Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras expressing or transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Oncogenes induce replication stress, re-sulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment cause toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overex-pressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but interestingly not by nucleoside supplementation. This suggest that cancer selectivity is unrelated oncogene-induced replication stress. We conclude that the molecular toxi-cological mechanisms how TH588 and TH1579 kill c-Myc overexpressing cells have several com-ponents and involves MTH1-independent proteosomal degradation of c-Myc itself, c-Myc driven transcription and CDK activation, and is likely unrelated to oncogene-induced replication stress.

Background: Oral cancer (OC) is serious health concerning issue that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft palate. The goal of this study is to look into new biomarkers and important pathways that might be used as diagnostic biomarkers and therapeutic candidates in OC. Methods: Publicly available repository the Gene Expression Omnibus (GEO) was responsible to collect OC-related datasets. GSE74530, GSE23558, and GSE3524 microarray datasets were collected to apply analysis. Minimum cut-off criteria of |log fold-change (FC)| > 1 and adjusted p < 0.05 were applied to figure out the up-regulated and down-regulated differential expression genes (DEGs) from the three datasets. After that only common DEGs in all three datasets were collected to apply further analysis. Gene ontology (GO) and Pathway analysis were implemented to explore the functional behaviors of DEGs. Then protein-protein interaction (PPI) networks were built to identify the most performed genes, clustering algorithm was also implemented to identify complex parts of PPI. TF-miRNA networks were also constructed to study deeply about OC-associated DEGs. Finally, top gene performers from PPI networks were used to apply drug signature analysis. Results: After applying filtration and cut-off criteria 2508, 3377, and 670 DEGs were found for GSE74530, GSE23558, and GSE3524 respectively, and 166 common DEGs were found in every dataset. The GO annotation remarks that most of the DEGs were associated with the terms of type I interferon signaling pathway. The pathways of KEGG reported that the common DEGs are related to the Cell cycle and Influenza A. The PPI network holds 88 nodes and 492 edges and CDC6 had the highest number of connections. 4 clusters were identified from the PPI. Drug signatures doxorubicin and resveratrol showed high significance according to the hub genes. We anticipate that our bioinformatics research will aid in the definition of the pathophysiology and the development of new therapies for OC.

From the formalism of the thermodynamics of irreversible processes and the theory of complex systems, characterization of longevity and aging and its relationship with the emergence and evolution of cancer was carried out. It was found that: 1. The rate of entropy production can be used as an index of robustness, plasticity, the aggressiveness of cancer, and as a measure of biological age; 2. The aging process, as well as the evolution of cancer, goes through what we have called “biological phase transition”; 3. The process of metastasis, which occurs through epithelial-mesenchymal transition (EMT), appears as a phase transition far from thermodynamic equilibrium and exhibits Shilnikov chaos-like dynamic behavior. This dynamic guarantees the robustness of the process and, in turn, its unpredictability; 4. It was shown that as the ferroptosis process is strengthened, the complexity of the dynamics associated with the emergence and evolution of cancer decreases. The theoretical framework developed contributes to a better understanding of the biophysical-chemical phenomena of longevity and aging and their relationship with cancer.

Triple-negative breast cancer (TNBC) is characterized by an active immune response. We evalu-ated intratumoral interrelation between FOXP3+ tumor-infiltrating lymphocytes and other cy-tokines in TNBC. Network analysis refined cytokines significantly correlate with FOPX3 in TNBC. Treatment response and prognosis imformation of patients and survival data from the TGCA and METABRIC databases were analyzed according to refined cytokines. Interleukin (IL)-33 was sig-nificantly expressed by TNBC cell lines than luminal cell lines (log2 fold change: 5.31, p <0.001) and IL-33 and TGFB2 showed a strong correlation with FOXP3 in the TNBC cell line. Immunohisto-chemistry demonstrated IL-33 high group was a significant predictor of complete response of neoadjuvant chemotherapy (odds ratio (OR) 4.12, p<0.05) and a favorable survival compared to IL-33 low group (OR 6.48, p<0.05) in TNBC. Survival data from TGCA and METABRIC revealed that FOXP3 was a significantly favorable marker in IL-33 high group com-pared to the low IL-33 low group (hazard ratio (HR) 2.1, p=0.02), and IL-33 high/TGFB2 high subgroup showed significant favorable prognosis in the FOXP3 high group compared to the FOPX3 low group in TNBC (HR 3.5, p=0.01). IL-33 and TGFB2 were key cytokines of intratumoral interrelation among FOXP3 in TNBC.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy which diagnosis and recurrences still challenge clinicians. New perspectives to overcome those issues could come from the study of extracellular vesicles (EVs) populations and content. Here, we aimed to elucidate the heterogeneity of EVs circulating in tumor and the changes in their microRNA content during cancer progression. Using a mouse model expressing BRAF^V600E, we isolated and characterized EVs from thyroid tissue by ultracentrifugations and elucidated their microRNA content by small RNA sequencing. Cellular origin of EVs was investigated by ExoView and that of deregulated EV-microRNA by qPCR on FACS-sorted cell populations. We found that PTC released more EVs bearing epithelial and immune markers, as compared to healthy thyroid, and that changes in EV-microRNAs abundance were mainly due to their deregulated expression in thyrocytes. Pathway analysis showed that the more abundant EV-microRNAs could impact on immune processes. Altogether, our work provides a full description of in vivo-derived EVs produced by, and within, normal and cancerous thyroid. We elucidated the global EV-microRNAs signature, the dynamic loading of microRNAs in EVs upon BRAF^V600E induction, and their cellular origin. Thyroid tumor-derived EV-microRNAs could support the establishment of a permissive immune microenvironment.

Background: A growing number of clinical practice guidelines (CPGs) with regards to non-pharmacological interventions for breast cancer survivors are available. However, given the limitations in guideline development methodologies and inconsistency of recommendations, it remains uncertain how best to design and implement such non-pharmacological strategies to tailor interventions for breast cancer survivors with varied health conditions, healthcare needs, and preferences. Aim: To critically appraise and summarise available non-pharmacological interventions for symptom management and health promotion that can be self-managed by breast cancer survivors based on the recommendations of the CPGs. Methods: Clinical practice guidelines which were published between January 2016 and September 2021 and described non-pharmacological interventions for breast cancer survivors were systematically searched in six electronic databases, nine relevant guideline databases, and five cancer care society websites. The quality of the included CPGs was assessed by four evaluators using the Appraisal of Guidelines for REsearch and Evaluation, second edition tool. Content analysis was conducted to synthesise the characteristics of the non-pharmacological interventions that were recommended by the included CPGs, such as the intervention’s form, duration and frequency, level of evidence, grade of recommendation, and source of evidence. Results: Fourteen CPGs were identified and analysed. Of the 14 CPGs appraised, only five were rated as high quality. The domain with the highest standardised percentage was “scope and purpose” (84.61%), while the “applicability” domain had the lowest standardised percentage (51.04%). Five guidelines were assessed as “recommended”, seven were rated as “recommended with modifications”, and the remaining two were considered “not recommended”. Regarding the content analysis, physical activity/exercise, meditation, hypnosis, yoga, music therapy, stress management, relaxation, massage, and acupressure were the common self-managed non-pharmacological interventions recommended by the 14 CPGs. Physical activity/exercise was the only self-managed non-pharmacological intervention that was mostly recommended for psychological and physical symptom management by the included CPGs. However, there were significant disparities in terms of level of evidence and grade of recommendation in the included CPGs. Conclusion: The recommendations for the self-managed non-pharmacological interventions were varied and limited among the 14 CPGs, and some were based on medium- and low-quality evidence. More rigorous methods are required to develop high-quality CPGs in order to guide clinicians in offering high-quality and tailored breast cancer survivorship care.

Skin cancer is an exquisite disease globally nowadays. Because of the poor contrast and apparent resemblance between skin and lesions, automatic identification of skin cancer is complicated. The rate of human death can be massively reduced if melanoma skin cancer can be detected quickly using dermoscopy images. In this research, an anisotropic diffusion filtering method is used on dermoscopy images to remove multiplicative speckle noise and the fast-bounding box (FBB) method is applied to segment the skin cancer region. Furthermore, the paper consists of two feature extractor parts. One of the two features extractor parts is the hybrid feature extractor (HFE) part and another is the convolutional neural network VGG19 based CNN feature extractor part. The HFE portion combines three feature extraction approaches into a single fused feature vector: Histogram-Oriented Gradient (HOG), Local Binary Pattern (LBP), and Speed Up Robust Feature (SURF). The CNN method also is used to extract additional features from test and training datasets. This two-feature vector is fused to design the classification model. This classifier performs the classification of dermoscopy images whether it is melanoma or non-melanoma skin cancer. The proposed methodology is performed on two ordinary datasets and achieved the accuracy 99.85%, sensitivity 91.65%, and specificity 95.70%, which makes it more successful than previous machine learning algorithms.

More than twenty-five years ago the Global Solar UV index (UVI) has been introduced as a simple means of visualizing the intensity of ultraviolet radiation and to alert people to the need for sun protection. In our survey among directors of 436 kindergartens in southern Germany we investigated the level of awareness and knowledge about the UVI as well as the practical consequences for sun protection in kindergartens. Less than half of the directors (n=208, 47.7%) had ever heard of the UVI, and only a small minority of them (n=34, 8.7%) used the daily UVI information to adapt sun protective measures in their kindergartens. Detailed knowledge about the UVI was a rarity among the respondents. The proportion of respondents with self-perceived detailed UVI knowledge was five times higher than actual knowledge assessed by an in-depth structured interview using open-ended questions about the UVI (14.2% vs. 2.8%). No clear relationship of UVI awareness, knowledge, and use to directors' age and gender was found. The UVI-related variables also showed no association with directors' knowledge of risk factors for skin cancer and their attitudes towards tanned skin. Overall, the results paint a sobering picture regarding the penetration of the UVI into sun protection policies of German kindergartens. Future public health campaigns should target increasing awareness and understanding of the UVI as well as its importance for sun protection of children.

We performed Bayesian network meta-analysis (NMA) to suggest frontline treatments for patients with high PD-L1 expression (at least 50%). A total of 5,237 patients from 22 studies were included in this NMA. In terms of progression-free survival, immune checkpoint inhibitors (ICIs) plus bevacizumab plus chemotherapy had the highest surface under the cumulative ranking curve (SUCRA) value (98.1%), followed by ICI plus chemotherapy (82.9%). In terms of overall survival (OS), dual immunotherapy plus chemotherapy had the highest SUCRA value (79.1%), followed by ICI plus bevacizumab plus chemotherapy (73.4%). However, there was no significant difference of survival outcomes among treatment regimens combined with immunotherapy. Moreover, ICI plus chemotherapy failed to reveal a significant OS superiority to ICI monotherapy (hazard ratio = 0.978, 95% credible internal: 0.771-1.259). In conclusion, this NMA indicates that ICI plus chemotherapy with/without bevacizumab might to be the best options in terms of OS for NSCLC with high PD-L1 expression. Considering there was no significant difference of survival outcomes among treatment regimens incorporating immunotherapy and ICI plus chemotherapy failed to show significant survival benefits over ICI monotherapy, however, ICI monotherapy may be reasonable as first-line treatment for advanced NSCLC with high PD-L1 expression and no targetable aberrations.

Studies have shown that STK11 mutation plays a critical role in affecting the lung adenocarcinoma (LUAD) tumor immune environment. By training an Inception-Resnet-v2 deep convolutional neural network model, we were able to classify STK11-mutated and wild type LUAD tumor histopathology images with a promising accuracy (per slide AUROC=0.795). Dimensional reduction of the activation maps before the output layer of the test set images revealed that fewer immune cells were accumulated around cancer cells in STK11-mutation cases. Our study demonstrated that deep convolutional network model can automatically identify STK11 mutations based on histopathology slides and confirmed that the immune cell density was the main feature used by the model to distinguish STK11-mutated cases.

Within phototherapy, a grand challenge in clinical cancer treatments is to develop a simple, cost-effective, and biocompatible approach to treat this disease using ultra-low doses of light. Carbon-based materials (CBM), such as graphene oxide (GO), reduced GO (r-GO), graphene quantum dots (GQDs), and carbon dots (C-DOTs), are rapidly emerging as a new class of thera-peutic materials against cancer. This mini-review summarizes the progress in lasts years re-garding the applications of CBM in photodynamic (PDT) and photothermal (PTT) therapies for tumor destruction. The current understanding of the performance of modified CBM, hybrids and composites, is also addressed. This approach seeks to achieve an enhanced healing action by im-proving and modulating the properties of CBM to treat various types of cancer. Metal oxides, organic molecules, biopolymers, therapeutic drugs, among others, have been combined with CBM to treat cancer by PDT, PTT, or synergistic therapies.

Complete pathologic response (pCR) predicts the long-term outcome of neoadjuvant treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers able to guide adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether shifts in the serum concentration of thymidine kinase 1 (sTK1) during NAC could be utilized as a biomarker. In the PROMIX trial, women with localized HER2- BC received neoadjuvant epirubicin/docetaxel in six cycles. sTK1 was measured with an ELISA in 54 patients at cycles 1-4 and in a total of 131 patients before and 48h after cycle 1. The prognostic significance of the results was evaluated by log-rank tests of Kaplan–Meier estimates. Treatment resulted in a 2-fold increase of sTK1 before and 3-fold increase 48h after the cycles, except for the first cycle, where half of patients reacted with a decrease (post/pre sTK1- ratio <1.12) and the other half reacted with an increase (ratio >1.12). OS rates in ER+ patients with ratios of >1.12 and <1.12 were 97.7% and 78% (p=0.005), respectively, and DFS rates were 90.7% and 68% (p=0.006), respectively. Thus, response of sTK1 at the first cycle of chemotherapy could be used both as an early biomarker for guidance of chemotherapy and for the study of inherent tumor chemo-sensitivity, which could predict long-term outcome prior to therapy.

Abstract: Perihilar cholangiocarcinoma (phCC) is the most common type of cholangiocarcinoma, accounting for approximately 60 % of cases, followed by the distal and then the intrahepatic forms. There is not a staging system that allows comparation of all series and extract some conclusions to increase the long-survival rate in this dismal disease. The extension of the resection, which theoretically dependes on the type of phCC, is not closed subject. As surgery is the only known way to achieve a cure, many aggressive approachs have been adopted. Despite extended liver resections and even vascular resections, margins are positive in around one third of patients. In the past two decades, with advances in diagnostic and surgical techniques, the surgical outcomes and survival rates have gradually improved, although variability is the rule, with morbidity and mortality rates ranging from 14% to 76% and from 0% to 19%, respectively. Extended hepatectomies and portal vein resection even right hepatic artery reconstruction for the left side tumors are frequently needed. Salvage procedures when arterial reconstruction is not feasible, as well as hepatopancreatoduodenectomy, are still under evaluation too. In this article, we discuss the aggressive surgical approach to phCC focused on vascular resection. Disparate results on the surgical treatment of phCC made it impossible to reach clear-cut conclusions.

Background: Ovarian cancer (OC) represents the eighth most common cancer and the fifth leading cause of cancer-related deaths among the female population. In the advanced setting, chemotherapy represents the first-choice treatment, despite a high recurrence rate. In the last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified the therapeutic scenario of many solid tumors. We sought to summarize the main findings regarding the clinical use of ICIs in the OC. Methods: We searched the PubMed, Embase, and Cochrane Databases, and conference abstracts from international congresses (such as ASCO, ESMO, SGO) for clinical trials, focusing on ICIs both as monotherapy and as combinations in the advanced OC. Results: 20 studies were selected, of which 16 were phase I or II and 4 phase III trials. ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab) were employed. No significant survival improvement was achieved; conversely, early terminations due to futility or toxicity were recorded. Combinations with chemotherapy, anti-VEGF, and, overall, PARP-inhibitors seem feasible and enhance the response rate and survival, notwithstanding a worse safety profile. Conclusions: The identification of biomarkers with a predictive role for ICIs’ efficacy is mandatory. Moreover, genomic and immune profiling of the OC might lead to an improved treatments selection and design of tailored trials.

Due to their well-defined plasmonic properties, gold nanorods (GNRs) can be fabricated with optimal light absorption in the near-infrared region of the electromagnetic spectrum, which make them suitable for cancer-related theranostic applications. However, their controversial safety profile, as a result of surfactant stabilization during synthesis, limits their clinical translation. We report a facile method to improve GNR biocompatibility through the presence of sodium dodecyl sulfate (SDS). GNRs (120 x 40 nm) were synthesized through a seed-mediated approach, using cetyltrimethylammonium bromide (CTAB) as a cationic surfactant to direct the growth of nanorods and stabilize the particles. Post-synthesis, SDS was used as an exchange ligand to modify the net surface charge of the particles from positive to negative while maintaining rod stability in an aqueous environment. GNR cytotoxic effects, as well as the mechanisms of their cellular uptake, were examined in two different cancer cell lines, Lewis lung carcinoma (LLC) and HeLa cells. We not only found a significant dose-dependent effect of GNR treatment on cell viability but also a time-dependent effect of GNR surfactant charge on cytotoxicity over the two cell lines. Our results promote a better understanding of how we can mediate the undesired consequences of GNR synthesis byproducts when exposed to a living organism, which so far has limited GNR use in cancer theranostics.

(1) Background: Mouse-mammary tumor virus (MMTV) might play a role in the etiology of some breast cancers in humans. The purpose of our study was to identify MMTV DNA sequences in breast tissue samples from breast cancer patients operated in our regional center from Romania. (2) Methods: We have selected 75 patients with non-metastatic breast cancer treated with curative intent and searched with PCR the MMTV-like DNA sequence in the breast cancer tissue and normal breast tissue obtained from the same patients. (3) Results: None of the examined samples was positive for MMTV-like target sequences on PCR. (4) Conclusions: We could not prove that MMTV plays a role in the etiology of breast cancer in our patient group. This finding is similar to findings of other geographically related research groups and might be due to the fact that only the Mus musculus domesticus mouse species was proven to carry infectious MMTV, but not the Mus musculus musculus species, which is specific to South-Eastern Europe and some parts of Asia.

The aim of this study was to determine whether a rowing training program improved the quantity and quality of physical activity and quality of life in female breast cancer survivors (stage I - 4.35%; II - 30.43%; III - 52.17%; and IV - 8.7%) diagnosed 6.57 ± 5.02 years previously, who had undergone a subsequent intervention (preservation 53.52%; total mastectomy 39.13% and double mastectomy 4.35%) and had a current mean age of 53.70 ± 7.88 years. The participants (N = 30) engaged in a 12-week training program, each week comprising three sessions and each session lasting 60-90 minutes. An anthropometric evaluation was performed before and after the program. The short form of the International Physical Activity Questionnaire (IPAQ-SF) and the Short Form 36 Health Survey (SF-36) were also administered. The results showed statistically significant improvements in levels of physical activity and in the dimensions of quality of life. We can conclude that a 12-week rowing training program tailored to women who have had breast cancer increases physical activity levels, leading to improved health status and quality of life.

Dietary factors play an important role in shaping the gut microbiome which, in turn, regulates the molecular events in colonic mucosa. The composition and resulting metabolism of the gut microbiome have been implicated in the development of colorectal cancer (CRC). Diets low in dietary fibers and phytomolecules as well as other lifestyle-related factors may predispose to CRC. Emerging evidence demonstrates that the predominance of microbes, such as Fusobacterium nucleatum, can predispose the colonic mucosa to malignant transformation. Dietary and lifestyle modifications have been demonstrated to restrict the growth of potentially harmful opportunistic organisms. In this study, we aim to present evidence regarding the relationship of dietary factors to the gut microbiome and development of CRC.

The aim of this study was to determine whether a rowing training program improved the quantity and quality of physical activity and quality of life in female breast cancer survivors (stage I - 4.35%; II - 30.43%; III - 52.17%; and IV - 8.7%) diagnosed 6.57 ± 5.02 years previously, who had undergone a subsequent intervention (preservation 53.52%; total mastectomy 39.13% and double mastectomy 4.35%) and had a current mean age of 53.70 ± 7.88 years. The participants (N = 30) engaged in a 12-week training program, each week comprising three sessions and each session lasting 60-90 minutes. An anthropometric evaluation was performed before and after the program. The short form of the International Physical Activity Questionnaire (IPAQ-SF) and the Short Form 36 Health Survey (SF-36) were also administered. The results showed statistically significant improvements in levels of physical activity and in the dimensions of quality of life. We can conclude that a 12-week rowing training program tailored to women who have had breast cancer increases physical activity levels, leading to improved health status and quality of life.

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancer (CRC) and the remaining genetic burden may be due to rare high-to-moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants; a coding variant in APC down-regulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5’ untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5´UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.

Conformal radiotherapy is a primary treatment in head and neck cancer, which putative adverse effects depend on relatively low doses of radiation delivered to increased volumes of normal tissues. Systemic effects of such treatment include radiation-induced changes in serum lipid profile, yet dose- and volume-dependence of these changes remain to be established. Here we analyzed levels of choline-containing phospholipids in serum samples collected consecutively during the radiotherapy used as the only treatment modality. The LC-MS approach applied in the study enabled the detection and quantitation of 151 phospholipids, including (lyso)phosphatidylcholines and sphingomyelins. No statistically significant differences were found in the pre-treatment samples from patients with different location and stage of cancer. To compensate for potential differences between schemes of radiotherapy the biologically effective doses were calculated and used in the search of correlations with specific lipid levels. We found that the levels of several phospholipids depended on the maximum dose delivered to the gross tumor volume and total radiation energy absorbed by the patient’s body. Increased doses correlated with increased levels of sphingomyelins and reduced levels of phosphatidylcholines. Noteworthy, serum phospholipid levels were associated mainly with volumes of normal tissues irradiated with relatively low doses (i.e., total accumulated dose 20 Gy), which indicated the importance of such effects on the systemic response of the patient’s organism to IMRT.

In patients with presumed pancreatic ductal adenocarcinoma (PDAC), biomarkers that may open for personalised, risk-adapted treatment are lacking. The study analysed the impact of circulating tumour cells (CTCs) on the patterns of recurrence and survival in 98 patients resected for PDAC with 5-10 years of follow-up. Preoperative samples were analysed by the CellSearch® system for EpCAM+/DAPI+/CK+/CD45- CTCs. CTCs were detected in 7 of the 98 patients. CTCs predicted a significantly shorter median DFS of 3.3 vs. 9.2 months and a median CSS of 6.3 vs. 18.5 months. Relapse status was confirmed by imaging for 87 patients. Of these, 58 developed distant metastases (DM) and 29 cases isolated local recurrence (ILR) as first event. All patients with CTCs experienced DM. pN-status and histological grade &gt;2 were other independent risk factors for DM, but only CTCs predicted significantly shorter cancer-specific, disease-free and post-recurrence survival. We conclude that CTC presence in resected PDAC patients predicted early distant metastasis and impaired survival. The impact of CTCs was comparable to that of histopathological risk factors and exceeded the effect size of other preoperative parameters. Thus, preoperative CTCs alone or in combination with histopathological factors may guide initial treatment decisions in patients with resectable PDAC in the future.

Extracellular vesicles are considered a novel therapeutic tool, due to their ability to transfer their cargoes to target cells. Different strategies to directly load extracellular vesicles with RNA species have been proposed. Electroporation has been used for the loading of non-active vesicles, however the engineering of vesicles already carrying a therapeutically active cargo is still under investigation. We here set up a coincubation method to increase the anti-tumor effect of extracellular vesicles isolated from human liver stem cells (HLSC-EVs). Using the coincubation protocol, vesicles were loaded with the anti-tumor miRNA-145, and their effect was evaluated on renal cancer stem cell invasion. Loaded HLSC-EVs maintained their integrity and miR transfer ability, and miR-145 was protected by RNAse digestion possibly due to its binding to RNA-binding proteins on HLSC-EV surface, such as Annexin A2. Moreover, miR-145 coincubated HLSC-EVs were more effective in inhibiting the invasive properties of cancer stem cells, in comparison to naïve vesicles. The protocol reported here exploits a well-described property of extracellular vesicles to bind nucleic acids on their surface and protect them from degradation, in order to obtain an effective miRNA loading that results in the increase of the effect of naïve active extracellular vesicles.

Sporadic colorectal cancer (CRC) develops through distinct molecular events. Loss of 18q chromosome is a conspicuous event in the progression of adenoma to carcinoma. There is limited information regarding the molecular effectors of this event. Earlier, we had reported ATP8B1 as a novel gene associated with CRC. ATP8B1 belongs to the family of P-type ATPases (P4 ATPase) that primarily function to facilitate the translocation of phospholipids. In this study, we attempt to implicate ATP8B1 gene located on chromosome 18q as a tumor suppressor gene. We studied indigenous patient data and confirmed the reduced expression of ATP8B1 in tumor samples. CRC cell lines were engineered with reduced and enhanced levels of ATP8B1 which provided a tool to study its role on cancer progression. Forced reduction of ATP8B1 expression either by CRISPR/Cas9 or shRNA was associated with increased growth and proliferation of CRC cell line - HT29. In contrast, overexpression of ATP8B1 resulted in reduced growth and proliferation of SW480 cell line. We generated a network of genes that are downstream of ATP8B1. Further, we provide predicted effect of modulation of ATP8B1 levels on this network and possible effect on fatty acid metabolism related genes. These results provide evidence in support of ATP8B1 being a tumor suppressor that may affect fatty acid metabolism in CRC.

Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modelling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.

There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised intermediate grade prostate cancer. There has therefore been a major focus on identifying molecular biomarkers that can add prognostic value to existing markers, including investigation of DNA methylation, which has a known role in tumorigenesis. In this review, we will provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis, and highlight the advances that have been made in this field. We cover the numerous studies into well-established candidate genes, and explore the technological transition that has enabled hypothesis-free genome-wide studies and the subsequent discovery of novel prognostic genes.

Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. Methods: MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Results: Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-Adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. Conclusion: This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

Lung cancer is known as lung carcinoma. It is a disease which is malignant tumor leading to the uncontrolled cell growth in the lung tissue. Lung Cancer disease is one of the most prominent cause of death in all over world. Early detection of this disease can assist medical care unit as well as physicians to provide counter measures to the patients. The objective of this paper is to approach an automated tool that takes influential causes of lung cancer as input and detect patients with higher probabilities of being affected by this disease. A neural network classifier accompanied by cross-validation technique is proposed in this paper as a predictive tool. Later, this proposed method is compared with another baseline classifier Gradient Boosting Classifier in order to justify the prediction performance.

Background: Prostate cancer (PCa) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of prostate adenocarcinomas (n=496) was utilized. The immune microenvironment was characterized using the CIBERSORTX tool to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Analyses of progression-free survival (PFS), distant metastases, and overall survival (OS) were performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by plasma cell, CD4+ Memory Resting T Cells (CD4 MR), M0 and M2 macrophage content (CD4 MRHighPlasma CellHighM0LowM2Low, CD4 MRLowPlasma CellHighM0LowM2Low, CD4 MRHighPlasma CellLowM0HighM2Low, and CD4 MRHighPlasma CellLowM0LowM2High). The two macrophage-enriched/plasma cell non-enriched clusters (3&4) demonstrated worse PFS (HR 2.24, 95% CI 1.46–3.45, p=0.0002) than the clusters 1&2. No metastatic events occurred in the non-macrophage-enriched clusters. Comparing clusters 3 vs 4, in patients treated by surgery alone, cluster 3 had zero progression events (p<0.0001). However, cluster 3 patients had worse outcomes after post-operative radiotherapy (p=0.018). Conclusion: Distinct tumor immune clusters with a macrophage-enriched phenotype and reduced plasma cell enrichment independently characterize an aggressive phenotype in localized prostate cancer that may differentially respond to treatment.

Efficiently targeted cancer therapy without causing detrimental side effects is necessary for alleviating patient care and improving survival rates. This paper presents observations of morphological changes in H1299 human lung cancer cells following W-band MMW irradiation (75 – 105 GHz) at a non-thermal power density of 0.2 mW/cm², investigated over 14 days of subsequent physiological incubation following exposure. Microscopic analyses of physical parameters measured indicate MMW irradiation induces significant morphological changes characteristic of apoptosis and senescence. The Immediate short-term responses translate into long-term effects, retained over the duration of the experiment(s); reminiscent of the phenomenon of Accelerated Cellular Senescence (ACS) achieving terminal tumorigenic cell growth. Further, results were observed to be treatment-specific in energy (dose) dependent manner and were achieved without the use of chemotherapeutic agents, ionizing radiation or thermal ablation employed in conventional methods; thereby overcoming associated side effects. Adaptation of the experimental parameters of this study for clinical oncology concomitant with current developmental trends of non-invasive medical endoscopy alleviates MMW therapy as an effective treatment procedure for human non-small cell lung cancer (NSCLC).

Background: Cutaneous squamous skin cell carcinoma (SCC) is the second most frequent type of non- melanoma skin cancer and the second cause of death by skin cancer in caucasian population. However, at present it is difficult to predict patients with worst SCC prognosis. Objective: To identify proteins whose expression level could predict SCC infiltration in SCC arising from actinic keratosis (AC). Methods: A total of 20 biopsies of 20 different patients were studied, 10 were from SCC-AK samples and 10 from normal skin. Early infiltrated SCC-AK were selected on histological examination and to determine the expression of proteins fresh skin samples were processed by 2DE-electrophoresis Results: The expression levels of three proteins namely alpha-hemoglobin, heat shock protein (Hsp)-27 and 70 were significantly increased in SCC-AK samples with respect to normal control skin. However, only the expression level of Hsp70 protein positively correlated with the level of SCC-AK dermis infiltration. Immnunohistological examination suggested that the increased expression of Hsp70 proteins seems to mainly occur in the keratinocytes cytoplasm. The increased cytoplasmic Hsp70 expression in SCC-AK was confirmed by Western-blot experiments. Conclusion: Cytoplasmic expression of Hsp70 could be potential biomarker of early infiltration of SCC arising from an AK. Keywords: actinic keratosis, cutaneous squamous cell carcinoma; cytoplasm, skin cancer; heat shock protein.

HIF-1α is a master regulator of oxygen homeostasis involved in different stages of cancer development. Thus, HIF-1α inhibition represents an interesting target for anti-cancer therapy. It was recently shown that HIF-1α interaction with NQO1 inhibits its proteasomal degradation, thus suggesting that targeting the stability of NQO1 could led to destabilization of HIF-1α as a therapeutic approach. Since the molecular interactions of NQO1 with HIF-1α are beginning to be unraveled, we review here our current knowledge on the intracellular functions and stability of NQO1, its pharmacological modulation by small ligands, and the molecular determinants of its roles as a chaperone of many different proteins including cancer-associated factors such as p53 and p73α. This knowledge is then discussed in the context of potentially targeting the intracellular stability of HIF-1α by acting on its chaperone, NQO1. This could result in novel anti-cancer therapies.

PD-1/PD-L1 axis is one key therapeutic target against tumor cell immune escape. Structurally essential to the PD-1/PD-L1-linked immune escape is the binding interface of the PD-1/PD-L1 complex structure. Incorporating currently available PD-1/PD-L1-related experimental structures, this article unveils two sets of experimentally observed inter-molecular electrostatic interactions which stabilize the binding interface of the PD-1/PD-L1 complex structure. For the first time, this article proposes an evolutionary structural hypothesis that, as a result of natural selection, PD-1 is able to genetically mutate itself to structurally disrupt the PD-1/PD-L1 axis towards the restoration of T cell-mediated anti-tumor immunity.

It is widely discussed that growth of GDP has a vague impact on environmental pollution due to the emissions of carbon dioxide from consumed fossil fuels in production, transportation and power generation, and creation of required instruments to control environmental pollution as well. Due to the fact that environmental pollution can be a reason of mortality increase in a society, the main purpose of this study is to investigate the relationship between economic growth, fossil fuel consumption, mortality (from cardiovascular disease, cancer, diabetes and chronic respiratory disease) and environmental pollution using Generalized Method of Moments (GMM) estimation technique in the case of CIS member states over the period of 1993-2018. The major results revealed CO2 emissions in in the region of CIS have a positive effect on increase of mortality from cardiovascular disease, cancer, diabetes and chronic respiratory disease. In regards to fossil fuel consumption, the estimation proved that this variable affects mortality from cardiovascular disease, cancer, diabetes and chronic respiratory disease positively. In addition, we found effect of economic growth, population growth and inflation rate positively, while any improvement in human development index (HDI) has a negative effect on increase of mortality from cardiovascular disease, cancer, diabetes and chronic respiratory disease in the CIS region. It is recommended that the CIS member states carry out different policies to improve energy transition indicating movement from fossil fuel energy sources to renewable ones. Moreover, we recommend the CIS member states to enhance various policies for easy access to the electricity from green sources and increase of renewable supply through improved technologies, sustainable economic growth, and increase of using green source in daily social life.

Papillomaviruses infect the skin and mucosal surfaces of diverse animal hosts with consequences ranging from asymptomatic colonization to highly malignant epithelial cancers. Increasing evidence suggests a role for papillomaviruses in the most common cutaneous malignancy of domestic cats, squamous cell carcinoma (SCC). Using total DNA sequencing we identified a novel feline papillomavirus in a nasal biopsy taken from a cat presenting with both nasal cavity lymphoma and recurrent squamous cell carcinoma affecting the nasal planum. We designate this novel virus as Felis catus papillomavirus 6 (FcaPV6). The complete FcaPV6 7453 bp genome was similar to those of other feline papillomaviruses and phylogenetic analysis revealed that it was most closely related to FcaPV3, although was distinct enough to represent a new viral species within the genus Taupapillomavirus. Archived excisional biopsy of the SCC, taken 20 months prior to presentation, was intensely positive on p16 immunostaining. FcaPV6, amplified using virus-specific, but not consensus, PCR was the only papillomavirus detected in DNA extracted from the SCC. Conversely, renal lymphoma, sampled at necropsy two months after presentation, tested negative on FcaPV6-specific PCR. In sum, using metagenomics we demonstrate the presence of a novel feline papillomavirus in association with cutaneous squamous cell carcinoma.

Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 5′ or 3′ untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC.

Nowadays the positive immune involvement in the eradication of tumor cells is assigned to the adaptive immune response. By awakening of in vivo responding T cells that are suppressed by the tumor and prevents immunological cure of the cancer. The adaptive immune response is a complex of different cells and protein molecules. Normally activated T cells are well-ordered by several late occurring inhibitors to contain the response to the unknown invaders and spare the normal cells. The tumor strengthens this inhibitory response to escape from immune elimination. Immunotherapy is to unleash the full capacity of the adaptive immune system by blocking this inhibitor response by monoclonal antibodies but with the potential drawback of autoimmune phenomena. Seen the success of the immunotherapy another feature of the immune system is overlooked. Cytokines and chemokines became in oblivion after their suspected necrosis of the tumor (TNF) did not fulfil their initial hope. When patients seek help for their complaints the ovarian cancer is in most cases already metastasized to the peritoneum and omentum. Here, we show that on the one hand chemokines produced by Th2, CD8 and NK cells inhibit cancer spreading and thus leads to a better operability and thus better survival. On the other hand, chemokine receptors are expressed by the tumor that are a decoy by binding chemokines that normally should attract antigen cross-presenting dendritic cells, which start an adaptive T cell response.

Patient-derived xenograft (PDX) models are created by engraftment of patients’ tumor tissues into immunocompetent mice. Since PDX model keep the characteristics of primary patient’s tumor such as gene expression profiles and drug sensitivity, it now becomes most reliable in vivo human cancer model. The engraftment rate are increased with the introduction of NOD/Scid based immunocompromised mice, especially, NK cell defective NOD strains such as NOD/Scid/IL2Rγnu (NOG/ NSG) mice and NOD/Scid/Jak3null (NOJ) mice. Success ratio differs from the origin of tumor: Gastrointestinal tumors tend to higher success rate and breast cancer is lower. Subcutaneous transplantation is most popular method to establish PDX, but some tumor needs orthotropic or renal capsule transplantation, and human hormone treatment is needed to establish hormone dependent cancers such as prostate and breast cancer. PDX library with patient’s clinical data, gene-expression patterns, mutational status, drug responsiveness and tumor architecture will be the powerful tool for developing specific biomarker and novel individualized therapy and establishing precision cancer medicine.

Sleep is essential for health. Indeed, poor sleep is consistently linked to the development of systemic disease, including depression, metabolic syndrome, and cognitive impairments. Further evidence has accumulated suggesting a role for sleep in cancer initiation and progression (primarily breast cancer). Indeed, patients with cancer and cancer survivors frequently experience poor sleep, manifested as insomnia, circadian misalignment, hypersomnia, somnolence syndrome, hot flushes, and nightmares. These problems are associated with a reduction in patients’ quality of life and increased mortality. Due to the heterogeneity among cancers, treatment regimens, patient populations, and lifestyle factors, the etiology of cancer-induced sleep disruption is largely unknown. Here, we discuss recent advances in understanding the pathways linking cancer and the brain and how this leads to altered sleep patterns. We describe a conceptual framework where tumors disrupt normal homeostatic processes, resulting in aberrant changes in physiology and behavior that are detrimental to health. Finally, we discuss how this knowledge can be leveraged to develop novel therapeutic approaches for cancer-associated sleep disruption, with special emphasis on host-tumor interactions.

The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates cellular proliferation, differentiation, apoptosis and tumorigenesis. Although the pro-oncogenic roles of C/EBPβ have been implicated in various human cancers, how it contributes to tumorigenesis or tumor progression has not been determined. Immunohistochemistry with human non-small cell lung cancer (NSCLC) tissues revealed that higher levels of C/EBPβ protein are expressed compared to normal lung tissues. Knockdown of C/EBPβ by siRNA reduced the proliferative capacity of NSCLC cells by delaying G₂/M transition of the cell cycle. In C/EBPβ-knockdown cells, a prolonged increase in phosphorylation of cyclin dependent kinase 1 at tyrosine 15 (Y15-pCDK1) was displayed with increased Wee1 and decreased Cdc25B expression, simultaneously. ChIP analysis showed that C/EBPβ bound to distal promoter regions of WEE1 and repressed WEE1 transcription through the interaction with histone deacetylase 2. Treatment of C/EBPβ-knockdown cells with a Wee1 inhibitor induced a decrease in Y15-pCDK1 and recovered cells from G₂/M arrest. In the xenograft tumors, the depletion of C/EBPβ significantly reduced tumor growth. Taken together, these results indicate that Wee1 is a novel transcription target of C/EBPβ that is required for the G₂/M phase of cell cycle progression, ultimately regulating proliferation of NSCLC cells.

The present work encompasses an application-oriented perspective to the possible employment of gold nanoparticles as nanomedicine in cancer therapeutics. The rationale of the work lies in the growing needs for assessment of advanced alternative treatment of cancer employing functionalized nanoparticles as nanomedicine. Gold nanoparticles fabricated via green chemistry methods by leaves of a time-honored medicinal plant, Piper betle were ascertained for their synthesis and properties under the umbrella of characterization of nanoparticles, through various techniques like UV-vis spectroscopy, FTIR spectroscopy, X-ray diffraction, and scanning electron microscopy. The cytotoxicity assay of well-characterized gold nanoparticles was monitored against lung cancer cell line (A549) by metabolic and imaging assays. MTT assay or the metabolic assay was performed for a range of nanoparticles’ concentrations. The results were promising and proved to be a leading-edge venture, envisaging the possibility of gold nanoparticles for cancer therapeutics.

The current clinical model for genetic-testing is based on clinical-criteria/family-history(FH) and a pre-defined mutation probability threshold. It requires people to develop cancer before identifying unaffected individuals in the family to target prevention. This process is inefficient, resource intense and misses >50% of individuals/mutation carriers at risk. Population genetic-testing can overcome these limitations. It is technically feasible to test populations on a large scale; genetic-testing costs are falling and the acceptability/awareness is rising. MEDLINE/EMBASE/Pubmed/CINAHL/PsychINFO databases were searched using a free-text and MeSH terms; reference lists of publications retrieved screened; additionally web-based platforms, Google, and clinical-trial registries were searched. Quality of studies were evaluated using appropriate check-lists. A number of studies have evaluated population-based BRCA-testing in the Jewish-population. This has been found to be acceptable, feasible, clinically-effective, safe, associated with high satisfaction rates and extremely cost-effective. Data support change in guidelines to population-based BRCA-testing in the Jewish-population. Population panel-testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 gene mutations is the most cost-effective genetic-testing strategy in general-population women and can prevent thousands more breast/ovarian cancers than current clinical-criteria based approaches. A few ongoing studies are evaluating population-based genetic-testing for multiple cancer susceptibility genes in the general-population but more implementation studies are needed. A future population-testing programme could also target other chronic diseases.

Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence and apoptosis. NF-kB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. Although these pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IkB degradation and NF-kB nuclear translocation. Under these stress conditions, the RelA component of NF-kB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to the anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly discuss how NF-kB-nucleoli crosstalk may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose.

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. Experimental approach: In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, western blot, RT-PCR, and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. Results: This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-AAQB as evidenced by inhibited cell viability and proliferation, as well as, attenuated migration, invasion and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates FOLFOX anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324 and inhibiting SOD2-mediated tumorigenicity. Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.

If environmental exposures are shown to cause an adverse health outcome, reducing exposure should reduce the disease risk. Links between exposures and outcomes are typically based on ‘associations’ derived from observational studies, and causality may not be clear. Randomised controlled trials to ‘prove’ causality are often not feasible or ethical. Here the history of evidence that tobacco smoking causes lung cancer – in observational studies – is compared to that of low sun exposure and/or low vitamin D status as causal risk factors for the autoimmune disease, multiple sclerosis. Evidence derives from in vitro and animal studies, as well as ecological, case-control and cohort studies, in order of increasing strength. For smoking and lung cancer, the associations are strong, consistent, and biologically plausible – the evidence is coherent or ‘in harmony’. For low sun exposure/vitamin D as risk factors for MS, the evidence is weaker, with smaller effect sizes, but coherent across a range of sources of evidence, and biologically plausible. The association is less direct – smoking is directly toxic and carcinogenic to the lung, but sun exposure/vitamin D modulate the immune system, which in turn may reduce the risk of immune attack on self-proteins in the central nervous system. Opinion about whether there is sufficient evidence to conclude that low sun exposure/vitamin D increase the risk of multiple sclerosis, is divided. General public health advice to receive sufficient sun exposure to avoid vitamin D deficiency (<50nmol/L) should also ensure any benefits for multiple sclerosis.

Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population and cleaved poly (ADP-ribose) polymerase (PARP) and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone. Furthermore, combined treatment of LA and TRAIL significantly decreased anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Fas-like inhibitor protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP) and enhanced the activation of pro-apoptotic proteins Bid compared to LA or TRAIL alone. In addition, combined treatment of LA and TRAIL upregulated the expression of Death receptor 4 (DR4) and downregulated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-B), inhibitory protein of kB family (p-IB) and FLIP in A549 and H1299 cells along with disrupted binding of XIAP with caspase3 or NF-B. Overall, these findings suggest that lambertianic acid enhances TRAIL-induced apoptosis via inhibition of XIAP/NF-B in TRAIL resistant NSCLCs.

Persistent cervical infection with high-risk Human papillomaviruses (hrHPVs) is a necessary, but not sufficient, condition for the development of cervical cancer. Therefore, there are other co-factors facilitating the hrHPV carcinogenic process, one of which is smoking. In order to assess the effect of smoking on high-risk (hr) HPV DNA positivity and on the expression of HPV E7 oncoprotein, as a surrogate of persistent hrHPV infection, we used data from women recruited for the PIPAVIR project, which examined the role of E7 protein detection in cervical cancer screening. Women were tested for hrHPV DNA, using Multiplex Genotyping and E7 protein, using a novel sandwich ELISA method, and gave information on their smoking habits. Among 1473 women, hrHPV prevalence was 19.1%. The odds ratio (OR) for hrHPV positivity of smokers compared to non-smokers was 1.785 (95%CI: 1.365-2.332, p<0.001). The ORs for E7 positivity, concerning hrHPV positive women, ranged from 0.720 to 1.360 depending on the E7 detection assay used, but this was not statistically significant. Smoking increases the probability of hrHPV infection, and smoking intensity is positively associated to this increase. Smoking is not related to an increased probability of E7 protein positivity for hrHPV positive women.

Computers and artificial intelligence affect every field of life nowadays. In medical image interpretation automatic decision making using algorithms are used increasingly in every sub-field and computer aided diagnosis (CAD) is one of the main tools available to medical science today. CAD systems are used as an augmented option for both the medical practitioner and the patients, with image analysis and interpretation being of primary importance. In particular, spatial relations are used in knowledge representation, and these relations can be used for effective medical image interpretation. In this paper, we put forth an algorithm for defining non-small cells lungs cancer (NSCLC) stages in lungs images interpretation using topological spatial relations. We show an application case study in event motion predictions for lung cancer staging scoring - tumor, nodes and metastasis (TNM) - with combined topological and directional relations.

Omega-3 polyunsaturated fatty acids (ω3-PUFAs), including docosahexaenoic acid (DHA), have been shown to exert anticancer effects by inducing apoptotic cell death. However, the mechanism for DHA-induced cell death in lung cancer is not fully understood. Here, we show that DHA induces apoptosis in two human EGFR mutant non-small cell lung cancer (NSCLC) cell lines, and that DHA-induced cell death is accompanied by SIRT6 activation and attenuated Hedgehog (Hh) signaling. Knockdown of SIRT6 using siRNAs inhibited DHA-induced apoptosis, whereas SIRT6 overexpression increased apoptotic cell death. DHA-induced SIRT6 activation was associated with downregulation of Hh signaling, and knockdown of SIRT6 resulted in augmentation of Hh signaling. Pretreatment of NSCLC cells with a Smoothened agonist prevented DHA-induced decreases in the levels of Hh signaling proteins and increases in cleaved PARP levels. Moreover, endogenous production of ω3-PUFAs in PC9 cells via fat-1 expression resulted in elevated SIRT6 levels and reduced levels of Hh signaling molecules, including Gli, following DHA treatment. Overall, these results implicate that ω3-PUFAs induce apoptosis by downregulating Hh signaling via SIRT6 activation in human EGFR mutant NSCLC cells. These findings suggest that ω3-PUFAs potentially represent an effective therapy for the chemoprevention and treatment of NSCLC.

Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung, and high VCAM-1 expression correlated with poor survival of lung cancer patients. VCAM-1 knockdown reduced invasion in A549 human lung cancer cells, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1-mediated A549 cell invasion. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed invasion in A549 and NCI-H1299 lung cancer cell lines. Taken together, these results suggest that VCAM-1-D6 is a novel therapeutic target in VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion.

BTB domain and CNC homology 1 (BACH1) is a highly expressed transcription factor in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion in aerobic glycolysis through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3- phosphate dehydrogenase (GAPDH). Pharmacological or genetic inhibition of BACH1 could reprogramme metabolic pathways, subsequently rendering metabolic vulnerability of cancer cells. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.

Nanosilver plays an important role in nanoscience and nanotechnology, and is becoming increasingly used for applications in nanomedicine. Nanosilver ranges in size from one to one hundred nanometers. Smaller particles more readily enter cells and interact with the cellular components. The exposure dose, particle size, coating, and aggregation state of the nanosilver, as well as the cell type or organism that it is tested on, all have a large determining factor on the effect and potential toxicity of nanosilver. A high exposure dose to nanosilver alters the cellular stress responses and initiates cascades of signaling that can eventually trigger organelle autophagy and apoptosis. This review summarizes the current knowledge of the effects of nanosilver on cellular metabolic function and response to stress. Both the causative effects of nanosilver on oxidative stress, endoplasmic reticulum stress, and hypoxic stress, as well as the effects of nanosilver on the responses to such stresses, are outlined. The interactions and effects of nanosilver on cellular uptake, oxidative stress (reactive oxygen species), inflammation, hypoxic response, mitochondrial function, endoplasmic reticulum function and the unfolded protein response, autophagy and apoptosis, angiogenesis, epigenetics, genotoxicity, and cancer development and tumorigenesis, as well as other pathway alterations are examined in this review.

Human papillomavirus (HPV), a DNA virus, causes one the most common sexually transmitted infections (STI), spreading through direct sexual contact to the anogenital and oropharyngeal regions. Although most infected individuals may be asymptomatic and naturally undergo viral clearance, in some individuals HPV causes carcinogenesis of the infected epithelia. HPV now accounts for over 70% of oropharyngeal carcinomas (OPC). More than 90% of these OPC are associated with HPV 16, one of the 14 high-risk subtypes. In recent years, HPV positive (HPV+) OPC has been one of the most rapidly rising cancers, by new cancer incidence rates, especially among men. The HPV driven OPCs present some unique infection driven cellular and molecular features, constituting distinct preventive, therapeutic and prognostic strategies, in contrast to HPV negative (HPV-) OPC. In this manuscript, we drive through the role of HPV, from a sexually transmitted infection to malignancy transformation landscape, while parsing through the significant immune response environment. In this comprehensive review we collate key literature around transmission and epidemiology of HPV, while addressing the current state of clinical management, diagnosis, prevention and screening strategies, that can help shed light on this critical area.

Abstract: This study aimed at investigating the effects of Valencia KK4-type peanut skin ethanolic extract (KK4-PSE) in combination with cisplatin or 5-fluorouracil (5-FU) against HeLa cells in vitro and in xenograft models. MTT assay showed that KK4-PSE, cisplatin, and 5-FU suppressed proliferation of HeLa cells in a dose and time dependent manner. Drug interactions by Chou-Talalay method demonstrated that KK4-PSE enhanced antiproliferative activity of 5-FU against HeLa cells with combination index (CI) values of 0.49 (48 h) and 0.60 (72 h), indicating a synergistic effect, while KK4-PSE combined with cisplatin exhibited an additive effect (CI = 1.02) (72 h) and antagonistic effect at 24 and 48 h exposures (CI = 1.12 and 1.18, respectively). In nude mouse xenograft models, the combination of 5-FU and KK4-PSE markedly reduced HeLa tumor weights compared with control and single agent treatments. The combination of KK4-PSE and 5-FU achieved greater tumor growth inhibition than that of the KK4-PSE-cisplatin combination. KK4-PSE mitigated hepatotoxicity induced by both cisplatin and 5-FU in nude mice. The spleen hyaloserositis was significantly reduced in the combination treatment of 5-FU and KK4-PSE. These findings suggest a potential of KK4-PSE to inhibit cervical cancer cell growth while alleviating the toxicities of cisplatin and 5-FU.

Background: The incidence of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) is increasing annually with a rise in the incidence of obesity and metabolic syndrome. Based on preliminary reports regarding the potential association of HCC and periodontitis, this study aimed to analyze the involvement of periodontal bacteria as well as the oral and intestinal bacterial flora in MASH-related HCC (MASH-HCC). Methods: Forty-one patients with MASH and 19 with MASH-HCC who completed survey questionnaires, underwent periodontal examinations, and subjected to sample collection (saliva, mouth-rinsed water, feces, and peripheral blood) participated in the study. Bayesian network analysis was used to analyze the causation between various factors, including MASH-HCC, examinations, and bacteria. Results: The occupancy rate of the genus Fusobacterium in the intestinal bacterial flora was significantly higher in in the MASH-HCC group than in the MASH group (p = 0.002), whereas that of Butyricicoccus (p = 0.022) and Roseburia (p &lt; 0.05) was significantly lower. Bayesian network analysis revealed the absence of periodontal pathogenic bacteria and enteric bacteria affecting HCC. However, HCC directly affected the periodontal bacterial species Porphyromonas gingivalis, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in the saliva, as well as the genera Lactobacillus, Roseburia, Fusobacterium, Prevotella, Clostridium, Ruminococcus, Trabulsiella, and SMB53 in the intestine. Furthermore, P. gingivalis in the oral cavity directly affected the genera Lactobacillus and Streptococcus in the intestine. Conclusion: MASH-HCC directly affects periodontal pathogenic and intestinal bacteria, and P. gingivalis may affect the intestinal bacteria associated with gastrointestinal cancer.

In the frame of our diversity-oriented research on multitarget small molecule anticancer agents, utilizing convergent synthetic sequences terminated by Sonogashira coupling reactions, a preliminary selection of representative alkyne-tethered vindoline hybrids was synthesized. The novel hybrids with additional pharmacophoric fragments of well-documented anticancer agents, including FDA-approved tyrosine-kinase inhibitors (imatinib and erlotinib) or ferrocene or chalcone units, were evaluated for their antiproliferative activity on malignant cell lines MDA-MB-231 (triple negative breast cancer), A2780 (ovarian cancer), HeLa (human cervical cancer) and SH-SY5Y (neuroblastoma) as well as human embryonal lung fibroblast MRC-5 served as reference non-malignant cell line for the assessment of the therapeutic window of the tested hybrids. The biological assays identified a trimethoxyphenyl-containing chalcone-vindoline hybrid (36) as a promising lead compound exhibiting submicromolar activity on A2780 cells with a marked therapeutic window. These results suggest that ovarian cancer might be considered as a prioritized target of treatment with 36.

: Carcinoma-associated fibroblasts (CAFs) are highly accumulated in the tumor surrounding stroma of primary epithelial ovarian cancer (OC). CAFs exert important functions for the vascularization, growth and progression of ovarian tumor cells. However, no attention has been shown to their origin so far. It has been mainly assumed that CAFs in primary OC arise from the activation of resident fibroblasts. Here, we compare CAFs with ovarian location to CAFs found in peritoneal implants from patients with advanced OC. Our findings show that CAFs from primary tumors and peritoneal metastases share the expression of mesothelial-related markers. Therefore, as in peritoneal carcinomatosis, CAFs in primary ovarian carcinomas could be originated via a mesothelia-to-mesenchymal transition (MMT) process. The detection of mesothelial-derived CAFs in tumors confined to the ovary and associated biomarkers could be the key to early detection of peritoneal spread in affected patients.

Simple summary This reassessment of the findings from our Phase I/II study seeks to evaluate the effectiveness of SBRT for treating local intermediate-high risk prostate cancer in the absence of androgen-deprivation therapy due to patient’s refusal, with a median follow-up of 6.5 years. Our primary focus is on analysing the treated areas compared to recurrence patterns in the seven patients who experienced local relapse. Additionally, we provide updated data on late toxicities of grade 2 or higher, both genitourinary and gastrointestinal. Abstract Objectives: We investigated spatial patterns between primary and recurrent tumor sites and assessed long-term toxicity after dose escalation stereotactic body radiation therapy (SBRT) to the dominant intraprostatic nodule (DIN). Materials and methods: In 33 patients with intermediate-high risk prostate cancer (PCa), doses up to 50 Gy were administered to the DIN. Recurrence sites were determined and compared to the original tumor development sites through multiparametric MRI and 68Ga-labelled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) images. Overlap rates, categorized as 75% or higher for full overlap, and 25-74% for partial overlap, were assessed. Long-term toxicity is reported. Results: All patients completed treatment, with only one receiving concomitant androgen deprivation therapy (ADT). Recurrences were diagnosed after a median of 33 months (range: 17-76 months), affecting 13 out of 33 patients (39.4%). Intraprostatic recurrences occurred in 7 patients (21%), with ≥ 75% overlap in two, a partial overlap in another two, and no overlap in the remaining three patient. Notably, 5 patients with intra-prostatic recurrences had synchronous bone and/or lymph node metastases, while six patients had isolated bone or lymph node metastasis without intraprostatic recurrences. Extended follow-up revealed grade 2 or higher late GU and GI toxicity in 18% (n=6) and 6% (n=2) of the patients. Conclusions: Among patients with intermediate-high risk PCa undergoing focal dose-escalated SBRT without ADT, DIN recurrences were infrequent. When present, these recurrences were typically located at the original site or adjacent to the initial tumor. Conversely, relapses beyond the DIN and in extra-prostatic (metastatic) sites were prevalent, underscoring the significance of systemic ADT in managing this patient population. Advances in knowledge: focal dose escalated prostate SBRT prevented recurrences in the dominant nodule, however extra-prostatic recurrence sites were frequent.

We aimed to directly compare the cost-effectiveness of the NELSON and NLST screening protocols, two trials influencing lung cancer screening implementation internationally. A decision-analytic model analyzing the cost-effectiveness of the NELSON protocols was manipulated to reflect the protocols of the NLST, while maintaining features specific to the Hungarian healthcare setting. In the NELSON protocol, there are three possible outcomes to the initial round of screening: positive, negative, or indeterminate, indicating an uncertain degree of suspicion for lung cancer. This pro-tocol differs from the NLST protocol, in which the only possible screening outcomes are positive or negative, with no indeterminate option. The NLST pathway for smokers aged 55-74 resulted in a 43 € increase in total average lifetime costs compared to the Hungarian screening pathway and re-sulted in a lifetime gain of 0.006 QALYs. The incremental costs and QALYs yield an ICER of 7875 €/QALY. Our results demonstrate that assigning any suspicious LDCT screen as a positive result (NLST protocol) rather than indeterminate (NELSON protocol) can yield a slight QALY gain that is worth the additional use of resources according to Hungary’s willingness to pay threshold. Our study provides insight on the cost-effectiveness, advantages, and disadvantages of various LDCT screening protocols for lung cancer and can assist other countries as they implement their screening programs.

In this study, we utilized the UniProt database to extract breast cancer genes Total 2658 genes in Homo sapiens are obtain. Then 166 genes are taken and after delating duplicates 158 genes were remains. These genes were then analyzed for their biological pathways using Gene Ontology enrichment analysis through the Genecodis platform, resulting in the identification of 12 unique genes involved in disease pathways. Protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape software, identifying ANLN,TREM1,LZTFL1,OXSM,PLA2G3,TAS2R13,ABCB10,ECT2,TRPC,BCAS3,PLA2G3,ZDHHC7 and ERBB2 as potential gene targets for breast cancer.

Background: Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation &gt; 10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Nest, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Results: Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in a MKN-45 GC cell xenograft model. Furthermore, combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE-33 cells. Conclusions: Therefore, targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.

Melatonin is an important hormone with a methoxy-indole structure. It is secreted regularly by the pineal gland of mammals. It takes part in many chemical, biological, and physiological activities of the body. Melatonin, acts as a basic hormone, and is responsible for circadian rhythm regulation and sleep control. It has been shown to occur in the highest concentration in organisms during the night times. In living organisms, many activities that have physiological, biological, hormonal, and psychological characteristics follows a certain rhythm. Body temperature, hormone levels, sleep-wakefulness, and some other cognitive functions in humans also change with the circadian rhythm. Its synthesis and release begin with darkness and end with light. This review aims to explore the functions of melatonin such as its stimulating effects on antioxidant enzymes, reducing lipid peroxidation, and protecting brain tissue from oxidative damage. It also has properties that stop the proliferation of cancer cells and prevent tumor growth. Melatonin, which was previously known only as an animal hormone, has been found to also exist in plants. Research has shown that melatonin is present in almost all plant species analyzed to date and that it performs functions similar to those in animals. In plants, it plays a vital role in dealing with various abiotic and biotic stresses. Melatonin acts as an important antioxidant in post-harvest technology and extends the post-harvest life of fruits and vegetables. It also takes part in the regulation of stress-specific genes and the activation of pathogenesis-related proteins and antioxidant enzymes. The most prominent roles of melatonin in plants include regulating circadian rhythm, growth, and development, and increasing tolerance to a wide range of environmental stress factors. The review reveals the effects of melatonin as an extremely important secondary metabolite, on human, animal, and plant metabolism. The use of PRISMA guidelines was used for reporting, search, selection, and synthesis. Information up to 2024 was searched from search engines for the occurrence, nature and function of melatonin. Key words such as structural function, hormonal function, secretion and metabolism were used in the search of publications.

Pharmacists must acquire the necessary knowledge to provide better drug therapy to patients. In other words, educational programs need to facilitate behavioral changes among pharmacists. Therefore, this study aimed to evaluate how the behavior of pharmacists changed after attending a palliative care educational program. We conducted a web-based questionnaire survey examining the behavior of pharmacists regarding palliative care before participating in the program, two months after participating in the program, and eight months after participating in the program, to determine the behavior and changes over time. For all questions, scores were higher at two and eight months after attending the program than before attending the program (P &lt;0.05). In addition, no significant difference was observed between two and eight months after attending the program for all questions (P =0.504-1.000). The knowledge gained from the educational program was used to repeatedly intervene with patients with cancer, to address the various symptoms they experienced and maintain their behavior. The proven effectiveness of this program serves as a stepping stone for a nationwide rollout across Japan’s 47 prefectures.

The identification of fetal cells in the blood and tissues of healthy mothers raised questions about the potential alloreactive origins of various diseases, such as autoimmunity, diabetes, arteriosclerosis, and cancer. However, the extent to which alloreactivity contributes to these diseases remains unverified. This study presents a basic mathematical disease model based on the genes’ origin and immunological interactions. This model, grounded in set theory, classifies these immunological interactions based on their intrinsic, extrinsic, and allogeneic nature. Therefore, this model offers an unexpected common theoretical foundation for understanding alloreactivity, genetic diseases, and infections. Furthermore, this model provides a valuable framework for scrutinizing the role of alloreactivity in health and disease.

Exosome-based therapy has emerged as a promising strategy for addressing diverse disorders, indicating the need for further exploration of the potential therapeutic effects of the exosome cargos. This study introduces "enhanced exosomes," a novel type of exosomes developed through a novel cell culture system. These specific exosomes may become potent therapeutic agents for treating ovarian disorders. In this study, we conducted a comparative analysis of the protein and miRNA cargo compositions of enhanced exosomes and naïve exosomes. Our findings revealed distinct cargo compositions in enhanced exosomes, featuring upregulated proteins such as EFEMP1, HTRA1, PAM, RSU1, and SDF4, suggesting their potential for treating ovarian disorders. MicroRNA profiling revealed that miR-1-3p, miR-103a-3p, miR-122-5p, miR-1271-5p, miR-133a-3p, miR-184, miR-203a-3p, and miR-206 are key players in regulating ovarian cancer and chemosensitivity by affecting cell cycle progression, cell proliferation, and cell development. We examined polycystic ovary syndrome and premature ovarian insufficiency and identified altered expression of various miRNAs, such as miR-106a-5p, miR-130b-5p, and miR-130b-3p, for diagnostic insights. This study highlights the potential of enhanced exosomes as new therapeutic agents for women's reproductive health, offering a detailed understanding of the impact of their cargo on ovarian disorders.

The development of multiple drug resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrated that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient derived xenograft (PDX) model of human breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemosensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, Doxorubicin (DOX). Using cell cycle arrest/release experiments we show that chemo-sensitive and -resistant MCF7 cells progress through the cell cycle at similar rates, but mitosis is delayed in MDR cells with elevated substrate levels. When treated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically-MDR human breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

Berberis vulgaris L. (Berberidaceae) is a shrub that has been widely used in European folk medicine as an anti-inflammatory and antimicrobial agent. The purpose of our study was to elucidate the mechanisms of antiproliferative action of the plant’s methanolic root extract (BVR) against colon cancer cells. Cytotoxicity and pro-apoptotic activity were determined in human colon adenocarcinoma cell lines (LS180 and HT-29) and control colon epithelial CCD841 CoN cells. According to the MTT assay, after 48 h of cell exposure, the IC50 values were as follows: 4.3; 46.1 and 50.2 µg/mL for LS180, HT-29, and CCD841 CoN cells, respectively, showing the greater sensitivity of cancer cells to BVR. The Cell Death Detection ELISAPLUS kit demonstrated that BVR induced programmed cell death only against HT-29 cells. RT-qPCR with relative quantification method showed significant changes in the expression of genes related to apoptosis in both colon cancer cell lines. The genes BCL2L1 (126.84-366.66%), BCL2L2 (277.08-330.12%), CASP3 (180.36-261.36%) and CASP9 (158.08-213.46%) had significantly elevated expression, while BCL2 (23.08-52.06%) had reduced expression. Furthermore, in a panel of antioxidant tests, BVR showed positive effects (63.93±0.01, 122.92±0.01, and 220.29±0.02 mg Trolox equivalents (TE)/g in the DPPH•, ABTS•+ and ORAC assays, respectively). In the lipoxygenase (LOX) inhibition test, BVR revealed 62,60±0.87% of enzyme inhibition. The chemical composition of BVR was determined using UHPLC-UV-CAD-MS/MS analysis and confirmed the presence of several known alkaloids, including berberine, as well as other alkaloids and two derivatives of hydroxycinnamic acid (ferulic and sinapic acid hexosides). This is the first such extensive assessment of the biological activity of BVR. The results are very promising and encourage for the use of BVR as a comprehensive chemopreventive agent (anti-inflammatory, antioxidant, and pro-apoptotic) in colorectal cancer.

Despite the recent availability of immune checkpoint inhibitors, not all patients affected by Non-Small Cell Lung Cancer (NSCLC) benefit from immunotherapy. The reason for this variability relies to a variety of factors which may allow the identification of novel biomarkers. Presently, a variety of biomarkers are under investigation, including the PD1/PDL1 axis, the tumor mutational burden, and the Microbiota. This latter is made by all bacteria and other microorganisms hosted in our body. The gut microbiota is the most represented and has been involved in different physiological and pathological events, including cancer. In this light, it appears that all conditions modifying gut microbiota can influence cancer, its treatment, and its treatment-related toxicities. The aim of this review is to analyze all conditions influencing the gut microbiota and, therefore, affecting response to immunotherapy, iRAEs and their management in NSCLC patients. The investigation of the landscape of these biological events can allow novel insights for optimal management of NSCLC immunotherapy.

Rarely has a chemical elicited as much controversy as has dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product. Then it was a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects in experimental animals. These publications showed contradictory results in vivo and in vitro, so that a thorough consideration of this compound in cancer is merited. Despite 50 years of experimentation, DCA’s future in therapeutics is uncertain. Without adequate clinical trials and lack of health authorities’ approval, DCA has been introduced in off -label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are limited thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in oncology treatment.

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. One of the undisputed values of SLN biopsy is its diagnostic accuracy in detecting low-volume metastases (LVM) via pathologic ultrastaging. In early-stage cervical cancer, the reported incidence of LVM ranges from 4 to 20%. The prognostic impact and the role of adjuvant treatment in patients with LVM is still unclear. Some non-prespecified analyses in prospective studies showed no impact on the oncologic outcomes compared to node-negative disease. However, the heterogeneity of the studies, the differences in the disease stage and the use of adjuvant treatment, and the concomitant pelvic lymphadenectomy (PLND) make any conclusion on this topic hard. Current guidelines suggest considering micrometastasis (MIC) as a node-positive disease, while isolated tumor cells (ITC) as a node-negative disease, with a low level of evidence. This review aims to highlight the unanswered questions about the definition, identification, prognostic and therapeutic role of LVM and underline the present and future challenges we are facing. We hope this review will guide further research, giving robust evidence on LVM and their impact on clinical practice.

An observational cohort study of patients diagnosed with endometrial cancer (EC) stage IA G1, or atypical endometrial hyperplasia (AHE), undergoing organ-preserving treatment, was conducted. Objective of the study: to determine CDO1, PITX2, and CDH13 gene methylation levels in early endometrial cancer and atypical hyperplasia specimens obtained before organ-preserving treatment in the patients with adequate response and with insufficient response to hormonal treatment. Materials and methods: 41 endometrial specimens obtained during diagnostic uterine curettage in women with EC (n=28) and AEH (n=13), willing to preserve reproductive function, were studied; 18 specimens of endometrial cancer IA stage G1 from peri- and early postmenopausal women (comparison group) were included in the study. The control group included 18 endometrial specimens from healthy women obtained by diagnostic curettage for missed abortion and/or intrauterine adhesions. Methylation levels were analyzed using the modified MS-HRM method. Results: All 13 women with AEH had complete response (CR) to medical treatment. In the group undergoing organ-preserving treatment for uterine cancer IA stage G1 (n=28), 14 patients had complete response (EC CR group) and 14 had not (non-CR). It was found that all groups had statistically significant differences in CDO1 gene methylation levels with the control group (p&lt;0.001) except for the EC CR group (p=0.21). The p-value of difference between EC CR and EC non-CR groups was &lt;0.001. The differences in PITX2 gene methylation levels between the control and study groups were also significantly different (p&lt;0.001), except for AEH group (p=0.21). For the difference between EC CR and EC non-CR groups, the p-value was 0.43. For CDH13 gene methylation levels, statistically significant differences were found between the control and EC non-CR groups (p&lt;0.001), and the control and EC comparison groups (p=0.005). When comparing the EC CR group with EC non-CR group, the p-value for this gene was &lt;0.001. Simultaneous assessment of CDO1 and CDH13 genes methylation allowed to accurately distinguish between EC CR and EC non-CR groups (AUC=0.96). Conclusion: Assessment of CDO1 and CDH13 gene methylation in endometrial specimens from patients with endometrial cancer (IA stage G1), planned for medical treatment, can predict the treatment outcome.

Atherosclerosis is associated with vascular diseases, diabetes, and cancers. The Jumonji C-domain-containing 6 (JMJD6) gene plays an important role in diverse biological processes. In addition, autoantibodies are reportedly useful in the early diagnosis and treatment of many diseases. Here, JMJD6 was identified by serological identification of antigens by recombinant cDNA expression cloning as an antigen recognized by serum IgG from patients with unstable angina pectoris. Then, we performed amplified luminescent proximity homogeneous assay-linked immunosorbent assay using purified recombinant antigens and found elevated levels of serum anti-JMJD6 antibodies (s-JMJD6-Abs) in patients with atherosclerosis-related diseases including ischemic stroke, acute myocardial infarction (AMI), diabetes mellitus (DM), and cancers including esophageal cancer (EC), gastric cancer, lung cancer, and mammary cancer, compared with those in healthy donors. The s-JMJD6-Ab levels were closely associated with hypertension, habitual smoking, and the intima-media thickness, an atherosclerosis index. The better postoperative survival status was shown in patients with EC from the JMJD6-Ab-positive group than the negative group, especially from JMJD6-Ab-positive/PD-L1-negative group and JMJD6-Ab-positive/p53-Ab-negative group than JMJD6-Ab-negative/PD-L1-positive group and JMJD6-Ab-negative/p53-Ab-positive group, respectively. Hence, JMJD6 autoantibodies may reflect atherosclerosis severity, thereby a potential biomarker for atherosclerosis-related diseases including ischemic stroke, AMI, DM, and cancers and for predicting EC prognosis.

Lymphoma is the most prevalent type of cancer in cats, and the search for alternative treatments is of utmost importance given the significant number of animals that exhibit tumor recurrence or are unresponsive to conventional chemotherapy treatment. Oncolytic viruses possess a unique ability to target and eliminate cancer cells while simultaneously stimulating an immune response against these malignant cells. The present study aimed to explore the oncolytic potential of Newcastle Disease Virus expressing green fluorescent protein (NDV-GFP) in a feline leukemia virus (FeLV)-positive lymphoma cell line. Our research suggests that NDV-GFP has a propensity to selectively target, infiltrate, and replicate with-in feline lymphoma cells, resulting in the induction of apoptosis in these cells, as opposed to non-tumor cells. Therefore, our research provides evidence supporting the development of novel oncolytic therapies based on NDV for the treatment of feline lymphomas.

The APIS Breast Cancer Subtyping Kit is an mRNA-based assessment of the three biomarkers routinely assessed in all newly diagnosed breast cancers (BC), estrogen receptor (ER), progesterone receptor (PR), and HER2 as well as an additional four genes that create a novel proliferation signature, MKI67, PCNA, CCNA2, KIF23. Taken together the data is used to produce a molecular sub-type for every sample. The kit was evaluated against the current standard protocol of immunohistochemistry (IHC) and/or in situ hybridization (ISH) in breast cancer patients. The data was presented at the weekly breast Multidisciplinary Team (MDT) meeting. 98 consecutive cases of pre-operative breast cancer core biopsies and two core biopsy of nodal metastases yielding 100 cases were assessed. IHC and APIS Results were available for 100 and 99 cases. ER was concordant in 97% cases, PR in 89% and HER2 results were concordant with IHC/ISH in 100% of the cases. Ki-67 IHC was discordant in 3% cases when compared with MK167 alone but discordant in 24% when compared with the four gene proliferation signature. In conclusion, our study, indicates that the APIS Breast Cancer Subtyping Kit is highly concordant when compared to the results produced for ER/PR/HER2 by IHC and/or ISH. The assay could play a role in the routine assessment of newly diagnoses Breast Cancer (BC) specimens.

Patient-derived tumor organoids (PDTOs) are a novel preclinical model of non-small cell lung cancer (NSCLC) for studying tumor biology and precision medicine, which recapitulates tumor morphology and gene expression profile. However, some issues such as low establishment rates, long-term production, and the loss of the immune microenvironment have hindered their widespread practical use. In this study, we investigated the efficacy of a recently introduced free-floating organoid production method to address these issues. The free-floating approach provided PDTO establishment success rate of over 90 % resulting in organoid formation within a short period of one week. These organoids retained the elements of the parental tumor morphology and contained stroma and immune cell populations, as confirmed by flow cytometry analysis. Importantly, we found that the cytokine and growth factor expression profiles of the free-floating organoids correlated with those of the original tumors in 58 % of cases, indicating the preservation of tumor-associated signaling pathways. Obtained organoids exhibited different responses to anticancer chemotherapeutics that might be a result of variable expression of drug resistance-associated genes. Considering the high establishment rate and short time of free-floating organoid production, this technique provides a valuable tool for a more accurate evaluation of therapeutic strategies and cancer biology studies.

This review explores the transformative impact of sensor technologies in early disease detection. It highlights recent advancements in nanotechnology-based sensors, particularly focusing on their applications in identifying disease biomarkers at early stages. The integration of these sensors with artificial intelligence for predictive analytics in healthcare is also discussed. Applications in cancer, infectious diseases, and chronic disease management underscore their diverse utility. Challenges in sensor technology adoption and future directions, including multiplexed sensors and wearable devices, are examined. This review underscores sensors' potential in enhancing disease management and patient outcomes.

Geijera Schott is a plant genus of the Rutaceae Juss. (rue and citrus) family, comprising six species which are all native to Oceania. Of the plants belonging to this genus, the most significant species that has a customary use is Geijera parviflora, which was used by Indigenous Australians, primarily as a pain reliever. Herein, a comprehensive review of the literature published on the genus Geijera from 1930-2023 was conducted. This is the first review for this plant genus and it highlights the chemical constituents reported to date, together with the range of pharmacological properties described from the various species and different parts of the plant. These properties include anti-inflammatory, anti-microbial, anti-parasitic, insect repellent, analgesic, neuroactive, and anti-cancer activities. Finally, a reflection on some of the important areas for future focused studies of this plant genus is provided.

Background and Objectives: Previous studies revealed anti-angiogenic, antiproliferative and anti-inflammatory effects of Vitamin D on cancer cells. Although this body of evidence supported the correlation of high Vitamin D levels with reduced incidence rates for various malignancies, contradictory results were reported regarding non-melanoma skin cancer (NMSC). Aim of this overview was to summarize the available evidence from the existing pool of systematic reviews and meta-analyses, focusing on Vitamin D serum status, dietary intake, and Vitamin D receptor (VDR) polymorphisms in correlation to NMSC incidence. Materials and Methods: A literature search in electronic databases was conducted from inception to January 2023. Inclusion criteria were systematic reviews and meta-analyses published in peer-reviewed journals, evaluating Vitamin D serum levels, dietary and/or supplementary intake, or VDR gene polymorphisms, and reporting data on NMSC. Results: A total of 10 studies were included in the data analysis models. A positive association between Vitamin D serum levels and NMSC is highlighted. However, dietary/supplementation of Vitamin D doesn’t exhibit a likewise strong linkage to NMSC. Despite the contradictory findings, VDR polymorphisms may play a crucial role in the intricate NMSC pathogenesis. Conclusions: This umbrella review showed that high Vitamin D levels are associated with increased NMSC incidence, potentially due to its direct correlation with increased sun exposure. Further research on VDR polymorphisms is suggested to explore their true effect size on NMSC risk.

In this paper, a relatively new hyper convolution spectra for characterization liquid, viscoelastic and solid samples is presented. Special attention is paid to the biophysical characterization of epithelial tissues and early detection of cancer of the skin, cervix, colon, and oral cavity. The method is based on the use of two types of white light, diffuse and polarized, from the same LED light sources. Based on the subtraction of the intensity values of these two lights and using the hyper convolution algorithm, the ratio of paired and unpaired electrons of tissue is obtained. This ratio correlates well with the state of the tissue: normal, irritating, precancerous, and cancerous. First, a proof-of-concept studies were performed, and later clinical studies on samples from one thousand two hundred fifteen people were performed. It showed that hyper Opto-Magnetic Imaging Spectroscopy (OMIS) can detect epithelial tissue cancers with an accuracy of 85-96%. Bearing in mind that the OMIS method also acquires the biophysical characteristics of the deeper skin layers (epidermis, basement membrane, dermis) by analysing convolution spectra of RGB channels of both diffuse and polarized white light, it is possible to apply this method in cosmetics (skin hydration, collagen, and elastin states, etc.). During OMIS applications, we noticed places where improvements could be made to increase method’s accuracy using advanced machine learning methodologies.

This research paper presents a deep learning approach to early detection of skin cancer using image augmentation techniques. The authors propose a two-stage image augmentation technique that involves the use of geometric augmentation and generative adversarial network (GAN) to classify skin lesions as either benign or malignant. This research utilized the public HAM10000 dataset to test the proposed model. Several pre-trained models of CNN were employed, namely Xception, Inceptionv3, Resnet152v2, EfficientnetB7, InceptionresnetV2, and VGG19. Our approach achieved accuracy, precision, recall, and F1-score of 96.90%, 97.07%, 96.87%, 96.97%, respectively, which is higher than the performance achieved by other state-of-the-art methods. The paper also discusses the use of SHapley Additive exPlanations (SHAP), an interpretable technique for skin cancer diagnosis, which can help clinicians understand the reasoning behind the diagnosis and improve trust in the system. Overall, the proposed method presents a promising approach to automated skin cancer detection that could improve patient outcomes and reduce healthcare costs.

Drug discovery utilizes high-throughput screening (HTS) methods applying target and cell-based assays. This review discusses the challenges and benefits associated with these assays in HTS. Discussed the strategies that can be applied for the development of screening assays through primary and secondary screens for target identification. Further discussion on identify-ing the most efficacious drugs following these approaches in cancer. Even though various drugs have been identified to treat cancer, there is high demand of more relevant phenotypic assays to produce desired diseased phenotype to only highlighting the specific targets instead of off-targets. Hopefully, the new developing strategies could provide innovative drugs to treat cancer patients to reduce mortality rate.

Serine/threonine kinase (AKT) signaling regulates diverse cellular processes and is one of the most important aberrant cell survival mechanisms associated with tumorigenesis, metastasis, and chemoresistance. Targeting AKT has become an effective therapeutic strategy for the treatment of many cancers. AKT3 (PKBγ), the least studied isoform of the AKT family, has emerged as a major contributor to malignancy. AKT3 is frequently overexpressed in human cancers, and many regulatory oncogenic or tumor suppressor small non-coding RNAs (ncRNAs), including microRNAs (miRNAs), have recently been identified to be involved in regulating AKT3 expression. Therefore, a better understanding of regulatory miRNA/AKT3 networks may reveal novel biomarkers for diagnosis of patients with cancer and provide invaluable information for developing more effective therapeutic strategies. The aim of this review is to summarize current research progress in the isoform-specific functions of AKT3 in human cancers and the roles of dysregulated miRNA/AKT3 in specific types of human cancers.

Green synthesis offers a superior alternative to traditional methods for producing metal and metal oxide nanoparticles. This approach is not only benign and safe but also cost-effective, scalable, and straightforward, operating under ambient conditions. Notable metals and metal oxide nanoparticles, such as manganese oxides, iron oxides, silver, and gold, have been produced using various bio-reductants derived from plant extracts. These biological agents not only expedite the reduction process but also stabilize the nanoparticles, serving dual roles as reducing and capping agents. This review presents the green synthesis of nanoparticles (NPs) obtained from biogenic wastes and plant extracts. The green-synthesized nanostructured MnO2 are evaluated as a potential photocatalyst for water treatment and as an electrode material in lithium-ion batteries and supercapacitors. The green-derived iron oxide nanoparticles are examined as promising antioxidant, anti-inflammatory, and anti-diabetic agents. Additionally, this review discusses the green synthesis of precious metal nanoparticles, specifically silver (Ag NPs) and gold (Au NPs), highlighting their potential medical applications in areas like antiviral treatments and cancer therapy.

Mathematical models of non-small cell lung cancer are powerful tools that use clinical and experimental data to describe various aspects of tumorigenesis. The developed algorithms capture phenotypic changes in the tumor and predict changes in tumor behavior, drug resistance, and clinical outcomes of anti-cancer therapy. The aim of this study was to propose a mathematical model that predicts the changes in the cellular composition of patient-derived tumor organoids over time with a perspective of translation of these results to the parental tumor, and therefore to possible clinical course and outcomes for the patient. Using the data on specific biomarkers of cancer cells (PD-L1), tumor-associated macrophages (CD206), natural killer cells (CD8), and fibroblasts (αSMA) as input, we proposed a model that accurately predicts the cellular composition of patient-derived tumor organoids at a desired time point. Combining the obtained results with “omics” approaches will improve our understanding of the nature of NSCLC. Moreover, their implementation into clinical practice will facilitate a decision-making process on treatment strategy and develop a new personalized approach in anti-cancer therapy.

Background. Currently, most of the research in breast cancer has been carried out in conventional two-dimensional (2D) cell culture due to its practical benefits, however, the three-dimensional (3D) cell culture is becoming the model of choice in cancer research because it allows cell-cell and cell-extracellular matrix (ECM) interactions, mimicking the native microenvironment of tumors in vivo. Methods. in this work, we evaluated the effect of 3D cell organization on the expression pattern of miRNAs (by Small-RNAseq) and mRNAs (by microarrays) in the breast cancer SKBR3 cell line and analyzed the biological processes and signaling pathways regulated by the differ-entially expressed protein-coding genes (DE-mRNAs) and miRNAs (DE-microRNAs) found in the organoids. Results. We obtained well-defined cell-aggregated organoids with a grape cluster-like morphology with a size up to 9.2×105 μm3. The transcriptomic assays showed that cell growth in organoids significantly affected (all p < 0.01) the gene expression patterns of both, miRNAs and mRNAs, finding 20 upregulated and 19 downregulated DE-microRNAs, as well as 49 upregulated and 123 downregulated DE-mRNAs. In silico analysis showed that a subset of 11 upregulated DE-microRNAs target 70 downregulated DE-mRNAs. These genes are involved in 150 gene on-tology (GO) biological processes such as regulation of cell morphogenesis, regulation of cell shape, regulation of canonical Wnt signaling pathway, morphogenesis of epithelium, regulation of cy-toskeleton organization, as well as in the MAPK and AGE-RAGE signaling KEGG-pathways. In-terestingly, hsa-mir-122-5p (Fold Change (FC)=15.4), hsa-mir-369-3p (FC=11.4), and hsa-mir-10b-5p (FC=20.1) regulated up to the 81 % of the 70 downregulated DE-mRNAs. Conclu-sion, the organotypic 3D cell-organization architecture of breast cancer SKBR3 cells impacts the expression pattern of miRNAs-mRNAs network mainly through overexpression of hsa-mir-122-5p, hsa-mir-369-3p, and hsa-mir-10b-5p. All these findings suggest that the interaction between cell-cell and cell-ECM as well as the change in the culture architecture impacts gene ex-pression, and therefore, support the pertinence of migrating breast cancer research from conven-tional cultures to 3D models.

Flaxseed has been recognized as a valuable source of nutrients and bioactive compounds, including proteins that possess various health benefits. In recent years, studies have shown that flaxseed proteins, including albumins, globulins, glutelin, and prolamins, possess anti-cancer properties. These properties are attributed to their ability to inhibit cancer cell proliferation, induce apoptosis, and interfere with cancer cell signaling pathways, ultimately leading to the inhibition of metastasis. Moreover, flaxseed proteins have been reported to modulate cancer cell mechanobiology, leading to changes in cell behavior and reduced cancer cell migration and invasion. This review provides an overview of the anti-cancer properties of flaxseed proteins, with a focus on their potential use in cancer treatment. Additionally, it highlights the need for further research to fully establish the potential of flaxseed proteins in cancer therapy.

Background: Micronutrient deficiencies are common at the time of cancer diagnosis and are associated with worse prognosis. Little is known about them in cancer rehabilitation. Methods: Data from routine health related quality of life (HRQOL) were analyzed at an inpatient cancer rehabilitation center. Rehabilitation patients completed the EORTC QLQ-C30 questionnaire before and after multidisciplinary rehabilitation treatment, and three month after discharge. Selenium and zinc status was measured in whole blood at these three time points. In case of selenium deficiency up to 600 µg selenium per day as sodium selenite was supplemented. Results: A total of 271 patients (breast, colon, and pancreatic cancer) were included in the analysis. There was clinically meaningful improvement in many domains of the EORTC QLQ-C30 during rehabilitation. However, effect often waned in the three months after. Prevalence for selenium deficiency varied between 34 to 90 percent depending on cancer type (breast &lt; colon &lt; pancreas). In contrast, zinc deficiency was rare. Daily selenium supplementation of 600 µg was more efficient to correct selenium deficiency compared to 300 µg selenium per day. Rehabilitation and increasing selenium status after rehabilitation were associated with improved global quality of life, physical and emotional functioning, and fatigue. In cancer patients with decreasing selenium status, values of global quality of life, physical and emotional functioning, and fatigue were back to the values at the beginning of rehabilitation. Conclusions: Selenium deficiency is common in cancer patients admitted to a cancer rehabilitation clinic. Selenium supplementation during rehabilitation effectively corrected selenium deficiency in most cases. The positive effects of rehabilitation persisted longer, when selenium status did not decrease after rehabilitation.

: Molecular targeting strategies have been used for years to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping that in mind, it is essential to know the role of each enzyme in a particular metabolic pathway. In this review, we are providing in-depth knowledge of various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase, which are associated with multiple types of cancer that depend on ceramide metabolism. Focus has also been given to discussing physicochemical properties of well-studied inhibitors of natural products origin and their related structures for these enzymes. Targeting ceramide metabolism exhibited promise in mono and combination therapies at preclinical stages to prevent cancer progression and paved the way for the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide metabolizing enzymes will help the medicinal chemist to design potent and selective small molecules for treating cancer progression at various levels.

Esterases are hydrolases that catalyze the hydrolysis of esters into the corresponding acids and alcohols. The development of fluorescent probes for detecting esterases is of great importance due to their wide spectrum of biological and industrial applications. These probes can provide a rapid and sensitive method for detecting the presence and activity of esterases in various samples, including biological fluids, food products, and environmental samples. Fluorescent probes can also be used for monitoring the effects of drugs and environmental toxins on esterase activity, as well as to study the functions and mechanisms of these enzymes in several biological systems. Additionally, fluorescent probes can be designed to selectively target specific types of esterases, such as those found in pathogenic bacteria or cancer cells. In this review, we summarize the recent fluorescent probes described for the visualization of cell viability and some applications for in vivo imaging. On the other hand, Positron Emission Tomography (PET) is a nuclear-based molecular imaging modality of great value to study the activity of enzymes in vivo. We provide some examples of PET probes for imaging acetylcholinesterases and butyrylcholinesterases in brain, which are valuable tools for diagnosing dementia and monitoring the effects of anticholinergic drugs on the central nervous system.

Lifetime cancer risk characterization of ambient PM-bound carcinogenic metals and polycyclic aromatic hydrocarbons (PAHs) were examined in the cities of Los Angeles (USA), Thessaloniki (Greece) and Milan (Italy), which share similar Mediterranean climates but are different in their urban emission sources and governing air quality regulations. The samples in Milan and Thessaloniki were mostly dominated by biomass burning activities whereas the particles collected in Los Angeles were primary impacted by traffic emissions. We analyzed the ambient PM2.5 mass concentration of Cadmium (Cd), Hexavalent Chromium (Cr(VI)), Nickel (Ni), Lead (Pb), as well as 13 PAH compounds in the PM samples, collected during both cold and warm periods at each location. The Pb exhibited the highest annual-average concentration in all 3 cities, followed by Ni, As, Cr(VI), Cd and PAHs, respectively. The cancer risk assessment based on outdoor pollutants was performed based on three different scenarios, with each scenario corresponding to a different level of infiltration of outdoor pollutants into the indoor environment. Thessaloniki exhibited rather high risk value associated with lifetime inhalation of As, Cr(VI) and PAHs. The highest cancer risk values were calculated in Milan where the lifetime risk of exposure to As, Cr(VI) and PAHs exceeded the US EPA standard across all scenarios by a considerable margin. The risk associated with Cr(VI) in Milan, which was the most significant among the investigated elements, ranged from (6.08±0.36)×10-6 to (9.82±0.58) ×10-6. In contrast, the estimated risks associated with metal and PAHs in Los Angeles were mostly comparable to the guideline value, even when the infiltration factor was assumed to be at peak. This observation highlights the impact of local air quality measures in improving the air quality and lowering the cancer risks in Los Angeles compared to the other two cities.

Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of small molecule inhibitors that cause resistance mutations. In recent years, various targeted protein degradation strategies have been developed based on the ubiquitin-proteasome system in the cytoplasm or the autophagy-lysosomal system during endocytosis. In this review, we describe and compare technologies for targeted inhibition and targeted degradation of the epidermal growth factor receptor (EGFR), one of the major proteins responsible for the onset and progression of many types of cancer. In addition, we have developed an alternative strategy, called alloAUTO, based on the binding of new heterocyclic compounds to an allosteric site located in close proximity to the EGFR catalytic site. These compounds cause targeted degradation of the transmembrane receptor, simultaneously activating both systems of protein degradation in cells. Damage to EGFR signaling pathways promotes inactivation of Bim sensor protein phosphorylation, which leads to disintegration of the cytoskeleton, followed by detachment of cancer cells from the extracellular matrix and, ultimately, to cancer cell death. This hallmark of targeted cancer cell death suggests an advantage over other targeted protein degradation strategies, namely that the fewer cancer cells survive, the fewer chemotherapy-resistant mutants appear.

This article presents a comparative analysis of three Machine Learning models, namely Logistic Regression, Decision Tree Classifier, and Random Forest Classifier, for prostate cancer detection. The models were trained and evaluated using clinical data, and their performance was assessed using various evaluation metrics. The results show that Logistic Regression achieved the highest accuracy (90%) among the three models, followed by Random Forest Classifier (76.67%) and Decision Tree Classifier (73.33%). Similarly, Logistic Regression demonstrated superior precision (95.65%) and F1 Score (93.62%), indicating its effectiveness in identifying true positive cases. However, the Decision Tree Classifier exhibited higher recall for the negative class (83.33%) compared to the positive class (70.83%), while Random Forest Classifier showed balanced recall for both classes (66.67% for negative and 79.17% for positive). These findings suggest that Logistic Regression outperforms the other models in terms of accuracy and precision, while the Decision Tree Classifier and Random Forest Classifier provide better recall for certain classes. The results highlight the potential of Machine Learning in prostate cancer detection and provide insights for further research and improvement of the models.

HCC is a highly aggressive malignancy with limited treatment options. In this study, novel conjugates, of NSAIDs - Ibuprofen and Ketoprofen with oleanolic acid oximes derivatives (OAO) were synthesized and their activity as modulators of signaling pathways involved in HCC pathogenesis was evaluated in normal THLE-2 liver cells and HCC derived HepG2 cells. The results demonstrated that conjugation with OAO derivatives reduces the cytotoxicity of parent compounds in both cell lines. In THLE-2 cells treatment with conjugates resulted in increased activation of the Nrf2-ARE pathway. An opposite effect was observed in HepG2 cells. In the later reduction of NF-κB was observed along with modulation of MAPK signaling pathways (AKT, ERK, p38, p70S6K, and JNK). Moreover, STAT3, STAT5, and CREB transcription factors on protein levels were significantly reduced as a result of treatment with IBU- and KET-OAO derivatives conjugates. The most active were conjugates with OAO-morpholide. Overall, the findings of this study demonstrate that IBU-OAO and KET-OAO derivatives conjugates modulate the key signaling pathways involved in hepatic cancer development. Their effect on specific signaling pathways varied depending on the structure of the conjugate. Since the conjugation of IBU and KET with OAO derivatives reduced their cytotoxicity, the conjugates may be considered good candidates for the prevention of liver cancer.

Despite being an abundant marine organism in Indonesia, black sea cucumber is still underutilised due to its slightly bitter taste. Previous studies have hinted at the potential of black sea cucumber as an anti-cancer agent. However, specific identification of bioactive compounds that can interact with cancer proteins is still lacking. In the same place, cancer ranks third as Indonesia's leading cause of death. Therefore, this study aims to identify potential anti-cancer compounds from black sea cucumbers using a comprehensive in silico drug discovery approach. This research uses machine learning, molecular docking, and ADMET analysis to identify bioactive compounds that specifically interact with cancer proteins. A combination of the Cascade Deep Forest algorithm and ECFP-AAIndex1 feature combination proved to be the most effective in predicting these interactions. Through molecular docking validation, four bioactive compounds with strong binding affinity were identified: Afimoxifene, Danazol, Taxifolin, and Terfenadine. ADMET analysis highlighted Taxifolin as the most promising candidate, as it passed most ADMET parameters. Further wet laboratory studies are required to confirm the effects and potential of these compounds as anti-cancer agents. This study builds a foundation for future investigations into alternative cancer treatments using abundant natural resources.

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, re-considering the immunohistochemical negative score of 0, 1+ or score of 2+/in situ hybridization (ISH) negative phenotype. In the present review we have outlined the needed criteria to exactly distinguish HER2 low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these group sof tumors. In particular, Trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC has been recently approved by the U.S. Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally we hope that new guidelines may help to codify HER2 low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.

Background: Areca nut and betel quid (ANBQ) chewing is a widespread carcinogenic habit. The BENIT (ClinicalTrials.gov - NCT02942745) is the first known randomized trial designed for ANBQ chewers. Methods: We compared intensive behavioral treatment intervention condition (IC) with control condition (CC) in the BENIT and included a 5-stage early stopping rule. We report the primary analysis at stage 3. English literate adults in Guam and Saipan who self-identified as ANBQ chewers with tobacco were enrolled between August 2016 and August 2020. IC participants (n=88) received five in-person sessions over 22 days and a brochure containing quitting advice. CC participants (n=88) received only the brochure. Participants were assessed at baseline and day-22 follow-up. Self-reported chewing status at day-22 was determined by a composite of two survey items with disparate wording and response options for cross-verification. Results: Cessation rates were 38.6% (IC) and 9.1% (CC). Proportional hazards regression revealed a p=0.0058, which met the Stage 3 criteria for significance and an estimated reduction in ANBQ chewing for IC compared to the CC of 71% (95% CI: 41%-88%). Conclusion: Robust self-reported intervention effects at day-22 suggests that intensive cessation programs such as BENIT should be further developed and implemented on a larger scale.

Prostate cancer is driven by acquired genetic alterations, including those impacting the epigenetic machinery. With African ancestry a significant risk factor for aggressive disease, we hypothesize that dysregulation among the roughly 656 epigenetic genes may contribute to prostate cancer health disparities. Interrogating prostate tumor genomic data from 109 men of southern African and 56 men of European Australian ancestry, we found African-derived tumors to present with a longer tail of epigenetic driver gene candidates (72 versus 10). Biased towards African-specific drivers (63 versus 9 shared), many are novel to prostate cancer (18/63) including several putative therapeutic targets (CHD7, DPF3, POLR1B, SETD1B, UBTF and VPS72). Through clustering of all variant types and copy number alterations, we describe two epigenetic PCa taxonomies capable of differentiating patients by ancestry and predicted clinical outcomes. We identified top genes in African and European-derived tumors that represent a multifunctional “generic machinery”, alteration to which may be instrumental in epigenetic dysregulation and prostate tumorigenesis. In conclusion, numerous somatic alterations in the epigenetic machinery drive prostate carcinogenesis but African-derived tumors appear to achieve this with greater diversity amongst such alterations. The greater novelty observed in African-derived tumors illustrates the significant clinical benefit to be derived from a much needed African tailored approach to prostate cancer healthcare aimed at reducing prostate cancer health disparities.

Eurycomanone and eurycomalactone are known quassinoids present in the roots and stems of Eurycoma longifolia. These compounds had been reported to have cytotoxic effects, however, their mechanism of action in a few cancer cell lines have yet to be elucidated. This study was aimed to investigate the anti-cancer effects and mechanisms of action of eurycomanone and eurycomalactone in cervical (HeLa), colorectal (HT29) and ovarian (A2780) cancer cell lines via Sulforhodamine B assay. Their mechanism of cell death was evaluated based on Hoechst 33342 assay and in silico molecular docking toward DHFR and TNF-α as putative protein targets. Eurycomanone and eurycomalactone exhibited in vitro anti-cancer effects manifesting IC50 values of 4.58 ± 0.090 µM and 1.60 ± 0.12 µM (HeLa), 1.22 ± 0.11 µM and 2.21 ± 0.049 µM (HT-29), and 1.37 ± 0.13 µM and 2.46 ± 0.081 µM (A2780) respectively. They induced apoptotic cancer cell death in dose- and time-dependent manners. Both eurycomanone and eurycomalactone were also predicted to have good inhibitory potential as demonstrated by the docking into TNF-α with binding affinity of -8.83 and -7.51 kcal/mol, respectively, as well as into DHFR with binding affinity results of -8.05 and -8.87 kcal/mol, respectively. These results support the evidence of eurycomanone and eurycomalactone as anti-cancer agents via apoptotic cell death mechanism that could be associated with TNF-α and DHFR inhibition as among possible protein targets.

Microbe bioengineering has the potential to improve the nutritional value and health benefits of food products. Modifying microbial cells to produce specific proteins or compounds that can improve human health is one approach. Penicillin and recombinant insulin are two examples of this. The production of recombinant insulin by genetically modified E. coli bacteria has transformed diabetes treatment by providing a consistent and cost-effective source of insulin. Previously, insulin was extracted from the pancreas of animals, which was an expensive process that frequently resulted in impurities that could cause adverse reactions. Bioengineered insulin is now the standard diabetes treatment, providing a safe and effective method of controlling blood glucose levels. Bacteria, for example, can be genetically modified to produce vitamins like B12, which are difficult to obtain from plant sources. Likewise, yeasts can be genetically modified to produce β-carotene, a precursor to vitamin A that is required for vision, immune function, and skin health. Overall, bioengineered microorganisms have the potential to provide significant health benefits by producing essential compounds and proteins. Because of ongoing advances in genetic engineering techniques and understanding microbial metabolism, the possibilities for improving human health through bioengineering are limitless.

MT4-MMP (or MMP-17) belongs to the Membrane-Type Matrix Metalloproteinases (MT-MMPs), a distinct subset of the MMP family that is anchored to the cell surface by a glycosylphosphatidylinositol (GPI) motif. Its expression in a variety of cancers is well documented. However, the molecular mechanisms by which MT4-MMP contributes to tumor development need further investigation. In this review, we aim to summarize the contribution of MT4-MMP in tumorigenesis, focusing on the molecular mechanisms triggered by the enzyme in tumor cell migration, invasiveness, and proliferation, in the tumor vasculature and microenvironment, as well as during metastasis. In particular, we highlight the putative substrates processed and signaling cascades activated by MT4-MMP that may underlie these malignancy processes and compare this with what is known about its role during embryonic development. Finally, MT4-MMP is a relevant biomarker of malignancy that can be used for monitoring cancer diseases progression in patients as well as a potential target for future therapeutic drug development.