Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

Parkinson's disease (PD) is a chronic neurodegenerative disease. At present, levodopa and other drugs are mainly used for dopamine supplementation therapy. However, the absorption of levodopa in the gastrointestinal tract is unstable and its half-life is short, and long-term use of levodopa will lead to the end-of-dose deterioration, dyskinesia, the "ON-OFF" phenomenon and other symptoms. Therefore, new preparations need to be developed to improve drug efficacy, reduce side effects or improve compliance of patients. Based on the above clinical needs, this review briefly introduced the preparation modification strategies for the treatment of PD through case analysis, in order to provide references for the research and development of related preparations.

Objective To explore the efficacy and safety of recombinant human anti-severe acute respiratory syn-drome coronavirus 2(anti-SARS-CoV-2)monoclonal antibody injection(F61 injection)in the treatment of patients with coronavirus disease 2019(COVID-19)combined with renal damage.Methods Patients with COVID-19 and renal damage who visited the PLA General Hospital from January to February 2023 were selected.Subjects were randomly divided into two groups.Control group was treated with conventional anti-COVID-19 therapy,while trial group was treated with conventional anti-COVID-19 therapy combined with F61 injection.A 15-day follow-up was conducted after drug administration.Clinical symptoms,laboratory tests,electrocardiogram,and chest CT of pa-tients were performed to analyze the efficacy and safety of F61 injection.Results Twelve subjects(7 in trial group and 5 in control group)were included in study.Neither group had any clinical progression or death cases.The ave-rage time for negative conversion of nucleic acid of SARS-CoV-2 in control group and trial group were 3.2 days and 1.57 days(P=0.046),respectively.The scores of COVID-19 related target symptom in the trial group on the 3rd and 5th day after medication were both lower than those of the control group(both P＜0.05).According to the clinical staging and World Health Organization 10-point graded disease progression scale,both groups of subjects improved but didn't show statistical differences(P＞0.05).For safety,trial group didn't present any infusion-re-lated adverse event.Subjects in both groups demonstrated varying degrees of elevated blood glucose,elevated urine glucose,elevated urobilinogen,positive urine casts,and cardiac arrhythmia,but the differences were not statistica-lly significant(all P＞0.05).Conclusion F61 injection has initially demonstrated safety and clinical benefit in trea-ting patients with COVID-19 combined with renal damage.As the domestically produced drug,it has good clinical accessibility and may provide more options for clinical practice.

Objective The leptin receptor,encoded by the LEPR gene,is involved in tumorigenesis.A potential functional variant of LEPR,rs1137101(Gln223Arg),has been extensively investigated for its contribution to the risk of digestive system(DS)cancers,but results remain conflicting rather than conclusive.Here,we performed a case-control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk. Methods A total of 1,727 patients with cancer(gastric/liver/colorectal:460/480/787)and 800 healthy controls were recruited.Genotyping of rs1137101 was conducted using a polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)assay and confirmed using Sanger sequencing.Twenty-four eligible studies were included in the meta-analysis. Results After Bonferroni correction,the case-control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population.The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS,gastric,and liver cancer in the Chinese population. Conclusion The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers(especially liver and gastric cancer)in the Chinese population.

Objective:To observe the recurrence condition of hepatitis B in different risk groups after liver transplantation in an attempt to provide useful information on whether to discontinue hepatitis B immunoglobulin (HBIG) in the future at an early stage.Methods:The patient population was divided into high, low-risk, and special groups [especially primary hepatocellular carcinoma (HCC)] according to the guidelines for the prevention and treatment of hepatitis B recurrence after liver transplantation. The recurrence condition and risk factors in this population were observed for hepatitis B. Measurement data were analyzed using a t-test and a rank-sum test. Count data were compared using a χ2 test between groups. Results:This study finally included 532 hepatitis B-related liver transplant cases. A total of 35 cases had HBV recurrence after liver transplantation, including 34 cases that were HBsAg positive, one case that was HBsAg negative, and 10 cases that were hepatitis B virus (HBV) DNA positive. The overall HBV recurrence rate was 6.6%. The recurrence rate of HBV was 9.2% and 4.8% in the high- and low-risk HBV DNA positive and negative groups before surgery ( P = 0.057). Among the 293 cases diagnosed with HCC before liver transplantation, 30 had hepatitis B recurrence after surgery, with a recurrence rate of 10.2%. The independent related factors for the recurrence of hepatitis B in patients with HCC after liver transplantation were HCC recurrence ( HR =181.92, 95% CI 15.99~2 069.96, P < 0.001), a high postoperative dose of mycophenolate mofetil dispersible tablets (MMF) ( HR =5.190, 95% CI 1.289~20.889, P = 0.020), and a high dosage of HBIG ( HR = 1.012, 95% CI 1.001~1.023, P = 0.035). Among the 239 cases who were non-HCC before liver transplantation, five cases (recurrence rate of 2.1%) arouse postoperative hepatitis B recurrence. Lamivudine was used in all cases, combined with on-demand HBIG prophylaxis after surgery. There was no hepatitis B recurrence in non-HCC patients who treated with entecavir combined with HBIG after surgery. Conclusion:High-barrier-to-resistance nucleotide analogues combined with long-term HBIG have a good effect on preventing the recurrence of hepatitis B after liver transplantation. The discontinuation of HBIG may be considered at an early stage after administration of a high-barrier-to-resistance nucleotide analogue in low-risk patients. Domestically, the HBV infection rate is high, so further research is still required to explore the timing of HBIG discontinuation for high-risk patients, especially those with HCC.

Objective:To construct a prognostic predictive model for patients with moderate to severe traumatic brain injury (msTBI) based on regional cerebral oxygen saturation (rScO 2) and transcranial Doppler ultrasound (TCD) monitoring parameters and validate its effectiveness. Methods:A retrospective cohort study was conducted to analyze the clinical data of 161 patients with msTBI who were treated at Henan Provincial People′s Hospital from January 2021 to December 2022, including 104 males and 57 females, aged 19-76 years [(53.1±12.8)years]. Glasgow coma scale (GCS) score was 3-12 points [(7.0±1.9)points]. Both rScO 2 and TCD monitoring were performed. Based on the results of prognostic evaluation of patients with the modified Rankin scale (mRS) score at 90 days after discharge, the patients were divided into good prognosis group (mRS score≤3 points, n=88) and poor prognosis group (mRS score of 4-6 points, n=73). The following data of the two groups were collected: the general data, clinical data, rScO 2 monitoring parameters and TCD monitoring parameters. Univariate analysis was employed to compare the differences in the relevant prognostic indicators. Multivariate Logistic stepwise regression analysis was conducted to determine the predictors of poor prognostic outcomes in msTBI patients and regression equations were constructed. A nomogram predictive model based on regression equations was drawn with R language. The discriminability of the model was evaluated by drawing the receiver operating characteristic (ROC) curve, to calculate the area under the curve (AUC), sensitivity, specificity, and Jordan index of the model, and measuring the consistency index (C index). Hosmer-Lemeshow (H-L) goodness of fit test was conducted to evaluate the fit of the model, and the calibration curve was used to evaluate the calibration degree of the model. Decision curve analysis (DCA) was employed to evaluate the clinical benefit and applicability of the model. Results:There were significant differences between the two groups in the clinical data (cerebral hernia formation, GCS on admission, acute physiology and chronic health evaluation II (APACHE II) score on admission, Rotterdam CT score on admission, oxygenation index on admission, mean arterial pressure on admission), rScO 2 monitoring parameters (mean rScO 2, maximum rScO 2, rScO 2 variability), TCD monitoring parameters [peak systolic blood flow velocity (Vs), average blood flow velocity (Vm), pulse index (PI)] ( P<0.05 or 0.01). The results of multivariate Logistic stepwise regression analysis showed that cerebral hernia formation ( OR=9.28, 95% CI 3.40, 25.33, P<0.01), Rotterdam CT score on admission ( OR=1.92, 95% CI 1.32, 2.78, P<0.01), rScO 2 variability ( OR=4.66, 95% CI 1.74, 12.43, P<0.01), Vs ( OR=0.66, 95% CI 0.61, 0.75, P<0.01) and PI ( OR=20.07, 95% CI 4.17, 16.50, P<0.01) were predictive factors for poor prognosis in patients with msTBI. The regression equation was constructed with the forementioned 5 variables: Logit [ P/(1- P)]=2.23×"brain hernia formation"+0.65×"Rotterdam CT score on admission"+1.54×"rScO 2 variability"-0.42×"Vs"+3.00×"PI"-6.75. The AUC of prognostic predictive model of msTBI patients was 0.90 (95% CI 0.85, 0.95), with the sensitivity and specificity of 86.3% and 78.4%, Youden index of 0.65 and C index of 0.90. H-L goodness of fit test showed that the calibration degree of the predictive model was accurate ( χ2 =12.58, P>0.05). The average absolute error of the calibration curve was 0.025, showing that the calibration of the model was good. DCA results showed that this model had higher net return rate than the reference model within the probability range of risk threshold (20%-100%), with good clinical application value in evaluating the risk of poor prognosis of msTBI patients. Conclusion:The model constructed based on the combination of rScO 2 and TCD monitoring parameters (rScO 2 variability, Vs and PI) with multiple clinical indicators (cerebral hernia formation and Rotterdam CT score on admission) has good predictive performance for the prognosis of msTBI.

Objective:To report single-center clinical experience with endovascular recanalization for non-acute symptomatic intracranial vertebral artery occlusion, to assess the feasibility and safety of endovascular recanalization and to propose the benefit group for selected patients.Methods:From January 2019 to December 2021, 92 patients with non-acute symptomatic intracranial vertebral artery occlusion who underwent endovascular recanalization were retrospectively analyzed. The patients were divided into three groups (low, medium and high-risk group) according to occlusion length, occlusion duration, occlusion nature, calcification of the occlusion segment, and occlusion angulation, and the indicators of patients in each group were analyzed, including the general baseline data of the patients, surgical status and follow-up results. The technical success and perioperative complication rates of low, medium and high-risk groups were calculated. Meanwhile, the differences between three groups were evaluated using the χ2 test for trend or ANOVA analysis. Results:The overall technical success rate of endovascular recanalization was 83.7% (77/92), and the perioperative complication rate was 10.9% (10/92). Among the 3 classification groups, the recanalization success rate from the low-risk group to the high-risk group was 100%, 93.3%, 27.8%( P=0.047), and gradually decreased; while the overall perioperative complication rate was 0, 10.0%, 38.9% ( P=0.001), and gradually increased; the proportion of 90-day mRS score 0-2 was 100%, 83.3%, 22.2% ( P=0.026), and progressively decreased; 77 patients with successful recanalization were followed up, the rate of restenosis/reocclusion was 0, 17.9%, 80.0%( P=0.001), and progressively increased. Patients in the low-and intermediate-risk groups performed well with endovascular recanalization. In 88 patients (4 patients lost to follow-up), a median clinical follow-up of 13 (7, 16) months, stroke or death beyond 30 days was 17.4% (16/92). Conclusions:Endovascular recanalization is safe and feasible for reasonably selected patients with non-acute symptomatic intracranial vertebral artery occlusion, especially in low-and medium-risk groups, and it also provides an alternative to conservative therapy for patients with non-acute symptomatic intracranial vertebral artery occlusion.

Objective To investigate the impact of audio-visual impairments on subjective well-being(SWB),and whether the depressive tendency mediate the association between them.Methods The China Health and Retirement Longitudinal Survey(CHARLS)conducted a questionnaire survey on people aged 45 and above,using multi-stage sampling at the county(district)-village(residential)-household-individual level.In the county(district)-village(residential)level sampling,proportional probability sampling(PPS)was used according to population scale.This study was based on CHARLS data from 2018,and the inclusion criteria were(1)age≥60 years old;(2)having a complete self-reported visual and hearing condition;(3)at least one of the three subjective well-being indicators of life satisfaction,subjective life expectancy,and self-rated health status should be included.Likert five-component scale was used in CHARLS to measure the subjective well-being of the elderly,and the Center for Epidemiology Studies Depression Scale-10(CESD-10)was used to measure the depressive mood of the elderly.We used multiple regression to explore the association between vision and hearing impairment with depressive tendency and subjective well-being;and explored possible mediating effects through a mediation model.Two-side P values<0.05 were considered statistically significant.Results Finally,7 620 people who met the standards were included.Individuals with audio-visual impairments had significantly higher levels of depression and lower levels of all three SWB measurements(all P values<0.05).Single vision impairment(SVI),single hearing impairment(SHI)and double sensory impairment(DSI)were associated with more depression tendencies,lower self-rated health(SRH),and subjective life expectancy(SLE).SVI and DSI were associated with lower life satisfaction.Depressive tendency partially mediated the association of DSI with LS and the associations of SVI,SHI,and DSI with SLE and SRH.Conclusion Audio-visual impairments are independently associated with lower SWB status among the elderly in China,and depressive tendency plays a mediating role in these observed associations.

This study was aimed at comparing performance differences among three metagenomic sequencing platforms,MGISEQ-2000,Illumina NextSeq 2000,and Ion GeneStudio S5 Plus,to optimize the sequencing process for trace samples.The three sequencing platforms were used to perform high-throughput sequencing on DNA standards and simulated samples.Through analysis of the quality of raw data and microbial detection capabilities,systematic differences among platforms were compared.The sequencing results were optimized for trace samples by incorporation of exogenous nucleic acids during the li-brary preparation process.In terms of data output per batch and base quality,MGISEQ-2000 surpassed the other two plat-forms.Illumina NextSeq 2000 had the lowest proportion of duplicate reads,whereas Ion GeneStudio S5 Plus had the highest proportion,and significant differences were observed across platforms(P＜0.001).In sequencing uniformity,MGISEQ-2000 and Illumina NextSeq 2000 were superior to Ion GeneStudio S5 Plus.MGISEQ-2000 provided a substantial advantage in microbial detection capability(P＜0.001),but the advantage diminished with decreasing bacterial fluid concentration.Ion GeneStudio S5 Plus had the shortest duration for single-batch sequencing.Moreo-ver,for trace samples with DNA content ≤0.05 ng,the experi-mental group(with added exogenous nucleic acids)achieved a higher number of reads than the control group(without exogenous nucleic acids),with a 11.09±8.03 fold increase.In conclu-sion,the different sequencing platforms each had advantages and disadvantages,thus allowing researchers to choose the appro-priate platform according to specific needs.Furthermore,the addition of exogenous nucleic acids improved the microorganism detection efficiency,and provided better support for subsequent diagnosis and evaluation of results.

Aim To investigate the protective effects of co-administered piperine on reversing the skeletal deterioration induced by fluoxetine.Methods Female ovariectomized rats were orally administered with estra-diol,fluoxetine,piperine and the mixture of piperine and fluoxetine for eight weeks,respectively.X-ray ab-sorption assay was used to determine bone mineral den-sity(BMD).microCT was used to analyze the effects of drug treatments on micro-architecture,three-bending test was performed to examine the biomechanical prop-erties.ELISA kits were employed to quantify the bone turnover markers in serum.Besides,rat primary osteo-blasts were cultured to investigate the osteoblastogene-sis and mineralization in the presence of fluoxetine with or without piperine.Results Compared with ovariec-tomized rats,the administration of estradiol and piper-ine significantly enhanced BMD and biomechanical properties with improved micro-architecture of trabecu-lar bones.Fluoxetine treatment further deteriorated BMD,biomechanical properties and micro-architecture of ovariectomized rats with accelerated bone turnover.Concomitant administration of piperine with fluoxetine significantly suppressed the deteriorating effects on skeleton by fluoxetine.In addition,fluoxetine reduced the differentiation and mineralization of primary osteo-blasts,whereas combined therapy showed promotional effects.Conclusions The administration of fluoxetine induces further bone loss in ovariectomized rats by in-hibiting osteoblastic differentiation and mineralization.The co-administration of piperine with fluoxetine rever-ses its skeletal deterioration.