Resistance to poly adenosine diphosphate(ADP)-ribose polymerase inhibitor(PARPi)presents a considerable obstacle in the treatment of ovarian cancer.F-box and tryptophan-aspartic(WD)repeat domain containing 11(FBXW11)modulates the ubiquitination of growth-and invasion-related factors in lung cancer,colorectal cancer,and osteosarcoma.The function of FBXW11 in PARPi therapy is still ambiguous.In this study,RNA sequencing(RNA-seq)showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi.FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer(HGSOC)tissues,and low levels of FBXW11 were associated with shorter overall survival(OS)and progression-free survival(PFS)in HGSOC patients.Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi,while knocking down FBXW11 made it less sensitive.The four-dimensional(4D)label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11(S100A11)and promoted its degradation through ubiquiti-nation.The increased degradation of S100A11 led to less efficient DNA damage repair,which in turn contributed to increased PARPi-induced DNA damage.The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models.In summary,our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S10OA11-mediated DNA damage repair.

Diabetes of the exocrine pancreas(DEP)used to be called pancreatic diabetes,pancreatogenic diabetes or type 3c diabetes mellitus.Currently,the incidence of DEP is higher than that of type 1 diabetes mellitus.The pathogenesis and clinical manifestations of DEP are related to primary pancreatic diseases.In terms of management,we need to consider both pancreatic endocrine and exocrine functions,and comprehensively treat diabetes mellitus and primary pancreatic diseases.By now,there has been no guideline related to DEP;its diagnostic criteria,differentiation with type 2 diabetes mellitus,and selection of hypoglycemic programs are challenges in clinical practice.This article reviews the clinical studies related to DEP,and summarizes the evolution of its terminology,pathogenesis,clinical manifestations,complications,diagnosis,treatment and management.

Fibrosis is a pathological condition characterized by the excessive deposition of extracellular matrix due to the imbalance between injury and repair.It can affect multiple organs,including the heart,lungs,liver,kidneys,and pancreas.The progression of fibrosis is usually slow and difficult to reverse,and it can severely impair organ functions.In industrialized countries,deaths caused by fibrosis account for up to 45％,resulting in a tremendous disease burden.Thus,there is an urgent need for drugs that can reverse or delay the progression of fibrosis.In recent years,remarkable progress has been made in the research on the pathogenesis of fibrosis in different organs,and relevant drugs targeting fibrosis are also under active development.This article briefly summarizes the drugs currently marketed and drugs at the clinical trial stage for treating fibrosis.

Resistance to poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi) presents a considerable obstacle in the treatment of ovarian cancer. F-box and tryptophan-aspartic (WD) repeat domain containing 11 (FBXW11) modulates the ubiquitination of growth-and invasion-related factors in lung cancer, colorectal cancer, and osteosarcoma. The function of FBXW11 in PARPi therapy is still ambiguous. In this study, RNA sequencing (RNA-seq) showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi. FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer (HGSOC) tissues, and low levels of FBXW11 were associated with shorter overall survival (OS) and progression-free survival (PFS) in HGSOC patients. Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi, while knocking down FBXW11 made it less sensitive. The four-dimensional (4D) label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11 (S100A11) and promoted its degradation through ubiquitination. The increased degradation of S100A11 led to less efficient DNA damage repair, which in turn contributed to increased PARPi-induced DNA damage. The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models. In summary, our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.

Objective:To systematically evaluate the risks of osteonecrosis of the jaw induced by bone-modifying agents (BMAs) in breast cancer patients with bone metastasis.Methods:Randomized controlled trials (RCTs) of BMAs in the treatment of breast cancer bone metastasis, in which osteonecrosis of the jaw were evaluated as one of adverse outcome indicators, were collected by searching relevant databases at home and abroad (up to June 25, 2024). Cochrane risk of bias tool was used to evaluate the quality of the included studies. R software (version 4.2.3) was used to conduct Bayesian network meta-analysis, drawing the network evidence plot, the league map of pairwise comparison, and the surface under the cumulative ranking curve for the risks of osteonecrosis of the jaw induced by BMAs in breast cancer patients with bone metastasis, and ranking the risks of osteonecrosis of the jaw caused by different BMAs. The effect sizes of osteonecrosis of the jaw were expressed by hazard risk ( HR) and its 95% confidence interval ( CI). Results:A total of 12 RCTs were included in the analysis, involving 26 047 patients. BMAs were used in 18 503 patients, including zoledronic acid (in 6 202 patients), ibandronate (in 4 817 patients), clodronate (in 3 897 patients), and denosumab (in 3 587 patients); 7 544 patients were treated with placebo or not be intervened. Among 26 047 patients, 272 occurred osteonecrosis of the jaw. The incidence of osteonecrosis of the jaw was 1.44% (267/18 503) in BMA treated patients and 0.07% (5/7 544) in placebo/non-intervention patients, respectively. The results of the network meta-analysis showed that the HR (95% CI) of osteonecrosis of the jaw caused by denosumab, zoledronic acid, ibandronate and clodronate in breast cancer patients with bone metastases were 18.12 (10.03-35.75), 11.42 (6.03-22.86), 5.92 (2.78-13.22) and 2.73 (0.99-7.20), respectively, compared with the patients in the placebo or non-intervention group. Compared with zoledronic acid or denosumab, ibandronate and clodronate had lower risks of inducing osteonecrosis of the jaw. There was no statistically significant difference in the risk of inducing osteonecrosis of the jaw by denosumab and zoledronic acid. Conclusions:Denosumab and zoledronic acid have a higher risk of inducing osteonecrosis of the jaw. Among BMAs, clodronate and ibandronate should be preferred in treatment of breast cancer patients with bone metastasis who have risk factors of osteonecrosis of the jaw.

Objective:To systematically evaluate the risks of osteonecrosis of the jaw induced by bone-modifying agents (BMAs) in breast cancer patients with bone metastasis.Methods:Randomized controlled trials (RCTs) of BMAs in the treatment of breast cancer bone metastasis, in which osteonecrosis of the jaw were evaluated as one of adverse outcome indicators, were collected by searching relevant databases at home and abroad (up to June 25, 2024). Cochrane risk of bias tool was used to evaluate the quality of the included studies. R software (version 4.2.3) was used to conduct Bayesian network meta-analysis, drawing the network evidence plot, the league map of pairwise comparison, and the surface under the cumulative ranking curve for the risks of osteonecrosis of the jaw induced by BMAs in breast cancer patients with bone metastasis, and ranking the risks of osteonecrosis of the jaw caused by different BMAs. The effect sizes of osteonecrosis of the jaw were expressed by hazard risk ( HR) and its 95% confidence interval ( CI). Results:A total of 12 RCTs were included in the analysis, involving 26 047 patients. BMAs were used in 18 503 patients, including zoledronic acid (in 6 202 patients), ibandronate (in 4 817 patients), clodronate (in 3 897 patients), and denosumab (in 3 587 patients); 7 544 patients were treated with placebo or not be intervened. Among 26 047 patients, 272 occurred osteonecrosis of the jaw. The incidence of osteonecrosis of the jaw was 1.44% (267/18 503) in BMA treated patients and 0.07% (5/7 544) in placebo/non-intervention patients, respectively. The results of the network meta-analysis showed that the HR (95% CI) of osteonecrosis of the jaw caused by denosumab, zoledronic acid, ibandronate and clodronate in breast cancer patients with bone metastases were 18.12 (10.03-35.75), 11.42 (6.03-22.86), 5.92 (2.78-13.22) and 2.73 (0.99-7.20), respectively, compared with the patients in the placebo or non-intervention group. Compared with zoledronic acid or denosumab, ibandronate and clodronate had lower risks of inducing osteonecrosis of the jaw. There was no statistically significant difference in the risk of inducing osteonecrosis of the jaw by denosumab and zoledronic acid. Conclusions:Denosumab and zoledronic acid have a higher risk of inducing osteonecrosis of the jaw. Among BMAs, clodronate and ibandronate should be preferred in treatment of breast cancer patients with bone metastasis who have risk factors of osteonecrosis of the jaw.

Humans ; Urinary Bladder Neoplasms/pathology* ; Carcinoma, Transitional Cell/pathology* ; Genetic Markers ; Biomarkers, Tumor/genetics* ; Urothelium/pathology*

The transformation from inflammation to cancer is a complex pathological process, in which the inflammatory state progresses to the formation of malignant tumors. Chronic pancreatitis (CP) is a progressively inflammatory and fibrosing disease, predominantly featuring acinar cell atrophy owing to the cellular damage and fibrosis of the pancreatic parenchyma. This review centers on elucidating how prolonged exposure to a chronic inflammatory environment prompts adaptive changes in acinar cells, which may ultimately lead to their conversion into cancerous cells. By delving into the pivotal role of acinar-to-ductal metaplasia, this article investigates the multi-stage pathway of CP progression into pancreatic cancer, as well as the underlying molecular regulatory networks. We aim to light on the profound mechanisms of CP's inflammation-driven carcinogenic transformation, and thus provide a scientific foundation for devising innovative preventive strategies and therapeutic interventions targeted at mitigating or halting this lethal conversion process.

Objective:To analyze the mutation spectrum and regional distribution of susceptibility pathogenic genes in Chinese chronic pancreatitis (CP) patients.Methods:A retrospective analysis was conducted on 1 758 sporadic CP patients who underwent gene sequencing for pathogenic mutations of four major susceptibility genes ( SPINK1, PRSS1, CTRC, and CFTR) at the First Affiliated Hospital of Naval Medical University from December 2010 to November 2022. Pathogenic mutations of four major susceptibility genes were detected by using the next-generation sequencing, and both known and novel pathogenic mutations were validated by Sanger sequencing. The ethnic and regional distributions of pathogenic mutations across different ethnic groups were compared. The ArcMap 10.7 software was used to provide the distribution map of common CP pathogenic mutations in China, and regional differences of these mutations were assessed. According to seven major geographical regions in China, we also evaluated the enrichment differences of CP pathogenic mutations in North China region, Northeast China region, East China region, Central China region, South China region, Southwest China region, and Northwest China region. Results:Among 1 758 CP patients, 50.23% (883/1 758) carried pathogenic mutations, and the SPINK1 pathogenic mutations were most predominated (39.31%). Among them, c.194+2T>C mutations accounted for 94.21% of all SPINK1 mutations. 32.59% (573/1 758) of patients carried single heterozygous mutation of one susceptibility gene, and 4.61% carried homozygous mutation of SPINK1 c.194+2T>C. There was no statistically significant difference on the overall pathogenic mutation carrying rate between Han and ethnic minority patients, whereas the mutation carrying rate of SPINK1 c.194+2T>C was significantly higher among Han patients than among ethnic minorities (37.48% vs 20.00%, P<0.05). Among 31 provinces and cities, the mutation carrying rate of CP patients in Tianjin, Guangdong, Yunnan, Hubei and Anhui were all higher than 60.00%. The SPINK1 mutations accounted for the highest proportion of pathogenic mutations across all provinces (33.33% to 61.54%), and SPINK1 c.194+2T>C was the most prevalent mutation. The mutation carrying rate of SPINK1 c.194+2T>C was higher than 40.00% in Jilin, Liaoning, Tianjin, Anhui, Jiangxi, Hubei, Henan, and Guangdong. Distribution analysis of seven geographic regions showed that the overall carrying rate of pathogenic mutations in North China region was significantly lower than that in Central China region (represented by Henan, Hubei, and Hunan; 38.38% vs 58.15%), and the differences were statistically significant ( P<0.05). Additionally, although the carrying rate of SPINK1 c.194+2T>C was highest in Central (41.85%) and Northeast China region (38.78%), no significant differences were found among different regions. Conclusions:Genetic factors was the main etiology of CP in China, with SPINK1 c.194+2T>C mutations being most prevalent. The carrying rates of common susceptibility genes of CP were highest in Central China region as well as SPINK1 c.194+2T>C mutation.

Objective:To analyze the mutation spectrum and regional distribution of susceptibility pathogenic genes in Chinese chronic pancreatitis (CP) patients.Methods:A retrospective analysis was conducted on 1 758 sporadic CP patients who underwent gene sequencing for pathogenic mutations of four major susceptibility genes ( SPINK1, PRSS1, CTRC, and CFTR) at the First Affiliated Hospital of Naval Medical University from December 2010 to November 2022. Pathogenic mutations of four major susceptibility genes were detected by using the next-generation sequencing, and both known and novel pathogenic mutations were validated by Sanger sequencing. The ethnic and regional distributions of pathogenic mutations across different ethnic groups were compared. The ArcMap 10.7 software was used to provide the distribution map of common CP pathogenic mutations in China, and regional differences of these mutations were assessed. According to seven major geographical regions in China, we also evaluated the enrichment differences of CP pathogenic mutations in North China region, Northeast China region, East China region, Central China region, South China region, Southwest China region, and Northwest China region. Results:Among 1 758 CP patients, 50.23% (883/1 758) carried pathogenic mutations, and the SPINK1 pathogenic mutations were most predominated (39.31%). Among them, c.194+2T>C mutations accounted for 94.21% of all SPINK1 mutations. 32.59% (573/1 758) of patients carried single heterozygous mutation of one susceptibility gene, and 4.61% carried homozygous mutation of SPINK1 c.194+2T>C. There was no statistically significant difference on the overall pathogenic mutation carrying rate between Han and ethnic minority patients, whereas the mutation carrying rate of SPINK1 c.194+2T>C was significantly higher among Han patients than among ethnic minorities (37.48% vs 20.00%, P<0.05). Among 31 provinces and cities, the mutation carrying rate of CP patients in Tianjin, Guangdong, Yunnan, Hubei and Anhui were all higher than 60.00%. The SPINK1 mutations accounted for the highest proportion of pathogenic mutations across all provinces (33.33% to 61.54%), and SPINK1 c.194+2T>C was the most prevalent mutation. The mutation carrying rate of SPINK1 c.194+2T>C was higher than 40.00% in Jilin, Liaoning, Tianjin, Anhui, Jiangxi, Hubei, Henan, and Guangdong. Distribution analysis of seven geographic regions showed that the overall carrying rate of pathogenic mutations in North China region was significantly lower than that in Central China region (represented by Henan, Hubei, and Hunan; 38.38% vs 58.15%), and the differences were statistically significant ( P<0.05). Additionally, although the carrying rate of SPINK1 c.194+2T>C was highest in Central (41.85%) and Northeast China region (38.78%), no significant differences were found among different regions. Conclusions:Genetic factors was the main etiology of CP in China, with SPINK1 c.194+2T>C mutations being most prevalent. The carrying rates of common susceptibility genes of CP were highest in Central China region as well as SPINK1 c.194+2T>C mutation.