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Cholangiocarcinoma (CCA) is a hepatobiliary carcinoma with uncontrolled cell proliferation, poor prognosis, and high mortality. The ovarian tumor structural domain (OTU) containing protein 6B (OTUD6B) belongs to the OTU deubiquitin family and is vital in tumor development. However, its expression and biological function in CCA remain unknown. The expression of OTUD6B in CCA was analyzed using TIMER2.0, UALCAN, and GEO databases. MTT, clonal formation assay, immunofluorescence staining, immunohistochemistry staining, and flow cytometry examined the regulation of OTUD6B on cell proliferation, cycle, and apoptosis. The effects of OTUD6B on tumor volume and weight were assessed using the xenograft tumor model. The activities of PTK2 and STAT3 were detected by western blot and CO‐IP. The biological database identified that OTUD6B was upregulated in CCA. In CCA cells, OTUD6B knockdown reduced CCA cell proliferation and promoted apoptosis. Cell cycle analysis indicated that the cycle stopped at the G0/G1 phase after OTU6B downregulation. Furthermore, OTUD6B knockdown resulted in a decrease in tumor volume and weight in xenograft tumor models. Mechanistically, OTUD6B is involved in the deubiquitination of PTK2. PTK2 further affected the phosphorylation of STAT3 thereby regulating the CCA process. Our study demonstrates that OTUD6B knockdown participates in the ubiquitination of PTK2 and phosphorylation of STAT3 to alleviate the process of CCA. These results suggest that OTUD6B may be a potential new strategy for CCA treatment. [ABSTRACT FROM AUTHOR]

Background and Aim: Refractory anastomotic leakage (RAL) after intersphincteric resection (ISR) usually leads to failure of protective stoma reversal in ultralow rectal cancers. The aim of this study is to assess the risk factors and oncological outcomes of both anastomotic leakage (AL) and RAL, and quality of life (QoL) of RAL after laparoscopic ISR (LsISR). Methods: A total of 371 ultralow rectal cancer patients with LsISR were enrolled from a tertiary colorectal surgery referral center. Risk factors for AL and RAL were identified by logistic regression. Three‐year disease‐free survival (DFS) of AL and RAL was analyzed by the Cox regression. QoL of RAL group (compared with non‐RAL group) was assessed using the European Organization for Research and Treatment of Cancer QLQ‐C30 and QLQ‐CR29 questionnaires. Results: The rates of AL and RAL after LsISR accounted for 8.4% (31/371) and 4.6% (17/371) in this cohort, respectively. Non‐left colic artery preservation (odds ratio [OR] = 3.491, P = 0.009), neoadjuvant chemoradiotherapy (nCRT) (OR = 6.038, P < 0.001), and lower anastomosis height (OR = 5.271, P = 0.010) were independent risk factors for AL, while nCRT (OR = 11.602, P < 0.001) was the only independent risk factor for RAL. Male (hazard ratio [HR] = 1.989, P = 0.014), age > 60 years (HR = 1.877, P = 0.018), and lymph node metastasis (HR = 2.125, P = 0.005) were independent risk factors of poor 3‐year DFS, but not RAL (P = 0.646). RAL patients have significantly worse global health status, worse emotional and social function scores at the late postoperative stage, and worse urinary and sexual function at the early postoperative stage (all P < 0.05). Conclusions: Neoadjuvant chemoradiotherapy was an independent risk factor for RAL after LsISR. RAL shows similar oncological outcomes, but with poor QoL. [ABSTRACT FROM AUTHOR]

The Ten-Eleven Translocation (TET) family genes are implicated in a wide array of biological functions across various human cancers. Nonetheless, there is a scarcity of studies that comprehensively analyze the correlation between TET family members and the molecular phenotypes and clinical characteristics of different cancers. Leveraging updated public databases and employing several bioinformatics analysis methods, we assessed the expression levels, somatic variations, methylation levels, and prognostic values of TET family genes. Additionally, we explored the association between the expression of TET family genes and pathway activity, tumor microenvironment (TME), stemness score, immune subtype, clinical staging, and drug sensitivity in pan-cancer. Molecular biology and cytology experiments were conducted to validate the potential role of TET3 in tumor progression. Each TET family gene displayed distinct expression patterns across at least ten detected tumors. The frequency of Single Nucleotide Variant (SNV) in TET genes was found to be 91.24%, primarily comprising missense mutation types, with the main types of copy number variant (CNV) being heterozygous amplifications and deletions. TET1 gene exhibited high methylation levels, whereas TET2 and TET3 genes displayed hypomethylation in most cancers, which correlated closely with patient prognosis. Pathway activity analysis revealed the involvement of TET family genes in multiple signaling pathways, including cell cycle, apoptosis, DNA damage response, hormone AR, PI3K/AKT, and RTK. Furthermore, the expression levels of TET family genes were shown to impact the clinical staging of tumor patients, modulate the sensitivity of chemotherapy drugs, and thereby influence patient prognosis by participating in the regulation of the tumor microenvironment, cellular stemness potential, and immune subtype. Notably, TET3 was identified to promote cancer progression across various tumors, and its silencing was found to inhibit tumor malignancy and enhance chemotherapy sensitivity. These findings shed light on the role of TET family genes in cancer progression and offer insights for further research on TET3 as a potential therapeutic target for pan-cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Zheng, Liu, Li, Xing, Zhang, Chen, Wang, Shao, Li, Jiang, Pan, Liu, Xu and Wu.)