Background Clozapine belongs to atypical antipsychotic drugs that has shown significant efficacy in treating schizophrenia.However,clozapine can induce arrhythmias in patients.Currently,there is a lack of systematic research on the types and incidence of clozapine-induced arrhythmias.Objective To explore the types and incidence of arrhythmias in patients with schizophrenia induced by clozapine through Meta-analysis,so as to provide references for clinical treatment.Methods On October 31,2022,a search was conducted through PubMed,Embase,Cochrane Library and China National Knowledge Infrastructure(CNKI)to collect relevant literature on clozapine-induced arrhythmia in patients with schizophrenia.Joanna Briggs Institute(JBI)was used to evaluate the quality of the included literature.Meta-analysis was conducted using Review Manager 5.4.Results A total of 12 studies were included,involving 42 490 schizophrenia patients taking clozapine.The incidence of arrhythmias caused by clozapine was 23％(95％CI:0.16～0.29).Among them,the incidence of tachycardia was 25％(95％CI:0.15～0.35),atrial arrhythmia was 6％(95％CI:-0.02～0.14),ventricular arrhythmia was 7％(95％CI:-0.02～0.16),conduction block was 2％(95％CI:0～0.04),QTc prolongation was 4％(95％CI:-0.04～0.12)and T-wave changes was 23％(95％CI:0.16～0.30).Conclusion Schizophrenia patients taking clozapine may increase their risk of developing arrhythmia,with tachycardia being the most prevalent.

Background::Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis (UC). Here, we developed a novel diagnostic criterion for assessing histological healing in UC patients.Methods::We conducted a retrospective cohort study in UC patients, whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People’s Hospital of Tongji University from January 2017 to May 2022. We identified an inflammatory cell enumeration index (ICEI) for assessing histological healing based on the proportions of eosinophils, CD177 + neutrophils, and CD40L + T cells in the colonic lamina propria under high power field (HPF), and the outcomes (risks of symptomatic relapses) of achieving histological remission vs. persistent histological inflammation using Kaplan-Meier curves. Intrareader reliability and inter-reader reliability were evaluated by each reader. The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness. The ICEI was further validated in a new cohort of UC patients from other nine university hospitals. Results::We developed an ICEI for clinical diagnosis of histological healing, i.e., Y = 1.701X 1 + 0.758X 2 + 1.347X 3 - 7.745 (X 1, X 2, and X 3 represent the proportions of CD177 + neutrophils, eosinophils, and CD40L + T cells, respectively, in the colonic lamina propria under HPF). The receiver operating characteristics curve (ROC) analysis revealed that Y <-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve (AUC) was 0.942 (95% confidence interval [CI]: 0.905-0.979) with a sensitivity of 92.5% and a specificity of 83.6% ( P <0.001). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.855 (95% CI: 0.781-0.909), and ICEI had good inter-reader reliability of 0.832 (95% CI: 0.748-0.894). During an 18-month follow-up, patients with histological healing had a substantially better outcome compared with those with unachieved histological healing ( P <0.001) using ICEI. During a 12-month follow-up from other nine hospitals, patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing. Conclusions::ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy. Therefore, ICEI provides a promising, simplified approach to monitor histological healing and to predict the prognosis of UC.Registration::Chinese Clinical Trial Registry, No. ChiCTR2300077792.

ObjectiveTo observe the therapeutic effects of Qishao Huoxue prescription on patients with lumbar disc herniation due to Qi stagnation and blood stasis and the effects of this prescription on hemorheological parameters and serum levels of inflammatory mediators. MethodA total of 86 patients with lumbar disc herniation due to Qi stagnation and blood stasis treated in the Wangjing Hospital of China Academy of Chinese Medical Sciences from January 2023 to February 2024 were selected and assigned according to the random number table into observation and control groups （n=43）. Patients in both groups received lumbar traction treatment. In addition， the observation group was orally treated with Qishao Huoxue prescription and the control group with celebrex for 3 weeks. The visual analogue scale （VAS） score， Oswestry disabilitiy index （ODI） score， 12-item Short-Form Survey （SF-12） score， traditional Chinese medicine （TCM） symptom score， hemorheological parameters ［whole blood high shear viscosity， middle shear viscosity， low shear viscosity， plasma viscosity （PV）， and fibrinogen （FIB）］， and the serum levels of inflammatory mediators ［tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， interleukin-1β （IL-1β）， and transforming growth factor-β₁ （TGF-β₁）］ were determined before and after treatment. In addition， the clinical efficacy and adverse reactions were observed and compared between the two groups. ResultAfter treatment， both groups showed declined VAS， ODI， and TCM symptom scores （P<0.05）， increased SF-12 physical component summary （PCS） and mental component summary （MCS） scores （P<0.05）. After treatment， the whole blood high shear viscosity， middle shear viscosity， low shear viscosity， PV， and FIB decreased in the observation group （P<0.05）， while they did not show significant variations in the control group. After treatment， both groups of patients showed reductions in TNF-α， IL-6， and IL-1β levels and an elevation in the TGF-β₁ level （P<0.05）. Compared with the control group after treatment， the observation group showed decreases in VAS， ODI， TCM symptom scores and main symptom scores （P<0.05）， no significant differences in the secondary symptom scores， increased PCS and MCS scores （P<0.05）. The observation group outperformed the control group in terms of recovering whole blood high shear viscosity， middle shear viscosity， low shear viscosity， PV， FIB， TNF-α， IL-6， IL-1β， and TGF-β₁ （P<0.05）. The total response rate in the observation group was 97.5% （40/41）， which was higher than that （88.1%， 37/42） in the control group （P<0.05）. No serious adverse reaction was observed in the two groups during the observation period. One case in the observation group showed subcutaneous bruising on the lower limbs， which gradually disappeared after withdrawal. ConclusionQishao Huoxue prescription demonstrated definite effect in treating lumbar disc herniation due to qi stagnation and blood stasis by recovering hemorheological parameters and inhibiting the expression of inflammatory mediators in the serum without inducing adverse reactions. It is worth applying in clinical practice.

As a branched chain amino acid, L-valine is widely used in the medicine and feed sectors. In this study, a microbial cell factory for efficient production of L-valine was constructed by combining various metabolic engineering strategies. First, precursor supply for L-valine biosynthesis was enhanced by strengthening the glycolysis pathway and weakening the metabolic pathway of by-products. Subsequently, the key enzyme in the L-valine synthesis pathway, acetylhydroxylate synthase, was engineered by site-directed mutation to relieve the feedback inhibition of the engineered strain. Moreover, promoter engineering was used to optimize the gene expression level of key enzymes in L-valine biosynthetic pathway. Furthermore, cofactor engineering was adopted to change the cofactor preference of acetohydroxyacid isomeroreductase and branched-chain amino acid aminotransferase from NADPH to NADH. The engineered strain C. glutamicum K020 showed a significant increase in L-valine titer, yield and productivity in 5 L fed-batch bioreactor, up to 110 g/L, 0.51 g/g and 2.29 g/(L‧h), respectively.
Valine ; Corynebacterium glutamicum/genetics* ; Metabolic Engineering ; Amino Acids, Branched-Chain ; Bioreactors

Objective:To investigate the expression of INHBA in colorectal cancer and its relationship with microsatellite status and clinicopathological features.Methods:Bioinformatics analysis was conducted based on Gene Expression Omnibus (GEO) database and Gene Expression Profiling Interaction Analysis (GEPIA) database, and the differentially expressed prognosis-related target genes in colorectal cancer were selected. Wax mass tissues of 107 patients with colorectal cancer who underwent surgery from January 2016 to June 2022 in the Third Affiliated Hospital of Jinzhou Medical University were collected, and the tissue microarrays were prepared. The clinicopathological microsatellite status [positive expressions of the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2 were mismatch repair proficient (pMMR), which represented low microsatellite instability or microsatellite stabilization; if any of these indexes was negative, it was judged to be mismatch repair deficient (dMMR), which represented high microsatellite instability] and INHBA expression in colorectal cancer tissues were detected by immunohistochemistry, data of the patients were retrospectively analyzed. The relationship between INHBA and microsatellite status as well as clinicopathological features was analyzed.Results:Three data sets of colorectal cancer were selected from GEO database: GSE110223 (13 cancer tissues, 13 paracancerous tissues), GSE110224 (17 cancer tissues, 17 paracancerous tissues), GSE113513 (14 cancer tissues, 14 paracancerous tissues), and the top 50 genes that were differentially up-regulated and down-regulated between cancer tissues and paracancerous tissues were screened. Intersection genes of 3 data sets were analyzed by Venn diagram, and 12 up-regulated genes and 17 down-regulated genes were screened out. According to GEPIA database, AQP8, ZG16 and INHBA genes among the up-regulated and down-regulated differential genes were associated with the prognosis of colorectal cancer. INHBA was higher expressed in colorectal cancer tissues than in paracancerous tissues (≥5 cm from the tumor margin) ( P < 0.05), and INHBA gene was selected for analysis. Immunohistochemical detection of collected colorectal cancer wax samples showed that the proportion of patients with high INHBA expression in colorectal cancer tissues was higher than that in paracancerous tissues [85.05% (91/107) vs. 67.29% (72/107), P < 0.05]. The high expression of INHBA in cancer tissues was related to the lesion site [right colon vs. left colon: 94.00% (47/50) vs. 77.19% (44/57)], maximum tumor diameter [>5 cm vs. ≤5 cm: 92.73% (51/55) vs. 76.92% (40/52)] and the depth of invasion [stage T 3-4 vs. stage T 1-2: 96.43% (54/56) vs. 72.55% (37/51)], differentiation degree [low and medium differentiation vs. high differentiation: 91.04% (61/67) vs. 75.00% (30/40)], lymph node metastasis [yes vs. no: 93.02% (40/43) vs. 78.13% (50/64)] (all P < 0.05), but had no correlation with age, sex, thrombus and nerve invasion (all P > 0.05). The proportion of patients with high expression of INHBA in colorectal cancer tissues in pMMR group was higher than that in dMMR group [93.22% (55/59) vs. 75.00% (36/48), χ2 = 6.91, P = 0.008]. Conclusions:INHBA is highly expressed in colorectal cancer tissues, and the highly expressed INHBA is closely related to clinicopathological features and microsatellite status of colorectal cancer. INBHA may be a new target for diagnosis, treatment and prognosis of colorectal cancer.

Objective To investigate the effects of formononetin (FMN) on cognitive behavior and inflammation in aging rats with chronic unpredictable mild stress (CUMS). Methods SD rats aged about 70 weeks were divided into healthy control group, CUMS model group, CUMS combined with 10 mg/kg FMN group, CUMS combined with 20 mg/kg FMN group and CUMS combined with 1.8 mg/kg fluoxetine hydrochloride (Flu) group. Except for healthy control group, other groups were stimulated with CUMS and administered drugs for 28 days. Sugar water preference, forced swimming experiment and open field experiment were used to observe the emotional behavior of rats in each group. HE staining was used to observe the pathological injury degree of brain equine area. The contents of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected by the kit. The apoptosis was tested by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) in the brain tissue. The levels of tumor necrosis factor α (TNF-α), inducible nitric oxide synthase (iNOS) and interleukin 6 (IL-6) in peripheral blood were measured by ELISA. Western blot analysis was used to detect Bcl2, Bcl2 associated X protein (BAX), cleaved caspase-9, cleaved caspase-3, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and phosphorylated nuclear factor κB p65 (p-NF-κB p65) in brain tissues. Results Compared with CUMS model group, sugar water consumption, open field activity time, open field travel distance and swimming activity time significantly increased in the CUMS combined with 20 mg/kg FMN group and the CUMS combined with 1.8 mg/kg Flu group. The number of new outarm entry increased significantly, while the number of initial arm entry and other arm entry decreased significantly. The pathological damage of brain equine area was alleviated, and the contents of 5-HT and 5-HIAA were significantly increased. The ratio of BAX/Bcl2 and the expression of cleaved caspase-9 and cleaved caspase-3 protein as well as the number of apoptotic cells were significantly decreased. The contents of TNF-α, iNOS and IL-6 were significantly decreased. The protein levels of TLR4, MyD88 and p-NF-κB p65 were significantly decreased. Conclusion FMN can inhibit the release of inflammatory factors by blocking NF-κB pathway and improve cognitive and behavioral ability of CUMS aged rats.
Rats ; Animals ; Horses ; NF-kappa B/metabolism* ; Signal Transduction ; bcl-2-Associated X Protein/metabolism* ; Toll-Like Receptor 4/metabolism* ; Caspase 3/metabolism* ; Caspase 9/metabolism* ; Interleukin-6/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Myeloid Differentiation Factor 88 ; Hydroxyindoleacetic Acid/pharmacology* ; Serotonin/metabolism* ; Rats, Sprague-Dawley ; Hippocampus/metabolism* ; Cognition

Background::Non-smokers account for a large proportion of lung cancer patients, especially in Asia, but the attention paid to them is limited compared with smokers. In non-smokers, males display a risk for lung cancer incidence distinct from the females—even after excluding the influence of smoking; but the knowledge regarding the factors causing the difference is sparse. Based on a large multicenter prospective cancer screening cohort in China, we aimed to elucidate the interpretable sex differences caused by known factors and provide clues for primary and secondary prevention.Methods::Risk factors including demographic characteristics, lifestyle factors, family history of cancer, and baseline comorbidity were obtained from 796,283 Chinese non-smoking participants by the baseline risk assessment completed in 2013 to 2018. Cox regression analysis was performed to assess the sex difference in the risk of lung cancer, and the hazard ratios (HRs) that were adjusted for different known factors were calculated and compared to determine the proportion of excess risk and to explain the existing risk factors.Results::With a median follow-up of 4.80 years, 3351 subjects who were diagnosed with lung cancer were selected in the analysis. The lung cancer risk of males was significantly higher than that of females; the HRs in all male non-smokers were 1.29 (95% confidence interval [CI]: 1.20-1.38) after adjusting for the age and 1.38 (95% CI: 1.28-1.50) after adjusting for all factors, which suggested that known factors could not explain the sex difference in the risk of lung cancer in non-smokers. Known factors were 7% (|1.29-1.38|/1.29) more harmful in women than in men. For adenocarcinoma, women showed excess risk higher than men, contrary to squamous cell carcinoma; after adjusting for all factors, 47% ([1.30-1.16]/[1.30-1]) and 4% ([7.02-6.75]/[7.02-1])) of the excess risk was explainable in adenocarcinoma and squamous cell carcinoma. The main causes of gender differences in lung cancer risk were lifestyle factors, baseline comorbidity, and family history.Conclusions::Significant gender differences in the risk of lung cancer were discovered in China non-smokers. Existing risk factors did not explain the excess lung cancer risk of all non-smoking men, and the internal causes for the excess risk still need to be explored; most known risk factors were more harmful to non-smoking women; further exploring the causes of the sex difference would help to improve the prevention and screening programs and protect the non-smoking males from lung cancers.

OBJECTIVE To observe the efficacy and safety of albumin-bound paclitaxel in the treatment of advanced non- small cell lung cancer （NSCLC）. METHODS Clinical data of patients with advanced NSCLC treated in our hospital from January 2018 to December 2021 were selected. According to their chemotherapy regimen，they were divided into albumin-bound paclitaxel group and paclitaxel group， with 100 patients in each group. Both groups received chemotherapy regimen containing Paclitaxel for injection （albumin-bound） or Paclitaxel injection for at least 2 cycles （every 21 days as a cycle）. The progression-free survival （PFS） and efficacy of the two groups were compared，and the occurrence of toxic and side effects were recorded. RESULTS The patients in albumin-bound paclitaxel group completed 430 cycles of chemotherapy， with an average of 4.3 cycles； patients in paclitaxel group completed 476 cycles of chemotherapy， with an average of 4.8 cycles. The median PFS （4.0 months） and the response rate （13.00%） of albumin-bound paclitaxel group were not significantly different from those of paclitaxel group （4.0 months，9.00%） （P＞0.05）. The disease control rate （99.00%） was significantly higher than that in paclitaxel group （89.00%）， and the incidences of leukopenia， neutropenia， thrombocytopenia，anemia， sensory neuropathy， fatigue，nausea and vomiting，joint myalgia in albumin-bound paclitaxel group were significantly lower than those in paclitaxel group （P＜0.05）. CONCLUSIONS Albumin-bound paclitaxel is effective in the treatment of advanced NSCLC， and it can better control the progression of the disease and is safer than ordinary paclitaxel.

Objective:To evaluate the effect of radical image-guided radiotherapy (IGRT) on the target dose in cervical cancer and investigate the appropriate application mode.Methods:Twenty patients with cervical cancer treated with helical tomotherapy (HT) in Seventh Medical Center of PLA General Hospital from 2012 to 2016 were selected. A megavoltage CT (MVCT) scan was performed before each treatment. The obtained MVCT images were used for dose parameter in the adaptive module of HT to obtain the actual dose (Plan 1) and the non-image-guided dose parameter was simulated (Plan 2). Each single dose distribution and the corresponding fused CT images were transferred to the software Mimvista 6.5 to obtain the total radiation dose parameter by dose superposition.Results:The motion of CTV, uterus and GTV in Plan 2 was significantly larger than that of Plan 1(all P<0.05), and the largest changes were seen in the ventrodorsal and uterine direction. The V 45Gy, V 50Gy, D 98% and D mean of CTV and uterus and V 50Gy of GTV in Plan 2 were significantly decreased compared with those in Plan 1(all P<0.05). The left-right motion of Plan 1 was negatively correlated with D 2% and D 98% of CTV and uterus (both P<0.05). The head-foot motion was negatively associated with V 45Gy and V 50Gy of GTV (both P<0.05). The ventrodorsal motion was negatively correlated with D 98% of uterus ( P<0.05). The left-right motion of Plan 2 was negatively correlated with D 2% of CTV and V 50Gy of uterus (both P<0.05). The head-foot motion was negatively associated with D 98% of CTV, and D 98%, D mean, V 45Gy and V 50Gy of uterus (all P<0.05). The ventrodorsal motion was negatively correlated with D 98% of CTV, D 98%, D mean, V 45Gy and V 50Gy of uterus, and D mean and V 45Gy of GTV (all P<0.05). Conclusions:In intensity-modulated radiotherapy for cervical cancer, the uterine body displacement is large and the low CTV area is mainly located in the uterine body. IGRT can significantly reduce the dosimetric deviation induced by organ movement.

Objective:To analyze the survival benefits and treatment related toxic effects of simultaneous integrated boost intensity-modulated radiotherapy (SIB-RT) for non-operative esophageal squamous cell carcinoma patients.Methods:The data of 2 132 ESCC patients who were not suitable for surgery or rejected operation, and underwent radical radiotherapy from 2002 to 2016 in 10 hospitals of Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group (3JECROG) were analyzed. Among them, 518 (24.3%) cases underwent SIB (SIB group) and 1 614 (75.7%) cases did not receive SIB (No-SIB group). The two groups were matched with 1∶2 according to propensity score matching (PSM) method (caliper value=0.02). After PSM, 515 patients in SIB group and 977 patients in No-SIB group were enrolled. Prognosis and treatment related adverse effects of these two groups were compared and the independent prognostic factor were analyzed.Results:The median follow-up time was 61.7 months. Prior to PSM, the 1-, 3-, and 5-years overall survival (OS) rates of SIB group were 72.2%, 42.8%, 35.5%, while of No-SIB group were 74.3%, 41.4%, 31.9%, respectively ( P=0.549). After PSM, the 1-, 3-, and 5-years OS rates of the two groups were 72.5%, 43.4%, 36.4% and 75.3%, 41.7%, 31.6%, respectively ( P=0.690). The univariate survival analysis of samples after PSM showed that the lesion location, length, T stage, N stage, TNM stage, simultaneous chemoradiotherapy, gross tumor volume (GTV) and underwent SIB-RT or not were significantly associated with the prognosis of advanced esophageal carcinoma patients who underwent radical radiotherapy ( P<0.05). Cox model multivariate regression analysis showed lesion location, TNM stage, GTV and simultaneous chemoradiotherapy were independent prognostic factors of advanced esophageal carcinoma patients who underwent radical radiotherapy ( P<0.05). Stratified analysis showed that, in the patients whose GTV volume≤50 cm 3, the median survival time of SIB and No-SIB group was 34.7 and 30.3 months ( P=0.155), respectively. In the patients whose GTV volume>50 cm 3, the median survival time of SIB and No-SIB group was 16.1 and 20.1 months ( P=0.218). The incidence of radiation esophagitis and radiation pneumonitis above Grade 3 in SIB group were 4.3% and 2.5%, significantly lower than 13.1% and 11% of No-SIB group ( P<0.001). Conclusions:The survival benefit of SIB-RT in patients with locally advanced esophageal carcinoma is not inferior to non-SIB-RT, but without more adverse reactions, and shortens the treatment time. SIB-RT can be used as one option of the radical radiotherapy for locally advanced esophageal cancer.