT provides a user-friendly interface for estimating the immune cell content by uploading gene expression profiling. We also present comprehensive visualization 2D/3D plots in mySORT so that users can easily make a comparison between different samples. Finally, we synthesized pseudo-bulk expression data from single-cell transcriptomic datasets of 17 melanoma and 16 head and neck cancer patients. The deconvolution results of microarray-based data in the previous study and synthetic pseudo-bulk data all proved the excellent performance of mySORT. We believe that mySORT can help researchers in all fields easily understand complex immune microenvironment. The website of mySORT is freely accessible on https://symbiosis.iis.sinica.edu.tw/mySORT/.

Multi-step evolution characterizes the carcinogenesis of GI malignancies, where the disease progresses through the accrual of genetic mutations, co-option of multiple host cellular factors and the acquisition of increasingly aggressive pathological features. Ensuing cancer complexity and plasticity are challenges for therapeutic approaches. On the other hand, disease inception is often triggered by a defined oncogenic event, which leads to escalating effects on gene expression, cellular metabolism, chromatin organization and ultimately cell identity. Decoding this molecular cascade of events is crucial to design strategies for early diagnosis as well as to tackle tumor onset. To this aim, the in vitro culture of non-transformed epithelial cells represents a major technical challenge. Genetic studies, combined with lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a specialized cell type in the pancreatic epithelium, following mutations of the KRAS oncogene. Ex vivo culture of pancreatic acinar cells has allowed the identification of early mutant KRAS-driven alterations. Primary acinar cells survive in vitro in organoid-like 3D spheroids, which can recapitulate histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary mouse pancreatic acinar cells, providing and historical and technical perspective. Impact for pancreatic cancer research will also be debated; in particular we will dissect the role of KRAS signaling in driving oncogenic transformation and highlight differences with canonical 2D culture of established cancer cell lines.

Stress Granules formation is a pro-survival mechanism helping cells to cope with environmental challenges. Stress Granules have been studied for two decades in fundamental research, and are now being examined in the context of human pathogenesis. Here, we review studies highlighting stress granules’ involvement in cancer development through translational pattern modification.

Accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions and can be repaired using homologous recombination (HR). HR is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here we discuss the current perspective on the RAD51 paralogs in vivo and in vitro function and their relationship with cancer in vertebrate models.

Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood. This study aims at understanding the molecular features within CTCs in relation to their metastatic potential. Using in vitro CTC models, in which breast cancer cell lines are cultured in non-adherent conditions simulating the microenvironment in the blood stream, we found that suspension culture resulted in resistance to TNF-related apoptosis inducing ligand (TRAIL)-mediated cell death. Such a resistance was directly correlated with a reduction in surface and total levels of DR5 protein. In the non-adherent state, cells underwent rapid autophagic flux characterized by an accumulation of autophagosome organelles. Notably, DR5 was translocated to autophagosomes and underwent lysosomal degradation. Our data suggest that CTCs may evade TNF cytokine mediated immune surveillance through downregulation of DR expression. The data warrants further studies in cancer patients to find the status of DRs and other molecular features within primary CTCs in relation to disease progression or chemoresistance.

Hypothesis: Anti-diabetic drugs modulate p-21 activated kinase (PAK) signaling Introduction: Type 2 diabetes mellitus (T2DM) is a chronic inflammatory disease associated with increased cancer risk. PAK signaling is implicated in cellular homeostasis when regulated, and cancer when unrestrained. Recent reports provided a role for PAK signaling in glucose homeostasis, but the role of PAKs in the pathogenesis of T2DM is unknown. Here we performed a mini-meta analysis to explore if anti-diabetic drugs modify PAK signaling pathways, and provide insight regarding modulation of these pathways to potentially reduce diabetes-associated cancer risk. Methods: PAK interacting partners in T2DM were identified using online STRING database. Correlation studies were performed via systematic literature review to understand the effect of anti-diabetic drugs on PAK signaling. Mini meta analysis correlated multiple clinical studies and revealed the overall clinical response rate and percentage of adverse events in piogliazone (n=53) and metformin (n=91) treated patients with PAK-associated diseases. Results: A total of 30 PAK interacting partners were identified (10: reduced beta-cell mass; 10: beta-cell dysfunction; 10: obesity-insulin resistance) which were highly associated with Wnt, and G-protein signaling. Anti-diabetic drug metformin activated signaling pathways upstream; whereas pioglitazone inhibited pathways downstream of PAK. Overall clinical response upon pioglitazone treatment was 53%. 79% of pioglitazone and 75% of metformin treated patients had adverse events. Pioglitazone reduced molecular-PAK biomarkers of proliferation (Ki67 and CyclinD1), and metformin had the opposite effect. Conclusions: PAK signaling in T2DM likely involves Wnt and G-protein signaling which may be altered by anti-diabetic drugs metformin and pioglitazone. Apart from the therapeutic limitations of adverse events, pioglitazone may be promising in chemoprevention, however long-term multi-centered studies, which initiate pioglitazone treatment early will be required to fully assess the full potential of these drugs.

Hypothesis: Anti-diabetic drugs modulate p-21 activated kinase (PAK) signaling Introduction: Type 2 diabetes mellitus (T2DM) is a chronic inflammatory disease associated with increased cancer risk. PAK signaling is implicated in cellular homeostasis when regulated, and cancer when unrestrained. Recent reports provided a role for PAK signaling in glucose homeostasis, but the role of PAKs in the pathogenesis of T2DM is unknown. Here we explored whether PAK signaling should be targeted via chemoprevention to reduce diabetes-associated cancer risk. Methods: PAK interacting partners in T2DM were identified using online STRING database. Systematic literature review provided the effect of anti-diabetic drugs on PAK signaling. Review of clinical studies revealed the overall clinical response rate and percentage of adverse events in piogliazone (n=53) and metformin (n=91) treated patients with PAK-dependent diseases. Results: A total of 30 PAK interacting partners were identified (10: reduced beta-cell mass; 10: beta-cell dysfunction; 10: obesity-insulin resistance) which were highly associated with Wnt, and G-protein signaling. Anti-diabetic drug metformin activated signaling pathways upstream; whereas pioglitazone inhibited pathways downstream of PAK. Overall clinical response upon pioglitazone treatment was 53%. 79% of pioglitazone and 75% of metformin treated patients had adverse events. Pioglitazone reduced molecular-PAK biomarkers of proliferation (Ki67 and CyclinD1), and metformin had the opposite effect. Conclusions: PAK signaling in T2DM involves Wnt and G-protein signaling which is altered by anti-diabetic drugs metformin and pioglitazone. Apart from the therapeutic limitations of adverse events, pioglitazone is promising in chemoprevention, however long-term multi-centered studies, which initiate pioglitazone treatment early will be required to fully assess the full potential of these drugs.

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 hours in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials.

(1) Background: This work aimed to conduct the first comparative study providing long-term data about patient reported outcome measures as well as donor-site scar assessment and aesthetic evaluation of the reconstructed breasts in patients with DIEP versus PAP flap breast reconstruction. (2) Methods: This prospective, single-center, matched cohort study included a total of 36 patients after DIEP and PAP flap breast reconstruction. Evaluation was done using the Breast-Q and POSAS questionnaire as well as the Breast Aesthetic Scale for cosmetic analysis by four plastic surgeons. (3) Results: Post-operative Breast-Q evaluation revealed no significant differences between both patient groups for the categories physical well-being donor-site, physical well-being breast and satisfaction with the breast. Scar evaluation of the donor-site region showed equivalent results for the thigh and the abdomen concerning the overall opinion of patients and observers. There was no significant difference between both methods of reconstruction for all aspects of breast aesthetics. (4) Conclusions: Similar results of donor-site morbidity, scar quality and aesthetic outcome of the breast in both the DIEP and PAP patient group have been demonstrated. Hence, in cases suitable for both types of reconstruction, the decision can be based on factors such as patients’ lifestyle, leisure activities and preferences.

Purpose: We aimed to develop a nomogram able to predict treatment failure, skeletal events and overall survival (OS) in patients with castration-resistant prostate cancer with bone metastases (CRPC-BM) treated with Radium-223 dichloride (223Ra). Patients and Methods: Patients from Castilla-La Mancha Spanish region was prospectively included in ChoPET-Rad multicenter study, from January 2015 to December 2022. Patients underwent baseline, interim, and end-of-treatment bone scintigraphy (BS) and 18F-Fluorocholine PET/CT (FCH PET/CT) scans, obtaining multiple imaging radiomics as well as clinical and biochemical variables during follow-up and studying their association with the previously defined end-points. Survival analysis was performed using Kaplan-Meier method and Cox regression. Multivariate logistic and Cox regression models were calculated, and these models were depicted by means of nomograms. Results: Median progression-free survival (PFS) and OS for our population were 4 and 14 months (mo), respectively. The variables that showed the most robust independent significant association with therapeutic failure were baseline alkaline phosphatase (AP) levels (p=0.022) and the characteristics of BM on CT portion of PET/CT (p=0.017). In the case of OS, the significant variables were therapeutic failure (p=0.038), the number of lines received after 223Ra (p

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. In this review, we discuss the role of IL-1β in NSCLC, its involvement in inflammatory pathways, and explore its potential role in the treatment of NSCLC.

Heterogeneous distribution of delivery or treatment modalities within the tumor mass is a crucial limiting factor for a vast range of theranostic applications. Understanding the interactions between a nanomaterial and the tumor microenvironment will help to overcome challenges associated with tumor heterogeneity as well as the clinical translation of nanotheranostic materials. This study aims to evaluate the influence of protein surface adsorption on gold nanoparticle (GNP) biodistribution using high resolution Computed Tomography (CT) preclinical imaging in C57BL/6 mice harboring Lewis Lung Carcinoma (LLC) tumors. LLC provides a valuable model for study due to its highly heterogenous nature which makes drug delivery to the tumor challenging. By controlling the adsorption of proteins on the GNP surface, we hypothesize that we can influence the intratumoral distribution pattern and particle retention. We performed an in vitro study to evaluate the uptake of GNPs by LLC cells and an in vivo study to assess and quantify the GNP biodistribution by injecting concentrated GNPs citrate stabilized or passivated with Bovine Serum Albumin (BSA) intratumorally into LLC solid tumors. Quantitative CT and Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) results both confirm the presence of particles in the tumor 9 days post-injection (n=8 mice/group). Significant difference is highlighted between citrate-GNP and BSA-GNP groups (**p < 0.005, Tukey’s multiple comparisons test), confirming the protein corona of GNPs modifies intratumoral distribution and retention of the particles. In conclusion, our investigations show that the surface passivation of GNPs influences the mechanism of cellular uptake and intratumoral distribution in vivo highlighting the spatial heterogeneity of the solid tumor.

Published in July 2018, TAILORx aimed to establish non-inferiority of endocrine therapy (ET) compared to addition of chemotherapy (CHT-ET) in hormone receptor positive, human epidermal receptor 2 negative (HR+/HER2-) breast cancer (BC) patients with a 21-gene intermediate (11-25) recurrence score (RS). While this hypothesis proved correct, the study did show benefit of addition of chemotherapy (CHT) in a subgroup of women under 50 years of age, and particularly in the RS 16-25. The aim of this present study was to look at how TAILORx findings, including changes in RS categories, impacted CHT implementation at one oncologic center in Basel, Switzerland, and to identify main factors leading to these changes. Methods: We conducted a retrospective study on HR+/HER2-, BC patients who underwent 21-gene genomic testing between 2010-2021, at our center. Patients with metastatic disease were not included. We identified 326 eligible patients, of which 165 had a BC diagnosis before TAILORx (cohort A) and 161 after TAILORx publication (cohort B). Results: Demographic and tumor characteristics were similar in the two cohorts, although cohort B included significantly more women under the age of 50 when compared to A (34% vs. 24%, p<0.001). Median age and mean RS results were comparable 59 (IQR 16) in A and 58 (IQR 19) years in B and 17.72 (SD9.59) in A and 17.89 (SD9.53) in B, respectively. Patients in cohort A were slightly more overweight when compared to B (55% vs. 40% respectively, p<0.001). Most patients had stage II tumors of NST histologic type. Tumors in cohort B had higher Ki-67 than cohort A (39% vs. 32%, p=0.010). When compared based on manufacturer’s and based on TAILORx thresholds there were no significant differences in RS distribution. However, changes in score category led to shifts in patient population distribution, leading to a 40% drop in the low RS (from 60% to 20%), a doubling in the intermediate RS (from 30% to 60%) and an increase of 5% in the high RS (from 8-10% to 15%). Most patients had conservative surgery, adjuvant radiotherapy (RT) and ET. Overall CHT recommendation and application did not differ significantly in B vs. A. There was a reduction of 1% in the intermediate RS (11-25) and an increase of 13% CHT-ET application in the high RS (>26) category. In cohort B we noticed an increase in CHT-ET application among women <50 years old (by 12.5%), in lobular carcinomas (by 10%), grade 3 tumors (by 2%), node positive BC (by 3%) and node negative (by 2%). Tumor board recommendation for CHT dropped by 1% in the post TAILORx era, with a notable reduction of 5% in the intermediate RS (11-25) category. However, overall CHT administration rate was 19% in cohort A and 22% in B (p=0.763). Tumor Board recommended CHT for 90% of the BC patients that would have otherwise been assigned to CHT according to new RS guidelines in A and for 85% in B, showing a trend for undertreatment. Logistic regression analysis showed significance of age in both cohort A (OR 1.05, 95% CI 1.01-1.11, p=0.03) and cohort B (OR 0.89, 95% CI 0.84-0.94), p<0.001), and of nodal status in both cohort A (=R 3.32 95% CI 1.09-10-06, p=0.034) and cohort B (OR 3.31, 95% CI 1.29-8.53, p=0.013), while intermediate and high RS seem to be more relevant in cohort A (OR 0.12, 95% CI 0.03-0.43, p=0.01 and OR 0.04, 95% CI 0.01-0.21, p<0.01). Overall logistic regression analysis showed relevance of age (OR 0.93, 95% CI 0.08-0.97, p=0.001), pN (OR 4.77, 95% CI 2.03-11.22, p<0.001) and RS categories (RS 11-25: OR 0.02, 95% CI 0.01-0.07, p<0.001; RS>26: OR 617.93, 95% CI 57.97-6587.16, p<0.001). Conclusion: Our findings are similar to those reported across several studies: while tumor board recommendation for CHT decreases in the intermediate RS category, there is an increase being reported in the high RS category, leading to overall minor changes in CHT application. Administration of CHT-ET seems to be increasing among younger women, with unfavorable histo-pathological factors, such as lobular carcinoma and G3 histologic grade. Before TAILORx there is a tendency for undertreatment (-10%), especially among older BC patients, which seems to be maintained and even deepened (-15%) in the post TAILORx era, pointing to a personalized decision-making approach among Swiss oncologists.

The emergence of acquired resistance to EGFR-TKIs is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after frontline osimertinib treatment failure because of a secondary mutation. We also established acquired re-sistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020 resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial to mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome sec-ondary mutations after front-line osimertinib. We found that off-target mechanisms that cause re-sistance to earlier generation TKIs will also cause resistance to 4G TKIs.

Peptide-based drugs are promising anticancer candidates due to their biocompatibility, and low toxicity. Particularly, tumor homing peptides (THPs) have the ability to bind specifically to can-cer cells receptors and tumor vasculature. Despite their potential to develop antitumor drugs, there are few available prediction tools to assist the discovery of new THPs. Two webservers based on machine learning models are currently active, the TumorHPD (https://webs.iiitd.edu.in/raghava/tumorhpd) and the THPep (http://codes.bio/thpep), and more recently the SCMTHP (SCMTHP (pmlabstack.pythonanywhere.com), based on scoring card method. Herein, a novel method based on network science and similarity searching implemented in the starPep toolbox (http://mobiosd-hub.com/starpep/) is presented for THPs discovery. The approach leverages from exploring the structural space of THPs with Chemical Space Networks (CSNs) and from applying centrality measures to identify the most relevant and non-redundant THPs sequences within the CSN. Such THPs were considered as queries (Qs) for multi-query similarity searches that applies a group fusion (MAX-SIM rule) model. The resulting multi-query similarity searching models (SSMs) were validated with three benchmarking datasets of THPs/non-THPs. Predictions achieved accuracies ranged from 92.64 to 99.18% and Matthews Correlation Coefficients between 0.894-0.98, outperforming state-of-the-art predictors. The best model was applied to repurpose AMPs from the starPep database as THPs, which were subse-quently optimized for the TH activity. Finally, 54 promising THP leads were discovered, and their sequences were analyzed to encounter novel motifs. These results demonstrate the potential of CSNs and multi-query similarity searching for a rapid and accurate identification of THPs.

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing the adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2)monoclonal antibody (mAb), H₂Mab-250/H₂CasMab-2. In flow cytometry and immunohistochemistry, H₂Mab-250 reacted with HER2-positive breast cancer cells but did not show the reactivity to normal epithelial cells. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both breast cancer and normal epithelial cells in flow cytometry. The human IgG₁ version of H₂Mab-250 (H₂Mab-250-hG₁) possesses compatible in vivo antitumor effects against breast cancer xenografts with trastuzumab despite the lower affinity and effector activation than trastuzumab in vitro. This study compared the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC) between H₂Mab-250-hG₁ and trastuzumab. Both H₂Mab-250-hG₁ and trastuzumab showed ADCC activity against CHO/HER2 and breast cancer cell lines (BT-474 and SK-BR-3) in the presence of human natural killer cells. Some tendency was observed that trastuzumab showed a more significant ADCC effect compared to H₂Mab-250-hG₁. Importantly, H₂Mab-250-hG₁ exhibited superior CDC activity in these cells compared to trastuzumab. Similar results were obtained in mouse IgG_2a types of both H₂Mab-250 and trastuzumab. These results suggest the different contributions of ADCC and CDC activities to the antitumor effects of H₂Mab-250-hG₁ and trastuzumab and indicate the future direction for the clinical development of H₂Mab-250-hG₁ against HER2-positive tumors.

Background: About 200 new ovarian cancer cases per year are diagnosed in Armenia, an upper-middle-income country. This study aims to summarize the survival outcomes of relapsed ovarian cancer patients in Armenia based on the type of relapse, risk factors, and the choice of systemic treatment. Methods: A retrospective case-control study including 228 patients with relapsed ovarian cancer from 3 different institutions. Results: The median age of the patients was 55. The median follow-up from the relapse and primary diagnosis was 21 and 48 months. The incidence of platinum-sensitive relapse was 81.6% (186), while platinum-resistant relapse was seen only in 18.4% (42) patients. Median survival of the patients starting from the primary diagnosis in the platinum-sensitive compared to the platinum-resistant group was 54 versus 25 months (p < 0.001), and median survival after relapse: was 25 versus 13 months, respectively 3- and 5-year survival in these groups were: 31.2% vs. 23.8%, and 15.1% vs. 9.5%, respectively (p = 0,113). Conclusions: Overall, despite new therapeutic approaches, ovarian cancer continues to be one of the deadly malignant diseases in women, especially, in developing countries with a lack of resources, where, in fact, the main available systemic treatment for the majority of patients remains chemo-therapy. Low survival rates emphasize the urgent need for more research on this group of patients with poor outcomes.

The Hippo pathway plays crucial roles in governing various biological processes during tumorigenesis and metastasis. Within this pathway, upstream signaling stimuli activate a core kinase cascade, involving MST1/2 and LATS1/2, which subsequently phosphorylates and inhibits the transcriptional co-activators YAP and its paralog TAZ. This inhibition modulates the transcriptional regulation of downstream target genes, impacting cell proliferation, migration, and death. Despite the acknowledged significance of protein kinases in the Hippo pathway, the regulatory influence of protein phosphatases remains largely unexplored. In this study, we conducted the first gain-of-functional screen for protein tyrosine phosphatases (PTPs) regulating the Hippo pathway. Utilizing a LATS kinase biosensor (LATS-BS), a YAP/TAZ activity reporter (STBS-Luc), and a comprehensive PTP library, we identified numerous novel PTPs that play regulatory roles in the Hippo pathway. Subsequent experiments validated PTPN12, a master regulator of oncogenic receptor tyrosine kinases (RTKs), as a previously unrecognized negative regulator of the Hippo pathway effectors, oncogenic YAP/TAZ, influencing breast cancer cell proliferation and migration. In summary, our findings offer valuable insights into the roles of PTPs in the Hippo signaling pathway, significantly contributing to our understanding of breast cancer bi-ology and potential therapeutic strategies.

The role of DNA mismatch repair (MMR) tumor testing in colon and endometrial carcinomas is well-established, yet the universal application of this testing faces challenges due to limited data on its efficacy in diverse populations. This retrospective study at a community hospital in Northern Indiana examined MMR immunohistochemistry (IHC) results across 549 cases. Our analysis found intact MMR expression in 469 cases, while 80 demonstrated MMR deficiency, translating to MMR deficiency rates of 10% in colon cancers and 22% in uterine carcinomas. Notably, only 16 patients (2.9%) were categorized as high microsatellite instability (MSI-H), a rate significantly lower than the 3-5-fold higher incidences reported in other Midwestern populations, including Ohio. These findings suggest that the benefits of universal cascade methylation testing, particularly in MLH1/PMS2 IHC-negative tumors, may vary significantly based on regional demographics. Given the notably lower MSI-H incidence in this study, re-evaluating reflex testing protocols in low-resource settings could lead to more targeted, cost-effective approaches without compromising diagnostic accuracy. This study challenges the one-size-fits-all approach to MMR testing, highlighting the need for tailored strategies that consider regional variations in cancer genetics.

Radiological imaging is essential for acute patient management in Intensive Care Units (ICUs); however, it introduces the risk of exposure to ionizing radiation. This review synthesizes research on radiation exposure in intensive care unit (ICU) settings, highlighting its rise during the COVID-19 pandemic and repetitive imaging. Our analysis extends to radiation safety thresholds, revealing that some ICU patients exceed annual occupational limits, emphasizing the need to balance diagnostic utility against potential long-term risks, such as cancer. Prospective studies have demonstrated an increase in the median Cumulative Effective Dose (CED) in patients with trauma over time, prompting calls for improved awareness and monitoring. Moreover, innovative dose-reduction strategies and optimized protocols, especially in neuro-ICU units, promise to mitigate these risks. This review highlights the essential but risky role of radiological imaging in critical care. It advocates rigorous radiation management protocols to safeguard patient health, while ensuring the continuity of high-quality medical care.

Background: Malnutrition was associated with worse survival outcomes, impaired quality of life, and deteriorated performance status across various cancer types. We aimed to identify risk factors for malnutrition in patients with epithelial ovarian(EOC) and impact on survival. Methods: In our prospective study, we included the patients with primary and recurrent EOC, tubal or peritoneal cancer conducted. We assessed serum laboratory parameters, body mass index, nutritional risk index, nutritional risk screening score(NRS-2002), and bio-electrical impedance analysis. Results: We recruited a total of 152. Patients >65 years-old, with ascites of >500 ml, or with platinum-resistant EOC showed statistically significant increased risk of malnutrition when evaluated by NRS-2002(p-values = 0.014, 0.001, and 0.007, respectively). An NRS-2002<3 was an independent predictive factor for complete tumor resectability (p=0.009). The patients with NRS-2002≥3 had a median overall survival(OS) of seven months (95% CI=0-24 months), as compared to the patients with NRS-2002<3 where median OS was 46 months(p=0,001). Phase angle(PhAα)≤ 4.5 was the strongest predictor of OS. Conclusion: Malnutrition is an independent predictor of incomplete cytoreduction in study population. It is an independent prognostic factor for poor OS. Preoperative nutritional assessment is an effective tool in identification of high-risk groups within EOC characterized by poor clinical outcome.

Background: Although autophagy is a pro-survival process of tumor cells, in particular conditions and when differently regulated by specific signals it can stimulate cell death. We previously demonstrated that the selective stimulation of the M2 muscarinic receptor subtype (M2 mAChR) negatively controls cell proliferation and survival and causes oxidative stress and cytotoxic and genotoxic effects in both GBM cell lines and GBM stem cells (GSCs). In this work, we have evaluated whether autophagy was induced as a downstream mechanism of the observed cytotoxic processes induced by M2 mAChR activation by the orthosteric agonist APE or the dualsteric agonist N-8-Iper. Methods: To assess the activation of autophagy, we analyzed the expression of LC3B by Western blot analysis and in LC3B-EGFP transfected cell lines. Apoptosis was assessed by Caspases 3 and 9 protein expression. Results: Our data indicate that activation of M2 mAChR by N-8-Iper promotes autophagy in both U251 and GB7 cells lines as suggested by the LC3B-II expression level and analysis of the transfected cells by fluorescence microscopy. Autophagy induction by M2 mAChRs is regulated by the decreased activity of the PI3K/AKT/mTORC1 pathway and upregulated by the pAMPK expression. Downstream autophagy activation, the increase of apoptosis was also observed in both cell lines after treatment with the two M2 agonists. Conclusions: N-8-Iper treatment causes autophagy via pAMPK upregulation, followed by apoptosis in both investigated cell lines. In contrast, the absence of autophagy in APE-treated GSC cells seems to indicate that cell death could be triggered by mechanisms alternative to those observed for N-8-Iper.

Breast cancer (BC) is the most common malignancy among women worldwide. In recent years, significant progress has been made in BC therapy. However, serious side effects resulting from the use of standard chemotherapeutic drugs, as well as the phenomenon of multidrug resistance (MDR), limit the effectiveness of approved therapies. Advanced research in the BC area is necessary to create more effective and safer forms of therapy to improve the outlook for individuals diagnosed with this aggressive neoplasm. For decades, plants and natural products with anti-cancer properties have been successfully utilized in treating various medical conditions. Anthracene derivatives are tricyclic secondary metabolites of natural origin that have been identified in plants, lichens, and fungi. They represent a few botanical families, e.g., Rhamnaceae, Rubia-ceae, Fabaceae, Polygonaceae, and others. The review comprehensively covers and analyzes the most recent advances in the anticancer activity of anthracene derivatives (emodin, aloe-emodin, hypericin, chrysophanol, rhein, and physcion) applied both individually, or in combination with other chemotherapeutic agents in in vitro and in vivo BC models.

ABSTRACT: Recurrent glioblastoma (rGBM) is a highly aggressive form of brain cancer that poses a significant challenge for treatment in neurooncology, and the survival status of patients after relapse usually means rapid deterioration, and also the leading cause of death among patients. In recent years, immunotherapy has emerged as a promising strategy for the treatment of recurrent glioblastoma by stimulate the body's immune system to recognize and attack cancer cells , which could be used as a in combination with other treatments such as surgery, radiation, and chemotherapy to improve outcomes for patients with recurrent glioblastoma, This therapy combines several key methods such as the use of monoclonal antibodies, chimeric antigen receptor T cell (CAR-T) therapy, checkpoint inhibitors, oncolytic viral therapy cancer vaccines, and combination strategies. In this review, we mainly document the latest immunotherapies for the treatment of glioblastoma and focus on the rGBM especially.

Cancer patients may experience significant distress. The “Emotion Thermometers” (ETs) are a short visual analogue scale used to screen patients for psychosocial risk. This study aimed to assess emotional distress in a large sample of cancer patients attending psychological services at an NGO, and to explore factors that may contribute to it. The ETs were answered by 899 cancer patients. They were, on average, 59.9 years old, the majority were female, had breast cancer, were under treatment or were disease-free survivors, and reported high levels of emotional distress, above the cut-off (≥5). A Generalized Linear Model was used to measure the association between the level of Distress and 33 items of the problem list. Four items - sadness, depression, sleep and breathing - were found to be significantly related to a higher level of Distress. Additionally, women and those who were in the palliative phase also had significantly higher levels of Distress. Conclusions: The results confirm the need for early emotional screening in cancer patients, as well as the relevance of attending to the characteristics of each patient. Additionally, they highlight the utility of the ETs for the clinical practice, allowing to optimize the referral to specialized psy-chosocial services.

The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that increase the risk of developing cancer at an earlier age compared to the risk for the general population. This article aims to provide a comprehensive analysis of three unique cases involving pediatric patients with CPS who were diagnosed with multiple simultaneous or metachronous cancers. The first case involves a child with embryonal rhabdomyosarcoma, nephroblastoma, glioma, and subsequent medulloblastoma. Genetic analysis identified two pathogenic variants in the BRCA2 gene. The second case involves a child with alveolar rhabdomyosarcoma, Xanthogranuloma Juvenile, gliomas, and subsequent JMML/MDS/MPS. A pathogenic variant in the NF1 gene was identified. The third case involves a child with pleuropulmonary blastoma and pediatric cystic nephroma/nefroblastoma in whom a pathogenic variant in the DICER1 gene was identified. Multiple simultaneous and metachronous cancers in pediatric patients with CPSs are a rare but significant phenomenon. Comprehensive analysis and genetic testing play crucial roles in understanding the underlying mechanisms and guiding treatment strategies for these unique cases. Early detection and targeted interventions are crucial for improving outcomes in these individuals.

(1) Background: This case presents a rare and challenging clinical scenario involving a 50-year-old female patient diagnosed with Inflammatory Carcinoma, a particularly aggressive and rapidly growing form of breast cancer. The disease is characterized by heat, redness, swelling and noticeable changes in the breast's skin texture, resembling the skin of an orange (peau d'orange). This case is important because it contributes to the limited clinical literature on such aggressive forms of breast cancer.; (2) Methods: The multidisciplinary approach was employed. Diagnostic procedures such as imaging tests, biopsy, and histopathological examination were performed to confirm the diagnosis of Inflammatory Carcinoma and assess the extent of the disease. The presence of the HER2 protein on the tumor cells supported the selection of a combination therapy involving systemic chemotherapy and targeted biological therapy.; (3) Results: The patient responded positively to the combination therapy consisting of systemic chemotherapy and targeted biological therapy. The aggressive nature of Inflammatory Carcinoma, characterized by rapid growth and distinct skin changes, was effectively addressed. The presence of the HER2 protein on the tumor cells indicated the potential efficacy of the combination therapy in aggressive forms of breast cancer.; (4) Conclusions: This case highlights the critical importance of a multidisciplinary approach in managing complex cases of breast cancer, especially rare and aggressive subtypes like Inflammatory Carcinoma. The positive response of the patient to the combination therapy involving systemic chemotherapy and targeted biological therapy demonstrates the potential for favorable outcomes in aggressive disease presentations.

(1) Background: This case report focuses on a 46-year-old female patient diagnosed with a rare and aggressive form of breast cancer known as rapidly growing, ulcerated breast cancer. The patient exhibited rapid progression of the disease, experiencing discomfort and noticeable changes in the size and texture of the affected breast over a short period of time; (2) Methods: An intensive neoadjuvant chemotherapy regimen was employed as the primary treatment approach. The patient's response to this treatment was closely monitored and assessed. Various diagnostic tests and imaging techniques were utilized to evaluate the extent of the disease and track its response to the chemotherapy; (3) Results: The patient's response to the neoadjuvant chemotherapy regimen was remarkable, resulting in a complete pathologic response. This outcome, although unusual in rapidly growing, ulcerated breast cancers, highlights the effectiveness of neoadjuvant chemotherapy in managing large, locally advanced breast cancers; (4) Conclusions: The multidisciplinary approach employed in managing this complex breast cancer case proved to be crucial to the patient's favorable outcome. Despite the aggressive nature of the disease and the challenges posed by the rapid growth and ulceration, the patient achieved a positive result. This case contributes to the limited clinical literature on such unusual and aggressive breast cancer cases, providing valuable insights for future clinical practice.8

Lung cancer is the leading cause of global cancer-related mortality resulting in ~1.8 million deaths annually. Systemic, molecular targeted, and immune therapies have provided significant improvements of survival outcomes for patients. However, drug resistance usually arises and there is an urgent need for novel therapy screening and personalized medicine. 3D patient-derived organoid (PDO) models have emerged as a more effective and efficient alternative for ex vivo drug screening than 2D cell culture and patient-derived xenograft (PDX) models. In this review, we performed an extensive search of lung cancer PDO-based ex vivo drug screening studies. Lung cancer PDOs were successfully established from fresh or biobanked sections/biopsy of lung tumors, PDXs, and pleural affusion. PDOs were subject to ex vivo drug screening with chemotherapy, targeted therapy and immune therapy agents. PDOs mainly recapitulated the genomic alterations, transcriptomic landscape and drug sensitivity of primary tumors. Although sample sizes of the previous studies were limited and some technical challenges remained, PDOs showed promise to screen novel therapy drugs. With the technical advance of high throughput, tumor-on-chip, combined microenvironment, and air-liquid interface (ALI), the drug screening using PDOs would serve better for precision care of lung cancer patients.

Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancer and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia et al. proposed an on-slide classification, however this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein-Barr virus (GC EBV+), GC with mismatch repair deficiency (GC dMMR), GC with epithelial-mesenchymal transformation (GC EMT), GC with functional loss of p53 due to mutation (GC p53m), CG with intact p53 (GC p53wt) and GC not otherwise specified (GC NOS). This classification also has provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms, and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC p53m cases were 23%, GC p53wt cases were 29% and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in Histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted.

Purpose: The purpose of this study was to evaluate the dosimetric impact of multiple channels compared to a single channel in high dose rate (HDR) vaginal cuff brachytherapy (VCBT). Methods and materials: Sample plans of HDR VCBT from both single and multiple channel cylinders at 2.5, 3.0 and 3.5 cm in diameter were created and analyzed. The doses were prescribed either at the 0.5 cm depth with 5.5 Gy for 4 fractions or at the cylinder surface with 8.8 Gy for 4 frac¬tions, in various treatment lengths ranging from 3 to 8 cm. A 0.5 cm ring target volume called PTV_Eval was contoured for each plan and served as the target volume for dosimetric evaluation. Mean doses and the doses covering 90% (D90), 10% (D10), and 5% (D5) of PTV_Eval were calculated and compared. The same treatment lengths, same prescription regimens, same target volume contouring and same plan evaluation methods were repeated for the similar size single channel and multiple channel cylinders. Results: The mean doses of both regimens with the multi-channel cases (6.3 to 7.1 Gy) were comparable to single channel ones (6.4 and 7.5 Gy). The ranges of D90, D10 and D5 were from 3.654 to 5.04 Gy, 8.44 to 10.08 Gy and 8.84 to 10.86 Gy in the multi-channel cases, but from 5.36 to 5.76 Gy, 7.40 to 9.97 Gy and 8.16 to 11.93 Gy in the single channel cases, respectively. Conclusion: The single channel and multiple-channel cylinder deliver a similar mean dose, but with marked heterogeneity in D90, D5 and D10 for the same prescription dose and target volume. Multi-channel cylinders adequately cover the target volume, but given the heterogeneity, increased treatment time and cost are best suited for asymmetric target volumes.

The accuracy of multi-parametric MRI (mpMRI) in pre-operative staging of prostate cancer (PCa) remains controversial. Objective: To evaluate the ability of mpMRI to accurately predict PCa extra-prostatic extension (EPE) on a side-specific basis using a risk-stratified 5-point Likert scale. This study also aimed to assess the influence of mpMRI scan quality on diagnostic accuracy. Patients and Methods: We included 124 men who underwent robot-assisted RP (RARP) as part of the NeuroSAFE PROOF study at our centre. Three radiologists retrospectively reviewed mpMRI blinded to RP pathology and assigned a Likert score (1-5) for EPE on each side of the prostate. Each scan was also ascribed a Prostate Imaging Quality (PI-QUAL) score for assessing the quality of the mpMRI scan, where 1 represents poorest and 5 represents best diagnostic quality. Outcome measurements and statistical analyses: Diagnostic performance is presented for binary classification of EPE including 95% confidence intervals and area under the receiver operating characteristic curve (AUC). Results: A total of 231 lobes from 121 men (mean age 56.9 years) were evaluated. 39 men (32.2%), or 43 lobes (18.6%) had EPE. Likert score ≥3 had sensitivity (SE), specificity (SP), NPV, PPV of 90.4%, 52.3%, 96%, 29.9%, respectively, and AUC was 0.82 (95% CI: 0.77-0.86). AUC was 0.63 (95% CI: 0.37-0.9), 0.77 (0.71-0.84) and 0.92 (0.88-0.96) for biparametric scans, PI-QUAL 1-3 and PI-QUAL 4-5 scans, respectively. Conclusions: MRI can be used effectively by genitourinary radiologists to rule out EPE and help inform surgical planning for men undergoing RARP. EPE prediction was more reliable when the MRI scan was a) multi-parametric and b) of a higher image quality according to the PI-QUAL scoring system.

Assisted reproductive technology has been developed significantly throughout the past few years, particularly diagnosing and treating male infertility. Many studies have been performed showing that Intracytoplasmic Sperm Injection (ICSI) is a successful method to attain clinical pregnancy and live birth through impaired spermatozoa characteristics or low sperm count, such as severe oligospermia. Severe oligospermia indicates low sperm count, which in some cases leads to azoospermia. Severe oligospermia can be caused by several factors such as genetics or medication. In search of efficient treatment for couples with Severe oligospermia, numerous retrospective and prospective researches have reported high pregnancy and live birth rates through testicular sperm for men with severe oligospermia and cryptozoospermia with or without high sperm DNA damage. The research showed that the use of testicular sperm in combination with ICSI yielded a high pregnancy rate and live births over another source of sperm, such as ejaculated sperms. Moreover, the use of ICSI in severe oligospermia has shown successful fertilization and pregnancy.

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study. 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1-mm portion of each lymph node was subjected to semi-serial sectioning at 200-μm intervals and examined by hematoxylin-eosin and immunohistochemistry with CK19; the remaining tissue was analysed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/μl), the sensitivity of the OSNA assay was 92%; specificity was 82%; diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis.

Associations between blood cancer and genetic predisposition, including both inherited variants and acquired mutations and epimutations, have been well characterized. However, the majority of these variants affect noncoding regions, making their mechanisms difficult to hypothesize and hindering the translation of these insights into patient benefits. Fueled by unprecedented progress in next-generation sequencing and computational integrative analysis, studies have started applying combinations of epigenetic, genome architecture and functional assays to bridge the gap between noncoding variants and blood cancer. These complementary tools have not only allowed us to understand the potential malignant role of these variants but also to differentiate key variants, cell types and conditions from misleading ones. Here, we briefly review recent studies that have provided fundamental insights into our understanding of how noncoding mutations at enhancers predispose and promote blood malignancies in the context of spatial genome architecture.