Long-term outcomes of vulvar or vaginal cancer patients undergoing laparoendoscopic single-site inguinal lymphadenectomy.

INTRODUCTION: Laparoendoscopic single-site inguinal lymphadenectomy (LESS-IL), a minimally invasive technique, has been reported in patients with vulvar or vaginal cancer regarding its safety and feasibility. However, the long-term outcomes, especially oncologic outcomes, are still lacking. We aimed to evaluate the long-term outcomes of LESS-IL to confirm its safety further. PATIENTS AND METHODS: Data were prospectively collected from patients with vulvar or vaginal cancer who underwent LESS-IL at our institution between July 2018 and June 2021. The patients were followed up for at least 12 months. All procedures were performed according to treatment standards. Short- and long-term complications and oncologic outcomes were analysed. RESULTS: A total of 16 patients undergoing 28 LESS-IL procedures were identified, amongst whom 4 underwent unilateral LESS-IL. The median numbers of excised groin lymph nodes were 9.0 (6.5-11.8) and 10.5 (8.3-12.0) in each left and right groin, respectively. Short-term complications occurred in 4 (25%) patients, including 18.7% lymphocele and 6.3% wound infection. Long-term complications regarding lower-limb lymphoedema appeared in 6 (37.5%) patients. Most short- and long-term complications were Clavien-Dindo 1 or 2, accounting for 90% of all post-operative issues. After a median follow-up of 27 (21.3-35.8) months, only 1 (6.3%) patient had isolated inguinal recurrence at 13 months postoperatively. No local or distant recurrence occurred. CONCLUSION: Our results suggest that LESS-IL is associated with little incidence of complications and promising oncologic outcomes, further demonstrating the safety and feasibility of the LESS-IL technique in patients requiring IL.

OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells.

Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 µg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 µM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.

OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes.

Rationale: Understanding the molecular mechanisms of deleterious cardiac remodeling is important for the development of treatments for heart failure. Recent studies have highlighted a role of deubiquitinating enzymes in cardiac pathophysiology. In the present study, we screened for alteration of deubiquitinating enzymes in experimental models of cardiac remodeling, which indicated a potential role of OTU Domain-Containing Protein 1 (OTUD1). Methods: Wide-type or OTUD1 knockout mice with chronic angiotensin II infusion and transverse aortic constriction (TAC) were utilized to develop cardiac remodeling and heart failure. We also overexpressed OTUD1 in mouse heart with AAV9 vector to validate the function of OTUD1. LC-MS/MS analysis combined with Co-IP was used to identify the interacting proteins and substrates of OTUD1. Results: We found that OTUD1 is elevated in mouse heart tissues following chronic angiotensin II administration. OTUD1 knockout mice were significantly protected against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis and inflammatory response. Similar results were obtained in the TAC model. Mechanistically, OTUD1 bounds to the SH2 domain of STAT3 and causes deubiquitination of STAT3. Cysteine at position 320 of OTUD1 exerts K63 deubiquitination to promote STAT3 phosphorylation and nuclear translocation, thereby increasing STAT3 activity to induce inflammatory responses, fibrosis, and hypertrophy in cardiomyocytes. Finally, OTUD1 overexpression by AAV9 vector increases Ang II-induced cardiac remodeling in mice and OTUD1-regulated responses can be inhibited by blocking STAT3. Conclusion: Cardiomyocyte OTUD1 promotes pathological cardiac remodeling and dysfunction by deubiquitinating STAT3. These studies have highlighted a novel role of OTUD1 in hypertensive heart failure and identified STAT3 as a target of OTUD1 in mediating these actions.

Automatic diagnosis of pneumothorax with M-mode ultrasound images based on D-MPL.

PURPOSE: To address the difficulties of M-mode ultrasound images classification in pneumothorax diagnosis and the shortcomings of existing neural network algorithms in this field, we proposed an M-mode ultrasound images classification model based on Disturbed Meta-Pseudo-Labels (D-MPL). METHODS: An M-mode ultrasound image augmentation system was designed to make the model more robust and generalizable. In D-MPL, teacher-generated pseudo-labeling was first taught to students through a soft mask, and additional disturbance data were added to the teacher network. As the loss of the teacher network continues to decline, disturbance data were injected to improve the generalization of the model to cope with image differences across patients in clinical settings. RESULTS: We compared the proposed model with four commonly used models, including MPL, EfficientnetB2, Inception V3, and Resnet101, in order to confirm its efficacy. Our model has an average specificity of 98.28%, sensitivity of 98.22%, F1-score of 98.23%, and AUC of 98.10%, according to the experiment findings, and its comprehensive performance is better than the above four models. CONCLUSION: The results demonstrated our model's superiority over the competition and its greater. The model proposed in this study is expected to assist doctors in the diagnosis of pneumothorax as an auxiliary mean.

Diacerein protects liver against APAP-induced injury via targeting JNK and inhibiting JNK-mediated oxidative stress and apoptosis.

BACKGROUND AND PURPOSE: An overdose of acetaminophen (APAP) causes acute liver damage and lead to liver failure. Therefore, it is of great clinical significance to find drugs for the treatment of APAP-induced liver injury. Diacerein is clinically used drug for the treatment of osteoarthritis. Here, we evaluate the pharmacological effects and potential mechanisms of diacerein in APAP-induced liver injury. METHODS AND RESULTS: C57BL/6 mice were treated with diacerein by gavage, followed by intraperitoneal injection of APAP (400 mg/kg) to induce acute liver injury in mice. RNA-sequencing analysis and in vitro kinase assay were performed to explore the underlying mechanisms of diacerein. The experimental results showed that pretreatment with diacerein could inhibit APAP-induced elevation of serum AST and ALT levels, hepatic histopathological damage, oxidative stress, hepatocyte death, and mitochondrial damage in mice. The RNA-sequencing analysis and in vitro kinase assay indicated that indicating that JNK (c-Jun N-terminal kinase) is involved in that liver-protective effects of Diacerein. Diacerein could directly and selectively inhibit JNK kinase phosphorylation in cell-free system. We further confirmed that diacerein inhibits APAP-activated JNK pathway to reduce injury response in mouse livers and cultured AML12 cells. Deficiency of JNK in AML12 cells abolished the anti-injury effects of diacerein. CONCLUSION: Our experimental results suggest that diacerein protects APAP-induced liver injury by the inhibition of JNK kinase phosphorylation, rendering diacerein may serve as a potential therapeutic drug for the prevention of acute liver injury.