Gemcitabine resistance remains a major challenge in the treatment of gallbladder cancer (GBC). Here, we elucidate a novel mechanism underlying gemcitabine resistance in GBC, centered on a self-reinforcing mitophagy/ROS/SENP3/Reptin loop. Gemcitabine-resistant GBC cells maintain significantly lower intracellular reactive oxygen species (ROS) levels than wild-type cells through enhanced mitophagy. This finding delineates a novel transcriptional mechanism that drives mitophagy under low ROS conditions. Mechanistically, this low ROS state decreases the protein abundance of the ROS sensor Sentrin/SUMO-specific protease 3 (SENP3), thereby promoting SUMOylation of its substrate, RuvB-like AAA+ ATPase 2 (Reptin), at the K456 site. SUMOylated Reptin translocates to the nucleus, where it acts as a transcriptional activator to specifically upregulate PTEN-induced putative kinase 1 (PINK1), a key mitophagy regulator. Enhanced PINK1 expression further amplifies mitophagy, effectively scavenging ROS and perpetuating the low ROS state that drives resistance, thus sustaining the gemcitabine-resistant phenotype. Clinically, low SENP3 expression and high Reptin expression correlate with poor gemcitabine response and shorter overall survival in GBC patients. Targeting this pathway, the Reptin ATPase inhibitor CB-6644 effectively suppressed PINK1 transcription, inhibited mitophagy, increased ROS accumulation, and reversed gemcitabine resistance both in vitro and in vivo. These findings identify the mitophagy/ROS/SENP3/Reptin loop as a core resistance mechanism in GBC, highlight SENP3 and Reptin as predictive biomarkers, and establish CB-6644 as a promising therapeutic agent to overcome gemcitabine resistance by disrupting this adaptive pathway.

Background:Pancreatic ductal adenocarcinoma (PDAC) is highly malignant with a poor prognosis, posing significant clinical challenges. SUMOylation, a reversible post-translational modification, plays a critical role in tumor progression, yet its prognostic significance in PDAC remains unclear. Methods:We assessed SUMOylation expression patterns and function in PDAC using Western blot and the SUMOylation inhibitor TAK-981. Differentially expressed SUMOylation substrate encoding genes (DE-SSEGs) were identified from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Project (GTEx) datasets. A SUMOylation-based prognostic model, Sscore, was constructed using LASSO and Cox regression. Additional analyses included somatic mutation, immune infiltration, TIDE, drug sensitivity, and single-cell RNA sequencing. The role of SAFB2 in PDAC was validated in vitro. Results:PDAC cells showed elevated SUMOylation, and its inhibition reduced cell proliferation. The Sscore model, based on DE-SSEGs (CDK1, AHNAK2, SAFB2), predicted overall survival and correlated with genome variation, immune infiltration, and drug sensitivity. Single-cell analysis further confirmed a link between high Sscore and malignancy. SAFB2, identified as a pivotal gene within the Sscore model, was significantly downregulated in PDAC tissues and cell lines; its overexpression was shown to inhibit PDAC cell proliferation, migration, and invasion by suppressing the Wnt/β-Catenin signaling pathway. Conclusion:This study underscores the role of SUMOylation in PDAC and introduces the Sscore as a prognostic tool. SAFB2 is identified as a potential tumor suppressor, offering new therapeutic targets for PDAC.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with poor prognosis. Efferocytosis, an essential process for clearing apoptotic cells, is involved in shaping immunosuppressive microenvironment, facilitating tumor immune evasion. This study aims to evaluate the prognostic value of efferocytosis-related biomarkers in PDAC and elucidate their underlying mechanisms, providing insights for personalized therapy.MethodsWe integrated bulk and single-cell transcriptomic data from public database to construct and validate an efferocytosis-related prognostic model for PDAC. Additionally, we analyzed the specimens from a cohort of 81 PDAC patients alongside cell experiments to elucidate the function of P2RY6. RNA-seq analysis was employed to uncover the effector pathways mediated by P2RY6.ResultsAn efferocytosis-based prognostic model, EFFscore, developed based on ADAM9, P2RY6, and CD36, can effectively assess the tumor phenotype of PDAC patients. The EFFscore is strongly associated with tumor evolution, malignant biological characteristics and microenvironmental interactions of PDAC. The essential mediator P2RY6 is significantly upregulated in PDAC tissue and cells, correlating closely with poor prognosis. Functional studies demonstrate that P2RY6 inhibition exhibits tumor-suppressive effects by activating the endoplasmic reticulum stress and enhancing anti-tumor immune responses. The P2RY6 receptor inhibitor, MRS-2578, emerges as a promising therapeutic candidate for PDAC treatment.ConclusionThe prognostic model EFFscore exhibits remarkable predictive performance, accurately reflecting the malignant potential of PDAC. P2RY6 serves as a key oncogenic factor driver in PDAC, its targeted inhibition significantly suppresses tumor progression, highlighting its dual potential as a diagnostic biomarker and therapeutic target.

The carnitine cycle is responsible for the transport of cytoplasmic fatty acids to the mitochondria for subsequent β-oxidation to maintain intracellular energy homeostasis. Recent studies have identified abnormalities in the carnitine cycle in various types of tumors; these abnormalities include the altered expression levels of carnitine cycle-related metabolic enzymes and transport proteins. Dysfunction of the carnitine cycle has been shown to influence tumorigenesis and progression by altering intracellular oxidative and inflammatory status or regulating tumor metabolic flexibility. Many therapeutic strategies targeting the carnitine cycle are actively being explored to modify the dysfunction of the carnitine cycle in patients with malignant tumors; such approaches include carnitine cycle-related enzyme inhibitors and exogenous carnitine supplementation. Therefore, here, we review the studies of carnitine in tumors, aiming to scientifically illustrate the dysfunction of the carnitine cycle in tumor progression and provide new ideas for further research.

The clinical diagnosis and treatment of dilation of the cholangiopancreatic duct in patients with ambiguous ampullary disease, termed unexplained dilation of the cholangiopancreatic duct (UDCD), is commonly difficult. This study aimed to evaluate the applicability of transduodenal ampullectomy (TDA) for the diagnosis and treatment of UDCD. We first proposed a surgical exploration procedure based on the TDA and applied it in a representative UDCD patient. We retrospectively analyzed the pathological diagnosis and prognosis of 14 patients at our hospital and 189 patients reported in existing studies who were treated with TDA between January 2010 and December 2022. TDA can be used to radically explore the ampullary region and harvest adequate pathological tissue, which is helpful for identifying the cause of UDCD. The diagnostic rate of intraoperative frozen pathology was greater than that of preoperative endoscopic biopsy (78.41

Abstract Background Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown. Methods Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels. Results Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor β (IR-β) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-β phosphorylation, ultimately resulting in IR-β inactivation. This inactivation of IR-β suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels. Conclusions These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

As digital medicine has exerted profound influences upon diagnosis and treatment of hepatobiliary diseases, our study aims to investigate the accuracy of three-dimensional visualization and evaluation (3DVE) system in assessing the resectability of hilar cholangiocarcinoma (hCCA), and explores its potential clinical value. The discovery cohort, containing 111 patients from April 2013 to December 2019, was retrospectively included to determine resectability according to revised criteria for unresectability of hCCA. 3D visualization models were reconstructed to evaluate resectability parameters including biliary infiltration, vascular involvement, hepatic atrophy and metastasis. Evaluation accuracy were compared between contrast-enhanced CT and 3DVE. Logistic analysis was performed to identify independent risk factors of R0 resection. A new comprehensive 3DVE classification of hCCA based on factors influencing resectability was proposed to investigate its role in predicting R0 resection and prognosis. The main outcomes were also analyzed in cohort validation, including 34 patients from January 2020 to August 2022. 3DVE showed an accuracy rate of 91

Objectives: To characterize a carbapenem-resistant Pseudomonas aeruginosa (CRPA) with an IncP-2 plasmid containing a novel transposon, Tn 6485h , which carries both blaIMP-45 and blaAFM-1 . Methods: Antimicrobial susceptibility testing and filter mating experiment were performed on PA942.The stability of the plasmid carrying both blaIMP-45 and blaAFM-1 was carried out. We determined the growth rate of the transconjugant to investigate fitness cost. Additionally, whole-genome sequencing and genomic analysis were performed on PA942.Results: PA942 strain was resistant to most antibiotics except for ciprofloxacin and colistin. Bioinformatics analysis confirmed that PA942 contains an IncP-2 plasmid with a novel transposon Tn 6485h carrying both blaIMP-45 and blaAFM-1 . The plasmid pPA942-IMP45 can be transferred into recipient bacteria PAO1 Rif with an efficiency of 2.2 x 10 -7 and the transconjugant PAO1 Rif / pPA942-IMP45 can be stably inherited for 10 generations in the absence of antibiotics. Conclusion: We report a carbapenem-resistant P. aeruginosa strain with an IncP-2 plasmid containing a novel transposon, Tn 6485h , which carries both blaIMP-45 and blaAFM-1 . The IncP-2 plasmid and transposon Tn 6485h may contribute to the spread of MBL genes. Therefore, effective measures to prevent the spread of these plasmids should be taken.(c) 2023 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Complex immune contexture leads to resistance to immunotherapy in hepatocellular carcinoma (HCC), and the need for new potential biomarkers of immunotherapy in HCC is urgent. Histone chaperones are vital determinants of gene expression and genome stability that regulate tumor development. This study aimed to investigate the effect of histone chaperones on tumor immunity in HCC. Bioinformatics analyses were initially performed using The Cancer Genome Atlas (TCGA) database, and were validated using the Gene Expression Omnibus (GEO) database and the International Cancer Genome Consortium (ICGC) database. Immune-related histone chaperones were screened with the Spearman rank coefficient. Consensus clustering was utilized to divide the HCC samples into two clusters. ESTIMATE, CIBERSORT and ssGSEA analyses were performed to assess immune infiltration. The expression of immunomodulatory genes, chemokines and chemokine receptors was analyzed to evaluate sensitivity to immunotherapy. The differentially expressed genes (DEGs) were included in weighted gene coexpression network analysis (WGCNA) to identify the hub genes. Enrichment analyses were used to investigate the functions of the hub genes. The Kaplan-Meier method and log-rank test were conducted to draw survival curves. A Cox regression analysis was utilized to identify independent risk factors affecting prognosis. HSPA8 and DEK were screened out from 36 known histone chaperones based on their strongest correlation with the ESTIMATE score. Cluster 2, with high HSPA8 expression and low DEK expression, tended to have stronger immune infiltration and better sensitivity to immunotherapy than Cluster 1, with low HSPA8 expression and high DEK expression. Furthermore, WGCNA identified 12 hub genes closely correlated with immune infiltration from the DEGs of the two clusters, of which FBLN2 was proven to be an independent protective factor of HCC patients. HSPA8 and DEK are expected to be biomarkers for precisely predicting the effect of immunotherapy, and FBLN2 is expected to be a therapeutic target of HCC.

Background This study aims to propose a novel classification system to standardize the treatment of hepatolithiasis. Methods A hepatolithiasis classification named LHO was proposed to represent the distribution of stones in the segmental bile ducts and the hepatic atrophy associated with the stones (L), the existence of stones or strictures in the hilar bile duct (H), and dysfunction of the Oddi sphincter (O), which can be used to formulate ideal surgical protocols. One hundred and forty-seven primary hepatolithiasis patients treated between 2013 and 2018 were classified into different types and divided into two groups. If the patient's actual surgical procedure matched the ideal surgical protocol, the patients were included in the matching group; otherwise, patients were included in the nonmatching group. The rates of residual stones, recurrence, and a good quality of life (QOL) were analyzed among the patients in the matching and nonmatching groups and previous reports. Results According to the classification of each patient, 77.6% of the patients were included in the matching group, and 22.4% were included in the nonmatching group. The rates of residual stones, recurrence, and a good QOL were significantly better in the matching group than in the nonmatching group (9.6% vs. 27.3%; 8.0% vs. 35.0%; 89.5% vs. 65.4%); the rates of residual stones and a good QOL were also better than those in previous reports (9.6% vs. 19.1%; 89.5% vs. 61.6%). Conclusions The LHO classification can comprehensively reflect the key points of treatment, which is beneficial for formulating effective and standardized surgical plans of hepatolithiasis.

Background We aimed to verify the role of hENT1 as a prognostic predictor for patients with resectable pancreatic ductal adenocarcinoma (PDAC) who underwent radical resection followed by intra-arterial infusion of gemcitabine-based regimen. Methods We collected surgical samples from 102 patients with resectable PDAC who received radical resection followed by intra-arterial infusion of gemcitabine-based regimen. The hENT1 expression with the help of immunohistochemistry was conducted using formalin-fixed and paraffin embedded tissues. The Kaplan–Meier analyses and Cox regression were used to evaluate the mortality hazard associated with the discrepancy between strong and weak of hENT1 expression. Patients’ clinical and pathological characteristics were compared between the two groups, then the role of hENT1 as a prognostic predictor was further explored. Results A total of 102 patients were included to assess the hENT1 expression. 50 patients were classified into high hENT1 expression group, the other 52 patients were attributed into low hENT1 expression group. High hENT1 expression was related to a significantly improved overall survival (OS) ( p = 0.014) and disease-free survival (DFS) ( p = 0.004). Both univariate ( p = 0.001) and multivariate analyses ( p < 0.001) indicated that high hENT1 expression was related to a decreased mortality. Conclusions High expression of hENT1 is positive prognostic factor for adjuvant intra-arterial gemcitabine-based chemotherapy in resectable PDAC.

PURPOSE:This study aimed to reveal the role of preoperative main pancreatic duct (MPD) stent placement in reducing the intraoperative main pancreatic duct injury rate and the incidence of postoperative pancreatic leakage following pancreatic tumor enucleation. METHODS:A retrospective cohort analysis was performed for all patients with benign/borderline pancreatic head tumors who were treated with enucleation. The patients were divided into two groups (standard vs. stent) depending on whether they underwent main pancreatic duct stent placement prior to surgery. RESULTS:Thirty-three patients were finally included in the analytical cohort. Compared with the standard group, patients in the stent group had a shorter distance between tumors and main pancreatic duct (p=0.01) and presented with larger tumors (p<0.01). The rates of POPF (grade B&C) were 39.1% (9/23) and 20% (2/10) in the standard and stent groups, respectively (p<0.01). Major postoperative complications occurred more frequently in the standard group than in the stent group (14 versus 2; p<0.01). No significant differences in mortality, in-hospital stay or medical cost were observed between the two groups (p>0.05). CONCLUSIONS:MPD stent placement prior to surgery may facilitate pancreatic tumor enucleation, minimize MPD injury and decrease the occurrence of postoperative fistula.

Objectives Primary gallbladder neuroendocrine carcinomas (GB-NEC) are malignant neoplasms that remained to be studied. In this study we aimed to summarize their clinicopathological characteristics, effective treatment and prognostic factors for patients with GB-NEC. Methods Patients with GB-NEC admitted to Shanghai Jiao Tong University Affiliated Sixth People's Hospital and Renji Hospital, School of Medicine, Shanghai Jiao Tong University from October 2012 to August 2020 were enrolled. Clinicopathological characteristics of our patients and those reported in previous studies were recorded. The Kaplan-Meier method and univariate and multivariate Cox regression analyses were used for survival analysis. Results Altogether 15 patients from our hospitals and 47 patients from previous studies were included. A total of 55 patients who underwent surgical resection, including R-0 and non-R-0 resection, had significantly longer overall survival compared with the other seven patients. A univariate analysis indicated that patients aged 60 years or older, with jaundice, carcinoid syndrome, non-R-0 resection, and advanced stage were associated with worse survival. A multivariate analysis showed that patients aged 60 years or older, carcinoid syndrome and non-R-0 resection, but not lymphadenectomy and adjuvant chemotherapy, were independently related to reduced survival. Conclusions R-0 resection should be the first-line treatment for GB-NEC. Older age, carcinoid syndrome and non-R-0 resection are independently associated with reduced survival after surgical resection.

Primary gallbladder neuroendocrine carcinomas (GB-NEC) are malignant neoplasms that remained to be studied. In this study we aimed to summarize their clinicopathological characteristics, effective treatment and prognostic factors for patients with GB-NEC. Patients with GB-NEC admitted to Shanghai Jiao Tong University Affiliated Sixth People's Hospital and Renji Hospital, School of Medicine, Shanghai Jiao Tong University from October 2012 to August 2020 were enrolled. Clinicopathological characteristics of our patients and those reported in previous studies were recorded. The Kaplan-Meier method and univariate and multivariate Cox regression analyses were used for survival analysis. Altogether 15 patients from our hospitals and 47 patients from previous studies were included. A total of 55 patients who underwent surgical resection, including R 0 and non-R 0 resection, had significantly longer overall survival compared with the other seven patients. A univariate analysis indicated that patients aged 60 years or older, with jaundice, carcinoid syndrome, non-R 0 resection, and advanced stage were associated with worse survival. A multivariate analysis showed that patients aged 60 years or older, carcinoid syndrome and non-R 0 resection, but not lymphadenectomy and adjuvant chemotherapy, were independently related to reduced survival. R 0 resection should be the first-line treatment for GB-NEC. Older age, carcinoid syndrome and non-R 0 resection are independently associated with reduced survival after surgical resection.

Gene expression profiling has been broadly performed in the field of cancer research. This study aims to explore the key gene regulatory network and focuses on the functions of microRNA (miR)-216a in pancreatic cancer (PC). PC datasets GSE15471, GSE16515, and GSE32676 were used to screen the differentially expressed genes (DEGs) in PC. A miRNA microarray analysis and gene oncology analysis suggested miR-216a as an important differentially expressed miRNA in PC. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that miR-216a and the DEGs are largely enriched on the phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. miR-216a targeted Wilms Tumor 1 (WT1), while WT1 promoted transcription activity of keratin 7 (KRT7). Upregulation of miR-216a reduced proliferation and invasiveness of PC cells, while further upregulation of WT1 blocked the functions of miR-216a. Silencing of KRT7 diminished the oncogenic role of WT1. The in vitro results were reproduced in vivo. High expression of miR-216a while poor expression of WT1 indicated better prognosis of PC patients. The miR-216a/WT1/KRT7 axis influenced the activity of the PI3K/AKT pathway. To conclude, this study evidenced that miR-216a suppressed WT1 expression and blocked KRT7 transcription, which inactivated the PI3K/AKT signaling and reduced PC progression.

胆道损伤是患者与医者永远的伤痛,其主要原因是医源性有创操作,主要见于胆囊切除术.虽然胆道损伤的危害性已被充分认识,但胆囊切除术后胆道损伤的发生率仍有0.5％[1],损伤修复失败及术后因胆管损伤性狭窄再手术的比例高达26.7％[2].因为有很多医源性胆道损伤并未被统计与报道,很多病例的术后随访资料不全,所以实际损伤的数字与术后再手术的比例会高于文献报道.胆道损伤的修复手术作为一种补救性手术,其总体原则应该是毕其功于一役,争取一次手术达到永久的修复.为达到上述目标,必须抓住术前评估、术中修复和术后管控与随访三个环节,确保患者在最合适的状态、最合适的时机用最合适的修复技术达到最完美的修复.

如果把肝胆胰外科比作外科的青藏高原,那么围肝门外科就是高原之巅——珠穆朗玛峰.围肝门是指围绕第一肝门的解剖区域.此狭小区域内汇聚众多肝胆疑难复杂疾病,解剖结构复杂、病理生理变化多样、手术难度与风险极大,疗效不尽人意.提高对围肝门疾病诊治规律的认知,深化诊治的系统性、安全性、可及性与有效性是今后很长一段时间内肝胆外科面临的难题与挑战.

目的·探讨胰门板降低技术在胰腺段胆总管囊肿切除术中的应用价值.方法·回顾性分析2016年 1月—2019年12月于上海交通大学医学院附属仁济医院收治的 15例董氏分型C2型的胆总管囊肿患者.采用胰门板降低技术对患者施行胰腺段胆总管囊肿切除术,术中验证术前对胆总管囊肿与主胰管汇合方式的判定,并对手术成功率、手术时间、术中输血率、术后并发症、术后病理结果、转归情况及随访情况(存活状况、远期并发症)进行分析.结果·7例(46.7％)患者呈现主胰管与胆总管囊肿远端的正常胆管汇合,8例(53.3％)呈主胰管与胆总管囊肿汇合,该术前判定结果得到术中证实.15例患者均经胰门板降低技术成功切除胰腺段胆总管囊肿,病变胆管残留率及主胰管损伤率均为0,手术时间为(170.0±22.7)min,术中输血率为0;其中有8例(53.3％)出现术后并发症,分别为生化级胰漏 1例、B级胰漏 1例、胃瘫 1例、生化级胰漏合并胆漏 1例、肠梗阻 1例、生化级胰漏合并肠梗阻 1例、腹腔积液伴感染1例、伤口感染 1例.术后病理学结果显示,所有患者均为胆总管囊肿伴黏膜慢性炎.经治疗后,患者均痊愈出院.经5～48个月的术后随访显示,患者均生存良好,无胆肠吻合口狭窄、胆管扩张和胆管癌变的发生.结论·采用胰门板降低技术实施胰腺段胆总管囊肿切除术安全有效.

目前肝门胆管癌手术方式是在肝十二指肠韧带淋巴结缔组织廓清的基础上,依据Bismuth分型,根据肿瘤侵犯肝门胆管的位置与范围,选择肝外胆管局部切除、半肝或扩大半肝联合尾状叶切除或肝移植,其中半肝联合尾状叶切除是主流术式.为减少无辜肝脏的牺牲,尽量保留余肝体积与功能,有学者提出了各种小范围肝切除.如何合理选择肝切除范围是值得深入探讨的问题.