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Aims Low caspofungin exposure is frequently encountered in patients with invasive candidiasis caused by Candida albicans. This study aimed to investigate the effects of caspofungin on C. albicans at sub-inhibitory concentrations. Methods and Results First, a comparative transcriptomics analysis was performed on C. albicans receiving caspofungin at sub-minimum inhibitory concentrations (sub-MICs). The results showed that caspofungin significantly changed the mRNA expression profile in DAY185, with DE-mRNAs enriched in the functions of cell wall biosynthesis, metabolism, etc. Subsequently, cellular fitness, cell aggregation, energy metabolism activity and the proportion of persister cells of C. albicans were quantitatively and/or qualitatively assessed after sub-MIC caspofungin exposure. No significant changes in cell fitness and aggregation formation were observed during treatment of C. albicans with sub-MIC caspofungin. In C. albicans aggregation treated with sub-MIC caspofungin, we observed a decrease in respiratory metabolism and an increase in persister cells; this effect was more pronounced in als1ΔΔ than in DAY185. Conclusions Pre-exposure to sub-MIC caspofungin suppresses C. albicans respiratory metabolism and promotes persister cell development. Significance and Impact of the Study Caspofungin should be used with caution in patients with C. albicans infections, as anti-infection therapy may fail due to persister cells.

Irregular hemorrhagic traumas always threaten the health of patients due to uncontrollable bleeding and wound infections. The traditional hemostatic materials show dissatisfactory hemostatic efficiency and antibacterial activity in solving these potential bleeding dangers. Herein, we proposed a kind of composites based on flexible wood membrane (FWM) loaded with chitosan/alginate derivative for accelerating rapid hemostasis and preventing infection. FWM was removed part of hemicellulose and lignin by using NaOH/Na

TP53 mutations correlate with inferior survival in many cancers. APR-246 is a compound to shift mutant p53 and exhibits anti-cancer effects. Among its effects, APR-246 facilitates the binding of restored p53 mutants to target genes and their transcription. A set of 2464 DLBCL cases from multiple cohorts including our center, was integrated to identify the type and localization of TP53 mutations and clinical impacts. APR-246 was applied in TP53-mutated DLBCL cells and xenograft mouse models to explore the anti-tumor effect. TP53 mutations frequency was 16% and TP53 mutations correlated with poor overall survival (OS) and progression-free survival (PFS) in all cases, especially in germinal center B-cell-like (GCB) and unclassified (UNC) subtypes. Notably, TP53 single mutations in the DNA binding domain (DBD) led to poor OS and PFS. Specifically, mutations in exon 7 correlated with poorer OS, while mutations in exons 5 and 6 associated with inferior PFS. APR-246 induces p53-dependent ferritinophagy of DLBCL cells with TP53 missense mutation on exon 7 and ferroptosis of DLBCL cells harboring wild-type TP53 and other TP53 mutations. TP53 mutations on exons 5, 6 and 7 are predictors of progression and survival. Targeting mutant p53 by APR-246 is a promising therapeutic approach for DLBCL patients.

Endoplasmic reticulum (ER) stress contributes to the pathogenesis of chronic liver diseases, but how hepatocytes respond to ER stress has not been clarified. Alpha-fetoprotein (AFP) is secreted by hepatoma cells and elevated levels of serum AFP are associated with development of liver malignancies.To investigate whether and how AFP could regulate ER stress and hepatocyte injury.The distribution of AFP and the degrees of ER stress in liver tissues and liver injury were characterized by histology, immunohistochemistry, and Western blot in biopsied human liver specimens, two mouse models of liver injury and a cellular model. The levels of AFP in sera and the supernatants of cultured cells were quantified by chemiluminescence.High levels of intracellular AFP were detected in liver tissues, particularly in the necrotic areas, from patients with chronic liver diseases and mice after carbon tetrachloride (CClER stress upregulated intra-hepatocyte AFP expression by activating ATF6 during the process of liver injury and intracellular AFP attenuated hepatocyte apoptosis and necroptosis by alleviating ER stress.

Aims: The purpose was to investigate the correlation between calcification and outcome in metastatic colorectal cancer (mCRC) patients who received bevacizumab plus chemotherapy as the first-line treatment. Methods: A single retrospective cohort study was conducted with all diagnosed mCRC cases who received bevacizumab and chemotherapy as the first-line therapy. Results: Among all enrolled patients (n = 159), 31 had tumor calcification. The median overall survival and progression-free survival were significantly better in patients with tumor calcification than in those without calcification. A higher objective overall response rate was also observed in the tumor calcification group. On multivariate analysis, tumor calcification was independently associated with overall survival and progression-free survival. Conclusions: Tumor calcification was independently associated with improved survival in mCRC patients treated with bevacizumab plus chemotherapy.

Employee safety behavior is a basic element of enterprise work safety. The results of accident investigations and risk assessments in enterprises indicate that management factors are some of the most important factors that affect employee safety behavior. The purpose of this study is to explore the relationship between the behavior of front-line managers (FLMs) and employee safety behavior by integrating a qualitative method, i.e., the interpretive structural model (ISM), and a quantitative method, i.e., the Bayesian network (BN). The results of the BN analysis showed that safety incentives and safety communication were the best predictors of safety participation, while safety supervision and safety control were the best predictors of safety compliance. Moreover, the results revealed that an instantaneous improvement of safety communication, safety incentives, safety supervision and safety guidance was the most effective joint measure to reach a high-level of safety behavior of employees in the workplace.

Lung adenocarcinoma (LUAD) remains the most common deadly disease and has a poor prognosis. More and more studies have reported that mitochondrial-related genes (MTRGs) were associated with the clinical outcomes of multiple tumors solely. In this study, we aimed to develop a novel prognostic model based on MTRGs. Differentially expressed MTRGs were identified from TCGA-LUAD and GSE31210 cohorts. Univariate Cox regression analysis was utilized to screen differentially expressed MTRGs that were related to prognosis of LUAD. Then, LASSO Cox regression analysis was used to develop a prognostic signature. ESTIMATE was used for estimating the fractions of immune cell types. In this study, we identified 44 overlapping differentially expressed MTRGs in TCGA-LUAD and GSE31210 cohorts. Among 44 overlapping differentially expressed MTRGs, nine genes were associated with prognosis of LUAD. When the penalty parameter lambda was the minimum, there were six genes meeting the conditions of constructing the signature, including SERPINB5, CCNB1, FGR MAOB, SH3BP5, and CYP24A1. The survival analysis suggested that prognosis of patients in the high-risk group was significantly worse than that in the low-risk group. Cox regression analyses showed that the risk score was an independent predictor of LUAD prognosis. As with the results of ESTIMATE score, the degree of immune cell infiltration in the low-risk group was higher than that in the high-risk group, such as TIL, Treg, and B cells. In addition, TMB and cancer stem cell infiltration were higher in the low-risk group than the high-risk group. In conclusion, we developed a novel MTRG signature acting as a negative independent prognostic factor. In the future, individualized treatments and medical decision-making may benefit from using the predicted model.

Nonsuicidal self-injury (NSSI) is prevalent in adolescents and is often linked to emotion dysregulation. However, it remains unknown which specific processes of emotion regulation and under what emotional context these processes are related to the risk for NSSI in samples of community-based adolescents. This study used two laboratory tasks to examine whether adolescents with a history of NSSI displayed difficulties in emotional reactivity and inhibitory control in response to negative and positive emotions. In Study 1, adolescents with/without a history of NSSI (N = 64; M

BACKGROUND AND OBJECTIVES: Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of renal significance (MGRS) due to the presence of monoclonal Ig–related kidney injuries. This study aimed to investigate the histopathologic spectrum and clinical characteristics associated with MGRS in a large cohort of patients with monoclonal gammopathy and biopsy-proven kidney diseases from a single Chinese nephrology referral center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients who presented with monoclonal gammopathy (monoclonal spike on serum and/or urine immunofixation tests) and underwent kidney biopsy in the Peking University First Hospital from January 1, 1999 to December 31, 2020 were enrolled in this retrospective study. Patients with malignant hematologic diseases were excluded. Clinical and laboratory data were collected from the electronic medical record system. Comparisons of patients with and without MGRS and with and without amyloidosis were performed. The clinical characteristics associated with MGRS were identified using multivariable logistic regression. RESULTS: A total of 700 patients with monoclonal gammopathy and kidney biopsy were identified. Thirteen patients with repeat kidney biopsies were analyzed separately. For the remaining 687 patients with one kidney biopsy, 261 patients (38%) had MGRS lesions, and the rest (426 patients, 62%) had non-MGRS kidney diseases. Ig-related amyloidosis accounted for the most MGRS cases (n=164, 63%), followed by monoclonal Ig deposition disease (n=23, 9%) and thrombotic microangiopathy (n=22, 8%). In the non-MGRS group, membranous nephropathy was the most common diagnosis (n=171, 40%). In the multivariable logistic regression model, the presence of abnormal serum free light chain ratio, older age, and greater proteinuria were independently associated with MGRS. CONCLUSIONS: Monoclonal Ig amyloidosis is the leading cause of MGRS in Chinese patients with monoclonal gammopathy. The presence of abnormal free light chain ratio, older age, and greater proteinuria were associated with MGRS.

Intracerebral hemorrhage (ICH) is a common subtype of stroke and places a great burden on the family and society with a high mortality and disability rate and a poor prognosis. Many findings from imaging and pathologic studies have suggested that cerebral ischemic lesions visualized on diffusion-weighted imaging (DWI) in patients with ICH are not rare and are generally considered to be associated with poor outcome, increased risk of recurrent (ischemic and hemorrhagic) stroke, cognitive impairment, and death. In this review, we describe the changes in cerebral blood flow (CBF) and DWI lesions after ICH and discuss the risk factors and possible mechanisms related to the occurrence of DWI lesions, such as cerebral microangiopathy, cerebral atherosclerosis, aggressive early blood pressure lowering, hyperglycemia, and inflammatory response. We also point out that a better understanding of cerebral DWI lesions will be a key step toward potential therapeutic interventions to improve long-term recovery for patients with ICH.

Background: Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer’s disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. Objective: The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD + CAA mice model. Methods: In the present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. Results: Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-β deposition through PAR-1/PAR-2 inhibition in the AD + CAA mice model compared with warfarin and no-treatment groups. Conclusion: The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD.

The present study aimed to explore the difference in the brain function and structure between patients with major depressive disorder (MDD) and healthy controls (HCs) using two-center and multi-modal MRI data, which would be helpful to investigate the pathogenesis of MDD.The subjects were collected from two hospitals. One including 140 patients with MDD and 138 HCs was used as primary cohort. Another one including 29 patients with MDD and 52 HCs was used as validation cohort. Functional and structural magnetic resonance images (MRI) were acquired to extract four types of features: functional connectivity (FC), amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and gray matter volume (GMV). Then classifiers using different combinations among the four types of selected features were respectively built to discriminate patients from HCs. Different templates were applied and the results under different templates were compared.The classifier built with the combination of FC, ALFF, and GMV under the AAL template discriminated patients from HCs with the best performance (AUC=0.916, ACC=84.8%). The regions selected in all the different templates were mainly located in the default mode network, affective network, prefrontal cortex.First, the sample size of the validation cohort was limited. Second, diffusion tensor imaging data were not collected.The performance of classifier was improved by using multi-modal MRI imaging. Different templates would be suitable for different types of analysis. The regions selected in all the different templates are possibly the core regions to investigate the pathophysiology of MDD.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the SARS-coronavirus 2(SARS-CoV-2) virus has become the greatest global public health crisis in recent years,and the COVID-19 epidemic is still continuing. However, due to the lack of effectivetherapeutic drugs, the treatment of corona viruses is facing huge challenges. In thiscontext, countries with a tradition of using herbal medicine such as China have beenwidely using herbal medicine for prevention and nonspecific treatment of corona virusesand achieved good responses. In this review, we will introduce the application of herbalmedicine in the treatment of corona virus patients in China and other countries, andreview the progress of related molecular mechanisms and antiviral activity ingredients ofherbal medicine, in order to provide a reference for herbal medicine in the treatment ofcorona viruses. We found that herbal medicines are used in the prevention and fightagainst COVID-19 in countries on all continents. In China, herbal medicine has beenreported to relieve some of the clinical symptoms of mild patients and shorten the length of hospital stay. However, as most herbal medicines for the clinical treatment of COVID-19still lack rigorous clinical trials, the clinical and economic value of herbal medicines in theprevention and treatment of COVID-19 has not been fully evaluated. Future work basedon large-scale randomized, double-blind clinical trials to evaluate herbal medicines andtheir active ingredients in the treatment of new COVID-19 will be very meaningful.

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; P < .001) and deep response (OR, 0.3; 95% CI, 0.2-0.6; P = .001). CXCR4 mutations (hazard ratio [HR], 2.0; 95% CI, 1.2-3.4; P = .01) and platelet count 100 K/uL or less (HR, 2.5; 95% CI, 1.3-4.9; P = .007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these 2 factors. The median PFS for patients with 0, 1, and 2 risk factors were not reached, 5 years and 3 years (P < .001). Patients with 2 risk factors had HR 2.2 (95% CI, 1.3-3.8; P = .004) compared with 1 factor, and patients with 1 factor had HR 2.3 (95% CI, 1.1-5.1; P = .03) compared with 0 factors. Age ≥65 years was the only factor associated with overall survival (HR, 3.2; 95% CI, 1.4-7.0; P = .005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy.

Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anti-cancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anti-cancer T cell functions.

BACKGROUND Thyroid functions (TFs) have been implicated in the initiation and propagation of psychiatric disorders. Observational studies have shown associations of TFs with psychiatric disorders. However, the relationship between TFs and psychiatric diseases were still unclear. METHODS Genetic instruments for 6 TF-realted indexes, including free thyroxine (FT4), triiodothyronine (FT3):FT4 ratio, thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb) concentration, hypothyroidism, and hyperthyroidism, were obtained from several genome-wide association studies (GWASs). Their associations with BD were evaluated using Psychiatric Genomics Consortium (PGC) datasets (41,917 cases and 371,549 controls). All GWAS summary statitics were from European ancestry. Mendelian randomization (MR) estimates from each genetic instrument were combined using inverse variance weighted (IVW) meta-analysis, with complementary methods (eg, weighted median and MR Egger). We also multiple sensitivity analyses to examine horizontal pleiotropy and heterogeneity. RESULTS Genetically predicted level of FT4 was significantly associated with BD (odds ratio (OR)=0.89, 95% confidence interval (CI): 0.83-0.95; P=4.65 × 10-3), survived after the Bonferroni correction (P

BACKGROUND: Cronkhite–Canada syndrome (CCS) is a disease of unknown etiology characterized by the presence of multiple gastrointestinal polyps, chronic diarrhea, loss of appetite, alopecia, onychodystrophy, and cutaneous hyperpigmentation. CCS is a rare disease with an incidence rate of 1 per million. Clinicians are not aware of this disease, and the discovery of gastrointestinal polyps is often a starting point for the diagnosis of this disease. By analyzing the endoscopic and pathological characteristics of CCS, this study aims to deepen our understanding of gastrointestinal polyposis and facilitate early diagnosis of CCS. METHODS: We screened databases, including the Chinese Biomedical Literature Database (CBM Web), the China Academic Journals Full-text Database (CJFD), and PubMed for CCS cases reported from January 2010 to January 2020, and conducted a retrospective analysis of endoscopic and pathological characteristics of these cases. RESULTS: The endoscopic data of the 76 retrieved cases revealed that CCS is gastrointestinal polyposis with the intensive and confluent distribution. The greater the number of polyps and the higher their distribution, the brighter their color. A pathological assessment revealed that both gastric polyps and intestinal polyps are mainly juvenile hamartomatous polyps and have a high malignant transformation rate. Interstitial edema, eosinophil infiltration, and cystic dilation of glands are common features of CCS polyps, distinguishing them from other gastrointestinal polyposis syndromes. CONCLUSION: CCS is a polyp disease different from other gastrointestinal polyposis. Analysis of its endoscopic and pathological characteristics can contribute to the understanding and early diagnosis of the disease.

Entropy is a measurement of brain signal complexity. Studies have found increased/decreased entropy of brain signals in psychiatric patients. There is no consistent conclusion regarding the relationship between the entropy of brain signals and mental illness. Therefore, this meta-analysis aimed to identify consistent abnormalities in the brain signal entropy in patients with different mental illnesses. We conducted a systematic search to collect resting-state functional magnetic resonance imaging (rs-fMRI) studies in patients with psychiatric disorders. This work identified 9 eligible rs-fMRI studies, which included a total of 14 experiments, 67 activation foci, and 1383 subjects. We tested the convergence across their findings by using the activation likelihood estimation method. P-value maps were corrected by using cluster-level family-wise error p 0.05 and permuting 2000 times. Results showed that patients with different psychiatric disorders shared commonly increased entropy of brain signals in the left inferior and middle frontal gyri, and the right fusiform gyrus, cuneus, precuneus. No shared alterations were found in the subcortical regions and cerebellum in the patient group. Our findings suggested that the increased entropy of brain signals in the cortex, not subcortical regions and cerebellum, might have associations with the pathophysiology across mental illnesses. This meta-analysis study provided the first comprehensive understanding of the abnormality in brain signal complexity across patients with different psychiatric disorders.

Thyroid cancer (TC) has increased globally, with a prominent increase in small, papillary thyroid cancers. PEST-containing nuclear protein (PCNP), a nuclear protein, has been found to be associated with human cancers in recent years. However, the role and molecular mechanism of PCNP in thyroid cancer remain underexplored. In the present study, the results showed that the expression levels of PCNP in human thyroid tissues were higher than those in adjacent non-tumor tissues. Overexpression of PCNP reduced the proliferation, migration, and invasion of human thyroid cancer cells and down-regulation of PCNP showed reverse effects. In addition, PCNP regulated cell cycle arrest through modifications in the expression of cell cycle regulating genes and PCNP affected apoptosis via activation of ERK/JNK/p38 pathway in thyroid cancer cells. Moreover, PCNP overexpression promoted autophagy by reducing the expression levels of Wnt/β-catenin pathway in TC cells, however, PCNP knockdown had opposite effects. Furthermore, PCNP overexpression reduced the growth of xenografted human thyroid cancer, whereas PCNP knockdown showed opposite trends. In conclusion

PURPOSE BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified. PATIENTS AND METHODS We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM ( NCT02677324 ). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years. RESULTS Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P–mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred. CONCLUSION Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.

Cyanidin-3-O-glucoside (C3G) is a kind of anthocyanin which shows strong anti-inflammation, anti-tumor and anti-oxidant properties. This paper was designed to explore the potential effects of C3G on diabetic retinopathy (DR). C57BL/6 mice were administrated with streptozotocin (STZ) or vehicle control for the establishment of diabetic models. To simulate hyperglycemia and hypoxia, D-glucose (30 mM) and CoCl2 (200 μm/l) were utilized to treat HRECs, respectively. The migration, invasion, inflammation and tube formation abilities of cells were evaluated with the adoption of wound healing, transwell, ELISA and tube formation assays, respectively. Besides, immunofluorescence staining was utilized to detect proliferation and retinal vessels. Evans blue permeation assay were performed to evaluate the vascular leakage in DR mice. Moreover, western blot and qPCR were used to quantify the mRNA and protein expressions of ionized calcium-binding adapter molecule (Iba)-1 and tight junction proteins. Results showed that C3G alleviated the inflammation, microglial activation and angiogenesis in DR mice. Moreover, the proliferation and inflammation of BV2 cells induced by high glucose (HG) were suppressed by C3G. Evans blue permeation assay demonstrated the potency of C3G in attenuating vascular leakage. In addition, C3G suppressed the migration, invasion and angiogenesis of human retinal endothelial cells (HRECs) DR model in vitro. By confirming the role of C3G in inhibiting vascular leakage regulated by microglia activation in early DR and angiogenesis in advanced DR, this study pointed out the potential of C3G as a therapeutic drug for DR management.

Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)–mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481, particularly BTKCys481Ser, are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88-mutated lymphoma cells, including ibrutinib-resistant BTKCys481Ser-expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained inhibition of HCK and BTK for 24 hours after single oral administration of KIN-8194 in an MYD88-mutated TMD-8 activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) and BCWM.1 Waldenström macroglobulinemia (WM) xenografted mice with wild-type BTK (BTKWT)– or BTKCys481Ser-expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT- and BTKCys481Ser-expressing TMD-8 DLBCL xenografted mice, including sustained complete responses of >12 weeks off treatment in mice with BTKWT-expressing TMD-8 tumors. The BCL_2 inhibitor venetoclax enhanced the antitumor activity of KIN-8194 in BTKWT- and BTKCys481Ser-expressing MYD88-mutated lymphoma cells and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser-expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK.

Background Cardiac rehabilitation (CR) is a proven model of secondary prevention in which patient education is a core component. Objectives to translate and culturally-adapt CR patient education for Mandarin-speaking patients living in China as well as immigrants, and offer recommendation for best practices in adaptation for both. Methods these steps were undertaken in China and Canada: (1) preparation; (2) translation and adaptation; (3) review by healthcare providers based on PEMAT-P; (4) think-aloud review by patients; and (5) finalization. Results Two independent Mandarin translations were undertaken using best practices: one domestic (China) and one international (immigrants). Input by 23 experts instigated revisions. Experts rated the language and content as culturally-appropriate, and perceived the materials would benefit their patients. A revised version was then administered to 36 patients, based on which a few edits were made to optimize understandability. Conclusions some important differences emerged between translations adapted for native versus immigrant settings.

MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.

Purpose Neoadjuvant chemotherapy (NACT) is increasingly adopted in the therapy of breast cancer (BC) patients with positive axillary nodes (cN+), but the reliability and feasibility of sentinel lymph node biopsy (SLNB) following NACT are still controversial. The objective of the present study is to conduct an updated meta-analysis on this issue. Methods A literature search was performed using PubMed, Cochrane, Embase, and Web of Science to identify papers published from January 1, 2000 to October 22, 2020 to research SLNB after NACT in BC patients. Studies that met the quality standard were enrolled for this meta-analysis. Results A total of 3578 participants from 27 trials were included in this meta-analysis. The pooled estimate of the identification rate (IR) for SLNB was 91 %, and the false negative rate (FNR) was 15 %. The pooled negative prediction value (NPV), accuracy, specificity, and sensitivity were 82 %, 89 %, 97 %, and 85 %, respectively. In subgroup analysis, the application of dual mapping could clearly decrease the FNR. The FNR was significantly high in the luminal types, and it declined as more sentinel lymph nodes (SLNs) were removed. Conclusion SLNB following NACT is now technically feasible for BC with cN+. However, it must be emphasized that the FNR is unacceptable high., Highlights • We performed a meta-analysis to provide a consensus regarding the application of SLNB post-NACT in cN + patients. • One comprehensive database search yielded 27 studies (3578 patients). • The pooled estimate of IR for SLNB was 91 %, and FNR was 15 %. • The application of dual mapping could clearly decrease the FNR.

Background Alterations in genes encoding chromatin regulatory proteins are prevalent in cancers and may confer oncogenic properties and molecular changes linked to therapy resistance. However, the impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types. Methods We comprehensively analyzed the genomic, transcriptomic and clinical data of The Cancer Genome Atlas (TCGA) dataset across 33 solid cancers. Results CNAs of the SWI/SNF components were identified in more than 25% of all queried cancers, and tumors harboring SWI/SNF CNAs demonstrated a worse overall survival (OS) than others in several cancer types. Mechanistically, the SCNA events in the SWI/SNF complex are correlated with dysregulated genomic features and oncogenic pathways, including the cell cycle, DNA damage and repair. Notably, the SWI/SNF CNAs were associated with homologous recombination deficiency (HRD) and improved clinical outcomes of platinum-treated ovarian cancer. Furthermore, we observed distinct immune infiltrating patterns and immunophenotypes associated with SWI/SNF CNAs in different cancer types. Conclusion The CNA events of the SWI/SNF components are a key process linked to oncogenesis, immune infiltration and therapeutic responsiveness across human cancers.

Objectives Caveolin family proteins, including caveolin-1 (Cav-1), caveolin-2 (Cav-2), and caveolin-3 (Cav-3), are identified as the principal protein components of caveolae in mammalian cells. Circulating form of caveolin family proteins can be used as a good potential biomarker for predicting disease. Methods To investigate the clinical significance of the serological levels of caveolin family proteins in patients with systemic lupus erythematosus (SLE), we evaluated the soluble serum levels of caveolin family proteins in patients with SLE by enzyme-linked immunosorbent assay (ELISA) and assessed their associations with various known clinical variables. Results The major findings of our study are as follows: Cav-2 was not detected in serum of SLE patients and normal controls (NCs). Serum Cav-1 and Cav-3 levels were higher in SLE patients compared with NCs. There were no significant correlations between serum Cav-1 and Cav-3 levels and SLE disease activity. Further analysis showed that serum Cav-3 may be more valuable as a marker than serum Cav-1 in SLE patients. Conclusion Serum levels of Cav-1 and Cav-3 might have a diagnostic role in patients with SLE. However, their predictive and prognostic value was not determined. Further studies are necessary to determine the potential clinical significance of these assays in SLE.

Accurate assessment of mitral regurgitation (MR) severity is critical in clinical diagnosis and treatment. No single echocardiographic method has been recommended for MR quantification thus far. We sought to define the feasibility and accuracy of the mask regions with a convolutional neural network (Mask R-CNN) algorithm in the automatic qualitative evaluation of MR using color Doppler echocardiography images. The authors collected 1132 cases of MR from hospital A and 295 cases of MR from hospital B and divided them into the following four types according to the 2017 American Society of Echocardiography (ASE) guidelines: grade I (mild), grade II (moderate), grade III (moderate), and grade IV (severe). Both grade II and grade III are moderate. After image marking with the LabelMe software, a method using the Mask R-CNN algorithm based on deep learning (DL) was used to evaluate MR severity. We used the data from hospital A to build the artificial intelligence (AI) model and conduct internal verification, and we used the data from hospital B for external verification. According to severity, the accuracy of classification was 0.90, 0.89, and 0.91 for mild, moderate, and severe MR, respectively. The Macro F1 and Micro F1 coefficients were 0.91 and 0.92, respectively. According to grading, the accuracy of classification was 0.90, 0.87, 0.81, and 0.91 for grade I, grade II, grade III, and grade IV, respectively. The Macro F1 and Micro F1 coefficients were 0.89 and 0.89, respectively. Automatic assessment of MR severity is feasible with the Mask R-CNN algorithm and color Doppler electrocardiography images collected in accordance with the 2017 ASE guidelines, and the model demonstrates reasonable performance and provides reliable qualitative results for MR severity.

Objective Currently, coronavirus disease 2019 (COVID-19) has spread worldwide and become a global health concern. Here, we report a familial cluster of six patients infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) in a northern Chinese region and share our local experience with regard the control of COVID-19. Methods The demographic data, clinical features, laboratory examinations, and epidemiological characteristics of enrolled cases were collected and analyzed. Two family members (Cases 1 and 2) had Hubei exposure history and were admitted to the hospital with a confirmed diagnosis of COVID-19; eight familial members who had contact with them during the incubation period underwent quarantine in a hospital. We closely followed up all the family members and analyzed their clinical outcome. Results Case 3 had negative SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) results but was suspected to have COVID-19 because of radiographic abnormalities. Cases 4 and 5 developed symptomatic COVID-19. Case 6 was considered an asymptomatic carrier as his SARS-CoV-2 RT-PCR result was positive. The other four family members with close contacts to COVID-19 patients had no evidence of SARS-CoV-2 infection. Conclusions Our findings suggest that COVID-19 has infectivity during the incubation period and preventive quarantine is effective for controlling an outbreak of COVID-19 infection.

Haematological diseases with pancreatic masses as the first symptom are clinically rare but should not be ignored. This case report describes a 60-year-old female patient with acute leukaemia that had a pancreatic mass as her first symptom. The patient was admitted and elastography combined with endoscopic ultrasound (EUS) guided fine needle aspiration biopsy (EUS-FNA) was used for diagnosis, treatment planning and determination of prognosis. The site selected for the EUS-FNA puncture was the caudal section of the pancreatic body and the posterior wall of the gastric body was used as the puncture point. The elastography view of the head of the pancreas was blue/green with predominant blue colour. A 19 G puncture needle with a slow-draw core and two stitches of micro-negative pressure were used. Cytology detected heterotypic cells, pancreatic puncture histopathology, the presence of pancreatic alveolar structures and heterotypic tumour cells in the interstitium. Immunohistochemistry of the pancreatic puncture tissue showed B-cell lymphoblast-derived tumours and bone marrow puncture indicated acute lymphoblastic leukaemia. The patient was diagnosed with acute lymphoblastic leukaemia invading the pancreas and was treated with chemotherapy. After treatment, her condition was stable. Follow-up is ongoing and there have been no signs of tumour recurrence or metastasis.

To investigate the distribution characteristics of the HIV genetic subtypes and the status quo of transmitted drug resistance among HIV/AIDS patients in Sichuan with no previous history of receiving antiretroviral therapy (ART).Adult HIV/AIDS patients who were hospitalized in Sichuan and who had no previous history of exposure to ART drugs exposure were enrolled. In-house sequencing of the HIV gene was done and phylogenetic tree was constructed to analyze the HIV genetic subtypes. The Stanford HIV drug resistance database was used to make online comparison of the drug resistance mutation sites and to determine the presence or absence of drug resistance, and the type and level of drug resistance.A total of 120 patients were enrolled for the study, and 120 blood samples were collected. The genetic subtypes of 87.5% (105/120) of the samples were successfully amplified. The distribution characteristics of HIV genotype were as follows, CRF01_AE accounted for 46.67% (49/105), CRF07_BC accounted for 39.05% (41/105), and the others genetic subtypes, 14.28% (15/105). There were no significant differences between the different genetic subtypes in sex, age, ethnicity, HIV transmission route, drug resistance, baseline HIV RNA and baseline CD4 (The main genetic subtypes of HIV/AIDS patients in Sichuan with no previous history of receiving ART were CRF01_AE and CRF07_BC. The incidence of transmitted drug resistance was low. The drug resistance detected in the study was predominantly resistance to NNRTIs. Baseline HIV drug resistance testing is of great significance for formulating effective ART regimens.

To compare the effects of direct fluorescence in situ hybridization (D-FISH) detection without sorting and CD138 immunomagnetic bead sorting technology combined with FISH (MACS-FISH) on cytogenetic analysis of patients with multiple myeloma (MM).FISH test results of 229 patients with initial MM were retrospectively analyzed. The patients were divided into two groups, 140 patients were tested with D-FISH and 89 patients with MACS-FISH. The combination probe was designed as P53, D13S319, RB1, 1q21, and IgH. Cytogenetic detection results were compared between the two groups.The total detection rate of cytogenetic abnormalities in D-FISH group was 52.9%, and that in MACS-FISH group was 79.8%. There was a significant difference in the cytogenetic abnormality rate between the two groups (P=0.020). The abnormal genes with the highest detection rate in the two groups were 1q21 and IgH, respectively, while the lowest was P53. There was no significant difference in the percentage of P53 positive cells (positive rate) between the two groups, while D13S319, RB1, 1q21, and IgH showed significant difference in positive cell rate (P=0.0002, P0.0001, P=0.0033, P=0.0032). There was no significant correlation between the proportion of plasma cells (PC) detected by bone marrow morphology and cytogenetic abnormality rate in the D-FISH group, while there was a correlation between the proportion of PC detected by flow cytometry and cytogenetic abnormality rate (r=0.364). The PC proportion detected by bone marrow morphology and flow cytometry in the MACS-FISH group had no correlation with the cytogenetic abnormality rate and positive cell rate of the 5 genes mentioned above. Additionally, the PC proportion detected by bone marrow morphology and flow cytometry showed significant difference (P0.0001).CD138 immunomagnetic bead sorting combined with FISH technology can significantly improve the abnormality detection rate of MM cytogenetics.CD138免疫磁珠分选结合荧光原位杂交技术在多发性骨髓瘤中的应用.比较未经分选直接进行荧光原位杂交（D-FISH）检测和CD138免疫磁珠分选结合荧光原位杂交（MACS-FISH）检测对多发性骨髓瘤（MM）患者细胞遗传学分析的影响。.回顾性分析229例初发MM患者的FISH检测结果，一组为140例采用D-FISH法，另一组为89例采用MACS-FISH法，设计探针组合为P53、D13S319、RB1、1q21和IgH，比较两组间细胞遗传学检测结果。.D-FISH组遗传学异常总检出率为52.9%，MACS-FISH组总检出率为79.8%，两组间的细胞遗传学异常检出率比较存在显著性差异（P=0.020）；两组中检出率最高的细胞遗传学异常基因分别为1q21和IgH，检出率最低的为P53；两组间P53阳性细胞率比较无显著性差异，而D13S319、RB1、1q21和IgH阳性细胞率比较均存在显著性差异（P=0.0002，P0.0001，P=0.0033，P=0.0032）。D-FISH组骨髓细胞形态学检测浆细胞比例与遗传学异常检出率无显著相关性，而流式细胞术检测浆细胞比例与遗传学异常检出率存在相关性（r=0.364）。MACS-FISH组骨髓细胞形态学和流式细胞术检测浆细胞比例与5种基因的检出率及阳性细胞率均无相关性。骨髓细胞形态学与流式细胞术的浆细胞比例检测结果存在显著性差异（P0.0001）。.CD138免疫磁珠分选技术结合FISH能显著提高MM细胞遗传学异常的检出率。.

The dietary glycemic index (GI) and glycemic load (GL) have garnered scholarly attention for their roles in weight management and glycemic control. Flaxseed is a good source of fiber, lignans, and omega-3 fatty acids. This study evaluated healthy individuals' acute glycemic response and satiety following the consumption of flaxseed-enriched snack bars.Nineteen healthy men and women consumed flaxseed bars or a glucose solution containing 50 g of available carbohydrates. Capillary blood glucose concentrations were obtained through the finger-prick test. The GI and GL values of the flaxseed bars were calculated using incremental area under the glucose response curve. Over 2 h, subjective satiety was examined at 0 (fasting), 15, 30, 45, 60, 90 and 120min following the consumption of flaxseed bars or saltine crackers containing 300 kcal by using a visual analogue scale (VAS).Compared with that of the glucose solution, the glucose concentrations of the flaxseed bars (15-90 min) were significantly lower (p0.001). The GI and GL values of the flaxseed bars were 30.0±23.0 and 2.3±0.2, respectively. Compared with saltine cracker consumption, flaxseed bars consumption resulted in lower hunger and higher satiety. The satiety index score of the flaxseed bars was 1.6 times higher than that of the saltine crackers.Although further studies are warranted to evaluate the long-term effects of flaxseed-enriched snacks on glycemia and energy balance, our findings suggest that the incorporation of flaxseed into snack bars is a viable strategy for the management of obesity and diabetes.

N6-methyladenosine (m

Background Neck pain is widespread among students in healthcare-related fields. Although neck pain is more prevalent in females, since most research involves mixed-sex samples we know very little about sex differences in contributors to neck pain. Thus, this study sought to explore sex differences in the risk factors for neck pain in this high-risk population. Methods This cross-sectional study was conducted in China in 2021 and included a sample of 1921 undergraduate healthcare students (693 males, 1228 females) from 7 health professional schools at Fujian Medical University. We collected data on neck pain symptoms, demographics, behavioral and psychological factors. Multiple regression analysis was conducted to examine sex differences in the risk factors of neck pain. Results The overall prevalence of neck pain was 41.6% with female students having a higher prevalence than male students (44.4% vs. 36.7%, respectively). The adjusted analyses showed that self-study time ≥ 6 h/day (OR = 1.44, 95% CI:1.13-1.83), flexed neck posture >20 degrees (OR = 2.19, 95% CI: 1.28-3.74), static duration posture >2 h (OR = 1.42, 95% CI: 1.02-1.97), and psychological distress (high: OR = 2.04, 95% CI:1.42-2.94; very high: OR = 2.50, 95% CI:1.57-3.74; respectively) were independent factors for neck pain in females. Among males, self-study time ≥ 6 h/day (OR = 1.43, 95% CI: 1.02-2.01) and psychological distress (moderate: OR = 2.04, 95% CI:1.28-3.25; high: OR = 2.37, 95% CI:1.49-3.79; very high: OR = 2.97, 95% CI:1.75-5.02; respectively) were significant risk factors for neck pain. Conclusions These findings suggest that the risk profiles of neck pain differ between females and males. The modifiable risk factors for neck pain, such as prolonged self-study time and elevated psychological distress, as well as poor posture among females, could be targeted through health promotion interventions in university settings.

Middle cerebral artery occlusion (MCAO) injury refers to impaired blood supply to the brain that is caused by a cerebrovascular disease, resulting in local brain tissue ischemia, hypoxic necrosis, and rapid neurological impairment. Nevertheless, the mechanisms involved are unclear, and pharmacological interventions are lacking. 25-Hydroxycholesterol (25-HC) was reported to be involved in cholesterol and lipid metabolism as an oxysterol molecule. This study aimed to determine whether 25-HC exerts a cerebral protective effect on MCAO injury and investigate its potential mechanism. 25-HC was administered prior to reperfusion in a mouse model of MCAO injury. 25-HC evidently decreased infarct size induced by MCAO and enhanced brain function. It reduced stimulator of interferon gene (STING) activity and regulated mTOR to inhibit autophagy and induce cerebral ischemia tolerance. Thus, 25-HC improved MCAO injury through the STING channel. As indicated in this preliminary study, 25-HC improved MCAO injury by inhibiting STING activity and autophagy as well as by reducing brain nerve cell apoptosis. Thus, it is a potential treatment drug for brain injury.

Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC., Circulating tumor cell (CTC) clusters are more efficient at mediating metastasis as compared to single cells and are associated with poor prognosis in breast cancer. Here, the authors show that ICAM1 is enriched in CTC clusters and its loss suppresses cell-cell interaction and CTC cluster formation, and propose ICAM1 as a therapeutic target for treating breast cancer metastasis.

Neuroimaging technique is a powerful tool to characterize the abnormality of brain networks in schizophrenia. However, the neurophysiological substrate of schizophrenia is still unclear. Here we investigated the patterns of brain functional and structural changes in female patients with schizophrenia using elastic net logistic regression analysis of resting-state functional magnetic resonance imaging data. Data from 52 participants (25 female schizophrenia patients and 27 healthy controls) were obtained. Using an elastic net penalty, the brain regions most relevant to schizophrenia pathology were defined in the models using the amplitude of low-frequency fluctuations (ALFF) and gray matter, respectively. The receiver operating characteristic analysis showed reliable classification accuracy with 85.7% in ALFF analysis, and 77.1% in gray matter analysis. Notably, our results showed eight common regions between the ALFF and gray matter analyses, including the Frontal-Inf-Orb-R, Rolandic-Oper-R, Olfactory-R, Angular-L, Precuneus-L, Precuenus-R, Heschl-L, and Temporal-Pole-Mid-R. In addition, the severity of symptoms was found positively associated with the ALFF within the Rolandic-Oper-R and Frontal-Inf-Orb-R. Our findings indicated that elastic net logistic regression could be a useful tool to identify the characteristics of schizophrenia -related brain deterioration, which provides novel insights into schizophrenia diagnosis and prediction.

Background: Transcatheter left atrial appendage closure (LAAC) is performed either in conscious sedation (CS) or general anesthesia (GA), and limited data exist regarding clinical outcomes for the two approaches. The aim of the study was to analyze the effect of CS versus GA on acute outcomes in a large patient cohort undergoing LAAC with a Watchman occluder. Methods: A cohort of 521 consecutive patients underwent LAAC with Watchman occluders at two centers (REGIOMED hospitals, Germany) between 2012 and 2018. One site performed 303 consecutive LAAC procedures in GA, and the other site performed 218 consecutive procedures in CS. The safety endpoint was a composite of major periprocedural complications and postoperative pneumonia. The efficacy endpoint was defined as device success. Results: After a 1:1 propensity score matching, 196 (CS) vs. 115 (GA) patients could be compared. In 5 (2.6%) cases CS was converted to GA. The primary safety endpoint (3.5% [CS] vs. 7.0% [GA], p = 0.18) and its components (major periprocedural complications: 2.5% vs. 3.5%, p = 0.73; postoperative pneumonia: 2.6% vs. 4.3%, p = 0.51) did not differ between the groups. Also, device success was comparable (96.9% vs. 93.9%, p = 0.24). Conclusions: In patients undergoing LAAC with the Watchman device, conscious sedation and general anesthesia showed comparable device success rates and safety outcomes. The type of anesthesia for LAAC may therefore be tailored to patient comorbidities, operator experience, and hospital logistics.

Corona Virus Disease 2019 (COVID-19), an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread rapidly worldwide, resulting in a pandemic with a high mortality rate. In clinical practice, we have noted that many critically ill or critically ill patients with COVID-19 present with typical sepsis-related clinical manifestations, including multiple organ dysfunction syndrome, coagulopathy, and septic shock. In addition, it has been demonstrated that severe COVID-19 has some pathological similarities with sepsis, such as cytokine storm, hypercoagulable state after blood balance is disrupted and neutrophil dysfunction. Considering the parallels between COVID-19 and non-SARS-CoV-2 induced sepsis (hereafter referred to as sepsis), the aim of this study was to analyze the underlying molecular mechanisms between these two diseases by bioinformatics and a systems biology approach, providing new insights into the pathogenesis of COVID-19 and the development of new treatments. Specifically, the gene expression profiles of COVID-19 and sepsis patients were obtained from the Gene Expression Omnibus (GEO) database and compared to extract common differentially expressed genes (DEGs). Subsequently, common DEGs were used to investigate the genetic links between COVID-19 and sepsis. Based on enrichment analysis of common DEGs, many pathways closely related to inflammatory response were observed, such as Cytokine-cytokine receptor interaction pathway and NF-kappa B signaling pathway. In addition, protein-protein interaction networks and gene regulatory networks of common DEGs were constructed, and the analysis results showed that ITGAM may be a potential key biomarker base on regulatory analysis. Furthermore, a disease diagnostic model and risk prediction nomogram for COVID-19 were constructed using machine learning methods. Finally, potential therapeutic agents, including progesterone and emetine, were screened through drug-protein interaction networks and molecular docking simulations. We hope to provide new strategies for future research and treatment related to COVID-19 by elucidating the pathogenesis and genetic mechanisms between COVID-19 and sepsis.

BackgroundCurrent immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy.MethodsSenescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy.ResultsWe report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo.ConclusionsThese studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy.

Patients with schizophrenia (SCZ) frequently exhibit an elevated risk of metabolic syndrome (MetS), which may lead to a worse clinical outcome. Even though these two phenotypes are genetically linked, little is known about their shared genetic determinants. Here, we investigated whether SCZ and MetS share genetic risk factors. To examine the genetic overlap between the two disorders, we applied a comprehensive genetic overlap analysis by integrating GWAS data for SCZ (n = 320,404) and MetS (n = 291,107) at the genome, genetic variants, and gene levels. At the genome level, we observed polygenic overlap between SCZ and MetS by utilizing LDSC (r

Depression in childhood negatively affects the growth and development, school performance, and peer or family relationships of affected children, and may even lead to suicide. Despite this, its etiology and pathophysiology remain largely unknown. Increasing evidence supports that gut microbiota plays a vital role in the development of childhood depression. However, little is known about the underlying mechanisms, as most clinical studies investigating the link between gut microbiota and depression have been undertaken in adult cohorts. In present study, a total of 140 school-aged children (6–12 years) were enrolled, including 92 with depression (male/female: 42/50) and 48 healthy controls (male/female: 22/26) from Lishui, Zhejiang, China. Illumina sequencing of the V3–V4 region of the 16S rRNA gene was used to investigate gut microbiota profiles while Bio-Plex Pro Human Cytokine 27-plex Panel was employed to explore host immune response. We found that, compared with healthy controls, children with depression had greater bacterial richness and altered β-diversity. Pro-inflammatory genera such as Streptococcus were enriched in the depression group, whereas anti-inflammatory genera such as Faecalibacterium were reduced, as determined by linear discriminant analysis effect size. These changes corresponded to altered bacterial functions, especially the production of immunomodulatory metabolites. We also identified the presence of a complex inflammatory condition in children with depression, characterized by increased levels of pro-inflammatory cytokines such as IL-17 and decreased levels of anti-inflammatory cytokines such as IFN-γ. Correlation analysis demonstrated that the differential cytokine abundance was closely linked to changes in gut microbiota of children with depression. In summary, key functional genera, such as Streptococcus and Faecalibacterium, alone or in combination, could serve as novel and powerful non-invasive biomarkers to distinguish between children with depression from healthy ones. This study was the first to demonstrate that, in Chinese children with depression, gut microbiota homeostasis is disrupted, concomitant with the activation of a complex pro-inflammatory response. These findings suggest that gut microbiota might play an important role in the pathogenesis of depression in school-aged children, while key functional bacteria in gut may serve as novel targets for non-invasive diagnosis and patient-tailored early precise intervention in children with depression.

Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/− mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPβ/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG.

Tumor-initiating cells with reprogramming plasticity or stem-progenitor cell properties (stemness) are thought to be essential for cancer development and metastatic regeneration in many cancers; however, elucidation of the underlying molecular network and pathways remains demanding. Combining machine learning and experimental investigation, here we report CD81, a tetraspanin transmembrane protein known to be enriched in extracellular vesicles (EVs), as a newly identified driver of breast cancer stemness and metastasis. Using protein structure modeling and interface prediction-guided mutagenesis, we demonstrate that membrane CD81 interacts with CD44 through their extracellular regions in promoting tumor cell cluster formation and lung metastasis of triple negative breast cancer (TNBC) in human and mouse models. In-depth global and phosphoproteomic analyses of tumor cells deficient with CD81 or CD44 unveils endocytosis-related pathway alterations, leading to further identification of a quality-keeping role of CD44 and CD81 in EV secretion as well as in EV-associated stemness-promoting function. CD81 is coexpressed along with CD44 in human circulating tumor cells (CTCs) and enriched in clustered CTCs that promote cancer stemness and metastasis, supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights machine learning as a powerful tool in facilitating the molecular understanding of new molecular targets in regulating stemness and metastasis of TNBC.

Background Karst-adapted plant, Lysionotus pauciflours accumulates special secondary metabolites with a wide range of pharmacological effects for surviving in drought and high salty areas, while researchers focused more on their environmental adaptations and evolutions. Nevadensin (5,7-dihydroxy-6,8,4'-trimethoxyflavone), the main active component in L. pauciflours, has unique bioactivity of such as anti-inflammatory, anti-tubercular, and anti-tumor or cancer. Complex decoration of nevadensin, such as hydroxylation and glycosylation of the flavone skeleton determines its diversity and biological activities. The lack of omics data limits the exploration of accumulation mode and biosynthetic pathway. Herein, we integrated transcriptomics, metabolomics, and microbial recombinant protein system to reveal hydroxylation and glycosylation involving nevadensin biosynthesis in L. pauciflours. Results Up to 275 flavonoids were found to exist in L. pauciflorus by UPLC-MS/MS based on widely targeted metabolome analysis. The special flavone nevadensin (5,7-dihydroxy-6,8,4'-trimethoxyflavone) is enriched in different tissues, as are its related glycosides. The flavonoid biosynthesis pathway was drawn based on differential transcripts analysis, including 9 PAL, 5 C4H, 8 4CL, 6 CHS, 3 CHI, 1 FNSII, and over 20 OMTs. Total 310 LpCYP450s were classified into 9 clans, 36 families, and 35 subfamilies, with 56% being A-type CYP450s by phylogenetic evolutionary analysis. According to the phylogenetic tree with AtUGTs, 187 LpUGTs clustered into 14 evolutionary groups (A-N), with 74% being E, A, D, G, and K groups. Two LpCYP82D members and LpUGT95 were functionally identified in Saccharomyces cerevisiae and Escherichia coli, respectively. CYP82D-8 and CYP82D-1 specially hydroxylate the 6- or 8-position of A ring in vivo and in vitro, dislike the function of F6H or F8H discovered in basil which functioned depending on A-ring substituted methoxy. These results refreshed the starting mode that apigenin can be firstly hydroxylated on A ring in nevadensin biosynthesis. Furthermore, LpUGT95 clustered into the 7-OGT family was verified to catalyze 7-O glucosylation of nevadensin accompanied with weak nevadensin 5-O glucosylation function, firstly revealed glycosylation modification of flavones with completely substituted A-ring. Conclusions Metabolomic and full-length transcriptomic association analysis unveiled the accumulation mode and biosynthetic pathway of the secondary metabolites in the karst-adapted plant L. pauciflorus. Moreover, functional identification of two LpCYP82D members and one LpUGT in microbe reconstructed the pathway of nevadensin biosynthesis.

Si-Wu-Tang (SWT) has become a common basic prescription for supplementing blood and regulating menstruation, and enjoys the reputation of "the first prescription in gynecology". It is often reported in the treatment of premature ovarian failure (POF). However, knowledge of its specific mechanism is still limited.This study aimed to identify the potential effects and underlying mechanisms of SWT on POF.After confirming the therapeutic effect of SWT on POF mice induced by cyclophosphamide, we further clarified the promoting effect of SWT on ovarian follicle development by detecting the expression of key factors related to follicle development in the ovary in different ways.Then, network pharmacology and gene expression profiling of POF from the GEO database were used to clarify the underlying mechanisms. Molecular biology and molecular docking analysis were applied for final mechanism verification.Our results showed that SWT increased body weight, ovarian index, reversed disordered serum hormone levels, and menstrual cycle in POF mice. After SWT treatment, the number of follicles at all levels in mice with POF also recovered. Using molecular biology techniques, it was proven that SWT can improve follicle development and angiogenesis in the microenvironment. The network pharmacology and gene expression profiling from the GEO database indicated that the PI3K/Akt signaling pathway may be the reason why SWT improves ovarian function in mice with POF. Subsequently, further Western blot and immunoprecipitation indicated that SWT indeed inhibited the PI3K/Akt signaling pathway in mice with POF. In addition, this conclusion was further confirmed by molecular docking experiments.SWT can improve ovarian function in POF mice induced by cyclophosphamide, and its mechanism is related to the inhibition of the PI3K/Akt signaling pathway.

Context Spontaneous abortion (SA) is a common disorder in early pregnancy. Circular RNAs (circRNAs) have been reported to exert important regulatory effects on trophoblast function and embryo development. Objective The aim of this study was to explore whether and how circRNAs regulate trophoblast function in SA during early pregnancy. Methods Cell proliferation, 5-bromo-2-deoxyuridine (BrdU) staining, Transwell, immunofluorescence, Western blot, RNA pull-down, and dual luciferase reporter assays were performed to investigate the effect of circRNA cyclin B1 (circ-CCNB1) on trophoblast function in HTR-8/SVneo and JEG-3 cells. Results An in vitro study demonstrated that upregulation of circ-CCNB1 significantly inhibited trophoblast proliferation and invasion compared with the controls using HTR-8/SVneo and JEG-3 cells, respectively. Moreover, miR-223 was downregulated in the villous tissues of patients with SA and was further predicted and shown to negatively interact with circ-CCNB1, which is involved in trophoblast proliferation and invasion. Using bioinformatics tools and subsequent RNA pull-down and dual luciferase assays, we found that miR-223 directly targets seven in absentia homolog-1 (SIAH1) and that upregulation of miR-223 decreased circ-CCNB1-induced SIAH1 expression levels in HTR-8/SVneo cells. Interestingly, upregulation of circ-CCNB1 suppressed trophoblast proliferation and invasion through inhibition of CCNB1 nuclear translocation induced by SIAH1. Downregulation of SIAH1 enhanced circ-CCNB1-suppressed CCNB1 nuclear protein expression in trophoblast cells. Conclusion Circ-CCNB1 served as a modulator of trophoblast proliferation and invasion by sponging miR-223, thus forming a regulatory network of circ-CCNB1/miR-223/SIAH1 in modulating CCNB1 nuclear translocation, which enabled us to elucidate the molecular mechanisms involved in normal embryo implantation or in SA.