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.

Introduction: Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Although the incidence is decreasing in developed countries, treatment results are still unsatisfactory. The standard treatment for locally advanced gastric cancer (LAGC) is gastrectomy with perioperative chemotherapy. Aim: Assessment of selected microRNAs (miRNAs) in chemoresistance in archival material from LAGC. Material and method: The research group consisted of archival material from 10 patients with LAGC. Histological material from each patient was used from a biopsy performed during gastroscopy and after surgery preceded by 4 cycles of neoadjuvant chemotherapy (NAC) according to the FLOT or FLO regimen. The expression of selected miRNAs was assessed in the tissue material, such as miRNA-21-3p, miRNA-21-5p, miRNA-106a-5p, miRNA-122-3p, miRNA-122-5p, miRNA-143-3p, miRNA-143-5p, miRNA-203a-3p, miRNA-203-5p, miRNA-551b-3p, miRNA-551b-5p and miRNA-574-3p. miRNA expression was assessed by quantitative chain reaction polymerase reverse transcriptase (qRT-PCR). The response to NAC was assessed by computed tomography of the abdomen, chest and histopathology after gastrectomy. The statistical analyses were performed using GraphPad Prism 9.The significance limit was set at p

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.

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.

Gastric cancer is the fifth most common and fourth deadliest cancer worldwide, with a bleak 5-year survival rate of about 20%. Despite significant research into its pathobiology, prognostic predictability remains insufficient due to pathologists’ heavy workloads and the potential for diagnostic errors. Consequently, there is a pressing need for automated and precise histopathological diagnostic tools. This study leverages Machine Learning and Deep Learning techniques to classify histopathological images into healthy and cancerous categories. By utilizing both handcrafted and deep features and shallow learning classifiers on the GasHisSDB dataset, we conduct a comparative analysis to identify the most effective combinations of features and classifiers for differentiating normal from abnormal histopathological images without employing fine-tuning strategies. Our methodology achieves an accuracy of 95% with the SVM classifier, underscoring the effectiveness of feature fusion strategies. Additionally, cross-magnification experiments produced promising results with accuracies close to 80% and 90% when testing the models on unseen testing images with different resolutions.

Breast cancer remains a major public health concern, and early detection can result in more treatment options, which are crucial for improving survival rates. Metabolomics offers the potential to develop blood-based screening and diagnostics tools that are less invasive and more cost-effective. However, the inherent complexity of metabolomic datasets makes identifying the most diagnostically relevant biomarkers a difficult task, with multiple studies demonstrating lim-ited agreement on the specific metabolites and pathways involved. This study aims to identify a set of biomarkers for early diagnosis of breast cancer using metabolomics data. Plasma samples from 185 breast cancer patients and 53 controls (CHTN) were analyzed. We utilized univariate Naïve Bayes, L2-regularized Support Vector Machines, and Principal Component Analysis (PCA), along with feature engineering techniques, to select the most informative features. Multiple ma-chine learning models, including Support Vector Machines, Multidimensional Scaling, Logistic Regression, and Ensemble Learning were utilized for classification. The best-performing feature set comprised 4 biomarkers and 2 demographic variables, achieving an accuracy of 98%, demon-strating the potential for a robust, cost-effective, non-invasive breast cancer screening and diagnostic tool.

Astragalus plants belong to the legume family and have obvious rhizosphere effect. The northwestern area of Yunnan China is the main distribution region of Astragalus plants with high application value, but low recognition and resource reserves. The aim of this research is to explore the species diversity of cultivable rhizosphere fungi derived from A. acaulis, A. forrestii, and A. ernestii growing in special high-cold environment of northwest Yunnan, and discover anti-infective components from these fungi. A total of 93 fungal strains belonging to 38 species in 18 genera were isolated and identified. Antibacterial and antimalarial screening yielded 10 target strains. Among them, the ethyl acetate crude extract of the fungus Aspergillus calidoustus AA12 from A. acaulis fermentation substance showed a broad antibacterial spectrum and the best antimalarial activity. Further chemical investigation led to the first discovery of seven compounds from the species of A. calidoustus, including a sesterterpine 6-epi-ophiobolin G (1), two sesquiterpenes penicisochroman A (2), pergillin (3) and 7-methyl-2-(1-methylethylethlidene)-furo[3,2-H]isoquinoline-3-one (4), and three polyketides trypacidin (5), 1,2-seco-trypacidin (6) and questin (7). Compound 1 exhibited moderate to strong antibacterial activity against six Gram-positive pathogens with the minimum inhibitory concentration (MIC) ranging from 25 to 6.25 μg/mL, and prominent inhibitory effect on the biofilm of Streptococcus agalactiae at MIC value of 3.125 μg/mL. This compound also displayed potent antimalarial activity against Plasmodium falciparum strains 3D7 and chloroquine-resistant Dd2 at the half maximal inhibitory concentration (IC50) values of 3.319 and 4.340 µmol/L at 72 h, respectively. This study contributed to our understanding of the cultivable rhizosphere fungi Astragalus-derived in special high-cold environment and further increased the library of fungi available for natural anti-infectious products screening.

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.

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.

Gastric cancer has become a serious worldwide health concern, emphasizing the cru-cial importance of early diagnosis measures to improve patient outcomes. While tradi-tional histological image analysis is regarded as the clinical gold standard, it is la-bor-intensive and manual. Recognizing this problem, there has been a rise in interest in using computer-aided diagnostics tools to help pathologists with their diagnostic ef-forts. In particular, deep learning (DL) has emerged as a promising solution in this sector. However, current DL models are still restricted in their ability to extract exten-sive visual characteristics for correct categorization. To tackle this limitation, this study proposes the use of ensemble models, which incorporate the capabilities of sev-eral deep learning architectures and use aggregate knowledge of many models to im-prove classification performance, allowing for more accurate and efficient gastric cancer detection. To see how well these proposed models performed, this study com-pared them to other works, all of which were based on the Gastric Histopathology Sub-size Images Database, a publicly available dataset for gastric cancer. This research demonstrated that the ensemble models achieved high detection accuracy across all sub-databases, with an average accuracy exceeding 99%. Specifically, ResNet50, VGGNet, and ResNet34 performed better than EfficientNet and VitNet. For the 80 × 80 pixel sub-database, ResNet34 exhibited an accuracy of approximately 93%, VGGNet achieved 94%, and the ensemble model excelled with 99%. In the 120 × 120 pixel sub-database, the ensemble model showed 99% accuracy, VGGNet 97%, and ResNet50 approximately 97%. For the 160 × 160 pixel sub-database, the ensemble model again achieved 99% accuracy, VGGNet 98%, ResNet50 98%, and EfficientNet 92%, high-lighting the ensemble model's superior performance across all resolutions. Overall, the ensemble model consistently provided an accuracy of 99% across the three sub-pixel categories. These findings showed that ensemble models may successfully detect criti-cal characteristics from smaller patches and achieve high performance. The findings will help pathologists diagnose gastric cancer using histopathological images, leading to earlier identification and higher patient survival rates.

The injury causes resistance in human gastric cancer (GC). This Adverse Outcome Pathway (AOP) entitled “Increases in cellular reactive oxygen species (ROS) and chronic ROS leading to human treatment-resistant gastric cancer (GC)” consists of molecular initiating event (MIE) as “Increases in cellular ROS” and “Chronic ROS”, followed by series of key events (KEs); “porcupine-induced Wnt secretion and Wnt signaling activation”, “beta-catenin activation”, “epithelial-mesenchymal transition (EMT), and adverse outcome (AO) as “human treatment-resistant GC” in the sequence. ROS has multiple roles in disease such as development and progression of cancer, or apoptotic induction causing anti-tumor effects. In this AOP, we focus on the role of sustained levels of chronic ROS to induce the therapy-resistance in human GC. EMT, which is cellular phenotypic change from epithelial to mesenchymal-like features, demonstrates cancer stem cell (CSC)-like characteristics in human GC. EMT is induced by Wnt/beta-catenin signaling, providing the rationale to have Wnt secretion and beta-catenin activation as KEs in the AOP.

Bartonella species, intracellular parasitic zoonotic pathogens, has drawn increasing attention for their diverse host range and associated human diseases. This study investigates Bartonella infection in small mammals in Yunnan Province, China, focusing on tissue tropism. 333 small mammals were sampled from 13 species, 3 orders, 4 families, and 4 genera in Heqing and Gongshan Counties. Conventional PCR and real-time quantitative PCR (qPCR) were utilized for detection and quantification, followed by bioinformatic analysis of obtained DNA sequences. Results show a 31.5% detection rate, varying across species. Notably, Apodemus chevrieri, Eothenomys eleusis, Niviventer fulvescens, Rattus tanezumi, Episoriculus leucops, Anourosorex squamipes, and Ochotona Thibetana exhibited infection rates of 44.4%, 27.7%, 100.0%, 6.3%, 60.0%, 23.5%, and 22.2%, respectively. Genetic analysis identified 30, 10, and 5 strains based on ssrA, rpoB, and gltA genes, with nucleotide identities ranging from 92.1% to 100.0%. Bartonella strains were assigned to B. grahamii, B. rochalimae, B. sendai, B. koshimizu, B. phoceensis, B. taylorii, and a new species identified in the Episoriculus leucops (GS136). Tissue distribution analysis revealed varied copy numbers across different tissues, with the highest load in spleen. These findings underscore Bartonella's diverse species and host range in Yunnan Province, highlighting its broad tissue tropism in small mammals.

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.

Cytologic diagnosis of extra‐adrenal paraganglioma presenting as a peripancreatic mass is challenging with a high rate of diagnostic error. We present a case of a peripancreatic mass identified by radiology as a gastrointestinal stromal tumor. Endoscopic ultrasound‐guided fine needle aspiration (FNA) of the mass showed a moderately cellular tumor composed of small to medium sized neoplastic cells with round to oval nuclei arranged singly and in loose clusters. The cells were positive for neuroendocrine markers (synaptophysin and chromogranin) and negative for CD117. A diagnosis of a neoplasm with a neuroendocrine tumor (NET) was made on FNA cytology. The subsequent surgical resection of the tumor revealed peripancreatic paraganglioma with immunohistochemistry positive for synaptophysin, chromogranin, and S100. The latter delineates the sustentacular cells. Although paraganglioma is a well recognized tumor, a detailed comparison of peripancreatic paraganglioma versus pancreatic/gastrointestinal NET is still lacking.

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):

EUS–TA in unresectable pancreatic cancer requires not only a tissue diagnosis but also tissue collection in anticipation of comprehensive genomic profiling. However, the optimal puncture target remains controversial. Therefore, the Primary and Metastatic Lesions in Pancreatic Cancer (PRIMATE) study was designed to clarify the optimal target by comparing the success rates for meeting OncoGuide NCC Oncopanel (NOP) analysis criteria on pre-check primary and metastatic lesion specimens obtained during the same EUS–TA session in patients with invasive pancreatic ductal adenocarcinoma. In this ongoing prospective study, two specimens, each from primary and metastatic lesions, are obtained by EUS–TA (typically using a 19G fine-needle biopsy needle) in patients with invasive pancreatic ductal adenocarcinoma. The primary endpoint is the proportion of EUS–TA specimens that meet NOP analysis criteria during pre-check (i.e., tumor cellularity ≥ 20% and tissue area ≥ 4 mm2), which are then compared between primary and metastatic lesions. This study has been approved by the National Cancer Center Institutional Review Board (Research No. 2022-168). The results of this study will be reported at an international conference and published in an international peer-reviewed journal. The trial registration number is UMIN 000048966.

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).

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.

Gastric cancer (GC) remains a significant global health challenge, with high mortality rates, especially in developing countries. Current treatments are invasive and have considerable risks, necessitating the exploration of safer alternatives. Quercetin (QRC), a flavonoid present in various plants and foods, has demonstrated multiple health benefits, including anticancer properties. This study investigates the therapeutic potential of QRC in the treatment of GC. We utilized advanced molecular techniques to assess the impact of QRC on GC cells, examining its effects on cellular pathways and gene expression. Our findings indicate that QRC significantly inhibits GC cell proliferation and induces apoptosis, suggesting its potential as a safer therapeutic option for GC treatment. Further research is required to validate these results and explore the clinical applications of QRC in cancer therapy

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.

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.

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

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.

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.

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.

Bladder cancer (BC) is one of the most lethal genitourinary malignancies owing to its propensity for recurrence and poor survival. The biochemical pathway, signal transducer and activator of transcription 3 (STAT3), has gained significance as a molecular pathway that promotes proliferation, invasion, and chemoresistance. In this study, we explored the targeting of STAT3 with TTI-101 and SH5-07 in bladder cancer (BCa) and elucidated the mechanisms in three-dimensional (3D) spheroid and tumoroid models. We optimized the growth of spheroids from human, rat, and mouse BCa cell lines (J82, NBT-II, and MB49, respectively), and tumoroids from BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine) induced rat bladder tumors. Cell viability was assessed using MTT and trypan blue assays. ATP production, ROS production, and calcium AM (CA)/EtBr staining were used to measure the spheroid and organoid inhibition and mitochondrial function. Western blot analysis was performed to evaluate the pharmacodynamic markers involved in cell proliferation, apoptosis, cancer stem cells (CSCs), and STAT3 signaling in BCa. We found that targeting STAT3 (using TTI-101 and SH5-07) significantly reduced the proliferation of BCa spheroids, and tumoroids, which was accompanied by decreased expression of pSTAT3, Cyclin D1, and PCNA. Our data also demonstrated that treatment with STAT3 inhibitors induced ROS production and cell death in BCa spheroids and organoids. STAT3 inhibition induced cell death was associated with the activation of caspase 3/7 and PARP cleavage. Moreover, TTI-101 and SH5-07 targets cancer stem cells by downregulating the expression of CD44 and CD133 in 3D models. This study provides the first evidence for the prevention of bladder cancer with small-molecule inhibitors TTI101 and SH5-07 via suppression of CSCs and STAT3 signaling.

Diffuse type of gastric cancer (GC) has an increasing prevalence worldwide, especially in Western countries, is usually diagnosed at advanced stages, and has no efficacious treatment options. Epidemiological studies have reported an increased mortality from GC after occupational exposure to well-studied pro-carcinogen that are metabolically activated by Cyp P450 enzymes through aryl hydrocarbon receptor (AhR). Substantial studies support the involvement of AhR in gastric carcinogenesis. However, little is known about the role of AhR in diffuse GC, as compared to intestinal GC. In a cohort of 29 gastric tumors, we described a significantly increased AhR protein and mRNA expression levels in GCs, independently of subtypes and clinical parameters. AhR and RhoA mRNA expression were correlated in diffuse GC. Further, our study characterized how AhR affects gene expression in diffuse GC. Using qRT-PCR, we compared the expression levels of AhR, Cyp1A1 and Cyp1B1 to the expression of genes in a panel previously described. In diffuse GC, Cyp1A1 expression correlated with genes involved in IGF signalling, EMT (VIM), migration (MMP2). In an in vitro assay using the poorly differentiated KATOIII epithelial cell line, two well-known ligands for AhR (TCDD and BaP) induced mRNA expression of CYP1A1, IL1b, as well as UGT1, NQO1 and AhRR to a lower extent. We also observed a strong increase in Cyp1B1 expression in diffuse GC, along with a lower TCDD-increased Cyp1B1 expression as compared to Cyp1A1 in KATOIII cells, and immunostaining in stromal cells. In intestinal GC, Cyp1B1 inversely correlated with several genes including IDO1 (generating endogenous kynurenin-e AhR ligand). Our data provide evidence for a major role of AhR in GC, as an environmental xenobiotics receptor, through different mechanisms and pathways in diffuse and intestinal GC. Our results support continued efforts to clarify the identities of exogenous AhR ligands in diffuse GC in order to define new therapeutic strategies.

During HIV-1 virus assembly the genomic RNA (vRNA) is selected for packaging by the viral protein Gag because it contains a specific packaging signal, Psi. While there have been numerous studies of Gag-Psi interactions, there is almost no information on kinetic aspects of this interaction. We have investigated the kinetics of Gag binding to different RNAs using switchSENSE DRX2 technology. We measured the association rate of Gag binding to monomeric Psi, to a “Multiple Binding Site Mutant” Psi that is inactive for genome packaging in vivo, and to a scrambled Psi. We discovered that Gag binds more rapidly to Psi RNA than to the mutant or scrambled RNAs. Furthermore, rapid Gag association kinetics are retained within sub-regions of Psi: Gag associates more rapidly with RNA containing only the 3’ two of the three Psi stem-loops than with monomeric RNA containing the 5’ two stem-loops or a scrambled RNA. No differences were detectable with individual Psi stem-loops. Interestingly, the rate of binding of Gag molecules to Psi increases with increasing Gag concentration, suggesting cooperativity in binding. The results are consistent with the hypothesis that selectivity in packaging derives from kinetic differences in initiation of particle assembly.

Lower cutoff levels in screening programs have led to an increase in the proportion of detected cases with transient hypothyroidism, leading to increase of the overall incidence of primary congenital hypothyroidism (CH) in several countries. We have performed retrospective evaluation on the data from 251,008 (96.72%) neonates screened for thyroid-stimulating hormone (TSH) level in dried blood spot specimens taken 48 hours after birth, between 2002 and 2015, using DELFIA method. A TSH value of 15 mIU/L was used as the cutoff point until 2010 and 10 mIU/L thereafter. Primary CH was detected in 127 newborns (1/1976) of which 81.1% had permanent and 18.9% had transient CH. The incidence of primary CH was increased from 1/2489 until to 2010 to 1/1585 thereafter (p=0.131). However, the incidence of permanent CH was slightly increased (p=0.922), while the transient CH incidence had 8-fold increasing after lowering the TSH cutoff level (p<0.001). In cases with permanent CH, we observed lower frequency for thyroid dysgenesis (82.7 vs. 66.7%) and higher frequency for normal in-situ thyroid gland (17.3 vs. 33.3%), for the period with reduced TSH cutoff value. Our findings support the impact of lower TSH cutoff on the increasing incidence of congenital hypothyroidism.

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.

Cervical cancer (CC) is the most common cancer in women worldwide and is almost always associated with repeated infections by human papillomavirus (HPV). Screening by traditional tests combined with biomarker identification techniques for low- or high-grade injuries, are becoming increasingly important in diagnosis and prognosis, avoiding countless deaths. This article explores existing literature on the main serum biomarkers and the identification of biomarkers associated with the oncogenesis of HPV expression in the identification of pre-cancerous lesions and of CC for an effective treatment, with reduction of recurrence, as well as we explain strategies for the development of biomarkers based on DNA, proteins and other markers. We also describe how markers of chromosomal instability host DNA, promoting hypo- or hypermethylation of DNA, as well as polymorphisms and epigenetic events in the p53 gene. Finally, we discuss changes in gene expression using cDNA microarray techniques and changes in the expression of proteins and markers identified through mass spectrometry.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants of emerging concern, recognized for their toxicity and potential carcinogenic properties. PFAS chemicals are reported to act as endocrine disruptors through their interactions with various nuclear receptors (NRs). Despite their significant impact, comprehensive screenings and detailed analyses of PFAS binding strengths at both the orthosteric and allosteric sites of NRs are currently lacking in the literature. Our study addresses this gap by focusing on the binding interaction analysis of both common and uncommon PFAS with key nuclear receptors such as the vitamin D receptor (VDR), peroxisome proliferator-activated receptor gamma (PPARγ), pregnane X receptor (PXR), and estrogen receptor alpha (ERα). We used advanced docking simulations to screen 9,507 PFAS chemicals at the orthosteric and allosteric sites of the PPARγ, PXR, VDR, and ERα. We verified the accuracy of our docking protocol through multiple docking procedures and validations. The python code used for PFAS chemical screening is deposited in the supplementary file. Among the PFAS assessed at the orthosteric site of the VDR, 21 demonstrated similar binding affinities compared to the calcitriol, while 130 PFAS, exhibited stronger binding affinities than calcitriol. At the VDR allosteric site, where lithocholic acid (LCA) natively binds, 412 PFAS matched the binding energies of LCA, and 2,229 showed even greater binding energies. Similar testing on the PXR, PPARγ, and ERα revealed that the orthosteric site of PPARγ had 1,863 PFAS binding with a higher affinity than native ligand ET1 and 693 PFAS binding at the allosteric site with greater affinity than T35 native ligand. At the PXR orthosteric site, 650 PFAS bound with a greater affinity than native ligand 4WH, while at the allosteric site, 9,148 PFAS demonstrated a greater binding affinity than the known allosetric ligand glycerol. At the orthosteric site of ERα, 40 PFAS displayed binding with a greater affinity than the native ligand estradiol and at the allosteric site, only 8 PFAS exhibited greater binding affinity than coactivator ligand SRC-1. Further, our mixture modeling analysis indicates that PFAS can bind in various combinations with themselves and with endogenous or native ligands simultaneously, to disrupt the endocrine system and cause carcinogenic responses. These findings reveal that PFAS can interfere with nuclear receptor activity by displacing endogenous or native ligands by binding to the orthosteric and allosteric sites. This study elucidates the mechanisms through which PFAS exert their endocrine-disrupting effects, potentially leading to more targeted environmental regulations and therapeutic strategies. Importantly, this study is the first to explore the binding of PFAS at allosteric sites and to model PFAS mixtures at nuclear receptors. Given the high concentration and persistence of PFAS in humans, this study called for the urgent need for further research into the carcinogenic mechanisms of PFAS and the development of intervention strategies that target nuclear receptors. Our ongoing studies extend these findings by further investigating the interactions of PFAS and co-exposed chemicals with nuclear receptors. These investigations are supported by experimental verification, which will enhance our understanding of PFAS broad effects and aid in the design of effective mitigation strategies.

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.

Newborn screening (NBS) is hailed as a public health success, but little is known about long-term outcomes following a positive newborn screen. There has been difficulty gathering long-term follow-up (LTFU) data consistently, reliably, and with minimal effort. Six programs developed and tested a core set of minimal LTFU data elements. After an iterative data collection process and the development of a data collection tool, the group agreed on minimal LTFU data elements. The denominator captured all infants with an NBS diagnosis, accounting for children who moved or died prior to the follow-up year. They also agreed on three LTFU outcomes: if the child was still alive, had contact with a specialist, and received appropriate care specific to their diagnosis within the year. The six programs representing NBS public health programs, clinical providers, and research programs provided data across multiple NBS disorders. In 2022, 83.8% (563/672) of the children identified by the LTFU programs were alive and living in the jurisdiction; of those, 92.0% (518/563) saw a specialist, and 87.7% (494/563) received appropriate care. The core LTFU data elements can be applied as a foundation to address the impact of early diagnosis by NBS within and across jurisdictions.

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide, often associated with a bad prognosis because of its asymptomatic phenotype until advanced stages, highlighting the need for its prevention and early detection. GC development is preceded by gastric preneoplasia lesions (GPNL), namely atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia (DYS). GC is currently diagnosed by endoscopy, which is invasive and costly and has limited effectiveness for the detection of GPNL. Therefore, the discovery of non-invasive biomarkers in liquid biopsies, such as blood samples, to identify the presence of gastric preneoplasia and/or cancer lesions at an asymptomatic stage, is of paramount interest. This comprehensive review provides an overview of plasma/serum proteins recently identified and their diagnostic performance for the prediction of GPNL and early cancer lesions. Autoantibodies appear as promising biomarkers for AG, IM and early gastric cancer detection, along with inflammation and immunity-related proteins and antibodies against H. pylori virulence factors. There is a lack of specific protein biomarkers to detect DYS. Despite the need for further investigation and validation, some emerging candidates could pave the way to develop reliable, non-invasive diagnostic tests for the detection and prevention of GC.

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.

The causal networks are important for understanding the signaling alterations in diseases. To reveal the network pathways affected in epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), which are related to poor prognosis of cancer, the molecular networks and gene expression in diffuse- and intestinal-type gastric cancer (GC) have been analyzed. The network pathways in GC were analyzed in Ingenuity Pathway Analysis (IPA). The analysis of the probe sets of which gene expression has significant differences between diffuse- and intestinal-type GC in RNA Sequencing publicly available data identified 1099 causal networks in diffuse- and intestinal-type GC. Master regulators of the causal networks included lenvatinib, pyrotinib, histone deacetylase 1 (HDAC1), mir-196, and erb-b2 receptor tyrosine kinase 2 (ERBB2). The analysis of the HDAC1-interacting network identified the involvement of regulation of EMT by growth factors pathway, coronavirus pathogenesis pathway, and vorinostat. The network had RNA-RNA interactions with microRNAs such as mir-10, mir-15, mir-17, mir-19, mir-21, mir-217, mir-223, mir-25, mir-27, and mir-34. These molecular networks revealed in the study may lead to the identification of drug targets for GC.

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.

The up-and-coming microfluidic technology is the most promising platform for designing anti-cancer drugs and new point-of-care diagnostics. Compared to conventional drug screening methods based on Petri dishes and animal studies, drug delivery in microfluidic systems has many advantages. For instance, these platforms offer high throughput drug screening, require a small amount of samples, provide an in vivo-like microenvironment for cells, and eliminate ethical issues associated with animal studies. Multiple cell cultures in microfluidic chips could better mimic the 3D tumor environment using low reagents consumption. The clinical experiments have shown that combinatorial drug treatments have a better therapeutic effect than monodrug therapy. So many attempts were performed in this field in the last decade. This review highlights the applications of microfluidic chips in anti-cancer drug screening and systematically categorizes these systems as a function of sample size and combination of drug screening. Finally, it provides a perspective on the future of the clinical applications of microfluidic systems for anti-cancer drug development.

In most industrialized countries, screening programs for cervical cancer have shifted from cytology (Pap smear or ThinPrep) alone on clinician-obtained samples to the addition of screening for human papillomavirus (HPV), its main causative agent. For HPV testing, self-sampling instead of clinician-sampling has proven to be equally accurate, in particular for assays that use nucleic acid amplification techniques. In addition, HPV testing of self-collected samples in combination with a follow-up Pap smear in case of a positive result is more effective in detecting precancerous lesions than a Pap smear alone. Self-sampling for HPV testing has already been adopted by some countries, while others have started trials to evaluate its incorporation into national cervical cancer screening programs. Self-sampling may result in more individuals willing to participate in cervical cancer screening, because it removes many of the barriers that prevent women, especially those in low socioeconomic and minority populations, from participating in regular screening programs. Several studies have shown that the majority of women who have been underscreened but who tested HPV-positive in a self-obtained sample, will visit a clinic for follow-up diagnosis and management. Additionally, a self-collected sample can also be used for vaginal microbiome analysis, which can provide additional information about HPV infection persistence as well as vaginal health in general.

For monitoring of chimeric antigen receptor (CAR) T-cell therapies antigen-based CAR detection methods are usually applied. However, for each target-antigen a separate detection system is required. Furthermore, when monitoring CAR T-cells in the blood of patients treated with bispecific antibodies or T-cell engagers (bsAbs/BiTEs) recognize the same antigen, these methods producing false-positive results in clinical diagnostics. Anti-CAR-linker monoclonal antibodies (mAbs) targeting the linker sequence between the variable domains of the antigen binding CAR fragment, promise an universal and unbiased CAR detection. To test this, we analyzed clinical specimens of all BCMA- and CD19 targeting CAR T-cell products currently approved for clinical use. We found a highly specific and sensitive CAR detection by using anti-CAR-linker mAb in blood cells from patients treated with Ide-cel, Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. For Ide-cel and Tisa-cel the sensitivity was significant lower compared to antigen-based CAR detection assays. Strikingly, the specificity of anti-CAR linker mAb was not affected by the simultaneous presence of bispecific blinatumomab or teclistamab for Axi-cel, Brexu-cel, Liso-cel or Ide-cel, respectively. Cilta-cel (containing an monomeric G4S-CAR linker) could not be detected by anti-CAR linker mAb. In conclusion, anti-CAR-linker mAbs are highly specific and useful for CAR T-cell monitoring but not universal applicable.

Tertiary lymphoid structures (TLSs) have become the focus of antitumor immunity. However, the prognostic significance of TLSs in epithelial ovarian cancer (EOC) treated with primary debulking surgery (PDS) or interval debulking surgery (IDS) remains unelucidated. This retrospective study examined the prognostic value of TLSs in tumor tissues obtained during PDS and IDS. Pathological specimens were collected from patients with EOC who underwent PDS or IDS between 2017 and 2020 at the National Cancer Center Hospital East. The correlation of tumor-infiltrating lymphocyte frequency, TLS presence, and PD-L1 expression with progression-free survival (PFS) and overall survival (OS) and the correlation between TLS and PD-L1 expression were analyzed. Overall, 25 specimens (15 from PDS and 10 from IDS) were analyzed. The presence of TLS was associated with a significantly longer OS in patients who underwent PDS but not in patients who underwent IDS. No correlation was identified between TLS and PFS in patients with PDS or with IDS. However, TLS was positively correlated with PD-L1 positivity. The prognostic impact of TLS, specifically in pre-chemotherapy specimens, and a positive correlation between TLS and PD-L1 indicate the potential of TLS as a meaningful biomarker for understanding antitumor immunity and developing immunotherapy for EOC.

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.

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.

Human Papillomavirus (HPV) self-sampling has the potential to increase cervical cancer screening (CCS) and reduce the cervical cancer burden in Medically Underserved Women (MUW). However, interventions promoting self-sampling are limited. We examined the effectiveness of an intervention study in increasing CCS among MUW. We conducted a quasi-experimental intervention study. Face-to-face verbal approach was to recruit MUW (n=85, mean age 48.57±11.02) living in a small city in the US. Behavioral intervention based on reframing, reprioritizing, and reforming (3R model) was used to educate the women about CCS in a group format. The women completed pre-and post-intervention assessments and followed-up interviews. The primary outcome was CCS uptake. Mixed methods analyses were conducted using a t-test for the primary outcome, PROCESS for mediation analysis, and NVivo for interview data. Majority of women (75%) completed self-testing. High-risk HPV prevalent among the women was 11%, and of those, 57% followed-up with physicians for care. We found that the significant increase in the women’s post-intervention screening behaviors was mediated by the increase in knowledge (Indirect Effect [IE] = .1314; 95% CI, .0104, .4079) and attitude (IE = .2167; 95% CI, .0291, .6050) scores, (p&lt;0.001). Interview analyses offered further explanations (see the explanations in parenthesis) why MUW found the intervention messages acceptable (encourages proactive behavior), feasible (simple and easy to understand), and appropriate (helpful and informative). Barriers including lack of trust and fear of results were identified. The findings suggest that an intervention that combines the 3R model and self-sampling may increase CCS among MUW.

The present investigation has been conducted on one hundred tissue fragments of breast cancer, collected and immediately cryopreserved following the surgical resection. The fragments were selected from patients with invasive ductal carcinoma of the breast, the most common and potentially aggressive type of mammary cancer, with the objective to increase the knowledge of breast cancer molecular markers, useful for diagnostic and prognostic categorization of patients, in assessing post-surgical therapeutic regimes. The proteomic screening, by 2D-IPG and mass spectrometry, allowed us to identify two main classes of protein clusters: proteins expressed ubiquitously at high levels in all patients, and proteins expressed sporadically among the same patients. Within the group of ubiquitous proteins, glycolytic enzymes and proteins with anti-apoptotic activity were predominant. Among the sporadic ones, proteins involved in cell motility, molecular chaperones and proteins involved in the detoxification appeared prevalent. The data of the present study indicates that the primary tumor growth is generally supported by two concurrent pathways: the inhibition of apoptosis and the stimulation of cellular proliferation. The second phase of the evolution of the tumor can be prematurely scheduled by the occasional presence of proteins involved in cell motility and in the defenses of the oxidative stress. To our knowledge this report on large-scales proteomics of breast cancer is currently a unique approach in the literature that offers the opportunity to evaluate the presence and recurrence of proteins to be used as prognostic indicators and susceptibility to metastasis in patients operated on for invasive ductal carcinoma of the breast.

Multi-cancer early detection (MCED) tests are being developed, but little is known about patient receptivity to their use for cancer screening. The current study assessed patient interest in such testing. Our team conducted a prospective, observational study among primary care patients in a large, urban health system. They were asked to complete a telephone survey that briefly described a new blood test in development to identify multiple types of cancer, but was not currently recommended or covered by insurance. The survey included items to assess respondent background characteristics, perceptions about MCED testing, and interest in having such an MCED test. We also used multivariable analyses to identify factors associated with patient interest in test use. In 2023, we surveyed 159 (32%) of 500 identified patients. Among respondents, 125 (79%) reported a high level of interest in having an MCED test. Interest was not associated with personal background characteristics, but was positively associated with the following expectations: testing would be recommended for cancer screening, be convenient, and be effective in finding early-stage disease (OR=11.70, 95% CI: 4.02, 34.04, p < 0.001). Research is needed to assess patient interest and actual uptake when detailed information on testing is presented in routine care.

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.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen progression–free survival (PSA-PFS) from ARSI initiation were assessed using Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA-PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥3.67 ng/ml at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS.

We assessed the impact of social determinants of health (SDOH) and psychosocial factors on screening behavior in a nationally representative sample of women in the US. A retrospective population-level cross-sectional sample was extracted from the 2022 Health Information National Trends Survey. Descriptive statistics were conducted for demographic characteristics and covariates. Population-based estimates with 95% confidence intervals (95% CI) were produced for Pap testing behaviors across study years. We used logistic regression models to assess Pap testing differences based on SDOH and psychosocial factors, adjusting for covariates, with a significance level of 0.05 for hypothesis testing. Women (n=2,224) with a mean age of 46.96 participated in the study. Our study found that 90% of women were interested in cervical cancer screening, with an 80% actual screening rate. Screening rates differed by age group and rurality. SDOH and psychosocial factors were associated with participants’ interest in screening and in actual screening behavior. The impacts of SDOH and psychosocial factors on screening behavior were 3% and 1%, respectively. The SDOH and psychosocial factors are associated with the uptake of cervical cancer screening among women in the United States. Policies must be directed at bridging the gap created by these SDOHs.

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.

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.

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.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

Since the identification of acquired immunodeficiency syndrome (AIDS) in 1981, approximately 85.6 million people have been infected with HIV, resulting in 40.4 million deaths. As of 2022, 53% of the 39 million people living with HIV are women and girls. Despite the advent of antiretroviral therapy (ART) improving survival rates, cervical cancer remains prevalent among HIV-infected individuals. By 2030, cervical cancer is projected to cause 727,500 new cases and 432,000 deaths globally. Human papillomavirus (HPV) is a well-known cause of cervical cancer, with HIV infection exacerbating the prevalence of high-risk HPV (HR-HPV) and cervical intraepithelial neoplasia (CIN). HIV and HPV share transmission routes, and HIV worsens cervical carcinogenesis by inhibiting tumour suppressor genes and altering cell cycle regulation. Chronic inflammation and cytokine imbalances, notably increased IL-10 levels, are linked to cervical cancer progression. Despite ART improving overall health, cervical cancer remains a significant issue, highlighting the need for better screening and prevention measures. A cross-sectional study in Brazil evaluated cytokine levels in cervicovaginal lavage among HIV-positive women, revealing a high prevalence of specific HPV types. ART has been shown to reduce the likelihood of developing squamous intraepithelial lesions (SILs) and HR-HPV prevalence, although its impact on invasive cervical cancer remains inconclusive. In a study in Accra, 250 sexually active HIV-positive women exhibited a high HPV prevalence, emphasising the need for regular screening. HPV testing, visual inspection with acetic acid (VIA), and cytology-based tests are primary screening methods, each with specific advantages and limitations. A systematic review and meta-analysis indicated that ART is associated with a lower prevalence of HR-HPV and high-grade cervical lesions, suggesting that early ART initiation may reduce cervical lesion incidence and progression. HPV is a significant cause of sexually transmitted diseases, with high prevalence in sub-Saharan Africa. Studies show a substantial burden of HPV among men in the region, underscoring the potential benefits of HPV vaccination programs. A study in Tanzania highlighted a high prevalence of HR-HPV among HIV-positive men, suggesting the efficacy of HPV vaccines irrespective of HIV status. Cervical cancer rates in sub-Saharan Africa are alarmingly high, necessitating targeted vaccination and prevention strategies.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role, and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

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.

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.

Transplant of human cancer cells into zebrafish larvae has emerged as a useful methodology in cancer research. Zebrafish have very low husbandry costs, are amenable to large-scale drug screening, and are unmatched for optical clarity in live animal imaging. However, there is currently no consensus on the ideal methods for xenograft of human cancer cells into zebrafish. Here, we have examined the effects of transplant site and housing temperature on both zebrafish larvae and human cancer cells using survival analyses, metabolomic approaches, and in vivo imaging. Our data show that while zebrafish larvae can adapt to the ideal conditions for mammalian cells, human cancer cells are highly sensitive to both temperature change and transplant site. Human cells housed in slightly cooler than physiologic temperatures had a significantly altered metabolism that resulted in changes in growth, survival, and response to chemotherapy. Cancer cells xenografted into the yolk of the larvae also had reduced proliferation and drug response compared to those xenografted into the soma, in part due to the differences in metabolites available at these sites. In total, temperature and transplant site can have profound effects on xenografted cells. Standardization of zebrafish xenograft methods will enhance data reproducibility between individual laboratories.

Abstract Objectives: The aim of this study is to understand the rationale for the lack of interest to perform regular opportunistic oral cancer screening (OCS) by primary care providers (PCPs) and the challenges they have in incorporating OCS into their annual examination protocol. Method: Sequential exploratory mixed methods were used. Both qualitative and quantitative data from PCPs working at Nebraska Medicine were obtained. One-on-one in-depth interviews were performed to identify PCP's perceptions and challenges in performing OCS. The themes identified in the qualitative study were used as a guide in the development of survey questionnaires. The survey was emailed to all the PCPs (N=100), whose information was available on the Nebraska Medicine publicly accessible website. Results: The response rate was 34%. Approximately 60% of the participants mentioned that they currently perform oral cancer screening, but only 3.8% of the providers answered that they were performing comprehensive oral cancer screening every time. Forty-eight percent of the providers identified time as the biggest challenge. Over 35.3% of the providers answered that they perform screenings for patients with a history of tobacco (i.e., smoking) or alcohol use. Conclusion: Around half of the participants identified lack of time as their primary challenge in performing OCS and lack of knowledge as their second main obstacle. Very few provided comprehensive OCS and visual examination of the oral cavity is the only step performed often. Keywords: Oral cancer screening - Primary care providers - Oropharyngeal cancer-early detection of cancer-cancer screening-care providers-Health care professionals, health care providers

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

G protein-coupled receptor 15 (GPR15, also known as BOB) is an extensively studied orphan GPCR involving HIV infection, colonic inflammation and smoking-related diseases. Recently, GPR15 was deorphanized and its corresponding natural ligand demonstrated an ability of inhibiting cancer cell growth. However, no study reported the potential role of GPR15 in a pan-cancer manner. Using large-scale publicly available data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we found that GPR15 expression is significantly lower in colon adenocarcinoma (COAD) than in normal tissues. And among 33 cancer types, GPR15 expression is significantly correlated with the prognoses of COAD, neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD) positively and stomach adenocarcinoma (STAD) negatively. This study also revealed that commonly upregulated gene set in the high GPR15 expression group (stratified via median) of COAD, HNSC, LUAD and STAD are enriched in immune systems, indicating that GPR15 might be considered as a potential target for cancer immunotherapy. Furthermore, we modelled the 3D structure of GPR15 and conducted the structure-based virtual screening. The top 8 hits compounds were screened and then subjected to molecular dynamics (MD) simulation for stability analysis. Our study provided novel insights into the role of GPR15 in a pan-cancer manner and discovered a potential hit compound for GPR15 antagonists.

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Despite advancements in treatment, the prognosis for patients with GBM remains poor due to its aggressive nature and resistance to therapy. CRISPR-based genetic screening has emerged as a powerful tool for identifying genes crucial for tumor progression and treatment resistance, offering promising targets for tumor therapy. In this review, we provide an overview of the recent advancements in CRISPR-based genetic screening approaches and their applications in GBM. We highlight how these approaches have been used to uncover genetic determinants of GBM progression and susceptibility to various therapies. Furthermore, we discuss ongoing challenges and future directions of CRISPR-based screening methods in advancing GBM research.

Background: In high-risk breast cancer patients with skin infiltration the administration of a uniform dose to superficial tissues is fundamental in order to reduce local skin relapse. A personalized bolus may prevent the potential standard bolus’ inadequate dose distribution due to air gaps between the bolus and the skin. In this pilot study, we introduced in clinical practice the use of a personalized 3D printed bolus filled with ultrasound transmission gel. Methods: Seven patients undergoing radiotherapy after mastectomy were selected. 3D printed bolus dosimetric assessment was performed with MOSFET dosimeters on an anthropomorphic phantom and subsequently on three selected cases with increasing bolus shape irregularity. Acute/late toxicity and local control was assessed. Results: Overall, for the clinical cases the percentage median difference between measured and calculated doses was -2.7% (-7.0%÷4.9%). Median follow-up was 21 months. After two years, one patient showed G2 pain, one patient manifested G1 telangiectasia, one patient showed G1 hyperpigmentation, and two patients had no relevant toxicity. Conclusions: Personalized 3D-printed bolus filled with ultrasound gel may easily reproduce the standard bolus’ consistency providing an accurate coverage of the target area with tolerable acute/late toxicity grades. This is a pilot study and further investigations are needed.

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.

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.

Marine microalgae are a rich reservoir of natural compounds, including bioactives. Nonetheless, these organisms remain fairly unexplored despite their potential biotechnological applications. Culture collections with diverse taxonomic groups and lifestyles are a good source to unlock this potential and discover new molecules for multiple applications such as the treatment of human pathologies or the production of aquaculture species. In the present work extracts from 33 strains (including 20 dinoflagellates, 4 diatoms and 9 strains from other 7 algal classes), cultivated under identical conditions were examined for antiviral, antibacterial, anti-inflammatory and anti-cancer activities. Among these, antiviral and anti-inflammatory activities were detected in a few strains while antibacterial tests showed positive results in most assays. In turn, most trials did not show any anti-cancer activity. Wide differences were observed between species within the same class, in particular dinoflagellates which were better represented in this study. These preliminary findings pave the way for in-depth characterization of extracts with highest signals in each test, identification of compounds responsible of the biological activities found, and a further screening of the CCVIEO culture collection.

Klebsiella pneumoniae (KP) is an important gram-negative zoonotic conditional pathogen. It can infect humans and a variety of farm animals, leading to infections such as pneumonia, meningitis and even sepsis. thereby posing a significant threat to public health. OmpX acts as a virulence protein that can participate in bacterial pathogenesis, mediates bacterial adhesion to and invasion of epithelial cells, and is involved in bacterial adaptation to the osmotic pressure of the external environment. In this study, MBs-SELEX was used as the main strategy for screening aptamers. Omp X was used as the target protein and Omp A as the counter-screening target. qPCR and flow cytometry were used to determine the nature and specificity of the obtained aptamers for the Omp X protein. The analysis showed that among the obtained aptamers, three aptamers, Apt-1, Apt-2 and Apt-3, were selected with Kd values of 62.50 nM, 22.05 nM and 7.9 nM, respectively. In addition, total internal reflection fluorescence microscopy (TIRFM) was used for the characterization of KP in complex with specific FITC-labeled aptamers (FITC-Apt-3) and AuNCs. The complexes were characterized by observing blue fluorescent dots from AuNCs and green fluorescent dots from FITC-labeled aptamers overlapping with bacterial presence. These results suggest that AuNCs and aptamers can specifically bind to target bacteria, forming complexes. Furthermore, in vitro results demonstrated that Apt-1, Apt-2 and Apt-3 inhibited bacterial growth, with Apt-3 having the most significant inhibitory effect. The results suggest that aptamers can selectively recognize membrane proteins, thereby disrupting bacterial cell membrane formation and effectively inhibiting bacterial growth. Aptamers have a potential mechanism to inhibit bacterial growth.

Accurate prostate volume estimation is crucial for effective prostate disease management. Ultrasound (US) imaging, particularly transrectal ultrasound, offers a cost-effective and rapid assessment. However, US images often suffer from artifacts and poor contrast, making prostate volume estimation challenging. This review explores recent advancements in deep learning (DL) techniques for automatic prostate segmentation in US images as a primary step for prostate volume estimation. We examine various DL architectures, including traditional U-Net modifications and innovative designs incorporating residual connections, multi-directional image data, and attention mechanisms. Additionally, we discuss pre-processing methods to enhance image quality, the integration of shape information, and strategies to improve the consistency and robustness of DL models. The effectiveness of these techniques is evaluated through metrics such as Dice Similarity Coefficient, Jaccard Index, and Hausdorff Distance. The review highlights the potential of DL in improving prostate volume estimation accuracy and reducing clinical workload, while also identifying areas for future research to enhance model performance and generalizability.

Background: Ovarian mesonephric-like adenocarcinoma (MLA) is a newly described histological type known for its aggressive behavior. This study aims to determine the frequency of ovarian MLA, review existing literature, and elucidate its clinicopathological characteristics, including potential therapeutic targets. Methods: We retrospectively reviewed the pathological diagnoses of 516 primary ovarian cancer surgical cases at our institution from 2010 to 2023. MLAs exhibiting typical morphological and immunohistochemical features were included. The frequency and clinicopathological characteristics of these cases were summarized. Additionally, we conducted a literature search using PubMed to collect and summarize previously reported cases of ovarian MLA. Results: Among the 516 primary ovarian cancer cases, we identified 3 cases (0.6%) of MLA. The patients were 52-76 years old, and the initial FIGO stages were IC1 (2 cases) and IIIB (1 case). All cases exhibited HRP, pMMR, PD-L1 negativity (CPS&lt;1), and HER2-low expression. Two cases experienced metastatic recurrence. A literature review identified 97 cases of MLA. MLA frequently exhibited KRAS mutations (90%, 38/42), with a recurrence rate of 39% (26/67). Conclusion: MLA accounted for 0.6% of malignant ovarian tumors at our institution, all of which were advanced or recurrent cases. These cases showed HRP, pMMR, and PD-L1 negativity, indicating a lack of current therapeutic targets. Literature also reports a high incidence of advanced and recurrent cases, highlighting the need for accurate diagnosis and the development of new treatments. The frequent KRAS mutations suggest a potential therapeutic target for recurrent or metastatic MLA.

To screen and validate immunosuppressive factors in luminal- and basal-like breast cancer cell lines and tissue samples associated with malignant phenotypes. The mRNA microarray datasets, GSE40057 and GSE1561, were downloaded and remodelled. Differentially expressed genes (DEGs) were identified. Enrichment analyses performed and the online resources, GOBO and Kaplan-Meier Plotter, were employed to screen for immunosuppressive factors associated with breast cancer malignant phenotypes. qRT-PCR and western blot were used to validate the expression of CD274 and IL8 in cell lines and immunohistochemical detected the MIF and VEGFA on tissue microarrays. The results showed that CD274 and IL8 were both upregulated in basal-like cell lines. That MIF expression was dramatically increased in patients with breast cancer metastases (p<0.05) and that VEGFA expression positively correlates with breast cancer pathologic grade (p<0.05).During the formation and development of breast cancer, immune-related genes are always activated, and immunosuppressive factors CD274, IL8, MIF and VEGFA are upregulated. Such molecules could be used as biomarkers for breast cancer prognosis. However, because individual immune-related factors can play several biological roles, the mechanistic relationship between immunosuppressive factors and breast cancer malignant phenotypes and the feasibility of their application as drug targets require further investigation.

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.

First-line treatment for advanced large-cell neuroendocrine carcinoma of the lung (LCNEC) has limited efficacy. This study aimed to explore the efficacy and safety of everolimus combined with EP regimen chemotherapy (etoposide + cisplatin, EP) in the first-line treatment for LCNEC. The patients were randomly assigned to the experimental or control group, with 20 patients in each group. The experimental group received the mTOR inhibitor everolimus 5 mg once a day combined with EP ivgtt, d1-3, every 3 weeks for 4–6 cycles. The control group received EP only and the infusion method was the same as that of the experimental group. The safety in the experimental group was controllable and not inferior to that in the control group. Serious adverse effects were observed in approximately 10% of patients. Objective response rate (ORR) for the experimental and control groups were 15% vs. 0 (P=0.231), disease control rate (DCR) was 100% vs. 32% (P

Background: Participation is low (43%) in Australia’s National Bowel Cancer Screening Program which provides a biennial Fecal Immunochemical Test kit mailed to the home of Australians aged 50-74 years. While several factors for non-participation have been identified, the role of mental and physical health on screening behaviour has not been assessed. Methods: Participants of the Australasian Colorectal Cancer Family Registry Cohort were asked to complete a questionnaire on their colorectal cancer screening in the past five years and a validated measure of mental and physical health. The association between mental and physical health and screening was determined for Australian participants aged 45-75 years who had never been diagnosed with colorectal cancer. Multivariable logistic regression was used to adjust for measured potential confounders. Results: Of the 1130 eligible participants, 819 reported colorectal cancer screening in the past five years (72%). After adjusting for potential confounders, there was no evidence that overall mental or physical health was associated with colorectal cancer screening. However, one specific scale, general health, was positively associated with colorectal cancer screening (p=0.014) with those reporting higher levels of general health undergoing screening.Conclusion: We found limited evidence that mental and physical health, as measured by a short questionnaire, are associated with colorectal cancer screening. A potential limitation is reverse causation where previous screening may have impacted mental or physical health. A more detailed study of physical and mental health as barriers or enablers of screening is needed.

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.

: Optical coherence tomography is a non-invasive imaging technique that provides three-dimensional visualization of subsurface tissue structures. OCT has been proposed and explored in literature as a tool to assess oral cancer status, select biopsy sites, or identify surgical margins. Our endoscopic OCT device can generate widefield (centimeters long) imaging of lesions at any location in the oral cavity – but it is challenging for raters to quantitatively assess and score large volumes of data. Leveraging a previously developed epithelial segmentation network, this work develops quantifiable biomarkers that provide direct measurements of tissue properties in three-dimensions. We hypothesize that features related to morphology, tissue attenuation, and contrast between tissue layers will be able to provide a quantitative assessment of disease status (dysplasia through carcinoma). This work retrospectively assesses seven biomarkers on a lesion-contralateral matched OCT dataset of lateral and ventral tongue (40 patients, 70 sites). Epithelial depth and loss of epithelial-stromal boundary visualization provide the strongest discrimination between disease states. The stroma optical attenuation coefficient provides distinction of benign lesions from dysplasia and carcinoma. The stratification biomarkers visualize subsurface changes which provides potential for future utility in biopsy site selection or treatment margin delineation.

Background: Radiotherapy in the head-and-neck area is one of the main curative treatment options. However, this comes at the cost of varying levels of normal tissue toxicity, affecting up to 80% of patients. Mucositis can cause pain, weight loss and treatment delay leading to worse outcomes and decreased quality of life. Therefore, there is an urgent need for an approach to predict normal mucosa response in patients prior to treatment. Methods: We here describe an assay to detect irradiation response in patient healthy oral mucosa tissue. Mucosa specimens from the oral cavity were obtained after surgical resection, cut into thin slices, irradiated, and cultured for three days. Seven samples were irradiated with X-ray and three additional samples were irradiated with both X-ray and protons. Results: Healthy oral mucosa tissue slices maintained normal morphology and viability for three days. We measured a dose-dependent response to X-ray irradiation and compared X-ray and proton irradiation in the same mucosa sample, using standardized automated image analysis. Furthermore, increased levels of inflammation inducing factors - major drivers in mucositis development - could be detected after irradiation. Conclusion: This model can be utilized for investigating mechanistic aspects of mucositis development and can be developed into an assay to predict radiation-induced toxicity in normal mucosa.

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

B-cell lymphoid malignancies is a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTK inhibitors, such as pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTK inhibitors. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTK inhibitors and the development of new therapeutic strategies highlight the ongoing advances, that are being made towards the pursue of cure of B-cell lymphoid malignancies.

Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Since the 70s, many countries have adopted different CRC screening programs which has resulted in a decrease in mortality. However, current screening test options still present downsides. The commercialized stool-based tests present high false-positive rates and low sensitivity, which negatively affects the detection of early stage carcinogenesis. The gold standard colonoscopy has low uptake due to its invasiveness and the perception of discomfort and embarrassment that the procedure may bring.In this review, we collected and described the latest data about alternative CRC screening techniques that can overcome these disadvantages. Web of Science and PubMed were employed as search engines for studies reporting on CRC screening tests and future perspectives. The searches generated 555 articles, of which 93 titles were selected. Finally, a total of 50 studies, describing 14 different CRC alternative tests, were included. Among the investigated techniques the main feature that could have an impact on CRC screening perception and uptake was the ease of sample collection. Urine, exhaled breath and blood-based tests promise to achieve good diagnostic performance (sensitivity of 63-100%, 90-95%, 47-97%, respectively) while minimizing stress and discomfort for the patient.

Breast cancer is a leading cause of death among women. Conventional screening methods, such as mammography, and ultrasound diagnosis are expensive and have significant limitations. Digital Image Elasto Tomography (DIET) is a new noninvasive breast cancer screening system that has a potential to be a low cost and reliable breast cancer screening tool. It is based on modal analysis of the breast mass, and stereographic 3D image analysis to detect the stiffer abnormal tissues. However, camera sensor noise, especially Gaussian noise is a major source of Optical Flow (OF) error in this approach to tumor detection. This work studies the performance of different conventional filters, including the standard Gaussian filter tool to remove this noise and produce more robust screening results. A radical approach, Multiple Frame Noise Removal (MFNR) is proposed, for use in this type of medical image processing instead of a Gaussian filter or other typical image noise removal tools. Its a multiple frame noise removal method where Probability Density Function (PDF) of noise is extracted from the multiple images by characterizing the same pixel positions in multiple images. The noise becomes deterministic, and hence easily removed. The proposed algorithm was applied to a data set from 10 phantom breast tests with a prototype DIET system, and 10 in-vivo samples from healthy women. Comparisons were made to an optimal Gaussian filter form that is commonly used. Reductions in OF error using these digitally imaged data sets was used to compare performance. Refinement of the images for medical applications requires higher PSNR, which was successfully achieved by using MFNR algorithm. In this study, the algorithm was used to improve the imaging results of a DIET system. The conventional wisdom that states that noise removal and detail preservation are contrasting effects is

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.

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.

This review provides an overview of eXplainable AI (XAI) methods for oncological ultrasound image analysis and compares their performance evaluations. A systematic search of Medline Embase and Scopus between March 25 and April 14 2024 identified 17 studies describing 14 XAI methods, including visualization, semantics, example-based, and hybrid functions. These methods primarily provided specific, local, and post-hoc explanations. Performance evaluations focused on AI model performance, with limited assessment of explainability impact. Standardized evaluations incorporating clinical end-users are generally lacking. Enhanced XAI transparency may facilitate AI integration into clinical workflows. Future research should develop real-time methodologies and standardized quantitative evaluative metrics.

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.

Abstract: Ovarian cancer (OC) ranks as the fifth most common cancer among women in the United States and globally, posing a significant health threat. Reactive oxygen species (ROS) have emerged as critical factors in the pathophysiology of this malignancy. ROS, characterized by their instability due to an unpaired electron, are involved in essential cellular functions and play a crucial role in the immune response under normal physiological conditions. However, an imbalance in ROS homeostasis, leading to excessive ROS production, results in oxidative stress (OS), which can cause indiscriminate damage to cellular structures and contribute to the pathogenesis of specific diseases, including OC. OC is primarily classified based on the originating cell type into epithelial, stromal, and germinal tumors, with epithelial tumors being the most prevalent. Despite advancements in medical technology, early detection of OC remains challenging, often leading to delayed treatment initiation. Current therapeutic approaches include surgical excision of tumor tissue, radiotherapy and chemotherapy. While these treatments are effective in early-stage OC, high mortality rates and frequent relapse underscore the urgent need for novel diagnostic and therapeutic strategies. This review aims to elucidate the role of ROS in OC, emphasizing the potential for developing innovative diagnostic tools and treatments that target ROS-mediated pathways. Given the critical impact of early detection and effective treatment, advancing our understanding of ROS in the context of OC could significantly enhance patient outcomes.

Systematic reviews represent a powerful instrument to summarize the existing evidence in medical literature. However, articles for a systematic review are hard to identify, and mostly require a structured search of the literature through a number of databases, using keyword-based search strategies, followed by the painstaking manual selection of pieces of evidence that are pertinent to the query. A.I. algorithms may offer solutions to reduce the workload on investigators. We applied BERTopic, a newer and much-recognized transformer-based topic-modeling algorithm, to two datasets of 6137 and 5309 articles of newly published systematic reviews in the area of peri-implantitis and bone regeneration in implant dentistry. In the two datasets, BERTopic identified 14 and 22 clusters, respectively, and it automatically created labels describing the nature of the topics for each individual cluster based on semantic interpretation of their titles. Most themes regarded the query theme, but in both conditions, BERTopic also uncovered articles related to off-themes, which composed around 30% of the dataset—with sensitivity up to 0.79 and specificities of at least 0.99. Our results suggest that adding a topic-modeling step to the screening process could potentially save working hours for researchers involved in systematic reviews of the literature.