Therapeutic effects of repetitive transcranial magnetic stimulation in patients with cerebral palsy: a systematic review and network meta-analysis.

The purpose of this study was to systematically evaluate the efficacy of repetitive transcranial magnetic stimulation in children with cerebral palsy and to compare the differences in efficacy of different treatment parameters. Computer searches of PubMed, Embase, Cochrane Library, Scopus, Web of Science, China Knowledge Network, Wanfang Data Knowledge Service Platform, Vipshop and China Biomedical Literature Database were conducted to collect randomized controlled trials (RCTs) of TMS to improve function in children with cerebral palsy. The search period was from the establishment of the database to April 2023. Two researchers independently screened the literature and extracted data information, and the risk of bias was assessed for the included studies using the Cochrane Systematic Evaluation Manual 5.1.0. Statistical analysis was performed using RevMan 5.4 and Stata software. A total of 18 studies containing 1675 patients with cerebral palsy were included, and r-TMS did not differ significantly from other treatments in improving language function [MD = 2.80, 95% CI (-1.51, 7.11), Z = 1.27, P = 0.20] after treatment. The results of the reticulated meta-analysis showed the best probability ranking of the effect of three different frequencies of r-TMS on motor function scores in children with cerebral palsy: combined LF-rTMS + HF-rTMS (49.8%) > LF-rTMS (45.6%) > HF-rTMS (4.6%) > conventional rehabilitation (0%). Publication bias showed no significant asymmetry in the inverted funnel plot, but the possibility of publication bias could not be excluded. The results of this study showed that r-TMS was not statistically significant in improving language function in children with cerebral palsy compared to conventional treatment. r-TMS was almost unanimously significantly effective in motor function in children with cerebral palsy according to current literature data, and the combined high- and low-frequency transcranial magnetic therapy was better than low-frequency transcranial magnetic therapy.

Efficacy of cognitive behavioral therapy for reducing pain susceptibility and increasing social engagement in patients with chronic low back pain: A systematic review and meta-analysis.

BACKGROUND: The objective of this study was to evaluate the efficacy of cognitive behavioral therapy in improving social engagement and pain susceptibility in patients with chronic low back pain (≥6 months duration). METHODS: From the initial to January 2023, 5 databases were searched for randomized controlled trials, literature screening, quality evaluation, and data extraction were performed by 2 independent researchers throughout, Meta-analysis was performed using RevMan 5.4 software, standardized mean difference (SMD) was calculated for different indicators, and the combined experimental and control groups were calculated using random-effects models or fixed-effects models effect sizes, and forest plots were drawn to present the results. RESULTS: A total of 16 studies containing 2527 patients with chronic nonspecific low back pain, all of whom had pain lasting longer than 6 months, were included, and after treatment, cognitive behavioral therapy (CBT) was superior to other treatments in improving social participation [SMD = -0.30, 95%CI (-0.60, -0.01), Z = 2.02, P = .04]. There was no significant difference from other treatments in improving patient depression [SMD = -0.07, 95%CI (-0.19, 0.05), Z = 1.11, P = .27] and anxiety [SMD = -0.07, 95%CI (-0.30, 0.16), Z = 0.52, P = .57]. Three papers describe the superiority of CBT over other treatments in improving sleep quality, but the metrics could not be combined due to too little literature. CONCLUSION: CBT can improve patients' social participation and pain susceptibility to some extent, but it does not show advantages for managing negative emotions (depression, anxiety). Due to the limited number and low quality of included literature, the above findings still need to be validated by conducting a large sample of high-quality RCTs.

Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity.

There is an urgent need for markers to predict the efficacy of different chemotherapy drugs. Herein, we examined whether microsatellite instability (MSI) status can predict tumor multidrug sensitivity and explored the underlying mechanisms. We downloaded data from several public databases. Drug sensitivity was compared between the high microsatellite instability (MSI-H) and microsatellite-stable/low microsatellite instability (MSS/MSI-L) groups. In addition, we performed pathway enrichment analysis and cellular chemosensitivity assays to explore the mechanisms by which MSI status may affect drug sensitivity and assessed the differences between drug-treated and control cell lines. We found that multiple MSI-H tumors were more sensitive to a variety of chemotherapy drugs than MSS/MSI-L tumors, and especially for CRC, chemosensitivity is enhanced through the downregulation of DDR pathways such as NHEJ. Additional DNA damage caused by chemotherapeutic drugs results in further downregulation of DDR pathways and enhances drug sensitivity, forming a cycle of increasing drug sensitivity.

Protective role of remote ischemic conditioning in renal transplantation and partial nephrectomy: A systematic review and meta-analysis of randomized controlled trials.

Objective: Studies have shown that remote ischemic conditioning (RIC) can effectively attenuate ischemic-reperfusion injury in the heart and brain, but the effect on ischemic-reperfusion injury in patients with kidney transplantation or partial nephrectomy remains controversial. The main objective of this systematic review and meta-analysis was to investigate whether RIC provides renal protection after renal ischemia-reperfusion injury in patients undergoing kidney transplantation or partial nephrectomy. Methods: A computer-based search was conducted to retrieve relevant publications from the PubMed database, Embase database, Cochrane Library and Web of Science database. We then conducted a systematic review and meta-analysis of randomized controlled trials that met our study inclusion criteria. Results: Eleven eligible studies included a total of 1,145 patients with kidney transplantation or partial nephrectomy for systematic review and meta-analysis, among whom 576 patients were randomly assigned to the RIC group and the remaining 569 to the control group. The 3-month estimated glomerular filtration rate (eGFR) was improved in the RIC group, which was statistically significant between the two groups on kidney transplantation [P < 0.001; mean difference (MD) = 2.74, confidence interval (CI): 1.41 to 4.06; I 2 = 14%], and the 1- and 2-day postoperative Scr levels in the RIC group decreased, which was statistically significant between the two groups on kidney transplantation (1-day postoperative: P < 0.001; MD = 0.10, CI: 0.05 to 0.15, I 2 = 0; 2-day postoperative: P = 0.006; MD = 0.41, CI: 0.12 to 0.70, I 2 = 0), but at other times, there was no significant difference between the two groups in Scr levels. The incidence of delayed graft function (DGF) decreased, but there was no significant difference (P = 0.60; 95% CI: 0.67 to 1.26). There was no significant difference between the two groups in terms of cross-clamp time, cold ischemia time, warm ischemic time, acute rejection (AR), graft loss or length of hospital stay. Conclusion: Our meta-analysis showed that the effect of remote ischemia conditioning on reducing serum creatinine (Scr) and improving estimate glomerular filtration rate (eGFR) seemed to be very weak, and we did not observe a significant protective effect of RIC on renal ischemic-reperfusion. Due to small sample sizes, more studies using stricter inclusion criteria are needed to elucidate the nephroprotective effect of RIC in renal surgery in the future.

A computational method for large-scale identification of esophageal cancer-related genes.

The incidence of esophageal cancer has obvious genetic susceptibility. Identifying esophageal cancer-related genes plays a huge role in the prevention and treatment of esophageal cancer. Through various sequencing methods, researchers have found only a small number of genes associated with esophageal cancer. In order to improve the efficiency of esophageal cancer genetic susceptibility research, this paper proposes a method for large-scale identification of esophageal cancer-related genes by computational methods. In order to improve the efficiency of esophageal cancer genetic susceptibility research, this paper proposes a method for large-scale identification of esophageal cancer-related genes by computational methods. This method fuses graph convolutional network and logical matrix factorization to effectively identify esophageal cancer-related genes through the association between genes. We call this method GCNLMF which achieved AUC as 0.927 and AUPR as 0.86. Compared with other five methods, GCNLMF performed best. We conducted a case study of the top three predicted genes. Although the association of these three genes with esophageal cancer has not been reported in the database, studies by other reseachers have shown that these three genes are significantly associated with esophageal cancer, which illustrates the accuracy of the prediction results of GCNLMF.

MMP9 Expression Correlates With Cisplatin Resistance in Small Cell Lung Cancer Patients.

Background: Cisplatin is the basis of the primary treatment for SCLC chemotherapy. However, the limited objective response rate and definite drug resistance greatly restrict the clinical potential and therapeutic benefits of cisplatin use. Therefore, it is essential to identify biomarkers that can discern the sensitivity of SCLC patients to cisplatin treatment. Methods: We collected two SCLC cohorts treated with cisplatin that included mutation data, prognosis data and expression data. The sensitivity of cisplatin was evaluated by the pRRophetic algorithm. MCPcounter, quanTIseq, and xCell algorithms were used to evaluate immune cell score. GSEA and ssGSEA algorithms were used to calculate immune-related pathway scores. Univariate and multivariate Cox regression models were employed, and survival analysis was used to evaluate the prognostic value of the candidate genes. Results: MMP9-High is related to improved clinical prognoses of patients with SCLC (HR = 0.425, p = 0.0085; HR = 0.365, p = 0.0219). Multivariate results showed that MMP-High could be used as an independent predictor of the prognosis of SCLC after cisplatin treatment (HR = 0.216, p = 0.00153; HR = 0.352; p = 0.0199). In addition, MMP9-High displayed a significantly lower IC50 value of cisplatin and higher immunogenicity than MMP9-Low SCLC. Compared with MMP9-Low SCLC, MMP9-High included significantly increased levels of T-cells, cytoxic lymphocytes, B-cells, NK-cells, and dense cells (DCS). Similarly, the activity of cytokine binding, B-cell, NK-cell mediated immune response chemokine binding, and antigen presentation pathways in MMP9-High was significantly higher than that in MMP9-Low. Conclusion: In this study, we identified that MMP9-High could be potentially considered a novel biomarker used to ascertain the improved prognosis of SCLC patients after cisplatin treatment. Furthermore, we indicated that the tumor immune microenvironment of MMP9-High SCLC is mainly characterized by a large number of infiltrated activated immune cells as well as activated immune-related pathways.

Fatty Acid Metabolic Signaling Pathway Alternation Predict Prognosis of Immune Checkpoint Inhibitors in Glioblastoma.

INTRODUCTION: Glioblastoma(GBM) is a highly malignant primary brain tumor. Even after undergoing surgery and chemotherapy, patients with this affliction still have little to no chance of survival. Current research on immunotherapy treatment for GBM shows that immune-checkpoint inhibitors (ICIs) may be a promising new treatment method. However, at present, the relationship between the fatty acid metabolic process and the prognosis of GBM patients who are receiving immunotherapy is not clear. METHODS: First, we downloaded a GBM cohort that had been treated with immunotherapy, which included the mutation and prognosis data, and the TCGA-GBM and Jonsson-GBM queues. CIBERSORT and single sample gene set enrichment analysis(ssGSEA) were used to evaluate immune cell scores. Gene set enrichment analysis (GSEA) was used to evaluate the patient's accessment score. The pRRophetic algorithm was used to evaluate the drug sensitivity of each patient. Univariable and multivariate cox regression analyses, as well as the Kaplan-Meier (KM) method, were used to evaluate the relationship between the fatty acid metabolic process and the prognosis of GBM patients. RESULTS: The univariate and multivariate cox regression models showed that the fatty acid metabolic process mutant-type (MT) can be used as an independent predictor of the efficacy of immunotherapy for GBM patients. In addition, fatty acid metabolic process MT is related with significantly longer overall survival (OS) time than the wild-type(WT) variant. However, the mutation status of the fatty acid metabolic process has nothing to do with the prognosis of GBM patients who are receiving conventional treatment. Our analysis showed that fatty acid metabolic process MT correlated with significantly increased natural killer T (NKT) cells and significantly decreased CD8+T cells. At the same time, GSEA analysis revealed that fatty acid metabolic process MT was associated with significantly increased immune activation pathways and an enriched fraction of cytokine secretion compared with WT. CONCLUSIONS: We found that fatty acid metabolic process MT may be used as an independent predictor of the efficacy of ICI treatment in GBM patients. Use of the fatty acid metabolic process MT will result in higher immunogenicity rates, a significant increase in the proportion of activated immune cells, and improvement of the immune microenvironment.

Successful treatment of EGFR T790M-mutant non-small cell lung cancer with almonertinib after osimertinib-induced interstitial lung disease: a case report and literature review.

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the standard treatment for EGFR T790M-positive non-small cell lung cancer (NSCLC). Osimertinib is one of the third-generation EGFR-TKIs and is currently the most advanced in clinical development. Interstitial lung disease (ILD) is a potentially fatal side effect of osimertinib use. Successful rechallenge with the second-generation TKI afatinib following osimertinib-induced ILD has been reported. However, few reports have discussed the safety and efficacy of third-generation TKI rechallenge in this patient population. In this paper, a case of lung adenocarcinoma is retrospectively analyzed, and the relevant literature is reviewed. The patient was initially diagnosed with early lung cancer, for which surgical treatment was performed. The postoperative diagnosis indicated stage IB (pT2N0M0) right lung adenocarcinoma. Genetic testing (amplification-refractory mutation system) revealed EGFR exon 19 deletion. More than 2 years after surgery, multiple metastases occurred in both lungs, so gefitinib (250 mg per day) was administered. However, 6 months after the start of gefitinib treatment, the tumor progressed. Lung tumor biopsy was performed for genetic testing (NGS) and an EGFR T790M mutation was observed. Subsequently, second-line treatment with osimertinib (80 mg per day) was given for 3 months. The evaluated response suggested a partial response (PR) with the occurrence of grade 3 ILD. Pemetrexed plus bevacizumab chemotherapy was subsequently administered, resulting in stable disease. However, following a severe drug reaction after six courses, the patient's chemotherapy was discontinued. Another third-generation TKI, almonertinib (110 mg per day), was rechallenged based on no ILD having been reported in a phase I/II study of this drug. After 4 months of almonertinib administration and 6 months without ILD recurrence, partial remission was attained. This is the first report of successful treatment with almonertinib after osimertinib-induced ILD. The results suggested that almonertinib had a significant effect in patients with EGFR T790M mutation, with fewer side effects and better survival benefits for patients with advanced lung cancer.

Effect of NCOR1 Mutations on Immune Microenvironment and Efficacy of Immune Checkpoint Inhibitors in Patient with Bladder Cancer.

Immune checkpoint blockade (ICB) therapy has significantly progressed the treatment of bladder cancer (BLCA). Multiple studies have suggested that specific genetic mutations may serve as immune biomarkers for ICB therapy. Additionally, the nuclear receptor corepressor 1 (NCOR1) gene is a new player in the field of immune tolerance and the development of immune cells. In the ICI-treated-cohort, NCOR1 mutations may be used as a biomarker to predict the prognosis of BLCA patients receiving ICIs. The overall survival (OS) of the NCOR1-mutant (NCOR1-MT) group was significantly longer than that of NCOR1-wild-type (NCOR1-WT) group (P = 0·031; HR [95%CI]: 0·25 [0·12-0·52]). In the TCGA-BLCA-cohort, compared with NCOR1-WT, NCOR1-MT was associated with known predictors of ICB therapy efficacy, such as higher tumor mutational burden (TMB), neoantigen load and the number of mutations in the DNA damage-repair pathway. In addition, NCOR1-MT tumors had highly infiltrating TILs, activated antitumor immunity, and a high expression of immune-related genes, suggesting that NCOR1 mutations may serve as a potential biomarker to guide ICB therapy in BLCA.

Comprehensive Landscape of Immune Infiltration and Aberrant Pathway Activation in Ischemic Stroke.

Ischemic stroke (IS) is a multifactorial disease caused by the interaction of multiple environmental and genetic risk factors, and it is the most common cause of disability. The immune microenvironment and inflammatory response participate in the whole process of IS occurrence and development. Therefore, the rational use of relevant markers or characteristic pathways in the immune microenvironment will become one of the important therapeutic strategies for the treatment of IS. We collected peripheral blood samples from 10 patients diagnosed with IS at the First Affiliated Hospital of Gannan Medical University and First Affiliated Hospital, Jinan" University, and from 10 normal people. The GSE16561 dataset was downloaded from the Gene Expression Omnibus (GEO) database. xCell, gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA) and immune-related gene analysis were used to evaluate the differences in the immune microenvironment and characteristic pathways between the IS and control groups of the two datasets. xCell analysis showed that the IS-24h group had significantly reduced central memory CD8+ T cell, effector memory CD8+ T cell, B cell and Th1 cell scores and significantly increased M1 macrophage and macrophage scores. GSEA showed that the IS-24h group had significantly increased inflammation-related pathway activity(myeloid leukocyte activation, positive regulation of tumor necrosis factor biosynthetic process, myeloid leukocyte migration and leukocyte chemotaxis), platelet-related pathway activity(platelet activation, signaling and aggregation; protein polymerization; platelet degranulation; cell-cell contact zone) and pathology-related pathway activity (ERBB signaling pathway, positive regulation of ERK1 and ERK2 cascade, vascular endothelial growth factor receptor signaling pathway, and regulation of MAP kinase activity). Immune-related signature analysis showed that the macrophage signature, antigen presentation-related signature, cytotoxicity-related signature, B cell-related signature and inflammation-related signature were significantly lower in the IS-24h group than in the control group. In this study, we found that there were significant differences in the immune microenvironment between the peripheral blood of IS patients and control patients, as shown by the IS group having significantly reduced CD8+ Tcm, CD8+ Tem, B cell and Th1 cell scores and significantly increased macrophage and M1 macrophage scores. Additionally, inflammation-related, pathological, and platelet-related pathway activities were significantly higher in the IS group than in the control group.

CAMSAP1 Mutation Correlates With Improved Prognosis in Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy.

Platinum-based chemotherapy is the first-line treatment for small cell lung cancer (SCLC). However, due to patients developing a resistance to the drug, most experience relapse and their cancer can become untreatable. A large number of recent studies have found that platinum drug sensitivity of various cancers is affected by specific gene mutations, and so with this study, we attempted to find an effective genetic biomarker in SCLC patients that indicates their sensitivity to platinum-based drugs. To do this, we first analyzed whole exome sequencing (WES) and clinical data from two cohorts to find gene mutations related to the prognosis and to the platinum drug sensitivity of SCLC patients. The cohorts used were the Zhujiang cohort (N = 138) and the cohort reported by George et al. (N = 101). We then carried out gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to investigate possible molecular mechanisms through which these gene mutations affect patient prognosis and platinum drug sensitivity. We found that for SCLC patients, CAMSAP1 mutation can activate anti-tumor immunity, mediate tumor cell apoptosis, inhibit epithelial-mesenchymal transition (EMT), improve prognosis, and improve platinum drug sensitivity, suggesting that CAMSAP1 mutation may be a potential biomarker indicating platinum drug sensitivity and patient prognosis in SCLC.

CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter.

Rationale: Chemoresistance frequently occurs in patients with small cell lung cancer (SCLC) and leads to a dismal prognosis. However, the mechanisms underlying this process remain largely unclear. Methods: The effects of chromodomain Y-like (CDYL) on chemoresistance in SCLC were determined using Western blotting, immunohistochemistry, cell counting kit-8 assays, flow cytometry, and tumorigenicity experiments, and the underlying mechanisms were investigated using mRNA sequencing, chromatin immunoprecipitation-qPCR, electrophoretic mobility shift assays, co-immunoprecipitation, GST pull down assays, bisulfite sequencing PCR, ELISA, and bioinformatics analyses. Results: CDYL is expressed at high levels in chemoresistant SCLC tissues from patients, and elevated CDYL levels correlate with an advanced clinical stage and a poor prognosis. Furthermore, CDYL expression is significantly upregulated in chemoresistant SCLC cells. Using gain- and loss-of-function methods, we show that CDYL promotes chemoresistance in SCLC in vitro and in vivo. Mechanistically, CDYL promotes SCLC chemoresistance by silencing its downstream mediator cyclin-dependent kinase inhibitor 1C (CDKN1C). Further mechanistic investigations showed that CDYL recruits the enhancer of zeste homolog 2 (EZH2) to regulate trimethylation of lysine 27 in histone 3 (H3K27me3) at the CDKN1C promoter region and promotes transcriptional silencing. Accordingly, the EZH2 inhibitor GSK126 de-represses CDKN1C and decreases CDYL-induced chemoresistance in SCLC. Principal conclusions: Based on these results, the CDYL/EZH2/CDKN1C axis promotes chemoresistance in SCLC, and these markers represent promising therapeutic targets for overcoming chemoresistance in patients with SCLC.

A novel mutation panel for predicting etoposide resistance in small-cell lung cancer.

PURPOSE: Platinum-based chemotherapy, consisting of etoposide and cisplatin (EP), has been the cornerstone of therapy for extensive-stage small-cell lung cancer (ES-SCLC) for decades. Despite the marked initial sensitivity of SCLC to chemotherapy, EP regimens cannot avoid the emergence of drug resistance in clinical practice. With the rise of new chemotherapy regimens in recent years and the primary resistance or insensitivity of ES-SCLC to EP regimens, it is desirable to be able to identify patients with resistant or insensitive ES-SCLC. METHODS: The sequencing and drug sensitivity data of SCLC cell lines were provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC). The data regarding sensitivity to etoposide of 54 SCLC cell lines were analyzed, and etoposide-sensitive cell lines and etoposide-resistant cell lines were differentiated according to the IC50 values defined by the GDSC. ROC curve analysis was performed on all mutations and combinations of mutations to select the optimal panel to predict resistance to etoposide. RESULTS: ROC analysis of etoposide resistance revealed that the most significant single gene mutation indicating resistance to etoposide was CSMD3, and the accuracy of predicting resistance to etoposide proved to be the highest when there was any mutation in CSMD3/PCLO/RYR1/EPB41L3, area under the curve =0.804 (95% confidence interval: 0.679-0.930,P <0.001). CONCLUSION: This study found that a panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide. These findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etoposide.

Multifunctional CD4 T cell responses in patients with active tuberculosis.

The roles of multifunctional CD4 T cells in human tuberculosis are not well defined. In this study, we found that patients with tuberculosis had decreased PMA/ionomycin stimulated multifunctional CD4 T cells, and increased Mycobacterium tuberculosis antigen-specific multifunctional CD4 T cells, when compared to individuals with latent tuberculosis infection and healthy controls. PMA/ionomycin stimulated IFN-γ+IL-2+TNF-α+ CD4 T cell responses were decreased in patients with smear-positive tuberculosis compared to those with smear-negative tuberculosis. The percentage of IFN-γ+IL-2+TNF-α+ CD4 T cells in smear positive tuberculosis patients negatively correlated with the grade of sputum smear Acid-Fast Bacilli and high-resolution computed tomography score. Therefore, our findings argue against the notion that Mycobacterium tuberculosis antigen-specific multifunctional Th1 responses in peripheral blood can serve as correlates of protective immunity against tuberculosis; they suggest that the decrease in PMA/ionomycin stimulated IFN-γ+IL-2+TNF-α+ CD4 T cells may be applied for clinical diagnosis of active tuberculosis.

Co-suppression of MDR1 (multidrug resistance 1) and GCS (glucosylceramide synthase) restores sensitivity to multidrug resistance breast cancer cells by RNA interference (RNAi).

Multidrug resistance (MDR) to chemotherapeutic agents is a major obstacle to successful treatment in patients with breast cancer. Besides overexpression of MDR1, the member of the ABC transporter family, glucosylceramide synthase (GCS) which allows cellular escape from ceramide-induced cellular apoptosis by mediating ceramide glycosylation was considered to be related with multidrug resistance (MDR) in breast cancer. To specifically and efficiently reverse MDR of breast carcinoma cells, two small interference RNA (siRNA) targeted multidrug resistance 1 (MDR1) and GCS mediated by plasmids were constructed and co-transfected into the MDR breast cancer cell line MCF-7/ADM. The results showed that both transient transfection and stable transfection of the two siRNA-expression plasmids could greatly decrease the relative expression of GCS mRNA and MDR1 mRNA, significantly lower than the controls (p < 0.01). Evaluation of chemosensitivity displayed a 96-fold reduction in drug resistance for Adriamycin. And the reversing effects could keep for a long period (at least 3 w). Our results demonstrated that co-inhibition of MDR1 and GCS could more effectively reverse MDR in drug resistant breast carcinoma cells in vitro.