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Introduction: Small cell lung cancer (SCLC) is prone to chemoresistance, which is closely related to genome homeostasis-related processes, such as DNA damage and repair. Nucleophagy is the elimination of specific nuclear substances by cells themselves and is responsible for maintaining genome and chromosome stability. However, the roles of nucleophagy in tumour chemoresistance have not been investigated. Objectives: The aim of this work was to elucidate the mechanism of chemoresistance in SCLC and reverse this chemoresistance. Methods: RNA-seq data from SCLC cohorts, chemosensitive SCLC cells and the corresponding chemoresistant cells were used to discover genes associated with chemoresistance and patient prognosis. In vitro and in vivo experiments were performed to verify the effect of high-mobility group box 1 (HMGB1) knockdown or overexpression on the chemotherapeutic response in SCLC. The regulatory effect of HMGB1 on nucleophagy was then investigated by coimmunoprecipitation (co-IP) and mass spectrometry (MS), and the underlying mechanism was explored using pharmacological inhibitors and mutant proteins. Results: HMGB1 is a factor indicating poor prognosis and promotes chemoresistance in SCLC. Mechanistically, HMGB1 significantly increases PARP1-LC3 binding to promote nucleophagy via PARP1 PARylation, which leads to PARP1 turnover from DNA lesions and chemoresistance. Furthermore, chemoresistance in SCLC can be attenuated by blockade of the PARP1-LC3 interaction or PARP1 inhibitor (PARPi) treatment. Conclusions: HMGB1 can induce PARP1 self-modification, which promotes the interaction of PARP1 with LC3 to promote nucleophagy and thus chemoresistance in SCLC. HMGB1 could be a predictive biomarker for the PARPi response in patients with SCLC. Combining chemotherapy with PARPi treatment is an effective therapeutic strategy for overcoming SCLC chemoresistance.

BackgroundNeoadjuvant immunotherapy holds promise in managing resectable locally advanced gastric cancer (GC), adenocarcinoma of the esophagogastric junction (AEG), and esophageal cancer (EC). However, consensus is lacking regarding the efficacy of programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors in neoadjuvant immunochemotherapy (NICT). This study aims to assess the added benefit of PD-1/PD-L1 inhibitors in neoadjuvant chemotherapy (NCT) for these malignancies.MethodsUp to October 2024, randomized controlled trials, case-control studies, and cohort studies that evaluated the addition of PD-1/PD-L1 inhibitors to NCT were systematically retrieved from electronic databases. The primary endpoints included pathologic complete response (pCR), major pathological response (MPR), overall survival (OS), and progression-free survival (PFS).ResultsThirteen studies published between 2021 and 2024 were analyzed. Statistical analyses revealed significantly higher pCR rates (OR: 2.73, P < 0.001) and MPR rates (OR: 2.99, P < 0.001) in the NICT group compared to NCT group. The PFS was also higher in the NICT group, although the difference did not reach statistical significance (HR: 0.50, P = 0.072).ConclusionThis meta-analysis demonstrates that NICT enhances pathological response rates in patients with resectable locally advanced GC, AEG, and EC. However, no significant long-term prognostic benefits were associated with NICT.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42024545725.

ObjectiveThis meta-analysis explores the impact of vitamin D supplementation on antibiotic utilization.MethodsWe systematically searched for relevant randomized controlled trials (RCTs) in PubMed, Web of Science, EMBASE, and Science Direct from inception to April 2024. These trials compared antibiotic use rates between groups receiving vitamin D supplements and placebo.ResultsWe included seven RCTs involving 35,160 participants. There was no significant difference in antibiotic use between the two groups in the general population (Odds Ratio [OR] = 0.98, p = 0.232), including elderly participants (OR = 0.98, p = 0.295). However, antibiotic use was lower in the intervention group compared to the placebo group among participants under 70 years of age (OR = 0.95, p = 0.015), those with relative vitamin D deficiency [25(OH)D

Objectives We aimed to explore the lived experiences and needs of women after a recent stillbirth event.Design Qualitative phenomenological study.Setting The current study was conducted in a tertiary obstetric hospital in East China between 25 January 2024 and 29 March 2024.Participants 14 women having experienced a stillbirth within the last 6 months.Results Researchers agreed on four key themes including individual variations in emotional reaction and recovery, physical recovery and concerns about future pregnancies, the critical role of social support systems and variations in perceptions of stillbirth as the death of a fetus versus a human being, along with related mourning rituals. These themes collectively highlight the multifaceted nature of the stillbirth experience, underscoring the complex interplay between personal, cultural and medical factors that shape women’s emotional and physical responses.Conclusions Post-stillbirth experiences among Chinese women are deeply individualised and influenced by a complex interplay of personal emotions, cultural contexts and medical interactions. It is imperative for healthcare systems to implement tailored care strategies beyond standard protocols to proactively address their varied emotional landscapes and physical concerns with an enhanced awareness of cultural sensitivities. Specialised training for healthcare providers should be devised to recognise and respond to the unique grief processes. Comprehensive support systems should be established to significantly enhance the recovery journey by providing essential resources and community connections.

[Objective] Water-rich sandy stratum is a common geological formation encountered in metro shield tunnel excavation. Seepage may occur under the influence of water pressure differences inside and outside the soil chamber. Therefore, it is essential to study the accurate calculation method for the critical supporting pressure on shield tunnel excavation face in water-rich sandy stratum under seepage condition. [Method] Using the 3D (three-dimensional) finite element upper and lower bound limit analysis method and Optum G3 software, stability studies are conducted on the shield excavation face under no-seepage condition. Through sensitivity analysis of key parameters, a calculation method for the excavation face critical supporting pressure without considering seepage condition is proposed. Considering the seepage action caused by the water level difference inside and outside the soil chamber, a 3D finite element analysis method and PLAXIS 3D software are employed to investigate the instability damage modes of shield excavation face in water-rich sandy stratum under steady-state seepage and fluid-soil coupling action. Through sensitivity analysis of water level difference, tunnel buried depth ratio, and internal friction angle, based on the calculation formula for excavation face critical supporting pressure without seepage, a calculation method for excavation face critical supporting pressure considering steady-state seepage condition is further proposed. [Result & Conclusion] The proposed formula allows for a relatively straight forward determination of the excavation face pressure during shield tunneling in water-rich sandy layers. For different groundwater conditions, the critical excavation face supporting pressure is ranked as follows: critical excavation face supporting pressure without seepage>critical excavation face supporting pressure with seepage>excavation face critical pressure under dry sand conditions. In the case of burial depth ratio C/D25°, the instability damage zone in front of the excavation face is limited to a certain range above the excavation face, with a slightly larger damage area when seepage occurs compared to situations without seepage.

Crop rotation increases crop yield, improves soil health, and reduces plant disease. However, few studies were conducted on the use of intensive cropping patterns to improve the microenvironment of saline soils. The present study thoroughly evaluated the impact of a three-year maize–peanut–millet crop rotation pattern on the crop yield. The rhizosphere soil of the crop was collected at maturity to assess the effects of crop rotation on the composition and function of microbial communities in different tillage layers (0–20 cm and 20–40 cm) of sandy saline–alkaline soils. After three years of crop rotation, the maize yield and economic benefits rose by an average of 32.07% and 22.25%, respectively, while output/input grew by 10.26%. The pH of the 0–40 cm tillage layer of saline–alkaline soils decreased by 2.36%, organic matter rose by 13.44%–15.84%, and soil-available nutrients of the 0–20 cm tillage layer increased by 11.94%–69.14%. As compared to continuous cropping, crop rotation boosted soil nitrogen and phosphorus metabolism capacity by 8.61%–88.65%. Enrichment of Actinobacteria and Basidiomycota increased crop yield. Crop rotation increases microbial community richness while decreasing diversity. The increase in abundance can diminish competitive relationships between species, boost synergistic capabilities, alter bacterial and fungal community structure, and enhance microbial community function, all of which elevate crop yields. The obtained insights can contribute to achieving optimal management of intensive cultivation patterns and green sustainable development.

Abstract The silent information regulator 2 homolog 1-NACHT, LRR and PYD domains-containing protein 3 (SIRT1-NLRP3) pathway has a crucial role in regulation of the inflammatory response, and is closely related to the occurrence and development of several inflammation-related diseases. NLRP3 is activated to produce the NLRP3 inflammasome, which leads to activation of caspase-1 and cleavage of pro-interleukin (IL)-1β and pro-IL-18 to their active forms: IL-1β and IL-18, respectively. They are proinflammatory cytokines which then cause an inflammatory response.SIRT1 can inhibit this inflammatory response through nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B pathways. This review article focuses mainly on how the SIRT1-NLRP3 pathway influences the inflammatory response and its relationship with melatonin, traumatic brain injury, neuroinflammation, depression, atherosclerosis, and liver damage. Video Abstract

Background: This study aimed to investigate the role of endoscopy screening in colorectal cancer (CRC). Methods: Up to January 2023, databases were searched for studies related to sigmoidoscopy and colonoscopy screening. The incidence of CRC, and/or CRC mortality were the main observation outcomes. Results: A total of 5 randomized controlled trials (RCTs) published from 2017 to 2022 were included. Among them, four studies used sigmoidoscopy screening and one study involved colonoscopy screening. Statistical results showed that the incidence (RR: 0.78, p

BackgroundLipopolysaccharides (LPS) is well known to manifest a miscarriage-inducing effector during early pregnancy and activate macrophage to induce M1 macrophage polarization. However, the role of macrophage polarization in LPS-related miscarriage-inducing effect is not apparent.MethodsIn this work, gene expression changes and the percentage of M1/M2 macrophages and monocytes in LPS-induced miscarried uterus were firstly analyzed by RNA sequencing (RNA-seq) and Flow Cytometry. To explore the origin that contributes to M1/M2 macrophage differentiation, the expression of monocyte chemotactic protein (MCP-1), CCL3, and CCL4, chemokines related to monocyte/macrophage migration, was tested by quantitative real time PCR (qRT-PCR).ResultsWe found that percentage of M1 macrophages rose, while the percentage of M2 macrophages declined down in the injected mice uterus. Meanwhile, the percentage of M1 and M2 macrophages showed no significant difference in the spleens of LPS injected mice compared to PBS injected control mice. Expression of Mcp-1, Ccl3, and Ccl4 and numbers of monocytes were remarkably up-regulated in LPS-induced miscarried mice uterus.ConclusionThese results indicated that polarization and proportion changes of macrophage in the uterus may contribute to miscarriage. Our work provides new evidence correlating the aberrant regulation of M1/M2 macrophage polarization with deleterious miscarriage-inducing effects. This will help us understand the roles of critical immune cell differentiation in maintaining normal pregnancy.

Rotate vector (RV) reducers are typical deceleration elements that moderate and increase torsion. They are widely applied in industrial robots and automatic machinery with the superiorities of compact structure, high precision, and overload resistance performance. However, the RV reducers also have disadvantages, such as low bearing capacity and short service life. As the core drive mechanism in an RV reducer, the bearing capacity for a cycloid-pin gear drive system directly affects the performance of the entire deceleration system. Therefore, the bearing capacity of an RV reducer should be improved by increasing the capacity of a cycloid-pin gear. In this paper, the design of a cycloid-pin gear is optimized to improve its bearing capacity. The tooth profile equations for cycloid gear and the meshing gap are derived based on the gear meshing principle. The bearing capacity for cycloid-pin gear is modeled by combining the contact strength theory with the multi-tooth contact bearing analysis. The effects of eccentricity, the radius of pin tooth distribution circle, pin teeth number, pin tooth radius, cycloid thickness, modification value of moved distance and equidistance on total volume, contact stress, and torsional stiffness are systematically researched. Then, a single-, double-, and three-objective optimization model is proposed based on the load-bearing capacity for cycloid-pin gear by taking these three factors as the objective function. Moreover, the parameters are optimized with the genetic algorithm, and the analyses for three optimizations are compared and discussed. The theoretical models are confirmed by the simulation analysis through ANSYS software. The results show that the bearing capacity for the cycloid-pin gear system can be largely enhanced after optimization.

Radical surgery is the most important treatment for colon cancer. The development and application of complete mesentery excision (CME)/D3 lymph node dissection has promoted the standardization of surgical techniques for colon cancer. Right colon cancer surgery is relatively complicated, and is a research hotspot currently. The issues involved the range of lymph node dissection, the range of bowel resection, and the method of bowel reconstruction. The medial border of lymph node dissection for right colon cancer is one of the controversies. The left side of the superior mesenteric vein is generally considered to be the medial border of CME/D3 dissection in right colon cancer surgery. However, with the in-depth development of related research, some scholars believed that the left side of the superior mesenteric artery should be used as the medial border for lymph node dissection. This approach is more consistent with the principle of CME, and can achieve complete lymph node dissection. However, its clinical significance still needs to be evaluated with further research. This article discusses the selection of medial border of lymph node dissection for right colon cancer, hoping to provide reference for clinical practice.

Abstract Background Little is known on the tumor microenvironment (TME) response after neoadjuvant chemotherapy (NACT) in gastric cancer on the molecular level. Methods Here, we profiled 33,589 cell transcriptomes in 14 samples from 11 gastric cancer patients (4 pre-treatment samples, 4 post-treatment samples and 3 pre-post pairs) using single-cell RNA sequencing (scRNA-seq) to generate the cell atlas. The ligand-receptor-based intercellular communication networks of the single cells were also characterized before and after NACT. Results Compered to pre-treatment samples, CD4+ T cells (P = 0.018) and CD8+ T cells (P = 0.010) of post-treatment samples were significantly decreased, while endothelial cells and fibroblasts were increased (P = 0.034 and P = 0.005, respectively). No significant difference observed with respect to CD4+ Tregs cells, cycling T cells, B cells, plasma cells, macrophages, monocytes, dendritic cells, and mast cells (P > 0.05). In the unsupervised nonnegative matrix factorization (NMF) analysis, we revealed that there were three transcriptional programs (NMF1, NMF2 and NMF3) shared among these samples. Compared to pre-treatment samples, signature score of NMF1 was significantly downregulated after treatment (P = 0.009), while the NMF2 signature was significantly upregulated after treatment (P = 0.013). The downregulated NMF1 and upregulated NMF2 signatures were both associated with improved overall survival outcomes based on The Cancer Genome Atlas (TCGA) database. Additionally, proangiogenic pathways were activated in tumor and endothelial cells after treatment, indicating that NACT triggers vascular remodeling by cancer cells together with stromal cells. Conclusions In conclusion, our study provided transcriptional profiles of TME between pre-treatment and post-treatment for in-depth understanding on the mechanisms of NACT in gastric cancer and empowering the development of potential optimized therapy procedures and novel drugs.

Background: To provide an understanding of important aspects of the participant recruitment and data collection, become aware of any potential problems, and obtain necessary information in order to design a large-scale randomized controlled trial (RCT) for lung cancer and colorectal cancer (CRC) screening in China. Methods: This feasibility study was a multicentered, open-label, pilot randomized trial. A total of 2696 participants who were at high risk of lung cancer were recruited from three screening centers and randomly allocated to arm 1 (n = 894), annual low-dose computed tomography (LDCT) plus a baseline colonoscopy; arm 2 (n = 902), biennial LDCT plus annual fecal immunochemical test (FIT) with OC-Sensor (OC-FIT); and arm 3 (n = 900), annual Insure-FIT plus Septin 9 blood test. Information on randomization, compliance, positivity rate, cancer case detection, and contamination with screening for lung cancer and CRC were collected. Results: Participant characteristics were similar across study arms. The compliance rate of annual LDCT screening in arm 1 was 86.4% (95% CI: 83.9%, 88.5%) at baseline (T0), and 69.0% (95% CI: 65.8%, 72.0%) and 70.7% (95% CI: 67.6%, 73.7%) at the following two rounds (T1 and T2). The compliance rates of biennial LDCT screening in arm 2 were similar to those in arm 1 in the corresponding rounds. The compliance rate was 55.5% (95% CI: 52.2%, 58.8%) for colonoscopy in arm 1, while the compliance rates of OC-FIT, Insure-FIT, and the Septin 9 test in arms 2 and 3 were all approximately 90% at T0, decreasing to 65%–80% at T1 and T2. The positivity rate, cancer case detection rate, and contamination rate of screening for lung cancer and CRC were also reported. Conclusion: In this pilot study, the feasibility of an RCT in China of lung cancer and CRC screening was demonstrated.

In order to analyze the resonance response of RV gear reducer system，the natural frequency of RV gear reducer system should be determined first. Taking RV-320E gear reducer as the research object and considering tangential degrees of freedom of crank shaft and cycloid wheel rotation motion，the 16 degrees of freedom dynamic model of RV gear reducer is established by centralized mass method. The dynamics differential equation of the system is established by Newton's second law and the differential equation of fixed axis rotation，and the natural frequency of the system is calculated. The influence of the material properties of the parts on the first-order natural frequency is analyzed and the influence graph is drawn.

Diverticulosis is a commonly acquired disease of the lower gastrointestinal tract, which may be associated with significant morbidity and adverse effects on quality of life. Although several national guidelines focused on the treatment of diverticulosis, multiple controversies remained regarding the disease management of diverticulosis. For some controversial issues, such as the role of antibiotics in mild diverticulitis, when and how to operate on patients with acute diverticulitis, there is no conclusion yet. To our knowledge, this is the first report of endoscopic therapy for anastomotic diverticulitis caused by stercorolith incarceration. In the current case, a 49-year-old woman complained of recurrent subumbilical pain without obvious inducement for half a year. Colonoscopy showed anastomotic diverticulum combined with stercorolith incarceration. After local inflammation relieved by conservative treatment, the patients received endoscopic mucosal incision and lithotomy. Then the diverticulum was closed with titanium clips. The abdominal pain of patient was completely relieved, and the reexamination of colonoscopy showed that the wound healed well after 1 year of follow-up. This case suggests that for anastomotic diverticulitis caused by stercorolith incarceration, endoscopic therapy can remove the stimulation factors better and avoid the recurrence and progression of the disease compared with conservative treatment. Moreover, endoscopic therapy achieves the maximum in minimally invasive surgery and reduces complications and surgical costs compared with radical surgery.

Rotate vector (RV) reducers are the two-stage deceleration device comprising involute and cycloid-pin gear transmission mechanisms. As the typical deceleration elements, they are widely applied in industrial robots, digitally controlled machine tools and automation fields due to their compact structure and high precision. However, a reducer may lose precision after a long-term operation. Moreover, pitting and metal peeling of internal components may also occur, leading to a fatigue failure. Therefore, it is necessary to conduct investigations on lifespan evaluation for RV reducers. In this study, the CRV-80E reducer is taken as the research object. Firstly, according to its transmission characteristics, the lifespan evaluation model for a standard RV reducer is established based on fatigue strength theory and Palmgren-Miner linear cumulative damage law, with the internal crankshaft bearing is considered as the key component. Then, the simulations are carried out on crankshaft bearing by the ANSYS Workbench and SKF SimPro. The contact stress, deformation on bearing rollers, and the rated lifespan of the reducer are simulated. Finally, the accelerated life test is conducted on an RV reducer by increasing the external load with the positioning precision as an output and criterion. After the test, the reducer is disassembled, and metal peeling failure is observed on the crankshaft bearing while other parts are relatively intact. The test results validate the feasibility and accuracy of the service life evaluation model and simulation analysis. This study provides a new research approach for researchers and manufacturers and a design reference for engineers to improve the lifespan of RV reducers by optimizing crankshaft bearings, which have a certain academic value. [ABSTRACT FROM AUTHOR]

Background: The curative criteria after endoscopic submucosal dissection for early gastric carcinoma were updated by the Japanese Gastric Cancer Association. No study has shown promising results with endoscopic submucosal dissection for early adenocarcinoma of esophagogastric junction based on the new curative criteria. The purpose of this study was to validate clinical efficacy of the application of the curative criteria of the 5th edition Japanese gastric cancer treatment guidelines for early adenocarcinoma of esophagogastric junction after endoscopic submucosal dissection. Methods: Patients who underwent endoscopic submucosal dissection for Siewert type II adenocarcinoma between January 2013 and June 2018 were eligible for this study. Clinical and pathological features and treatment outcomes were retrospectively reviewed using medical records. Results: The success rate for en-bloc resection was 97.2% (172/177) and the curative resection rate was 71.2% (126/177). Additional endoscopic submucosal dissection or radical surgery was conducted in 10 patients (5.6%) who did not fulfil the curative resection criteria, while one patient with curative resection remedied with endoscopic submucosal dissection because of recurrence. According to eCura scoring system, 94 patients (53.1%) were categorized into eCura A, 34 patients (19.2%) into eCura B, 11 patients (6.2%) into eCura C-1, and 38 patients (21.5%) into eCura C-2. Five patients categorized as eCura C-2 underwent radical surgery, two of whom have lymph node metastasis. Conclusions: Endoscopic submucosal dissection for early adenocarcinoma of esophagogastric junction that met the expanded criteria of the 5th edition Japanese gastric cancer treatment guidelines were acceptable and should be the standard treatment instead of surgical resection.

Background: To observe and preliminarily evaluate the efficacy and safety of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in the treatment of non-ampullary duodenal lesions (NADLs). Methods: This retrospective observational study included 84 patients who underwent endoscopic resection (ER) with non-ampullary duodenal lesions, between March 2010 and November 2020, at the Cancer Hospital of the Chinese Academy of Medical Sciences (Beijing, China). Data on patient demographics, therapeutic outcomes, and follow-up results were analyzed. Results: There were 44 patients undergoing EMR, and 40 patients accepting ESD. The overall en bloc resection rate was 98.8% (83/84). For the neoplastic lesions, the overall en bloc resection rate and curative rate were 98.5% (67/68) and 89.7% (61/68), respectively. The procedure-related bleeding and perforation rates were 2.4% and 10.7%, respectively. Univariate analysis results indicated that the main correlation factor of non-curative pathologic resection was tumor size (p = 0.004) and resection size (P < 0.01). There showed a higher curative rate in patients with tumors less than 25 mm in diameter. Multivariate logistic regression analyses determined that the tumor size (OR 0.935; 95% CI 0.878-0.995; P = 0.035) was associated with non-curative resection. No recurrences were observed in patients who had undergone a complete ER during a follow-up period of 42.8 months (range, 3-127 months). Conclusion: Endoscopic resection is an effective, safe, and feasible treatment for non-ampullary duodenal lesions.

Context Severe nephrotoxicity greatly limits the clinical use of the common effective chemotherapeutic agent cyclophosphamide (CYP). Huaiqihuang (HQH) is a Chinese herbal complex with various pharmacological activities, widely used for treating kidney disease. Objective This study estimates the protective effect of HQH against CYP-induced nephrotoxicity in rats. Materials and methods Four groups of 10 Sprague-Dawley rats were pre-treated with once-daily oral gavage of 3 and 6 mg/kg HQH for 5 days before receiving a single dose of CYP (200 mg/kg i.p.) on the 5th day; the control group received equivalent dose of saline. Renal function indices, morphological changes, oxidative stress, apoptosis and inflammatory mediators were measured. In addition, phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were analysed. Results Both doses of HQH reduced the levels of serum creatinine (31.27%, 43.61%), urea nitrogen (22.66%, 32.27%) and urine protein (12.87%, 15.98%) in the CYP-treated rats, and improved histopathological aberrations. Additionally, HQH decreased the production of MDA (37.02%, 46.18%) and increased the activities of antioxidant enzyme CAT (59.18%, 112.25%) and SOD (67.10%, 308.34%) after CYP treatment. HQH protected against CYP-induced nephrotoxicity by modulating apoptosis-related protein and suppressing the inflammatory responses. Furthermore, the phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were significantly boosted in CYP-treated rats, which was also abrogated by HQH treatment. Conclusions HQH effectively protected against CYP-induced nephrotoxicity, which was associated with regulating oxidative stress, apoptosis and inflammation, and so HQH may be a useful agent for treating nephrotoxicity caused by CYP.

Abstract Background Umbilical cord-derived mesenchymal stem cell (UCMSCs) transplantation has been widely studied in premature ovarian failure (POF). However, the underlying mechanism remains elusive. This study aims to investigate the protective properties and mechanisms of heme oxygenase-1 (HO-1) expressed in UCMSCs in restoring the ovarian function of POF mice. Methods In in vitro and in vivo experiments, mice were treated with the presence or absence of the HO-1/shHO-1-transfected UCMSCs, and the administration of SP600125 or anisomycin, the inhibitor or activator of JNK. The viability and apoptosis of granulosa cells (GCs) at different time points of co-cultivation were assessed in vitro. In in vivo experiments, mouse ovarian function was assessed by detecting the serum levels of hormone and observing the ovarian morphological changes. Multiple molecular indices of JNK/Bcl-2 signal pathway were performed. And the autophagy changes in GCs were assessed by detecting the associated cytokines and observing the intracellular autophagosome accumulation. Additionally, the spleen levels of CD8+CD28− T cells and serum levels of interleukin 10 (IL-10) were tested to evaluate the immune mechanisms involved. Results UCMSCs transfected with shHO-1 or treated with SP600125 inhibited GCs’ viability and promoted its apoptosis in a time-dependent manner in vitro. In in vivo experiments, mice in both groups showed little therapeutic efficiency which presented as the increased extent of ovarian fibrosis with decreased number of functional follicles, and disordered hormone production. Additionally, the JNK/Bcl-2-associated cytokines were obviously declined. The inhibited autophagy-related cytokines, the chromatin condensation and abound vacuolar autophagosome in GCs, and weakened fluorescence intensity by MDC were observed. The downregulated levels of CD8+CD28− T cells and serum levels of IL-10 were also detected. The damages above can be alleviated with HO-1-MSCs treatment or anisomycin administration. Conclusions HO-1 expressed in UCMSCs is critical in restoring the ovarian function in POF mice with UCMSC transplantation, which is mediated by the activation of JNK/Bcl-2 signal pathway-regulated autophagy and upregulating the circulating of CD8+CD28− T cells.

BackgroundWhile the elderly population account for an indispensable proportion in pancreatic ductal adenocarcinoma (PDAC), these patients are underrepresented in clinical trials. Whether surgery offered the same benefit for elderly patients as that for younger cohort and which factors affected long-term outcome of elderly population remained unclear.AimsThis study aims to evaluate long-term prognosis of elderly PDAC patients (≥70 years old) after surgery and to investigate potential prognostic factors.MethodsThis retrospective study included PDAC patients receiving radical resection from January 2012 to July 2019 in Zhongshan Hospital Fudan University. Patients were divided into young (

A large proportion of anti-tumor immunity research is focused on major histocompatibility complex class I (MHC-I) molecules and CD8+ T cells. Despite mounting evidence has shown that CD4+ T cells play a major role in anti-tumor immunity, the role of the MHC-II molecules in tumor immunotherapy has not been thoroughly researched and reported. In this study, we defined a MHC-II signature for the first time by calculating the enrichment score of MHC-II protein binding pathway with a single sample gene set enrichment analysis (ssGSEA) algorithm. To evaluate and validate the predictive value of the MHC class II (MHC-II) signature, we collected the transcriptome, mutation data and matched clinical data of bladder cancer patients from IMvigor210, The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) databases. Comprehensive analyses of immunome, transcriptome, metabolome, genome and drugome were performed in order to determine the association of MHC-II signature and tumor immunotherapy. We identified that MHC-II signature is an independent and favorable predictor of immune response and the prognosis of bladder cancer treated with immune checkpoint inhibitors (ICIs), one that may be superior to tumor mutation burden. MHC-II signature was significantly associated with increased immune cell infiltration and levels of immune-related gene expression signatures. Additionally, transcriptomic analysis showed immune activation in the high-MHC-II signature subgroup, whereas it showed fatty acid metabolism and glucuronidation in the low-MHC-II signature subgroup. Moreover, exploration of corresponding genomic profiles highlighted the significance of tumor protein p53 (TP53) and fibroblast growth factor receptor 3 (FGFR3) alterations. Our results also allowed for the identification of candidate compounds for combined immunotherapy treatment that may be beneficial for patients with bladder cancer and a high MHC-II signature. In conclusion, this study provides a new perspective on MHC-II signature, as an independent and favorable predictor of immune response and prognosis of bladder cancer treated with ICIs.

BackgroundLocal recurrence of esophageal squamous cell neoplasia (ESCN) and metachronous ESCN was associated with severe background esophageal multiple Lugol-voiding lesions (LVLs) even though the primary early ESCNs were treated with endoscopic resection (ER). The aim of this study is to explore the feasibility and effectiveness of combination treatments of ER and radiofrequency ablation (RFA) in patients with early ESCNs with synchronous multiple LVLs.MethodsA total of 329 patients with early ESCNs and synchronous multiple LVLs received ER combined with RFA from September 2010 to September 2020. Clinical and pathological features and treatment outcomes were retrospectively reviewed using medical records. Factors associated with background esophageal multiple LVLs before combined treatment were analyzed.ResultsThe proportion of complete response (CR) was 96.7% after primary RFA, while 90.3% patients achieved CR for the last endoscopic examinations regardless if inside or outside the treatment area (TA). Degeneration of background esophageal multiple LVLs occurred in 70.2% of patients. The grade of background esophageal multiple LVLs before combined treatment was closely related to gender, smoking, and drinking. The incidence of metachronous ESCNs outside the TA of ER and local recurrence in the TA of ER was 3.9% and 1.2%, respectively.ConclusionsProphylactic RFA treatment of multiple LVLs together with ER treatment of the primary ESCNs may be effective in reducing the incidence of metachronous ESCNs and local recurrence through improving the background esophageal mucosa.

Objective: Resistance to immune checkpoint inhibitors (ICIs) has been a massive obstacle to ICI treatment in metastatic urothelial carcinoma (MUC). Recently, increasing evidence indicates the clinical importance of the association between hypoxia and immune status in tumor patients. Therefore, it is necessary to investigate the relationship between hypoxia and prognosis in metastatic urothelial carcinoma.Methods: Transcriptomic and clinical data from 348 MUC patients who underwent ICI treatment from a large phase 2 trial (IMvigor210) were investigated in this study. The cohort was randomly divided into two datasets, a training set (n = 213) and a testing set (n = 135). Data of hypoxia-related genes were downloaded from the molecular signatures database (MSigDB), and screened by univariate and multivariate Cox regression analysis to construct a prognosis-predictive model. The robustness of the model was evaluated in two melanoma cohorts. Furthermore, an external validation cohort, the bladder cancer cohort, from the Cancer Genome Atlas (TCGA) database, was t used to explore the mechanism of gene mutation, immune cell infiltration, signaling pathway enrichment, and drug sensitivity.Results: We categorized patients as the high- or low- risk group using a four-gene hypoxia risk model which we constructed. It was found that patients with high-risk scores had significantly worse overall survival (OS) compared with those with low-risk scores. The prognostic model covers 0.71 of the area under the ROC curve in the training set and 0.59 in the testing set, which is better than the survival prediction of MUC patients using the clinical characteristics. Mutation analysis results showed that deletion mutations in RB1, TP53, TSC1 and KDM6A were correlated with hypoxic status. Immune cell infiltration analysis illustrated that the infiltration T cells, B cells, Treg cells, and macrophages was correlated with hypoxia. Functional enrichment analysis revealed that a hypoxic microenvironment activated inflammatory pathways, glucose metabolism pathways, and immune-related pathways.Conclusion: In this investigation, a four-gene hypoxia risk model was developed to evaluate the degree of hypoxia and prognosis of ICI treatment, which showed a promising clinical prediction value in MUC. Furthermore, the hypoxia risk model revealed a close relationship between hypoxia and the tumor immune microenvironment.

Important evidence indicates that the microbiota plays a key role in esophageal squamous cell carcinoma (ESCC). Here, paired saliva and brush specimens were obtained from 276 participants undergoing upper gastrointestinal endoscopic examination before or during screening for upper gastrointestinal (UGI) cancer. The esophageal microbiota was investigated by 16S rRNA gene profiling and next-generation sequencing. We observed that as the disease progressed, the α diversity in the saliva and cell brush samples decreased. Linear discriminant analysis effect size (LEfSe) results showed that in both the saliva and cell brush specimens, Granulicatella, Rothia, Streptococcus, Gemella, Leptotrichia and Schaalia were common biomarkers in patients with low-grade dysplasia, Lactobacillus was a common biomarker in patients with high-grade dysplasia, and Bosea, Solobacterium, Gemella, and Peptostreptococcus were common biomarkers in patients with esophageal cancer. The top 3 genera in the saliva and cell brush specimens had areas under the curve (AUCs) of 87.16 and 89.13%, respectively, to distinguish ESCC patients from normal people. The PICRUSt2 results identified in brush samples that patients with ESCC had decreased nitrate reductase functions. Our results suggest that future studies can focus on the function of the characteristic bacteria in ESCC.

Urothelial cancer (UC) is one of the common refractory tumors and chemotherapy is the primary treatment for it. The advent of immune checkpoint inhibitors (ICI) has facilitated the development of treatment strategies for UC patients. To screen out UC patients sensitive to ICI, researchers have proposed that PD-L1, tumor mutation burden and TCGA molecular subtypes can be used as predictors of ICI efficacy. However, the performance of these predictors needs further validation. We need to identify novel biomarkers to screen out UC patients sensitive to ICI. In our study, we collected the data of two clinical cohorts: the ICI cohort and the TCGA cohort. The result of the multivariate Cox regression analysis showed that glycogen metabolism score (GMS) (HR = 1.26, p = 0.017) was the negative predictor of prognosis for UC patients receiving ICI treatment. Low-GMS patients had a higher proportion of patients achieving complete response or partial response to ICI. After the comparison of gene mutation status between high-GMS and low-GMS patients, we identified six genes with significant differences in mutation frequencies, which may provide new directions for potential drug targets. Moreover, we analyzed the immune infiltration status and immune-related genes expression between high-GMS and low-GMS patients. A reduced proportion of tumor-associated fibroblasts and elevated proportion of CD8+ T cells can be observed in low-GMS patients while several immunosuppressive molecules were elevated in the high-GMS patients. Using the sequencing data of the GSE164042 dataset, we also found that myeloid-derived suppressor cell and neutrophil related signature scores were lower in α-glucosidase knockout bladder carcinoma cells when compared to the control group. In addition, angiogenesis, classic carcinogenic pathways, immunosuppressive cells related pathways and immunosuppressive cytokine secretion were mainly enriched in high-GMS patients and cell samples from the control group. Finally, we suspected that the combination treatment of ICI and histone deacetylase inhibitors may achieve better clinical responses in UC patients based on the analysis of drug sensitivity data. In conclusion, our study revealed the predictive value of GMS for ICI efficacy of UC patients, providing a novel perspective for the exploration of new drug targets and potential treatment strategies.

Abstract Background Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a few studies have evaluated PD-L1 expression in esophageal squamous cell carcinoma (ESCC) with a large Chinese cohort. Our present study is to evaluate the association of PD-L1 expression with clinicopathological features on ESCC. Methods Using tissue microarray and immunohistochemistry, PD-L1 expression on tumor cells and tumor-infiltrating immune cells was studied in 378 advanced ESCC patients without neoadjuvant chemoradiotherapy. Its correlation with clinicopathological parameters was analyzed. Results PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells. PD-L1 expression in tumor cells was significantly correlated with age, degree of differentiation, T stage, N stage and metachronous hematogenous metastasis, and PD-L1 expression in tumor-infiltrating immune cells was significantly associated with N stage (P