Embryo transfer at the blastocyst stage has become popular in assisted reproductive technology, but it is still a challenge for embryologists to select the embryos with the highest implantation potential. We aimed to investigate whether blastocyst development speed and blastocyst quality affect pregnancy and perinatal outcomes in single frozen–thawed blastocyst transfer (SFBT) cycles. We therefore conducted a meta-analysis to compare the pregnancy and perinatal outcomes after day 5 versus day 6 SFBT. Pregnancy and perinatal outcomes of SFBT included HCG positive rate, clinical pregnancy rate (CPR), live birth rate (LBR), miscarriage rate (MR), multiple pregnancy rate (MPR), ongoing pregnancy rate (OPR), ectopic pregnancy rate (EPR), mean birth weight, low birth weight (LBW) rate, rate of macrosomia, mean gestational age at birth, preterm birth rate, birth defects rate, and sex ratio (female/male). A total of 106 316 participants were included in this meta-analysis and were assigned to the D5 ( n  = 66 329) and D6 ( n  = 39 987) SFBT groups. Pooled analysis showed that the D5 SFBT group had a higher HCG positive rate (RR 1.24, 95% CI 1.14–1.34), CPR (RR 1.28, 95% CI 1.22–1.34), OPR (RR 1.36, 95% CI 1.21–1.53), LBR (RR 1.39, 95% CI 1.32–1.47), and a lower MR (RR 0.78, 95% CI 0.73–0.83) than the D6 SFBT group. No significant difference was observed between the D5 and D6 SFBT groups in other pregnancy and perinatal outcomes. Subgroup analysis comparing poor-quality D5 blastocysts with high-quality D6 blastocysts revealed no significant differences in most outcomes, except for a lower HCG positive rate (RR 0.92, 95% CI 0.87–0.97) and a higher rate of macrosomia (RR 2.13, 95% CI 1.05–4.31) in the poor-quality D5 group. The findings suggested that transfer D5 blastocysts should be prioritized over D6 blastocysts in SFBT in clinical practice. Besides, poor-quality D5 blastocysts and D6 high-quality blastocysts exhibited comparable outcomes. Given the overall low quality of available evidence, the association between the pregnancy outcomes and blastocyst development speed requires further investigation.

Lung cancer outcomes depend on early detection and accurate lesion delineation, yet conventional segmentation methods remain clinically detached by yielding scanner sensitive pixel masks that do not align with radiologist language or reporting standards. To address this limitation, we propose BiomedLoop, a text guided framework that integrates semantic descriptions with spatial quantification to mirror routine diagnostic practice. Our pipeline couples localization via fine-tuned Grounding DINO and refinement using SEEM, which is enhanced by a novel Uncertainty Aware Feature Modulator to ensure boundary sensitive representation. A core innovation involves converting mask derived geometric descriptors into structured pseudo text prompts to fine tune the localization pathway, enabling supervision even on datasets without native radiology reports. Additionally, the system outputs structured reports compliant with the TID 1500 specification. Extensive experiments across five public benchmarks demonstrate that BiomedLoop yields elevated Dice similarity coefficients and consistently lower Hausdorff distances relative to both conventional CNN architectures and Segment Anything Model variants. Collectively, these results show that systematic semantic spatial joint modeling successfully bridges the critical disconnect between traditional segmentation and clinical utility in resource limited settings.

The molecular mechanisms by which the epidemiologically linked bacterium Fusobacterium nucleatum (Fn) promotes Esophageal Squamous Cell Carcinoma (ESCC) malignancy are poorly defined. Here, we identify the key signaling pathways involved. We first established the intratumoral microbiota profile to focus on Fn's role in ESCC. Using integrated models, we then confirmed that Fn promotes tumor growth, which a cisplatin (CDDP)-induced senescence model also showed contributes to chemoresistance. Finally, by analyzing key signaling molecules, we elucidated the mechanisms by which Fn drives proliferation and treatment resistance. We began by observing a positive correlation between Fn enrichment and elevated TLR4/STAT3 signaling in ESCC patients. Subsequent experiments in cells and animals confirmed that this correlation functionally contributes to increased tumor aggressiveness. At the mechanistic level, Fn-derived lipopolysaccharide (LPS) acts as the key trigger, activating the TLR4/MYD88/TRIF/STAT3 axis to drive pro-inflammatory signaling and SASP, thereby leading to chemoresistance. Therapeutically, curcumin counters this by directly inhibiting Fn and blocking the pathway, thereby suppressing tumor growth, attenuating SASP, and restoring drug sensitivity. The inhibition of the Fn-activated TLR4/MYD88/TRIF/STAT3 cascade represents a key mechanism through which curcumin blocks ESCC progression, identifying it as a promising candidate for therapeutic development.

Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant and phase II detoxification genes, plays a dual role in colorectal cancer (CRC) progression by maintaining redox homeostasis while paradoxically fostering chemoresistance. Programmed cell death (PCD) pathways, including apoptosis, ferroptosis, and autophagy, play a crucial role in the pathogenesis and therapeutic responsiveness of CRC, largely through mechanisms mediated by reactive oxygen species (ROS). Emerging evidence highlights that pharmacological agents or natural compounds targeting PCD trigger ROS accumulation, selectively impairing the survival of CRC cells due to their increased dependency on ROS. Although Nrf2's dual roles have been extensively characterized, the specific interactions between Nrf2-mediated redox regulation and PCD modulation are not yet fully understood, thereby constraining the advancement of redox-based therapeutic strategies. This review synthesizes recent advances in Nrf2 activity modulation within PCD-centric CRC treatment paradigms, emphasizing its context-dependent roles in ROS management. Furthermore, we propose rational strategies to harness Nrf2 inhibitors or activators, either as monotherapies or in combination with conventional regimens, to overcome chemoresistance and amplify therapeutic efficacy. By bridging mechanistic insights with therapeutic potential, this work underscores Nrf2 as a pivotal node for redefining redox-targeted CRC interventions. This narrative review systematically summarizes literature on Nrf2, ROS, and PCD pathways (apoptosis, ferroptosis, autophagy) in CRC. Literature searches were conducted in PubMed and Web of Science using the following keywords: (“Nrf2” OR “NFE2L2”) AND (“colorectal cancer” OR “CRC”) AND (“apoptosis” OR “ferroptosis” OR “autophagy” OR “programmed cell death” OR “ROS” OR “oxidative stress”). Searches were limited to English-language articles published between 2010 and 2024, with priority given to recent (2018–2024) in vivo and in vitro, clinical, and mechanistic studies. Reviews and studies focusing on other cancers were excluded. Additional articles were identified via reference lists of key reviews and original studies. Data were synthesized to highlight mechanistic links between Nrf2, ROS, and PCD, as well as translational therapeutic strategies.

Ferroptosis has emerged as a potential therapeutic target for chemotherapy of cancer. However, non-small cell lung cancer (NSCLC) exhibits high tolerance to ferroptosis due to inherent resistance. To increase NSCLC vulnerability, we present a TRPV1-targeting approach that self-delivers intracellular irons and TRPV1 agonist (N-oleoyldopamine, OLDA) to provoke simultaneous apoptosis and ferroptosis in NSCLC. Intracellular release of OLDA activates TRPV1 channels, triggering Ca2+ overload and mitochondrial/ER stress to induce apoptosis, while Fe3+ ions drive Fenton reactions, depleting GPX4/GSH and elevating lipid peroxides to induce ferroptosis. FeOLDA demonstrated selective cytotoxicity toward A549 NSCLC cells over normal bronchial epithelial BEAS-2B cells. In vivo studies demonstrate that FeOLDA effectively suppresses tumor growth without weight loss or multi-organ toxicity associated with cisplatin. This dual-action platform offers a lung cancer-targeted and efficient strategy for NSCLC treatment.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with a poor prognosis, often necessitating multimodal treatment approaches. While cisplatin (CDDP) remains the first-line chemotherapeutic agent, treatment failure frequently occurs due to drug resistance. To address this challenge, the FTO inhibitor FB23-2 has emerged as a promising candidate to enhance therapeutic efficacy. Consequently, this study aims to evaluate the combined efficacy of CDDP and FB23-2 in HNSCC and investigate their synergistic mechanisms. Using CCK-8 assays, colony formation assays, and flow cytometry for proliferation and cell cycle analysis, we observed that the CDDP-FB23-2 combination synergistically suppressed HNSCC proliferation. This treatment induced S/G2 phase cell cycle arrest and subsequent mitotic catastrophe. We further validated these findings in vivo using 4NQO-induced HNSCC mouse models. Additionally, drug safety was assessed via H&E staining of visceral organs, which revealed that a semi-combined regimen reduced treatment-related side effects. Mechanistic investigations involving immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), co-immunoprecipitation (Co-IP), and western blot analyses demonstrated that FB23-2 potentiated CDDP-induced DNA damage while inhibiting DNA repair mechanisms, thereby promoting apoptotic cell death. Specifically, FB23-2 blocked the assembly and nuclear translocation of XPF/ERCC1 complexes in CDDP-treated cells, directly increasing cellular sensitivity to CDDP. Collectively, our findings demonstrate that FB23-2 enhances CDDP sensitivity in HNSCC by targeting the XPF/ERCC1 complex, providing a theoretical basis and experimental support for their clinical application in HNSCC treatment.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, continues to be a leading cause of cancer-related deaths worldwide, despite the development of new treatment options, including systemic regimens, locoregional treatments, transplantation, and resection. Significant etiological and genetic heterogeneity, an immunosuppressive tumor microenvironment, dose-limiting toxicities, and high rates of post-treatment recurrence continue to inhibit robust responses. Given the crucial role of the liver in iron metabolism and oxidative homeostasis, ferroptosis-a controlled, iron-dependent cell death triggered by glutathione depletion, GPX4 inactivation, and lipid peroxidation, has become a potential therapeutic vulnerability in HCC. However, the risk of off-target oxidative damage, insufficient intratumoral transport, and the poor solubility and pharmacokinetics of small-molecule ferroptotic inducers limit the therapeutic application of ferroptosis induction.The current review is novel to the best of our knowledge, focusing on a targeted and current synthesis of nanomaterials delivering ferroptotic inducers in order to induce ferroptosis in HCC as a next-generation therapeutic paradigm. We describe how constructed nanoplatforms allow for spatiotemporally controlled ROS formation and iron-catalyzed lipid peroxidation, while also improving tumor-selective accumulation of ferroptosis triggers, extending circulation, and improving stability. In order to transform ferroptotic stress into antitumor immunity, we highlight ferroptotic inducing nanomaterials that co-deliver ferroptosis inducers alongwith chemotherapeutics or photothermal/photodynamic agents, and immunomodulatory designs that invoke innate immune pathways like cGAS–STING. This work establishes ferroptosis-inducing nanomedicine as a new and quickly developing field with the potential to overcome resistance, expand therapeutic windows, and enhance long-term outcomes for patients with HCC.

Background:Observational studies suggest that Helicobacter pylori (H. pylori) is associated with an increased risk of gastric cancer, yet the effect of H. pylori eradication on gastric cancer risk in patients with intestinal metaplasia (IM) or dysplasia remains controversial. The purpose of this study was to summarize the evidence from randomized controlled trials (RCTs) investigating H. pylori eradication on gastric cancer risk in patients with IM or dysplasia to determine the evidence base. Methods:PubMed, Embase, Cochrane Library, Web of science and China National Knowledge Internet database were searched for RCTs published through May 2024 in adults with IM or dysplasia comparing the risk of gastric cancer following H. pylori eradication versus no eradication therapy. Relative risk (RR) with its 95% confidence interval (CI) using random-effects model were employed for the effect estimate. Sensitivity, meta-regression, and subgroup analyses were also calculated. Results:Sixteen RCTs involving 15,027 patients with IM or dysplasia met the inclusion criteria. In a pooled analysis, H. pylori eradication resulted in a 45% reduction in RR for gastric cancer risk relative to no eradication (RR: 0.55; 95% CI: 0.46-0.67; p < 0.001). H. pylori eradication significantly reduced the risk of gastric cancer in patients with dysplasia (RR: 0.51; 95% CI: 0.32-0.82; p = 0.005), and IM (RR: 0.61; 95% CI: 0.40-0.93; p = 0.022). Further, if the study conducted in countries other than those in Asia, sample size <500, percentage of male <50.0%, follow-up duration <5.0 years, and low study quality, then there was no significant association between H. pylori eradication and a decreased risk of gastric cancer. Conclusion:H. pylori eradication is protective against gastric cancer in patients with IM or dysplasia. Systematic review registration:INPLASY202530010, https://inplasy.com/.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age at diagnosis of 68 years. The outcomes in older or unfit AML patients on intensive chemotherapy are poor, and thus, it is necessary to explore alternative strategies. In recent years, non-intensive therapies have transformed the standard of care for this population. Despite the increasing number of randomized clinical trials (RCTs) and cohort studies in this area, the optimal treatment approach remains unclear. We sourced four databases, PubMed, Embase, Cochrane, and Web of Science, until July 07, 2024, to identify all Phase II/III randomized controlled trials (RCTs) and cohort studies evaluating low-intensity treatments for older AML patients. Overall survival (OS), recurrence-free survival (RFS), complete remission (CR), complete remission with incomplete hematologic recovery (CRi), overall response rate (ORR), and adverse events (AEs) graded ≥ 3 were analyzed using a Bayesian fixed-effects network meta-analysis (NMA). A total of 4920 patients across 26 trials were included. In terms of improving OS, AZA + VEN, LDAC + glasdegib, and LDAC + VEN (SUCRA = 0.936, 0.898, and 0.718, respectively) were the most effective treatments. For CR, ORR, and CRi, AZA + VEN ranked highest among all therapies (SUCRA = 0.836, 0.911, and 0.829, respectively). This systematic review and network meta-analysis suggest that AZA + VEN is superior to the current standard of care, particularly in improving OS, CR, ORR, and CRi. LDAC + glasdegib also demonstrated promising efficacy and warrants further investigation.

Cardiovascular diseases represent the principal cause of death and comorbidity among people with diabetes. Ferroptosis, an iron-dependent non-apoptotic regulated cellular death characterized by lipid peroxidation, is involved in the pathogenesis of diabetic cardiovascular diseases. The susceptibility to ferroptosis in diabetic hearts is possibly related to myocardial iron accumulation, abnormal lipid metabolism and excess oxidative stress under hyperglycemia conditions. Accumulating evidence suggests ferroptosis can be the therapeutic target for diabetic cardiovascular diseases. This review summarizes ferroptosis-related mechanisms in the pathogenesis of diabetic cardiovascular diseases and novel therapeutic choices targeting ferroptosis-related pathways. Further study on ferroptosis-mediated cardiac injury can enhance our understanding of the pathophysiology of diabetic cardiovascular diseases and provide more potential therapeutic choices.

It is disputable whether chromosomal translocations lead to an inferior embryo development. The purpose of this study was to evaluate whether structural rearrangements (SR) affect blastocyst formation as compared to monogenic disorders in preimplantation genetic testing (PGT) cycles. A total of 791 PGT-SR cycles and 757 PGT-M cycles from January 2021 to May 2023 were included. Lower blastocyst formation (graded 3BB or higher) rate was detected in the PGT-SR group compared with the control PGT-M group. In addition, lower proportion of day 5 blastocysts was found in the PGT-SR group compared with the control PGT-M group. Overall, a comparatively 12.7

INTRODUCTION:Embryo transfer at the blastocyst stage has become popular in assisted reproductive technology, but it is still a challenge for embryologists to select the embryos with the highest implantation potential. We aimed to investigate whether blastocyst development speed and blastocyst quality affect pregnancy and perinatal outcomes in single frozen-thawed blastocyst transfer (SFBT) cycles. MATERIAL AND METHODS:We therefore conducted a meta-analysis to compare the pregnancy and perinatal outcomes after day 5 versus day 6 SFBT. Pregnancy and perinatal outcomes of SFBT included HCG positive rate, clinical pregnancy rate (CPR), live birth rate (LBR), miscarriage rate (MR), multiple pregnancy rate (MPR), ongoing pregnancy rate (OPR), ectopic pregnancy rate (EPR), mean birth weight, low birth weight (LBW) rate, rate of macrosomia, mean gestational age at birth, preterm birth rate, birth defects rate, and sex ratio (female/male). RESULTS:A total of 106 316 participants were included in this meta-analysis and were assigned to the D5 (n = 66 329) and D6 (n = 39 987) SFBT groups. Pooled analysis showed that the D5 SFBT group had a higher HCG positive rate (RR 1.24, 95% CI 1.14-1.34), CPR (RR 1.28, 95% CI 1.22-1.34), OPR (RR 1.36, 95% CI 1.21-1.53), LBR (RR 1.39, 95% CI 1.32-1.47), and a lower MR (RR 0.78, 95% CI 0.73-0.83) than the D6 SFBT group. No significant difference was observed between the D5 and D6 SFBT groups in other pregnancy and perinatal outcomes. Subgroup analysis comparing poor-quality D5 blastocysts with high-quality D6 blastocysts revealed no significant differences in most outcomes, except for a lower HCG positive rate (RR 0.92, 95% CI 0.87-0.97) and a higher rate of macrosomia (RR 2.13, 95% CI 1.05-4.31) in the poor-quality D5 group. CONCLUSIONS:The findings suggested that transfer D5 blastocysts should be prioritized over D6 blastocysts in SFBT in clinical practice. Besides, poor-quality D5 blastocysts and D6 high-quality blastocysts exhibited comparable outcomes. Given the overall low quality of available evidence, the association between the pregnancy outcomes and blastocyst development speed requires further investigation.

Gastric cancer (GC) remains a global clinical challenge due to late diagnosis, high heterogeneity, and poor prognosis. Tumor stemness has emerged as a key factor driving tumor aggressiveness and therapeutic resistance. However, the systematic characterization of high-stemness GC cells and their molecular features remains limited. We integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA-seq data to identify and characterize high-stemness GC cells. Stemness scores were calculated using CytoTRACE, and malignant cells were classified into high stemness (top 25% CytoTRACE-scored cells, HighStem), dynamic transition stemness (DTStem), and low stemness (LowStem) subpopulations based on the quartile method cutoff. ScPagwas and cell-cell communication profiling were used to explore genomic instability, genetic susceptibility, and microenvironmental interactions. HighStem-specific co-expression modules were identified via high-dimensional WGCNA (hdWGCNA), and features were screened using six machine learning algorithms. A benchmark model was constructed for HighStem prediction and interpreted using SHAP analysis. HighStem GC cells exhibited enhanced intercellular signaling, metabolic reprogramming, and stemness-related pathway activity. Five genes-APMAP, MAPRE1, GLB1, TSPAN6, and CDKN2A-were identified as robust HighStem features. Spatial and bulk transcriptomic validation confirmed their tumor-specific expression and prognostic relevance. The Support Vector Machine (SVM) model incorporating these genes achieved high accuracy (AUC = 0.973) in distinguishing HighStem cells, demonstrating strong clinical utility at the scRNA-seq level. In addition, experimental validation through knockdown of core genes (APMAP, CDKN2A, TSPAN6, MAPRE1, and GLB1) in SGC7901 and HGC-27 gastric cancer cell lines revealed a significant reduction in JAK1-STAT3 pathway activity, supporting their functional involvement in tumor stemness regulation. Furthermore, knockdown of these genes increased the sensitivity of GC cells to chemotherapeutic agents like 5-FU and cisplatin, indicating their potential role in chemoresistance. This study provides a comprehensive molecular and functional characterization of high-stemness GC cells. The identified signature genes and predictive models offer novel insights into GC stemness biology and could guide personalized therapeutic strategies. Furthermore, our findings suggest that the core genes identified in this study may serve as potential biomarkers for predicting treatment outcomes and monitoring therapeutic resistance in GC.

With the development of medical and health care, esophageal cancer (EC) has become a disease of concern to the scientific research community. At present, among all treatment regimens for EC, surgical resection is conducive to the prognosis of early patients neoadjuvant therapies are recommended for advanced patients. However, treatments now are not satisfactory in suppressing the progression of EC. Ferroptosis is one distinctive cell death mode, noted for the accumulation of iron as well as lipotoxicity, which induce cell membrane to breakdown. As a star protein of ferroptosis related pathway, GPX4 is related to the homeostatic imbalance of tumor immune microenvironment (TIME) of EC, thereby regulating the onset as well as progression of the cancer. In our manuscript, we present the mechanisms involved in ferroptosis, the functions of ferroptosis in the TIME. We also focused on the progression about ferroptosis in EC, as well as targeting ferroptosis-related pathways to delay the development of EC. We expect that these contents can expand fresh insights and aim for EC therapeutic strategy in clinical practice.

Background:Multiple myeloma (MM) is a hematological malignancy with limited treatment options for patients with relapsed/refractory MM (RRMM). Teclistamab, a B-cell maturation antigen (BCMA) × CD3 bispecific antibody, has shown promising results in clinical trials and real-world studies. Methods:PubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library, ClinicalTrials.gov, and meeting libraries were searched from inception to 14 November 2024. The assessed outcomes included overall survival (OS), progression-free survival, time to next treatment, duration of response, overall response rate (ORR), ≥complete response (≥CR), ≥very good partial response (≥VGPR), VGPR, partial response, and adverse events. Results:In total, 34 studies involving 4,064 patients were included. In pairwise meta-analysis, teclistamab demonstrated superior OS [hazard ratio (HR) = 0.69, 95% confidence interval (CI): 0.54-0.89; p = 0.037] compared to existing RRMM treatments. Real-world studies showed comparable ORR (62%, 95% CI: 58%-66%) but slightly lower survival outcomes, possibly because of shorter follow-up times and higher-risk populations. Subgroup analyses revealed enhanced efficacy with combination therapies (ORR: 85% vs 62%, p < 0.0001) and notable clinical benefits in the China cohort (≥VGPR: 77%, ≥CR: 58%). Safety profiles indicated manageable cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, though infection risks required vigilant management. Conclusions:Teclistamab continues to be a promising and effective treatment option for RRMM patients, including those previously exposed to BCMA-targeted therapies, and offers new hope for overcoming resistance and achieving better early disease control. Further research is needed to optimize its application in diverse populations, particularly in Asian cohorts. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42025633838.

PARP inhibitors (PARPi) are increasingly vital in treating, particularly in individuals exhibiting homologous recombination deficiency (HRD), harnessing synthetic lethality to target tumor cells. However, PARPi resistance severely restricts their sustained efficacy, posing a significant clinical obstacle requiring a detailed exploration of its mechanisms and solutions. This review elucidates the underlying mechanisms of PARPi resistance, assesses biomarker-driven predictive tools, and explores novel strategies to improve therapeutic outcomes. This review critically assesses biomarker-driven strategies for resistance prediction, such as genomic profiling, functional assays, dynamic circulating tumor DNA (ctDNA) monitoring, and emerging markers, to refine patient stratification. Moreover, this review systematically dissects PARPi resistance, including genomic alterations, homologous recombination (HR) restoration, replication fork stabilization, enhanced drug efflux, reduced PARP1 trapping, and microenvironmental influences. In addition, therapeutic tactics to prevent or overcome resistance are evaluated, encompassing sequential PARPi use, combinations with chemotherapy, immunotherapy, antiangiogenic agents, and DNA damage response (DDR) inhibitors, alongside innovative approaches like antibody-drug conjugates (ADCs). Bridging mechanistic and clinical perspectives, this review promotes a multidisciplinary approach to optimize PARPi-based treatments, addressing current challenges in ovarian cancer management.

Objective This phase Ib trial aimed to assess the safety and efficacy of sintilimab plus bevacizumab (sintilimab/bev), followed by resection in patients with potentially resectable intermediate-stage hepatocellular carcinoma (HCC) and explore the clinical implications of circulating tumour DNA (ctDNA) and T cell receptor (TCR) repertoire.Methods and analysis Eligible patients with intermediate-stage HCC received sintilimab/bev treatment. Patients with partial response or stable disease for at least two consecutive evaluations and technically resectable received hepatectomy. Postoperatively patients continued to receive sintilimab/bev until tumour recurrence or intolerable toxicities for up to 12 months. The primary endpoints were treatment safety and event-free survival (EFS). Plasma ctDNA measurements and TCR repertoire were analysed.Results 30 patients were enrolled. 17 (56.7%) patients received liver resection. Grade 3 treatment-related adverse events occurred in seven patients (23.3%). No grade 4/5 AE or postoperative mortality was observed. The median EFS of the 30 patients was 16.3 months (95% CI 13.4 to 19.2). The 12-month and 24-month survival rates were 93.2% and 82.0%, respectively. Of the 17 patients who received hepatectomy, the median recurrence-free survival was 14.1 months (95% CI 8.9 to 19.4). A lower ctDNA measurement and higher TCR repertoire were associated with better tumour response or patients’ survival.Conclusions The study suggested systemic therapy with sintilimab/bev was safe and effective in patients with intermediate-stage HCC, and resection in selected patients was associated with improved survival. ctDNA measurement and TCR repertoire may help identify patients who may benefit from sintilimab/bev treatment and patients with a higher risk of tumour recurrence.Trial registration number NCT04843943.

BackgroundWe aim to evaluate the global, regional, and national burden of Uterine Cancer (UC) from 1990 to 2019.MethodsWe gathered UC data across 204 countries and regions for the period 1990-2019, utilizing the Global Burden of Disease Database (GBD) 2019 public dataset. Joinpoint regression analysis was employed to pinpoint the year of the most significant changes in global trends. To project the UC trajectory from 2020 to 2044, we applied the Nordpred analysis, extrapolating based on the average trend observed in the data. Furthermore, the Bayesian Age-Period-Cohort (BAPC) model with integrated nested Laplace approximations was implemented to confirm the stability of the Nordpred analysis predictions.ResultsGlobally, the age-standardized rate (ASR) of incidence for UC has increased from 1990 to 2019 with an Average Annual Percentage Change (AAPC) of 0.50%. The ASR for death has declined within the same period (AAPC: -0.8%). An increase in the ASR of incidence was observed across all Socio-demographic Index (SDI) regions, particularly in High SDI regions (AAPC: 1.12%), while the ASR for death decreased in all but the Low SDI regions. Over the past 30 years, the highest incidence rate was observed in individuals aged 55-59 (AAPC: 0.76%). Among 204 countries and regions, there was an increase in the ASR of incidence in 165 countries and an increase in the ASR of deaths in 77 countries. Our projections suggest that both the incidence and death rates for UC are likely to continue their decline from 2020 to 2044.ConclusionsUC has significantly impacted global health negatively, with its influence stemming from a range of factors including geographical location, age-related and racial disparities, and SDI.

Background and Aims:Necroptosis is critical for regulating intestinal epithelial cells (IECs). Butyric acid (BA), produced during intestinal microbial metabolism, protects the intestinal epithelial barrier. However, whether necroptosis occurs in IECs during liver cirrhosis and whether sodium butyrate (NaB) can regulate necroptosis have not yet been reported. In this study, we aimed to investigate whether IECs undergo necroptosis in cirrhosis and whether NaB can regulate necroptosis and the related regulatory mechanisms. Methods:Serum levels of RIPK3, MLKL, and Zonulin, as well as fecal BA levels, were measured and correlated in 48 patients with liver cirrhosis and 20 healthy controls. A rat model of liver cirrhosis was established, and NaB was administered. The expressions of MLKL, p-MLKL, and tight junction proteins were measured. We conducted an in vitro investigation of the effect of NaB on necroptosis in the HT29 cell line. Results:Serum levels of RIPK3, MLKL, and Zonulin in the liver cirrhosis group were higher, while fecal BA levels were lower than those in the control group. Zonulin levels were positively correlated with RIPK3 and MLKL levels, while fecal BA levels were negatively correlated with serum MLKL levels, but not with RIPK3 levels. NaB reduced the mRNA and protein expression of MLKL but had no effect on RIPK1 and RIPK3 in vitro. Rescue experiments demonstrated that NaB inhibited necroptosis through E2F1-mediated regulation of MLKL. Conclusions:NaB alleviates intestinal mucosal injury and reduces necroptosis in IECs in liver cirrhosis. It also inhibits the necroptosis of IECs and protects the intestinal barrier by reducing E2F1 expression and downregulating MLKL expression levels. These results can be employed to develop a novel strategy for treating complications arising from liver cirrhosis.