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A more common and noninvasive predicting biomarker for programmed cell death 1 (PD-1) antibody remains to be explored. We assessed 46 patients with advanced gastric cancer who received PD-1 antibody immunotherapy and 425-genes next-generation sequencing (NGS) testing. Patients who had a > 25% decline in maximal somatic variant allelic frequency (maxVAF) had a longer progression free survival (PFS) and higher response rate than those who did not (7.3 months vs 3.6 months, p  = 0.0011; 53.3% vs 13.3%, p  = 0.06). The median PFS of patients with undetectable and detectable post-treatment circulating tumor DNA (ctDNA) was 7.4 months vs. 4.9 months ( p  = 0.025). Mutation status of TGFBR2, RHOA, and PREX2 in baseline ctDNA influenced the PFS of immunotherapy ( p  < 0.05). Patients with alterations in CEBPA, FGFR4, MET or KMT2B ( p  = 0.09) gene had greater likelihood of immune-related adverse events (irAEs). ctDNA can serve as a potential biomarker of the response to immunotherapy in advanced gastric cancers, and its potential role in predicting irAEs worth further exploration.

جاء هذا الكتاب تحت عنوان «الثقة في النظرية : نجاح لنظام التنمية \"البديل\" الخاص ‏بالصين» وهو من تأليف (مايا غيو) وترجمة عبد الرحمن النجار. يبحث الكتاب في التطور الصيني السريع خلال الستة عقود الماضية، والدور ‏الذي لعبه الحزب الشيوعي الصيني في تحويل الصين إلى دولة اشتراكية حديثة ‏مزدهرة وقوية وديمقراطية ومتطورة ثقافيا ويستكشف ويستكشف فيما إذا كان صعود الصين يهدد ‏نموذج التنمية الغربي وخاصة بعد أن أضحى صعود الصين حقيقة لا جدال فيها. يعتبر هذا الكتاب من أنجح الكتب التي نشرت عن الصين اليوم. فهو يقدم حججا ‏مقنعة حول نهوض الصين. وتستند الآراء المعبر عنها في الكتاب ليس فقط إلى 60 ‏عاما من تاريخ جمهورية الصين الشعبية وإنجازاتها الملحوظة في العقود الثلاثة ‏الماضية، ولكن أيضا على تاريخها الحديث منذ عام 1840، وتاريخها الذي دام ‏‏2000 عام كدولة موحدة، وحضارتها ذات ال 5000 سنة. وتعكس المقابلات التي ‏أجرتها المؤلفة \"مايا غيو\" مراقبتها الدقيقة للصين اليوم. إذ تضمنت أشخاصا من ‏دوائر مختلفة، تشمل مجالات خبرتهم السياسة والاقتصاد والمجتمع والوضع الوطني ‏وتاريخ دبلوماسية الحزب الشيوعي الصيني والاستراتيجية العسكرية وإدارة ممتلكات ‏الدولة والرعاية الصحية والأعمال التجارية الخاصة. وتختلف موضوعات المقابلات ‏على نطاق واسع؛ فمن النظم والنظرية والتطوير والإصلاح، إلى نوعية الحياة ‏والاستراتيجية والدبلوماسية وجميع من كان فيها يؤيدون التعلم من الحضارات ‏الإنسانية، ولكنهم يصرون في الوقت نفسه على ضرورة اتخاذ مسار يناسب الصين ‏بدلا من استنساخ النموذج الغربي. يأتي هذا الكتاب من ضمن سلسلة تتألف من ثلاثة كتب وهي : الثقة في المسار : ‏نموذج جديد لقوة صاعدة، الثقة في النظرية : فلسفة الصين لنظام دولي جديد، والثقة ‏في النظام : نجاح نظام التنمية \"البديل\" في الصين. بما يوفر للقارئ مقاربة نظرية ‏وواقعية لمسار الصين ونظريتها ونظامها، ويشرح أسباب ثقة الدولة الصينية في ‏خياراتها.

Background Natural killer (NK) cells play a major role in body’s fighting against various types of cancers. Their infiltration in the tumor microenvironment (TME) of gastric cancer (GC) are significantly decreased, which has been reported as a robust prognostic marker. However, the causes leading to NK cells loss in GC TME remains poorly understood. Methods We constructed a non-contact co-culturing system and humanized xenograft tumor mice model to detect the influence of GC microenvironment on NK-92 or primary human NK cells viability by flow cytometry. Then through using the specific inhibitors for different types of cell death and examining the surrogate markers, we confirmed ferroptosis in NK cells. Inspired by the accidental discoveries, we constructed a NK-92 cell strain with high expression of GPX4 and treated the humanized xenograft tumor mice model with the NK-92 cells. Results We found L-KYN, mainly generated through indoleamine 2, 3-dioxygenase (IDO) from GC cells, impaired NK cells viability in TME. Further analysis revealed L-KYN induced ferroptosis in NK cells via an AHR-independent way. Moreover, we found NK cells with higher GPX4 expression showed resistance to L-KYN induced ferroptosis. Based on this, we generated GPX4 over-expressed NK-92 cells, and found these cells showed therapeutic potential towards GC. Conclusions Our study revealed a novel mechanism to explain the decline of NK cell number in GC TME. Notably, we also developed a potential immunotherapy strategy, which might be beneficial in clinical treatment in the future.

Background Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognitive ability. Exosomes derived from bone-marrow mesenchymal stem cells (BMSC-exos) are extracellular vesicles that can execute the function of bone-marrow mesenchymal stem cells (BMSCs). Given the versatile therapeutic potential of BMSC and BMSC-exos, especially their neuroprotective effect, the aim of this study was to investigate the potential effect of BMSC-exos on AD-like behavioral dysfunction in mice and explore the possible molecular mechanism. Methods BMSC-exos were extracted from the supernatant of cultured mouse BMSCs, which were isolated from the femur and tibia of adult C57BL/6 mice, purified and sorted via flow cytometry, and cultured in vitro. BMSC-exos were identified via transmission electron microscopy, and typical marker proteins of exosomes were also detected via Western blot. A sporadic AD mouse model was established by intracerebroventricular injection of streptozotocin (STZ). Six weeks later, BMSC-exos were administered via lateral ventricle injection or caudal vein injection lasting five consecutive days, and the control mice were intracerebroventricularly administered an equal volume of solvent. Behavioral performance was observed via the open field test (OFT), elevated plus maze test (EPM), novel object recognition test (NOR), Y maze test (Y-maze), and tail suspension test (TST). The mRNA and protein expression levels of IL-1β, IL-6, and TNF-α in the hippocampus were measured via quantitative polymerase chain reaction (qPCR) and Western blot, respectively. Moreover, the protein expression of Aβ 1-42 , BACE, IL-1β, IL-6, TNF-α, GFAP, p-Tau (Ser396), Tau5, synaptotagmin-1 (Syt-1), synapsin-1, and brain-derived neurotrophic factor (BDNF) in the hippocampus was detected using Western blot, and the expression of GFAP, IBA1, Aβ 1−42 and DCX in the hippocampus was measured via immunofluorescence staining. Results Lateral ventricle administration, but not caudal vein injection of BMSC-exos improved AD-like behaviors in the STZ-injected mouse model, as indicated by the increased number of rearing, increased frequency to the central area, and increased duration and distance traveled in the central area in the OFT, and improved preference index of the novel object in the NOR. Moreover, the hyperactivation of microglia and astrocytes in the hippocampus of the model mice was inhibited after treatment with BMSC-exos via lateral ventricle administration, accompanied by the reduced expression of IL-1β, IL-6, TNF-α, Aβ 1-42, and p-Tau and upregulated protein expression of synapse-related proteins and BDNF. Furthermore, the results of the Pearson test showed that the preference index of the novel object in the NOR was positively correlated with the hippocampal expression of BDNF, but negatively correlated with the expression of GFAP, IBA1, and IL-1β. Apart from a positive correlation between the hippocampal expression of BDNF and Syt-1, BDNF abundance was found to be negatively correlated with markers of glial activation and the expression of the inflammatory cytokines, Aβ 1-42 , and p-Tau, which are characteristic neuropathological features of AD. Conclusions Lateral ventricle administration, but not caudal vein injection of BMSC-exos, can improve AD-like behavioral performance in STZ-injected mice, the mechanism of which might be involved in the regulation of glial activation and its associated neuroinflammation and BDNF-related neuropathological changes in the hippocampus.

Bladder cancer (BCa) is one of the common malignancies. Circular RNAs (circRNAs) play regulatory roles in cancer progression. CircITGA7 is a circRNA generated from several exons of ITGA7. The potential role of circITGA7 in BCa remains unknown and needs to be explored. Quantitative real time polymerase chain reaction (qRT‐PCR) was used to assess circITGA7 and miR‐330‐3p expression in BCa tissues and cell lines. Kaplan–Meier analysis was used to evaluate the overall survival of these BCa patients. The biological function of circITGA7 was examined by overexpression of circITGA7 using CCK‐8, EdU, wound‐healing, and Transwell assays. Xenograft assay was performed to further validate the in vitro results. To explore the mechanism of circITGA7, luciferase reporter, RNA pull‐down, fluorescence in situ hybridization (FISH) assays were employed to examine the binding interaction among circITGA7, miR‐330‐3p and kruppel‐like factor 10 (KLF10). Western blot was used to study the protein levels of KLF10.CircITGA7 was downregulated in BCa tissues and cell lines and indicated longer overall survival. Moreover, circITGA7 restricted cell proliferation, migration and invasion of BCa through negatively regulating miR‐330‐3p. The in vivo model showed that circITGA7 influenced the tumor growth. Besides, the overexpression of miR‐330‐3p promoted cell progression by directly targeting KLF10. Mechanistically, circITGA7 inhibited BCa progression by activating KLF10 via targeting miR‐330‐3p.CircITGA7 alleviates BCa cell progression via circITGA7/hsa‐miR‐330‐3p/KLF10 axis, which may provide novel therapeutic targets for BCa.

Cancer is a leading cause of death worldwide, particularly because of its high mortality rate in patients who are diagnosed at late stages. Conventional biomarkers originating from blood are widely used for cancer diagnosis, but their low sensitivity and specificity limit their widespread application in cancer screening among the general population. Currently, emerging studies are exploiting novel, highly-accurate biomarkers in human body fluids that are obtainable through minimally invasive techniques, which is defined as liquid biopsy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs generated mainly by pre-mRNA splicing. Following the rapid development of high-throughput transcriptome analysis techniques, numerous circRNAs have been recognized to exist stably and at high levels in body fluids, including plasma, serum, exosomes, and urine. CircRNA expression patterns exhibit distinctly differences between patients with cancer and healthy controls, suggesting that circRNAs in body fluids potentially represent novel biomarkers for monitoring cancer development and progression. In this study, we summarized the expression of circRNAs in body fluids in a pan-cancer dataset and characterized their clinical applications in liquid biopsy for cancer diagnosis and prognosis. In addition, a user-friendly web interface was developed to visualize each circRNA in fluids ( https://mulongdu.shinyapps.io/circrnas_in_fluids/ ).

Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is one of the leading causes of cancer-related death and is associated with a poor prognosis. The tumor microenvironment (TME) of HCC comprises immune, immunosuppressive, and interstitial cells with hypoxic, angiogenic, metabolic reprogramming, inflammatory, and immunosuppressive features. Exosomes are nanoscale extracellular vesicles that secrete biologically active signaling molecules such as deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), microribonucleic acid (miRNA), proteins, and lipids. These signaling molecules act as messengers in the tumor microenvironment, especially the tumor immunosuppressive microenvironment. Exosomal circRNAs reshape the tumor microenvironment by prompting hypoxic stress response, stimulating angiogenesis, contributing to metabolic reprogramming, facilitating inflammatory changes in the HCC cells and inducing tumor immunosuppression. The exosomes secreted by HCC cells carry circRNA into immune cells, which intervene in the activation of immune cells and promote the overexpression of immune checkpoints to regulate immune response, leading tumor cells to acquire immunosuppressive properties. Furthermore, immunosuppression is the final result of a combination of TME-related factors, including hypoxia, angiogenesis, metabolic reprogramming, and inflammation changes. In conclusion, exosomal circRNA accelerates the tumor progression by adjusting the phenotype of the tumor microenvironment and ultimately forming an immunosuppressive microenvironment. HCC-derived exosomal circRNA can affect HCC cell proliferation, invasion, metastasis, and induction of chemoresistance. Therefore, this review aimed to summarize the composition and function of these exosomes, the role that HCC-derived exosomal circRNAs play in microenvironment formation, and the interactions between exosomes and immune cells. This review outlines the role of exosomal circRNAs in the malignant phenotype of HCC and provides a preliminary exploration of the clinical utility of exosomal circRNAs.

China is one of the countries affected most by natural hazards. With the rapid urbanization process, the susceptibility of Chinese cities to natural disasters increases. In this paper, we propose an integrated natural disaster urban resilience evaluation framework for Chinese cities. We aggregate city-level economic, social, infrastructural, and environmental indicators of 39 major Chinese cities from 2002 to 2017 and convert them to a multi-dimensional resilience index using factor analysis. We validate our measure by showing that cities with larger resilience indices have lower natural disaster losses. We further investigate the regional characteristics of our urban resilience index and find that Chinese cities improved their resilience to natural hazards across the years. Although cities in the eastern coastal area tend to be more resilient than cities in other regions, the gap has been narrowed. Our paper provides some insights into how cities may measure and improve their urban resilience system.

Thermoplastic polyurethanes (TPUs) and other elastomers are widely used in many applications for the advantages they provide in terms of high elasticity, lightness, resistance to breakage, and impact resistance. These materials exhibit strong hysteresis in the large strain stress-strain behavior, known as cyclic softening or the Mullins effect. Despite the extensive studies on this phenomenon and the importance of Poisson’s ratio, how the Poisson’s ratio of these materials changes during cyclic uniaxial tests is still unclear. Here, we measure the nonlinear Poisson’s ratio of TPU and investigate its correlation with cyclic softening using two-dimensional digital image correlation (2D-DIC) combined with the reference sample compensation (RSC) method. This accuracy-enhanced method can effectively eliminate the measurement errors induced by the unavoidable out-of-plane displacements and lens distortion. We find that the Poisson’s ratio of TPUs also exhibits large hysteresis in the first cycle and then approaches a steady state in subsequent cycles. Specifically, it starts from a relatively low value of 0.45 ± 0.005 in the first loading, then increases to 0.48 ± 0.005 in the first unloading, and remains largely constant afterward. Such a change in the Poisson’s ratio results in a slight volume increase (≈1%) at a maximum strain of 17.5%. Our findings are useful for those who use finite element method to analyze the mechanical behavior of TPU, and shed new light on understanding the physical origin of cyclic softening.