Cancer stem cells remain a challenge to isolate and characterize because of their plastic phenotype. Using a microfluidic lab-on-a-chip based on ultra-high frequency dielectophoresis, we measured the electromagnetic signature of colorectal cancer cells and demonstrated that cancer stem cells show a distinct and lower electromagnetic signature than differentiated cells. The release of extracellular vesicles from tumor cells can drive tumor progression and metastasis development. As extracellular vesicles from cancer stem cells carry more aggressive content, we treated colorectal cancer cells with these vesicles to test whether the lab-on-a-chip can detect a change in phenotype. The electromagnetic signature of treated cells is modified in comparison to untreated cells and sometimes even when no biological change is observed. The lab-on-a-chip provides rapid and relevant result without prior labeling compared to conventional biological approaches. It could be useful in the clinic for early detection of cancer stem cells in the tumor mass and for monitoring the aggressive potential of extracellular vesicles in the bloodstream in order to adapt therapeutic management and prevent relapse.

Background: We previously found that QNBC tumors are more frequent in African Americans compared to TNBC tumors. To characterize this subtype further, we sought to determine the miRNA-mRNA profile in QNBC patients based on race. Methods: Both miRNA and mRNA expression data were analyzed from TCGA and validated using datasets from the METABRIC, TCGA proteomic, and survival analysis by KMPLOT. Results: miRNA-mRNAs which include FOXA1 and MYC (mir-17/20a targets); GATA3 and CCNG2 (mir-135b targets); CDKN2A, CDK6, and B7-H3 (mir-29c targets); and RUNX3, KLF5, IL1-β, and CTNNB1 (mir-375 targets) were correlated with basal-like and immune subtypes in QNBC patients and associated with a worse survival. Conclusion: Thus, QNBC tumors have an altered gene signature implicated in racial disparity and poor survival.

The presence of mutated genes strongly correlates with the incidence of cancer. Decades of research, however, has not yielded any specific causative gene or set of genes for the vast majority of cancers. The Cancer Genome Atlas program was supposed to provide clarity but it only gave much more data without any accompanying insight into how the disease begins and progresses. It may be time to notice that epidemiological studies consistently show that the environment, not genes, has the principal role in causing cancer. Since carcinogenic chemicals in our food, drink, air and water are the primary culprits, we need to look at the biochemistry of cancer, with a focus on enzymes which invariably facilitate transformations in a cell. In particular, attention should be paid to the rate-limiting enzyme in DNA synthesis, ribonucleotide reductase (RnR) whose activity is tightly linked to tumor growth. Besides circumstantial evidence that cancer is induced at this enzyme’s vulnerable free-radical-containing active-site by various carcinogens, its role in initiating retinoblastoma and HPV-related cervical cancers is well documented. Blocking the activity of malignant RnR is a certain way to arrest cancer.

Epithelial-mesenchymal transition (EMT) networks are essential in acquiring the drug resistance and cancer malignant features in cancer stem cells (CSCs). In this regard, gene expression profiles in diffuse- and intestinal-type gastric cancer (GC) have been analyzed to reveal the network pathways in EMT and CSCs, since the diffuse-type GC has much more mesenchymal features than intestinal-type GC that has the intestinal features. The study results revealed that the activation state of several canonical pathways related to cell cycle regulation was altered. The canonical pathway on Cell cycle: G1/S checkpoint regulation was activated in diffuse-type GC, and canonical pathways on Cell cycle control of chromosomal replication and Cyclins and cell cycle regulation were activated in intestinal-type GC. Canonical pathway related to Role of BRCA1 in DNA damage response was activated in intestinal-type GC, where BRCA1, which is related to G1/S phase transition was up-regulated in intestinal-type GC. Several microRNAs (miRNAs), including mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451, and mir-605, were identified to have direct relationships of RNA-RNA interaction in Cell cycle: G1/S checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in EMT conditions. The alterations in activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC would indicate the significance of cell cycle regulation in EMT.

It has now known that at least 10% of samples with pancreatic cancers (PC) contain a causative mutation in the known susceptibility genes, suggesting the importance of identifying cancer-associated genes that carry the causative mutations in high-risk individuals for early detection of PC. In this study, we develop a statistical pipeline using a new concept, called gene-motif, that utilizes both mutated genes and mutational processes to identify 4,211 3-nucleotide PC-associated gene-motifs within 203 significantly mutated genes in PC. Using these gene-motifs as distinguishable features for pancreatic cancer subtyping results in identifying five PC subtypes with distinguishable phenotypes and genotypes. Our comprehensive biological characterization reveals that these PC subtypes are associated with different molecular mechanisms including unique cancer related signaling pathways, in which for most of the subtypes targeted treatment options are currently available. Some of the pathways we identified in all five PC subtypes, including cell cycle and the Axon guidance pathway are frequently seen and mutated in cancer. We also identified Protein kinase C, EGFR (epidermal growth factor receptor) signaling pathway and P53 signaling pathways as potential targets for treatment of the PC subtypes. Altogether, our results uncover the importance of considering both the mutation type and mutated genes in the identification of cancer subtypes and biomarkers.

Until recently, research on the molecular signatures of HPV-associated head and neck cancers mainly focused on their differences with respect to HPV-negative HNSCCs. However, given the continuing high incidence level of HPV-related HNSCC, the time is ripe to characterize the heterogeneity that exists within these cancers. Here, we review research thus far on HPV-positive HNSCC molecular subtypes, and their relationship with clinical characteristics and HPV integration into the host genome. Different omics data including host transcriptomics and epigenomics, as well as HPV characteristics, can provide complementary viewpoints. Keratinization, mesenchymal differentiation, immune signatures, stromal cells, and oxidoreductive processes all play important roles.

Next Generation Sequencing based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. ATM germ-line heterozygosity has been described as able to increase tumor susceptibility. In particular, families that carry heterozygous germ-line variants of ATM gene show a 5- to 9-fold risk of developing breast cancer. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients. Nowadays, more than 170 potential missense variants and several truncating mutations have been identified in ATM gene. Here we present the molecular characterization a new ATM deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics’ Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed to identify a new inactivating deletion of exons 19-27 of ATM gene. DNA breakpoint was characterized both at DNA and RNA level

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of various epithelial cancers. Despite sharing the same pathogenic variant (PV), Lynch syn-drome variant heterozygotes (LSVH) exhibit considerable phenotypic variability in cancer risk. The role of Human Leukocyte Antigen (HLA) in modifying cancer risk prompted our investiga-tion into whether HLA variations act as genetic modifiers influencing age at cancer diagnosis in a unique cohort of LSVH carrying a PV in the hMLH1 gene in South Africa. Within our extensive LS cohort, 426 individuals carried the same hMLH1 PV (MLH1:c.1528C>T). We selected 100 indi-viduals with the greatest diversity in age at cancer diagnosis and the oldest unaffected individu-als for high-throughput HLA genotyping of 12 HLA class I and II loci using next-generation se-quencing. Statistical analyses employed Kaplan-Meier survival analyses with Logrank tests and Cox proportional hazards. Following the robust application of statistical correction methods, six HLA alleles (3.2%) were significantly associated with a young age at cancer diagnosis. Notably, HLA-B*15:17 and HLA-DPB1*55:01 correlated significantly with very young colorectal cancer (CRC) diagnosis (Mean age: 21y [17-25]; HR = 71.59; q

Malignant melanoma (MM) is the most fatal form of skin cancer, accounting for 90% of all skin cancer deaths. Multiple dysregulated cellular pathways are involved in MM, including the MAPK/ERK and PI3K/PTEN/AKT pathways, which can be targeted with novel targeted inhibitors. However, these blockades can be overcome through the activation of alternative pathways, leading to treatment resistance. The high immunogenicity of MM has been exploited using checkpoint inhibitors resulting in improved survival outcomes of patients with advanced MM. However, their side effect profile and prohibitive cost remain a challenge and the survival outcomes for patients with metastatic MM remain poor. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, metastasis, and treatment resistance. CSCs reside within the MM tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system (RAS), expressed in many cancer types, including MM. This article reviews the current treatment of advanced MM with targeted therapy and immune checkpoint blockers, highlights the emergence of mRNA vaccine. It also discusses the MM TME and its relationship with CSCs, and the local immune system and the paracrine RAS. It highlights the regulation of the MAPK/ERK and PI3K/AKT/mTOR pathways by the RAS via prorenin receptor and angiotensin II receptor 1, and how this relates to the CSCs and treatment resistance. This underscores the potential multi-modal therapeutic strategy by concurrent targeting of multiple components of the TME.

Abstract: This article reports the results of an ecological study of cancer incidence rates by state in the US for the period 2016-2020. The goals of this study were to determine the extent to which solar UVB doses still reduced cancer risk compared to findings reported in 2006 for cancer mortality rates for the periods 1950–1969 and 1970-1794 as well as cancer incidence rates for the period 1998–2002 and to determine which factors were recently associated with cancer risk. The cancer data for non-Hispanic white (European American) men and women were obtained from the Centers for Disease Control and Prevention. Indices were obtained for solar UVB at the surface for July 1992, and alcohol consumption, and diabetes and obesity prevalence near the 2016–2020 period. Lung cancer incidence rates were also used in the analyses as a surrogate for smoking, diet, and air pollution. The cancers for which solar UVB is significantly associated with reduced incidence are bladder, brain (males), breast, corpus uteri, esophageal, gastric, non-Hodgkin’s lymphoma, pancreatic, and renal cancer. Lung cancer was significantly associated with colorectal, laryngeal, and renal cancer. Diabetes was also significantly associated with breast, liver, and lung cancer. Obesity prevalence was significantly associated with breast, colorectal and renal cancer. Alcohol consumption was associated with bladder and esophageal cancer. Thus diet has become a very important driver of cancer incidence rates. The role of solar UVB in reducing risk of cancer has been reduced due to people spending less time outdoors, wearing sunscreen that blocks UVB but not UVA radiation, and population increases in overweight and obesity, which lowers 25-hydroxyvitamin D concentrations and generates systemic inflammation, a risk factor for cancer. The dietary approach that would reduce the risk of diabetes, obesity, lung cancer, and, therefore cancer, would be one based mostly on whole-plants and restrictions on red and processed meats and ultraprocessed foods. Solar UVB exposure for a few minutes before applying sunscreen and taking vitamin D supplements would also help reduce risk of cancer.Keywords: alcohol consumption; cancer incidence;

(1) Background: Sentinel lymph node (SLN) mapping represents an accurate and feasible technique for the surgical staging of endometrial and cervical cancer. This is commonly performed by conventional laparoscopy or robotic-assisted laparoscopy, but in recent years, a new retroperitoneal transvaginal natural orifice transluminal endoscopic surgery (vNOTES) approach has been described. This technique provides easy visualization of lymphatic afferent vessels and pelvic lymph nodes, early SLNs assessment, and a coherent mapping methodology following the lymphatic flow from caudal to cranial. However, only a few publications have reported it. Following the IDEAL (Idea Development Exploration Assessment Long-term follow-up) framework, research concerning this technique is at stage 2a, with only small case series as evidence of its feasibility. Its standardized description appears necessary to provide the surgical homogeneity required to move further. (2) Methods: description of a standardized approach for retroperitoneal pelvic SLN mapping by vNOTES. (3) Results: we described a 10-step approach to successfully perform retroperitoneal vNOTES SLN mapping, including pre-, intra-, and postoperative management. (4) Conclusions: This IDEAL stage 2a study could help other surgeons approach this new technique, and it proposes a common methodology necessary to evolve through future IDEAL stage 2b (multi-center studies) and stage 3 (randomized controlled trials) studies.

Lung cancer is one of the leading causes of cancer-related mortality globally. Pulmonary nodules are one of the risk factors and their discovery rate has been increasing. Based on the nodule size and growth rate, their malignancy propensity is determined; however, it is very challenging to distinguish between benign and cancerous nodules. Many tumour-associated antigens (TAA) have been studied as blood biomarkers for lung cancer, most commonly the Cytokeratin 19 fragment (CYFRA 21-1), squamous cell carcinoma antigen (SCC Ag), carbohydrate antigen (CA19-9) and carcinoembryonic antigen (CEA). Due to their low sensitivity, TAAs are not recommended as tools for the early detection of lung cancer. However, cancer testis antigens (CTAs) are highly specific for carcinomas but their expression is more commonly associated with advanced stages of cancer and poor prognosis. Despite the fact that TAAs may provide useful insights for the diagnosis and prognosis of early lung cancer, their potential to do so has yet to be demonstrated.

Within the oligometastatic state, oligo-recurrent lymph node disease in prostate cancer represents an interesting clinical entity characterized by a relatively indolent biology that makes it unique: it can be treated radically, and its treatment is usually associated with a long period of control and excellent survival. Additionally it is an emergent situation that we are facing more frequently, mainly due to: a) the incorporation into clinical practice of the PSMA PET that provides strikingly increase superior images in comparison to conventional imaging, with higher sensitivity and specificity; b) the higher detection rates of bone and node disease with extremely low levels of PSA; and c) the availability of high-precision technology in radiotherapy treatments with the incorporation of stereotaxic body radiotherapy (SBRT) or stereotaxic ablative radiotherapy (SABR) technology that allows the safe administration of high doses of radiation in a very limited number of fractions with low toxicity and excellent tolerance. This approach of new image-guided patient management is compelling for doctors and patients since it can potentially contribute to improve the clinical outcome. In this work we discuss the available evidence, areas of debate, and potential future directions concerning the utilization of new imaging guided SBRT for the treatment of nodal recurrence in prostate cancer.

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well-documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well-understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1-4 to provide context for past and current efforts to translate STEAP1-4 into the clinic.

Cancer survival continues to improve in high-income countries, partly explained by advances in screening and treatment. Previous studies have mainly examined the relationship between individual dietary components and cancer prognosis in tumours with good therapeutic response (breast, colon and prostate cancers). The aim of this review was to assess qualitatively (and quantitatively where appropriate) the associations of dietary patterns and cancer prognosis from published prospective cohort studies, as well as the effect of diet interventions by means of randomized controlled trials (RCT). A systematic search was conducted in PubMed, and a total of 35 prospective cohort studies and 14 RCT published between 2011 and 2021 were selected. Better overall diet quality was associated with improved survival among breast and colorectal cancer survivors; adherence to the Mediterranean diet was associated to lower risk of mortality in colorectal and prostate cancer survivors. A meta-analysis using a random-effects model showed that higher versus lower diet quality was associated with a 23% reduction in overall mortality in breast cancer survivors. There was evidence that dietary interventions, generally combined with physical activity, improved overall quality of life, though most studies were in breast cancer survivors. Further cohort and intervention studies in other cancers are needed to make more specific recommendations.

The advent of high throughput sequencing has enabled researchers to systematically evaluate the genetic variations in cancer, resulting in identifying many cancer-associated genes. Although cancers in the same tissue are widely categorized in the same group, they demonstrate many differences concerning their mutational profiles. Hence there is no “silver bullet” for the treatment of a cancer type. This reveals the importance of developing a pipeline to identify cancer-associated genes accurately and re-classify patients with similar mutational profiles. Classification of cancer patients with similar mutational profiles may help discover subtypes of cancer patients who might benefit from specific treatment types. In this study, we propose a new machine learning pipeline to identify protein-coding genes mutated in a significant portion of samples to identify cancer subtypes. We applied our pipeline to 12270 samples collected from the International Cancer Genome Consortium (ICGC), covering 19 cancer types. Here we identified 17 different cancer subtypes. Comprehensive phenotypic and genotypic analysis indicates distinguishable properties, including unique cancer-related signaling pathways, in which, for most of them, targeted treatment options are currently available. This new subtyping approach offers a novel opportunity for cancer drug development based on the mutational profile of patients. We also comprehensive study the causes of mutations among samples in each subtype by mining the mutational signatures, which provides important insight into their active molecular mechanisms. Some of the pathways we identified in most subtypes, including the cell cycle and the Axon guidance pathways, are frequently observed in cancer disease. Interestingly, we also identified several mutated genes and different rates of mutation in multiple cancer subtypes. In addition, our study on “gene-motif” suggests the importance of considering both the context of the mutations and mutational processes in identifying cancer-associated genes. The source codes for our proposed clustering pipeline and analysis are publicly available at: https://github.com/bcb-sut/Pan-Cancer.

Prostate cancer is a leading cause of death among men but its genomic characterization and best therapeutic strategy are still under debate. The Genomic Fabric Paradigm (GFP) considers the transcriptome as a multi-dimensional mathematical object subjected to a dynamic set of expression correlations among the genes. Here, GFP is applied to gene expression profiles of three (one primary, and two secondary) cancer nodules and the surrounding normal tissue from a surgically removed prostate tumor. GFP was used to determine the regulation and rewiring of the P53 signaling, apoptosis, prostate cancer and several other pathways involved in survival and proliferation of the cancer cells. Genes responsible for the block of differentiation, evading apoptosis, immortality, insensitivity to anti-growth signals, proliferation, resistance to chemotherapy and sustained angiogenesis were found as differently regulated in the three cancer nodules with respect to the normal tissue. The analysis indicates that even histo-pathologically equally graded cancer nodules from the same tumor have substantially different transcriptomic organizations, raising legitimate questions about the validity of meta-analyses comparing large populations of healthy and cancer humans. The study suggests that GFP may provide a personalized alternative to the biomarkers’ approach of cancer genomics.

Obesity, type 2 diabetes, and different forms of cancers are among the leading human diseases and highly complex in terms of diagnostic and therapeutic approaches. Diabetes and cancer are among the most frequent and complex diseases and based on epidemiological evidence and study it can be concluded that the patients suffering from diabetes are considered to be significantly at higher risk for a number of cancer types. Both these diseases are among the highly complex and heterogeneous in nature. There are a number of evidences which support the hypothesis that these diseases interlinked and obesity may aggravate the risk(s) of both these diseases type 2 diabetes and different types of cancers. Multi-level unwanted alterations such as (epi-)genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major source which promotes a number of complex diseases and such heterogeneous level of complexities are considered as the major barrier in the development of therapeutic. With so many known challenges, it is critical to understand the relationships and the common shared causes between type 2 diabetes and cancer which is difficult to unravel and understand. Furthermore, the real complexity arises during diagnosis from contended corroborations that specific drug(s) (individually or in combination) during diagnosis process of type 2 diabetes may increase or decrease the cancer risk or affect cancer prognosis. In this review article, we have presented the recent and most updated evidences from the studies where the origin, biological background, correlation between them have been presented or proved. Furthermore, we have summarized the methodological challenges and tasks that are frequently encountered. we have also outlined the physiological links between type 2 diabetes and cancers. Finally, we have presented and summarized the outline of the hallmarks for both these diseases diabetes and cancer.

Previously, we demonstrated that IR triggers the invasion/migration of A549 cells via activation of an EGFR–p38/ERK–STAT3/CREB-1–EMT pathway. Here, we have demonstrated the involvement of a novel intracellular signaling mechanism in γ-ionizing radiation (IR)-induced migration/invasion. Expression of receptor-interacting protein (RIP) 1 was initially increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to IR. IR-induced RIP1 is located downstream of EGFR and involved in the expression/activity of matrix metalloproteases (MMP-2 and MMP-9) and vimentin, suggesting a role in epithelial-mesenchymal transition (EMT). Our experiments showed that IR-induced RIP1 sequentially induces Src-STAT3-EMT to promote invasion/migration. Inhibition of RIP1 kinase activity and expression blocked induction of EMT by IR and suppressed the levels and activities of MMP-2, MMP-9, and vimentin. IR-induced RIP1 activation was additionally associated with stimulation of the transcriptional factor NF-κB. Specifically, exposure to IR triggered NF-κB activation and inhibition of NF-κB suppressed IR-induced RIP1 expression followed by a decrease in invasion/migration as well as EMT. Based on the collective results, we propose that IR concomitantly activates EGFR and NF-κB and subsequently triggers the RIP1–Src/STAT3–EMT pathway, ultimately promoting metastasis.

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

Epidemiological data indicate that 5.8% of cancer deaths world-wide are attributable to alcohol consumption. The risk of cancer is higher in tissues in closest contact on ingestion of alcohol, such as the oral cavity, pharynx and esophagus. The risk of these cancers is increased even in people who have only one alcoholic drink per day. However, since ethanol is not mutagenic and the carcinogenic metabolite of ethanol (acetaldehyde) is mostly produced in the liver, it is not clear why alcohol use preferentially exerts a local carcinogenic effect. It is well known that ethanol causes cell death at the concentrations present in alcoholic beverages; however, this effect has been overlooked probably because dead cells cannot give rise to cancer. Here I discuss that the cytotoxic effect of ethanol on the cells lining the oral cavity, pharynx and esophagus activates the division of the stem cells located in deeper layers of the mucosa to replace the dead cells. Every time stem cells divide, they become exposed to unavoidable errors associated with cell division (e.g., mutations arising during DNA replication and chromosomal alterations occurring during mitosis) and also become highly vulnerable to the genotoxic activity of endogenous and exogenous DNA-damaging agents (e.g., reactive oxygen species, acetaldehyde and tobacco carcinogens). Alcohol consumption probably increases the risk of developing cancer of the oral cavity, pharynx and esophagus by promoting the accumulation of cell divisions in the stem cells that maintain these tissues in homeostasis. Because the cytotoxic activity of ethanol is concentration-dependent, the risk of these cancers will not only increase with increasing amounts of ethanol, but also with increasing concentrations; an ounce of whisky is probably more carcinogenic when taken undiluted than when taken mixed with non-alcoholic beverages. The local cytotoxic effect of ethanol can also explain the known synergistic effect of alcohol and tobacco use on the risk of these cancers. Understanding the mechanisms of carcinogenicity of alcohol is important to reinforce the epidemiological evidence and to raise public awareness of the strong link between alcohol consumption and cancer.

Flavonoids are secondary plant metabolites involved in biological activity that are present in plentiful proportions in many plant origin foods and beverages. Owing to their chemical difference and qualities that make them beneficial for human health, they have received a lot of focus in research. This review therefore presents an account on the chemical structure of flavonoids, food sources and their metabolism with emphasis on bioavailability. And they also examine their antioxidant, anti-inflammatory, anticancer, cardiovascular protective, neuroprotective, and antimicrobial properties and reveal related molecular processes. In addition, it overviews the clinical data concerning their possible use in the prevention and treatment of chronic diseases. Some of the problems that attend current flavonoid research are also dealt with; such issues as variation in the bioactivity of flavonoids and scarcity of clinical studies. This review is designed to present current state of knowledge and to provoke further research concerning the further potential of flavonoids in enhancing human health.

Plant-Derived Extracellular Vesicles (PDEVs) contain high levels of antioxidants, especially when deriving from organic. PDEVs from different vegetal sources has shown an increased antioxidant power, compared to PDEVs from single plants, suggesting a synergistic effect of the bioactives constitutively expressed in the PDEVs from single fruits. With this study we wanted to investigate the beneficial effects of a mix of PDEVs on human skin cells. We found detectable levels of Citric Acid, Ascorbic Acid, Glutathione, Catalase and SOD in a mix of PDEVs deriving from 5 different fruits (Grape, Red Orange, Papaya, Pomegranate and Tangerine). We then treated H2O2-conditioned fibroblasts with the mix of PDEVs. The results showed that the PDEVs ‘mix reverted the H2O2-induced redox imbalance, restoring the mitochondrial homeostasis, with a strong reduction of mitochondrial anion superoxide and increase of sirtuin levels. The antioxidant action was consistent with a wound repair on a lesion produced in a Fibroblasts’ monolayer. This result was consistent with an increased level of Vimentin and Matrix Metalloproteinase-9, whose expression is directly related to the efficiency of the reparative processes. These data support a beneficial role of PDEVs in both preventing and treating skin injuries, through their potent antioxidant and reparative activities.

Rising obesity and associated multi-systemic complications amplify the health burden. Euphorbia kansui (EK) extract is clinically recognized for managing obesity. In human study, 240 obese individuals were categorized into two cohorts: those receiving solely herbal medicine (HM group), and those administered EK concomitantly with herbal medicine (EK group). An in vivo examination using C57BL/6-Lepob/Lepob mice elucidated mechanisms involving macrophages and gut microbiota, with associated metabolic advantages. The clinical study revealed a significant 7.22% body weight reduction during 91.55 average treatment days, and examined 16.71% weight loss at 300 days after treatment. In the whole subjects, 60.4%, 21.3% and 6.3% achieved weight reductions exceeding 5%, 10% and 15%, respectively. Impressively, the EK group exhibited superior weight loss compared to the HM group (EK: -7.73% vs. HM: -6.27%, p=0.012). The anti-obesity effect was positively associated with EK therapy frequency and herbal medicine duration. In vivo, EK significantly improved insulin sensitivity and mitigated infiltration of adipose tissue macrophages (ATMs) by modulating the CD11c+ and CD206+ subtypes. EK also correlated with increased Bacteroidetes and Firmicutes populations and reduced Proteobacteria and Verrucomicrobia. Consequently, EK is an effective adjunctive anti-obesity therapy offering metabolic benefits by modulating ATMs and gut microbiota profiles.

Background. Coronary artery disease (CAD) with extensive stenosis presents significant clinical challenges. This case report details the management and outcomes of a 61-year-old male with a notable history of CAD, initially treated with coronary artery bypass grafting (CABG), followed by an innovative intravenous hydrogen and oxygen nanobubble therapy due to recurrent symptoms.Case Presentation. Mr. BH was diagnosed with significant stenosis in the left anterior descending (LAD) artery and left circumflex (LCx) artery, initially managed by CABG. Recurring symptoms led to the adoption of a novel treatment involving hydrogen and oxygen nanobubbles. Following treatment initiation, Mr. BH experienced substantial improvements in physical capacity and symptomatic relief, with an ability to climb 22 flights of stairs and resolution of previous symptoms such as dyspnea and cough. Despite these improvements, subsequent imaging revealed in-stent restenosis and progression of graft disease.Discussion. The application of hydrogen and oxygen nanobubbles as a therapy in CAD is explored, highlighting potential mechanisms such as reduction of oxidative stress and improvement in endothelial function. This case contrasts the effects of conventional surgical and pharmaceutical interventions with the novel nanobubble therapy, illustrating both the benefits and complexities of managing advanced CAD with innovative treatments.Conclusion. While Mr. BH showed clinical improvement with nanobubble therapy, the development of new severe stenosis and restenosis underscores the need for further research to understand the long-term efficacy and mechanisms of nanobubble therapy in complex CAD cases. This case suggests that while innovative therapies may provide symptomatic relief and functional improvement, they do not obviate the need for ongoing surveillance and possibly further intervention.

The aim of this article is to present the course of the COVID-19 pandemic in Poland in 2020-2022, the formation of ad hoc health and anti-crisis policies, an assessment of crisis management and the perceived impact of the pandemic and anti-crisis measures.The paper draws on literature, official reports on the pandemic, data from Eurostat and other information from state institutions and public organisations.Particular attention was paid to the analysis and evaluation of the objectives, instruments and effects of the policies pursued by the state in a coordinated manner, i.e. the anti-pandemic policy and the anti-crisis policy. The anti-pandemic policy in Poland has failed to protect the country from significant personal losses and negative impacts on the health of the population and demographic processes.The anti-crisis policy of the state carried out with the mobilisation of businesses and disciplined society, in the form of anti-crisis shields supplemented and adjusted on an ongoing basis, allowed Poland to avoid a deep crisis and economic recession. Attention was drawn to the need to coordinate the management of health and economic crises nationally and internationally, and to the need to have a medium-term anti-crisis state strategy and a system for the early detection of crisis symptoms.

Litsea martabanica root's antioxidant and AChE activity showed promise as a pesticide detoxification agent in our previous study. In addition to roots, its leaves can help mitigate pesticide exposure, although there is limited scientific evidence supporting their efficacy. However, the use of roots in many countries, such as Thailand, could contribute to environmental degradation, as highland communities traditionally cut down whole trees to obtain them. This study aims to evaluate the antioxidant activity and anti-pesticide potential of water extracts from L. martabanica leaves instead of its roots through in vitro and in vivo investigations. The findings showed that L. martabanica water extracts and fractions demonstrated varied antioxidant activity. The water extract, obtained using traditional extraction methods, was chosen for in vivo experiments. Rats received the extract followed by chlorpyrifos exposure for 16 days. Results indicated reduced acetylcholinesterase activity in chlorpyrifos-exposed rats, while treatment with leaf extract led to increased activity, suggesting its potential as a detoxifying agent. Histopathological examination revealed no liver cell necrosis and showed liver cell regeneration, indicating potential protection against free radical-induced liver damage without affecting rat liver weight or biochemical profiles. Utilizing L. martabanica leaves for healthcare purposes holds promise without negative environmental impact.

Musculoskeletal infections (MIs) are among the most difficult-to-treat staphylococcal diseases. The limited availability of effective antibiotics has encouraged the development of innovative strategies such as combinatory therapy to combat MI. The aim of this study was to investigate the in vitro antistaphylococcal activity of anti-inflammatory and the antimicrobial combinatory effect of celecoxib with oxacillin. The minimum inhibitory concentrations (MICs) of 17 anti-inflammatory drugs were determined for standard strains and clinical isolates of S. aureus strains, counting methicillin-resistant strains (MRSA), by the broth microdilution method. The fractional inhibitory concentration indices (FICIs) were evaluated by the checkerboard assays. Celecoxib produced the most potent antistaphylococcal effect against all the tested strains (MIC ranging from 32 to 64 mg/mL), followed by diacerein against MRSA3 and MRSA ATCC 33592 (MIC 64 mg/mL). Several synergistic effects were observed for tested S. aureus strains, including MRSA (FICI ranging from 0.087 to 0.471). The strongest synergistic interaction (FICI 0.087) was obtained against MRSA ATCC 33592 at a celecoxib concentration of 2 mg/mL with a 19-fold oxacillin MIC reduction (from 512 to 26.888 mg/mL). This is the first report on the antistaphylococcal combinatory effect of celecoxib with oxacillin. Our findings suggest celecoxib and its combination with oxacillin as perspective agents for research focused on the development of novel therapies for MI caused by S. aureus. Thus, this study presents novel findings that celecoxib could, in some cases, resensitise MRSA strains to become susceptible to certain β-lactams (e.g., oxacillin) not previously tested.

Background and Aims: The impact of antibody response after direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV)-infected recipients before and after liver transplantation (LT) is still undetermined. Methods: In this observational cohort study, we aimed to explore the association of changes in anti-HCV antibody titers after pre-LT DAA therapy with allograft injury, including biliary complications (BCs) and acute cellular rejection (ACR). Results: A total of 153 cases were enrolled from January 2015 to February 2021. Serum anti-HCV antibody titers were assessed before and after (day 30) LT. Among all recipients, 31/153 (20.3%) had pre-LT DAA therapy (DAA group) and 122/153 (79.7%) did not undergo pre-LT DAA therapy (DAA-naïve group). Higher incidence of post-LT BCs was observed in the DAA group (P = 0.028). Compared with the DAA-naïve group, the DAA group had a significantly higher mean level of anti-HCV titer upregulation (P = 0.0024); furthermore, among the recipients with BCs (n = 28) and ACR (n = 41), those in the DAA group exhibited significantly higher mean levels of anti-HCV antibody titer upregulation (P < 0.005). Conclusion: In conclusion, we speculated that anti-HCV antibody titer upregulation, which might have been induced by restoration of HCV-specific immune responses with pre-LT DAA therapy, were associated with post-LT allograft injury.

Bioactive surface coatings have retained the attention of researchers and physicians due to their versatility and range of applications in orthopedics, particularly in infection prevention. Antibacterial metal nanoparticles (mNPs) are a promising therapeutic, with vast application opportunities on orthopedic implants. The current research aimed to construct a polyelectrolyte multilayer on a highly porous titanium implant using alternating thin film coatings of chitosan and alginate via the layer-by-layer (LbL) self-assembly technique, along with the incorporation of silver nanoparticles (AgNPs) or titanium dioxide nanoparticles (TiO2NPs), for antibacterial and osteoconductive activity. These mNPs were characterized for their physicochemical properties using quartz crystal microgravimetry with dissipation system, nanoparticle tracking analysis, scanning electron microscopy, and atomic force microscopy. Their cytotoxicity and osteogenic differentiation capabilities were assessed by AlamarBlue and alkaline phosphatase (ALP) activity assays, respectively. The antibiofilm efficacy of the mNPs tested against Staphylococcus aureus. The LbL polyelectrolyte coating was successfully applied to the porous titanium substrate. A dose-dependent relationship between nanoparticle concentration and ALP as well as antibacterial effects was observed. TiO2NP samples were also less cytotoxic than AgNP counterparts, although similarly antimicrobial. Together, these data serve as a proof-of-concept for a novel coating approach for orthopedic implants with antimicrobial and osteoconductive properties.

Macrophages play a pivotal role in the process of healing burns. One of the major risks in the course of burns healing, in the absence of regenerating epidermis, is infections which greatly contribute to morbidity and mortality in such patients. Therefore, it is widely agreed that accelerating recruitment of macrophages into burns may contribute to faster regeneration of the epidermis and thus, decreasing the risk of infections. This review describes a unique method for rapid recruitment of macrophages into burns and activation of these macrophages to mediate accelerated regrowth of the epidermis and healing of burns. The method is based on application of bio-degradable “alpha-gal” nanoparticles to burns. These nanoparticles present multiple alpha-gal epitopes (Gal alpha1-3Gal beta1-4GlcNAc-R) which bind the abundant natural anti-Gal antibody that constitutes ~1% of immunoglobulins in humans. Anti-Gal/alpha-gal nanoparticles interaction activates the complement system, resulting in localized production of the complement cleavage-peptides C5a and C3a that are highly effective chemotactic factors for monocytes derived macrophages. The macrophages recruited into the alpha-gal nanoparticles treated burns are activated following interaction between the Fc portion of anti-Gal coating the nanoparticles and the multiple Fc receptors on macrophages cell membranes. The activated macrophages secrete a variety of cytokines/growth factors that accelerate the regrowth of the epidermis and regeneration of the injured skin, thereby cutting the healing time by half. Studies on healing of thermal injuries in the skin of anti-Gal producing mice, demonstrated a much faster recruitment of macrophages into burns treated with alpha-gal nanoparticles than in control burns treated with saline and healing of the burns within 6 days, whereas healing of control burns takes ~12 days. alpha-Gal nanoparticles are non-toxic, and do not cause chronic granulomas or keloids. These findings suggest that alpha-gal nanoparticles treatment may harness anti-Gal for inducing similar accelerated burn healing effects also in humans.

We here investigate the dynamical behavior of a fractional-order predator-prey system with anti-predator behavior and Holling IV type functional response. First we study the non-negativity, existence, uniqueness, and boundedness of solutions to the system from a mathematical analysis perspective. Then, we analyze the stability of its equilibrium points and the possibility of bifurcations using stability analysis methods and bifurcation theory, and prove the existence of a supercritical Hopf bifurcation in the system. After providing numerical simulations to illustrate the conclusions theoretically derived, by summarizing those various analytical results obtained, we finally present three interesting conclusions that can contribute to better understanding and preservation of ecological systems.

Laser direct writing allows for the fabrication of complex structures, which is particularly advantageous in micro-optic applications. However, the increasing demand for optics quality requires the lowest optical power loss, which can occur from unwanted reflections. This research demonstrates the possibility of forming an anti-reflective coating on hybrid-polymer micro-lenses fabricated by employing laser direct writing (LDW), without changing their geometry. Such coating deposited by atomic layer deposition (ALD) decreased the reflection from 3.3 % to 0.1 % at the wavelength of 633 nm for one surface of SZ2080™.

Inhibition of quorum sensing (QS)-dependent biofilm formation and virulence is extensively investigated as a novel approach to combat bacterial pathogens by impeding their ability to cause antibiotic-tolerant diseases. Such strategies are considered a promising alternative to conventional antibacterial therapy since interrupting the central cell-to-cell communication system imposes less selective pressure on the target pathogen. In this study, novel hybrid compounds composed of anthranilic acids substituted with halogens at different positions of the phenyl ring, and 4-(2-aminoethyl/4-aminobuthyl)amino-7-chloroquinoline linked via 1,3,4-oxadiazole were synthesized using standard procedures. Their anti-QS activities were evaluated using Chromobacterium violaceum ATCC31532 (anti-biofilm and bactericidal activities) and Pseudomonas aeruginosa PAO1 (anti-biofilm/-virulence activities). The results showed that compounds 15–19 and 23 inhibited the production of violacein, the QS-inducible pigment, in C. violaceum to a similar extent as the model QS inhibitor - quercetin (83.5–90%). Compound 15 exhibited the strongest effect on P. aeruginosa in the anti-biofilm screening, reducing its ability to form biofilm by almost 50%, while compounds 16 and 19 were able to reduce the biofilm formation by approximately 30%. However, compound 23 did not demonstrate significant anti-biofilm activity and only inhibited pyocyanin production in P. aeruginosa. In conclusion, this study suggests that 1,3,4-oxadiazoles 15, 16, and 19 are the most promising compounds for future research as novel QS inhibitors against Gram-negative bacteria equipped with different QS signaling pathways.

Purpose: Inflammation of various degrees is common among humans. There are associated side effects with orthodox delivery systems and anti-inflammatory agents hence the study investigated the characteristics of herbal lipospheres and the anti-inflammatory potency of the lipospheres formulated from Pentaclethra macrophylla with the view to having a drug with a better delivery system and lesser side effects.Methods: Herbal lipospheres were formulated using solidified reverse micellar solutions (SRMS) of P90H and goat fat and characterized for particle size and morphology, pH – time dependent analysis, encapsulation efficiency (EE%) and Fourier Transform infrared spectroscopy. The in vitro antinociceptive and anti-inflammatory study were carried out using membrane stabilization by hypotonicity induced haemolysis and determination of anti-platelet aggregatory activity models. The in-vivo anti-nociceptive and anti-inflammatory studies on egg albumin and formaldehyde induced arthritis models were done. Total white blood cell count and differential blood count were carried out on the rats. Results: The results showed that there was no change in pH for the PM unloaded lipospheres and 2.5g of PM-loaded lipospheres from Day 1 to Day 7, but mild variation in the rest of the formulations. The EE ranged from 35.2% to 94% increasing according to the drug concentration. The photomicrographs of the lipospheres showed that the particles were spherical in shape. The particle sizes were within the acceptable range for lipospheres. FTIR showed no interaction. In the arthritis study, PM-loaded lipospheres inhibited edema consistently throughout the duration of observation. Inhibition of membrane increased steadily with an increase in concentration of PM in the lipospheres and the standard drug. The platelet aggregatory inhibition decreased steadily with an increase in concentration of the PM in the lipospheres as well as the standard. The T50 dose of PM had the highest percentage of WBC and it decreased as the treatment doses increased from T100 to T200. There was no significant differences among the Neutrophil counts of the different groups.Conclusion: The study, therefore, showed that the methanol extract of Pentaclethra macrophylla formed efficient herbal lipospheres with antinociceptive and anti-inflammatory activities.

Enteric protozoan pathogenic infections significantly contribute to the global burden of gastrointestinal illnesses. Their occurrence is considerable within remote and indigenous communities and regions due to reduced access to clean water and adequate sanitation. The robustness of these pathogens means requirement of harsh treatment methods such as medicinal drugs or antibiotics. However, such treatments impact the gut microbiome, and create dysbiosis, often leading to opportunistic pathogens, anti-microbial resistance, or functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). Recent studies have shown that these impacts do not remain confined to gut, and are reflected across the gut-brain, gut-liver, and gut-lung axes, among others. Therefore, apart from the medicinal treatment, nutritional supplementation is also a key aspect of providing the recovery from this dysbiosis. Future proteins, prebiotics, probiotics, synbiotics, and food formulations offer a good solution to remedy this dysbiosis. Furthermore, the nutritional supplementation also helps to build a resilience against the opportunistic pathogens and potential future infections and disorders that may arise due to the dysbiosis. Systems biology techniques have shown to be highly effective tools to understand the biochemistry of these processes. Systems biology techniques characterises the fundamental host-pathogen interaction biochemical pathways, at various infection and recovery stages. This same mechanism also allows to track the impact of abovementioned treatment methods of gut microbiome remediation. This manuscript is organised in sections delving into system biology approaches and upcoming developments to understand (1) Infection mechanism and current global status; (2) Cross-organ impacts of dysbiosis, particularly within gut-liver and gut-lung axes; (3) Nutritional interventions. It highlights the impact of antimicrobial resistance (AMR) and Multi-drug resistance (MDR) from a perspective of protozoal infections. It also highlights the role of nutritional interventions to add resilience against the chronic problems caused by these phenomena.

The post-hoc analysis presented here aimed to address the influence of endogenous vitamin D in the immunological mechanism underlying effective mite allergoid-immunotherapy (AIT). Previously, we have shown that one subpopulation of T regulatory cells results in phenotypically identifiable as functionally potentiated and memory cells in allergic children after 12 months of this immunoactive treatment. Indeed, AIT is the only known treatment able to reshape the detrimental immune response against the allergen into a not noxious one. Besides, VD is widely considered an immunoregulatory molecule endogenously produced and exogenously provided with foods and supplements that might interact with AIT mechanism and affect its outcome. Therefore, a post-hoc analysis of the clinical and immunological data of three different cohorts of allergic patients was performed. One cohort (N=70) was on standard symptoms-controlling pharmacological treatment while the other two (N=60 and N=35, respectively) were treated with AIT for 12 months. Among the first were observed a lower mean endogenous VD level (&lt;22 ng/ml) along with worse symptoms and higher use of medications. Remarkably, the comparison between two sub-cohorts of patients with serum VD above (N=32) or below (N=28) a cut-off value set at mean value (27 ng/ml) revealed that optimal improvement of all clinical and immune parameters was achieved (as expected by effective AIT), irrespective of the VD level. Notably, the third analysis, carried out on one cohort of AIT patients also taking concomitantly VD3 as food supplement (N=19), was distinguished by uppermost overall treatment outcome (amelioration of symptoms, lowest medications requirement, and reduction of total and allergen-specific IgE) as well as the increase of allergen-specific tolerogenic memory T regulatory cells. These findings suggest that endogenous VD level affects allergy severity and allergen immunotherapy effectiveness. Also, VD3 might be investigated as an add-on supplement to get the best out of immunotherapy in VD deficient/insufficient allergic patients. The immunogenic but low-allergenic mite allergoid used as bioactive agent might have contributed to minimize allergic and highlight immunological effects described here.

Understanding the complex interactions between metabolism and the immune system (“meta-flammation”) is crucial for the identification of key immunomodulatory factors as potential therapeutic targets in obesity and in cardiovascular diseases. Cathelicidin antimicrobial peptide (CAMP) is an important factor of innate immunity and is expressed in adipocytes. CAMP therefore might play a role as an adipokine in metaflammation and adipose inflammation. Toll-like receptor (TLR) 9 is another component of the innate immune system that is expressed and functionally active in adipocytes. The aim of the present study was to investigate the impact of TLR9 signaling on CAMP expression in adipocytes and in adipose tissue. CAMP gene expression in murine 3T3-L1 and human SGBS adipocytes and in murine and human adipose tissues was quantified by real-time PCR. TLR9 knockdown was applied in murine 3T3-L1 adipocytes via siRNA transfection. Adipocyte inflammation was induced in vitro by TNFα stimulation. Serum CAMP concentrations in TLR9 knockout (KO) and in wildtype mice were quantified by ELISA. CAMP gene expression was considerably increased in 3T3-L1 adipocytes during differentiation. TNFα significantly induced CAMP gene expression in mature adipocytes, which was antagonized by inhibitors of NF-κB and PI3K signaling. Cell-free nucleic acids (cfDNA) as endogenous TLR9 ligand significantly impaired CAMP gene expression, whereas synthetic agonistic and antagonistic TLR9 ligands had no effect. Cellular TLR9 knockdown reduced adipocyte CAMP gene expression in vitro and male TLR9 knockout mice exhibited lower systemic CAMP concentrations than wildtype mice. CAMP and TLR9 gene expression were correlated positively in murine and human subcutaneous but not in intraabdominal/visceral adipose tissues. These findings suggest a regulatory role of TRL9 in adipocytic CAMP expression as a novel putative molecular mechanism in adipose tissue innate immunity.

In the history of civil aircraft transportation, ice formation has been identifies as a key factor in the safety of flight. Anti-icing and deicing system have emerged through the years with the aim to prevent or to eliminate ice formation on wing airfoil, control surface and probes. Modern flying machine demand more efficiency in order to reduce the carbon footprint and increase the sustainability of flight transport. In order to achieve this goal the need to have efficient aircraft with efficient and low power consuming system is fundamental. This paper proposes a new model for ice accretion using computational fluid dynamics (CFD). This model permits to simulate the shape of the ice formed over a profile varying boundary conditions (i.e.- speed, liquid water content and so on). The proposed model takes into account also the amount of heat transferred between water and the surrounding environment and includes the effects of air turbulence on the ice formation process. The CFD simulations have been validated with NASA experimental outcome and show good agreement. The proposed model can be also used to investigate the effects of various parameters such as air speed, Liquid Water Content and air temperature on the ice formation process. The results evidences that the proposed model can accurately predict ice formation process and is suitable to optimize the design of anti-icing or deicing system for aircraft and helicopters. This approach is not limited to aerospace but can also be exported to other applications such as transportation, wind turbine, energy management and infrastructure.

SARS-CoV-2 breakthrough infections, associated with waning immunity, increase systemic antibody levels. In this study, we analyzed the impact of the infection timing on the magnitude of the systemic humoral response and whether breakthrough infections also boost antibody levels in the salivary compartment. We observed that the combination of infection plus vaccination, regardless of infection timing, produced a sharp increase of systemic antibodies, being higher in subjects infected after third doses. Moreover, despite high systemic antibody levels, breakthrough infections after dose 3 occurred and boosted antibody levels in the salivary compartment. These results lead to rethink the current vaccination strategies against COVID-19 and the use of salivary anti-SARS-CoV-2 antibodies for disease surveillance and vaccination follow-up.

The COVID-19 pandemic affects all parameters, especially health care professionals, drugs and medical supplies. The KERRA is a mixed medicinal plant capsule that is used for the treatment of patients with high fever with food and drug administration approved by FDA Thailand. Recently, KERRA showed quicker recovery for COVID-19 patients. Therefore, it is possible that some ingredients in KERRA could inhibit SARS-CoV-2. In this study, two important replication-related enzymes in SARS-CoV-2, a main protease and an RNA-dependent RNA polymerase (RdRp), were used to study the effect of KERRA. The results showed that KERRA inhibited the SARS-CoV-2 main protease and SARS-CoV-2 RdRp with IC50 values of 49.91 ± 1.75 ng/mL and 36.23 ± 5.23 µg/mL, respectively. KERRA displayed no cytotoxic activity on macrophage cells at concentrations lower than 1 mg/mL and exhibited anti-inflammatory activity. Additionally, KERRA was against a feline coronavirus (feline infectious peritonitis [FIP]) infection with an EC50 value of 134.3 g/mL. This study supports the potential use of KERRA as a candidate drug for COVID-19.

Novel pH responsive semi-interpenetrating polymer hydrogels based on tamarind gum-co-poly(acrylamidoglycolic acid) (TMGA) polymers have been synthesized using simple free radical polymerization in the presence of bis[2-(methacryloyloxy)ethyl] phosphate as a crosslinker and potassium persulfate as a initiator. In addition, these hydrogels have been used as templates for green synthesis of silver nanoparticles (13.4±3.6 nm in diameter, TMGA-Ag) by using leaf extract of Teminalia bellirica as reducing agent. Swelling kinetics and equilibrium swelling behavior of the TMGA hydrogels have been investigated in various pH environment the maxium % equilibrium swelling behavior observed i.e., 2882±1.2. The synthesized hydrogels and silver nanocomposites have been characterized by the UV, FTIR, XRD, SEM and TEM. TMGA and TMGA-Ag hydrogels have been investigated to study the characteristics of drug delivery and antimicrobial study. Doxorubicin hydrochloride, a chemotherapeutic agent successfully encapsulated with maximum encapulstaion efficiency i.e., 69.20±1.2 and performed in vitro release studies in pH physiological and gastric environment at 37 ℃. The drug release behavior is examined with kinetic models such as zero order, first order, Higuchi, Hixson Crowell, Korsmeyer-Peppas. These release data was the best fitted with the Korsemeyer-Peppas transport mechanism with n=0.91. Treatment effect on HCT116 Cell, human colon cancer cells were assessed with cell viability and cell cycle analysis. Antimicrobial activity of TMGA-Ag hydrogels is studied against to Staphylococcus aureus and Klebsiella pneumonia. Finally, the results demonstrate that TMGA and TMGA-Ag are promising candidates for anti-cancer drug delivery and inactivation of pathogenic bacteria, respectively.

Porifera, commonly referred to as marine sponges, have stood out as major producers of marine natural products (MNPs). Sponges of the genus Phorbas have attracted much attention along years. They are widespread in all continents, and several structurally unique compounds have been identified from species of this genus. Terpenes, mainly sesterterpenoids, represent the great majority of secondary metabolites isolated from Phorbas species, even though several alkaloids and steroids have also been reported. Many of these compounds have shown a variety of biological activities. Particularly, Phorbas sponges have been demonstrated to be a source of cytotoxic metabolites. In addition, MNPs exhibiting cytostatic, antimicrobial and anti-inflammatory activities, have been isolated and structurally characterized. This work brings an overview of Phorbas secondary metabolites reported since the first study published in 1993 until 2020, and their biological activities.

Oxidative stress initiates and facilitates the disruption of the structural integrity of hepatic mitochondria, which leads to steatosis, steatohepatitis, fibrosis, and cirrhosis. It is now evident that mitochondrial dysfunction could be responsible for alcoholic liver disease (ALD). The challenge in treating ALD has been the limited availability of hepatoprotective agents and the lack of highly efficient delivery systems. Recent studies have shown that mitochondria-targeted therapies could address mitochondrial dysfunction (MD), which may greatly improve hepatoprotection and ALD treatment. This mini-review discusses the potential role of mitochondria-targeted antioxidants (MTAs) in the maintenance of hepatocellular integrity. This report also considers the mechanism of liver injury induced by alcohol and the progression of ALD from a mitochondrial oxidative damage perspective as well as the possible mechanistic actions of hepatoprotective antioxidants. Preliminary studies suggest the prospect of MTAs as anti-ALD and hepatoprotective agents.

Objectives: This study was undertaken to reveal therapeutic effects and the preliminary mechanism of Chinese medicine formula Qianlie Tongli decoction (QTD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods: A total of 50 male C57BL/6 mice were randomly divided into five groups. All groups except the control group were injected subcutaneously T2 peptide emulsion, which induced the CP/CPPS model. After the induction of CP/CPPS, the model group was given 0.9% NaCl by oral gavage while low-dose, medium-dose, and high-dose groups were treated with Chinese medicine formula. Micturition habits and pain behavior of mice were analyzed for each group. Hematoxylin and eosin staining were used to investigate prostate inflammation. The serum level of tumor necrosis factor-α (TNF-α) was measured by enzyme-linked immunosorbent assay (ELISA) kit. Key findings: Chinese medicine formula significantly reduced the number of urine spots and improved pain response frequency in the medium-dose and high-dose group. The high-dose group showed reduced considerably inflammatory lesion and inflammatory cell infiltration than the low-dose and medium-dose groups. Serum levels of TNF-α in the high-dose group were significantly reduced compared with the model group. Conclusions: The results demonstrated the therapeutic effects of Qianlie Tongli decoction in CP/CPPS mice by analyzing clinically relevant symptoms (urinary tract system, pelvic pain, and prostate inflammation), and preliminary explored the inflammatory-related treatment mechanisms by measuring TNF-α.

Citrus peel has been used in Asian traditional medicine for the treatment of cough, asthma, and bronchial disorders. However, the anti-inflammatory effect of quercetogetin (QUE), a polymethoxylated flavone isolated from the peel of citrus unshui is poorly understood. We investigated the anti-inflammatory effect and the molecular mechanisms of QUE in lipopolysaccharide (LPS)-induced RAW264.7 cells. QUE inhibited the production of NO and prostaglandin E2 by suppressing the LPS-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 at both the mRNA and protein levels. QUE suppressed the production of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. QUE also inhibited the translocation of the nuclear factor kappa B subunit, p65, into the nucleus by interrupting the phosphorylation of IκB-α in LPS-induced RAW 264.7 cells. Based on the finding that QUE significantly decreased p-ERK protein expression in LPS-induced RAW264.7 cells, we confirmed that suppression of the inflammatory process by QUE was mediated through the MAPK pathway. This is the first report on the strong anti-inflammatory effects of QUE, which is a compound that can potentially be used as a therapeutic agent for inflammatory diseases.

The aim of the study was to determine the possibility of suppression of the prostaglandin synthesis by new derivatives of N-phenylanthranilic acids; they inhibit the activity of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme using the method of a flexible molecular docking. For the docking studies the crystallographic structural models with high resolution from Protein Data Bank were used: mPGES-1 in the complex with glutathione (pdb code 4AL0). A flexible molecular docking was carried out using the Molecular Operating Environment (MOE) software package. According to the results of the docking studies four scoring functions were calculated (Affinity dG Scoring, Alpha HB Scoring, London dG Scoring, GBVI/WSA dG Scoring). The values of the scoring functions calculated indicate the thermodynamic probability and energy favorability of forming complexes between molecules of the substances under research and the specified receptor, in which arrangement of ligands in the active site of the receptor and residues of amino acids of side chains are of similar geometry and types of binding of the known inhibitors of mPGES-1 determined on the basis of the crystallographic studies.

From the aerial parts of Salvia ballotiflora, eleven diterpenoids were isolated, among them, four icetexanes, and one abietane (1–5), which are first reported. Their structures were established by spectroscopic means, mainly ¹H and ¹³C NMR, including 1D and 2D homo- and hetero-nuclear experiments. Most of the isolated diterpenoids were tested for their antiproliferative, anti-inflammatory, and radical scavenging activities using the sulforhodamine B assay on six cancer cell lines, the TPA induced ear edema test in mice, and the reduction of the DPPH assay, respectively. Some diterpenoids showed anti-proliferative activity, these being icetexanes 6 and 3, which were the most active with IC₅₀ (µM) = 0.27 ± 0.08 and 1.40 ± 0.03, respectively, for U251 (human glioblastoma) and IC₅₀ (µM) = 0.0.46 ± 0.05, and 0.82 ± 0.06 for SKLU-1 (human lung adenocarcinoma), when compared with adriamycin (IC₅₀ (µM) = 0.08 ± 0.003, and 0.05 ± 0.003, as the positive control, respectively. Compounds 3 and 10 showed significant reduction of the induced ear edema of 37.4 ± 2.8 and 25.4 ± 3.0% (at 1.0 µmol/ear), respectively. Compound 4 was the sole active diterpenoid in the antioxidant assay (IC₅₀ = 98. 4 ± 3.3), using α-tocopherol as positive control, IC₅₀ (µM) = 31.7 ± 1.04. The diterpenoid profile found is of chemotaxonomic relevance and reinforces the evolutionary link of S. ballotiflora with other members of the section Tomentellae.

High pressure crystallization technique has been successfully used to prepare an elusive form II of a non-steroidal anti-inflammatory drug, Mefenamic acid. Single crystal of form II was grown at 0.3 GPa from an 4:1 methanol/ ethanol mixture as a solvent using Diamond Anvil Cell. Comparison of crystal structures show that the efficient packing of MA molecules in Form II results from the structural flexibility of MA acid molecules. Compression studies performed on the single crystal of form I resulted in 14 % decrease of unit cell volume up to 2.5 GPa. No phase transition was observed up to this pressure. A reconstructive phase transition is required to induce conformational changes in the structure, which is confirmed by crystallization at high pressure results.

We summarize structural instabilities exhibited by the one dimensional (1D) (arene)2X family of organic conductors in relation with their electronic and magnetic properties. With a charge transfer of one electron to each anion X these salts exhibit a quarter-filled (hole) conduction band located on the donor stacks. Compounds built with donors such as fluorenthene and perylene derivatives and anions X such PF6 or AsF6 exhibit a high temperature (TP~170K) conventional Peierls transition which is announced by a sizeable regime of 1D 2kF charge density wave fluctuations (kF is the Fermi wave vector of the 1D electron gas located on Per stacks). Surprisingly, and probably because of the presence of a multi-sheet warped Fermi surface, the Peierls transition is considerably reduced in the perylene series α-(Per)2[M(mnt)2] where X is the dithiolate molecule with M=Au, Cu, Co and Fe. A special attention is devoted in this paper to physical properties of α-(Per)2[M(mnt)2] salts which with M=Pt, Pd and Ni incorporate segregated S=1/2 1D antiferromagnetic (AF) dithiolate stacks with 1D metallic Per stacks. We analyse conjointly the structural and magnetic properties of these salts in relation with the 1D spin-Peierls (SP) instability located on the dithiolate stacks. We show that the SP instability of the Pd and Ni derivatives occurs in the classical (adiabatic limit) while the SP instability of the Pt derivative occurs in the quantum (anti-adiabatic limit). Furthermore we show that in the Pd and Ni derivatives frustrated 1st neighbour direct and 2nd neighbour indirect (through a fine tuning with the mediated 2kF RKKY coupling interaction on Per stacks) AF interactions add their contribution to the SP instability to open a singlet-triplet gap. Our analysis of the data show unambiguously that magnetic α-(Per)2[M(mnt)2] salts are a typical realization of the physics predicted for two chain 1D Kondo lattices.

High-grade advanced ovarian, fallopian tube and primary peritoneal (HGAOC) cancer are malignancies in which, apart from surgical treatment, systemic treatment plays an important role. The improvement in treatment results is associated with the introduction of polyADP-ribose polymerase inhibitors (PARPis). The aim of this study is to present a cross-section of patients treated for HGAOC, in one center, including the distribution of treatment principles following the most up-to-date guidelines. We observed patients who reported to the Department of Gyneacological Oncology between January 2018 and December 2023. We analyzed 437 women with a first diagnosis of HGAOC, who had not been treated before. The introduction of combined treatment with bevacizumab and PARPi into the first line of treatment, regardless of any remnants left during cytoreductive surgery, was introduced in November 2022. Since then, 30% (18/60) of patients (14 with olaparib and 4 with niraparib) have used the above regimen. Previously, in May 2021 - October 2022, it was 27% of patients (13/81 with olaparib and 9/81 with niraparib). Among patients starting treatment in January 2018 - April 2021, only 4.7% (5/106) received the platinum + paclitaxel + olaparib regimen. In both groups – with and without BRCA1/2 pathogenic or likely- pathogenic variant, significantly more patients used PC + PARPi or PC + BEV + PARPi in periods II and III than in period I (p<0.01). The introduction of modern treatment in our center very quickly changed the structure of patient treatment. Carriers of BRCA1/2 pathogenic or likely-pathogenic variant had previously received only chemotherapy, disappeared after the introduction of PARPi, in favor of new therapies. Most patients with no BRCA1/2 pathogenic or likely-pathogenic variant, who used PARPi in therapy in our center – received niraparib and therefore they are beneficiaries of molecular diagnostics in the field of HRD.

The human scalp is a common site of skin cancer in humans, with non-melanoma skin cancer being exceedingly common. In this review, two dermatologists with extensive experience in cutaneous oncology will discuss unique features of the epidemiology of cancer of the scalp. Clinical observations on these common skin cancers lead to insight into the pathogenesis and potential prevention and treatment of cutaneous scalp neoplasia. Our hypothesis is that the presence of hair protects against the development of skin cancer, but not by serving as a physical shield, but rather by providing a continuous IL-17 biased immunosurveillance. Loss of hair allow release from immunosurveillance, resulting in expansion of neoplastic cells towards skin cancer. Both hair follicles and metabolic changes in stroma allow permissiveness for tumor promotion.

Colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide and is responsible for numerous deaths. 5-fluorouracil (5-FU) is an effective chemotherapy drug commonly used in the treatment of CRC, either as monotherapy or in combination with other drugs. However, half of CRC cases are resistant to 5-FU-based therapies. To contribute to the understanding the mechanisms underlying CRC resistance or recurrence after 5-FU-based therapies, we performed a comprehensive study integrating in silico, in vitro and in vivo approaches. We identified differentially expressed genes and enrichment of pathways associated with recurrence after 5-FU-based therapies. Using these bioinformatic data as a starting point, we selected a group of drugs that restored 5-FU sensitivity to 5-FU resistant cells. Interestingly, treatment with the novel Rac1 inhibitor, 1A-116, reversed morphological changes associated with 5-FU resistance back to a control-like status. Moreover, our in vivo studies have shown that 1A-116 affected tumor growth and the development of metastasis. All our data allowed us to postulate that targeting Rac1 represents a promising avenue for the development of new therapies for patients with CRC resistant to 5-FU-based therapies.

Reactive oxygen species (ROS) are produced during cellular metabolism and in response to environmental stress. While low levels of ROS play essential physiological roles, excess ROS can damage cellular components, leading to cell death or transformation. ROS can also regulate protein interactions in cancer cells, thereby affecting processes such as cell growth, migration, and angiogenesis. Dysregulated interactions occur via various mechanisms, including amino acid modifications, conformational changes, and alterations in complex stability. Understanding ROS-mediated changes in protein interactions is crucial for targeted cancer therapies. In this review, we examine the role that ROS mechanisms in regulating pathways through protein-protein interactions.

Ewing sarcoma (ES) is an aggressive bone and soft-tissue pediatric cancer. High vitronectin (VN) expression has been associated with poor prognosis in other cancers, and we aimed to determine the utility of this extracellular matrix glycoprotein as a biomarker of aggressiveness in ES. Silk-fibroin plus gelatin-tyramine hydrogels (HGs) were fabricated with and without cross-linked VN and cultivated with A673 and PDX73 ES cell lines for two and three weeks. VN secretion to culture media was assessed using ELISA. Morphometric analysis was applied for phenotypic characterization. VN release to culture media was higher in 3D-models than in monolayer cultures, and intracellular, intercellular and pericluster presence was also observed. A673-HGs showed lower density of clusters but a proportion of larger clusters than PDX73-HGs, which presented low cluster circularity. The cluster density of A673-HGs without added VN was higher than with added VN, and slightly lower in the case of PDX73-HGs. Furthermore, a culture time of three weeks provided no benefits in cluster growth compared to two weeks, especially in A673 -HGs. These advances in 3D modeling and digital quantification pave the way for future studies in ES and other cancers to deepen understanding about intra- and intercellular heterogeneity and anti-adhesion VN therapies.

(1) Background: We aim to construct a machine learning (ML) algorithm to predict the risk of distant metastasis (DM) of T1 and T2gallbladder cancer (GBC); (2) Demographic and clinical pathological data of T1 and T2 GBC patients were extracted from the National Institutes of Health (NIH)’s Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015 to develop seven ML algorithm models. Models were evaluated based on accuracy, precision, recall rate, F1- score, and area under the receiver operating characteristic curve (AUC); (3) Results:A total of 4371 patients were included in the study, of whom 764 (17.4%) developed DM. Multivariate logistic regression showed that age, histology, tumor size, T and N stages were independent factors in GBC with DM. A novel nomogram was established to predict distant metastasis in early T stage GBC patients. Evaluation indicators of the best model Random Forest (RF) were as follows: accuracy (0.828), recall rate (0.862), precision (0.811), F1- score (0.836), and AUC value (0.913); (4) Con-clusions: The RF model constructed in this study could accurately predict distant metastasis in GBC patients, which may provide clinicians with more personalized clinical decision-making recom-mendations.

Purpose: Inflammation and neutrophils play a central role in both Covid-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on Covid-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations. Methods: We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during Covid-19 infection. Additionally, a unicenter prospective cohort provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and severity of Covid-19 disease. Results: Prior to Covid-19, 25% of patients with cancer exhibited elevated dNLR, which increase to 55% at the time of Covid-19 diagnosis. We developed the FLARE score, incorporating both tumor and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p<0.0001). The score proved to be an independent predictor of early mortality. The prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe Covid-19 infection. Conclusions: A pre-existing tumor-induced pro-inflammatory state significantly impacts Covid-19 outcomes in patients with cancer. The FLARE score serves as an easy-to-use and worldwide accessible effective tool to predict outcomes in this population, while circulating neutrophil subpopulations might provide additional information and could help refine outcome prediction.

This study investigates the microbial composition of a commercially available Swiss fermented milk and colostrum product with a history of use in chronic condition management since 2014. The analysis, performed using the Axiom Microbiome Array, identified a high number of targets corresponding to microbial species classified as probiotics belonging to the Bifidobacteriaceae family. The array provided 28 unique targets, each corresponding to a specific microbe. Next, the amino acid sequences of beta-galactosidase and sialidase from Bifidobacteria and humans were studied because these enzymes are responsible for the production of GcMAF (Gc protein-derived Macrophage Activating Factor) from the Gc protein that is abundant in colostrum. The Bifidobacterial enzymes showed striking functional similarities with their human counterparts. In addition, the study explores the potential health benefits of this product with a focus on GcMAF and chondroitin sulfate, a glycosaminoglycan highly represented in milk and colostrum. The high concentration of specific Bifidobacteria strains contributes to these benefits through two mechanisms: enhanced GcMAF production and activation of chondroitin sulfate, which in turn exhibits GcMAF-like activity. These findings suggest that the Bifidobacteria-rich Swiss product could offer health benefits through these combined mechanisms.

Background: To evaluate derived neutrophil to lymphocyte ratio (dNLR) in predicting the prognosis of patients with locally advanced oral squamous cell carcinoma (LAOSCC), and the survival benefits from docetaxel, cisplatin, and 5-FU (TPF) induction chemotherapy (IC); Methods: Patients from a phase III trial involving TPF IC in stage III/IVA OSCC patients (NCT01542931) were enrolled. Receiver operating characteristic curves were built and area under the curve was computed to determine dNLR cutoff points. Kaplan-Meier estimates of survival and Cox proportional hazards models were used for longitudinal analysis; (3) Results: 224 patients were identified (median age, 55.4 yr; range, 26 to 75 yr; median follow-up, 90 months; range, 3.2 to 93 months); Cutoff points for dNLR was 1.555. Multivariate analysis showed dNLR was an independent negative predictive factor for survival (overall survival (OS): hazard ratio (HR) = 1.154, 95% confidence interval (CI): 1.018-1.309, P = 0.025, disease-free survival (DFS): HR = 1.123, 95% CI: 0.260-1.000, P = 0.050, local recurrence-free survival (LRFS): HR = 1.134, 95% CI: 1.002-1.283, P = 0.047, distant metastasis-free survival (DMFS): HR = 1.146, 95% CI: 1.010-1.300, P = 0.035). Low dNLR combining cTNM stage III disease predicts benefit from TPF IC for the patients [OS (χ² = 4.674, P = 0.031), DFS (χ² = 7.134, P = 0.008), LRFS (χ² = 5.937, P = 0.015) and DMFS (χ² = 4.832, P = 0.028)]; (4) Conclusions: dNLR is an independent negative predictive factor in LAOSCC patients. Patients of cTNM stage III and low dNLR can benefit from TPF IC.

Colorectal cancer (CRC), found in the intestinal tract, is initiated, and progresses through various mechanisms, including dysregulation of signalling pathways. Several signalling pathways, such as EGFR and MAPK, involved in cell proliferation, migration, and apoptosis, are often dysregulated in CRC. Although cannabidiol (CBD) has previously induced apoptosis and cell cycle arrest in vitro in CRC cell lines, its effects on signalling pathways have not yet been determined. An in silico analysis was used here to assess partner proteins that can bind to CBD and docking simulations were used to predict precisely where CBD would bind to these selected proteins. A survey of current literature was used to hypothesize the effect of CBD binding on such proteins. The results predict that CBD could interact with EGFR, RAS/RAF isoforms, MEK1/2, and ERK1/2. The predicted CBD-induced inhibition might be due to CBD binding to the ATP binding site of the target proteins. This prevents the required phosphoryl transfer to activate substrate proteins and/or CBD binding to the DFG motif, thus reducing catalytic activity.

Prostate cancer (PCa) ranks as the second most fatal and sixth most prevalent cancer among males globally. This study focuses on leveraging deep learning networks to detect the Gleason grading of prostate cancer from histopathology images stained with Hematoxylin and Eosin (H&amp;E). Six pathologists annotated the images, resulting in six distinct labels for each input image. A common ground truth label was established through majority voting approach. Subsequently, the dataset was trained using architectures: UNeT, UNeT++, DeepLabV3, DeepLabV3+, and GAN based segmentation network. Notably, GAN based network demonstrated superior performance, achieving an F1-score of 0.872 and a Jaccard Index of 0.777, outperforming the other architectures considered in this study.

Deuterium is a heavy nonradioactive isotope of hydrogen, having a neutron as well as a proton, making it twice as heavy. It is a natural element, present at 156 parts per million in seawater. The ATPase pumps in the mitochondria utilize proton motive force to drive ATP synthesis, and deuterons damage the pumps, producing a stutter that can cause reactive oxygen release and inefficiencies in ATP synthesis. Cellular metabolism incorporates several novel mechanisms to assure low deuterium content in the mitochondria and other organelles. Nicotinamide adenine dinucleotide (NAD) is a major carrier of deuterium depleted (deupleted) protons to supply the mitochondria. Many enzymes, especially flavoproteins, are able to use proton tunneling to fractionate out deuterium. In this paper, we argue that the amino acid proline is able to trap and sequester deuterium, and that peptidyl prolyl isomerases (PPIases) play a central role in facilitating deuterium trapping in proline-rich proteins, most notably collagen. The endothelial glycocalyx also sequesters deuterium in gelled water lining the blood vessels, creating a battery and promoting low deuterium in the circulation. Excess deuterium promotes cancer growth, and cancer cells release large quantities of lactate via aerobic glycolysis to help reverse deuterium overload, systemically.

A useful perioperative nutritional therapy for highly invasive esophageal cancer surgical cases needs to be developed. We clarified the usefulness of amino acid-enriched nutritional therapy using glutamine (Gln)/arginine (Arg)/calcium β-hydroxy-β-methylbutyrate (HMB) products on the short-term postoperative outcomes of minimally invasive esophagectomy for esophageal cancer. Altogether, 114 patients (Gln/Arg/HMB group) received perioperative nutritional therapy with Gln/Arg/HMB products, and we retrospectively investigated the change in nutritional parameters including skeletal muscle mass, occurrence of postoperative complications, and short-term postoperative outcomes in this group. The results were compared between the Gln/Arg/HMB and control groups (79 patients not receiving the Gln/Arg/HMB products). The incidence of all postoperative complications, sputum expectoration disorder, and pleural effusion of grade ≥III was significantly lower in the Gln/Arg/HMB group (62.0% vs. 38.6%, p = 0.001; 44.3% vs. 28.1%, p = 0.020; 27.8% vs. 13.2%, p = 0.011, respectively). The psoas muscle area and postoperative body weight was significantly higher at 1 month and 1 year after surgery in the Gln/Arg/HMB group than in the control group (93.5% vs. 99.9%, p &lt; 0.001; 92.0% vs. 95.4%, p = 0.006). Perioperative amino acid-enriched nutritional therapy may improve the short-term postoperative outcomes, nutritional status, and skeletal muscle mass of esophageal cancer surgical patients.

Human epidermal growth factor receptor 2 (HER2), a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, plays a crucial role in cell proliferation, survival, and differentiation. Aberrant HER2 signaling is implicated in various cancers, particularly breast and Gastric cancer, where HER2 overexpression or amplification correlates with aggressive tumor behavior and poor prognosis. Her2 activating mutations contribute to accelerated tumorigenesis and metastasis. This review provides an overview of HER2 biology, signaling pathways, mechanisms of dysregulation, diagnostic approaches, and therapeutic strategies targeting HER2 in cancer. Understanding the intricate details of HER2 regulation is essential for developing effective targeted therapies and improving patient outcomes.

Over the past 10 years, developments in precision oncology have led to a rise in the demand for predictive tools that assist the screening and stratification of patients for treatment. The possibility digitizing tissue slide images has led to the creation of artificial intelligence (AI) and machine learning algorithms in digital pathology, which could ultimately improve patient care. In this context, we assessed a variety of AI-based computational models for digital pathology. In this review, we described the latest AI applications in oncology, current challenges and future prospects.

Liver cancer is the fourth leading cause of cancer-related death worldwide. In Mexico, there is a high burden of liver cancer mortality in rural states, which affects both women and men equally. Thus, we aimed to describe the demographic and clinical characteristics of hepatocellular cancer (HCC) by sex in Mexico. Demographic and clinical information were extracted retrospectively from the medical records of patients with HCC initially treated (2015-2022) at participating institutions of a national survey across the country. The male-to-female ratio was calculated at the national and regional levels and the results were stratified by sex. Among 697 HCC patients, the age at diagnosis was 65.4±11.9y and 20% were diagnosed at ≥75y. The male-to-female ratio was 1.4:1, ranging from 1:1 in the northwestern and southwestern regions to 2.1:1 in the western region. The proportion of cirrhosis was similar between sexes; however, the etiologies for cirrhosis differed: cryptogenic cirrhosis was higher in women and alcohol consumption was higher in men. Men had a higher proportion of advanced HCC, poor/undifferentiated tumors, and ≥4 nodules than women. HCC in the Mexican population affects men and women at a 1.4:1 male-to-female ratio. This unique proportion by sex could be explained by the differences in the prevalence of risk factors across our heterogeneous country.

This study investigated a novel radioimmunotherapy strategy for targeting tumor angiogenesis. We developed a radiopharmaceutical complex by labeling an anti-adenosine triphosphate syn-thase (ATPS) monoclonal antibody (mAb) with the radioisotope 177Lu using DOTA as a chelating agent. 177Lu-DOTA-ATPS mAb demonstrated high labeling efficiency (99.0%) and stability in se-rum. MKN-45 cancer cells exhibited the highest cellular uptake, which could be specifically blocked by unlabeled ATPS mAb. In mice, 177Lu-DOTA-ATPS mAb accumulated significantly in tumors, with a tumor uptake of 16.0 ± 1.5%ID/g on day 7. 177Lu-DOTA-ATPS mAb treatment sig-nificantly reduced the viability of MKN-45 cells in a dose-dependent manner. In a xenograft tumor model, this radioimmunotherapy strategy led to substantial tumor growth inhibition (82.8%). Furthermore, combining 177Lu-DOTA-ATPS mAb with sunitinib, an anti-angiogenic drug, en-hanced the therapeutic efficacy of sunitinib in the mouse model. Our study successfully developed 177Lu-DOTA-ATPS mAb, a radioimmunotherapy agent targeting tumor blood vessels. This ap-proach demonstrates significant promise for inhibiting tumor growth, both as a single therapy and in combination with other anti-cancer drugs.

Kisspeptin, a key neuropeptide derived from the KISS1 gene, is renowned for its critical role in regulating the hypothalamic-pituitary-gonadal axis and reproductive hormone secretion. Beyond its primary function in reproductive biology, emerging research has illuminated its influence in various cancers, mediating significant effects through its interaction with the G-protein coupled receptor, Kisspeptin receptor. This interaction has been implicated in modulating cellular pro-cesses such as proliferation and metastasis, making it a potential target for therapeutic interven-tion. Our study initially screened ten kisspeptin-10 analogs through cytotoxic effects of kisspep-tin-10 (KP10) and its analogs in several cancer types, including cervical, prostate, breast, and gastric cancers, with a particular focus on cervical cancer where the most profound effects were observed. Further exploration using kinase array assays revealed that these analogs specifically alter key kinases involved in cancer progression. Migration assays demonstrated a substantial decrease in cell motility, and Bioluminiscence Resonance Energy Transfer assays confirmed these analogs strong interactions with the kisspeptin receptor. Overall, our results indicate that these KP10 analogs not only hinder cervical cancer cell proliferation but also curtail migration through targeted modulation of kinase signaling, suggesting their potential as therapeutic ayfgents in managing cervical cancer progression. This comprehensive approach underscores the therapeutic promise of exploiting kisspeptin signaling in cancer treatment strategies.

This longitudinal study aimed to analyze the effects of a team rowing-based training program on physical fitness and anthropometric parameters in female breast cancer survivors (n=40; 56.78±6.38 years). Participants were divided into two groups: one rowed in fixed seat rowing (FSR) boats (n=20; 56.35±4.89 years) and the other in sliding seat rowing (SSR) boats (n=20; 57.20±7.7 years). Both groups engaged in two 75-minute sessions per week for 24 weeks. Significant improvements were observed in both groups in terms of weight (FSR: -1.93 kg, SSR: -1.75 kg), body mass index (FSR: -0.73 kg/m², SSR: -0.67 kg/m²), waist circumference (FSR: -2.83 cm, SSR: -3.66 cm), and hip circumference (FSR: -2.02 cm, SSR: -2.88 cm). Muscle strength improved in lower extremities (jump test: FSR: 2.99 cm, SSR: 3.11 cm) and upper extremities (dominant: FSR: 4.13 kgf, SSR: 4.34 kgf; non-dominant: FSR: 3.67 kgf, SSR: 3.32 kgf). Aerobic capacity also improved, with the SSR group showing a greater increase (FSR: 63.05 m, SSR: 93.65 m). Flexibility tests revealed better results in the SSR group for both dominant (SSR: 1.75 cm vs. FSR: -5.55 cm) and non-dominant limbs (SSR: 1.72 cm vs. FSR: -3.81 cm). These findings suggest that the type of rowing modality can influence physical fitness outcomes, with the SSR group showing superior improvements compared to the FSR group.

Background: Colorectal cancer (CRC) patients experienced multiple chemotoxicity affecting treatment compliance, survival, and quality of life (QOL). Prior research shows clinician-reported chemotoxicity (i.e., grading scales or diagnostic codes) predicts rehospitalization and cancer survival. However, a comprehensive synthesis of clinician-reported chemotoxicity is still lacking. Objectives: We conducted a systematic review and meta-analysis to determine the chemotoxicity's prevalence and risk factors in CRC. Methods: A systematic search from 2009 to 2024 yielded 30 studies for review, with 25 included in the meta-analysis. Results: Pooled prevalences of overall, non-hematological, and hematological moderate-to-severe toxicities were 45.7%, 39.2%, and 25.3%, respectively. The most common clinician-reported chemotoxicities were gastrointestinal (GI) toxicity (22.9%) and neuropathy or neutropenia (17.9%). Significant risk factors at baseline were malnutritional status, frailty, impaired immune or hepato-renal functions, short telomere lengths, low gut lactobacillus levels, age, female sex, aggressive chemotherapy, and low QOL. Age was associated with neutropenia (β: -1.44) and GI toxicity (β:1.85) (Ps 65 y.o.) had higher prevalences of overall (OR: 1.14) and GI (OR: 1.65) toxicities, but a lower prevalence of neutropenia (OR: 0.65) than younger adults (Ps

Background: Ultraviolet (UV) radiation from the sunlight can harm skin cells, causing short-term effects, such as sunburns and long-term effects, such as pigmentation changes, changes in the skin's immune responses, and increased risk of skin cancer. These conditions can be largely prevented with proper sun protection measures and behavioural changes. This study aims to assess the knowledge on sun protection behaviour and baseline knowledge of medical students from the “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania. Methods: Data in this cross-sectional study were collected through a Google Forms questionnaire, which was distributed from November 2023 to December 2023 via digital communication channels to students across all academic years. STROBE guidelines were consulted for data synthesis; Results: A total of 668 stu-dents responded. The student cohort demonstrated a commendable level of awareness of the risks associated with sun exposure and the advantages of employing sun protection factor (SPF); how-ever, the incidence of sunburns remained notably elevated (72.3%). Further analysis revealed cor-relations among gender, academic year, presence of photosensitizing conditions, and adherence to SPF application. Additionally, there is a need to improve understanding of the appropriate appli-cation techniques for SPF, as only 11.5% of the students exhibited proficiency in this regard; Con-clusions: As future healthcare providers, medical students hold significance in promoting healthy behaviours in the broader community. This study indicates that while their knowledge about sun protection is satisfactory, there is scope for enhancement.

Epidemiological studies point cholesterol as a possible key factor for both prostate cancer incidence and progression. So, it could represent a targetable metabolite as the most aggressive tumors also appear to be sensitive to therapies designed to decrease hypercholesterolemia, such as statins. However, whether and how cholesterol, through its dietary uptake and its metabolism, could be important for early tumorigenesis, remains unknown. Oncogene clonal induction in Drosophila melanogaster accessory gland allows to reproduce tumorigenesis from initiation to early progression, where tumour cells undergo basal extrusion to form extra-epithelial tumors. Here we show that these tumors accumulate lipids, and especially esterified cholesterol, as in human late carcinogenesis. Interestingly, high cholesterol diet displays limited effect on accessory gland tumorigenesis. On the contrary, cell-specific downregulation of cholesterol uptake, intracellular transport or metabolic response, impairs the formation of such tumors. Furthermore, in this context, high cholesterol diet suppresses this impairment. Taken together, these results reveal that during early tumorigenesis, tumour cells strongly increase their uptake and use of dietary cholesterol to specifically promote the step of basal extrusion. Interestingly, expression data from primary prostate cancer tissues indicate an early signature of redirection from cholesterol de novo synthesis to uptake. Altogether, these results suggest by which mechanism reduction of dietary cholesterol could lower the risk and slow down the progression of prostate cancer.

Background: Malnutrition commonly affects patients with oral squamous cell carcinoma (OSCC), which contributes to worsening prognosis. Moreover, specific strategies for diagnosing and managing malnutrition in OSCC are lacking. Methods: This retrospective study included 52 consecutive patients with OSCC who underwent surgery at the University Hospital of Palermo (I) from Jan 2020 to May 2023. In-hospital nutritional support was provided by a dedicated team. The patients were compared with a historical control group of 11 patients. The nutritional treatment consisted of standard oral (ON) or artificial nutrition (AN). Traditional measurements, including bioimpedance-derived body composition and volumetric reconstruction of the posterior paraspinal muscles at the C3 level based on magnetic resonance imaging (MRI-C3), were obtained in 16 patients to investigate sarcopenia. Results: The patients were categorized according to TNM stage: groups A (TNM stages I-III) and B (IVa-IVc). The prevalence of group A patients was 59.6% in the case group and 90.9% in the control group (P

Limb-salvage surgery is the first choice for treatment of primary or metastatic bone tumors when possible to perform. Rehabilitation plays a major role after surgery, with the aim of improving function and maintaining the highest possible quality of life. Megaprostheses are currently the most frequent type of limb reconstruction used to treat the bone defect after tumor resection and The Modular Universal Tumor And Revision System (MUTARS®)is currently among the most used tumor and revision systems. Several studies have evaluated the causes and rate of failure of this system, but only few studies investigated the rehabilitative outcomes in terms of function and quality of daily life. The aim of this narrative review is to explore the correlations between functional outcomes and quality of life after implant of MUTARS® prostheses surgery in patients with bone tumor of the lower extremities. A comprehensive search was conducted on PubMed and Scopus using the following MESH terms: “MUTARS”, “Megaprosthesis”, “bone”, “tumors”, “metastasis”, “lower limb”, “rehabilitation”, “outcome”, “quality of life”, and 12 studies were included. The most frequent oncological pathology was found to be primitive bone tumors treated with modular prosthesis. Outcome measures used were Henderson et al classification, HHS, MSTS, VAS, ROM,LSR, KPS and quality of life questionnaire. Reconstruction of the lower limbs with the MUTARS® system seemed to be a valid treatment option after bone tumor resection. Rehabilitation after MUTARS® surgery is very relevant, but currently, functional and rehabilitative outcomes are inadequately represented in the literature. Therefore, further studies are needed to define best rehabilitation protocols in clinical practice after oncological orthopedic surgery.

Introduction: The World Health Organization (WHO) recommends visual inspection with acetic acid (VIA) for cervical cancer screening (CCS) in lower-resource settings; however, quality varies widely, and it is difficult to maintain a well-trained cadre of providers. The Smartphone-Enhanced Visual Inspection with Acetic acid (SEVIA) program was designed to offer secure sharing of cervical images and real-time supportive supervision to health care workers providing screening in semirural Tanzania, in order to improve quality and accuracy of visual assessment of the cervix for treatment. The purpose of this evaluation was to document early learnings from patients, providers, and higher-level program stakeholders, on barriers and enablers to program implementation. Methods: From September 9th to December 8th, 2016, observational activities and open-ended interviews were conducted with image reviewers (n= 5), providers (n=17), community mobilizers (n=14), patients (n=21), supervisors (n=4) and implementation partners (n=5) involved with SEVIA. Sixty-six interviews were conducted at 14 facilities, in all 5 of the program regions. Results SEVIA was found to be a highly regarded tool for the enhancement of CCS services in Northern Tanzania. Acceptability, adoption, appropriateness, feasibility, and coverage of the intervention were highly recognized. It appeared to be an effective means of improving good clinical practice among providers and fit seamlessly into existing roles and processes. Barriers to implementation included network connectivity issues, and community misconceptions and adoption of CCS more generally. Conclusion: SEVIA is a practical and feasible mobile health intervention and tool that easily integrated into the National CCS program to enhance quality of care. With the introduction of HPV DNA testing as a primary screening strategy for cervical cancer prevention in settings such as Tanzania, the role of a mobile health platform for program surveillance, tracking follow-up care, and quality assurance of visual assessment of the cervix for treatment (in women who test positive for high-risk HPV) further supports the importance of programs, such as SEVIA, in low resource contexts. Further expansion of the program, especially to rural areas where screening providers can benefit from virtual support for screening services through the use of the mobile App, could strengthen the delivery of services within the national cervical cancer prevention program.

The evaluation of nanostructured biomaterials and medicines is associated with 2D cultures that provide insight into the biological mechanisms at the molecular level, while critical aspects of the tumor microenvironment (TME) are provided by the study of animal xenograft models. More realistic models that can histologically reproduce human tumors are provided by tissue engineering methodologies of co-culturing cells of varied phenotypes, to provide 3D tumor spheroids that recapitulate the dynamic TME in 3D matrices. The novel approaches of 3D tumor models are combined with tumor tissue engineering (TTE) scaffolds including hydrogels, bioprinted materials, decellularized tissues, fibrous and nanostructured matrices. This review focuses on the use of nanostructured materials in cancer therapy and regeneration, and the development of realistic models for studying TME molecular and immune characteristics. Tissue regeneration is an important aspect of TTE scaffolds for restoring the normal function of the tissues, while providing cancer treatment. Thus, this article reports recent advancements on the development of 3D TTE models for antitumor drug screening, studying of tumor metastasis, and tissue regeneration. Also, this review identifies the great opportunities of 3D TTE scaffolds in the evaluation of the immunological mechanisms and processes involved in the application of immunotherapies.

Intrinsic subtype of triple-negative breast cancer (TNBC) is based on genomic evaluation. In this study, we report the survival and pathological complete response (pCR) rates of TNBC patients subtyped by IHC and treated with neoadjuvant chemotherapy (NACT). A retrospective cohort of 187 TNBC patients who received NACT between 2008 and 2017 was used, and IHC subtyping was performed on biopsy specimens before chemotherapy. The subtyping revealed predominant basal-like tumors (IHC-BL, 61%), followed by basal-like immune-suppressed (IHC-BLIS, 31%), mesenchymal tumors (12.5%), luminal androgen receptor tumors (IHC-LAR, 12%) and basal-like immune-activated (IHC-BLIA, 10.9%). The pathological complete response (pCR) rate varied among subtypes, with IHC-BLIA showing the highest (30.0%) and IHC-LAR showing the lowest (4.5%). IHC-BLIS led in recurrence sites. Overall and disease-free survival analyses did not show significant differences among subtypes. Although, IHC-BLIA demonstrated a trend toward better survival and IHC-mesenchymal worse. Patients who achieved pCR exhibited significantly better disease-free survival and overall survival than non-responders. This study underscores the potential of IHC-based subtyping in TNBC management, highlighting distinct response patterns to neoadjuvant chemotherapy and potential implications for treatment strategies. Further research is warranted to validate these findings and explore tailored therapeutic approaches for specific TNBC subtypes.

The G-protein-coupled estrogen receptor (GPER; G protein-coupled estrogen receptor 30, also known as GPR30) is a novel estrogen receptor and has emerged as a promising target for ovarian cancer. GPER, a seven-transmembrane receptor, suppresses cellular viability and migration in studied ovarian cancer cells. However, its impact on the fallopian tube, which is the potential origin of high-grade serous (HGSC) ovarian cancer, has not been addressed. This study was conducted to evaluate the relationship of GPER, ovarian cancer subtypes, i.e., high-grade serous cell lines (OV90 and OVCAR420), as well as potential HGSC ovarian cancer origin (i.e., the fallopian tube cell line FT190). The selective ligand assessed here is the agonist G-1, which was utilized in an in vitro study to characterize its effects on cellular viability and migration. As a result, this study has addressed the effect of a specific GPER antagonist in combination with an agonist on cell viability, providing a better understanding of the effects of these compounds on our diverse group of studied cell lines. Strikingly, attenuated cell proliferation and migration behaviors were observed in the presence of G-1. Thus, our in vitro study reveals the impact of the origin of HGSC ovarian cancers and highlights the GPER agonist G-1 as a potential therapy for ovarian cancer.

Lung cancer remains the main cause of global cancer-related deaths. Currently low-dose computed tomography (LD-CT) shows a 20% reduction of mortality. However, its clinical suitability is hindered by cost, radiation, and some false positives. Thus, the discovery non-invasive and less-expensive biomarker is urgent needed. In this scenario, proteins released in biological fluids could be considered interesting biomarkers for their role in cancer development. We conducted a pioneering case-control pilot study aimed at assessing the usefulness of Raf Kinase Inhibitory Protein (RKIP) and its phosphorylated form (pRKIP) as potential early-stage lung cancer biomarkers. Urine and Blood samples of two consecutive and independent cohorts of lung cancer patients and healthy controls were screened by means of a novel experimental ELISA assay designed to evaluate both forms of the biomarker. Although urinary levels of RKIP were not statistically different between the lung cancer group and high-risk healthy group, serum ones instead increased significantly in early stage LC patients and permitted to discriminate LC patients from both low-risk (HS) and high-risk healthy subjects (HR-HS) with an overall 93% accuracy (AUC 0.93) when LC was compared to HS and 74% (AUC 0.73) when it was compared to high-risk group. Of note, the analysis of RKIP/pRKIP ratio also showed a high accuracy (90% - AUC 0.95) in discriminating LC patients from HS and more importantly, it allowed to identify LC patients compared to HR-HS, with a higher accuracy (79% - AUC 0.79) than RKIP alone. We hypothesize that serum RKIP levels may be correlated to the activation of the immune systems against the tumor during the first phases of its development. Our study identified a preliminary, non-invasive, RKIP and pRKIP profile able to discriminate with high specificity and sensitivity the early-stage lung cancer patients from high-risk Healthy Subjects. These results, although preliminary, suggest the utility of measuring RKIP/pRKIP as potential new screening test for lung cancer and provide the basis for future validation studies.

Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those above the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult’s fitness level are reviewed in the neoadjuvant, surgical, adjuvant and metastatic settings of colon and rectal cancers. Immunotherapy is shown as an effective option treatment in older adults that have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field.

Mast cells are tissue-resident immune cells distributed in all tissues and strategically located close to blood and lymphatic vessels and nerves. Thanks to the expression of a wide array of receptors, mast cells act as tissue sentinels, able to detect the presence of bacteria and parasites and to respond to different environmental stimuli. Mast cells originate from bone marrow progenitors that enter the circulation and mature in peripheral organs under the influence of microenvironment factors, thus differentiating in heterogeneous tissue-specific subsets. Even though mast cell activation has been traditionally linked to IgE-mediated allergic reactions, a role for these cells in other pathological conditions including tumor progression has recently emerged. However, several aspects of mast cell biology remain to be clarified. The advent of single-cell RNA sequencing platforms has provided the opportunity to understand mast cell origin and differentiation as well as the phenotype and functions within different tissues, including the gut. This review recapitulates how single cell transcriptomic studies provided insight into mast cell development as well as into the functional role of intestinal MC subsets in health and disease.

Severe cancer pain significantly diminishes patients' quality of life, leading to increased reliance on caregivers. Although opioid analgesics are effective, they may induce opioid-induced bowel dysfunction (OIBD) with symptoms such as nausea, vomiting, drowsiness, and constipation. While controlled-release oxycodone is a viable option, its prolonged use can lead to opi-oid-induced constipation (OIC). Addressing this, a relative novel formulation - a fixed 2:1 ratio of oxycodone and naloxone in prolonged release - aims to provide analgesia while alleviating OIC. This review critically assesses the evidence on the efficacy, safety, and patient experience of ox-ycodone/naloxone prolonged release in managing severe cancer pain, emphasizing the necessity for a targeted approach in this patient population.

Differential diagnosis of solid pancreatic lesions (SPLs) using B-mode endoscopic ultrasonography (EUS) is challenging. Detective flow imaging (DFI) offers the potential for detecting low-flow vessels in the pancreas, thus enhancing diagnostic accuracy. This study aimed to investigate DFI-EUS findings of SPLs and analyze their differential diagnostic accuracy for pancreatic cancer. This retrospective study included patients with pathologically confirmed SPLs who underwent EUS between April 2021 and June 2023. Expert endosonographers, blinded to the patients’ clinical data, evaluated images obtained through B-mode, eFLOW, and DFI-EUS. Frame rate and vessel detection sensitivity between eFLOW and DFI were compared, and diagnostic criteria for pancreatic cancer were established. This study included 104 patients, most diagnosed with pancreatic cancer. DFI-EUS demonstrated a significantly higher vessel visualization rate (96%) in SPLs compared to eFLOW (27%). Additionally, DFI showed a superior frame rate, sensitivity (99%), and accuracy (88%) in detecting pancreatic cancer, although with a modest specificity (43%). On DFI-EUS, characteristics such as hypovascular, peritumoral, or spotty vessel findings were suggestive of pancreatic cancer. DFI-EUS significantly improved the visualization of vascular structures within the SPLs, highlighting its efficacy as a diagnostic modality for pancreatic cancer.

Cancer cells require substantial amounts of energy and substrates for their metabolic hyperactivity, enabling the synthesis of new cells at the expense of healthy ones. Preliminary in vitro data suggest that a mix of free essential amino acids (EAA-mix) can promote cancer cell apoptosis by enhancing autophagy. This study aimed to confirm, both in vitro and in vivo, whether EAA intake could influence the development of colon cancer in mice. We investigated changes in cancer proliferation in CT26 cells treated with EAA-mix, and in mice fed with EAA rich modified diets (EAARD) as compared to those on a standard laboratory diet (StD). CT26 cells were injected subcutaneously (s.c.) or intraperitoneally (i.p.). After 21 days, tumors were removed and measured. In vitro data corroborated that EAA-mix impairs cancer growth by inducing autophagy and apoptosis. In vivo data revealed that mice on StD developed significantly larger (s.c.) and more numerous (i.p.) cancers than those on EAARD. EAA administration appears to influence cancer cell survival with notable anti-proliferative properties.

Pancreatic cancer stands out as one of the most lethal forms of malignancies, representing 2% of all cancer cases and contributing to 5% of cancer-related fatalities. Therefore, early detection of pancreatic cancer is crucial for enhancing treatment outcomes. Various hereditary cancer syndromes have been linked to an elevated risk of developing pancreatic cancer, suggesting potential benefits from surveillance strategies for individuals at risk. Presently, precision medicine employs PARP inhibitor therapy for pancreatic cancer patients carrying germline variants in Homologous Recombination Repair (HRR) genes. Our objective was to ascertain the occurrence of germline pathogenic/likely pathogenic variants in genes predisposing to cancer among pancreatic cancer patients. Methodologically, we analyzed 184 pancreatic cancer patients referred to our laboratory for genetic examination. Utilizing a Next-Generation Sequencing (NGS) approach, we scrutinized 52 genes implicated in hereditary cancer predisposition. Our findings revealed that 21% of the patients analyzed harbored germline pathogenic/likely pathogenic variants. Within this subset, 48% exhibited positive results in pancreatic cancer susceptibility genes, namely ATM (17%), BRCA1 (12%), BRCA2 (7%), CDKN2A (7%), and PALB2. Significantly, 64.3% of the pathogenic variants were associated with genes involved in the HRR pathway (ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCL, MRE11, PALB2, RAD50, RAD51B and RAD51C). In conclusion, our study underscores the significance of multigene genetic testing for pancreatic cancer patients, with 21% of individuals yielding findings linked to pancreatic or other cancer predisposition. Moreover, patients carried pathogenic/likely pathogenic variants in HRR genes, potentially benefiting from targeted therapies such as PARP inhibitors or platinum-based treatments.

The purpose of this longitudinal study was to determine the effects of a rowing training program on physical fitness and body composition in female breast cancer survivors (56.78 ± 6.38 years). Over six months, the participants (n=40) performed two training sessions per week for an average of 75 minutes, combining resistance and muscle strength exercises with rowing. To evaluate the impact of the program, physical fitness tests and anthropometric measurements were carried out before and after the training protocol. The results show statistically significant improvements in measures such as weight (-1.84 kg), BMI (-0.7 kg/m2), hip (-3.24 cm) and waist circumference (-2.45 cm). In addition, variables associated with physical fitness also improved including leg strength (3.04 cm), dominant handgrip strength (4.24 kgf), non-dominant handgrip strength (3.49 kgf), aerobic endurance (78.35 m) and muscle flexibility (3.96 cm). We can therefore conclude that a rowing-based exercise program is an effective strategy to improve physical fitness in this type of population, yielding improvements in both anthropometric measurements and basic physical capacity variables, essential factors for better health and quality of life.

Although a growing number of evidence emphasizes superior of VATS over conventional thoracotomy, still is little known about early postoperative diaphragm muscle function after lobectomy via these two approahces. To fill the gap in existing literature, we conducted comparative study between VATS and conventional thoracotomy in terms of postoperative diaphragm muscle function, assessing its contractility, strength, magnitude of effort and potential risk of dysfunction such as: atrophy and paralysis. A total of 59 patients (30 after VATS), who underwent anatomical pulmonary resection at our institution, were enrolled into this study. The control group was consisted of 28 health subjects without medical condition could contribute to diaphragm dysfunction. Diaphragm muscle was assessed before and after surgery using ultrasonography. We found that both surgical approaches were associated with postoperative impairment of diaphragm muscle function - compared to baseline data. Postoperative reduction of diaphragm contraction was demonstrated in all of 59 patients. In case of control group, the differences between measurements were no observed. We noted that lobectomy via thoracotomy was linked with greater percentage of patients with diaphragm paralysis or/and atrophy that VATS. Similar findings were observed in refer to diaphragm magnitude effort, as well as, diaphragm contraction strength, where minimal invasive surgery was associated with better diaphragm function parameters - in comparison to thoracotomy. Disturbance of diaphragm work was reported both at operated and non-operated side. Upper right and left lobectomy was connected with greater diaphragm function impairment than other segments. In conclusion, VATS technique seems to be less invasive than conventional thoracotomy providing a better postoperative function of a main respiratory muscle.

Evolutionary Cancer Cell Biology (ECCB) reveals that the majority of cancer hallmarks trace their origins back to the premetazoic era, approximately 2300 to 1750 million years ago. These cancer hallmarks share deep homology with the oxygen-sensitive non-gametogenic NG (Urgermline), which evolved from the common ancestor of Amoebozoan, Metazoan, and Fungi (AMF). The genes, gene modules, and gene regulatory networks of the premetazoic cell system are preserved in the ancestral genome compartment of metazoans and humans. The Urgermline serves as a blueprint for all germ and stem cell lineages, including parasitic amoebae. As observed in amoebae, DNA double-strand breaks (DSBs) manifest in the homologous recombination (HR) genes of NG germlines and stem cell lineages when exposed to specific hyperoxic conditions, referred to as AMF hyperoxia, characterized by an oxygen content exceeding 6.0%. The cells lose their stemness and differentiation potential but persist in proliferation as low-grade polyploids (4n) through defective symmetric cell division (DSCD phenotype). Genomic integrity can be restored through homotypic cell and nuclear fusion, resulting in the formation of high-grade polyploids known as multinuclear genome repair syncytia (MGRSs), or by inductive hyperpolyploidization of more than 64n, as observed in single-celled polyploid giant cancer cells (PGCCs). Interestingly, low-, middle-, and high-grade polyploidization are not exclusive to cancer. Therefore, we investigate (i) functional polyploidies that occur in healthy cells, including humans, mammals, and protists, (ii) dysfunctional polyploidies that occur in cells with impaired homologous recombination (HR) and irreparable DNA DSB defects, and (iii) the restoration of genome integrity through cyst-like and high-grade polyploidization events. Additionally, we explore dysfunction in aging stem cells, hepatocytes, and cardiomyocytes

The binding activity of various trastuzumab biosimilars versus the branded trastuzumab towards the glycosylated extracellular domain of the HER2 target in the presence of pertuzumab was in-vestigated. We employed size exclusion chromatography with tetra-detection methodology to simultaneously determine absolute molecular weight, concentration, molecular size, and intrinsic viscosity. All trastuzumab molecules in solution exhibit analogous behavior in their binary action towards HER2 regardless of the order of addition of trastuzumab/pertuzumab. This analogous behavior of all trastuzumab molecules, including biosimilars, highlights the robustness and con-sistency of their binding activity towards HER2. Furthermore, the addition of HER2 to a mixture of trastuzumab and pertuzumab leads to increased formation of high-order HER2 complexes, up to concentrations of one order of magnitude higher than in the case of sequential addition. The observed increase suggests a potential synergistic effect between these antibodies, which could enhance their therapeutic efficacy in HER2-positive cancers. These findings underscore the im-portance of understanding the complex interplay between therapeutic antibodies and their target antigens, providing valuable insights for the development of more effective treatment strategies.

Cancer, characterized by abnormal cell proliferation driven by genetic mutations, remains a significant health challenge. Tailoring effective therapies depends on factors like tumor location, grade, and stage, alongside patient condition. Leveraging Nano-carrier encapsulated drugs offers a promising avenue, as they accumulate preferentially at tumor sites, enhancing therapeutic efficacy while mitigating side effects. Polymeric Nano-carriers, with their customizable properties, further optimize drug delivery efficiency and specificity. Incorporating active targeting ligands such as antibodies, carbohydrates, peptides, folates, and aptamers-onto polymeric nanoparticle surfaces through techniques like functionalization, adsorption, and conjugation plays a pivotal role in directing therapeutic agents to tumor cells. Consequently, polymeric nanoparticles emerge as the carrier of choice for delivering drugs to various tumor types, including breast, colon, lung, prostate, liver, and spleen tumors.

Chemical combinations are believed to reduce drug toxicity, delay cancer cell growth, and achieve enhanced efficacy compared with single active drugs. This research investigated the synergistic effect of DOX and Zm-093, a new sulfonamide derivative, on improving the potential for inducing apoptosis in breast cancer (BC) cell lines. First, the Zm-093 compound was synthesized and its structure was confirmed by FT-IR and NMR. Then, the IC50 values for DOX and Zm-093 were calculated to be 1.21 and 51.24 μM, respectively. To investigate the synergistic effect, Compusyn software was utilized to calculate the combination index (CI). Different methods, including western blotting, flow cytometry, and TUNEL, were used to evaluate the potential synergistic effects of these compounds on inducing apoptosis in MCF-7 cells. Combining the indexes obtained at all concentrations revealed synergistic results. The proapoptotic proteins Bax, tBid, and caspase-3, however, increased 2.4, 3.3, and 5.7 times more than those in the control group. Flow cytometry analysis and the TUNEL method in cells treated with DOX and Zm-093 showed that apoptosis was significantly higher than in other groups. The results confirmed the synergistic effect of DOX and ZM-093 on apoptotic factors expression in MCF-7 cells.

A detailed review of the scientific literature was undertaken to examine the most recent developments in plasma processing in the field of medicine. The first part of the review includes a detailed breakdown of the different types of coatings that can be applied onto medical devices using plasma, with a specific focus on antimicrobial surfaces. The developments during 2023 in plasma deposited biocompatible, drug delivery and adhesive coatings are described and specific applications in additive manufacturing are highlighted. The use of plasma and plasma activated liquids as standalone therapeutics continues to evolve and pertinent advances in this field are described. In addition, the combination of plasma medicine with conventional pharmaceutical interventions was reviewed and key emerging trends were highlighted, including the use of plasma to enhance drug delivery directly into tissue. The potential synergies between plasma medicine and chemotherapeutics for oncology and infection treatment is a growing area and recent advancements are noted. Finally, the use of plasma to control excess antibiotics and to intentionally degrade such materials in waste streams is described.

Abstract Epithelial ovarian carcinoma (EOC) is the fifth-leading cause of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant disease to the peritoneum. EOC is poorly responsive to immune check-point inhibitors due to immunologic features including limited tumor mutational burden (TMB), poor infiltration by immune cells and active immunosuppression. Thus, novel strategies are needed to overcome the frequent lack of preexisting immunity in patients with EOC. We developed and tested an autologous dendritic cell (DC)-based vaccine (DCVAC) which has recently been shown to be safe and to significantly improve progression-free survival (PFS) in two independent randomized phase II clinical trials enrolling patients with EOC (SOV01, NCT02107937; SOV02, NCT02107950). In addition, our exploratory data analyses suggest that the clinical benefits of DCVAC were more pronounced in patients with EOC with lower than-median TMB and scant CD8+ T cells infiltration. Thus, DC-based vaccine stands out as a promising clinical tool to jumpstart anticancer immunity in patients with immunologically „cold“ EOC. Our findings underscore the need for personalized immunotherapy and clinical relevance of potential tumor-related biomarkers within immunotherapy field. Additional clinical trials are needed to address these strategies as well as the potential value of TMB and immune infiltrate at baseline as biomarkers to guide the clinical management of EOC.

Inappropriate expression of histone deacetylase (HDAC6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway are common aberrations observed in cancers. LASSBio-2208, was previously described as a dual inhibitor in the nanomolar range of HDAC6 and PI3Kα, being three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its DMPK in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on MCF-7 (IC50 = 23 µM), CCRF-CEM (IC50 = 8.54 µM) and MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on hPBMC. In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by PAMPA-GIT and low permeation through the blood-brain barrier by PAMPA-BBB, exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentration corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells.

Expression of miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA. In addition, expression of tumor suppressor gene RECK is associated with miR-21 overexpression in high-grade cervical lesions. In the present study we analyze the role of miR-21 in RECK gene regulation in cervical cancer cells. To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression using siRNAs. We analyzed the expression of miR-21 and RECK, as well as functional effects on cell proliferation and migration. We found that in cervical cancer cells there was an inverse correlation between miR-21 expression and RECK mRNA and protein expression. SiRNAs to miR-21 increased luciferase reporter activity in construct plasmids containing the RECK-3′-UTR microRNA response elements MRE21-1, MRE21-2, and MRE21-3. The role of miR-21 in cell proliferation was also analyzed and cancer cells transfected with siRNAs exhibited a markedly reduced cell proliferation and migration. Our findings indicate that miR-21 post-transcriptionally down-regulates the expression of RECK to promote cell proliferation and cell migration inhibition in cervical cancer cell survival. Therefore, miR-21 and RECK may be potential therapeutic targets in gene therapy for cervical cancer.

The flavonoid silymarin (SMN) has been widely used in preclinical and clinical studies to treat various types of cancer, either alone or in combination with chemotherapy agents. Herein, we investigated the therapeutic efficacy of SMN and its combination with capecitabine (CAP) and irinotecan (IRI) in a mouse model of colon cancer. A modified diet supplemented with SMN (2500 ppm) with mono- and combined therapy of CAP and IRI were used following 1, 2 dimethylhydrazine (DMH)-induced colon cancer. The lipid profile, liver function tests, and cytokine levels were measured. Additionally, the lipid peroxidation and inflammation indices as well as the antioxidant activities were examined. Eventually, western blotting analysis for colonic BAX and Bcl-2 levels and histopathological examination of colon sections were carried out. SMN alone and in combination with the chemotherapeutic agents could attenuate the DMH-induced hyperlipidemia and elevated liver function enzyme levels. SMN supplementation with chemotherapy agents could also improve antioxidant activity and reverse the elevated levels of lipid peroxidation and inflammatory markers. Furthermore, significant upregulation of BAX and downregulation of Bcl-2 were observed. Besides, carcinogen-induced polyp multiplicity, dysplastic, and inflammatory changes were ameliorated considerably by treatment regimens. Our results showed that the potential anticancer properties of SMN could enhance the therapeutic effects of chemotherapy agents and reduce hepatotoxicity.

Muscle-enriched A-type lamin-interacting protein (MLIP) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53, and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP's involvement in pro-survival pathways and its potential implications in cancer cells' metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP's potential impact on cancer biology and contribute to developing innovative therapeutic strategies.

Studies at the molecular, systemic, and epidemiological levels have shown that chronic metal exposure is linked to significant health consequences, including cancer, affecting hundreds of millions worldwide. Subtle and convoluted mechanisms underline metals' toxicity and carcinogenicity. The use of sensors for carcinogenic metals' trace detection is on the rise due to their selectivity, simplicity, and affordability. Biotechnology and microelectronics in the development of sensors have grown complementarily in recent years. This study offers a comprehensive overview of current research and advancements in developing sensors for detecting carcinogenic metals. Here, we have focussed on the developed biosensor platforms for group 1 carcinogens, i.e., arsenic, nickel, cadmium, chromium, and beryllium, along with their brief roles in human carcinogenesis. This review also looks at the importance of sensing such metal exposure in humans from a larger perspective, hoping to influence future research toward early prevention and treatment of illnesses like cancer.

Background: Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC) and inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1ß and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. Design, Setting, and Participants: The study included two independent cohorts of n=92 and n=102 patients who underwent radical cystectomy for BC. Specimen from BC and benign urothelium (n=22 and n=39) were processed to a tissue microarray and immunohistochemically stained for IL-1ß, IL-1RA, AKT and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. Outcome measurements and statistical analysis: Association with outcome was assessed using Wilcoxon Kruskal-Wallis tests, Chi-square tests or linear regression, dependent on the variable’s category. Kaplan–Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Results: Both, IL-1ß and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p&lt;0.005). IL-1ß was associated with vascular invasion (210 vs. 183, p&lt;0.02), lymphatic invasion (210 vs. 180, &lt;0.05) and G3 cancer (192 vs. 188, &lt;0.04). Survival analysis revealed favorable RFS, CSS, and OS in case of high IL-1ß expression (p&lt;0.02, &lt;0.03 and &lt;0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1ß expression on RFS, CSS and OS. IL-1ß and IL-1ß/IL-1RA ratio were positively correlated to AKT expression (p&lt;0.05 and &lt;0.01, respectively). Additionally, high expression of Ki-67 (&gt;15%) correlated with higher levels of IL-1β (p=0.01). Conclusions: Overexpression of IL-1ß and IL-1RA is frequently found in BC, with a prognostic significance observed for IL-1ß protein expression. The observed link between the IL-1ß / IL-1RA axis and AKT signaling may indicate possible autophagy activation processes beside the known tumor-promoting effects of AKT.

To investigate whether high body mass index (BMI) increases the risk of recurrence and corre-lates with higher glucose uptake in recurrent lesions in post-menopausal female patients with breast cancer. The hospital database was searched to retrieve breast cancer patients, who had undergone an [18F]FDG PET/CT scan before neoadjuvant chemotherapy and curative-intent sur-gery. BMI was calculated at the baseline [18F]FDG PET/CT scan. There was a median follow-up of 5 years after the baseline PET/CT scan to identify: recurrence in the breast (T_rec); lymph nodes (N_rec); distant locations (M_rec). Furthermore, SUVmax was measured in the sites of recur-rence. A chi-square test was used to investigate any difference in the frequency of any recur-rence, T_rec, N_rec, and M_rec between overweight women (BMI≥25 kg/m2) and women with a BMI<25 kg/m2 (p<0.05). SUVmax, was compared using a t-test (p<0.05) between the two groups. A total of post-menopausal 142 women (BMI: 26.84±5.59; 84 overweight and 58 with normal weight) were retrieved. There were 48 recurrences at the follow-up. The chi-square test demon-strated in overweight women an increased frequency of any recurrence (35 vs. 13; p=0.025) and T_rec (15 vs. 2; p=0.018) and a higher T_rec SUVmax (4.74±2.90 vs. 1.85 ± 0.63; p=0.09) compared to women with a BMI<25 kg/m2. BMI seems to correlate with an increased rate of recurrence, espe-cially in the breast, and a higher glucose uptake in post-menopausal patients with recurrent breast cancer.