Cryo-EM structures reveal two allosteric inhibition modes of PI3KαH1047R involving a re-shaping of the activation loop.

PI3Kα is a lipid kinase that phosphorylates PIP2 and generates PIP3. The hyperactive PI3Kα mutation, H1047R, accounts for about 14% of breast cancer, making it a highly attractive target for drug discovery. Here, we report the cryo-EM structures of PI3KαH1047R bound to two different allosteric inhibitors QR-7909 and QR-8557 at a global resolution of 2.7 Å and 3.0 Å, respectively. The structures reveal two distinct binding pockets on the opposite sides of the activation loop. Structural and MD simulation analyses show that the allosteric binding of QR-7909 and QR-8557 inhibit PI3KαH1047R hyper-activity by reducing the fluctuation and mobility of the activation loop. Our work provides a strong rational basis for a further optimization and development of highly selective drug candidates to treat PI3KαH1047R-driven cancers.

n-3 polyunsaturated fatty acids alleviate the progression of obesity-related osteoarthritis and protect cartilage through inhibiting the HMGB1-RAGE/TLR4 signaling pathway.

Osteoarthritis (OA) is a common joint degenerative disease. There is currently no cure for OA. Dietary fatty acids have potential value in the prevention and treatment of OA. n-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory effects, but their anti-OA mechanism remains unclear. High-mobility group box 1 (HMGB1) promotes inflammation and participates the pathogenesis of OA. The purpose of this study was to investigate the protective effect of n-3 PUFAs on cartilage and whether n-3 PUFAs could exert an anti-OA effect through inhibiting HMGB1-RAGE/TLR4 signaling pathway. We established an obesity-related post-traumatic OA mice model and an in vitro study was conducted to explore the regulatory mechanism of n-3 PUFAs on HMGB1 and its signal pathway against OA. We found that diet rich in n-3 PUFAs alleviated OA-like lesions of articular cartilage with the decrease of HMGB1-RAGE/TLR4 signaling protein in mice. In SW1353 cells, DHA significantly reduced the expression of HMGB1-RAGE/TLR4 signaling protein which was up-regulated by IL-1ß stimulation. HMGB1 overexpression reversed the inhibitory effect of DHA on HMGB1-RAGE/TLR4 signaling pathway. The activation of SIRT1 may participate the inhibitory effect of DHA on HMGB1-RAGE/TLR4 signaling pathway. In conclusion, n-3 PUFAs could attenuate the progression of obesity-related OA and exert protective effect on cartilage by inhibiting HMGB1-RAGE/TLR4 signaling pathway, which may be associated with the activation of SIRT1. Dietary n-3 PUFAs supplements can be considered as a potential therapeutic substance for OA.

Histone H3 Acetylation Is Involved in Retinoid Acid-Induced Neural Differentiation through Increasing Mitochondrial Function.

Histone acetylation and mitochondrial function contribute importantly to neural differentiation, which is critically associated with neurodevelopmental disorders such as Down Syndrome (DS). However, whether and how histone acetylation regulates mitochondrial function and further affects neural differentiation has not been well described. In this study, when treated with retinoid acid (RA), the human neuroblastoma SH-SY5Y cell line was used as a neural differentiation model. We found that the acetylation of histone H3, especially H3 lysine 14 acetylation (H3K14ac), and mitochondrial function, including biogenesis and electron transport chain, were enhanced during neural differentiation. Specific inhibition of histone acetyltransferases (HATs) induced neural differentiation deficits, accompanied by downregulation of mitochondrial function. Furthermore, RA receptors (RARs) interacting with HATs were involved in the increased H3K14ac and the enhanced mitochondrial function during the neural differentiation process. Finally, receptor-interacting protein 140 (RIP140), a co-repressor of RARs, was also involved in regulating histone acetylation. RIP140 overexpression inhibited histone acetylation and mediated negative feedback on target genes which are involved in RA signaling. These findings evidenced that when interacting with RARs which had been negatively regulated by RIP140, RA promoted neural differentiation by promoting H3K14ac and enhanced mitochondrial function. This provides a molecular foundation for further investigations into abnormal neural development.

[Evaluation of Efficacy and Prognosis Analysis of Stage III-IV SMARCA4-deficient 
Non-small Cell Lung Cancer Treated by PD-1 Immune Checkpoint Inhibitors plus 
Chemotherapy and Chemotherapy].

BACKGROUND: The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC. METHODS: 46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC. RESULTS: Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC. CONCLUSIONS: Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.

Diagnostic efficacy of metagenomic next generation sequencing in bronchoalveolar lavage fluid for proven invasive pulmonary aspergillosis.

Objective: To assess the diagnostic efficacy of metagenomic next generation sequencing (mNGS) for proven invasive pulmonary aspergillosis (IPA). Methods: A total of 190 patients including 53 patients who had been diagnosed with proven IPA were retrospectively analyzed. Using the pathological results of tissue biopsy specimens as gold standard, we ploted the receiver operating characteristic (ROC) curve to determine the optimal cut-off value of mNGS species-specific read number (SSRN) of Aspergillus in bronchoalveolar lavage fluid (BALF)for IPA. Furthermore, we evaluated optimal cut-off value of mNGS SSRN in different populations. Results: The optimal cut-off value of Aspergillus mNGS SSRN in BALF for IPA diagnosis was 2.5 for the whole suspected IPA population, and 1 and 4.5 for immunocompromised and diabetic patients, respectively. The accuracy of mNGS was 80.5%, 73.7% and 85.3% for the whole population, immunocompromised and diabetic patients, respectively. Conclusions: The mNGS in BALF has a high diagnostic efficacy for proven IPA, superioring to Aspergillus culture in sputum and BALF and GM test in blood and BALF. However, the cut-off value of SSRN should be adjusted when in different population.

Research on the dynamic evolution and convergence of collaborative capacity of pollution control and carbon reduction: from the perspective of whole-process governance.

Under the strategic goals of achieving peak carbon neutrality, deepening the battle against pollution, and building a beautiful China, improving the collaborative capacity of pollution control and carbon reduction is an important means to achieve comprehensive green and low-carbon transformation of the social economy. Starting from the essential requirements of improving the collaborative capacity of pollution control and carbon reduction, based on the whole-process governance perspective of "source-process-end-of-pipe," build an evaluation index system, measure the collaborative capacity, quantify the spatial differences, analyze the evolution characteristics, and explore the improvement path. The study found that China's collaborative capacity of pollution control and carbon reduction is characterized by homogeneous agglomeration and unbalanced regional development. Intra-regional differences are the main source of the differences, sorting by contribution is "Eastern > Western > Central > Northeast." After taking into account the factors of green transformation of industry, the input of scientific and technological elements, and opening to the outside world, the differences have gradually narrowed. Among them, the green transformation of industry is instrumentally in bridging the gap in eastern, central, and northeastern, the input of scientific and technological elements is instrumentally in bridging the gap between regions and the eastern and northeast, and opening to the outside world is instrumentally in bridging the gap between regions and the western. The scientific measurement and improvement of this capacity will provide the factual basis and path choice for achieving the task goal of "significantly improving China's collaborative capacity of pollution control and carbon reduction by 2030," which is of great practical significance for building a higher-quality, more sustainable, and greener pattern of the collaborative capacity of pollution control and carbon reduction.

Analysis of the Current Situation and Factors Influencing the Clinical Thinking Ability of Nursing Undergraduates.

Context: Clinical thinking encompasses the critical analysis, judgment, and decision-making pertaining to the existing or potential nursing problems of patients. It plays a pivotal role in effectively executing clinical nursing work in alignment with the prescribed nursing procedures. Proficient clinical thinking empowers nurses with the capability to identify, analyze, and resolve problems. Objective: The study intended to investigate the current situation of clinical thinking ability of nursing students and its influencing factors, so as to improve their clinical thinking ability. Methods: This was a cross-sectional study and the research took place at Taizhou University in Taizhou, Zhejiang province, China in the Faculty of Nursing. 143 full-time undergraduate nursing students at the University were selected for the cross-sectional survey, including a general questionnaire and a clinical thinking ability questionnaire for undergraduate nursing students. The respondents included nursing students in their sophomore, junior and senior years. Results: The survey results obtained between the first and the third year of study were included. Age of the participants ranged from 18 to 24 years, with an average age of 21.58 ± 2.45 years. The professional knowledge score of undergraduate nursing students in this survey was found to be 52.59 ± 13.93; ​the score of professional emotion was 14.21 ± 2.40; ​the score of professional will was 19.51 ± 2.15; ​the score of professional values was 14.40 ± 2.31; ​the professional skill score was 18.52 ± 2.06; the professional expectation was found to be 12.73 ± 1.30; and ​the total score was (99.26 ± 7.96). All dimensions and total scores of clinical ability of thinking among undergraduate nursing students in this survey were found to be average. Conclusions: Clinical thinking of undergraduate nursing students is found to be of a medium level, and the main influencing factors are grade and the satisfaction of teachers. Nursing colleges and practice hospitals should unite to adopt various ways to help nursing undergraduates cultivate and improve their clinical thinking ability.

Phosphorylated Ser187-SNAP25-modulated hyperfunction of glutamatergic system in the vmPFC mediates depressive-like behaviors in male mice.

Dysfunctional glutamatergic neurotransmission contributes importantly to the pathophysiology of depression. However, the underlying neural mechanisms of glutamatergic dysfunction remain poorly understood. Here, we employed chronic unpredictable mild stress (CUMS) to induce depression-like behavior in male mice and to assess the alterations of glutamatergic system within the ventromedial prefrontal cortex (vmPFC). Male mice subjected to CUMS showed an increase in levels of glutamate content, synaptosomal GluN2B-NMDA receptors (GluN2B-NMDARs) and phosphorylated synaptosomal associated protein 25 KD of Ser187 (pSer187-SNAP25), which is involved in synaptic vesicular fusion processes in the vmPFC. Downregulation of pSer187-SNAP25 via the TAT-S187 fusion peptide efficiently alleviated CUMS-induced depressive-like behaviors in male mice by reversing the increase of glutamate content and synaptosomal GluN2B-NMDARs. These findings demonstrated a critical role for pSer187-SNAP25-mediated glutamatergic dysfunction in CUMS-induced depressive-like behaviors, suggesting the potential of pS187-SNAP25 inhibitors for further investigation on depression management.

[Correlation Analysis between Thyroid Function Abnormality and Efficacy in Patients 
with Advanced Non-small Cell Lung Cancer after Immunotherapy].

BACKGROUND: Thyroid function abnormality (TFA) is one of the common adverse reactions in patients with advanced non-small cell lung cancer (NSCLC) treated with immunotherapy, but the risk factors of TFA and its relationship with efficacy are not completely clear. The purpose of this study was to explore the risk factors of TFA and its relationship with efficacy in patients with advanced NSCLC after immunotherapy. METHODS: The general clinical data of 200 patients with advanced NSCLC in The First Affiliated Hospital of Zhengzhou University from July 1, 2019 to June 31, 2021 were collected and analyzed retrospectively. χ² test and multivariate Logistic regression were used to explore the risk factors of TFA. Kaplan-Meier curve was drawn and Log-rank test was used for comparison between groups. Univariate and multivariate Cox analysis was used to explore the efficacy factors. RESULTS: A total of 86 (43.0%) patients developed TFA. Logistic regression analysis showed that Eastern Cooperative Oncology Group Performance Status (ECOG PS), pleural effusion and lactic dehydrogenase (LDH) were factors influencing TFA (P<0.05). Compared with normal thyroid function group, the median progression-free survival (PFS) of patients in the TFA group was significantly longer (19.0 months vs 6.3 months, P<0.001), and the objective response rate (ORR) (65.1% vs 28.9%, P=0.020) and disease control rate (DCR) (100.0% vs 92.1%, P=0.020) of the TFA group were better than those of the normal thyroid function group. Cox regression analysis showed that ECOG PS, LDH, cytokeratin 19 fragment (CYFRA21-1) and TFA were factors influencing prognosis (P<0.05). CONCLUSIONS: ECOG PS, pleural effusion and LDH may be risk factors affecting the occurrence of TFA and TFA may be a predictor of the efficacy of immunotherapy. Patients with advanced NSCLC who have TFA after immunotherapy may obtain better efficacy.

Zebrafish ppp1r21 mutant as a model for the study of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease that progresses to fibrosis and cirrhosis, resulting from the gradual destruction of intrahepatic bile ducts. Exploring genetic variants associated with PBC is essential to understand the pathogenesis of PBC. Here we identify a zebrafish balloon dog (blg) mutant with intrahepatic bile duct branching defects, exhibiting several key pathological PBC-like features, including immunodominant autoantigen PDC-E2 production, cholangiocyte apoptosis, immune cell infiltration, inflammatory activation, and liver fibrosis. blg encodes the protein phosphatase 1 regulatory subunit 21 (Ppp1r21), which is enriched in the liver and its peripheral tissues and plays a vital role in the early intrahepatic bile duct formation stage. Further studies show an excessive activation of the PI3K/AKT/mTOR pathway in the hepatic tissues in the mutant, while treatment with the pathway inhibitor LY294002 and rapamycin partially rescues intrahepatic bile duct branching defects and alleviates the PBC-like symptoms. These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.

Possible genetic cross-talk between Down syndrome and obstructive sleep apnea revealed by transcriptomic analysis.

PURPOSE: Down syndrome (DS) is linked to a higher prevalence of obstructive sleep apnea (OSA) than in the general population, which in turn contributes to worse cognitive impairment in DS. However, the shared pathogenic mechanisms for DS and OSA remain incompletely illustrated. This study was designed to decipher the genetic cross-talk between DS and OSA by bioinformatics approach. METHODS: Transcriptomic datasets of DS (GSE59630) and OSA (GSE135917) were accessed from the Gene Expression Omnibus (GEO) repository. After screening out the common differentially expressed genes (DEGs) for DS and OSA, gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out. A protein-protein interaction (PPI) network was then constructed to determine essential modules and hub genes. Finally, based on hub genes, transcriptional factor (TF)-gene interaction and TF-miRNA regulatory networks were constructed. RESULTS: DS and OSA showed 229 DEGs. Functional analyses revealed how oxidative stress and inflammatory response were critical in the progression of DS and OSA. Ten significant hub genes were identified, including TLR4, SOD1, IGF1, FGF2, NFE2L2, PECAM1, S100A8, S100A9, FCGR3A, and KCNA1, which were candidate targets for DS and OSA. CONCLUSIONS: We found that DS and OSA display similarities in their pathogenesis. Key genes and signaling pathways revealed to be in common between the two conditions could lead us to new therapeutic targets for DS and OSA.

Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design.

Selective CDK2 inhibitors have the potential to provide effective therapeutics for CDK2-dependent cancers and for combating drug resistance due to high cyclin E1 (CCNE1) expression intrinsically or CCNE1 amplification induced by treatment of CDK4/6 inhibitors. Generative models that take advantage of deep learning are being increasingly integrated into early drug discovery for hit identification and lead optimization. Here we report the discovery of a highly potent and selective macrocyclic CDK2 inhibitor QR-6401 (23) accelerated by the application of generative models and structure-based drug design (SBDD). QR-6401 (23) demonstrated robust antitumor efficacy in an OVCAR3 ovarian cancer xenograft model via oral administration.

Profiling Blautia at high taxonomic resolution reveals correlations with cognitive dysfunction in Chinese children with Down syndrome.

Introduction: Down syndrome (DS), the presence of a supernumerary chromosome 21, is associated with cognitive dysfunction caused by early neurodegenerative processes. Alterations in the gut microbiota were observed in Chinese children with DS, and the genus Blautia was associated with cognitive function in these children. Therefore, it is crucial to understand the detailed composition of this group at the species level and to explore the effect of specific species on cognitive function. Methods: In this study, Blautia-specific amplicon sequencing was conducted to identify the specific Blautia species in 15 children with DS and 15 matched healthy children. Results: The taxonomic analyses suggested that the Blautia taxa were clustered by disease status. The diversity of Blautia at the species level differed between DS patients and healthy controls, with the abundances of Blautia massiliensis and Blautia argi decreasing in DS children, while Blautia faecis was increased. Acetic acid, one of the metabolites of Blautia, was significantly reduced in the DS group. Of particular interest, Kyoto Encyclopaedia of Genes and Genomes analysis revealed decreased modules related to starch and sucrose metabolism and glycolysis. In addition, B. argi was positively related to DS cognitive scores, and B. faecis was negatively related to cognitive function, implying its role on the DS cognitive impairments. Discussion: Our study has important implications for understanding the important effects of specific species of Blautia on cognitive function and thus possibly provides a new strategy for future studies of cognitive improvement in individuals with DS.

Trait creativity, personality, and physical activity: a structural equation model.

BACKGROUND: Previous studies have shown that personality affects creativity, and physical activity and is associated with cognitive function. However, the relationship among physical activity, creativity, and personality remains unclear. This study sought to examine the relationship among personality, physical activity, and creativity to identify relevant risk factors of trait creativity. Structural equation modeling (SEM) was used to assess the effect of personality (extraversion, agreeableness, conscientiousness, neuroticism, and openness) on physical activity, the effect of physical activity on creativity traits. METHODS: A total of 296 university students were recruited for this study. The survey was administered by WeChat. The self-reported questionnaires included questions related to demographic information, creativity (from the Williams Creativity Assessment Packet), the Big Five personality traits, and physical activity. A correlation analysis was conducted and the structural equation models were constructed using SPSSAU. RESULTS: The SEM analysis showed that openness in personality was positively correlated with physical activity. Physical activity was negatively correlated with curiosity, challenging, risk-taking, and imagination. CONCLUSIONS: Among university students, openness may be a profound positive factor affecting physical activity. Moreover, physical activity was also associated with trait creativity. Consideration should be given to assessing personality traits and physical activity to ensure the selection of more creative students.

Oxygen Therapy Confers Little Benefit in Patients with Acute ST-Segment Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis.

Objective: We aimed to investigate the clinical benefit of oxygen therapy in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods: We searched PubMed, Embase and the Cochrane Library from database inception to June 2020 to identify randomized controlled trials (RCTs) on oxygen therapy in acute STEMI. Literature screening, data extraction and study quality assessment were independently carried out by the 2 investigators according to the predefined eligibility criteria, and RevMan 5.3 analysis software was utilized for all analyses. Results: Finally, 5 RCTs with a total of 4824 patients with STEMI were eligible for further meta-analysis. The RCT results demonstrated that oxygen therapy exerted non-significant effects in reducing the risks for short-term all-cause mortality (risk ratio [RR] = 1.21; 95% CI, 0.80-1.53; P = .53), cardiac arrest (RR = 1.20; 95% CI, 0.94-1.54; P = .79), recurrent myocardial infarction (MI) (RR = 0.68; 95% CI, 0.43-1.08; P = .10) and cardiogenic shock (RR = 0.81; 95% CI, 0.58-1.15; P = .24) and the incidence of other outcome indicators of acute STEMI. Conclusions: Oxygen therapy does not provide more benefits than adverse effects in patients with acute STEMI. Personalized oxygen treatment based on dynamic oxygen saturation is recommended in patients with hypoxia. Supplemental oxygen in patients with acute STEMI has no effect on reducing infarct size, and has no benefit in all-cause mortality, cardiogenic shock, etc.

Current Situation and Factors Influencing the Disaster Response Capability of Undergraduate Nursing Students.

Context: China is a country in which frequent natural disasters occur, but there is a lack of disaster education in Chinese institutions of higher education. Nursing students should receive disaster and emergency training in addition to their professional medical training. Objective: Our study aimed to investigate the current situation and disaster knowledge and training needs of nursing students and to increase the disaster first aid knowledge of college nursing students. Design: This was a cross-sectional study. Setting: The study took place at Taizhou University in Taizhou, Zhejiang, China. Participants: Participants were 443 full-time undergraduate nursing students at Taizhou University in China. Outcome Measures: This cross-sectional survey included a general questionnaire and an undergraduate nursing student disaster nursing ability questionnaire. Results: The survey results were from the first to the third year of study. Students were age 20 to 23 years, with an average age of 20.57±1.85 years. The largest group (35.44%) was made up of juniors. The scores of 3 dimensions of this survey were: dimension of physical and mental quality dimension (3.76 ± 0.71), theoretical system dimension (3.00 ± 0.57) and practical competencies dimension (2.89 ± 0.68). The ability to adapt to rescue needs at the disaster site and whether or not the student had heard of the term "disaster nursing" is the dominant factor affecting the disaster nursing skills of undergraduate nursing students. Conclusions: The disaster relief of male undergraduate nursing student seniors is more positive and their physical and mental quality is better than female nursing students, but knowledge of disaster prevention and practical capability in disaster relief remain weak and there is a lack of a corresponding theoretical system and competence in practical knowledge and skills. It is recommended that systematic disaster nursing education at universities be improved. Knowledge of disaster rescue should be taught systematically to improve awareness of disaster procedures and response and improve the level of practical skills in disaster rescue. We should learn from the educational approach and models of disaster nursing training in developed countries in order to establish a disaster nursing education model in China.

[Predictive Value of LIPI and iSEND Immune Scoring System 
in Immunotherapy of Advanced Non-small Cell Lung Cancer].

BACKGROUND: This study retrospectively analyzed the application value of lung cancer immunotherapy prognostic index (LIPI) and iSEND immune scoring system in advanced non-small cell lung cancer (NSCLC) patients treated with immunotherapy in China, in order to find guidance for clinical development of NSCLC treatment plan. METHODS: The clinical data of 178 patients with advanced NSCLC treated with immunotherapy were analyzed retrospectively. LIPI and iSEND immune scores were performed, receiver operating characteristic (ROC) curves were drawn, and the predictive values of two models for objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) were compared. Kaplan-Meier method was used for survival analysis, and Cox regression analysis method was used for univariate analysis and multivariate analysis. RESULTS: The area under the curver (AUC) of ORR, DCR and PFS predicted by iSEND immune score were 0.616, 0.634 and 0.631 respectively; LIPI were 0.789, 0.750 and 0.732 respectively, which were higher than iSEND immune score (P<0.05). The median PFS of patients in LIPI score groups 0, 1 and 2 were 9.9 months, 6.1 mon and 3.7 mon respectively; The median PFS of patients with good, moderate and poor iSEND immune scores were 9.9 mon, 7.0 mon and 3.5 mon respectively, with statistically significant differences (P<0.001). In the immunotherapy subgroup, the median PFS of patients with different LIPI and iSEND immune scores was also statistically significant. Cox regression analysis showed that the derived neutrophil to lymphocyte ratio (dNLR), lactic dehydrogenase (LDH) and PFS were independently correlated (P<0.05). CONCLUSIONS: LIPI and iSEND immune scoring system can effectively predict the efficacy and prognosis of advanced NSCLC treated with immunotherapy, and LIPI has higher predictive value than iSEND immune scoring system.

Colitis and colorectal tumors should be further explored and differentiated.

The original article by Yuichi et al explored whether the Japan Narrow-Band Imaging Expert Team classification and the pit pattern classification are suitable for diagnosing neoplastic lesions in patients with ulcerative colitis. In this letter, we offer some other perspectives. Risk factors for colorectal tumors include type 2 diabetes. Among genetic factors, the deletion or mutation of some genes, such as the p53 gene, can lead to colorectal tumors. There are significant gender differences in the occurrence and development of colorectal tumors. Some non-genetic factors, such as smoking, are also associated with the development of colorectal tumors. These all suggest that colorectal tumors are not only caused by ulcerative colitis, and we suggest further exploration and differentiation between colitis and colorectal tumors.

Exosomal circWDR62 promotes temozolomide resistance and malignant progression through regulation of the miR-370-3p/MGMT axis in glioma.

Exosome-mediated delivery of circular RNAs (circRNAs) is implicated in cancer progression. However, the role of exosomal circRNAs in the chemotherapy resistance of tumours remains poorly understood. Here we identified a novel circRNA, circWDR62. It was found that circWDR62 expression was upregulated in TMZ-resistant glioma cells and TMZ-resistant glioma cell-derived exosomes compared with their controls by using high-throughput microarray analysis and quantitative real-time polymerase chain reaction, and high circWDR62 expression was associated with poor prognosis of glioma. Functionally, downregulation of circWDR62 expression could significantly inhibit the TMZ resistance and malignant progression of glioma. Further mechanistic studies showed that circWDR62 plays a role by sponging miR-370-3p as a competing endogenous RNA. Rescue experiments confirmed that MGMT is the downstream target of the circWDR62/miR-370-3p axis in glioma. In addition, circWDR62 could be transported between TMZ-resistant and TMZ-sensitive glioma cells via exosomes. Exosomal circWDR62 from TMZ-resistant cells conferred TMZ resistance in recipient sensitive cells while also enhancing the proliferation, migration and invasion of these cells. A series of clinical and in vivo trials corroborated that exosomal circWDR62 could promote TMZ chemoresistance and malignant progression of glioma. Our results demonstrate for the first time that exosome-mediated delivery of circWDR62 can promote TMZ resistance and malignant progression via targeting of the miR-370-3p/MGMT axis in vitro and in vivo in glioma, providing a new therapeutic strategy. Moreover, exosomal circWDR62 in human serum may serve as a promising therapeutic target and prognostic marker for glioma therapy.

Fuzhuan brick tea affects obesity process by modulating gut microbiota.

The effect of Fuzhuan brick tea (FBT) on metabolism in obese mice is mediated by regulation of N-methyltransferase by aryl hydrocarbon receptor. The expression of the phosphatidylethanolamine N-methyltransferase gene is regulated by many transcription factors, and those specific to this effect need further investigation. Experimental animal studies have been designed to observe the effects of a single drug or the sequential effects of drugs. A washout period should be included if different drugs (e.g., antibiotics and FBT) are given to avoid or reduce additive effects or synergy. Currently, most experimental studies performed in mice used only male animals. However, experience has revealed that the results of using only male mice are very likely to have sex differences.