Empirical Solution of Stress Intensity Factors for the Inclined Inner Surface Crack of Pipe under External Pressure and Axial Compression

Based on fracture mechanics theory, a finite element method was used to determine the stress intensity factors of the inclined crack on the inner surface of the pipe under axial compression load and external pressure. The effects of different influencing factors on the stress intensity factor along the crack front considering crack closure were systematically explored, which were different to those under internal pressure. The effects of high aspect ratio on K_II, the crack inclination asymmetry caused by curvature and the effects of the friction coefficient on the stress intensity factors of the pipe with an inclined inner surface crack under axial compression load and external pressure were explored in this paper. To be fit for defect assessment, the solutions for stress intensity factors K_II and K_III were derived, and new correction factors f_θ and f_μ were proposed in the empirical solutions to accommodate the crack inclination asymmetry and the friction coefficient, respectively.     

Integration of ER protein quality control mechanisms defines β cell function and ER architecture

Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and β cell loss. Using focused ion beam scanning electron microscopy powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and β cell function.     

Effects of water exercise on body composition and components of metabolic syndrome in older females with sarcopenic obesity

[Purpose] Very few studies have been conducted on the benefits of water exercise for older adults with sarcopenic obesity. Whether the water exercise intervention is effective for improving sarcopenia and/or obesity remains unclear. This study aimed to investigate the effects of water exercise on body composition and components of metabolic syndrome in older females with sarcopenic obesity. [Participants and Methods] Participants (aged ≥60 years) were divided into a water exercise group and a control group. Water-based strength and endurance exercises were performed three times a week for 12 weeks. Lean soft tissue mass, fat mass, and body fat percentage were measured by dual-energy x-ray absorptiometry. [Results] Two-way analysis of variance revealed significant interactions (time × group) for total body fat percentage and leg body fat percentage. In the exercise group, leg body fat percentage significantly decreased after the intervention, but no significant change was observed in the control group. The components of metabolic syndrome showed no significant interactions in either group (time × group). [Conclusion] No significant changes were observed in the components of metabolic syndrome. However, 12-week water exercise may be effective for reducing fat mass in females with sarcopenic obesity.     

原发性肝癌诊疗指南(2022年版)

  目的  探索经肝动脉化疗栓塞（transcatheter arterial chemoembolization, TACE）为基础的不同方案治疗不可切除肝细胞癌（unresectable hepatocellular carcinoma,uHCC）患者的疗效和安全性,以及TACE联合酪氨酸激酶抑制剂（tyrosine kinase inhibitors,TKIs）和免疫检査点抑制剂（immune checkpoint inhibitors,ICIs）的最佳时机。  方法  回顾性分析2016年4月至2021年12月期间在南方医科大学南方医院接受基于TACE治疗的555例uHCC患者资料。根据不同治疗方案分为：TACE组(n=317)、TACE+TKIs组(n=66)、TACE+ICIs组(n=33)、TACE+TKIs+ICIs组(n=139)。在亚组分析中,根据不同的联合时间将TACE+TKIs+ICIs组分为 “TACE前”和“TACE后”组。采用单因素、多因素Cox回归分析影响OS的预后因素。  结果  TACE+TKIs+ICIs组获得最长的OS(21.9个月,95% CI: 17.2～26.6,P=0.030)和PFS(8.3个月,95% CI: 7.3～9.3,P=0.004)。在亚组分析中,“TACE后”组比“TACE前”组获得更长的OS(26.8个月vs.19.2个月,P=0.011)。 TACE组、TACE+TKIs组、TACE+ICIs组、TACE+TKIs+ICIs组的ORR分别为32.8%、41.1%、42.4%、52.5%（P=0.001）,DCR分别为59.6%、71.2%、69.7%、82.7%（P<0.001）。不良反应事件与既往研究相似。Cox回归分析提示肿瘤数量、肝外转移及治疗方案是患者OS的独立预后因素（均P<0.05）。  结论  TKIs或ICIs可以提高TACE治疗uHCC患者的OS和PFS,TKIs+ICIs联合TACE生存获益更佳。首次TACE术后3个月内联合“TKIs+ICIs”治疗方案的总生存期获益更显著。     

Polatuzumab Vedotin联合利妥昔单抗和苯达莫司汀治疗复发/难治性弥漫大B细胞淋巴瘤的单中心疗效和安全性分析

  目的  探讨真实世界大B细胞淋巴瘤（large B-cell lymphoma,LBCL）嵌合抗原受体-T（chimeric antigen receptor-T,CAR-T）细胞治疗失败后的结局。   方法  回顾性分析2018年7月至2022年12月于南昌大学第一附属医院接受CD19 CAR-T细胞治疗后出现疾病复发/难治性16例LBCL患者的临床资料,分析其后续治疗和预后。  结果  16例患者中男性10例、女性6例,中位年龄53.5（16～72）岁,其预后极差,中位总生存期（median overall survival,mOS）仅为5.7个月（95%CI：5.1～6.3）。积极后续抗肿瘤治疗患者12例（75%）,mOS为9.8个月（95%CI：3.3～16.3）;姑息治疗4例（25%）,mOS仅为2.1个月（95%CI：0～4.8）,差异具有统计学意义（P<0.05）。后续抗肿瘤方案包括Pola-BR为4例（33.3%）、BTK抑制剂4例（33.3%）、抗PD-1抗体2例（16.7%）和免疫化疗2例（16.7%）,最佳疗效为部分缓解4例（33.3%）。BTK抑制剂组2例（50%）为部分缓解,mOS为10.8个月（95%CI：3.4～18.1）,较其他方案似有获益趋势,但差异无统计学意义（P>0.05）。  结论  CAR-T治疗后复发或进展的LBCL患者预后差,治疗手段局限,如何合理化分层使用后线治疗策略未来值得探索。     

A thalamic circuit facilitates stress susceptibility via melanocortin 4 receptor‐mediated activation of nucleus accumbens shell

AimsCentral melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress‐induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress.MethodsChronic social defeat stress (CSDS) was used to develop depressive‐like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit.ResultsCSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVT^Glu‐NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling.ConclusionsOur results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress‐induced depressive‐like behavior.     

Targeting PYCR2 inhibits intraperitoneal metastatic tumors of mouse colorectal cancer in a proline‐independent approach

Whether proline deficiency is a metabolic vulnerability in colorectal tumors is unknown. The aim of this study was to investigate the effects of proline metabolism‐related genes and exogenous proline on the progression of colorectal cancer (CRC). We aimed to further clarify the role of pyrroline‐5‐carboxylate reductase (PYCR) 2, a key enzyme of proline synthesis, in the regulation of colorectal intraperitoneal metastatic tumors. This study was carried out based on The Cancer Genome Atlas (TCGA) data, database analysis, single‐cell functional analysis, tissue microarray, cell experiments, and animal models. We found that, PYCR2 mRNA and protein levels were upregulated in CRC. The mRNA level of PYCR2 was closely related to the prognosis and tumor metastasis of CRC patients. The upregulated PYCR2 expression was at least partly due to low promoter methylation levels. The nomogram constructed based on PYCR2 expression and clinical characteristics of CRC showed good accuracy in predicting lymph node metastasis. Pycr2 knockdown inhibited epithelial–mesenchymal transition (EMT) of mouse CRC cells. Proline supplementation did not rescue the inhibition of mouse CRC cell proliferation and migration by Pycr2 knockdown. Proline supplementation also did not rescue the suppression of subcutaneous tumors and intraperitoneal metastatic tumors in mice by Pycr2 knockdown. PYCR2 co‐expressed genes in TCGA‐CRC were enriched in epigenetic modification‐related biological processes and molecular functions. Four small molecules with the lowest binding energy to the PYCR2 protein were identified. Collectively, Pycr2 knockdown inhibited mouse CRC progression in a proline‐independent approach. PYCR2 may be a promising tumor metastasis predictor and therapeutic target in CRC.