Chemotherapy causes primordial follicle apoptosis, resulting in premature ovarian insufficiency (POI) and infertility. In this study, we found that intraperitoneal injection of retinoic acid (RA) and calcitriol partially reversed the cyclophosphamide and doxorubicin treatment-induced decrease in primordial follicles in neonatal mouse ovaries. Furthermore, RA and calcitriol co-treatment reversed cyclophosphamide treatment-induced PI3K/Akt activity and FOXO3a nuclear export in the oocytes within primordial follicles, suggesting that the oocyte transcriptional activity was decreased, which in turn reduced the binding of chemotherapeutic drugs to DNA. Consistent with these findings, RA and calcitriol co-treatment reversed cyclophosphamide treatment-induced changes in reactive oxygen species (ROS), DNA damage response proteins (γH2AX, p-CHK2, p-p53, PUMA, BAX, Cleaved Caspase-3, and cPARP), and antioxidant proteins (NRF2, HO-1, and GPX4). Moreover, RA and calcitriol co-treatment preserved fertility in cyclophosphamide-treated mice without impairing cyclophosphamide's antitumor efficacy in MCF-7 tumor-bearing mice. Thus, RA and calcitriol protect mouse primordial follicles from cyclophosphamide treatment-induced apoptosis by inhibiting cyclophosphamide treatment-induced oocyte transcriptional activity and enhancing antioxidant capacity. Our results suggest a potential strategy for preserving ovarian reserve during chemotherapy in female cancer patients.

BackgroundPancreatic cancer (PC) is a fatal malignancy, with glycolysis and T cells playing crucial roles in its pathogenesis. This study explored prognosis-related genes in glycolysis and T cells in PC using bioinformatics methods.MethodsWe first quantified distinct T-cell subsets via immune infiltration analysis of the TCGA-PAAD cohort and extracted T cell-related genes (T-RGs). Differentially expressed genes (DEGs) were obtained from GSE28735 and TCGA-PAAD. Intersecting these DEGs with T-RGs and glycolysis-related genes (G-RGs) yielded candidate genes. We screened prognostic genes using univariate Cox and LASSO regression, built a prognostic model in TCGA-PAAD and validated it in GSE57495. A nomogram was constructed for survival prediction, its reliability verified by calibration and ROC curves. We compared immune microenvironment, pathway enrichment, mutation landscape and drug sensitivity between high- and low-risk subgroups, and built lncRNA-miRNA-mRNA regulatory networks. In vitro and in vivo mouse tumorigenesis assays explored GPR87’s potential involvement in glycolytic activity and CD8+ T cell infiltration. Seahorse analysis, glucose uptake detection and immunohistochemistry further explored roles in glucose metabolism and anti-tumor immunity.ResultsMET, KDELR3, AK4, and GPR87 were determined as prognostic genes. In the training set, this exploratory prognostic model showed moderate predictive performance, with area under the curve values of 0.72, 0.71, and 0.71 at 1, 2, and 3 years, respectively. The risk score and N-stage were identified as independent prognosis predictors, and the developed nomogram demonstrated moderate predictive performance. Functional pathways revealed enrichment in 44 pathways. There were 17 differential immune cells. In addition, risk scores were correlated with 28 immune checkpoints. The regulatory network comprised 26 miRNAs and 50 lncRNAs. Furthermore, computationally predicted correlations between prognostic genes and 60 drugs were identified in different risk groups. In vitro and in vivo experiments demonstrated that GPR87 knockdown inhibits the proliferation, migration, and clonogenic ability of PC cells while promoting their apoptosis. Furthermore, GPR87 expression was negatively correlated with CD8+ T cell, and GPR87 knockdown inhibited glycolysis in pancreatic cancer cells.ConclusionMET, KDELR3, AK4, and GPR87 were identified as candidate prognostic genes in PC, providing preliminary hypothesis-generating insights that require validation in independent institutional or prospective clinical cohorts before any clinical application.

Cordycepin, a natural nucleoside analogue, exhibits anti-inflammatory and antitumor activity in multiple malignancies. However, the molecular basis of its action in pancreatic cancer and its potential role in chemosensitization remain incompletely defined. In this study, the effects of cordycepin on malignant phenotypes of pancreatic cancer cells were investigated in vitro. Network pharmacology was applied to identify candidate targets and construct a disease-drug-target-pathway network. Reverse virtual screening and molecular docking were used to predict key binding proteins, while RNA sequencing identified downstream pathways regulated by cordycepin. Target engagement was validated using cellular thermal shift assays, molecular docking, and molecular dynamics simulations. The underlying mechanistic pathways were further confirmed by functional experiments, and the therapeutic efficacy of cordycepin in combination with gemcitabine was evaluated. Our results demonstrated that cordycepin reduced the growth of pancreatic cancer cells and induced G2/M phase arrest and apoptosis. Network pharmacology identified 56 hub targets enriched in oncogenic pathways, including PI3K/AKT pathway. Reverse virtual screening revealed 111 candidate binding proteins, and intersection with hub targets highlighted five key effectors: CDK2, GSK3B, IL2, NOS3, and PARP1. Transcriptomic profiling showed marked disruption of cell cycle pathways, and CDK2 was validated as a direct molecular target of cordycepin. Cordycepin suppressed TNNI2 transcription by inhibiting the CDK2/E2F2 axis. Furthermore, cordycepin acted synergistically with gemcitabine to enhance antitumor responses and promote apoptosis in pancreatic cancer models. Collectively,cordycepin exerts antitumor activity in pancreatic cancer by targeting the CDK2/E2F2 axis to suppress malignant progression and by concurrently sensitizing cells to gemcitabine, thus holding promise as a therapeutic agent.

In recent years, the incidence and mortality rates of pancreatic cancer have been rising, posing a severe threat to human health. Tumor heterogeneity remains a critical barrier to advancing diagnosis and treatment efforts. The lack of specific early symptoms, limited early diagnostic methods, high biological complexity, and restricted therapeutic options contribute to the poor outcomes and prognosis of pancreatic cancer. Therefore, there is an urgent need to explore the different subtypes in-depth and develop personalized therapeutic strategies tailored to each subtype. Increasing evidence highlights the pivotal role of molecular subtyping in treating pancreatic cancer. This review focuses on recent advancements in classifying molecular subtypes and therapeutic approaches, discussed from the perspectives of gene mutations, genomics, transcriptomics, proteomics, metabolomics, and immunomics.

Pancreatic cancer (PC) is one of the most lethal types of cancer, as current treatments are largely ineffective. Our research uncovers that PPP2R2B is overexpressed in a majority of PC cases, playing a significant role in the growth and spread of PC tumors. Knockdown of PPP2R2B inhibits PC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while promoting cell apoptosis. Conversely, overexpression of PPP2R2B enhances these processes, leading to increased proliferation, migration, invasion, and EMT, and reduced apoptosis. Further analysis showed that reducing PPP2R2B levels in PC inactivates the MAPK pathways—ERK, JNK, and p38, ultimately promoting PC growth. The addition of an ERK inhibitor reverses the effects of PPP2R2B knockdown, restoring cell proliferation, migration, and invasion. Our experiments in live subjects demonstrate that removing PPP2R2B inhibits tumor growth in PC mouse models and alters the levels of proteins involved in EMT and cell death. These findings demonstrate that PPP2R2B contributes to PC progression by modulating EMT and apoptosis through the ERK/MAPK pathway. Targeting PPP2R2B or its downstream signaling pathways may offer a promising therapeutic strategy for pancreatic cancer.

Background:At the time of diagnosis, 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are already at an unresectable advanced stage. The median overall survival (mOS) with traditional AG chemotherapy is only 8.5 months. The bispecific antibody Cadonilimab targeting PD-1 and CTLA-4 has shown immuno-oncological synergy in solid tumors, but evidence in PDAC is limited. Methods:This study is a single-center retrospective study that included 14 patients with advanced pancreatic ductal adenocarcinoma. These patients received Cadonilimab (10 mg/kg, Q3W) in combination with AG chemotherapy. The primary endpoint was the disease control rate (DCR, RECIST 1.1). Results:The disease control rate (DCR) reached 85.7%, and the objective response rate (ORR) was 14.3%; the median progression-free survival (mPFS) was 7.87 months, and the median overall survival (mOS) was 11.45 months. Among patients with a decrease in CA19-9, the median overall survival was significantly prolonged (12.92 vs 8.89 months, P = 0.027); patients with a platelet-lymphocyte ratio (PLR) ≤ 165.62 had a significantly better mOS (12.37 vs 8.74 months, P = 0.025). Although the incidence of grade 3 treatment-related adverse events was 57.1%, no grade 4 treatment-related toxic events were observed. Conclusion:In conclusion, cadonilimab combined with AG chemotherapy demonstrated promising antitumor activity and manageable safety in PDAC. Dynamic monitoring of PLR and CA19-9 may aid efficacy evaluation, but these exploratory findings require confirmation in prospective multicenter trials.

Through bibliometric analysis, this paper summarizes the growing literature and analyses the development trends and hot spots in the research field of the association between intravenous anesthesia and tumors. A literature overview was conducted using relevant articles retrieved from the Web of Science Core Collection published between 1991 and 2024. Bibliometric websites and tools (VOSviewer, CiteSpace, and bibliometric R package) are used to analyze the co-occurrence of keywords and reference citations, detailing countries, institutions, authors, references, journals, and keywords. A total of 1198 relevant articles were included in the study. The USA, China, and Germany have the largest number of publications, with the USA and China having the most interagency cooperation and Germany relatively less cooperation. The institution that publishes the most articles is the University of National Defense Medical Center, and the journal that publishes the most articles is Anesthesiology. The five most productive authors are Li J., Liu J., Zhang B., Yu X.J., and Xu J. “Surgery”, “anaesthesia”, and “propofol” are the most common keywords. In recent years, research has focused mainly on intravenous anesthesia and tumor survival. Both Western countries and China have made outstanding contributions to intravenous anesthesia and tumors. In recent years, the number of publications in China has steadily increased, and the quality and influence of these articles deserve recognition. Future research should focus on the key areas of intravenous anesthesia, tumor recurrence, and survival.

Background: Reactive oxygen species (ROS)-mediated apoptosis of intestinal epithelial cells and tight junction (TJ) protein loss play critical roles in mycophenolic acid (MPA)-induced disruption of intestinal epithelial barrier function, yet no effective therapeutic strategies exist. Schisanhenol (Sal), a major component of the traditional Chinese medicine Wuzhi capsule, exhibits strong antioxidant activity. Objectives: The present study aimed to investigate the protective efficacy and mechanisms of Sal against MPA-induced damage to the intestinal mechanical barrier. Methods: Caco-2 cells were exposed to MPA (10 μM), Sal (5, 10, and 25 μM), or ML385 (2 μM) for 24 hours. Cell viability was measured via a Cell Counting Kit-8 (CCK-8) assay. The expression of apoptosis-related and TJ proteins was evaluated through Western blot analysis. Flow cytometry was used to quantify the percentage of apoptotic Caco-2 cells. Immunofluorescence assays were performed to assess the localization of TJ proteins. Intracellular ROS levels were measured using H2DCFDA staining. Oxidative and antioxidative biomarker levels were quantified using specific assay kits. Results: Sal significantly increased the viability of MPA-treated cells. It also upregulated Bcl-2 expression and reduced apoptosis. Furthermore, Sal increased the expression of the TJ proteins ZO-1 and occludin. Additionally, Sal upregulated the MPA-mediated decrease in Nrf2/HO-1 expression, reduced intracellular ROS accumulation, and increased the levels of antioxidants, including SOD, CAT, and GSH. However, ML385 partially abrogated the protective effects of Sal. Conclusions: Schisanhenol alleviates MPA-induced intestinal mechanical barrier damage via modulation of the Nrf2 signaling pathway, highlighting its antioxidant and antiapoptotic properties.

Some clinical studies have found that some patients develop cholangitis after using platinum drugs. However, whether there is a correlation between platinum drugs and the occurrence of cholangitis remains controversial. This study aims to determine the association between platinum drugs and cholangitis by exploring the FAERS database. Reports of platinum-related cholangitis in the FAERS database from the first quarter of 2004 to the second quarter of 2024 were collected and analyzed. Disproportional analysis, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM) algorithms, is used in data mining to quantify the signals of platinum-related cholangitis. Further analysis of different platinum drugs showed that the use of three types of platinum drugs, oxaliplatin, cisplatin and carboplatin, is all associated with the occurrence of cholangitis. Among female patients who used platinum-based drugs, the use of each of the three platinum-based drugs was significantly correlated with the occurrence of cholangitis. However, among male patients who used platinum-based drugs, a correlation with the occurrence of cholangitis was only observed for oxaliplatin use. In addition, patients with carboplatin induced cholangitis had the highest hospitalization rate, and patients with oxaliplatin induced cholangitis had the highest mortality rate. The results of this study confirm that there is a strong correlation between the use of platinum drugs and the occurrence of cholangitis. Furthermore, this conclusion has also been confirmed in the female population using platinum-based drugs. We also found that patients with oxaliplatin-related cholangitis had the highest mortality rate and patients with carboplatin-related cholangitis had the highest hospitalization rate.

Alcohol-associated liver disease (ALD) remains a predominant cause of chronic hepatic pathology, and effective therapeutic strategies are needed. Krüppel-like factor 15 (KLF15) is a member of the KLF family of zinc-finger transcription factors and is ubiquitously expressed in metabolically active tissues, with a particularly high abundance in the liver. KLF15 has been implicated in various hepatic disorders. In this study, we investigated the pathophysiological role of KLF15 in ALD. We established a National Institute on Alcohol Abuse and Alcoholism (NIAAA) model in mice by feeding them an ethanol Lieber–DeCarli liquid diet containing 5

Pancreatic cancer (PC) is one of the most lethal types of cancer, as current treatments are largely ineffective. Our research uncovers that PPP2R2B is overexpressed in a majority of PC cases, playing a significant role in the growth and spread of PC tumors. Further analysis showed that reducing PPP2R2B levels in PC inactivates the MAPK pathways—ERK, JNK, and p38—impacting epithelial-mesenchymal transition (EMT) and apoptosis processes, ultimately promoting PC growth. Our experiments in live subjects demonstrate that removing PPP2R2B inhibits tumor growth in PC mouse models and alters the levels of proteins involved in EMT and cell death. Thus, our work highlights the crucial role of PPP2R2B as a new factor that promotes cancer progression by influencing EMT and cell death through the MAPK pathway in pancreatic cancer.

Pancreatic cancer (PC) is heterogeneous cancer having a high death rate and poor prognosis. The perioperative variables, such as anesthetics, may affect the cancer progression. Ciprofol is an intravenous anesthetic widely used recently. We aimed to explore the influence of ciprofol on PC and investigate its possible pathway. The proliferation, migration and invasion roles and apoptosis of ciprofol in human PC cells were examined using methylthiazolyldiphenyl-tetrazolium bromide, trans well and flow cytometery analysis. Then the putative targeted genes were examined using RNA-sequencing (RNA-seq) analysis. When differentially expressed genes (DEGs) were found, a protein-protein interaction network and pathway analyses were made. Moreover, MMP1 gene expression was confirmed in PC cells using quantitative real-time PCR. PANC-1 cells of PC were significantly suppressed with ciprofol in a dose-dependent and time-dependent way, and 20µg/mL ciprofol significantly suppressed tumor cell aggressiveness. Additionally, the RNA-seq analysis demonstrated that ciprofol controls the expression of 929 DEGs. 5 of 20 hub genes with increased connection were selected. Survival analysis demonstrated that MMP1 may be involved in the carcinogenesis and establishment of PC, reflecting the possible roles associated with ciprofol. Moreover, one target miRNA (hsa-miR-330-5p) of MMP1 was identified.

The myelin and lymphocyte protein (MAL) family is a novel gene family first identified and characterized in 2002. This family is comprised of seven members, including MAL, MAL2, plasmolipin, MALL, myeloid differentiation‑associated marker (MYADM), MYADML2 and CMTM8, which are located on different chromosomes. In addition to exhibiting extensive activity during transcytosis, the MAL family plays a vital role in the neurological, digestive, respiratory, genitourinary and other physiological systems. Furthermore, the intimate association between MAL and the pathogenesis, progression and metastasis of malignancies, attributable to several mechanisms such as DNA methylation has also been elucidated. In the present review, an overview of the structural and functional properties of the MAL family and the latest research findings regarding the relationship between several MAL members and various cancers is provided. Furthermore, the potential clinical and scientific significance of MAL is discussed and directions for future research are summarized.

What is Known and Objective. Voriconazole (VRC) increases the blood concentration of Tacrolimus (TAC). However, the patterns of changes in TAC trough concentration (TAC C0) and dose-adjustment regimens after VRC discontinuation have not been reported. We aimed to explore the changing pattern of TAC C0 after VRC discontinuation and provide strategies for TAC dose adjustment and blood concentration monitoring in renal transplant recipients. Methods. The clinical data of 46 renal transplant patients pre- and during VRC medication and VRC discontinuation were retrospectively recorded, including doses and concentrations 0 of TAC and VRC; biochemical indicators such as liver and kidney function; and CYP3A5, CYP3A4, and CYP2C19 gene types. Results and Discussion. After discontinuing VRC for 2-4 days, 81% of the patients returned to their initial TAC dose, although TAC C0 and TAC dose-adjusted trough concentration (C/D) were 2.43-fold and 3.35-fold higher, respectively, than pre-VRC administration. After 5-7 days, TAC C0 and C/D gradually recovered. TAC C/D was significantly higher after VRC discontinuation when the VRC trough concentration (VRC C0) was greater than 2.43 mg/L; CYP3A5, CYP3A4, and CYP2C19 genotypes and the administration of erythromycin did not affect the change in TAC C/D. What is New and Conclusion. TAC C/D remains elevated 2-4 days after discontinuing VRC compared to pre-VRC administration, with gradual recovery observed 5-7 days after VRC discontinuation. To avoid excessive blood TAC C0 , the initial TAC dose should not be immediately reinstated upon VRC discontinuation for 2-4 days. VRC C0 are a critical factor influencing the change in TAC C/D ratio after VRC discontinuation.

BACKGROUND:M2-polarized tumor-associated macrophages (TAMs) predominate in tumor microenvironment (TME) and serve primary functions in tumor progression, including growth, angiogenesis, metastasis, immunosuppression, chemoresistance, and poor prognosis. The reversal of M2 polarization provides a new treatment strategy for cancer. Presently, the molecular mechanisms of M2 polarization have yet to be fully characterized, and there is a lack of effective therapeutic targets and drugs. Cancer cells initiate an immunosuppressive TME by recruiting macrophages and promoting M2 polarization through the secretion of inflammatory factors. Accordingly, blocking cancer cell-induced TAM M2 polarization may present a more effective strategy from the perspective of cancer cells. Hedyotis diffusa Willd (HDW) possesses immunomodulatory and antitumor properties, and is a precious and direct source of small molecule natural products with a dual function of inhibition of tumor growth and tumor cell-mediated M2 polarization. OBJECTIVE:To identify a new target promoting gastric cancer (GC) cell growth and GC cell-mediated M2 polarization from mRNA profiles of GC cells treated with HDW injection (HDI) and to excavate a natural product from HDI that can regulate related mRNA and inhibit the aforementioned effects. METHODS:RNA sequencing (RNA-seq) was used to analyze HDI-regulated differentially expressed mRNAs (HRmRNAs) in MKN45 cells. Weighted gene co-expression network analysis (WGCNA), univariate and multivariate Cox regression analysis, KM survival curves, and association analysis between HRmRNA and clinical characteristics/tumor infiltrating immune cells (TIICs) individually were utilized to screen out the target HRmRNA associated with prognosis and M2 macrophage infiltration in GC. shRNA lentiviral vectors were used for stably silencing, and transient overexpressing plasmids were constructed for overexpression. CCK8, EdU, colony formation, migration and invasion assays were used to validate the function of drugs and molecules in GC. HDI constituent analysis was performed using UHPLC-QE-MS. A network of HDI constituent-hub transcription factor (TF)-HRmRNA was constructed based on RNA-Seq, network pharmacology and TFs prediction. Exosome isolation and identification were performed using ultracentrifugation, NTA, TEM and western blot. Apoptosis and macrophage phenotypes were determined by flow cytometric analysis. Small RNA-Seq made exosomal miRNA identification. Small molecule interaction with targets were analyzed using molecular docking, SPR and CETSA. The direct relationship between transcription factors and promoters was verified using ChIP-QPCR and dual-luciferase reporter gene assay. A nude mice xenograft tumor model was established for vivo validation. RESULTS:HDI inhibited MKN45 cell proliferation, migration, invasion and promoted apoptosis. RNA-Seq identified 2583 HRmRNAs. PLXNC1 was screened out as the target HRmRNA associated with prognosis and M2 macrophage infiltration in GC. PLXNC1 promoted GC cell proliferation and facilitated TAMs M2 polarization by transferring GC cell-derived exosomal miR-92b-5p, inhibiting SOCS7-STAT3 interactions and subsequently activating STAT3 in macrophages. M2 TAMs induced by PLXNC1-mediated GC cell-derived exosomes promoted GC cell migration and invasion. PLXNC1 regulated exosomal miR-92b-5p through the MEK1/MSK1/CREB1 pathway. STAT3 could transcriptionally regulate PLXNC1 expression in GC cells. The network of HDI constituent-hub TF-HRmRNA showed epigallocatechin gallate (EGCG) from HDI targeted STAT3 to transcriptionally regulate PLXNC1 expression. EGCG as a natural product directly bound to STAT3 to diminish its nuclear localization, resulting in the transcriptional repression of PLXNC1 and the reversal of M2 polarization induced by PLXNC1-mediated GC cell-derived exosomes. CONCLUSION:PLXNC1 is a novel target exerting dual effects on GC cell proliferation and GC cell-mediated M2 polarization. EGCG derived from HDI inhibits GC cell proliferation and targets STAT3 to inhibit M2 polarization induced by PLXNC1-mediated exosomes derived from GC cells, which may be a multi-target therapeutic agent for GC cell proliferation and immune microenvironment.

Background Nutritional deficiencies remain serious medical and public health issues worldwide, especially in children. This study aims to analyze cross-country inequality in four common nutritional deficiencies (protein-energy malnutrition, dietary iron deficiency, vitamin A deficiency and iodine deficiency) among children from 1990 to 2019 based on Global Burden of Disease (GBD) 2019 data. Methods Prevalence and disability-adjusted life years (DALYs) data as measures of four nutritional deficiency burdens in people aged 0 to 14 years were extracted from the GBD Results Tool. We analyzed temporal trends in prevalence by calculating the average annual percent change (AAPC) and quantified cross-country inequalities in disease burden using the slope index. Results Globally, the age-standardized prevalence rates of dietary iron deficiency, vitamin A deficiency and iodine deficiency decreased, with AAPCs of -0.14 (-0.15 to -0.12), -2.77 (-2.96 to -2.58), and -2.17 (-2.3 to -2.03) from 1999 to 2019, respectively. Significant reductions in socio-demographic index (SDI)-related inequality occurred in protein-energy malnutrition and vitamin A deficiency, while the health inequality for dietary iron deficiency and iodine deficiency remained basically unchanged. The age-standardized prevalence and DALY rates of the four nutritional deficiencies decreased as the SDI and healthcare access and quality index increased. Conclusions The global burden of nutritional deficiency has decreased since 1990, but cross-country health inequalities still exist. More efficient public health measures are needed to reduce disease burdens, particularly in low-SDI countries/territories.

ObjectiveThe objective of this research is to scrutinize adverse events (AEs) linked to Trifluridine/Tipiracil (TFTD/TPI), using data from the FDA Adverse Event Reporting System (FAERS) database.MethodsThe AEs data related to TFTD/TPI were collected from the fourth quarter of 2015 through the fourth quarter of 2023. After normalizing the data, multiple signal quantification techniques including Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Bayesian approaches such as Bayesian Confidence Propagation Neural Network (BCPNN) and the Multi-item Gamma Poisson Shrinker (MGPS) were used for overall and subgroup analysis and visualization analyses were performed.ResultsFrom the FAERS database, we analyzed 13,520,073 reports, identifying 8,331 as primary suspect (PS) AEs for TFTD/TPI, occurring across 27 organ systems. The study retained 99 significant disproportionality Preferred Terms (PTs) across four algorithms and unveiled unexpected serious AEs such as iron deficiency and intestinal perforation, hepatic failure, cholangitis and so on. The median onset of TFTD/TPI-associated AEs was 44 days (IQR 20-97 days), with most occurring within the first 30 days of treatment.ConclusionThis research uncovers critical new safety signals for TFTD/TPI, supporting its clinical monitoring and risk identification.

Background: The recently identified carcinogenic long non-coding RNA (lncRNA) MIR4435-2HG has been validated to contribute to the initiation and progression of several malignancies. Nonetheless, its specific mechanistic function in pancreatic cancer (PC) is yet to be determined. This study aims to investigate the expression and functional role of MIR4435-2HG in PC and to elucidate its potential mechanism. Methods: This study employed The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx)-Pancreas datasets for the analysis of MIR4435-2HG expression in PC and normal pancreatic tissues and its relations with prognosis in PC. Moreover, quantitative real-time polymerase chain reaction (qRTPCR) was employed for analyzing MIR4435-2HG, miR-128-3p, and ABHD17C expressions within cells and tissues. Cell proliferation and apoptosis were detected in vitro through Cell Counting Kit 8 (CCK-8) assay and flow cytometry while utilizing transwell and wound healing assays to assess cell migration and invasion. Predicting miR-128-3p binding sites with MIR4435-2HG or ABHD17C was conducted via the online tool starBase and validated through a dual-luciferase reporter (DLR), RNA pull-down and RNA binding protein immunoprecipitation (RIP) assays. Herein, we deployed Western blot to assess protein expression levels. The in vivo role of MIR4435-2HG was studied using tumor xenografts. Results: MIR4435-2HG overexpression exhibited a correlation with poor prognosis in PC. Knocking down MIR4435-2HG significantly hindered the proliferative, invading, and migrating PC cell abilities, accompanied by apoptosis induction, counteracted via a miR-128-3p inhibitor. Moreover, MIR4435-2HG could directly bind to miR-128-3p. Additionally, miR-128-3p directly targeted ABHD17C. Furthermore, in vitro as well as in vivo experiment results elucidated that knocking down MIR4435-2HG hindered PC progression by suppressing ABHD17C expression via miR-128-3p upregulation. Conclusions: MIR4435-2HG can serve as a dependable target for PC diagnosis and treatment by modulating the miR-128-3p/ABHD17C axis to promote its progression.

Background:The dilemma of pancreatic cancer treatment has become a global challenge. For this reason, effective, feasible, and new medical methods are currently much-needed. Betulinic acid (BA) has been valued as a potential therapy for pancreatic cancer. However, the mechanism by which BA exerts an inhibitory effect on the development of pancreatic cancer remains elusive.Methods:A rat model and two cell models of pancreatic cancer were established, and the effect of BA on pancreatic cancer was verified in vivo and in vitro by using MTT, Transwell, flow cytometry, RT-PCR, Elisa and immunohistochemistry. At the same time, miR-365 inhibitors were introduced to test whether BA played a role in mediating miR-365.Results:BA can significantly inhibit the proliferation and invasion of pancreatic cancer cells and promote apoptosis. In vivo experiments, BA can significantly lower the number of cancer cells and tumor volume in the rat model of pancreatic cancer. In vitro, it was found that BA inhibited the protein level and phosphorylation level of AKT/STAT3 by mediating the expression of miR365/BTG2/IL-6. Like BA, miR-365 inhibitors also significantly inhibited cell viability and invasion ability, and inhibited the protein level and phosphorylation level of AKT/STAT3 by changing the expression of BTG2/IL-6, and their combination had a synergistic effect.Conclusion:BA inhibits AKT/STAT3 expression and phosphorylation by modulating miR-365/BTG2/IL-6 expression, and BA inhibits the progression of pancreatic cancer through the aforementioned mechanism.

ObjectivePancreatitis poses a serious medical problem worldwide. This study aims to explore the epidemiological trends of pancreatitis from 1990 to 2019, analyze the association between disease burden and age, period and birth cohort, and subsequently present a forecast of pancreatitis incidence and deaths.MethodsEpidemiologic data were gathered from the Global Health Data Exchange query tool. Joinpoint regression model was used to calculate the average annual percentage changes (AAPCs). Age-period-cohort analysis was utilized to estimate the independent effects of age, period and birth cohort. We also predicted the global epidemiological trends to 2044.ResultsGlobally, the incident cases and deaths of pancreatitis increased 1.63-and 1.65-fold from 1990 to 2019, respectively. Joinpoint regression analysis showed that the age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) decreased over the past three decades. The age effect indicates that older people have higher age-specific incidence and death rates. The period effect on incidence and deaths showed downward trends from 1990 to 2019. The cohort effect demonstrated that incidence and death risk peaked in the earlier birth cohort and were lower in the latest birth cohort. Incident cases and deaths of pancreatitis may significantly increase in the next 25 years. The ASIRs were predicted to slightly increase, while the ASDRs were predicted to decrease.ConclusionEpidemiologic patterns and trends of pancreatitis across age, period and birth cohort may provide novel insight into public health. Limitations of alcohol use and prevention strategies for pancreatitis are necessary to reduce future burden.