Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool.

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.

BCLAF1 drives esophageal squamous cell carcinoma progression through regulation of YTHDF2-dependent SIX1 mRNA degradation.

Esophageal cancer ranks among the most prevalent malignant tumors, and esophageal squamous cell carcinoma (ESCC) constitutes its predominant histological form. Despite its impact, a thorough insight into the molecular intricacies of ESCC's development is still incomplete, which hampers the advancement of targeted molecular diagnostics and treatments. Recently, B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) has come under investigation for its potential involvement in tumor biology, yet its specific role and mechanism in ESCC remain unclear. In this study, we observed a marked increase in BCLAF1 expression in ESCC tissues, correlating with advanced tumor stages and inferior patient outcomes. Our comprehensive in vitro and in vivo studies show that BCLAF1 augments glycolytic activity and the proliferation, invasion, and spread of ESCC cells. By employing mass spectrometry, we identified YTHDF2 as a key protein interacting with BCLAF1 in ESCC, with further validation provided by colocalization, co-immunoprecipitation, and GST pull-down assay. Further investigations involving MeRIP-seq and RIP-seq, alongside transcriptomic analysis, highlighted SIX1 mRNA as a molecule significantly upregulated and modified by N6-methyladenosine (m6A) in BCLAF1 overexpressing cells. BCLAF1 was found to reduce the tumor-suppressive activities of YTHDF2, and its effects on promoting glycolysis and cancer progression were shown to hinge on SIX1 expression. This research establishes that BCLAF1 fosters glycolysis and tumor progression in ESCC through the YTHDF2-SIX1 pathway in an m6A-specific manner, suggesting a potential target for future therapeutic intervention.

TRANS-CNN-Based Gesture Recognition for mmWave Radar.

In order to improve the real-time performance of gesture recognition by a micro-Doppler map of mmWave radar, the point cloud based gesture recognition for mmWave radar is proposed in this paper. Two steps are carried out for mmWave radar-based gesture recognition. The first step is to estimate the point cloud of the gestures by 3D-FFT and the peak grouping. The second step is to train the TRANS-CNN model by combining the multi-head self-attention and the 1D-convolutional network so as to extract the features in the point cloud data at a deeper level to categorize the gestures. In the experiments, TI mmWave radar sensor IWR1642 is used as a benchmark to evaluate the feasibility of the proposed approach. The results show that the accuracy of the gesture recognition reaches 98.5%. In order to prove the effectiveness of our approach, a simply 2Tx2Rx radar sensor is developed in our lab, and the accuracy of recognition reaches 97.1%. The results show that our proposed gesture recognition approach achieves the best performance in real time with limited training data in comparison with the existing methods.

Fault monitoring method of domestic waste incineration slag sorting device based on back propagation neural network.

The main monitoring points of traditional sorting equipment fault monitoring methods are usually limited to the inlet and outlet, making it difficult to monitor the internal equipment, which may affect the accuracy of fault monitoring. Therefore, a new fault monitoring method based on back propagation neural network has been studied and designed, which is mainly applied to the sorting device of domestic waste incineration slag. The fault monitoring modeling variables of the domestic waste incineration slag sorting device are selected to determine the operation status of the sorting device. Based on back propagation neural network, a fault monitoring model for the sorting device of municipal solid waste incinerator slag is constructed, and the fault data of the sorting device is trained in the model, so that the fault data of the sorting device can be optimized faster, thus improving the accuracy of fault monitoring. Through comparative experiments with traditional methods, it has been confirmed that this fault monitoring method based on back propagation neural network has significant advantages in detection performance, demonstrating its potential in practical applications.

Hippo cooperates with p53 to maintain foregut homeostasis and suppress the malignant transformation of foregut basal progenitor cells.

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut.

Integrin ß8 prevents pericyte-myofibroblast transition and renal fibrosis through inhibiting the TGF-ß1/TGFBR1/Smad3 pathway in diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the leading causes to develop end-stage kidney disease worldwide. Pericytes are implicated in the development of tissue fibrosis. However, the underlying mechanisms of pericytes in DKD remain largely unknown. We isolated and cultured primary pericytes and rat mesangial cells (HBZY-1). Western blot and qRT-PCR analysis were used to explore the role and regulatory mechanism of Integrin ß8/transforming growth factor beta 1 (TGF-ß1) pathway. We also constructed pericyte-specific Integrin ß8 knock-in mice as the research objects to determine the role of Integrin ß8 in vivo. We discovered that reduced Integrin ß8 expression was closely associated with pericyte transition in DKD. Overexpressed Integrin ß8 in pericytes dramatically suppressed TGF-ß1/TGF beta receptor 1 (TGFBR1)/Smad3 signaling pathway and protected glomerular endothelial cells (GECs) in vitro. In vivo, pericyte-specific Integrin ß8 knock-in ameliorated pericyte transition, endothelium injury and renal fibrosis in STZ-induced diabetic mice. Mechanistically, Murine double minute 2 (MDM2) was found to increase the degradation of Integrin ß8 and caused TGF-ß1 release and activation. Knockdown MDM2 could partly reverse the decline of Integrin ß8 and suppress pericytes transition. In conclusion, the present findings suggested that upregulated MDM2 expression contributes to the degradation of Integrin ß8 and activation of TGF-ß1/TGFBR1/Smad3 signaling pathway, which ultimately leads to pericyte transition during DKD progression. These results indicate MDM2/Integrin ß8 might be considered as therapeutic targets for DKD.

Technologies evolution in robot-assisted fracture reduction systems: a comprehensive review.

Background: Robot-assisted fracture reduction systems can potentially reduce the risk of infection and improve outcomes, leading to significant health and economic benefits. However, these systems are still in the laboratory stage and not yet ready for commercialization due to unresolved difficulties. While previous reviews have focused on individual technologies, system composition, and surgical stages, a comprehensive review is necessary to assist future scholars in selecting appropriate research directions for clinical use. Methods: A literature review using Google Scholar identified articles on robot-assisted fracture reduction systems. A comprehensive search yielded 17,800, 18,100, and 16,700 results for "fracture reduction," "computer-assisted orthopedic surgery," and "robot-assisted fracture reduction," respectively. Approximately 340 articles were selected, and 90 highly relevant articles were chosen for further reading after reviewing the abstracts. Results and Conclusion: Robot-assisted fracture reduction systems offer several benefits, including improved reduction accuracy, reduced physical work and radiation exposure, enhanced preoperative planning and intraoperative visualization, and shortened learning curve for skill acquisition. In the future, these systems will become integrated and practical, with automatic preoperative planning and high intraoperative safety.

Radiologic Identification of Pathologic Tumor Invasion in Patients With Lung Adenocarcinoma.

Importance: It is currently unclear whether high-resolution computed tomography can preoperatively identify pathologic tumor invasion for ground-glass opacity lung adenocarcinoma. Objectives: To evaluate the diagnostic value of high-resolution computed tomography for identifying pathologic tumor invasion for ground-glass opacity featured lung tumors. Design, Setting, and Participants: This prospective, multicenter diagnostic study enrolled patients with suspicious malignant ground-glass opacity nodules less than or equal to 30 mm from November 2019 to July 2021. Thoracic high-resolution computed tomography was performed, and pathologic tumor invasion (invasive adenocarcinoma vs adenocarcinoma in situ or minimally invasive adenocarcinoma) was estimated before surgery. Pathologic nonadenocarcinoma, benign diseases, or those without surgery were excluded from analyses; 673 patients were recruited, and 620 patients were included in the analysis. Statistical analysis was performed from October 2021 to January 2022. Exposure: Patients were grouped according to pathologic tumor invasion. Main Outcomes and Measures: Primary end point was diagnostic yield for pathologic tumor invasion. Secondary end point was diagnostic value of radiologic parameters. Results: Among 620 patients (442 [71.3%] female; mean [SD] age, 53.5 [12.0] years) with 622 nodules, 287 (46.1%) pure ground-glass opacity nodules and 335 (53.9%) part-solid nodules were analyzed. The median (range) size of nodules was 12.1 (3.8-30.0) mm; 47 adenocarcinomas in situ, 342 minimally invasive adenocarcinomas, and 233 invasive adenocarcinomas were confirmed. Overall, diagnostic accuracy was 83.0% (516 of 622; 95% CI, 79.8%-85.8%), diagnostic sensitivity was 82.4% (192 of 233; 95% CI, 76.9%-87.1%), and diagnostic specificity was 83.3% (324 of 389; 95% CI, 79.2%-86.9%). For tumors less than or equal to 10 mm, 3.6% (8 of 224) were diagnosed as invasive adenocarcinomas. The diagnostic accuracy was 96.0% (215 of 224; 95% CI, 92.5%-98.1%), diagnostic specificity was 97.2% (210 of 216; 95% CI, 94.1%-99.0%); for tumors greater than 20 mm, 6.9% (6 of 87) were diagnosed as adenocarcinomas in situ or minimally invasive adenocarcinomas. The diagnostic accuracy was 93.1% (81 of 87; 95% CI, 85.6%-97.4%) and diagnostic sensitivity was 97.5% (79 of 81; 95% CI, 91.4%-99.7%). For tumors between 10 to 20 mm, the diagnostic accuracy was 70.7% (220 of 311; 95% CI, 65.3%-75.7%), diagnostic sensitivity was 75.0% (108 of 144; 95% CI, 67.1%-81.8%), and diagnostic specificity was 67.1% (112 of 167; 95% CI, 59.4%-74.1%). Tumor size (odds ratio, 1.28; 95% CI, 1.18-1.39) and solid component size (odds ratio, 1.31; 95% CI, 1.22-1.42) could each independently serve as identifiers of pathologic invasive adenocarcinoma. When the cutoff value of solid component size was 6 mm, the diagnostic sensitivity was 84.6% (95% CI, 78.8%-89.4%) and specificity was 82.9% (95% CI, 75.6%-88.7%). Conclusions and relevance: In this diagnostic study, radiologic analysis showed good performance in identifying pathologic tumor invasion for ground-glass opacity-featured lung adenocarcinoma, especially for tumors less than or equal to 10 mm and greater than 20 mm; these results suggest that a solid component size of 6 mm could be clinically applied to distinguish pathologic tumor invasion.

Development and evaluation of an external quality control and internal quality control containing real-time RT-PCR assay for the detection of o'nyong-nyong virus.

O'nyong-nyong fever is a mosquito-borne tropical viral disease while few molecular diagnostic tools have been established for its surveillance until now. In the current study, a single-step, dual-color real-time reverse transcription polymerase chain reaction (RT-PCR) assay which contained both external quality control (EQC) and internal quality control (IQC) prepared by armored RNA technique was developed and evaluated for the detection of o'nyong-nyong virus (ONNV). Results showed that the assay was established successfully without cross-reaction with genetically related or symptom-alike diseases, which showed high specificity of the assay. The coefficient of variation of the assay was 0.97%, far less than 5%, indicating good repeatability of the assay. The lower limit of detection of the assay could reach as low as 100 copies of genome equivalent. During evaluation, the assay could correctly detect ONNV from spiked human serum samples and Anopheles species mosquito samples, while no ONNV positive was observed either from serum samples of patients with acute febrile illness or from local Anopheles species mosquitoes, suggesting no ONNV had been transmitted locally. In conclusion, the assay could potentially provide a valuable platform for ONNV molecular detection, which may improve the preparedness for future o'nyong-nyong fever outbreaks.

Impact of minimally invasive total mesoesophageal excision and minimally invasive esophagectomy on failure patterns of locally advanced esophageal squamous cell carcinoma: a matched cohort study with long-term follow-up.

BACKGROUND: The effects of minimally invasive total mesoesophageal excision (MITME) on the long-term prognosis of locally advanced esophageal squamous cell carcinoma (ESCC) remain unknown. The objective of this study was to compare the static and dynamic failure patterns of MITME and minimally invasive esophagectomy (MIE) for locally advanced ESCC. METHODS: We use propensity score matching (PSM) method to analyze the postoperative failure patterns of the two groups. Cumulative event curves were analyzed for cumulative incidence of failure between different groups, and independent prognostic factors were assessed using time-dependent multivariate analyses. The risk of dynamic failure calculated at 12-month intervals was compared between the two groups using the lifetime table. RESULTS: A total of 366 ESCC patients were studied by 1:1 PSM for T stage and TNM stage (MITME group, n = 183; MIE group, n = 183). In the matched cohort, there was significant differences between the MITME and MIE groups in the failure pattern of regional lymph node recurrence (0.5 vs 3.8%, P = 0.032) and non-tumor death (10.9 vs 31.7%, P < 0.001). The cumulative event curve found that the 5-year cumulative failure rate was lower in the MITME group than in the MIE group (3.3 vs 17.1%, P = 0.026) after 5 years of survival. In addition, multivariate Cox regression analysis showed that MIE was an independent poor prognostic factor for a high cumulative failure rate in locally advanced ESCC patients at 5 years after surgery (HR:4.110; 95% CI 1.047-16.135; P = 0.043). The dynamic risk curve showed that the MITME group had a lower risk of failure within 5 years after surgery than the MIE group. CONCLUSION: Considering that MITME can significantly improve the postoperative failure pattern and the benefit lasts for at least 5 years, it is feasible to use MITME as a treatment for locally advanced ESCC.

miRNA-124 Prevents Rat Diabetic Retinopathy by Inhibiting the Microglial Inflammatory Response.

Diabetic retinopathy (DR) is characterized by vasoregression and glial activation. miRNA-124 (miR-124) reduces retinal microglial activation and alleviates vasoregression in a neurodegenerative rat model. Our aim was to determine whether miR-124 affects vascular and neural damage in the early diabetic retina. Diabetes was induced in 8-week-old Wistar rats by streptozotocin (STZ) injection. At 16 and 20 weeks, the diabetic rats were intravitreally injected with miR-124 mimic, and retinae were analyzed at 24 weeks. Microvascular damage was identified by evaluating pericyte loss and acellular capillary (AC) formation. Müller glial activation was assessed by glial fibrillary acidic protein (GFAP) immunofluorescence staining. Microglial activation was determined by immunofluorescent staining of ionized calcium-binding adaptor molecule 1 (Iba1) in whole mount retinae. The neuroretinal function was assessed by electroretinography. The expression of inflammation-associated genes was evaluated by qRT-PCR. A wound healing assay was performed to quantitate the mobility of microglial cells. The results showed that miR-124 treatment alleviated diabetic vasoregression by reducing AC formation and pericyte loss. miR-124 blunted Müller glial- and microglial activation in diabetic retinae and ameliorated neuroretinal function. The retinal expression of inflammatory factors including Tnf-α, Il-1ß, Cd74, Ccl2, Ccl3, Vcam1, Tgf-ß1, Arg1, and Il-10 was reduced by miR-124 administration. The elevated mobility of microglia upon high glucose exposure was normalized by miR-124. The expression of the transcription factor PU.1 and lipid raft protein Flot1 was downregulated by miR-124. In rat DR, miR-124 prevents vasoregression and glial activation, improves neuroretinal function, and modulates microglial activation and inflammatory responses.

Cellular phenotypic transitions in diabetic nephropathy: An update.

Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetes and is the most common cause of end stage renal disease (ESRD). Renal fibrosis is the final pathological change in DN. It is widely believed that cellular phenotypic switching is the cause of renal fibrosis in diabetic nephropathy. Several types of kidney cells undergo activation and differentiation and become reprogrammed to express markers of mesenchymal cells or podocyte-like cells. However, the development of targeted therapy for DN has not yet been identified. Here, we discussed the pathophysiologic changes of DN and delineated the possible origins that contribute to myofibroblasts and podocytes through phenotypic transitions. We also highlight the molecular signaling pathways involved in the phenotypic transition, which would provide valuable information for the activation of phenotypic switching and designing effective therapies for DN.

Regulation of Podocyte Injury by CircHIPK3/FUS Complex in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and is one of the leading causes of end-stage kidney disease. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that play important roles in various diseases, yet their roles in DKD are poorly understood. CircRNA HIPK3 (circHIPK3), a highly conserved circRNA, is closely related to various cellular functions, including cell proliferation and apoptosis. The association between circHIPK3 and diabetic complications has been well demonstrated in multiple previous studies. However, the role of circHIPK3 in podocyte injury in DKD remains unclear. Herein, we discovered that circHIPK3 expression is markedly elevated in cultured podocytes under high-glucose (HG) conditions and glomeruli of diabetic mice, which is closely associated with podocyte injury in DKD. Functionally, lentivirus-mediated knockdown of circHIPK3 dramatically suppresses HG-induced podocyte apoptosis in vitro. Therapeutically, silencing circHIPK3 by adeno-associated virus-mediated RNA interference ameliorates podocyte injury and albuminuria in STZ-induced diabetic mice. Mechanistically, circHIPK3 facilitates the enrichment of fused in sarcoma (FUS) on the ectodysplasin A2 receptor (EDA2R) promoter, resulting in the upregulation of EDA2R expression and activation of apoptotic signaling. Taken together, these results indicate circHIPK3/FUS/EDA2R axis as a therapeutic target for podocyte injury and DKD progression.

Does time to esophagectomy following neoadjuvant immunochemotherapy for locally advanced esophageal squamous cell carcinoma affect outcomes?

Objectives: Neoadjuvant immunochemotherapy (nICT) is a novel pattern for locally advanced esophageal squamous cell carcinoma (ESCC), and the time to surgery (TTS) is recommended as 4-6 weeks. However, there were some patients with prolonged TTS(> 6 weeks). This study aimed to explore whether prolonged TTS (> 6 weeks) would affect the outcomes. Methods: Patients diagnosed with locally advanced ESCC between January 2020 and March 2022 and undergoing esophagectomy following nICT were identified based on a prospectively collected database. Primary outcome measures were pathological complete response (pCR) and disease-free survival (DFS), and the secondary outcomes were 30-day postoperative mortality and morbidity, surgical time, postoperative hospital stay, and hospital expense. Results: Total of 95 patients were included for analysis, with 52 patients in the standard TTS group and 43 patients in the prolonged TTS group. The clinical and demographic characteristics of the two groups were comparable. The prolonged group had a median 18 days longer TTS(P<0.001). The pCR rate was 23.08% (12/52) in the standard group and 16.28% (7/43) in the prolonged group (P=0.41). Multivariate regression analysis further indicated that TTS wasn't an independent factor in predicting pCR (P=0.41). The median follow-up time was 10.5 months in the standard TTS group and 11.2 months in the prolonged TTS group. A total of five recurrences occurred with two events in the standard TTS group and three events in the prolonged TTS group, and no significant difference was observed in DFS(P=0.60). Both groups were comparable in postoperative hospital stays, total hospital stay, hospital expenses, and comprehensive complications index (CCI). The complications and major complications were also similar in both groups. Spearman test further indicated that there was no linear correlation among TTS with hospital expenses, postoperative hospital stays, hospital stay, CCI index, lymph nodes moved number, or surgical time, with a p-value of 0.48, 0.63, 0.80, 0.92, 0.09, 0.38 respectively. Conclusions: Based on present evidence, TTS after completion of nICT is not of major importance concerning pathological response, disease-free survival, and short-term postoperative outcomes.

Flavonoids in Treatment of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a progressive systemic disease, which changes the function and structure of the kidneys irreversibly over months or years. The final common pathological manifestation of chronic kidney disease is renal fibrosis and is characterized by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. In recent years, numerous studies have reported the therapeutic benefits of natural products against modern diseases. Substantial attention has been focused on the biological role of polyphenols, in particular flavonoids, presenting broadly in plants and diets, referring to thousands of plant compounds with a common basic structure. Evidence-based pharmacological data have shown that flavonoids play an important role in preventing and managing CKD and renal fibrosis. These compounds can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress and inflammation. In this review, we summarize the function and beneficial properties of common flavonoids for the treatment of CKD and the relative risk factors of CKD.

Textbook outcome after minimally invasive esophagectomy is an important prognostic indicator for predicting long-term oncological outcomes with locally advanced esophageal squamous cell carcinoma.

Background: The textbook outcome (TO) emerges as a novel prognostic factor in surgical oncology. The present study aimed to evaluate the effect of TO on the risk of death and recurrence in patients with esophageal squamous cell carcinoma (ESCC) after minimally invasive esophagectomy (MIE). Methods: The study involved retrospective analysis of 528 patients with ESCC who were subjected to MIE from January 2011 to December 2017. TO included 8 parameters: complete resection; microscopically tumor-negative resection margins (R0); ≥15 lymph nodes removed and examined; no serious postoperative complications; no postoperative intervention; no re-admission to the intensive care unit (ICU); hospital stay ≤21 days; and no readmission ≤30 days. The Cox and logistic regression model were used to analyze the prognostic factors of survival and risk factors for TO. Results: Among the 528 patients with ESCC who were subjected to MIE, 53.2% reached TO. In the case of patients with locally advanced ESCC, 5-year overall survival (OS) was 51.1% (41.2-61.2%) for the TO group but 33.7% (23.7-43.7%) for the non-TO group (HR =0.644, 95% CI: 0.449-0.924, P=0.015). Similarly, 5-year disease-free survival (DFS) was 47.6% (38.0-57.2%) for the TO group but 29.1% (20.1-38.1%) for the non-TO group (HR =0.671, 95% CI: 0.479-0.940, P=0.018). In addition, 5-year recurrence-free survival (RFS) was 62.9% (53.7-72.1%) for the TO group but 39.8% (29.4-50.2%) for the non-TO group (HR =0.606, 95% CI: 0.407-0.902, P=0.012). Multivariate logistic regression analysis further showed that age, American Society of Anesthesiology (ASA) score, intraoperative blood loss, and smoking status acted as independent risk factors for TO. The results of the multivariate analysis assisted in the establishment of a nomogram for the prediction of TO occurrence. This nomogram exhibited satisfactory consistency and prediction ability [area under the receiving operator characteristic (AUROC) =0.717]. Conclusions: The present study showed that achieving of TO after MIE improves survival rate and reduce the recurrence rate in patients with locally advanced ESCC. The study further determined the independent factors associated with TO achievement and established a prediction model.

Mitochondrial Oxidative Stress and Cell Death in Podocytopathies.

Podocytopathies are kidney diseases that are driven by podocyte injury with proteinuria and proteinuria-related symptoms as the main clinical presentations. Albeit podocytopathies are the major contributors to end-stage kidney disease, the underlying molecular mechanisms of podocyte injury remain to be elucidated. Mitochondrial oxidative stress is associated with kidney diseases, and increasing evidence suggests that oxidative stress plays a vital role in the pathogenesis of podocytopathies. Accumulating evidence has placed mitochondrial oxidative stress in the focus of cell death research. Excessive generated reactive oxygen species over antioxidant defense under pathological conditions lead to oxidative damage to cellular components and regulate cell death in the podocyte. Conversely, exogenous antioxidants can protect podocyte from cell death. This review provides an overview of the role of mitochondrial oxidative stress in podocytopathies and discusses its role in the cell death of the podocyte, aiming to identify the novel targets to improve the treatment of patients with podocytopathies.

Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1.

Podocyte injury and loss are critical events in diabetic nephropathy (DN); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that asparaginyl endopeptidase (AEP) protects against podocyte injury through modulating the dynamics of the cytoskeleton. AEP was highly upregulated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes; however, AEP gene knockout and its compound inhibitor treatment accelerated DN in streptozotocin-induced diabetic mice, whereas specific induction of AEP in glomerular cells attenuated podocyte injury and renal function deterioration. In vitro, elevated AEP was involved in actin cytoskeleton maintenance and anti-apoptosis effects. Mechanistically, we found that AEP directly cleaved the actin-binding protein cofilin-1 after the asparagine 138 (N138) site. The protein levels of endogenous cofilin-1 1-138 fragments were upregulated in diabetic podocytes, consistent with the changes in AEP levels. Importantly, we found that cofilin-1 1-138 fragments were remarkably unphosphorylated than full-length cofilin-1, indicating the enhanced cytoskeleton maintenance activity of cofilin-1 1-138. Then we validated cofilin-1 1-138 could rescue podocytes from cytoskeleton disarrangement and injury in diabetic conditions. Taken together, our data suggest a protective role of elevated AEP in podocyte injury during DN progression through cleaving cofilin-1 to maintain podocyte cytoskeleton dynamics and defend damage.

Outcomes of minimally invasive total mesoesophageal excision: a propensity score-matched analysis.

BACKGROUND: This study aimed to investigate the safety and efficacy of minimally invasive total mesoesophageal excision (TME) for esophageal cancer. METHODS: We retrospectively collected data from patients with esophageal cancer who underwent esophagectomy at our center between January 2011 and June 2017. Among 611 eligible patients, 302 underwent minimally invasive total mesoesophageal excision (the TME group) and 309 underwent non-total mesoesophageal excision (the NME group). Outcomes were compared after 1-to-1 propensity score matching, and subgroup analyses were performed for cases involving pT1-2 or pT3-4a disease. RESULTS: The propensity score matching produced 249 pairs of patients. The TME group had a shorter operative time (P < 0.001), lower intraoperative bleeding (P < 0.001), and a shorter postoperative hospital stay (P < 0.001). There were no significant differences between the two groups in the number of removed lymph nodes, 30-day mortality, or postoperative complications. In addition, both groups had similar 3-year rates of overall survival (OS) and disease-free survival (DFS). However, the 3-year recurrence rate in the esophageal bed was significantly lower in the TME group (P = 0.033). Furthermore, among patients with pT3-4a disease, the TME group had better 3-year rates of OS, DFS, and recurrence. CONCLUSION: Minimally invasive total mesoesophageal excision appears to be a safe technique that can reduce tumor recurrence in the esophageal bed. Furthermore, this technique provided survival benefits for patients with pT3-4a disease.

Neoadjuvant Immunotherapy Combined Chemotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Esophageal Squamous Cell Carcinoma: A Propensity Score-Matched Study.

BACKGROUND: Combination of neoadjuvant immunotherapy and chemotherapy (nICT) is a novel treatment for locally esophageal cancer squamous cell carcinoma (ESCC). This study aimed to evaluate the potential effect of nICT on surgery safety by comparing short-term outcomes between the surgery alone group and the nICT followed by surgery group. METHODS: A retrospective analysis was performed to identify patients (from January 2017 to July 2021) who underwent surgery for ESCC with or without nICT. A propensity score matching (PSM) comparison (1:1) was conducted to reduce selection biases and balance the demographic and oncologic characteristics between groups. RESULTS: After PSM, the nICT group (n = 38) was comparable to the surgery alone group (n = 38) in the following characteristics: age, sex, BMI, ASA status, smoking, tumor location, lymph node resection, clinical stage, anastomotic location, surgical approach, and surgical approach. The operation time and incidence of postoperative pneumonia in the nICT group were higher than those in the control group (p < 0.05). However, other complications and major complications were comparable between the two groups. There was no significant difference between the two groups in intraoperative blood loss, ICU stay time, postoperative hospital stay, and hospitalization cost. The 30-day mortality, 30-day readmission, and ICU readmission rates were also similar in the nICT and control groups. In the nICT group, the pathological complete response rate in primary tumor was 18.4%, and the major pathological response rate in tumor was 42.1%. CONCLUSIONS: Based on our preliminary experience, nICT followed by surgery is safe and effective with acceptable increased operation risk, manageable postoperative complications, and promising pathological response. Further multicenter prospective trials are needed to validate our results.