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Family conflict is a risk factor for suicidal behaviors among adolescents. However, few longitudinal studies have investigated this association and explored the mediation effect of behavioral and emotional problems. This study aimed to examine the longitudinal association between family conflict, internalizing and externalizing problems, and suicidal behaviors in a large sample of Chinese adolescents.This longitudinal study of 7,072 adolescents was based on the Shandong Adolescent BehaviorHealth Cohort (SABHC). Participants completed a self-administrated questionnaire to assess family conflict, internalizing and externalizing problems, suicidal behaviors, and family demographics at baseline. Excluding adolescents with any suicidal behavior at baseline (N = 839), others (N = 6,233) were allowed to report their internalizing and externalizing problems and suicidal behaviors one-year later. Path analyses were conducted to examine the mediation relationship of internalizing and externalizing problems between family conflict and suicidal behaviors.Of 6,233 participants, mean age was 14.52 at baseline and 51.2% were males. Adolescents with subsequent suicidal behaviors reported higher scores in family conflict, internalizing and externalizing problems (Ps 0.01). Path analyses showed that internalizing and externalizing problems played a significant mediating role in the associations of family conflict with suicidal behaviors after adjusting for covariates.Family conflict is associated with suicidal behaviors in adolescents, which is partially mediated by internalizing and externalizing problems. Internalizing problems is the major mediator between family conflict and suicidal thought or suicide plan; however, internalizing and externalizing problems play similar mediating roles in the family conflict-suicide attempt link.

HIV-1 latency posts a major obstacle for HIV-1 eradication. Currently, no desirable latency reversing agents (LRAs) have been implicated in the “Shock and Kill” strategy to mobilize the latently infected cells to be susceptible for clearance by immune responses. Identification of key cellular pathways that modulate HIV-1 latency helps to develop efficient LRAs. In this study, we demonstrate that the Wnt downstream β-catenin/TCF1 pathway is a crucial modulator for HIV-1 latency. The pharmacological activation of the β-catenin/TCF1 pathway with glycogen synthase kinase-3 (GSK3) inhibitors promoted transcription of HIV-1 proviral DNA and reactivated latency in CD4+ T cells; the GSK3 kinase inhibitor 6-bromoindirubin-3′-oxime (6-BIO)-induced HIV-1 reactivation was subsequently confirmed in resting CD4+ T cells from cART-suppressed patients and SIV-infected rhesus macaques. These findings advance our understanding of the mechanisms responsible for viral latency, and provide the potent LRA that can be further used in conjunction of immunotherapies to eradicate viral reservoirs., GRAPHICAL ABSTRACT

Prolonged mobile phone use has been demonstrated to be associated with mental health problems and suicidal behavior in adolescents. This study examined the mediating role of depressive symptoms in the association between duration of mobile phone use (DMPU) and suicidal behavior in adolescents.A total of 6,923 participants from the Shandong Adolescent BehaviorHealth Cohort (SABHC) were included in the analysis. Participants completed a self-administered questionnaire to assess DMPU on weekdays and weekends, mental disorders, insomnia symptoms, depressive symptoms, suicidal behavior (thought, plan, or attempt), and family demographics in November-December 2015. One year later, a follow-up survey was conducted to ask participants to report their depressive symptoms and suicidal behavior. Path analyses with logistic regressions were performed to examine the mediating role of depressive symptoms in the DMPU-suicidal behavior link.Of the sample, mean age was 14.58 (SD = 1.45) and 3,455 (49.9 %) were female at baseline. 12.12 % of participants reported having ever suicidal behavior during the past 12 months at baseline, and 10.63 % reported having ever suicidal behavior during 1-year follow-up. Path analyses showed that the depressive symptoms played a partial mediating role in the association of DMPU on weekdays and weekends with subsequent suicidal behavior. After controlling for covariates, depressive symptoms accounted for 33.6 % and 58.6 % of the total effect of DMPU on weekdays and weekends on suicidal behavior, respectively.All variables were measured based on self-report.The link between DMPU and suicidal behavior was partially mediated by depressive symptoms. Prolonged mobile phone use and depressive symptoms should be assessed and intervened to prevent suicidal behavior in adolescents.

Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation. As an essential trace element, iron is vital for many biological processes. Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation. Ferroptosis, a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids (PUFAs), is a promising therapeutic target for therapy-resistant cancers. Previous studies have reported that long noncoding RNA (lncRNA) is a group of critical regulators involved in modulating cell metabolism, proliferation, apoptosis, and ferroptosis. In this review, we summarize the associations among iron metabolism, ferroptosis, and ferroptosis-related lncRNA in tumorigenesis. This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.

Pathogenic variants in the CACNA1A gene have been associated with episodic ataxia type 2, familial hemiplegic migraine, and spinocerebellar ataxia 6. With increasing use of clinical genetic testing, associations have expanded to include developmental delay, epilepsy, paroxysmal dystonia, and neuropsychiatric disorders. We report 47 individuals with 33 unique likely pathogenic or pathogenic CACNA1A variants. A machine learning method, funNCion, was used to predict loss-of-function (LoF)/gain-of-function (GoF) impact of genetic variants, and a heuristic severity score was designed to analyze genotype/phenotype correlations. Commonly reported phenotypes include developmental delay/intellectual disability (96%), hemiplegic migraines (36%), episodic ataxia type 2 (32%), epilepsy (55%), autism spectrum disorder (23%), and paroxysmal tonic upward gaze (36%). Severity score was significantly higher for predicted GoF variants, variants in the S5/S6 helices, and the recurrent p.Val1392Met variant. Seizures/status epilepticus were correlated with GoF and were more frequent in those with the p.Val1392Met variant. Our findings demonstrate a breadth of disease severity in CACNA1A-related disease and suggest that the clinical phenotypic heterogeneity likely reflects diverse molecular phenotypes. A better understanding of the natural history of CACNA1A-related disease and genotype/phenotype correlations will help inform prognosis and prepare for future clinical trials.

Iron metabolism dysregulation is tightly associated with cancer development. But the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various metabolic processes via integrating signaling pathway. In this study, we revealed one iron-triggered lncRNA, one target of YAP, LncRIM (LncRNA Related to Iron Metabolism, also named ZBED5-AS1 and Loc729013), which effectively links the Hippo pathway to iron metabolism and is largely independent on IRP2. Mechanically, LncRIM directly binds NF2 to inhibit NF2-LATS1 interaction, which causes YAP activation and increases intracellular iron level via DMT1 and TFR1. Additionally, LncRIM-NF2 axis mediates cellular iron metabolism dependent on the Hippo pathway. Clinically, high expression of LncRIM correlates with poor patient survival, suggesting its potential use as a biomarker and therapeutic target. Taken together, our study demonstrated a novel mechanism in which LncRIM-NF2 axis facilitates iron-mediated feedback loop to hyperactivate YAP and promote breast cancer development.

Little is known about the association between perceived social support (PSS) and suicidal ideation in Chinese adolescents. This study was to examine the association of perceived social support and suicidal ideation (SI) and the mediating role of depressive symptoms in a large sample of adolescents in China.A total of 11,831 adolescents who participated in the baseline Shandong Adolescent BehaviorHealth Cohort were included for analysis. Perceived social support, depressive symptoms, and other variables were assessed by a self-administrated questionnaire. Path analysis was used to estimate the association between PSS, depressive symptoms, and suicidal ideation.The prevalence rate of SI in the past year was 12.5%. Suicidal ideation and depressive symptoms were significantly associated with low PSS from family, friends, and significant others. Path analysis revealed that depressive symptoms partially mediated the relationship between PSS from family, friends, and significant others and suicidal ideation. After controlling for covariates, the mediation effect proportion of depressive symptoms on the associations between perceived social support from family, friends, and significant others and SI ranged from 19.20% to 62.12%.As this is a cross-sectional study, no causal relationship could be made.Depressive symptoms partially mediated the association between perceived social support and suicidal ideation. Longitudinal research is needed to better understand the association between social support and suicidal ideation in adolescents.

Attempts to determine why some patients respond to electroconvulsive therapy (ECT) are valuable in schizophrenia. Schizophrenia is associated with aberrant dynamic functional architecture, which might impact the efficacy of ECT. We aimed to explore the relationship between pre-treatment temporal variability and ECT acute efficacy. Forty-eight patients with schizophrenia and 30 healthy controls underwent functional magnetic resonance imaging to examine whether patterns of temporary variability of functional architecture differ between high responders (HR) and low responders (LR) at baseline. Compared with LR, HR exhibited significantly abnormal temporal variability in right inferior front gyrus (IFGtriang.R), left temporal pole (TPOsup.L) and right middle temporal gyrus (MTG.R). In the pooled patient group, ∆PANSS was correlated with the temporal variability of these regions. Patients with schizophrenia with a distinct dynamic functional architecture appear to reveal differential response to ECT. Our findings provide not only an understanding of the neural functional architecture patterns that are found in schizophrenia but also the possibility of using these measures as moderators for ECT selection.

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10(−16)). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.

Frequent nightmares are related to depressive symptoms in adolescents. Little is known about pathways from frequent nightmares to depressive symptoms. This study aimed to examine the mediation effect of nightmare distress in the association between frequent nightmares and depressive symptoms in a large sample of Chinese adolescents.A total of 11,831 adolescents who participated in the baseline survey of Shandong Adolescent Behavior and Health Cohort were included in the analysis. A self-administered questionnaire was used to measure nightmare frequency, nightmare distress, depressive symptoms, sleep duration, insomnia, and demographic characteristics. Linear regressions and mediation analyses were performed to examine the associations between frequent nightmares, nightmare distress and depressive symptoms.Of 11,831 participates, 50.9% were males and the mean age was 14.97 ± 1.45. Adolescents with frequent nightmares scored significantly higher on nightmare distress (t = 29.87, P 0.001) and depressive symptoms (t = 20.05, P 0.001) than those adolescents without frequent nightmares. Frequent nightmares (β = 1.04, 95% CI: 0.48-1.60) and nightmare distress (β = 0.30, 95% CI: 0.28-0.32) were associated with depressive symptoms. Mediation analyses showed that nightmare distress accounted for 63.76% of the total effects in the entire sample, 51.17% in males and 80.00% in females, respectively.No causality could be made from the cross-sectional data and possible information bias due to self-report.The association between frequent nightmares and depressive symptoms appears to be substantially mediated by nightmare distress. Assessing and intervening distress associated with frequent nightmares may have important clinical implications for reducing the risk of depression in adolescents.

Cytogenetic abnormalities have been proven to be the most valuable parameter for risk stratification of childhood acute lymphoblastic leukemia (ALL). However, studies on the prevalence of cytogenetic abnormalities and their correlation to clinical features in Chinese pediatric patients are limited, especially large-scale studies.We collected the cytogenetics and clinical data of 1541 children newly diagnosed with ALL between 2001 and 2014 in four Chinese hospitals, and retrospectively analyzed their clinical features, prognosis and risk factors associated with pediatric ALL.All of these patients had karyotyping results, and some of them were tested for fusion genes by fluorescence in situ hybridization or reverse-transcription polymerase chain reaction. Overall, 930 cases (60.4%) had abnormal cytogenetics in this study, mainly including high hyperdiploidy (HHD, n=276, 17.9%), hypodiploidy (n=74, 4.8%), t(12;21)/TEL-AML1 (n=260, 16.9%), t(1;19)/E2A-PBX1 (n=72, 4.7%), t(9;22)/BCR-ABL (n=64, 4.2%), and t(v;11q23)/MLL rearrangements (n=40, 2.6%). The distribution of each cytogenetic abnormality was correlated with gender, age, white blood cell count at diagnosis, and immunophenotype. In addition, multivariate analysis suggested that t(v;11q23)/MLL rearrangements (OR: 2.317, 95%CI: 1.219-3.748, P=0.008) and t(9;22)/BCR-ABL (OR: 2.519, 95%CI: 1.59-3.992, P0.001) were independent risk factors for a lower event-free survival (EFS) rate in children with ALL, while HHD (OR: 0.638, 95%CI: 0.455-0.894, P=0.009) and t(12;21)/TEL-AML1 (OR: 0.486, 95%CI: 0.333-0.707, P0.001) were independent factors of a favorable EFS.The cytogenetic characteristics presented in our study resembled other research groups, emphasizing the important role of cytogenetic and molecular genetic classification in ALL, especially in B-ALL.

To explore the correlation between different body mass index (BMI) and prognosis of mantle cell lymphoma (MCL).The clinical characteristics and biological indices of 108 patients with MCL treated in Fujian Medical University Union Hospital were retrospectively analyzed, and the effects of different BMI on overall survival (OS) and progression-free survival (PFS) were analyzed. The correlation between BMI and B symptoms, LDH and Ki-67 was further observed. Furthermore，the differences of BMI between Autologous peripheral blood stem cell transplantation(Auto-PBSCT) and conventional chemotherapy groups were explored.Among 108 patients, the median age at diagnosis was 59（25-79） years old, and the male to female ratio was 4.4∶1. 88.89% of patients with Ann Arbor staging III-IV, 63.89% with bone marrow involvement, and 49.07% with splenic infiltration. Patients with BMI ≥ 24 kg/mBMI is an independent prognostic factor for PFS and OS in MCL, and may be influenced by the effect of B symptoms on BMI.体质指数对套细胞淋巴瘤预后的影响.探讨不同的体质指数（BMI）与套细胞淋巴瘤（MCL）预后的相关性.回顾性分析福建医科大学附属协和医院收治的108例套细胞淋巴瘤患者的临床特征、生物学指标，分析不同的BMI对MCL患者总生存期（OS）和无进展生存期（PFS）的影响。进一步观察BMI与B症状、LDH及Ki-67指数的相关性，以及BMI在自体外周血造血干细胞移植（Auto-PBSCT）和常规化疗组中的差异.108例患者确诊时中位年龄59（25-79）岁，男女比例是4.4∶1。Ann Arbor 分期Ⅲ-Ⅳ期患者占88.89%，骨髓累及者占63.89%，脾脏浸润者占49.07%。以BMI≥24 kg/mBMI是套细胞淋巴瘤患者PFS和OS的独立预后因素，可能受B症状对BMI的影响.

Oleanolic acid can inhibit edema and exhibit obvious inhibitory activity to inflammatory by activating of the pituitary-adrenal cortical system, inhibiting the synthesis or release of PGs, inhibiting endotoxin-mediated release of HMGB1 by endothelial cells or regulating MAPK, PI3K/Akt/NF- κB/ICAM-1/JAK/STAT signaling pathways, etc. In recent years, an increased number of interesting research work has been carried out on the anti-inflammatory activity and mechanisms of OA derivatives, such as acyloxyimino derivative, 3-acetylated derivatives, novel 3,5-disubstituted isoxazoles derivatives, acetate, ester derivatives and oximes derivatives. The review summaries and highlights the updated advances on the anti-inflammatory activity and mechanism of OA and its derivatives.

Purpose The aim of this study was to establish individualized nomograms to predict survival outcomes in older female patients with stage IV breast cancer who did or did not undergo local surgery, and to determine which patients could benefit from surgery. Methods A total of 3,129 female patients with stage IV breast cancer aged ≥70 years between 2010 and 2015 were included in the Surveillance, Epidemiology, and End Results program. Multivariate Cox regression analysis was used to identify risk factors for overall survival (OS) and breast cancer-specific survival (BCSS). Survival analysis was performed using the Kaplan–Meier plot and log-rank test. Nomograms and risk stratification models were constructed. Results Patients who underwent surgery had better OS (HR = 0.751, 95% CI [0.668–0.843], P, Graphical abstract Image 1, Highlights • The effect of surgery in older patients with stage IV breast cancer (BC) is discussed. • The proportion of older patients with stage IV BC who underwent surgery declined. • A specific group of older patients with stage IV BC can benefit from surgery. • Nomograms can be used to predict the prognosis of older patients with stage IV BC.

OBJECTIVE: To investigate the distribution of body mass index (BMI) and risk factors for obesity in children with Diamond-Blackfan Anemia (DBA). METHODS: The children with DBA who attended National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, from January 2003 to December 2020 were enrolled as subjects. The related clinical data and treatment regimens were recorded. The height and weight data measured within 1 week before or after follow-up time points were collected to calculate BMI. The risk factors for obesity were determined by multivariate regression analysis in children with DBA. RESULTS: A total of 129 children with DBA were enrolled, among whom there were 80 boys (62.0%) and 49 girls (38.0%), with a median age of 49 months (range 3-189 months). The prevalence rate of obesity was 14.7% (19/129). The multivariate logistic regression analysis showed that the absence of ribosomal protein gene mutation was closely associated with obesity in children with DBA (adjusted OR=3.63, 95%CI: 1.16-11.38, adjusted P=0.027). In children with glucocorticoid-dependent DBA, obesity was not associated with age of initiation of glucocorticoid therapy, duration of glucocorticoid therapy, and maintenance dose of glucocorticoids (P>0.05). CONCLUSIONS: There is a high prevalence rate of obesity in children with DBA, and the absence of ribosomal protein gene mutation is closely associated with obesity in children with DBA.

To investigate the therapeutic effect of acupuncture stimulation combined with administration of"Gushen Zhuyu Tang"(decoction for consolidating kidney to eliminate blood stasis, DCKEBS) in the treatment of lumbar disc herniation (LDH) patients.A total of 147 patients with LDH were randomly divided into DCKEBS, acupuncture and DCKEBS+acupuncture groups (After the treatment, the VAS and M-JOA scores, contents of serum TNF-α, MMP-2, Caspase-3 and Caspase-9 were significantly decreased (Acupuncture combined with DCKEBS can relieve pain, improve lumbar muscle strength and lumbar movement function, and reduce serum TNF-α, MMP-2, Caspase-3 and Caspase-9 levels in LDH patients.

To investigate the clinical application of two elastic pedicle internal fixation systems in single-segment lumbar disc herniation fenestration.A retrospective analysis of 64 patients with lumbar intervertebral disc herniation treated by surgery from June 2019 to March 2021. According to the different elastic fixation systems placed during the operation, the patients were divided into ordinary pedicle screw elastic rod link group (elastic rod group) and a special elastic pedicle screw rigid rod fixed connection group (elastic screw group). There were 33 cases in the elastic rod group, including 18 males and 15 females, aged from 30 to 69 years old with an average of(49.18±10.23) years old;and 31 cases in the elastic screw group, including 16 males and 15 females, aged from 32 to 68 with an average of (49.81±9.24) years old. The operation time, intraoperative blood loss, postoperative wound drainage, and postoperative landing time of the two groups were recorded separately. The visual analogue scale (VAS), Japanese Orthopaedic Association (JOA) score, and Oswestry Disability Index (ODI) were compared before and 3, 12 months after operation. The height of the adjacent vertebral space on the lateral DR film before and 12 months after the operation was measured. The clinical efficacy was evaluated by Macnab standard.All the patients successfully completed the operation, and were followed up. The operation time, intraoperative blood loss, postoperative wound drainage and postoperative landing time in the elastic rod group were(63.73±12.01) min, (89.55±16.07) ml, (81.67±16.00) ml, (3.45±0.75) d , while in the elastic nail group was (62.96±11.54) min, (88.35±17.14) ml, (82.29±15.40) ml, (3.29±0.78) d, the difference was not statistically significant. The symptoms of low back pain and lower extremity numbness were significantly improved in all patients after operation. There was no significant difference in VAS, JOA score and ODI between the two groups before and after surgery (In fenestrated nucleus pulposus extraction for lumbar disc herniation, the two elastic pedicle internal fixation systems are equally effective and can be used. The elastic screw internal fixation system has certain advantages when the distance between the two vertebral bodies is short, and the elastic rod cannot be placed or is difficult to be placed, and it is more widely used.

Funder: AIR@InnoHK Programme, We analysed the effectiveness of various non-pharmaceutical interventions in containing the 2022 Omicron outbreak in China. The results show that the Rapid Antigen Test contributed to containing the outbreak, reducing the reproduction number by 0.788 (95% CI:−0.306, 1.880) in studied cities.

Objective Clozapine is the most effective therapy for schizophrenia. This study compared the bioequivalence of a generic formulation of clozapine (ChangZhou Pharmaceutical Factory Co. Ltd. Jiangsu, China) to the brand name formulation (Clozaril, HLS Therapeutics, Inc., Philadelphia, PA, USA) after multiple doses in Chinese schizophrenic patients. Materials and methods This was a randomized, open-label, multiple-dose, 2-way crossover study in which patients with schizophrenia received the generic clozapine or Clozaril 100 mg twice daily for 10 days before crossing over to the alternate formulation for the next 10 days. Blood samples were collected at regular intervals during each treatment period, and plasma concentration of clozapine was determined by high-performance liquid chromatography. Results 26 patients were enrolled, of whom 24 completed the study and were included in the steady-state analyses. The mean AUC0-12 was 6,003.29 h×ng/mL for generic clozapine and 6,347.53 h×ng/mL for Clozaril. The mean Cmax,ss was 698.52 ng/mL for generic clozapine and 739.75 ng/mL for Clozaril. The ratio of the adjusted geometric means and its 90% CI of the ratios for AUC0-12 was 96.24% (89.60 - 103.36%), and for Cmax,ss was 95.90% (88.91 - 103.44%). A total of 66 adverse events were reported by 22 (84.62%) subjects. Among them, 34 occurred in 17 (65.38%) patients during dosing of generic clozapine, and 32 occurred in 16 (61.54%) patients during dosing of brand-name clozapine. Conclusion The result demonstrated that the generic clozapine was bioequivalent to brand-name clozapine (Clozaril). This would provide physicians with reassurance that patients who receive the studied generic clozapine will achieve similar plasma drug concentrations to those of brand-name clozapine (Clozaril).

Background:. There were few studies on real-world data about autologous hematopoietic stem cell transplantation (auto-HSCT) or allogeneic HSCT (allo-HSCT) in peripheral T-cell lymphoma (PTCL). This study aimed to investigate the clinical outcomes of patients who received auto-HSCT or allo-HSCT in China. Methods:. From July 2007 to June 2017, a total of 128 patients who received auto-HSCT (n = 72) or allo-HSCT (n = 56) at eight medical centers across China were included in this study. We retrospectively collected their demographic and clinical data and compared the clinical outcomes between groups. Results:. Patients receiving allo-HSCT were more likely to be diagnosed with stage III or IV disease (95% vs. 82%, P = 0.027), bone marrow involvement (42% vs. 15%, P = 0.001), chemotherapy-resistant disease (41% vs. 8%, P = 0.001), and progression disease (32% vs. 4%, P

Oncogene-derived metabolic reprogramming is important for anabolic growth of cancer cells, which is now considered to be not simply rely on glycolysis. Pentose phosphate pathway and tricarboxylic acid cycle also play pivotal roles in helping cancer cells to meet their anabolic and energy demands. The present work focused on gankyrin, a relatively specific oncogene in hepatocellular carcinoma (HCC), and its impact on glycolysis and mitochondrial homeostasis. Metabolomics, RNA-seq analysis, and subsequent conjoint analysis illustrated that gankyrin regulated the pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and mitochondrial function and homeostasis, which play pivotal roles in tumor development. Mechanistically, gankyrin was found to modulate HCC metabolic reprogramming via TIGAR. Gankyrin positively regulated the transcription of TIGAR through Nrf2, which bound to the antioxidant response elements (AREs) in the promoter of TIGAR. Interestingly, TIGAR feedback regulated the transcription of Nrf2 and subsequently gankyrin by promoting nuclear importation of PGC1α. The loop between gankyrin, Nrf2, and TIGAR accelerated glucose metabolism toward the PPP and TCA cycle, which provided vital building blocks, such as NADPH, ATP, and ribose of tumor and further facilitated the progression of HCC.

BACKGROUND This study aimed to investigate the optimum time to reintroduce the original antiplatelet drugs after upper gastrointestinal hemorrhage in patients as secondary prevention for cardiovascular and cerebrovascular diseases. MATERIAL AND METHODS After the upper gastrointestinal bleeding stopped, patients were randomly divided according to the oral antiplatelet drugs administered. The aspirin group was further divided into 3-day and 7-day aspirin groups. The patients who took aspirin and clopidogrel were randomly divided into 3 groups: 0-day aspirin+3-day clopidogrel; 0-day aspirin+7-day clopidogrel; and 3-day aspirin+7-day clopidogrel. The recovery time, rebleeding rate, incidence of cardiovascular and cerebrovascular events, and death were observed. RESULTS The 3-day aspirin group had more rebleeding, reduced risk of cardiovascular and cerebrovascular events, and a similar mortality rate compared to the other groups. In the aspirin+clopidogrel group, the 0-day aspirin+3-day clopidogrel group had the highest rebleeding rate and the lowest risk of cardiovascular and cerebrovascular events. The 3-day aspirin+7-day clopidogrel group had the highest risk of cardiovascular and cerebrovascular events and increased hospitalization time. The risk of rebleeding and cardiovascular and cerebrovascular events was lower in the 0-day aspirin+7-day clopidogrel group, and the overall mortality rate was the lowest in this group. CONCLUSIONS In patients receiving only aspirin, this drug should be reintroduced as soon as possible after peptic ulcer hemorrhage. Aspirin and clopidogrel are dual antiplatelet drugs used for the secondary prevention of cardiovascular diseases. In patients under dual-drug therapy, aspirin should not be stopped, while clopidogrel should be restarted in about 7 days.

This study aimed to investigate the research trend of traditional Chinese medicine(TCM) against premature ovarian fai-lure(POF) from 1989 to 2021 by bibliometrics and explore the research status, research hotspots, and advances in international co-operation, knowledge structure, and active topics.The research articles on POF published from database inception to December 28, 2021, were retrieved from Web of Science and China National Knowledge Infrastructure(CNKI) and visually analyzed for countries, journals, authors, institutions, and keywords by CiteSpace 5.8.R3.A total of 1 468 articles were included, including 217 in English and 1 251 in Chinese.Since 1989, there has been an overall upward trend in the number of articles, with China serving as the main contributor.The core authors of Chinese articles are from a cooperative team represented by FENG Yi-xuan, REN Yu-lan, LING Le-le, and TENG Xiu-xiang.BETTERLE C is the author with the highest number of published articles in this international research field.The articles are mainly published by TCM journals and universities, and Human Reproduction accounts for the highest proportion of publications in the international research(11 articles, 5.07%).In the retrieved research articles, the research contents mainly focus on the treatment methods, research methods, and mechanism of action of TCM in the treatment of POF, wherequot;Zuogui Pillsquot;quot;genequot;quot;cellquot;quot;modelquot;quot;expressionquot;, etc.are the current research hotspots.quot;Acupuncturequot;quot;data miningquot;quot;systematic reviewquot;quot;oxidative stressquot;quot;activationquot; may be the potential topics in the follow-up research development.Future development should focus on the scientific interpretation and analysis of the theory and practice of TCM by modern scientific and technological methods.The research on informatization, digitization, and knowledge of TCM theory and practice is pivotal to promoting the internationalization and modernization of TCM, which can help researchers explore new directions for future research and identify new perspectives for potential collaboration in the field.

Background Situs inversus totalis (SIT) is a relatively rare congenital abnormality in which the major thoracic and abdominal visceral organs are reversed from their usual positions. In patients with SIT and bronchial carcinoma, surgical difficulty increases sharply. It has been reported that the video-assisted thoracic surgery (VATS) still poses the operator to a challenge situation. The similarity of surgical positions and the flexibility of the mechanical arm in robotic surgery, may be beneficial to SIT patients due to reducing technical difficulties. Here, we present a first case of SIT patient with lung cancer, in which Da Vinci robot-assisted thoracic surgery (RATS) was performed successfully. Case presentation A 66-year old patient, previously diagnosed with SIT since childhood, came to our hospital with two pulmonary nodules in his left lung field. The bigger one had increased somewhat for the last 2 years of follow-up. Software Mimics was preoperatively carried out to analyze anatomical variations. RATS was conducted to complete left upper lobectomy and left middle wedge resection. The patient had no intraoperative complications and was discharged day 5 after the operation. Conclusions This is the first report of a successful robot-assisted lung cancer resection in a patient with SIT. In such challenging cases as lung cancer and rare anomaly as SIT, RATS is more advantageous and suitable than VATS with the help of software Mimics utilized for 3D reconstruction, which can identify the anatomical abnormalities and facilitate the surgical procedures.

The R-type voltage-gated Ca

Background Exploring drugs that reverse drug resistance and increase the sensitivity of chemotherapy drugs could significantly improve treatment effect of cancer. Our study explored the reversal effect and possible molecular mechanisms of emodin on cisplatin resistance in A549/DDP cells. Methods The IC50 and resistance index of cells were determined by Cell Counting Kit-8 assay. The ability of cell proliferation was evaluated by wound healing assay. Transwell assay was used to detect cell invasion and migration. Apoptosis induction rate was determined by flow cytometry assay and 4',6- diamidino- 2-phenylindole staining. Intracellular concentration was determined by HPLC. Western blot analysis was applied to determine expressions of nuclear factor kappa beta (NF-κB) and its downstream proteins. Results In this study, we found that the growth inhibitory effect of cisplatin was significantly enhanced by emodin in A549/DDP cells. The combined use of emodin with DDP can effectively promote lung cancer cells apoptosis and inhibit cell migration and invasion. Further investigation indicated that reinforcement effect of emodin and DDP may be associated with inhibition of NF-κB pathway and drug efflux-related proteins such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and Glutathione S-transferase (GST). The key role of NF-κB was further confirmed by the application of NF-κB inhibitor Ammonium pyrrolidinedithiocarbamate. The intervention of both can significantly increase A549/DDP cell apoptosis and inhibit DDP-induced upregulation of P-gp, MRP and GST. Conclusions Emodin reverses the cisplatin resistance of tumor cells by down-regulating expression of P-gp, MRP and GST, increasing the intracellular accumulation in A549/DDP cells, and the effect may be associated with the NF-κB pathways.

Background Necrotic pulmonary lesions manifest as relatively low-density internally on contrast-enhanced computed tomography (CT). However, using CT to differentiate malignant and benign necrotic pulmonary lesions is challenging, as these lesions have similar peripheral enhancement. With the introduction of dual-energy spectral CT (DESCT), more quantitative parameters can be obtained and the ability to differentiate material compositions has been highly promoted. This study investigated the use of kVp-switching DESCT in differentiating malignant from benign necrotic lung lesions. Methods From October 2016 to February 2019, 40 patients with necrotic lung cancer (NLC) and 31 with necrotic pulmonary mass-like inflammatory lesion (NPMIL) were enrolled and underwent DESCT. The clinical characteristics of patients, CT morphological features, and DESCT quantitative parameters of lesions were compared between the two groups. Binary logistic regression analysis was performed to identify the independent prognostic factors differentiating NPMIL from NLC. Receiver operating characteristic (ROC) curves were used to assess the diagnostic performance of single-parameter and multiparametric analyses. Results Significant differences in age, C-reactive protein concentration, the slope of the spectral curve from 40 to 65 keV (K40–65 keV) of necrosis in non-contrast-enhanced scanning (NCS), arterial phase (AP) and venous phase (VP), effective atomic number of necrosis in NCS, and iodine concentration (IC) of the solid component in VP were observed between groups (all p 40–65 keV of necrosis in NCS, and IC of the solid component in VP were the most effective factors for differentiating NLC from NPMIL, with an AUC of 0.966 and percentage of correct class of 88.7%. Conclusions DESCT can differentiate malignant from benign necrotic lung lesions with a relatively high accuracy.

Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

Background:. Norepinephrine infusion decreases hypotension after spinal anesthesia during cesarean section. This study aimed to compare the efficacy of norepinephrine infusion and ephedrine bolus against post-spinal hypotension in parturients. Methods:. In this double-blinded, randomized controlled clinical trial, parturients scheduled for elective cesarean section were randomly allocated to receive norepinephrine infusion (0.05 μg·kg−1·min−1) just before spinal anesthesia continuing for 30 min or ephedrine bolus (0.15 mg/kg) just before spinal anesthesia. A rescue bolus (5 μg norepinephrine for the norepinephrine group, and 5 mg ephedrine for the ephedrine group) was administered whenever hypotension occurred. Our primary outcome was the incidence of hypotension within 30 min of spinal anesthesia administration. Secondary outcomes included maternal and neonatal outcomes 30 min after spinal block, and neonatal cerebral oxygenation 10 min after birth. Results:. In total, 190 patients were enrolled; of these patients, 177 were included in the final analysis. Fewer patients suffered hypotension in the norepinephrine group than in the ephedrine group (29.5% vs. 44.9%, odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.28–0.95, P = 0.034). Moreover, the tachycardia frequency was lower in the norepinephrine group than in the ephedrine group (OR: 0.22, 95% CI: 0.11–0.44, P

Objective To minimize the adverse events of uterine compression suture in controlling postpartum hemorrhage (PPH) and to search for a prophylactic approach to potential PPH. Methods A retrospective analysis was performed in 39 women with removable retropubic uterine compression suture (RRUCS) to stop PPH due to uterine atony during cesarean section (CS). The procedure was to suspend and compress the uterus to the retropubic abdominal wall using an absorbable suture. Results The technique was sufficient to stanch bleeding immediately in 36 patients (92.31%, 36/39). No morbidity or abnormalities occurred in women who underwent RRUCS. Subsequent pregnancies occurred in 10 cases, but the others lacked the desire for future pregnancy. Conclusion RRUCS is a simple, safe, and effective technique in controlling atonic PPH; it is also used as a prophylactic application in patients with potential PPH after CS.

Background Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample. Methods Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry. Results We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP. Conclusions Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.

Juniperus indica Bertol. is an herbal plant that belongs to the genus Juniperus, which is commonly used in traditional medicine to refresh the mind and for diuretic use. However, few studies have reported the function of J. indica Bertol. Hence, this study aimed to investigate the anti-tumor and synergistic potential of J. indica Bertol. extract (JIB extract) for melanoma cells. Our results indicated the anti-melanoma activity of JIB extract. JIB extract induced cell cycle arrest at the G0/G1 phase and decreased cyclin and cdk protein expressions. In addition, AKT/mTOR signaling and MAPK signaling were inhibited by JIB extract to suppress melanoma cell growth and proliferation. Additionally, JIB extract induced B16/F10 cell apoptosis via the caspase cascade. According to the JIB extract's anti-melanoma capacity, to assess the synergistic effects of cisplatin and JIB extract. The results demonstrated that JIB extract combined with cisplatin enhanced the inhibition of cell growth, proliferation, and survival through the obstruction of cell cycle progression and AKT/mTOR and MAPK signaling as well as the induction of cell apoptosis. Collectively, our results indicate that JIB extract showed anti-tumor effects and synergized with cisplatin against B16/F10 cells, indicating the possibility of JIB extract to be developed as adjuvant therapy for melanoma.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with great invasiveness and resistance to chemotherapy, which presents a treatment challenge. In this study, we investigated the antitumor effect of Cedrol, a sesquiterpene alcohol isolated from Cedrus atlantica, against GBM cells in vitro and in vivo. Cedrol was found to potently inhibit cell growth and induce intracellular ROS generation and DNA damage response. In addition, Cedrol induced significant G0/G1 cell cycle arrest and cell apoptosis via the extrinsic (Fas/FasL/Caspase-8) and intrinsic (Bax/Bcl-2/Caspase-9) pathways. In addition, Cedrol had a synergistic effect with temozolomide (TMZ) and reduced drug resistance by blockage of the AKT/mTOR pathway. Cedrol suppressed tumor growth in both orthotopic and xenograft GBM animal models with low or no short-term acute toxicity or long-term accumulative toxicity. In a molecular docking study, Cedrol targeted the androgen receptor (AR), and reduced DHT-mediated AR nuclear translocation, downstream gene KLK3/TMPRSS2 expression and cell proliferation. Our study demonstrates that Cedrol may be a potential candidate for drug development for single or combination treatment with TMZ in GBM therapy.

Fifty percent of Asians are born without a supratarsal fold (also called single eyelid), and double eyelid blepharoplasty is one of the most commonly performed and most popular facial cosmetic surgeries in the Asian population. However, patients with single eyelid frequently present with concomitant mild blepharoptosis (degree of ptosis, ≤2 mm), which often fails to cause the attention of surgeons and misses correction.A retrospective study of all patients who underwent double eyelid blepharoplasty and blepharoptosis correction simultaneously with the modified levator aponeurosis plication technique was performed from June of 2017 to June of 2020.A total of 108 patients (155 eyelids) underwent double eyelid blepharoplasty and blepharoptosis correction simultaneously with the modified levator aponeurosis plication technique and were enrolled in the study. The average follow-up period was 11.8 ± 4.5 months. There was a statistically significant difference between the preoperative margin reflex distance 1 (MRD1) and postoperative MRD1 (2.93 ± 0.37 vs 4.21 ± 0.39 mm, P = 0.000), and the mean MRD1 improvement was 1.28 ± 0.50 mm. Sufficient correction was obtained in 148 eyelids (95.5%), whereas undercorrection was observed in 5 eyelids (3.2%) and overcorrection was observed in 2 eyelids (1.3%). One hundred two patients (94.4%) were completely satisfied with the final result.All patients had smooth and elegant upper eyelid margin curve, and no patients complained of distortion of the eyelid margin contour and foreign body sensation.There were no cases of hematoma, infection, suture exposure, corneal abrasion, and keratitis in any patient.This modified levator aponeurosis plication introduced in this study is a simple and effective method for creating double-eyelid crease and correcting mild blepharoptosis simultaneously, and provides a satisfactory outcome. As such, we recommend this method in treating patients with both single eyelid and mild blepharoptosis.

During development, cells constantly undergo fate choices by differentiating, proliferating, and dying as part of tissue remodeling. However, we only begin to understand the mechanisms of these different fate choices. Here, we took the lepidopteran insect

Background Accurate diagnosis of unexplained cervical lymphadenopathy (CLA) using medical images heavily relies on the experience of radiologists, which is even worse for CLA patients in underdeveloped countries and regions, because of lack of expertise and reliable medical history. This study aimed to develop a deep learning (DL) radiomics model based on B-mode and color Doppler ultrasound images for assisting radiologists to improve their diagnoses of the etiology of unexplained CLA. Methods Patients with unexplained CLA who received ultrasound examinations from three hospitals located in underdeveloped areas of China were retrospectively enrolled. They were all pathologically confirmed with reactive hyperplasia, tuberculous lymphadenitis, lymphoma, or metastatic carcinoma. By mimicking the diagnosis logic of radiologists, three DL sub-models were developed to achieve the primary diagnosis of benign and malignant, the secondary diagnosis of reactive hyperplasia and tuberculous lymphadenitis in benign candidates, and of lymphoma and metastatic carcinoma in malignant candidates, respectively. Then, a CLA hierarchical diagnostic model (CLA-HDM) integrating all sub-models was proposed to classify the specific etiology of each unexplained CLA. The assistant effectiveness of CLA-HDM was assessed by comparing six radiologists between without and with using the DL-based classification and heatmap guidance. Results A total of 763 patients with unexplained CLA were enrolled and were split into the training cohort (n=395), internal testing cohort (n=171), and external testing cohorts 1 (n=105) and 2 (n=92). The CLA-HDM for diagnosing four common etiologies of unexplained CLA achieved AUCs of 0.873 (95% CI: 0.838–0.908), 0.837 (95% CI: 0.789–0.889), and 0.840 (95% CI: 0.789–0.898) in the three testing cohorts, respectively, which was systematically more accurate than all the participating radiologists. With its assistance, the accuracy, sensitivity, and specificity of six radiologists with different levels of experience were generally improved, reducing the false-negative rate of 2.2–10% and the false-positive rate of 0.7–3.1%. Conclusions Multi-cohort testing demonstrated our DL model integrating dual-modality ultrasound images achieved accurate diagnosis of unexplained CLA. With its assistance, the gap between radiologists with different levels of experience was narrowed, which is potentially of great significance for benefiting CLA patients in underdeveloped countries and regions worldwide.

Background Hydroquinone (HQ) is a phenolic metabolite of benzene with a potential risk for hematological disorders and hematotoxicity in humans. In the present study, an integrative analysis of microRNA (miRNA) and mRNA expressions was performed to identify potential pathways and miRNA-mRNA network associated with benzene metabolite hydroquinone-induced hematotoxicity. Methods K562 cells were treated with 40 μM HQ for 72 h, mRNA and miRNA expression changes were examined using transcriptomic profiles and miRNA microarray, and then bioinformatics analysis was performed. Results Out of all the differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) induced by HQ, 1482 DEGs and 10 DEMs were up-regulated, and 1594 DEGs and 42 DEMs were down-regulated. HQ-induced DEGs were involved in oxidative stress, apoptosis, DNA methylation, histone acetylation and cellular response to leukemia inhibitory factor GO terms, as well as metabolic, Wnt/β-catenin, NF-κB, and leukemia-related pathways. The regulatory network of mRNAs and miRNAs includes 23 miRNAs, 1108 target genes, and 2304 potential miRNAs-mRNAs pairs. MiR-1246 and miR-224 had the potential to be major regulators in HQ-exposed K562 cells based on the miRNAs-mRNAs network. Conclusions This study reinforces the use of in vitro model of HQ exposure and bioinformatic approaches to advance our knowledge on molecular mechanisms of benzene hematotoxicity at the RNA level.

OBJECTIVE: To study the association between paroxysmal nocturnal hemoglobinuria (PNH) clone and immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA). METHODS: A retrospective analysis was performed on the medical data of 151 children with SAA who were admitted and received IST from January 2012 to May 2020. According to the status of PNH clone, these children were divided into a negative PNH clone group (n=135) and a positive PNH clone group (n=16). Propensity score matching was used to balance the confounding factors, and the impact of PNH clone on the therapeutic effect of IST was analyzed. RESULTS: The children with positive PNH clone accounted for 10.6% (16/151), and the median granulocyte clone size was 1.8%. The children with positive PNH clone had an older age and a higher reticulocyte count at diagnosis (P0.05). The positive PNH clone group had a significantly lower overall response rate than the negative PNH clone group at 6, 12, and 24 months after IST (P

As a non-invasive detection method and an advanced imaging method, magnetic resonance imaging (MRI) has been widely used in the research of schizophrenia. Although a large number of neuroimaging studies have confirmed that MRI can display abnormal brain phenotypes in patients with schizophrenia, no valid uniform standard has been established for its clinical application. On the basis of previous evidence, we argue that MRI is an important tool throughout the whole clinical course of schizophrenia. The purpose of this commentary is to systematically describe the role of MRI in schizophrenia and to provide references for its clinical application.

Ginseng is a traditional medicine with a complex chemical composition, wide bioactivity and unique pharmacological action. Many studies have confirmed that ginsenosides are the active ingredients of ginseng, and ginsenosides have always been the focus of different researchers. With the development of modern separation and analysis technology, more than 150 kinds of ginsenosides have been isolated. The ginsenosides Rb1, Rb2, Rc, Rg1 and Re account for more than 80% of total ginsenosides, and other saponins, such as Rd, Rg3 and Rh2, which are minor constituents, accounting for only a small portion of the total amount. In recent years, ginsenosides have been found to possess strong pharmacological activities, such as antioxidation, clearing of oxygen free radicals, reducing calcium overload and anti-apoptosis. Ginsenosides play a protective role in ischemia-reperfusion injury. This paper reviews the protective effects of ginsenosides on myocardial ischemia and ischemiareperfusion injury.

Ferroportin is an iron exporter essential for releasing cellular iron into circulation. Ferroportin is inhibited by a peptide hormone, hepcidin. In humans, mutations in ferroportin lead to ferroportin diseases that are often associated with accumulation of iron in macrophages and symptoms of iron deficiency anemia. Here we present the structures of the ferroportin from the primate Philippine tarsier (TsFpn) in the presence and absence of hepcidin solved by cryo-electron microscopy. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. Both structures are in an outward-facing conformation, and hepcidin binds between the two domains and reaches one of the ion binding sites. Functional studies show that TsFpn is an electroneutral H+/Fe2+ antiporter so that transport of each Fe2+ is coupled to transport of two H+ in the opposite direction. Perturbing either of the ion binding sites compromises the coupled transport of H+ and Fe2+. These results establish the structural basis of metal ion binding, transport and inhibition in ferroportin and provide a blueprint for targeting ferroportin in pharmacological intervention of ferroportin diseases., Ferroportin is an iron exporter essential for releasing cellular iron into circulation and is inhibited by a peptide hormone, hepcidin. Here authors present cryo-EM structures of the ferroportin from the primate Philippine tarsier (TsFpn) with and without hepcidin and show that TsFpn is an electroneutral H+ /Fe2+ antiporter.

Duane retraction syndrome (DRS) is a neuromuscular dysfunction of the eyes. Although many causative genes of DRS have been identified in Europe and the United States, few reports have been published in regard to Chinese DRS. The aim of the present study was to explore the genetic defect of DRS in a Chinese family. Exome sequencing was used to identify the disease-causing gene for the two affected family members. Ophthalmic and physical examinations, as well as genetic screenings for variants in chimerin 1 (CHN1), were performed for all family members. Functional analyses of a CHN1 variant in 293T cells included a Rac-GTP activation assay, α2-chimaerin translocation assay, and co-immunoprecipitation assay. Genetic analysis revealed a NM_001822.7: c.637T > G variant in the CHN1 gene, which resulted in the substitution of a highly conserved C1 domain with valine at codon 213 (NP_001813.1: p.(Phe213Val)) (ClinVar Accession Number: SCV001335305). In-silico analysis revealed that the p.(Phe213Val) substitution affected the protein stability and connections among the amino acids of CHN1 in terms of its tertiary protein structure. Functional studies indicated that the p.(Phe213Val) substitution reduced Rac-GTP activity and enhanced membrane translocation in response to phorbol-myristoyl acetate (PMA). Together with previous studies, our present findings demonstrate that CHN1 may be an important causative gene for different ethnicities with DRS.

Glioblastoma (GBM) is a common and aggressive brain tumor with a median survival of 12-15 months. Temozolomide (TMZ) is a first-line chemotherapeutic agent used in GBM therapy, but the occurrence of drug resistance limits its antitumor activity. The natural compound cedrol has remarkable antitumor activity and is derived from Cedrus atlantica. In this study, we investigated the combined effect of TMZ and cedrol in GBM cells in vitro and in vivo. The TMZ and cedrol combination treatment resulted in consistently higher suppression of cell proliferation via regulation of the AKT and MAPK signaling pathways in GBM cells. The combination treatment induced cell cycle arrest, cell apoptosis, and DNA damage better than either drug alone. Furthermore, cedrol reduced the expression of proteins associated with drug resistance, including O6-methlyguanine-DNA-methyltransferase (MGMT), multidrug resistance protein 1 (MDR1), and CD133 in TMZ-treated GBM cells. In the animal study, the combination treatment significantly suppressed tumor growth through the induction of cell apoptosis and decreased TMZ drug resistance. Moreover, cedrol-treated mice exhibited no significant differences in body weight and improved TMZ-induced liver damage. These results imply that cedrol may be a potential novel agent for combination treatment with TMZ for GBM therapy that deserves further investigation.

BackgroundKnowledge on the epidemiological features and transmission patterns of novel coronavirus disease (COVID-19) is accumulating. Detailed line-list data with household settings can advance the understanding of COVID-19 transmission dynamics.MethodsA unique database with detailed demographic characteristics, travel history, social relationships, and epidemiological timelines for 1407 transmission pairs that formed 643 transmission clusters in mainland China was reconstructed from 9120 COVID-19 confirmed cases reported during 15 January–29 February 2020. Statistical model fittings were used to identify the superspreading events and estimate serial interval distributions. Age- and sex-stratified hazards of infection were estimated for household vs nonhousehold transmissions.ResultsThere were 34 primary cases identified as superspreaders, with 5 superspreading events occurred within households. Mean and standard deviation of serial intervals were estimated as 5.0 (95% credible interval [CrI], 4.4–5.5) days and 5.2 (95% CrI, 4.9–5.7) days for household transmissions and 5.2 (95% CrI, 4.6–5.8) and 5.3 (95% CrI, 4.9–5.7) days for nonhousehold transmissions, respectively. The hazard of being infected outside of households is higher for people aged 18–64 years, whereas hazard of being infected within households is higher for young and old people.ConclusionsNonnegligible frequency of superspreading events, short serial intervals, and a higher risk of being infected outside of households for male people of working age indicate a significant barrier to the identification and management of COVID-19 cases, which requires enhanced nonpharmaceutical interventions to mitigate this pandemic.

Objective Hepatitis B virus X protein (HBx) is a pivotal factor for HBV-induced hepatitis. Herein, we sought to investigate HBx-mediated NLR pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis under oxidative stress. Methods The effect of HBx on the NLRP3 inflammasome was analyzed by enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence in hepatic HL7702 cells. Pyroptosis was evaluated by western blotting, lactate dehydrogenase release, propidium iodide staining, and transmission electron microscopy. NLRP3 expression in the inflammasome from liver tissues was assessed by immunohistochemistry. Results In hydrogen peroxide (H2O2)-stimulated HL7702 cells, HBx triggered the release of pro-inflammatory mediators apoptosis-associated speck-like protein containing a CARD (ASC), interleukin (IL)-1β, IL-18, and high-mobility group box 1 (HMGB1); activated NLRP3; and initiated pro-inflammatory cell death (pyroptosis). HBx localized to the mitochondria, where it induced mitochondrial damage and production of mitochondrial reactive oxygen species (mitoROS). Treatment of HL7702 cells with a mitoROS scavenger attenuated HBx-induced NLRP3 activation and pyroptosis. Expression levels of NLRP3, ASC, and IL-1β in liver tissues from patients were positively correlated with HBV DNA concentration. Conclusions The NLRP3 inflammasome was activated by elevated mitoROS levels and mediated HBx-induced liver inflammation and hepatocellular pyroptosis under H2O2-stress conditions.