Aging induced chronic inflammation deteriorated bone loss in elderly population. This study aimed to investigate the underling mechanism of bone-immune crosstalk with aging. In clinical, we identified novel inflammatory markers as predictors for osteoporosis in old people, indicating a close relationship between immune system and bone strength. In animal study, more pro-inflammatory macrophages (M1) was identified in aged bone, suggesting a possible mechanism sheered by the altered bone-inmmune interplay. Transcriptomic analyses on senescent bone marrow mesenchymal stem cells (MSCs) suggested that immune signaling and osteoclasts differentiation were involved in MSCs aging. Moreover, single-cell sequencing data analyses (GSE145477) screened 4 co-deferentially expressed genes in this bone-immune system with aging. They were TREM2, TYROBP (encodes DAP12), SYK, and PIK3CD. Then, we established cells co-culture system and verified the age-reduced TREM2 accompanied with DAP12-SYK inactivation, leading to more M1 polarization. Conditioned medium experiments results were consistent with these changes. Pharmacological activation of TREM2-DAP12-SYK axis by a small molecule compound, ADAM10 inhibitor, recovered the macrophages aging and decreased their pro-inflammatory polarization. Therefore, we speculated that the increased M1 polarization by aging-reduced TREM2-DAP12-SYK signaling might be responsible for inflammatory micro-environment in bone tissue. Together, this study elaborated the bone-immune crosstalk with aging through the inflammatory signaling alteration and provided new treatment targets for senile osteoporosis.

Acute kidney injury (AKI) represents a prevalent and critical complication of upper gastrointestinal bleeding (UGIB). Predicting AKI is essential for timely intervention. This retrospective research leveraged data from the MIMIC-IV 3.1 database and data from patients hospitalized at the Second Hospital of Hebei Medical University (HMUSH). The Boruta algorithm was employed in the training set to determine independent predictors of AKI. The study developed a nomogram based on logistic regression results to forecast AKI in UGIB. Its performance was evaluated using ROC curves, calibration curves, and decision curve analysis (DCA) in training, validation, and external validation sets. This study incorporated 2,020 patients suffering from UGIB and 421 participants admitted to HMUSH. The Boruta algorithm identified 9 key predictors of AKI: age, creatinine-to-albumin ratio (CAR), prothrombin time (PT), alanine transaminase (AST) to aspartate aminotransferase (ALT) ratio (DeRitis), blood urea nitrogen (BUN), total bilirubin (TBIL), platelet count (PLT), pneumonia, and ascites. A nomogram was plotted utilizing these independent predictors. The nomogram demonstrated robust accuracy with area under the curve values of 0.776, 0.744, and 0.785 for the training set, validation set, and external validation set, respectively. Calibration curves disclosed good agreement between predicted and observed incidence rates of AKI. Additionally, the DCA disclosed net clinical benefit of the nomogram. This study presented a tool developed to forecast the likelihood of developing AKI in individuals with UGIB. The tool is potentially useful for guiding timely intervention and improving clinical results. Not applicable.

BACKGROUND:Ovarian cancer (OC) is a malignancy among female globally. Circular RNAs (circRNAs) are a family of circular endogenous RNAs generated from selective splicing, which take part in many traits. Former investigation suggested that hypoxia microenvironment induced aerobic glycolysis promotion malignant progression of OC. METHODS:This research aimed to use FISH and RT-qPCR to investigate circ-PHC3 expression in OC cells and tissues after high-throughput sequencing. Our team made the luciferase reporter assay to validate circ-PHC3 downstream target. Transwell migration assay, 5-ethynyl-20-deoxyuridine, and cell counting kit-8 were applied to investigate both proliferation and migration. In vivo tumorigenesis and metastasis assays were performed to investigate the circ-PHC3 role in OC. The outputs elucidated that circ-PHC3 expression incremented in OC cells and tissues. circ-PHC3 downregulation inhibited OC cell proliferation as well as migration in in vivo and in vitro experiments. Metabolic studies confirmed that downregulation circ-PHC3 inhibit hypoxic induced aerobic glycolysis. RESULTS:The luciferase results validated that miR-512-3p and SLC2A1/HK2 were circ-PHC3 downstream targets. SLC2A1/HK2 overexpression or miR-512-3p inhibition reversed OC cell migration after circ-PHC3 silencing. Also, SLC2A1/HK2 overexpression reversed OC cell migration and proliferation post miR-512-3p upregulation. CONCLUSIONS:Results demonstrate that circ-PHC3 downregulation inhibits OC progression and metastasis via SLC2A1/HK2 expression regulation and miR-512-3p sponging.

Background: Aging is a complex physiological process, regulated by multiple intertwined mechanisms. In this process, Sirt1 played a vital role with evidences increasing continually. Given the rapid expansion of research in this area, a comprehensive overview of the intellectual landscape is needed to guide future investigations. Based on, we conducted a bibliometric analysis of the relevant literature and visualized the results. Our study aimed to consolidate the current knowledge and provide insights into evolving research trends, thereby contributing to a deeper understanding of Sirt1's roles in aging process. Methods: On August 14th, 2024, we retrieved 2434 issues in Web of Science Core Collection (searching period from 2005 to 2024). Using VOSviewer, Citespace and bibliometrix, we analyzed these records in terms of annual publications/citations, spatiotemporal distribution, collaborations between regions/institutions/authors, co-references, and keywords. Result: We identified a stable development trend of researching on Sirt1 and aging. In the last 2 decades, the average growth rate of publication numbers was 34.52%, while in recent 5 years it fell to 10.8%. So far, China and the United States were more conductive and influential in this field. Their publications accounted for 39.56% and 26.17%, respectively. Of interests, since Hungary's publication numbers just accounted for 7% of the publications worldly, it had the strongest average citations. Besides, some institutions and countries had varieties of publications, but weak link strength, meaning further collaborations of them were needed in future study. Importantly, keywords analysis indicated that oxidative stress and calorie restriction were the main hot-spots of this field. Besides, inflammation, DNA damage, metabolism, mitochondrial dysfunction and autophagy might be new research directions in Sirt1 and aging. Conclusions: Above all, this study provided further insights into recent advances and future progression in researches on Sirt1 and aging.

Hemangioma most commonly occurs in the head and neck, rarely affects the digestive tract, and often presents without any clinical signs. The treatment of esophageal hemangioma has been widely reported internationally. However, reports on the sole application of endoscopic band ligation for the treatment of esophageal hemangioma are relatively rare. The patient was a 47-year-old woman with a large esophageal hemangioma initially misdiagnosed as isolated esophageal varices. The lesion was a single varicose vein (1.2 cm in diameter) located on the left wall of the esophagus, approximately 23 cm to 28 cm from the incisors. Endoscopic ultrasound revealed thickened variceal walls with a honeycomb-like heterogeneous hypoechoic pattern, and Doppler imaging detected blood flow signals. CT indicated a venous mass (1.3 cm × 1.2 cm × 5 cm) in the mid-esophagus with a honeycomb-like internal structure, which was highly suggestive of esophageal hemangioma. No arterial origin was observed, the superior and inferior venae cava appeared normal, and there were no signs of cirrhosis. The esophageal hemangioma was endoscopically ligated twice. Four months later, repeat examination revealed smooth mucosa at the surgical site and complete disappearance of the esophageal hemangioma with the formation of a white scar. This case suggests that endoscopic band ligation may be a safe and effective minimally invasive treatment for large esophageal hemangioma.

Background:Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a novel class of antihyperglycemic agents, have raised concerns regarding bone safety. This meta-analysis aimed to evaluate the specific effect of adjunctive SGLT2i therapy on fracture risk in patients with type 1 diabetes mellitus (T1DM). Methods:We systematically searched four databases (PubMed, Embase, Cochrane Library and Web of Science Core Collection) to identifyall eligible randomized controlled trials (RCTs) investigating SGLT2i as adjunctive therapy to insulin in T1DM. Fracture risk was defined as primary outcome, while glycemic parameters, non-glycemic outcomes, and other safety index serving as secondary endpoints. Pooled ORs (95% CIs) were calculated, with dose-stratified subgroup analyses. Risk of bias was assessed using the Cochrane Collaboration Risk-of-Bias tool (RoB 2). Results:Our analysis included 10 RCTs comprising 6,731 T1DM patients. All included studies were deemed to be at low or moderate risk of bias. Pooled analysis revealed no significant association between SGLT2i use and fracture risk (OR 0.98, 95% CI [0.63-1.51]). This null finding remained consistent across subgroup analyses. Fracture odds ratios in the low-, moderate-, and high-dose subgroups were 0.78 (95% CI [0.11-5.58]), 1.08 (95% CI [0.55-2.11]), and 0.90 (95% CI [0.50-1.63]), respectively. SGLT2i significantly improved glycemic control, including HbA1c, fasting plasma glucose, and time in range. It also reduced body weight and blood pressure. However, SGLT2i treatment increased the risk of diabetic ketoacidosis (OR 3.52, 95% CI [2.16-5.71]) and genital tract infections (OR 3.69, 95% CI [2.85-4.78]). Conclusion:This meta-analysis provides reassuring evidence that adjunctive SGLT2 inhibitor use is not associated with increased fracture risk in insulin-treated patients with T1DM patients. Nonetheless, the substantially elevated risks of diabetic ketoacidosis and genital tract infections necessitate vigilant clinical monitoring and risk mitigation strategies to ensure safe use of these agents.

The objective of this study was to elucidate the relationship between two single nucleotide polymorphisms (SNPs) rs7176005 and rs6493497 in CYP19 gene and the risk of polycystic ovary syndrome (PCOS) in Northern Chinese women. In this case-control study, a total of 340 women with PCOS and 340 matched healthy controls were recruited. Polymerase chain reaction ligase detection reaction (PCR-LDR) method was used to investigate two SNPs (rs7176005 and rs6493497) in the 5’-flanking region of CYP19 gene exon 1. We observed a significant association of rs7176005 and rs6493497 with reduced risk of PCOS. Compared with CC genotype, a significant association of CT genotype (p = 0.019), TT genotype (p < 0.001) and combined CT + TT genotype (p < 0.001) with reduced risk of PCOS was observed. The result of linkage disequilibrium analysis showed that these two SNPs are in complete linkage disequilibrium (r2 = 1). For rs7176005 SNP, compared with CC genotype, CT, TT and CT + TT genotypes reduced the risk of PCOS. The age, BMI-adjusted OR were 0.650 (95

Background:Small intestine varicose vein is a common ectopic varicose vein of digestive tract. Duodenum is the most bleeding ectopic varicose vein. The possible clinical manifestations include black stool and blood in stool. Because of the special location of ectopic varicose veins, it is difficult to detect early in clinic. This patient has multi-site varicose veins, and the treatment process is tortuous, combined treatment of medicine and surgery. Case Description:This case report presents a 58-year-old male with alcoholic liver cirrhosis, with black stools as the main clinical manifestation. There is a history of abdominal surgeries such as splenectomy in the past. Through gastroscopy, enteroscopy, and other examinations, multiple ectopic varicose veins in the duodenum and jejunum were found. After conventional endoscopic treatment, there was still active bleeding. Later, combined surgical treatment successfully stopped the bleeding. The patient no longer had black stools and was discharged from the hospital after his condition improved. Conclusions:Ectopic varicose veins are an important complication of portal hypertension. Clinical awareness of the possible presence of ectopic varicose veins is essential for early detection and management in patients with gastrointestinal bleeding whose source is uncertain. Clinically, the understanding of ectopic varicose vein rupture and bleeding should be enhanced. A clear diagnosis can be made through enteroscopy. In terms of treatment, the first consideration should be to reduce portal pressure. Simple endoscopic treatment may have a poor effect. Relevant risk factors can be studied to conduct primary prevention for high-risk patients in advance.

This research aimed to assess the relationship between creatinine-to-albumin ratio (CAR) and clinical outcomes among individuals with upper gastrointestinal bleeding (UGIB), with a particular focus on the association between CAR and 30-day and 90-day all-cause mortality (ACM). Patient data were obtained from the Medical Information Mart for Intensive Care IV version 3.1 (MIMIC-IV 3.1) and the intensive care unit of the Second Hospital of Hebei Medical University (HMUSH). The included individuals were stratified into four groups according to CAR quartiles. The 30-day ACM served as the primary outcome, and the 90-day ACM as the secondary outcome. Clinical outcomes across groups were compared by Kaplan–Meier curves. Cox proportional hazards (PH) regression and restricted cubic spline (RCS) models were applied to examine the association between CAR and mortality outcomes. Moreover, subgroup analyses were carried out. In total, 1,685 individuals from the MIMIC-IV cohort and 408 individuals from the HMUSH cohort were enrolled. Kaplan–Meier curves demonstrated that higher CAR values were related to increased risks of 30-day and 90-day ACM (log-rank < 0.05). Cox PH regression indicated that those in the highest CAR quartile had 211

Ovarian cancer (OV) has the highest mortality rate among gynecological cancers and shows varied responses to chemotherapy combined with PARP inhibitors based on homologous recombination deficiency (HRD) subtypes. This study enrolled 143 Chinese OV patients to determine the HRD score grouping threshold using genomic features, dividing patients into HRD-high and HRD-low groups. Multi-omics sequencing was conducted on 70 patients receiving adjuvant chemotherapy with PARP inhibitors. In this study, TP53 mutations enriched in the HRD-high group, while ARID1A, PIK3CA, and PTEN mutations were more common in the HRD-low group. HRD-high patients exhibited stronger immune activation, including elevated STAT1 expression, HLA signatures, and increased M1 macrophage infiltration, correlating with better prognosis. Additionally, peripheral blood analysis revealed higher bMSI and maxVAF levels in HRD-low patients compared to HRD-high patients, suggesting ctDNA as a potential tool for dynamic monitoring post-treatment. This study identified distinct molecular and immune profiles between HRD subgroups in Chinese ovarian cancer patients. Patients with HRD-high and STAT1 expression ≥ 74 suggests PARPi benefit.

BACKGROUND:The pathophysiology of diabetic kidney disease (DKD) is complex. Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression. Previous studies have revealed that nuclear receptor subfamily 4 group A member 1 (NR4A1) may serve as a novel pathogenic element in DKD; however, the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown. AIM:To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms. METHODS:Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD. Typically, 45 mmol/L glucose [high glucose (HG)] was used to activate HK-2 cells to mimic the DKD model in vitro. HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1. RESULTS:NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells. Concurrently, NOD-like receptor protein 3 (NLRP3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways were triggered, and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro. These alterations were significantly reversed via NR4A1 silencing. CONCLUSION:Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.

BACKGROUND:Gastric mucosa-associated lymphoid tissue (MALT) lymphoma presents with various clinical presentations and endoscopic features. While gastric lesions are primarily assessed via endoscopic forceps biopsy, pathological confirmation of MALT lymphoma is frequently challenging, with low detection rates commonly observed. CASE SUMMARY:We describe a 61-year-old male patient with gastric MALT lymphoma due to intermittent abdominal discomfort lasting over six months. The initial endoscopic forceps biopsy was suggestive of gastric lymphoma. Confirmation of the MALT lymphoma diagnosis was ultimately obtained through a jumbo biopsy specimen harvested via endoscopic submucosal dissection (ESD). CONCLUSION:We report a case of gastric MALT lymphoma diagnosed through ESD, highlighting its potential as a diagnostic tool when forceps biopsy yields negative or inconclusive results.

Ovarian immature teratomas (OITs) are malignant tumors originating from the ovarian germ cells that mainly occur during the first 30 y of a female's life. Early age of onset strongly suggests the presence of susceptibility gene mutations for the disease yet to be discovered. Whole exon sequencing was used to screen pathogenic mutations from pedigrees with OITs. A rare missense germline mutation (C262T) in the first exon of the BMP15 gene was identified. In silico calculation suggested that the mutation could impair the formation of mature peptides. In vitro experiments on cell lines confirmed that the mutation caused an 84.7% reduction in the secretion of mature BMP15. Clinical samples from OIT patients also showed a similar pattern of decrease in the BMP15 expression. In the transgenic mouse model, the spontaneous parthenogenetic activation significantly increased in oocytes carrying the T allele. Remarkably, a mouse carrying the T allele developed the phenotype of OIT. Oocyte- specific RNA sequencing revealed that abnormal activation of the H- Ras/MAPK pathway might contribute to the development of OIT. BMP15 was identified as a pathogenic gene for OIT which improved our understanding of the etiology of OIT and provided a potential biomarker for genetic screening of this disorder.

Abstract The Development of precision medicine relies on well-characterized experimental models that carry naive, induced, or engineered genomic and epigenetic features targetable by certain treatments. Patient-derived xenografts (PDX) and cell lines can serve as such in vivo and in vitro models by harboring abnormalities such as somatic and driver mutations, dysregulated gene expression and silencing, microsatellite instability, gene fusions, copy number amplification and loss of heterozygosity. In addition, cell lines can also be engineered to introduce sometimes rare-occurring abnormalities that the engineered cell line shares an identical genetic background with its parental cell line, thus providing a clearly contrasting pair to evaluate treatment specificity. With the advancement of disease research and drug discovery, existing cell lines can no longer meet the needs of various types of drug discovery. To evaluate drug efficacy more quickly and accurately, Kyinno has constructed and identified more than 4,000 engineered cell lines, including overexpressed cell lines constructed through transposon systems or lentivirus infection, gene-edited cell lines constructed through CRISPR-Cas9 technology, and reporter cell lines targeting multiple signaling pathways and membrane receptors. Besides, InnoPanelTM, a panel of over 1000 engineered cell lines was established and characterized to cover a wide range of heavily targeted genes such as CLDN18.1, CLDN18.2, LAG3, OX40, PD-L1, PD-L2, and TIM3. Cell line families were also developed for genes with multiple known driver mutations. All cell lines are annotated with background information, engineering details, functional characterization, and efficacy studies. Furthermore, we developed xenografts for several engineered cell lines and showed that the combination of cell lines and xenografts can accelerate drug development. Additionally, all of this information can be accessed in our free database, InnoPediaTM. The database also offers browsing, searching, and analytical capabilities for over 600 commonly used tumor cell lines and thousands of engineered cell lines with essential genomic and pharmacological data, cell line efficacy data for nearly 2000 common anti-tumor drugs, and comprehensive details for over 100 standard antibodies. Our engineered cell lines are now registered in the online cell line database Cellosaurus, which is available on the ExPASy server. Citation Format: Siyu Li, Chang Liu, Na Wang, Yuqing Hu, Jinying Ning, Feng Hao. InnoPanelTMand InnoPediaTM: resources of engineered cell lines and xenografts for drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6916.

In recent years, a common-used antidiabetic drug, liraglutide, was identified with extra effects on lipid metabolism. Its effects against excessive lipid deposition in bone marrow were gained much attention but not well established. Our aim in the present study is to explore the interaction of miRNAs-mRNAs altered by liraglutide administration during bone marrow adipogenesis in diabetes. To establish the diabetic animal model, rats were treated with high fat diet (HFD) and STZ injection. We then identified the lowering effect of liraglutide on lipids metabolism in the diabetes. During this process, high-throughput sequencing and bioinformatics analyses on miRNAs extracted from bone marrow mesenchymal stem cells (BMSCs) were conducted after liraglutide administration. We then identified five differentially expressed miRNAs (miRNA-150-5p, miRNA-129-5p, miRNA-201-3p, miRNA-201-5p, and miRNA-214-5p). The expressions of the DE miRNAs were verified as temporal specific expression patterns in Day 3 and in Day 7. Among them, miRNA-150-5p expression was more stable and consistent with the sequencing data. Of interest, miR-150-5p overexpression facilitated adipogenesis of BMSCs. But this promotion was alleviated by liraglutide. The predicted target gene of miR-150-5p, GDF11, was validated to be involved in liraglutide alleviated BMSCs’ lipid accumulation in diabetes. In vitro, liraglutide increased the GDF11 expression, rescued its down-expression by siGDF11 and inhibit the adipogenesis of BMSCs cultured in high glucose medium. In vivo, liraglutide reversed the HFD-STZ induced excessive lipid droplets by up-regulation of GDF11 expression, which was discounted by agomiR-150-5p injection. Above all, liraglutide might alleviate bone marrow fat accumulation via inactivating miR-150-5p/GDF11 axis in diabetes.

Background: Ataxia telangiectasia mutated (ATM), an apical DNA damage response gene, is a commonly mutated gene in tumors, and its mutation could strengthen tumor immunogenicity and alter the expression of PD-L1, which potentially contributes to immune checkpoint inhibitors (ICIs) therapy. Methods: The characteristics of ATM mutation and its relationship with the ICIs-treated clinical prognosis have been analyzed comprehensively in this paper. The overall frequency of ATM mutations has been found to be 4% (554/10953) in the cancer genome atlas (TCGA) cohort. Results: Both the TMB and MSI levels in patients with ATM mutations were significantly higher than those in patients without mutations (P < 0.0001). The median TMB was positively correlated with the frequency of ATM mutations (r = 0.54, P = 0.003). In the TCGA cohort, patients with ATM mutations had better clinical benefits in terms of overall survival (OS, hazard ratio (HR) = 0.736, 95% CI = 0.623 - 0.869), progression-free survival (PFS, HR = 0.761, 95% CI = 0.652 - 0.889), and disease-free survival (DFS, HR = 0.686, 95% CI = 0.512 - 0.919)] than patients without ATM mutations. Subsequently, the verification results showed ATM mutations to be significantly correlated with longer OS in ICIs-treated patients (HR = 0.710, 95% CI = 0.544 - 0.928). Further exploration indicated ATM mutation to be significantly associated with regulated anti-tumor immunity (P < 0.05). Conclusion: Our findings highlight the value of ATM mutation as a promising biomarker to predict ICIs therapy in multiple tumors.