We present the case of a 35-year-old male with first degree family history of gastric cancer (father diagnosed at the age of 45), that was presumed to have gastric cancer himself when evaluating the features of his upper endoscopy performed after hematemesis. Surprisingly, no cancer cells were found in the biopsies. Thanks to a different diagnostic suspicion subsequent to performing a full clinical history, a more favorable diagnosis was reached: gastric syphilis.

It is highly likely that the wearing of face masks reduces the rate of respiratory infections (e.g. SARS-CoV-2), to protect both the user and those around them. This paper sets out to review the areas that effect the efficacy of masks, the materials, design, hygiene and fit testing, in order to make recommendations as to how to make mask from resources found in most homes for when commercial models are unavailable. This paper finds that a mask constructed with a filter made from high thread count cotton is likely to provide a reasonable level of protection (~70% filtration) and that if a layers of other materials such as chiffon or silk is added the filtration may be much higher (~90%). There is also some promise in less available materials such as vacuum cleaner bags and air conditioner filters. Examples of fabric and rigid designs are reviewed but most are limited by the fit to the users which is hard to determine in a home setting. It would be extremely helpful if a method was devised for people to test or be tested for the fit of home made masks. In the mean time careful thought should be given to whether the user judges a good fit. Users should also be careful to practice other means of hygiene and distancing.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track response to therapy, and parse causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).

Precision agriculture (PA) is a holistic, sustainable, innovative systems approach that assists farmers in production management. Adopting PA could improve sustainable food security and community economic sustainability. Developing an understanding of PA adoption attributes is needed to assist extension practitioners to promote adoption and better understand the innovation adoption phenomena. A systematic review of literature was conducted to investigate PA adoption. Thirty-three publications were examined, and four themes were found among the reviewed publications. The results were interpreted using Rogers’ diffusion of innovations framework to address the research objectives. Of the reviewed literature, we found relative advantage and compatibility were two dominant attributes to strengthen the adoption of PA, and the complexity attribute was rarely used to promote the adoption of PA. This study shows that change agents do not fully use five attributes of innovation when they promote PA technology to stakeholders to adopt. Thus, we recommend studies from the agricultural extension specialists’ perspectives in the future may determine contributions to motivate farmers’ adoption of PA, in particular related to complexity.

Gene regulation is vital for cellular function and homeostasis, involving diverse mechanisms controlling specific gene products and contributing to tissue-specific gene expression. Dysregulation leads to diseases, emphasizing the need for understanding these mechanisms. Non-coding regions, notably enhancers and super-enhancers (SEs), act as crucial gene regulators, orchestrating transcriptional activity via transcription factors (TFs). SEs, with high activity, are pivotal in cell identity and disease progression. Current computational approaches focus on individual regulators like TFs and miRNAs, neglecting SE interactions. We emphasize incorporating SEs into models to enhance understanding. Experimental studies have recently linked miRNAs and TFs to SEs. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) provides valuable SE information. In this review, we categorize computational methods leveraging TF and miRNA data into three areas and explore challenges integrating enhancers/SEs. These include unraveling indirect regulatory networks, identifying network motifs, and enriching pathway identification by dissecting gene regulators, including SEs. We hypothesize that addressing these challenges will enhance our understanding of gene regulation, aiding in identifying therapeutic targets and disease biomarkers. We believe that understanding the role of ChIP-Seq data in predicting the effect of miRNA on gene regulation is crucial to construct statistical/computational model that would tackle these challenges.

Gastric cancer is an aggressive disease with increasing global incidence in recent years. Human epidermal growth receptor 2 (HER2) is overexpressed in approximately 10-20% of gastric cancers. The implementation of targeted therapy against HER2 as part of the standard of care treatment in metastatic disease has improved the prognosis of this subset of patients. However, gastric cancer still has high mortality rates and urgently requires new treatment strategies. The combination of immunotherapy with HER2-targeted therapies has shown synergistic effects in preclinical models, being the rationale behind exploring this combination in clinical trials in locally advanced and metastatic settings. Additionally, the irruption of antibody-drug conjugates and other novel HER2-targeted agents has led to the development of numerous clinical trials showing promising results. This review presents the molecular mechanisms supporting the use of HER2-targeted drugs in combination with immunotherapy and provides an overview of the therapeutic scenario of HER2-positive disease. We focus on the role of immunotherapy but also summarize emerging therapies and combinations under clinical research that may change the standard treatment in HER-2 positive disease in the future.

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

This study was to identify clinical cancer biomarkers for recurrent gastric cancer survivors using artificial intel-ligence. From a hospital-based cancer registry database in Taiwan, the datasets of the incidence of recurrence and clinical risk features were included in 2476 gastric cancer survivors. We benchmarked Random forest with MLP, C4.5, AdaBoost, and Bagging algorithms on metrics and leveraged synthetic minority oversampling technique (SMOTE) for imbalanced dataset issues, cost-sensitive learning for risk assessment, and SHapley Additive ex-Planations (SHAP) for feature importance analysis in this study. Our proposed Random forest outperformed the other models with an accuracy of 87.9%, a recall rate of 90.5%, an accuracy rate of 86% and F1 of 88.2% on re-current category by a 10-fold cross-validation in a balanced dataset. We identified clinical features of recurrent gastric cancer, which are the top five features, stage, number of regional lymph node involvement, Helicobacter pylori, BMI(body mass index), and gender, which significantly affect the prediction model's output, are worth paying attention to in the following causal effect analysis. Using an artificial intelligence model, the risk factors for recurrent gastric cancer could be identified and cost-effectively ranked according to their feature importance. In addition, they should be crucial clinical features to provide physicians with the knowledge to screen high-risk patients in gastric cancer survivors as well.

Gastric cancer is a challenging public health concern worldwide and remains a leading cause of cancer-related mortality. The primary risk factor implicated in gastric cancer development is infection with Helicobacter pylori. H. pylori induces chronic inflammation affecting the gastric epithelium, which can lead to DNA damage and promotion of precancerous lesions. Disease manifestations associated with H. pylori are attributed to virulence factors with multiple activities and its capacity to subvert host immunity. One of the most significant H. pylori virulence determinants is the cagPAI gene cluster, which encodes a type IV secretion system and the CagA toxin. This secretion system allows H. pylori to inject the CagA oncoprotein into host cells, causing multiple cellular perturbations. Despite the high prevalence of H. pylori infection, only a small percentage of affected individuals develop significant clinical outcomes, while most remain asymptomatic. Therefore, understanding how H. pylori triggers carcinogenesis and its immune evasion mechanisms is critical in preventing gastric cancer and miti-gating the burden of this life-threatening disease. This review aims to provide an overview of our current under-standing of H. pylori infection, its association with gastric cancer and other gastric diseases, and how it subverts the host immune system to establish persistent infection.

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

From their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses [1]. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3 to 10% of reported cases [2-5]. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches have been taken for the treatment of BRAF mutant cancers. In this review we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.

Cancer treatment is a significant focus in medicine owing to the increasing global incidence. Patients with advanced cancers that do not respond to conventional therapies have limited options and an unfavorable prognosis. Consequently, researchers are investigating complementary approaches to conventional treatments. One such approach is alkalization therapy, which aims to neutralize the acidic tumor microenvironment (TME) by increasing its pH level. The acidic TME promotes inflammation, tumor progression, and drug resistance. Alkalization therapy has been demonstrated to be effective for various cancers. In addition, natural products, such as triterpenoids, parthenolides, fulvic acid, Taxus yunnanensis, and apple pectin have the potential to alleviate symptoms, maintain physical fitness, and improve treatment outcomes of cancer patients through their anti-inflammatory, antioxidant, and anticancer properties. In this review, we focus on the effects of alkalization therapy and natural products on cancer. Furthermore, we present a case series of advanced cancer patients who received alkalization therapy and natural products alongside standard treatments, resulting in long-term survival. We posit that alkalization therapy together with the supplementation of natural products may confer benefits to cancer patients by mitigating the side effects of chemotherapy and complementing standard treatments. However, further research is warranted to validate these clinical findings.

Advances in gastric cancer screening and endoscopic technology have made it possible to detect and treat gastric cancer at an early stage. As a result, about 40% of all gastric cancers have now been resected by endoscopic treatment in Japan. In endoscopic diagnosis, magnifying endoscopic observation using band-limited light such as narrow band imaging (NBI) has significantly improved the accuracy of gastric cancer diagnosis. At the same time, in endoscopic treatment, endoscopic submucosal dissection (ESD) has contributed to increase explosively the number of gastric cancers which could be resected endoscopically. In recent years, the construction of algorism for endoscopic diagnosis and treatment with a view to personalized medicine has been explored, and endoscopic use for gastric cancer managements is expected to develop further in the future. Keywords (5 words):

Background: Interleukin (IL)-33 is a member of interleukin (IL)-1 family of cytokines which has been linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has direct effect on human gastric epithelial cells (GES-1) and on human gastric adenocarcinoma cell line (AGS) and gastric carcinoma cell line (NCI-N87), assessing its role in regulation of cell proliferation and cell cycle, apoptosis and necrosis. Cell cycle regulation was also determined in ex vivo gastric cancer samples obtained during endoscopy and surgical procedures. Methods: cell lines and tissue samples underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assay, we also evaluated apoptosis by Caspase 3/8 Activity assay and Annexin V assays. Cell cycle were analyzed by means of Propidium Iodine assay and gene expression regulation was assessed by RT-PCR Profiling. Results: we found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell line, while it can stimulate proliferation and reduce apoptosis in normal epithelial cell line. These effects are also confirmed by the analysis of cell cycle gene expression which showed a reduced expression of proproliferative genes in cancer cells, in particular genes involved in G0/G1 and G2/M checkpoint. These results are confirmed by the gene expression analysis on surgical and bioptic specimens. Conclusions: the aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell type-dependent fashion.

Gastric Cancer (GC) is the fifth most frequently diagnosed malignant tumor and the third cause of cancer mortality worldwide. For advanced GC, a large number of novel drugs and combinations have been tested, but results are still disappointing and the disease incurable in the majority of cases. In this regard, it is critical to investigate the molecular mechanisms underlying GC development. Angiogenesis is one of the hallmarks of cancer with a fundamental role in GC growth and progression and ramucirumab, a monoclonal antibody binding to vascular endothelial growth factor-2 (VEGFR-2) is approved in the treatment of advanced and pretreated GC. However, no predictive biomarkers for ramucirumab have been identified so far. MicroRNAs (miRNAs) are a class of evolutionally conserved single-stranded noncoding RNAs playing an important role, via post-transcriptional regulation, in essentially all biologic processes such as cell proliferation, differentiation, apoptosis, survival, invasion, and migration. Notably, in our review, we focused on miRNAs involved in angiogenic pathways in GC. Moreover, we evaluated the possible prognostic and predictive role of angiogenesis-related miRNAs as novel biomarkers of GC.

Epithelial-mesenchymal transition (EMT) plays an important role in the acquisition of cancer stem cell (CSC) feature and drug resistance, which are the main hallmarks of cancer malignancy. Although previous findings have shown that several signaling pathways are activated in cancer progression, the precise mechanism of signaling pathways in EMT and CSCs are not fully understood. In this study, we focused on the intestinal and diffuse-type gastric cancer (GC), and analyzed the gene expression of public RNAseq data to understand the molecular pathway regulation in different subtypes of gastric cancer. Network pathway analysis was performed by Ingenuity Pathway Analysis (IPA). Total 2815 probe set IDs were significantly different between intestinal- and diffuse-type GC data in cBioPortal Cancer Genomics. The 10 genes including male-specific lethal 3 homolog (Drosophila) pseudogene 1 (MSL3P1), CDC28 protein kinase regulatory subunit 1B (CKS1B), DEAD-box helicase 27 (DDX27), golgi to ER traffic protein 4 (GET4), chromosome segregation 1 like (CSE1L), translocase of outer mitochondrial membrane 34 (TOMM34), YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), ribonucleic acid export 1 (RAE1), par-6 family cell polarity regulator beta (PARD6B), and MRG domain binding protein (MRGBP) were found to have difference in gene expression in intestinal- and diffuse-type GC. Total 463 direct relationships with 3 molecules (MYC, NTRK1, UBE2M) were found in the biomarker-filtered network generated by network pathway analysis. The networks and features in intestinal- and diffuse-type GC have been investigated and profiled in bioinformatics. Our results revealed the signaling pathways networks in intestinal- and diffuse-type GC, bringing new light for the elucidation of drug resistance mechanisms in CSCs.

Introduction: Gastric cancer (GC) is one of the most common cancers in the world. It is a very aggressive and heterogeneous tumor. GC does not cause symptoms, so it is often diagnosed in an advanced stage and associated with poor prognosis. Despite new treatment options, it still remains a therapeutic problem. An important element determining the method of treatment of locally advanced gastric cancer (LAGC) is the assessment of lymph node metastases in preoperative and postoperative imaging and/or histopathological examination.Aim: The assessment of lymphovascular invasion (LVI) in histopathological examination in patients with LAGC after gastrectomy. The groups of patients were divided into patients who received preoperative chemotherapy, patients without preoperative chemotherapy, and all patients. Additionally, we assessed the correlation between the presence of LVI and the number of lymph nodes collected during gastrectomy.Material and method: We collected patients with histologically confirmed GC after gastrectomy. The collected samples were divided into three subgroups: patients with neoadjuvant chemotherapy (NAC), patients without NAC, and all patients. Histopathological examination assessed the presence of LVI infiltration. We then assessed the correlation between the presence of LVI and the presence of lymph node metastasis in GC. Additionally, we assessed the correlation between LVI and the number of lymph nodes evaluated in patients in each group. The statistical analyses were performed using Statistica v13.3 and Microsoft Excel 2021. The significance limit was set at p<0.05.Results:The presence of LVI strongly correlated with node involvement, and the result was statistically significant in all patients and the group of patients treated with NAC. The difference was not statistically significant in the group not treated by NAC. Additionally, we did not observe a correlation between the presence of LVI and the number of metastatic lymph nodes in GC.Summary and Conclusions: The presence of LVI in a patient with GC indicates a high probability of lymph node metastasis, which should translate into therapeutic procedures. Assessment of LVI may help identify potential patients with lymph node metastases, particularly in patients undergoing endoscopic resection without planned lymphadenectomy. It is advisable to expand research on a larger scale in order to establish clear standards in this area.

Background: The aim of the present study was to determine the correlation between obesity, serum levels of leptin and proximal gastric cancer. Methods: Sixty-four gastric cancer patients operated on with curative intent were included in the study. We determined the correlation between the preoperative serum levels of leptin and the tumor`s location. Results: Serum leptin levels were correlated significantly with the proximal third location (p = 0.04), gastric outlet obstructing tumors (p < 0.0001), CRP levels (p = 0.03) and BMI (p < 0.0001). Patients with high serum levels of leptin had significantly more intestinal types of gastric cancer (p = 0.033) and better differentiation compared to patients with low serum leptin levels (p = 0.009). The linear regression model determined the proximal tumor location (beta: 0.467; p = 0.045), BMI (beta: 0.657; p = 0.001), high preoperative serum albumin (beta: 0.563; p = 0.016) and the presence of pyloric stenosis (beta: 0.525; p = 0.006) as related significantly to serum leptin levels. The Cox proportional hazard model identified age (HR: 0.003; 95%CI: 0-0.794; p = 0.041), preoperative serum levels of leptin (HR: 0.125; 95%CI: 0.018-0.887; p = 0.037) and the number of extracted LNs (HR: 0.001; 95%CI: 0-0.677; p = 0.038) as independent prognostic factors. Conclusions: Serum levels of leptin were significantly elevated in patients with proximal gastric cancer, suggesting that the leptin`s effect might be due to its systemic secretion. This might explain the higher incidence of proximal gastric cancer in obese patients. Elevated serum leptin levels were an independent prognostic factor.

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1-2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2 and neuroendocrine carcinoma: NEC) on the basis of Ki-67 proliferation index and mitotic count according to the 2010 WHO classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic backround together with preclinical studies to develop new agents, including those already under investigation for SCLC, will be needed to improve the prognosis.

Gastric cancer is the 5th most common disease in the world and the 4th most common cause of death. It is diagnosed through esophagogastroduodenoscopy with biopsy, however there are limitations in finding lesions in the early stages. Recently, research has been actively conducted to use liquid biopsy to diagnose various cancers, including gastric cancer. Various substances derived from cancer are reflected in the blood. By analyzing these substances, it was expected that not only the presence or absence of cancer but also the type of cancer can be diagnosed. However, the amount of these substances is extremely small, and even these have various variables depending on the characteristics of the individual or the characteristics of the cancer. To overcome these, we collected methylated DNA fragments using MeDIP and compared them with normal plasma to characterize gastric cancer tissue or patient’s plasma. And we attempted to diagnose gastric cancer using the characteristics of cancer reflected in the blood through the cancer tissue and patient’s plasma. As a result, we confirmed that the consistency of common methylated fragments between tissue and plasma was approximately 41.2%, and found the possibility of diagnosing and characterizing cancer using the characteristics of the fragments through SFR and 5'end-motif analysis.

Tumor invasion, metastasis, and recrudesce remain a considerable challenge in the treatment of gastric cancer (GC). Herein, we first identified that RBFOX3 (RNA binding protein fox-1 homolog 3) was significantly up-regulated in GC tissues and negatively linked to the survival rate of GC patients. RBFOX3 promoted cell division and cell cycle progression in vitro as well as in vivo. Furthermore, RBFOX3 increased cell invasion and migration ability. Interestingly, both the suppression of GC cell multiplication and invasion moderated by the silencing of RBFOX3 was rescued by HTERT up-regulation. Additionally, RBFOX3 augmented the resistance of GC cells to 5-fluorouracil (5-Fu) by repressing RBFOX3. Mechanistically, exogenous up-regulation of RBFOX3 triggered promoter activity and HTERT expression thereby enhancing the division and development of GC cells. Importantly, our findings revealed that RBFOX3 interacted with AP-2β to modulate the HTERT expression as demonstrated by co-immunoprecipitation analysis. In conclusion, our study indicates that high expression of RBFOX3 promotes GC progression and development but predicts worse prognosis by stimulating HTERT signaling. Moreover, the results suggest that the RBFOX3/AP-2β/HTERT pathway is a novel target for the development of therapeutic agents for the prevention and treatment of GC reappearance and metastasis.

The p53 tumor suppressor protein is an activator of transcription. Diverse stress factors lead to various sets of posttranslational modifications of p53 what results in different sets of upregulat-ed genes. We noticed that actinomycin D and nutlin-3a (A+N) synergize in inducing activating phosphorylations of p53 and upregulation of selected p53-target genes. Here we found that one of these genes is DUSP13, which codes for poorly-studied, dual-specificity phosphatase having at least two isoforms, one expressed in testis and the other in skeletal muscles. In cancer cells ex-posed to A+N, DUSP13 is expressed from an alternative promoter in intron, what results in ex-pression of isoform named TMDP-L1. The luciferase reporter tests demonstrated that this pro-moter is activated by both endogenous and ectopically expressed p53. We showed for the first time that mRNA expressed from this promoter actually produces the protein, which can be de-tected by Western blotting in all examined cancer cell lines with wild-type p53 exposed to A+N. In some cell lines it is also induced by clinically relevant camptothecin or by nutlin-3a acting alone. This isoform, fused with green fluorescent protein localizes in perinuclear region of cells. Thus, TMDP-L1 isoform may be an important element of p53-regulated stress response system.

In order to provide a new direction for the diagnosis and treatment of gastric cancer, the differentially expressed blood-based miRNAs in gastric carcinoma were obtained and analyzed from the datasets GSE113486, GSE112264 and GSE113740 by the SangerBox, the miRNA - target genes prediction, GO and KEGG functional enrichment analyses with DAVID 6.8, and the STRING database with Cytoscape, respectively. The correlation between the key miRNAs expression and the prognosis and diagnostic value of gastric cancer patients were detected by survival prognosis and ROC curve. QRT-PCR was used to detect the possible key miRNAs expression in human blood species. The dataset GSE108307 which shows the miRNAs affected by H. pylori infection was analyzed by GEO2R. The expression level of CagA and the clinically used gastric cancer markers were detected in human blood species for contrast. Five key blood-based miRNAs were determined, including hsa-miR-124-3p, hsa-miR-125a-3p, hsa-miR-29b-3p, hsa-miR-4276, and hsa-miR-575.The detection in human blood species as well as the cross analysis with H. pylori infection and clinically used markers expression suggested the importance and efficacy of the specific miRNAs in the early diagnosis and monitoring of gastric carcinoma. The study identified potential novel blood miRNA biomarkers of gastric cancer by bioinformatics and human blood species detection, which may give a new possibility of the important biomarkers for the diagnosis and prognosis of gastric cancer.

1) Background: When women receive a diagnosis of a gynecologic malignancy, they can have questions about their diagnosis or treatment that can result in voice queries to virtual assistants. Recent advancement in artificial intelligence (AI) has transformed the landscape of medical information accessibility. The Google virtual assistant (VA) outperformed Siri, Alexa, and Cortana in voice queries presented prior to the explosive implementation of AI in early 2023. The efforts presented here focus on determining if advances in AI in the last 12 months improved the accuracy of Google VA responses related to gynecologic oncology. (2) Methods: Previous questions were utilized to form a common basis for queries prior to 2023 and responses in 2024. Correct answers were obtained from the UpToDate medical resource. Responses related to gynecologic oncology were obtained using Google VA, as well as the generative AI chatbots Google Bard/Gemini and Microsoft Bing-Copilot. (3) Results: The AI narrative responses varied in length and positioning of answers within the response. Google Bard/Gemini achieved an 87.5% accuracy rate, while Microsoft Bing-Copilot reached 83.3%. In contrast, the Google VA’s accuracy in audible responses improved from 18% prior to 2023 to 63% in 2024. (4) Conclusion: While the accuracy of the Google VA has improved in the last year, it underperformed Google Bard/Gemini and Microsoft Bing-Copilot so that there is considerable room for further improved accuracy.

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 Rho guanine nucleotide exchange factor (RGNEF) protein encoded by the ARHGEF28 gene has been implicated in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Biochemical and pathological studies have shown that RGNEF is a component of the hallmark neuronal cytoplasmic inclusions in ALS-affected neurons. Additionally, a heterozygous mutation in ARHGEF28 has been identified in a number of familial ALS (fALS) cases that may give rise to one of two truncated variants of the protein. Little is known about the normal biological function of RGNEF or how it contributes to ALS pathogenesis. To further explore RGNEF biology we have established and characterized a yeast model and characterized RGNEF expression in several mammalian cell lines. We demonstrate that RGNEF is toxic when overexpressed and forms inclusions. We also found that the fALS-associated mutation in ARGHEF28 gives rise to an inclusion-forming and toxic protein. Additionally, through unbiased screening using the split-ubiquitin system, we have identified RGNEF interacting proteins, including two ALS-associated proteins. Functional characterization of other RGNEF interactors identified in our screen suggest that RGNEF functions as a microtubule regulator. Our findings indicate that RGNEF misfolding and toxicity may cause impairment of the microtubule network and contribute to ALS pathogenesis.

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.

Gastric cancer (GC) is one of the most common malignancies around the world, and the incidence of GC is increasing in the past decades. In addition to genetic modifications, epigenetic alterations catalyzed by DNA methyltransferases (DNMTs) are a well-characterized epigenetic hallmark in gastric cancer. Nowadays, DNA methylation landscape is essential for maintaining the silence of tumor suppressor genes (TSGs). As an important group of peptide, TFF family has been confirmed to function as a TSG in various kinds of cancers. However, whether TFFs could be modified by DNA methylation in gastric cancer remains unknown. In this study, we initially screened out two expression profiles about GC from Gene Expression Omnibus (GEO) database. The higher expressions of TFF1 and TFF2 were observed in GC tumor tissues than normal tissues. Additionally, we illustrated that the expressions of TFF1/TFF2 were associated to the overall survival (OS) and tumor free survival (TFS) of GC patients via through the Kaplan-Meier analysis. Subsequently, the integrative analysis was performed to estimate the DNA methylation level of each site in TFF1/TFF2 CpG islands. Importantly, our findings indicated that hyper-methylation of cg01886855 and cg26403416 were separately responsible for the downregulation of TFF1 and TFF2 in GC samples. Besides, utilizing the gain of function assay, we demonstrated that TFF1/TFF2 could suppress the proliferation of GC cells. Based on these results, We identified that TFF1 and TFF2 acted as the putative tumor suppressors in gastric cancer, which suggested that TFFs could be two candidate biomarkers for predicting tumor recurrence in gastric cancer patients. Furthermore, these findings highlight a potential therapeutic approach in targeting the TFFs for the treatment of gastric cancer.

With the continuous progress in modern medicine, the early detection rate of gastric cancer has increased, and the mortality rate has decreased. However, gastric cancer remains the third leading cause of cancer-related death worldwide, with a high recurrence rate. Metastasis is the leading cause of death and recurrence of gastric cancer, which greatly hinders treatment success. Cancer development is a complex process involving multiple sequential steps. In the metastatic cascade, local invasion may be considered an initial, crucial step in the development of a malignant tumor, which leads to distant metastasis. Epithelial-mesenchymal transformation (EMT) is one of the most important developmental processes that occur during tumor invasion. EMT confers certain basic abilities to cancer cells, such as migration, invasion and anti-apoptotic ability, thus initiating and increasing metastasis. However, little is known about the molecular mechanisms that promote EMT and gastric cancer cell metastasis. A number of recent studies have found that circular RNAs（circRNAs）are associated with gastric cancer EMT, regulating the EMT process and promoting the occurrence and development of tumors. Because of their unique continuous circular structure, circRNAs have relatively high stability in plasma and cells, making them more suitable as diagnostic biomarkers in malignant tumors. Therefore, understanding the mechanism of circRNAs in EMT in gastric cancer is an important research direction to actively prevent tumor metastasis and improve the therapeutic effect on advanced malignant tumors.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and elderly. Infections caused by this species are exceptionally challenging to treat due to its multiresistance to antimicrobials. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on paediatric infections caused by E. anophelis. Accurate identification with MALDI-TOF, or using molecular techniques, is crucial because of varying susceptibilities among species. Early, accurate diagnosis and prompt effective treatment optimize outcomes.

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.

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responds to immunotherapy. The relationships between tumor DNA damage response, the immune system and immunotherapy have recently attracted attention. Accumulating evidence indicate that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsible to immunotherapy, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of gastric adenocarcinoma. The results showed that DRGS high score patients showed significantly better therapeutic outcomes compared to DRGS low score patients (P < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocytes infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival and may benefit more from ICB therapy, as compared to the low-score patients. Therefore, the DRGS and its scoring system may have implications in tailoring immunotherapy in gastric cancers.

Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitates the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA 177Lu-octreotide with the ALK inhibitor lorlatinib. Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, 177Lu-octreotide, combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Combination treatment with 177Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. Increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with 177Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both 177Lu-octreotide and lorlatinib, with BID downregulated and HRK upregulated on days 2 and 7, respectively. The data suggests that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with 177Lu-octreotide.

Lipopolysaccharides are a type of polysaccharide mainly present in the bacterial outer membrane of Gram-negative bacteria. Recent studies have revealed that lipopolysaccharides contribute to the immune response of the host by functioning as a cancer antigen. We retrospectively recruited 198 patients with gastric cancer who underwent surgery. The presence of lipopolysaccharides was determined using immunohistochemical staining, with the intensity score indicating positivity. The relationship between lipopolysaccharides and CD8, PD-L1, TGFBI (a representative downstream gene of TGF-β signaling), E-cadherin, and claudin-4 (epithelial–mesenchymal transition markers) was also investigated. Thereafter, we identified 20 patients with advanced gastric cancer receiving nivolumab and investigated the relationship between lipopolysaccharides and nivolumab sensitivity. After staining for lipopolysaccharides in the nucleus of cancer cells, 150 negative (75.8%) and 48 positive cases (24.2%) were found. The lipopolysaccharide-positive group showed increased cancer stromal TGFBI expression (p &lt; 0.0001) and PD-L1 expression in cancer cells (p = 0.0029). Lipopolysaccharide positivity was significantly correlated with decreased E-cadherin expression (p = 0.0055) and claudin-4 expression (p = 0.029); however, no significant correlation was found between lipopolysaccharide expression and overall survival rate (p = 0.71). Among cases receiving nivolumab, the lipopolysaccharide-negative and -positive groups had a disease control rate of 66.7% and 11.8%, respectively (p = 0.049). Lipopolysaccharide positivity was associated with TGF-β signaling and epithelial–mesenchymal transition and was considered to promote therapeutic resistance to nivolumab.

We have previously discussed the pathological characteristics, clinical characteristics, detection methods, pathogenesis, and treatment of Epstein–Barr virus (EBV)-positive gastric cancer, but we have not discussed the unique immune microenvironment in EBV-positive gastric cancer. Here, we reviewed studies on the immune microenvironment in EBV-positive gastric cancer and found that CD8+ T lymphocytes and a small number of CD204+ macrophages infiltrate the immune microenvironment in EBV-positive gastric cancer. Moreover, immune checkpoints, such as IDO1 and PD-L1, are expressed at high levels in EBV-positive gastric cancer. Lastly, we also analyzed the mechanisms underlying the formation of the immune microenvironment in EBV-positive gastric cancer. Our findings and conclusions have significance in clinical guidance and provide research direction for basic experiments.

Gastric cancer, also known as stomach cancer, is a cancer which develops from the lining of the stomach. Accumulated evidences and epidemiological studies have been indicated that natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action did not elucidate yet. Particularly, experimental studies have been showed that natural products displayed a protective effect against gastric cancer via numerous molecular mechanisms such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Although chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy and immunotherapy, but its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. Additionally, intake of naturally occurring phytochemicals could increase the efficacy of gastric chemotherapy and chemotherapeutics resistance. However, natural product structural stability and powerful bioactivity are important to develop novel treatments for gastric cancer that may minimize such adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural products on prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

Abstract Background: Gastric cancer, particularly adenocarcinoma, is a significant global health concern. Environmental risk factors, such as Helicobacter pylori infection and diet, play a role in its development. Purpose: This study aimed to characterize the chemical composition and evaluate the in vitro antibacterial and antitumor activities of AOME. Additionally, morphological changes in gastric cancer cell lines were analyzed. Study design: AOME was analyzed using HPLC-MS/MS and its antibacterial activity against H. pylori was assessed using the broth microdilution method. MIC and MBC values were determined, and positive and negative controls were included in the evaluation. Methods: Anticancer effects were assessed through in vitro experiments using AGS, KATO-III, and SNU-1 cancer cell lines. The morphological changes were examined through SEM and TEM analyses. Results: AOME contained several compounds, including caffeic acid, rutin, and hyperoside. The extract displayed significant antimicrobial effects against H. pylori, with consistent MIC and MBC values of 3.70 ± 0.09 mg/mL. AOME reduced cell viability in all gastric cancer cell in a dose and time-dependent manner. Morphological analyses revealed significant ultrastructural changes in all tumor cells lines, suggesting the occurrence of cellular apoptosis. Conclusions: This study demonstrated that AOME possesses antimicrobial activity against H. pylori and potent antineoplastic properties in gastric cancer cell lines. AOME holds promise as a natural resource for innovative nutraceutical approaches in gastric cancer management. Further research and in vivo studies are warranted to validate its potential clinical applications.

Gastric cancer is among the top 5 causes of cancer-related death worldwide. Preoperative chemotherapy has been established as an option in patients with locally advanced gastric cancer. However, chemotherapy yields variable results, owing to the cellular and molecular heterogeneity of this disease. Identifying patients who did or did not respond to preoperative therapy can allow clinicians to alter treatment modalities and provide important information related to prognostication. Pathologic response to preoperative therapies, called Tumor Response Grade (TRG), has been evaluated to quantify treatment response. Multiple systems for TRG have been established. However, literature has demonstrated inconsistent results for TGR systems and prognosis, possibly due to variability in interpretation of tumor response between systems and interobserver variability. Radiographic response to preoperative therapies using RECIST 1.1 criteria and endoscopically-assessed tumor response have demonstrated association with survival; however their use in gastric cancer remains challenging given the inability to accurately and consistently identify and measure the tumor, especially in the setting of neoadjuvant therapy where treatment-related changes can obscure the gastric wall layers. This review is focused on summarizing the available literature related to evaluating TRG in gastric cancer, as well as providing a brief overview on the use of radiographic and endoscopic methods to assess response to preoperative therapies. Lastly, we outline future directions regarding the use of a universal TRG system to guide care and assist with prognosis.

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

Objective: To investigate the protein expression levels of cyclin‑dependent kinase subunit 2 (CKS2) and cluster of differentiation (CD) 47 in gastric cancer (GC) and their clinical significances. Methods: A total of 126 GC patients who underwent radical resection were selected as study subjects. Additionally, 32 patients with benign gastric tumor, 42 patients with low-grade intraepithelial neoplasia (LGIEN), and 49 patients with high-grade intraepithelial neoplasia (HGIEN) who underwent surgery were selected as the control groups. Immunohistochemistry was used to detect the expression of CKS2 and CD47 in surgical specimens. We statistically analyzed the clinical significance of the expression of the two factors. Results: (1) The positivity rates for CKS2 in benign gastric tumor tissue, LGIEN tissue, HGIEN tissue, and GC tissue gradually increased, i.e., 6.3% (2/32), 30.9% (13/42), 38.8% (19/49), and 60.3% (76/126), respectively, and the positivity rates for CD47 were 18.8% (6/32), 38.1% (16/42), 46.9% (23/49), and 65.9% (83/126), respectively. (2) High expression of CKS2 and CD47 were associated with tumor diameter, Lauren classification, number of lymph node metastases, and TNM stage. In addition, the immunohistochemical scores for CKS2 and CD47 were positively correlated (r=0.625, P=0.000). (3) The median follow-up time of 126 patients was 46.5 months, and the overall survival rate was 40.5% (51/126). Survival analysis showed that compared with that in the CKS2 (-) group, the overall survival rate for patients in the CKS2 (+) group was significantly worse (25.0% vs 64.0%, 2=15.67, P=0.000) and that compared with the CD47 (-) group, the CD47 (+) group had significantly worse overall survival (30.1% vs 60.5%, 2=15.67, P=0.000). (4) The overall survival rates of CKS2(+)CD47(+) group, CKS2(+)CD47(-) group, CKS2(-)CD47(+) group, and CKS2 (-)CD47 (-) group were 20.0%(13/65), 58.3%(7/12), 57.1%(8/14), 65.7% (23/35), respectively, the prognosis of patients in CKS2(+)CD47(+) group was significantly poor. Conclusion: High expression levels of CKS2 and CD47 were closely related to the occurrence of GC and can be used as independent risk factors to assess the prognosis of patients.

Transfer RNA fragments (tRFs) have gene silencing effects similarly to miRNAs, can be sorted into extracellular vesicles (EVs) and are emerging as potential circulating biomarkers for cancer diagnosis. We aimed at analyzing the expression of tRFs in gastric cancer (GC) and understanding their potential as biomarkers. We explored miRNA datasets from gastric tumors and normal adjacent tissues (NAT) from TCGA repository, and proprietary 3D-cultured GC cell lines and corresponding EVs, in order to identify differentially represented tRFs using MINTmap and R/Bioconductor packages. Selected tRFs were validated in patient-derived EVs. We found 613 Differentially Expressed (DE)-tRFs in the TCGA dataset, of which 19 were concomitantly upregulated in TCGA gastric tumors and present in 3D-cells and EVs, but barely expressed in NAT. Moreover, 20 tRFs were expressed in 3D-cells and EVs and downregulated in TCGA gastric tumors. Of these 39 DE-tRFs, 9 tRFs were also detected in patient-derived EVs. Interestingly, the targets of these 9 tRFs affect neutrophil activation and degranulation, cadherin binding, focal adhesion and cell-substrate junction, highlighting these pathways as major targets of EV-mediated crosstalk with the tumor microenvironment. Furthermore, as they are present in four distinct GC datasets and can be detected even in low quality patient-EV derived samples, they hold promise as GC biomarkers. By repurposing already available NGS data, we could identify and cross-validate a set of tRFs holding potential as GC diagnosis biomarkers.

Gastric cancer is an intractable disease with a high incidence of peritoneal dissemination and obstructive symptoms (e.g. ileus, jaundice, and hydronephrosis) arising from accompanying marked fibrosis. Microenvironmental interactions between cancer cells and stromal cells are the suggested cause of the disease. Transforming growth factor (TGF-β) is an intriguing cytokine exhibiting dual roles in malignant disease, acting as an important mediator of cancer invasion, metastasis, and angiogenesis as well as exhibiting antitumor functions. Moreover, the TGF-β pathway contributes to the generation of a favorable microenvironment for tumor growth and metastasis throughout the steps of carcinogenesis. Among these effects, TGF-β induces the epithelial-to-mesenchymal transition with prometastatic functions, contributes to the conversion of stromal cells to carcinoma-associated fibroblasts, and suppresses the function of immune cells, which compromises the antitumor immune response, leading to cancer progression and stromal fibrosis. In this review, we address the role of the essential TGF-β signaling pathway in the regulation of the activities of components of the tumor microenvironment of gastric cancer and how this contributes to tumor progression and stromal fibrosis. We then explore the potential to optimize therapy that inhibits TGF-β signaling in the preclinical and clinical settings of gastric cancer.

Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of IDO1, synergism between H pylori and EBV coinfection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism.

Helicobacter pylori (H. pylori) is known to play a significant role in the development of peptic ulcer diseases and gastric cancer. Previous studies have reported the existence of polymorphism in the ureC gene of H. pylori. However, the relationship between genetic sequence variations in ureC and the pathogenesis of peptic ulcer diseases remains unclear. We aimed to investigate the associations between ureC sequence variations and the development of gastric ulcer and gastric cancer. PCR amplification and DNA sequencing to analyze ureC sequences, and conducted phylogenetic analysis using MEGA X software. Samples from Taiwanese patients with gastric ulcer and gastric cancer were included in this study. PCR was used to amplify the ureC gene from these samples, followed by DNA sequencing. The obtained sequences were then subjected to phylogenetic analysis using MEGA X software. In addition, ureC sequences from different geographical regions, including China and other countries, were included in the analysis for comparison. Analysis of the ureC se-quences from Taiwanese samples revealed that 6 out of 7 gastric ulcer samples clustered together in one group, while the sequences from 7 out of 8 gastric cancer samples were distributed across other groups. Phylogenetic analysis incorporating ureC sequences from different geographical regions showed that Taiwanese ureC sequences could be divided into two distinct groups, although the bootstrap values supporting this separation were low. Notably, the ureC sequences from China formed a distinct group with a high bootstrap value, separate from sequences from all other countries. There are two genotypes of ureC sequences present in Taiwanese samples, with one genotype showing a closer association with gastric cancer. Additionally, the ureC sequences from China appear to be unique and separate from those obtained from other countries, indicating the presence of genetic diversity in ureC sequences among H. pylori strains from different regions, potentially contributing to differences in disease outcomes. Further research is needed to elucidate the specific mechanisms by which ureC sequence variations may influence the pathogenesis of peptic ulcer diseases and gastric cancer.

Human papillomavirus (HPV) uses the cellular trafficking machinery to reach the cell nucleus and initiate a successful infection. The HPV capsid consists of two proteins: L1 (the major capsid protein) and L2 (minor capsid protein), and L2 is known to be responsible for trafficking the viral genome to the nucleus. From previous studies, we know that many cellular proteins interact with L2 and are involved in the trafficking process at different stages of the infectious entry process. To further investigate how HPV-16 achieves successful viral entry, we have performed a mass spectrometry analysis to identify novel interacting proteins that associate with incoming HPV-16 virions. We show that HPV-16 pseudovirions interact with a group of cellular cargo proteins (COPI), and here we confirm that this is mediated by the direct binding of L2, but not L1, to the COPB1 subunit. We also show that the ability of L2 to interact with COPB1 is conserved in both low- and high-risk HPV types. Furthermore, we also show that the interaction is essential for successful infection entry of multiple HPV types, thereby identifying a novel constituent of the infectious entry pathway of the HPV.

Globally, gastric cancer is a major cause of cancer mortality, with a 5-year survival rate of 32% for locally advanced and metastatic gastric cancer. This systematic literature review summarized the clinical, safety, and humanistic outcomes associated with systemic regimens given as first line therapy for locally advanced and metastatic gastric cancer. The search included articles published in English in PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and the American Society of Clinical Oncology meeting library, from inception to April 2022. Phase II and III randomized controlled trials conducted among western populations diagnosed with stage III and IV locally advanced and metastatic gastric cancer were included. Two investigators independently reviewed the studies, conducted data extraction, and assessed risk of bias in accordance with PRISMA guidelines. Twenty-four randomized controlled trials totaling 8,705 patients were included. Median overall survival ranged from 5.0-13.1 months, median progression-free survival ranged from 2.0-7.7 months, and objective response ranged from 13.0-64.1%. Two studies reported higher quality of life outcomes. Grade 3 and 4 adverse events were reported in most studies. Improvement in clinical outcomes can be seen in recently published randomized controlled trials for locally advanced and metastatic gastric cancer.

Background: Gastric cancer (GC) is one of the leading malignancy diseases worldwide, especially in Asian. CAST is a potential oncogene in GC carcinogenesis process. The character of macrophage infiltration in GC microenvironment was also unaddressed. Methods: We first applied machine searching in gene candidate evaluation of GC. CAST expression was analyzed via the Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. Protein-protein interaction (PPI) network was downloaded from STRING. We investigated the impact of CAST on clinical prognosis using Kaplan-Meier plotter. The correlations between CAST and Lgr5 and macrophage infiltration in GC was surveyed via TIMER 2.0. Finally, GeneMANIA was also used to evaluate the possible functional linkage between genes. Results: After machine-assisted searching, CAST expression was found signicant difference in the overall survival of GC patients. STRING revealed CAST related proteomics and transcriptomics associations, mainly about CAPN family. Moreover, CAST significantly impacts the prognosis of GC from other datasets validation. Notably, high CAST expression was correlated with worse overall survival in GC patients (hazard ratio = 1.59; logrank P = 9.4 x 10-8). CAST and Lgr5 expressions were both positively correlated with WNT 2 and WNT 2B. Among GC patients in several datasets, CAST and macrophage infiltration evaluated together showed no obvious trend toward poor clinical overall survival. Conclusion: CAST plays an important role in GC clinical prognosis and is associated with WNT 2/WNT 2B/Lgr5. Our study denmostrated that CAST in GC overall survival is regulated by macrophage infiltration.

Melanoma is the most aggressive form of skin cancer. In the advanced stage of development it is resistant to currently available therapeutic modalities. Increased invasiveness and metastatic potential depend on a number of proteins involved in various signal transduction pathways. Hippo signaling plays an important role in malignant transformation. Dysfunctions of the Hippo pathway initiate the expression of tumor growth factors and is associated with tumor growth and metastasis formation. This review summarizes the recent achievements in studying the role of the Hippo pathway in melanoma pathogenesis and points to the potential specific targets for anti-melanoma therapy.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with complex carcinogenesis. Although there has been significant progress in the treatment of HCC over the past decades, drug resistance to chemotherapy remains a major obstacle in its successful management. In this study we were able to reduce chemoresistance in cisplatin-resistant HepG2 cells by either silencing the expression of transglutaminase type 2 (TG2) using siRNA or by pre-treatment of cells with the TG2 enzyme inhibitor cystamine. Further analysis revealed that, whereas the full-length TG2 isoform (TG2-L) was almost completely cytoplasmic in its distribution, the majority of the short TG2 isoform (TG2-S) was membrane-associated in both parental and chemoresistant HepG2 cells. Following induction of cisplatin toxicity in non-chemoresistant parental cells, TG2-S together with cisplatin quickly relocated to the cytosolic fraction. Conversely, no cytosolic relocalisation of TG2-S or nuclear accumulation cisplatin was observed following identical treatment of chemoresistant cells, where TG2-S remained predominantly membrane-associated. This suggests that deficient subcellular relocalisation of TG2-S from membranous structures into the cytoplasm may limit the apoptic response to cisplatin toxicity in chemoresistant cells. Structural analysis of TG2 revealed the presence of binding motifs for interaction of TG-S with the membrane scaffold protein LC3/LC3 homologue that could contribute to a novel mechanism of chemotherapeutic resistance in HepG2 cells.

The Infierno glacier is located in Aragon (Spain), Pyrenees mountain range, southern slope, the only one in this country that still preserves white glaciers. These are the southernmost glaciers in Europe and are currently in rapid regression. The work analyzes the evolution of the glacier between 2016 and 2022 (taking as "year zero" or starting point, 2015). In addition to the observations on the glacier itself, the variables (precipitation, temperatures, snow volumes and thicknesses) that allow understanding this evolution are studied. The results offer strong regression, with thickness losses in that period of 4.6 m and retreat of its front of 14.9 m. The evolution has frequent trend changes, linked to the interannual climatic irregularity characteristic of this mountain range. The main explanatory factor is the thermal increase. The thermal anomalies with respect to the average reference values have increased, in this period, +0.55° C. The year 2022 has been particularly warm and has recorded the greatest regression of the glacier (between May and August, the thermal anomalies were between +4° C and +2° C). Regarding precipitations, they have irregular tendencies and show a decreasing trend (-9% in the same period of time).

Despite significant advances in tumor biology and clinical therapeutics, metastasis remains the primary cause of cancer-related deaths. While RNA-seq technology has been used extensively to study metastatic cancer characteristics, challenges persist in acquiring adequate transcriptomic data. To overcome this challenge, we propose MetGen, a generative contrastive learning based on deep learning model. MetGen generates synthetic metastatic cancer expression profiles using primary cancer and normal tissue expression data. Our results demonstrate that MetGen generates comparable samples to actual metastatic cancer samples, and we discuss the learning mechanism of MetGen. Additionally, we demonstrate MetGen's interpretability using metastatic prostate cancer and metastatic breast cancer. MetGen has learned highly relevant signatures in cancer, tissue, and tumor microenvironment, such as immune response and the metastasis process, which potentially fosters a more comprehensive understanding of metastatic cancer biology. The development of MetGen represents a significant step toward the study of metastatic cancer biology by providing a generative model that identifies candidate therapeutic targets for the treatment of metastatic cancer.

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

Submucosal invasion is a critical step in gastric cancer (GC) progression, which greatly enhances metastasis risk. Cancer stem cells are responsible for invasion, metastasis, and tumor growth. To identify stem cell-related markers associated with submucosal invasion in GCs, we investigated the expression of candidate cancer stem cell (CSC) markers (CD133, CD44, and ALDH1A) and intestinal stem cell (ISC) markers (EPHB2, OLFM4, and LGR5) in early GCs with submucosal invasion. Remarkably, expression of all ISC markers and CD133 was frequently confined to the basal area of the lamina propria (basal pattern) in mucosal cancer. The proportion of stem cell marker-positive cells substantially increased during submucosal invasion. Given that ISC markers are restricted to the crypt base of the normal intestinal mucosa, these findings suggest that many early GCs may retain hierarchical characteristics. CD44 expression showed a focal pattern, ALDH1A was predominantly expressed diffusely, and there was no expansion of CD44 or ALDH1A expression in the submucosal cancer cells. RSPO2 from muscularis mucosa seem to be partly responsible for the increased expression of ISC markers in GC cells at the basal areas. We also found that ISC markers were correlated with CDX2 expression in GCs, indicating that ISC markers are involved in the intestinal differentiation in GCs. Interestingly, ISC markers (EPHB2 and OLFM4) and CD133 showed a positive impact on clinical outcomes. In particular, the prognostic value of EPHB2 was significant for intestinal-type GCs in a multivariate analysis. In summary, ISC markers and CD133 showed a basal distribution pattern along with enhanced expression in submucosal invading cells in early GCs. EPHB2 was an independent prognostic marker in intestinal-type GCs.

Background: We investigated the tumor immune response in gastric cancer patients receiving third line nivolumab monotherapy to identify immune-related biomarkers for better patient se-lection. Methods: Nineteen patients (10 males, median age 67 years) who received nivolumab as a third or later line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. Results: DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR, OS, PFS) to previous trials. Individual immunograms showed no significant changes before and ear-ly-on-treatment, nor consistent alterations among DCB cases. The intratumoral immune response was suppressed by previous treatments in most third or later line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in on-treatment tumors, but clonal re-placement did not impact efficacy. High T cells/Tregs ratios and a low UV radiation response gene signature were linked to DCB and treatment response. Conclusions: This study emphasizes the tumor immune response's importance in nivolumab ef-ficacy for gastric cancer. High T cells/Tregs ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. Larger cohort validation is crucial to optimize immune checkpoint inhibitors in gastric cancer treatment.

Abstract: (1) Background: Surgery is the best curative option for Gastric Cancer (GC). However, morbimortality associated with surgery still a significant problem. Thus, it is essential to determine the preoperative surgical risk, to optimize outcomes in higher risk patients. (2) Methods: Patients who underwent curative gastrectomy between January 2010 and December 2013 were included, obtaining a sample of 131 patients, and the acuity of the scales understudy was evaluated. The predictive power of the scales was evaluated through calibration and discrimination. (3) Results and Conclusions: Regarding mortality, the scales demonstrated good calibration, with POSSUM and P-POSSUM obtaining the best O:E ratio. The scales presented good discrimination, with POSSUM showing the best result. Considering morbidity, the scales showed good calibration and discrimination. POSSUM and P-POSSUM seem to have potential in predicting morbidity and mortality when applied to the studied population, but there is a need for further studies in this area.

The number of long-term cancer survivors increases continually. Understanding their needs is crucial to ensure an adequate follow-up. The aim of our study was to summarize the current literature concerning needs and what in-fluences these needs. A Scoping review of systematic reviews was conducted according to the recommendations of the Joanna Briggs Institute (JBI). Four electronic databases were searched. Of 414 retrieved papers, 11 met the eligi-bility criteria. Needs were aggregated into six domains (health-related information, health system, mental, practical, relationship and physical) and 15 categories. The lack of adequate information and the lack of access and/or conti-nuity of supportive care were the most prominent needs. Female gender, younger age, a low level of family and/or social support, and higher educational level were identified as risk factors. Employment and relationship status can affect the needs both in a positive or negative way. The weeks or months after the end of the treatments are partic-ularly critical and needs can be emphasized during this period. Cancer survivors could also leave positive changes. The variety of needs affects the quality of life of cancer survivors. The current Swiss healthcare system is not de-signed to support these people. Needs assessments should be systematically provided to ensure a better awareness on the part of health professionals and to allow an individual, holistic, and integrated follow-up.

Background: Gastric cancer (GC) is the second most prevalent cancer in Korea, significantly impacting morbidity and mortality. While advancements in early detection and treatment have improved survival rates, managing post-surgical recovery remains vital. Herbal medicine (HM) has emerged as a potential adjunct therapy to enhance recovery and quality of life (QoL) in patients post-GC surgery. Methods: This systematic review and meta-analysis evaluated the efficacy and safety of HM in the post-surgical recovery of GC patients. We searched both Korean and international databases, identifying 16 randomized controlled trials (RCTs) meeting our criteria. We assessed study quality using the Cochrane Risk of Bias tool and analyzed data with Review Manager Software (RevMan). Results: Our analysis included 1,546 patients from the selected studies, demonstrating that HM significantly improved gastrointestinal recovery times, including time to first flatus, bowel movement, and return of bowel sounds. Significant improvements were also seen in nutritional markers such as albumin and prealbumin, alongside beneficial effects on immune markers like CD3+ and CD4+ levels. QoL assessments using WHOQOL-BREF and QLQ-C30 scores indicated substantial improvements. HM had a favorable safety profile, showing a reduced incidence of adverse effects compared to controls. Conclusion: The findings suggest that HM can significantly enhance recovery and improve the quality of life following gastric cancer surgery, with a favorable safety profile. However, due to considerable heterogeneity in study results, extended clinical trials and rigorous follow-ups are recommended to assess long-term effects and side effects comprehensively.

In 2022, the new WHO Classification of Endocrine and Neuroendocrine Tumors, Fifth Edition (beta version) (WHO 5th) was published. The importance of understanding the molecular genetics of thyroid tumors as revealed by large-scale genomic analyses such as The Cancer Genome Atlas (TCGA). Consequently, the WHO 5th was fundamentally revised, resulting in a systematic classification based on tumor cell-of-origin and clinical risk. This paper outlines following critical points of the WHO 5th. 1. Genetic mutations in follicular cell-derived neoplasms (FDN) highlight the role of mutations in the MAP kinase pathway, including RET, RAS, and BRAF, as drivers of carcinogenesis. Differentiated thyroid cancers such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) have specific genetic alterations that correlate with morphological classifications: RAS-like tumors (RLTs) and BRAF p.V600E-like tumors (BLTs), respectively. 2. The Framework for benign lesions have revised. The WHO 5th introduces new categories such as "developmental abnormalities" and "thyroid follicular nodular disease" in benign FDN. 3. Low-Risk Tumors include NIFTP, TT-UMP, and HTT. 4. PTC histological variants are reclassified as "subtypes" in the WHO 5th. 5. The concept of high-grade carcinomas is introduced, encompassing poorly differentiated thyroid carcinoma (PDTC), differentiated high-grade thyroid carcinoma (DHGTC), and high-grade medullary thyroid carcinoma (MTC). 6. Squamous cell carcinoma is included in anaplastic thyroid carcinoma (ATC) in the WHO 5th due to shared genetic and prognostic features. 7. Hürthle cell adenoma/carcinoma is renamed oncocytic thyroid adenoma/carcinoma. 8. Other miscellaneous tumors are classified into salivary gland-type carcinomas of the thyroid, thyroid tumours of uncertain histogenesis, thymic tumours within the thyroid, and embryonal thyroid neoplasms. The WHO 5th thus emphasizes the importance of classifying tumors based on genetic abnormalities together with histomorphology, aiding in accurate pathological diagnosis and treatment selection, including molecular-targeted therapies.

Introduction: Signet-ring cells are typically associated with mucin-secreting epithelium thus most commonly found in a gastrointestinal tract, however not exclusively. Primary signet ring cell carcinoma of the prostate is a rare and poorly differentiated, aggressive acinar adenocarcinoma variant with a grim prognosis. Clinical case: In June of 2023 a 54-year-old Caucasian male came to the hospital complaining of lower urinary tract obstructive symptoms with occasional macrohematuria, non-specific body aches, and shortness of breath. A prostate specimen obtained in transurethral resection of the prostate was sent for histopathological examination. After a series of extraprostatic diagnostic workups including fibrogastroduodenoscopy, colonoscopy computed tomography imaging, and immunohistochemical studies, the patient was diagnosed with primary prostatic signet-ring cell adenocarcinoma st. IV. Unfortunately, the patient with the disease this advanced, PE, and third-degree thrombocytopenia was not a candidate for chemotherapy and died of cardiopulmonary insufficiency later that week. Discussion: Prostatic signet-ring cell carcinoma accounts for 0.02% of all prostate adenocarcinoma cases. Due to its nature and epidemiology, a diligent extraprostatic investigation has to be carried out. The disease often presents with unremarkable clinical symptoms and variable serum prostate-specific antigen results which may contribute to its late diagnosis which together with inconsistent immunohistochemical findings and unpredictable response to hormonal treatment pose both diagnostic and therapeutic challenges that negatively affect the prognosis. Conclusion: The study highlights the importance of a multidisciplinary approach and the need for diagnostic and therapeutic consensus within the research community in search of the primary site of the disease which may positively influence the prognosis.

Structural variations (SVs) play a key role in the pathogenicity of hematological malignancies. Optical genome mapping (OGM) is an emerging technology that enables genome-wide detection of all classes of SVs at a high resolution and sensitivity. Identification of cryptic SVs leading to gene disruption or predicted novel gene fusions could be important drivers for cancer development and/or portend a prognostic relevance, which could be used to modify the treatment plan. A cohort of 106 consented cases that had a successful OGM analysis performed were included in the study. Demographic, clinical, laboratory and treatment data were collected. Routine diagnostic and prognostic testing were done on the peripheral blood and bone marrow aspirate as indicated. Additional samples of peripheral blood and/or bone marrow were sent for OGM testing. OGM led to a change in risk stratification in 17/66 (25.75%) of patients with hematological malignancies, the majority of these patients (15/66, 22.72%), having their risk stratification upgraded with a resulting change in treatment of 14 patients. This study highlights the ability of OGM to detect rare, cryptic and clinically relevant variants that potentially impact disease diagnosis, risk stratification and actionable treatment targets.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying non-invasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small non-coding RNA such as microRNA and transfer RNA-derived fragments (tRF). Here we performed small-RNA next-generation sequencing for urine EVs, serum EVs and serum supernatant from 41 patients with non-muscle invasive BC (27 stage Ta, 14 stage T1) and 15 non-cancer patients (NCP) with benign cystoscopy findings. Serum and urine samples were collected before transurethral resection of bladder tumors (TUR-b) and at routine postsurgery check-ups. Expression levels of tRFs in presurgery samples were compared to those at postsurgery check-ups and to NCPs. To strengthen the reliability of our results, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between BC patients with stage T1 disease and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing presurgery to postsurgery samples, and four DEtRFs were found when comparing presurgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC.

Tumor infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, and total TILs (CD4+, CD8+, Treg, B cells) within chemotherapy-treated tumors compared to chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic response with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherpy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

With reference to electromagnetic interaction and Abdus Salam’s strong (nuclear) gravity, 1) Square root of ‘reciprocal’ of the strong coupling constant can be considered as the strength of nuclear elementary charge. 2) ‘Reciprocal’ of the strong coupling constant can be considered as the maximum strength of nuclear binding energy. 3) In deuteron, strength of nuclear binding energy is around unity and there exists no strong interaction in between neutron and proton. $G_s\cong 3.32688\times {10}^{28}{\mathrm{m}}^3{\mathrm{kg}}^{-1}{\sec }^{-2}$ being the nuclear gravitational constant, nuclear charge radius can be shown to be, $R_0\cong \frac{2G_s{m}_p}{c^2}\cong 1.24\mathrm{fm}.$ $e_s\cong \left(\frac{G_s{m}_p^2}{\hslash c}\right)e\cong 4.716785\times {10}^{-19}\mathrm{C}$ being the nuclear elementary charge, proton magnetic moment can be shown to be, ${\mu }_p\cong \frac{e_s\hslash }{2m_p}\cong \frac{e{G}_s{m}_p}{2c}\cong 1.48694\times {10}^{-26}\mathrm{J}{.\mathrm{T}}^{-1}.$ ${\alpha }_s\cong {\left(\frac{\hslash c}{G_s{m}_p^2}\right)}^2\cong 0.1153795$ being the strong coupling constant, strong interaction range can be shown to be proportional to $\exp \left(\frac{1}{{\alpha }_s^2}\right).$ Interesting points to be noted are: An increase in the value of ${\alpha }_s$ helps in decreasing the interaction range indicating a more strongly bound nuclear system. A decrease in the value of ${\alpha }_s$ helps in increasing the interaction range indicating a more weakly bound nuclear system. From $Z\cong 30$ onwards, close to stable mass numbers, nuclear binding energy can be addressed with, ${\left(B\right)}_{A_s}\cong Z\times \left\{\left(\frac{1}{{\alpha }_s}+1\right)+\sqrt{\sqrt{30\times 31}}\right\}\left(m_n-m_p\right)c^2\approx Z\times 19.66\mathrm{MeV}.$ With further study, magnitude of the Newtonian gravitational constant can be estimated with nuclear elementary physical constants. One sample relation is, $\left(\frac{G_N}{G_s}\right)\cong \frac{1}{2}{\left(\frac{m_e}{m_p}\right)}^{10}\left[\sqrt{\frac{G_F}{\hslash c}}/\left(\frac{\hslash }{m_{e}c}\right)\right]$ where $G_N$ represents the Newtonian gravitational constant and $G_F$ represents the Fermi’s weak coupling constant. Two interesting coincidences are, ${\left(m_p/m_e\right)}^{10}\cong \exp \left(1/{\alpha }_s^2\right)$ and $2G_s{m}_e/c^2\cong \sqrt{G_F/\hslash c}.$

Tumor microenvironment including cancer-associated fibroblasts (CAF) has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell – tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF into their pathological counterparts. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise, and highly accurate for the measurement of the drug and the mains metabolites. The lower limit of quantification resulted 1 ng/mL. The curve range of 1-500 ng/mL and 50-2000 ng/mL, for plasma and tumor homogenate respectively, was appropriate for the analysis, as demonstrated by the accuracy between 96.8% and 102.4% for plasma and 96.6-102.3% for tumor. The inter-days precision and accuracy determined on quality controls at 3 different levels were in ranges of 6.9%-7.5% and 99.3-101.0% and 0.96-1.91% and 102.3-105.8% for plasma and tumour, respectively.

Predictive biomarkers for immune checkpoint inhibitors (ICI), such as PD-L1 expression (TPS), remain limited in clinical applications. Improved novel ICI predictive biomarkers are urgently needed. We evaluated a live single-cell functional liquid biopsy cytokine profiling platform to track immunotherapy treatment response and outcomes. Peripheral blood mononuclear cell samples of healthy donors and NSCLC patients undergoing ICI-based therapies were collected longitudinally pre-/post-treatment under IRB-approved protocols. Samples were enriched for CD4+ and CD8+ T-lymphocytes and analyzed on the IsoLight platform. The single T-cells were captured in microchambers on IsoCode chips for cytokines profiling. Functional polyfunctionality data from 55,775 single cells were analyzed using the IsoSpeak software, kappa coefficient, and Kaplan-Meier survival plots. We found a significant difference between responders and non-responders in CD8+ T-cells’ changes in overall polyfunctionality and polyfunctional strength index (ΔPSI). ΔPSI score in CD8+ T-cells performed better than PD-L1 TPS and, when combined with PD-L1 TPS, strongly correlated with early ICI treatment response with a kappa coefficient of 1.0 (p=0.003). High CD4+ T-cells ΔPSI predicted a strong trend of improved PFS (3.9-fold) and OS (3-fold). In conclusion, single peripheral T-cell polyfunctionality dynamics analysis is a promising liquid biopsy profiling platform as NSCLC ICI predictive biomarker regardless of oncogene-addiction status.

Gastric perforations and leaks are significant complications that can arise from various gastrointestinal disorders and surgical interventions. Over the past decade, endoscopic techniques have emerged as effective method for managing these conditions. Furthermore, as endoscopic resection techniques have grown in popularity, the risk of acute and delayed perforations has also grown. This review aims to provide an in-depth analysis of the endoscopic management strategies employed in the management of gastric perforations and leaks. We will discuss the etiology, diagnostic modalities, and various endoscopic techniques utilized, and emerging trends in endoscopic management. Our attempt in writing this review paper is to educate and guide clinicians in making informed decisions when faced with gastric perforations and leaks.

Recombinant α1-microglobulin (A1M) is proposed as protector during 177Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of 177Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but, the radioprotecting action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after 177Lu-octreotate and/or A1M administration. Mice were injected with 177Lu-octreotate and/or A1M, while control mice received saline or A1M vehicle solution. Bone marrow, kidney medulla, and kidney cortex were sampled after 24 hours or 7 days. Differential protein expression was analyzed with tandem mass spectrometry. Dosimetric estimation was based on 177Lu activity in kidney. PHLDA3 was the most prominent radiation responsive protein in kidney tissue. In general, no statistically significant difference in expression of radiation-related proteins was observed between the irradiated groups. Most canonical pathways were identified in bone marrow from the 177Lu-octreotate+A1M group. Altogether, tissue-dependent proteomic response followed exposure to 177Lu-octreotate alone or together with A1M. Combining 177Lu-octreotate with A1M did not inhibit the radiation induced protein expression early after exposure, and late effects should be further studied.

Culex quinquefasciatus is an important target for vector control because of its ability to transmit pathogens that cause disease. Most populations are resistant to pyrethroids and often to organophosphates, the two most common classes of active ingredients used by public health agencies. A knockdown resistance (kdr) mutation, resulting in a change from a leucine to phenylalanine in the voltage gated sodium channel, is one mechanism contributing to the pyrethroid resistant phenotype. Enzymatic resistance has also been shown to play a very important role. Recent studies have shown strong resistance in populations even when kdr is relatively low which indicates factors other than kdr may be larger contributors to resistance. In this study, we examined on a statewide scale (over 70 populations), the strength of the correlation between resistance in the CDC bottle bioassay and the kdr genotypes and allele frequencies. Spearman correlation analysis showed only moderate (-0.51) and weak (-0.29) correlation between the kdr genotype and permethrin and deltamethrin respectively. The frequency of the kdr allele was an even weaker correlate. These results indicate, in contrast to Aedes aegypti, assessing kdr in populations of Culex quinquefasciatus is not a good surrogate for phenotypic resistance testing.

Gastric cancer (GC) is a highly heterogeneous, complex disease and the fifth most common cancer worldwide (about one million cases and 784 000 deaths worldwide in 2018). CG is lately diagnosed and guarantees a poor prognosis for GC (the 5-year survival rate is less than 20%, but in early detection can reach 90%). This study evaluated the transcriptional profile in tumor gastric samples to find genes highly expressed during tumor establishment and use the related proteins as targets to find new anticancer molecules. Data was collected at Gene Expression Omnibus (GEO) bank to obtain 3 dataset matrices that analyze gastric tumor tissue versus normal gastric tissue, performed microarray using GPL570 platform, and from different sources. The genes found in silico analysis were confirmed in several lines of GC cells by RT-qPCR. The protein data bank was used to find the correspondent proteins. Then a structural-based virtual screening was done to find molecules, and docking analysis was done using the DockThor server. Our results of transcriptomic analysis, together with RT-qPCR, confirm the high expression of the genes AJUBA, FBXL13, CCDC69, CD80 and NOLC1 in GC lines. Based on that, the correspondent proteins were used in SBVS analysis. Five molecules, one each target, MCULE-2386589557-0-6, MCULE-7343047040-0-1, MCULE-5230409338-0-3, MCULE-9178344200-0-1 and MCULE -5881513100-0-29. All molecules have favorable pharmacokinetic, pharmacodynamic and toxicological properties. Molecular docking analysis revealed that the molecules interact with proteins in critical sites for their activity. Using a virtual screening approach, a molecular docking study was performed for proteins encoded by genes that play important roles in cellular functions for carcinogenesis. Combining a systematic collection of public microarray data with a comparative meta-profiling, RT-qPCR, SBVS, and molecular docking analysis provided a suitable approach to find genes involved in GC and work the correspondent protein to strive for new molecules with anticancer properties.

Background: Laparoscopic surgery produces lesser postoperative inflammation with a smaller cytokine and leptin response, and might thus reduce postoperative anorexia compared to open surgery. The aim of the present study was to determine the role of serum leptin in postoperative anorexia after laparoscopic gastric cancer surgery. Methods: Fifty-four consecutive patients with adenocarcinoma of the stomach were operated on either with open or laparoscopic surgery. Correlations were determined between the serum levels of leptin, clinico-pathological characteristics, serum haemoglobin and albumin. Results: Serum leptin levels on day seven were correlated significantly to gender (p=0.004), BMI (p=0.002) and tumour grade (p=0.033). In the patients with CRP < 100 mg/l the leptin levels on day seven were significantly lower after the laparoscopic operation (p=0.042) and in patients with lower BMI (p=0.001). The linear regression model determined a significant correlation between the relative concentration of leptin on day seven and laparoscopic surgery (Beta -0.688; p < 0.0001), gender, BMI, location of the tumour, T stage, N stage, perioperative therapy, tumour grade, perineural invasion, Lauren histological type and ulceration. In patients with CRP levels below 100 mg/ml the serum level of albumin on day seven after surgery was significantly higher in patients after laparoscopic surgery. Conclusion: Laparoscopic surgery produced significantly lower relative leptin concentrations on day seven, and higher serum albumin levels in the subgroup with CRP levels below 100 mg/l at discharge. These results suggested that laparoscopic gastric cancer surgery might reduce postoperative leptin response, leading to a better nutritional status at discharge compared to open surgery.

Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.

Aim. To study the processes of lipid peroxidation and the activity of antioxidant defense enzymes depending on the chemiluminescent activity of neutrophilic granulocytes in patients with gastric cancer associated with H. pylori infection, depending on the stage. Materials and methods. 39 patients with stage I-II gastric cancer and 30 patients with stage III-IV gastric cancer were examined. The study of the chemiluminescent activity of neutrophilic granulocytes was carried out, the parameters of the lipid peroxidation system and antioxidant protection in plasma were determined using the spectrophotometric method. Statistical data processing was performed using the Statistica 7.0 software package (StatSoft, USA). Results. In patients with gastric cancer associated with H. pylori infection, regardless of stage, the proportion of neutrophilic granulocytes with normal activity does not exceed 1/3 of the total number of patients, the remaining 2/3 of patients have an altered chemiluminescent activity of neutrophilic granulocytes: in patients with gastric cancer by I -II stage of the disease, the majority revealed a reduced function of neutrophilic granulocytes, and in patients with gastric cancer stage III-IV of the disease, the majority showed increased chemiluminescent activity of neutrophilic granulocytes. In all patients with gastric cancer associated with H. pylori infection, regardless of the stage of the disease, an increase in lipid peroxidation processes with activation of antioxidant defense enzymes was detected. Conclusion. In all patients with gastric cancer associated with H. pylori infection, regardless of the stage of the disease, an increase in lipid peroxidation processes with activation of antioxidant defense enzymes was detected. At the same time, there are no statistically significant differences between the indicators of the system lipid peroxidation - antioxidant protection depending on the stage of gastric cancer and the chemiluminescent activity of neutrophilic granulocytes, which probably indicates that all reactive oxygen species produced by neutrophilic granulocytes in the respiratory burst are consumed locally, minimally affecting the development of oxidative stress in the blood plasma.

The details of the solar flare production mechanisms are not yet completely understood. One of the standing questions is the anisotropy of the X-ray flux, especially in strong flares. It can be studied indirectly by analysing the characteristics of flares at different positions on the visible disc. In this paper, the durations, peak and integral fluxes of strong (X-class) solar flares from cycles 22--25 are considered with respect to their apparent position on the Sun. It is found that there exists a significant north--south asymmetry in all three parameters, which also varies depending on the phase of the solar cycle (with general predominance of the south). This confirms the results of previous studies. A weaker and less significant east--west asymmetry is found as well, partly supported by literature. A previously undetected centre-to-limb asymmetry is reported (in favour of the limb) in all three parameters. All three asymmetries are enhanced during the solar minimum, which could hint at their connection to the large scale magnetic structuring of the Sun. The prevalence of strong solar flares near the limb at the solar minimum has clear space weather warning implications.

Since 1742, the year in which the Prussian Christian Goldbach wrote a letter to Leonhard Euler with his Conjecture in the weak version, mathematicians have been working on the problem. The tools in number theory become the most sophisticated thanks to the resolution solutions. Euler himself said he was unable to prove it. The weak guess in the modern version states the following: any odd number greater than 5 can be written as the sum of 3 primes. In response to Goldbach's letter, Euler reminded him of a conversation in which he proposed what is now known as Goldbach's strong conjecture: any even number greater than 2 can be written as a sum of 2 prime numbers. The most interesting result came in 2013, with proof of weak version by the Peruvian Mathematician Harald Helfgott, however the strong version remained without a definitive proof. The weak version can be demonstrated without major difficulties and will not be described in this article, as it becomes a corollary of the strong version. Despite the enormous intellectual baggage that great mathematicians have had over the centuries, the Conjecture in question has not been validated or refuted until today.

In this article, many experimental similarities between electromagnetic fields (which are applied in systems of electrons, atoms, and liquids) and strong interaction fields (which are applied in systems of quarks, nucleons, and nuclei) are reviewed. The currently accepted theories describing electromagnetic fields differ fundamentally from those describing strong fields. Therefore, the many similarities are quite surprising, and some are not adequately explained even today. Several such unexplained similarities are listed among the top open problems in particle physics, such as the “EMC effect,” the “proton spin crisis,” and the “strong CP problem.” This paper highlights, for the first time, the underlying common characteristics of these problems, potentially offering valuable contribution to future explanations.

Background: Hashimoto’s thyroiditis (HT) is an autoimmune disease that progressively leads to thyroid gland destruction and hypothyroidism. Patients produce antibodies against two thyroid-specific antigens: thyroglobulin and thyroid peroxidase. As a result of the abnormal amount of thyroid hormone produced and its autoimmune etiology, patients with HT display a higher frequency of either autoimmune or non-autoimmune dermatological disorders. On ultrasound examination, HT can be detected by observing an enlarged thyroid gland with hypoechoic parenchymal regions or by observing a small gland indicating atrophy and diffusely heterogeneous parenchyma. Changes in the parenchymal vascularity can be observed as decreased or increased levels of vascularization. Objective: This study aimed to analyze the role of clinical data and ultrasound evaluation of patients with HT in suggesting an association with dermatological disorders. Patients and methods: Complete dermatological and endocrinological assessments as well as ultrasonography of the thyroid and lymphnodes were performed in HT patients. Results: The data obtained showed that a family history of thyroid disease, increased diameter of the inferior thyroid artery, and the presence of cervical lymphadenopathy were more frequent in the group of patients with dermatological diseases. Taken together, our results suggest the usefulness of ultrasound in determining a possible association between HT and dermatological disorders.

The FAS ligand (FASLG) is expressed on lymphocytes, which employ it to activated death receptors on targets cells. Cancer cells are generally resistant to apoptosis triggered by FASLG. In this work we found a way to circumvent this resistance by treatment with actinomycin D (ActD) and nutlin-3a (Nut3a). We selected this drug combination based on our transcriptomic data showing strong activation of proapoptotic genes, including the ones for receptor mediated apoptosis, in cells exposed to actinomycin D and nutlin-3a. To test our hypothesis, we pre-exposed cancer cell lines to this drug combination for 45h and next we treated them with recombinant FASLG. This almost instantaneously killed most cells. Actinomycin D and nutlin-3a strongly synergized in the sensitization because the effect of the drugs acting solo was not as spectacular as the drug combination, which together with FASLG killed more than 99% of cells. Based on the caspase activation pattern (caspase-8, caspase-9, caspase-10), we conclude that both extrinsic and intrinsic pro-apoptotic pathways were engaged. In engineered p53-deficient cells this pro-apoptotic effect was completely lost. Therefore, the combination of ActD+Nut3a activates p53 in an extraordinary way, which overcomes the resistance of cancer cells to apoptosis triggered by FASLG. Interestingly, other combinations of drugs, e.g., etoposide + nutlin-3a, actinomycin D + RG7112 and actinomycin D + idasanutlin had similar effect. Moreover, normal human fibroblasts are less sensitive to death induced by ActD+Nut3a+FASLG. Our findings create the opportunity to revive the abandoned attempts of cancer immunotherapy employing the recombinant FAS ligand.

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

Background: Cell proliferation and the cell cycle are fundamental to tumor development, with mitosis playing a crucial role in cell division. Understanding the complexities of the cell cycle and mitosis is critical for cancer research, especially in the context of developing therapeutic strategies. Objective: This review highlights mitotic poisons as potential anti-cancer pharmacotherapeutics, particularly their structural and functional group diversity presenting opportunity for semi-synthesis of new derivatives with multi-target mechanisms relevant for cancer pharmacotherapeutics. Also, the review explores naturally occurring mitotic poisons and inhibitors of microtubule-dependent molecular motors as promising cancer pharmacotherapeutics. Methods: A comprehensive review of literature from 2004 to 2023 was conducted, covering studies on cell proliferation, mechanism of cell cycle regulation, mitosis, cytokinesis, and anti-cancer drug development. The published literature was collected primarily from PubMed, Scopus, Medline, Web of Science Core Collections, Google Scholar and other relevant scientific databases using keywords including but not limited to mitotic poisons and cancer, sources of mitotic poisons, mechanism of mitotic poisons, targets of mitotic poisons and structural diversity of mitotic poisons. The efficacy and limitations of various mitotic poisons and their impact on different cancer types were examined. Recent advancements in targeted therapeutic interventions for various cancers were also explored. Results: The effectiveness and limitations of mitotic poisons, including Taxanes, Epothilones, Colchicine, Vinca alkaloids, Berberine, Laulimalide, and Pseudolaric acid B, were highlighted. Drugs targeting mitotic kinases such as CDKs, Aurora kinases, PLK1, and WEE1 inhibitors were reported. Inhibiting kinesin motor proteins such as Eg5 and KIF15 to interfere with spindle formation and cell division were discussed, along with specific genomic alterations in KIF genes and the discovery of KIFC1 as potential for future research and drug development. Conclusion: Targeting microtubules and mitotic kinases, along with inhibiting kinesin motor proteins, show promise for cancer pharmacotherapeutics. The combination of targeted therapies, patient stratification based on biomarkers (such as low alpha-1 acid glycoprotein and high p63 expression), and exploration of alternative natural sources of mitotic poisons and analogues can significantly advance cancer pharmacotherapy to improve patient outcomes.

Adenoviruses (Ads) have been extensively manipulated for the development of cancer selective replication, leading to cancer cell death or oncolysis. Clinical studies using E1-modified oncolytic Ads have shown that this therapeutic platform was safe, but with limited efficacy, indicating the necessity of targeting other viral genes for manipulation. To improve the therapeutic efficacy of oncolytic Ads, we treated the entire Ad genome repeatedly with UV-light and have isolated AdUV which efficiently lyses cancer cells as reported previously [1]. In this report, we show that no mutations were observed in the early genes (E1 or E4) of AdUV while several mutations were observed within the Ad late genes which have structural or viral DNA packaging functions. This study also reported the increased release of AdUV from cancer cells. In this study, we found that AdUV inhibits tumor growth following intratumoral injection. These results indicate the potentially significant role of the viral late genes, in particular the DNA packaging genes, to enhance Ad oncolysis.

The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection, and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley Rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and were killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis and evaluation of biological effects was performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function and cancer and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples are needed for validation.

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

Here we analyze three well-known conjectures: (i) the existence of infinitely-many twin primes, (ii) Goldbach’s strong conjecture, and (iii) Polignac’s conjecture. We show that the three conjectures are related to each other. In particular, we see that in analysing the validity of the Goldbach’s strong conjecture, one must consider also the existence of an infinite number of twin primes. As a consequence of how we approach this analysis, we also observe that if this conjecture is true, then so is Polignac’s conjecture. Our first step is an analysis of the existence of infinitely-many twin primes numbers. For this, using the formula 4((n−1)!+1) ≡ −n (mod n(n + 2)) – satisfied if and only if (n, n + 2) are twin primes –, together with Wilson’s theorem, we obtain conditions that must be met for two numbers to be twin primes. Our results, obtained from an analytic and functional study, lead us to conclude that there may exist infinitely-many twin primes. Next, we consider the validity of the Goldbach’s strong conjecture. After showing that the conjecture is true for the first even numbers, we notice a pattern that we analyze for any even number, reducing it to three cases: (i) when the even number 2n is two times a prime number n; (ii) when the even number 2n is such that n = 2m, with 2m − 1 and 2m + 1 twin primes; (iii) all other cases, i.e., for any 2n even number ∀n ∈ N with n > 1, n prime or not, with independence of n = 2m being 2m−1 and 2m+1 twin primes or not. In this last case we show that one can always find a certain r ∈ N such that 1 < r < n satisfying that n−r and n+r are primes, so that their sum is 2n. In this case we use the reduction to absurd method, and our results lead us to conclude that Goldbach’s strong conjecture is true to the best of our calculations, as well as the Polignac’s conjecture.

There are gravitational field and baryonic matter (star, planet, gases etc.) in our world; gravitational field is much more fundamental for that the relativistic mass of the gravitational field of a neutron star is almost 10²¹ times the mass of the neutron star. And, it is astonishing that the relativistic mass density of the gravitational field on the surface of a neutron star can be larger than the mass density of the neutron star. It is well known that, in the weak gravitational field a light line appears a straight line while in the strong field it is a curved line. It is stressed that the result measured in the strong field is more fundamental for that in a galaxy the measurable object is generally with strong field. It results in that the way that the result measured on the Earth with weak field is used as the universal standard need be revised as gravity is studied in the scale of a galaxy. It seems that a new theory of gravity need be developed for the new observations.

This paper is given to the investigation of warm inflation using Modified Chaplygin gas in the background of locally rotationally symmetric Bianchi Identity type I. We find out the field equations and perturbations parameters such as; scalar power spectrum, scalar spectral index, scalar potential and tensor to scalar ratio under slow roll approximation. We find out these parameters in directional of Hubble parameter during the Logamediate inflationary regime in weak and strong case. These comological parameters shows that the anisotropic model is also compatible WMAP$7$ with recent observational data Planck $2018$.

Metabolomics profiling for accurate and reliable quantification of organic acids that carry a carboxylic acid functional group in complex biological samples, remains a major analytical challenge in clinical chemistry research. Several procedural barriers associated with quantification of clinically important carboxylic containing metabolites (CCMs) including spontaneous decarboxylation during ionization, poor chromatographic resolution, and retention on a reverse-phase column, limit the sensitivity, specificity, and reproducibility of multiple-reaction monitoring (MRM) based LC-MS assay development. We report a targeted metabolomics-based analytical method for the quantification of CCMs using phenylenediamine derivatization. Accurate and sensitive quantification of CCMs is successfully demonstrated in an array of biological matrices. Recovery of metabolites from different matrices (plasma, serum, urine, saliva, tissues, and cell extracts), ranged from 90% to 105%, with all the CVs ≤ 10%. The method showed linearity over a broad dynamic range from 0.1 ng/mL to 10 µg/mL with linear regression coefficients of 0.99 for most of the metabolites tested herein, that covers broad-based applicability with the analysis of biological samples. In most cases the LODs were as low as 0.01 ng/mL. The phenylenediamine-based derivatization of carboxyl acid library consisting of more than 70 endogenous metabolites was constructed for metabolite identification, which spanned more than 40 biological pathways. The library included a wide-variety of structurally variant CCMs such as amino acids/conjugates, short to medium chain organic acids, di/tri-carboxylic acids/conjugates, fatty acids and some ring-containing CCMs. We compared the CCMs profiles of pancreatic cancer cells with normal pancreatic epithelial cells to test and validate the biological utility of this method. The comparative profiling between cancerous and normal cells resulted in the identification of potential biomarkers in pancreatic cancer, and their correlation with several key metabolic pathways such as central carbon energy metabolism, protein metabolism, including TCA cycle, glycolysis, Gln-Glu pathway, and biosynthesis of amino acids and unsaturated fatty acids was established. The method, described herein, for the first time enables the sensitive and highly specific quantification of CCMs on small sample size with high reproducibility in a high throughput manner. Given the biological and functional significance of this class of metabolites, this mass spectrometry based targeted quantitative assay, fills an important gap and is likely to support a wide range of applications for basic, clinical, and translational research.

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.

This study focuses on the potential medicinal properties of Campsis radicans L. extracts and its aim is to investigate the antioxidant and antiproliferative effects of these extracts on the human colon adenocarcinoma cell line (HT-29). Cytotoxic activity in the HT-29 cell line was evaluated, and the 3-dimensional structures of phenolic compounds were obtained using the GC-MS method. Docking simulations were performed with AutoDock Vina, targeting proteins that are crucial in the apoptotic pathway (Bax, Bcl-2, and Caspase-3). Drug similarities and ADMET estimates of the phenolic compounds were obtained from databases. The highest antioxidant activity of Campsis radicans L. plant was observed in ethanol and water extracts, with notable inhibition capacities. While the total phenolic content was highest in ethanol, water, and ether extracts respectively the total flavonoid content was highest in ethanol, then ether, and water extracts. Certain elements were undetectable in mineral determination, and others exceeded the toxic doses for plants. The water extract exhibited dose-dependent cytotoxic activity in the HT-29 cell line, with an IC50 value of 4.47 mg/mL. Molecular docking results revealed the binding of phenolic molecules to the active sites of apoptotic pathway proteins. The findings suggest that Campsis radicans L. plant possesses cytotoxic properties, significant phenolic and flavonoid content, and a high antioxidant capacity. These properties make it a potential candidate for treatment use, emphasizing its potential therapeutic value in the HT-29 cell line. Further research and exploration on the identified phenolic compounds could contribute to the development of novel therapeutic agents.

The neuroglial extracellular matrix (ECM) provides critical support and physiological cues for the proper growth, differentiation, and function of neuronal cells in the brain. However, in most in vitro settings that study neural physiology, cells are grown as monolayers on stiff surfaces that maximize adhesion and proliferation, and therefore lack the physiological cues that ECM in native neuronal tissues provides. Macromolecular crowding (MMC) is a biophysical phenomenon based on the principle of excluded volume that can be harnessed to induce native ECM deposition by cells in culture. Here, we show that MMC using two species of Ficoll with vitamin C supplementation significantly boosts deposition of relevant brain ECM by cultured human astrocytes. Dopaminergic neurons co-cultured on this astrocyte-ECM bed prepared under MMC treatment showed longer and denser neuronal extensions, a higher number of pre ad post synaptic contacts, and increased physiological activity as evidenced by higher frequency calcium oscillation, compared to standard co-culture conditions. When the pharmacological activity of various compounds was tested on MMC-treated co-cultures, their responses were enhanced, and for apomorphine, a D2-receptor agonist, it was inverted in comparison to control cell culture conditions, thus emulating responses observed in in vivo settings. These results indicate that macromolecular crowding can harness the ECM-building potential of human astrocytes in vitro forming an ultra-flat 3D microenvironment that makes neural cultures more physiological and pharmacological relevant.

Mutations in epidermal growth factor receptor (EGFR) occur in about 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) have been developed, targeting EGFR activity. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. These models are particularly effective in identifying optimal responders to specific treatments, thereby enhancing therapeutic efficacy. We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, representing two distinct generations of EGFR TKIs, to accurately simulate the drugs’ distribution within the primary tumor and metastatic sites following oral administration. These models were integrated with a pathophysiological mechanistic model of EGFR-mutant LUAD, enabling the representation of the effects of both gefitinib and osimertinib on EGFR activation-induced signaling pathways. This comprehensive model outputs detailed evolutions of the primary tumor and each metastatic site, facilitating the evaluation of patient progression in alignment with RECIST guidelines (version 1.1). Notably, the model encapsulates the heterogeneity within the tumor, through the representation of various subclones, each characterized by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002 and FLAURA clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. The model adeptly replicated the time to progression observed in real clinical trials in EGFR-mutant LUAD patients receiving gefitinib or osimertinib as first-line therapy. In addition, the model was able to reproduce the results from a retrospective study comparing gefitinib and osimertinib, a study that was not used to inform the model. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a vital investigational tool for deriving pertinent insights and informing treatment strategies, particularly in identifying optimal responders to various generations of EGFR TKIs. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the required patient cohort size in such trials, optimizing resource utilization.

Cervical cancer is one of the ailments that endangers the health of women all over the world and causes infertility. Fortunately, this disease can be avoided. Both the results and participation rates of the current preventative strategy remain poor. Hence, preventative or early detection methods remain challenging and open. In gynecology and computer science fields, few studies on identifying cervical cancer are based on behavior risk factor and machine learning. Moreover, various social and behavioral aspects might often make it more difficult to detect cervical cancer especially in low‑ and middle‑income countries (LMICs). Accordingly, focus on predicting the presence of cervical cancer through behavioral risk factors is the basic structure of this research. We proposed an approach to classify cervical cancer from a social-behavioral perspective using logistic regression to predict cervical cancer. We got significantly improved outcomes than the existing methods. Moreover, we used feature engineering to formulate less dimensionality as a pre-processing step and optimized parameters to be prepared for classification phase. The results proved that using the logistic regression with regularization type L1 had a promising performance. The accuracy of Logistic Regression (LR) L1 was 97.2%. Such results support the proposed work as a reliable classification predictive tool.

High hopes were associated with the new anti-angiogenic medicament, bevacizumab, which due to the possibility of binding to isoform A of vascular endothelial growth factor (VEGF), inhibited the creation of new blood vessels. However, not only blood vessels are responsible for the tumor cells' spread. During the process of tumor growth, lymphangiogenesis is mediated by other isoforms of the VEGF family, specifically VEGF-C and VEGF-D, which are independent of the bevacizumab action. Therefore, based on the mechanism of bevacizumab action and the processes of angio- and lymphangiogenesis, we formed three hypotheses: 1) if the lymph nodes in the primary ovarian cancers are metastatic, the outcome of bevacizumab treatment is worsened; 2) concerning the second-line treatment, bevacizumab will act in a weakened manner if the recurrence occurs in lymph nodes compared to local recurrences; 3) patients treated by bevacizumab are more likely to have recurrences in lymph nodes. These hypotheses raise the issue of the existing gap of knowledge, which concerns the effect of bevacizumab on the metastatic lymph nodes.

Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration-resistance is often developed during the course of treatment, though its influences require further understanding. This study explores the human microbiome for its implications in castration-resistance and metastasis in prostate cancer. RNA sequencing data was downloaded for bone and soft tissue biopsies of patients with metastatic castration-resistant prostate cancer. These sequences were mapped to bacterial sequences to yield species-level abundance approximations. Numerous species were found to correlate to the expression of known markers of castration-resistance, including AR, PI3K, and AKT. Castration-resistance-associated signaling pathways were also enriched with these species, including PI3K-AKT signaling and endocrine resistance. For their implications in cancer aggression and metastasis, cancer stem cell markers were further explored for relation to these species. EGFR and SLC3A2 were widely downregulated with greater abundance of most species. Our results suggest that the microbiome is heavily associated with castration-resistance and stemness in prostate cancer. By considering the microbiome’s importance in these factors, we may better understand the highly aggressive and highly invasive nature of prostate cancer, allowing for needed improvement in the treatment of this disease.

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

Gastric outlet obstruction (GOO) poses a common and challenging clinical scenario, characterized by mechanical blockage in the pylorus, distal stomach, or duodenum, resulting in symptoms such as nausea, vomiting, abdominal pain, and early satiety. Its diverse etiology encompasses both benign and malignant disorders. The spectrum of current treatment modalities extends from conservative approaches to more invasive interventions, incorporating procedures like surgical gastroenterostomy (SGE), self-expandable metallic stents (SEMS) placement, and the advanced technique of endoscopic ultrasound-guided gastroenterostomy (EUS-GE). While surgery is favored for longer life expectancy, stents are preferred in malignant gastric outlet stenosis. The novel EUS-GE technique, employing a lumen-apposing self-expandable metal stent (LAMS), combines the immediate efficacy of stents with the enduring benefits of gastroenterostomy. Despite its promising outcomes, EUS-GE is a technically demanding procedure requiring specialized expertise and facilities.

Chronic gastroduodenal symptoms are prevalent worldwide, and there is a need for new diagnostic and treatment approaches. Several overlapping processes may contribute to these symptoms, including gastric dysmotility, hypersensitivity, gut-brain axis disorders, gastric outflow resistance, and duodenal inflammation. Gastric Alimetry® (Alimetry, New Zealand) is a non-invasive test for evaluating gastric function that combines body surface gastric mapping (high-resolution electrophysiology) with validated symptom profiling. Together, these complementary data streams enable important new clinical insights into gastric disorders and their symptom correlations, with emerging therapeutic implications. A comprehensive database has been established, currently comprising >2,000 Gastric Alimetry tests, including both controls and patients with various gastroduodenal disorders. From studies employing this database, this pa-per presents a systematic methodology for Gastric Alimetry test interpretation, together with an extensive supporting literature review. Reporting is grouped into four sections: Test Quality, Spectral Analysis, Symptoms, and Conclusions. This review compiles, assesses, and evaluates each of these aspects of test assessment, with discussion of relevant evidence, example cases, limitations, and areas for future work. The resultant interpretation methodology is recommended for use in clinical practice and research to assist clinicians in their use of Gastric Alimetry as a diagnostic aid, and is expected to continue to evolve with further development.

At nuclear scale, we present three heuristic relations pertaining to strong and electroweak coupling constants. With these relations, close to beta stability line, it is possible to study nuclear binding energy with a single energy coefficient of magnitude $\left(\frac{1}{{\alpha }_s}\right)\left[\frac{e^2}{4\pi {\epsilon }_0{R}_0}\right]\approx 10.0\text{MeV}\text{.}$ With reference to up and down quark masses, it is also possible to interpret that, nuclear binding energy is proportional to the mean mass of $\left[\left(2m_u+m_d\right)\text{and}\left(m_u+2m_d\right)\right]\approx 10.0\text{MeV}.$

Dipeptidyl peptidase 9 (DPP9) is a multifunctional intracellular protease with roles in tumour growth, inflammation and mitochondrial function. We developed a hepatocyte-specific DPP9 knockout mouse (DPP9-KO) to explore DPP9 in a mouse model of hepatocellular carcinoma (HCC). DPP9-KO mice were generated by crossing Albumin-Cre mice (Wt/Wt Cre+/+) with DPP9 floxed mice (Fl/Fl Cre-/-). Mice were treated with Diethylnitrosamine and Thioacetamide then an atherogenic High Fat Diet until 28 weeks of age. DPP9-KO mice had reduced liver and subcuta-neous adipose tissue mass and lower fasting plasma glucose, fewer small macroscopic liver nod-ules compared to DPP9-WT mice. However, there were no differences in the total number of mac-roscopic liver nodules, tumour burden, inflammation score and steatosis score. Consistent with the known ability of DPP9 to suppress NLRP1 activation, activated caspase-1 protein was ele-vated in DPP9-KO mouse liver. Additionally, Nfkbib, Cxcl10 and Ccl5 mRNA and protein levels of autophagy marker beclin1 and tumour suppressor p53 were increased. In conclusion, DPP9 de-pletion in hepatocytes may reduce liver cancer initiation, via mechanisms that may include in-creased autophagy and innate tumour suppression in this experimental model. Finally, the data supports DPP9 having a role in glucose regulation by the liver.

New setting is introduced to study the global powerful alliance. Global powerful alliance is about a set of vertices which are applied into the setting of neutrosophic graphs. Neighborhood has the key role to define this notion. Also, neighborhood is defined based on strong edges. Strong edge gets a framework as neighborhood and after that, too close vertices have key role to define global powerful alliance based on strong edges. The structure of set is studied and general results are obtained. Also, some classes of neutrosophic graphs excluding empty, path, star, and wheel and containing complete, cycle and r-regular-strong are investigated in the terms of set, minimal set, number, and neutrosophic number. Neutrosophic number is used in this way. It’s applied to use the type of neutrosophic number in the way that, three values of a vertex are used and they’ve same share to construct this number. It’s called “modified neutrosophic number”. Summation of three values of vertex makes one number and applying it to a set makes neutrosophic number of set. This approach facilitates identifying minimal set and optimal set which forms minimal-global-powerful-alliance number and minimal-global-powerful-alliance-neutrosophic number. Two different types of sets namely global-powerful alliance and minimal-global-powerful alliance are defined. Global-powerful alliance identifies the sets in general vision but minimal-global-powerful alliance takes focus on the sets which deleting a vertex is impossible. Minimal-global-powerful-alliance number is about minimum cardinality amid the cardinalities of all minimal-global-powerful alliances in a given neutrosophic graph. New notions are applied in the settings both individual and family. Family of neutrosophic graphs has an open avenue, in the way that, the family only contains same classes of neutrosophic graphs. The results are about minimal-global-powerful alliance, minimal-global-powerful-alliance number and its corresponded sets, minimal-global-powerful-alliance-neutrosophic number and its corresponded sets, and characterizing all minimal-global-powerful alliances, minimal-t-powerful alliance, minimal-t-powerful-alliance number and its corresponded sets, minimal-t-powerful-alliance-neutrosophic number and its corresponded sets, and characterizing all minimal-t-powerful alliances. The connections amid t-powerful-alliances are obtained. The number of connected components has some relations with this new concept and it gets some results. Some classes of neutrosophic graphs behave differently when the parity of vertices are different and in this case, cycle, and complete illustrate these behaviors. Two applications concerning complete model as individual and family, under the titles of time table and scheduling conclude the results and they give more clarifications and closing remarks. In this study, there’s an open way to extend these results into the family of these classes of neutrosophic graphs. The family of neutrosophic graphs aren’t study deeply and with more results but it seems that analogous results are determined. Slight progress is obtained in the family of these models but there are open avenues to study family of other models as same models and different models. There’s a question. How can be related to each other, two sets partitioning the vertex set of a graph? The ideas of neighborhood and neighbors based on strong edges illustrate open way to get results. A set is global powerful alliance when two sets partitioning vertex set have uniform structure. All members of set have more amount of neighbors in the set than out of set and reversely for non-members of set with less members in the way that the set is simultaneously t-offensive and(t-2)-defensive. A set is global if t=0. It leads us to the notion of global powerful alliance. Different edges make different neighborhoods but it’s used one style edge titled strong edge. These notions are applied into neutrosophic graphs as individuals and family of them. Independent set as an alliance is a special set which has no neighbor inside and it implies some drawbacks for these notions. Finding special sets which are well-known, is an open way to purse this study. Special set which its members have only one neighbor inside, characterize the connected components where the cardinality of its complement is the number of connected components. Some problems are proposed to pursue this study. Basic familiarities with graph theory and neutrosophic graph theory are proposed for this article.