Clinical significance and potential pathogenesis of VCAN in adult non-cystic fibrosis bronchiectasis: a retrospective study.

BACKGROUND: The pathogenesis of adult non-cystic fibrosis (CF) bronchiectasis is complex, and the relevant molecular mechanism remains ambiguous. Versican (VCAN) is a key factor in inflammation through interactions with adhesion molecules. This study constructs a stable panoramic map of mRNA, reveals the possible pathogenesis of bronchiectasis, and provides new ideas and methods for bronchiectasis. METHODS: Peripheral blood and tissue gene expression data from patients with bronchiectasis and normal control were selected by bioinformatics analysis. The expression of VCAN in peripheral blood and bronchial tissues of bronchiectasis were obtained by transcriptome sequencing. The protein expression levels of VCAN in serums were verified by the enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of VCAN in co-culture of Pseudomonas aeruginosa and bronchial epithelial cells were verified by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the biological function of VCAN was detected by the transwell assay. RESULTS: The expression of VCAN was upregulated in the bronchiectasis group by sequencing analysis (P < 0.001). The expression of VCAN in the bronchial epithelial cell line BEAS-2B was increased in P. aeruginosa (P.a), which was co-cultured with BEAS-2B cells (P < 0.05). The concentration of VCAN protein in the serum of patients with bronchiectasis was higher than that in the normal control group (P < 0.05). Transwell experiments showed that exogenous VCAN protein induced the migration of neutrophils (P < 0.0001). CONCLUSIONS: Our findings indicate that VCAN may be involved in the development of bronchiectasis by increasing the migration of neutrophils and play an important role in bronchial pathogenesis.

Fusion Surgery for Lumbar Spondylolisthesis: A Systematic Review with Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: This study aimed to systematically evaluate the optimal surgical fusion approach for lumbar spondylolisthesis, to provide the latest and most reliable evidence for future clinical practice. METHODS: A comprehensive search of the PubMed, Ovid-Embase, Web of Science, Cochrane, and Scopus databases was conducted from inception to September 1, 2023, to identify relevant records. Two independent reviewers performed the literature screening, data extraction, and assessment of study quality. RESULTS: Fifteen randomized controlled trials involving 892 patients met the inclusion criteria. The network evidence plot showed that posterolateral fusion and posterior lumbar interbody fusion (PLIF) were the most used fusion techniques. The network meta-analysis results revealed that minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) had a significantly greater improvement in the Oswestry Disability Index (ODI) compared to endoscopic-TLIF, while PLIF had a significantly better fusion effect than posterolateral fusion. Furthermore, no statistically significant differences were observed between other fusion surgeries in terms of improving ODI, fusion rate, complications, or the improvement of visual analog scale-low back pain. The surface under the cumulative ranking curve results indicated that MIS-TLIF had the greatest potential for improving ODI, visual analog scale-low back pain, and complications, while PLIF had the greatest potential for increasing fusion rates. However, the existing selection bias, measurement bias, reporting bias, and publication bias may have reduced the reliability of the meta-analysis results. CONCLUSIONS: Among the various fusion surgeries for lumbar spondylolisthesis, MIS-TLIF appears to provide the greatest benefit to patients. However, more high-quality, large-scale studies are needed to further investigate the treatment efficacy of different fusion surgeries for lumbar spondylolisthesis.

Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer.

Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulation. However, the relationship and roles of CST1 and OXPHOS in esophageal squamous cell carcinoma (ESCC) remains unclear. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Transcriptome sequencing analysis revealed that CST1 is closely associated with OXPHOS. Based on a real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence, co-immunoprecipitation, and addition of the OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we determined that CST1 affects mitochondrial complex I enzyme activity by interacting with the GRIM19 protein to elevate OXPHOS levels, and a reciprocal regulatory relationship exists between OXPHOS and the MEK/ERK pathway in ESCC cells. Finally, an in vivo study demonstrated the potential of CST1 in ESCC metastasis through regulation of the OXPHOS and MEK/ERK pathways. This study is the first to reveal the oncogenic role of CST1 in ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate the OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS is a promising target for ESCC treatment.

Preoperative Adjacent Facet Joint Osteoarthritis Is Associated with the Incidence of Adjacent Segment Degeneration and Low Back Pain after Lumbar Interbody Fusion.

STUDY DESIGN: A retrospective cohort study. PURPOSE: To analyze the association between preoperative adjacent facet joint osteoarthritis (FJOA) and outcomes of lumbar interbody fusion (LIF). OVERVIEW OF LITERATURE: Whether preoperative adjacent FJOA is associated with the incidence of radiological adjacent segment degeneration (RASD) and low back pain (LBP) relief after lumbar fusion remains unknown. METHODS: The study included patients who underwent LIF. The demographic characteristics and radiographic and surgical data were collected and evaluated. The included patients were divided into control group and FJOA group based on the preoperative adjacent facet joint Pathria grade. Preoperative and last follow-up LBP Visual Analog Scale (VAS) score, leg pain (LP) VAS, Oswestry Disability Index (ODI) and RASD were evaluated and compared. The improvement rates in VAS and ODI were calculated and compared between the two groups. Logistic regression was used to analyze the risk factors of LBP relief and incidence of RASD. RESULTS: In total, 197 patients (control group, 86; FJOA group, 111) were included, and the median follow-up was 46 months. The VAS and ODI in both groups significantly improved after surgery. At the last follow-up, the FJOA group had higher VAS and lower VAS improvement rates of LBP than the control group (p<0.05). However, no significant difference in the LP VAS and ODI was found between the two groups. The incidence of RASD in the FJOA group was significantly higher than that in the control group (48.6% vs. 30.2%, p=0.034). Multivariate logistic regression analysis showed that preoperative adjacent FJOA was significantly associated with LBP relief (odds ratio [OR], 0.691; 95% confidence interval [CI], 0.498-0.958) and the postoperative incidence of RASD (OR, 1.406; 95% CI, 1.020-1.939). CONCLUSIONS: The preoperative FJOA in the adjacent segments was significantly associated with LBP following LIF. Patients with preoperative FJOA were more likely to have RASD following lumbar fusion surgery.

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients with Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

BACKGROUND: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. METHODS: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. RESULTS: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes (P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. CONCLUSIONS: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

SCAN: Spatiotemporal Cloud Atlas for Neural cells.

The nervous system is one of the most complicated and enigmatic systems within the animal kingdom. Recently, the emergence and development of spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) technologies have provided an unprecedented ability to systematically decipher the cellular heterogeneity and spatial locations of the nervous system from multiple unbiased aspects. However, efficiently integrating, presenting and analyzing massive multiomic data remains a huge challenge. Here, we manually collected and comprehensively analyzed high-quality scRNA-seq and ST data from the nervous system, covering 10 679 684 cells. In addition, multi-omic datasets from more than 900 species were included for extensive data mining from an evolutionary perspective. Furthermore, over 100 neurological diseases (e.g. Alzheimer's disease, Parkinson's disease, Down syndrome) were systematically analyzed for high-throughput screening of putative biomarkers. Differential expression patterns across developmental time points, cell types and ST spots were discerned and subsequently subjected to extensive interpretation. To provide researchers with efficient data exploration, we created a new database with interactive interfaces and integrated functions called the Spatiotemporal Cloud Atlas for Neural cells (SCAN), freely accessible at http://47.98.139.124:8799 or http://scanatlas.net. SCAN will benefit the neuroscience research community to better exploit the spatiotemporal atlas of the neural system and promote the development of diagnostic strategies for various neurological disorders.

Combination of serum CST1 and HE4 for early diagnosis of endometrial cancer.

Purpose: Optimal serological biomarkers have been absent for the early diagnosis of endometrial cancer, to date. In this study, we aimed to define the diagnostic performances of individual and combined detection of serum cysteine protease inhibitor 1 (CST1) with traditional tumor markers, including glycated antigen 125 (CA125) and human epididymis protein 4 (HE4), in patients with early-stage endometrial cancer (EC). Methods: The performances of individual and combined detection of serum CST1, HE4, and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay, respectively. A training data set of 67 patients with early EC, 67 patients with endometrial benign lesion (EBL), and 67 healthy controls (HC) was used to develop a predictive model for early EC diagnosis, which was validated by an independent validation data set. Results: In the training data set, serum CST1 and HE4 levels in the early EC group were significantly higher than in EBL/HC groups (P < 0.05), while there was no significant difference of serum CA125 level between the early EC and EBL/HC groups (P > 0.05). Serum CST1 and HE4 exhibited areas under the curve (AUC) of 0.715 with 31.3% sensitivity at 90.3% specificity, and 0.706 with 23.9% sensitivity at 95.5% specificity, respectively. Combined detection of serum CST1 and HE4 exhibited an AUC of 0.788 with 49.3% sensitivity at 92.5% specificity. The combination of serum CST1 and HE4 showed promise in diagnosis. Conclusion: CST1 is a prospective serological biomarker for early EC diagnosis, and the combination of CST1 and HE4 contributes to the further improvement in the diagnosis of patients with early-stage EC.

The Third Channel-Assisted Unilateral Biportal Endoscopic Technique for Lumbar Spinal Stenosis Combined with Contralateral Disc Herniation.

Unilateral biportal endoscopic (UBE) spine surgery is an emerging minimally invasive surgical (MIS) technique that has gained popularity for treating lumbar spinal stenosis, particularly in Eastern Asia. The traditional UBE technique, with two portals on one side, can achieve successful unilateral laminotomy for bilateral decompression (ULBD) and, therefore, demonstrates favorable clinical outcomes. However, in the case of lumbar spinal stenosis combined with contralateral disc herniation, it is very difficult to remove the contralateral disc herniation, especially the loose disc fragment within the deep disc. Here, a third channel of the traditional UBE technique was developed to do the discectomy within the ipsilateral endoscopic vision, with which the instruments can go vertically into the contralateral disc, allowing easy discectomy. This technique can not only achieve adequate decompression of the bilateral spinal canal but also effectively remove contralateral herniated disc fragments. This technique avoids performing another UBE procedure on the opposite side, which can potentially shorten the duration of the operation, minimize blood loss and tissue damage, and ensure sufficient neural decompression. This paper will introduce the indications and surgical operation procedures, as well as present a classical case report and follow-up data, to facilitate the application of the third channel-assisted UBE (T-UBE) technique for spine surgeons.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Effect of spinal-pelvic sagittal balance on the clinical outcomes after lumbar fusion surgery.

BACKGROUND: Spinal-pelvic sagittal balance is important for maintaining energy-efficient posture in normal and diseased states.Few reports to date have evaluated the effect of spinal-pelvic sagittal balance on clinical outcomes after lumbar interbody fusion in patients with lumbar degenerative diseases (LDD). METHODS: A total of 303 patients treated with posterior lumbar interbody fusion surgery for lumbar degenerative disease from January 2012 to December 2019 were enrolled in this retrospective study according to the inclusion criteria. Preoperative and postoperative spinal-pelvic sagittal parameters including pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS) and lumbar lordosis (LL) of the patients were evaluated and compared. 163 patients whose postoperative PI-LL ≤ 10° were divided into the spinal-pelvic match group (Group M), while 140 patients were divided into the spinal-pelvic mismatch group (Group MM). Preoperative and postoperative Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) for back pain of both groups were compared. RESULTS: There was no significant difference between the two groups in demographic and surgical data, except for blood loss in surgery. LL, PI, PT and SS of the patients at final follow-up were all statistically different from the preoperative values in the two groups(P < 0.05). There was no significant difference in LL, PI, PT and SS between the two groups before surgery. At the final follow-up, LL, PI and PT differed significantly between the two groups(P < 0.05). Compared with the preoperative results, ODI and VAS of low back in both groups decreased significantly at the final follow-up (P < 0.05). Significant differences in VAS and ODI were found between the two groups at the final follow-up (P < 0.05). The improvement rates of VAS and ODI of Group M are both significantly higher than Group MM. Regression analysis showed that age and spinal-pelvic match had significant effects on the improvement of patients' low back pain at the final follow-up. CONCLUSIONS: lumbar interbody fusion can significantly improve the prognosis of patients with LDD. In terms of outcomes with an average follow-up time of more than 2 years, the spinal-pelvic match has a positive effect on patients' quality of life and the release of low back pain.

Early prognostication of critical patients with spinal cord injury: A machine learning study with 1485 cases.

STUDY DESIGN: A retrospective case-series. OBJECTIVE: The study aims to use machine-learning (ML) to predict the discharge destination of spinal cord injury (SCI) patients in the intensive care unit (ICU). SUMMARY OF BACKGROUND DATA: Prognostication following SCI is vital, especially for critical patients who need intensive care. METHODS: Clinical data of patients diagnosed with SCI were extracted from a publicly available ICU database. The firstly recorded data of the included patients were used to develop a total of 98 ML classifiers, seeking to predict discharge destination (e.g. death, further medical care, home). The micro-average area under the curve (AUC) was the main indicator to assess discrimination. The best average-AUC classifier and the best death-sensitivity classifier were integrated into an ensemble classifier. The discrimination of the ensemble classifier was compared with top death-sensitivity classifiers and top average-AUC classifiers. Additionally, prediction consistency and clinical utility were also assessed. RESULTS: A total of 1485 SCI patients were included. The ensemble classifier had a micro-average AUC of 0.851, which was only slightly inferior to the best average-AUC classifier (P=0.10) The best average-AUC classifier death sensitivity was much lower than that of the ensemble classifier. The ensemble classifier had a death sensitivity of 0.452, which was inferior to top 8 death-sensitivity classifiers, whose micro-average AUC were inferior to the ensemble classifier (P<0.05). Additionally, the ensemble classifier demonstrated a comparable Brier score and superior Net benefit in the decision curve analysis, when compared to the performance of the origin classifiers. CONCLUSIONS: The ensemble classifier shows an overall superior performance in predicting discharge destination considering discrimination ability, prediction consistency and clinical utility. This classifier system may aid in the clinical management of critical SCI patients in the early phase following injury. LEVEL OF EVIDENCE: 3.

Exploring calcium channel blocker as a candidate drug for Pseudomonas aeruginosa through network pharmacology and experimental validation.

Calcium channel blocker (CCB) is known to possess antibacterial effects. We aimed to apply network pharmacology (docking and protein-protein interaction [PPI] analyses) to predict the potential targets and mechanisms of CCB against Pseudomonas aeruginosa (PA) as well as to verify the effect of these drugs. The chemical structures of three CCBs were obtained through the Drug Bank platform. The potential channel proteins, efflux pump proteins and ion channel proteins of CCB against bacteria were derived from the literature. These proteins were collected through the PDB and Uniprot platform. The binding mode of the docking complexes was simulated by the CB-Dock platform and Discovery Studio 2019 Client software. The PPI network was constructed by the String platform and Cytoscape 3.8.2 platform. GO was explained by the PANTHER platform. The pathway diagram was drawn with the Pathway Builder Tool 2.0 software. The inhibitory effect of CCB on PA was verified through antibacterial experiments. Finally, 76 proteins were obtained: the iron channel protein of PA demonstrated a good docking relationship with all three CCBs, and the optimum binding energy was approximately -9.0 kcal/mol. GO analysis (biological process [BP], cellular component [CC], and molecular function [MF]) of protein genes showed a good docking relationship (optimum binding energy <-8.0 kcal/mol). The MF annotation results indicated that the target of CCB may be present on the PA membrane protein. The ion channel protein PPI enrichment p-value was 6.65e-08, and PfeA showed the strongest correlation. The experimental results suggested that CCB could inhibit the growth of PA. CCB might be an effective and interesting antimicrobial treatment strategy as CCB can potentially inhibit the growth of PA.

Construction and validation of a novel IGFBP3-related signature to predict prognosis and therapeutic decision making for Hepatocellular Carcinoma.

Background: IGFBP3 plays a pivotal role in carcinogenesis by being anomalously expressed in some malignancies. However, the clinical value of IGFBP3 and the role of IGFBP3-related signature in HCC remain unclear. Methods: Multiple bioinformatics methods were used to determine the expression and diagnostic values of IGFBP3. The expression level of IGFBP3 was validated by RT-qPCR and IHC. A IGFBP3-related risk score (IGRS) was built via correlation analysis and LASSO Cox regression analysis. Further analyses, including functional enrichment, immune status of risk groups were analyzed, and the role of IGRS in guiding clinical treatment was also evaluated. Results: IGFBP3 expression was significantly downregulated in HCC. IGFBP3 expression correlated with multiple clinicopathological characteristics and demonstrated a powerful diagnostic capability for HCC. In addition, a novel IGRS signature was developed in TCGA, which exhibited good performance for prognosis prediction and its role was further validated in GSE14520. In TCGA and GSE14520, Cox analysis also confirmed that the IGRS could serve as an independent prognostic factor for HCC. Moreover, a nomogram with good accuracy for predicting the survival of HCC was further formulated. Additionally, enrichment analysis showed that the high-IGRS group was enriched in cancer-related pathways and immune-related pathways. Additionally, patients with high IGRS exhibited an immunosuppressive phenotype. Therefore, patients with low IGRS scores may benefit from immunotherapy. Conclusions: IGFBP3 can act as a new diagnostic factor for HCC. IGRS signature represents a valuable predictive tool in the prognosis prediction and therapeutic decision making for Hepatocellular Carcinoma.

Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders.

Triggering receptor expressed on myeloid cell 2 (TREM2) signaling often drives opposing effects in traumatic versus demyelinating CNS disorders. Here, we identify two distinct phenotypes of microglia and infiltrating myeloid populations dependent on TREM2 expression levels at the acute stage and elucidate how they mediate the opposing effects of TREM2 in spinal cord injury (SCI) versus multiple sclerosis animal models (experimental autoimmune encephalomyelitis [EAE]). High TREM2 levels sustain phagocytic microglia and infiltrating macrophages after SCI. In contrast, moderate TREM2 levels sustain immunomodulatory microglia and infiltrating monocytes in EAE. TREM2-ablated microglia (purine-sensing phenotype in SCI and reduced immunomodulatory phenotype in EAE) drive transient protection at the acute stage of both disorders, whereas reduced phagocytic macrophages and lysosome-activated monocytes lead to contrasting neuroprotective and demyelinating effects in SCI versus EAE, respectively. Our study provides comprehensive insights into the complex roles of TREM2 in myeloid populations across diverse CNS disorders, which has crucial implications in devising TREM2-targeting therapeutics.

Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies.

BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which revealed the systematic and central nervous system (CNS) antitumor activities for EGFR T790M-mutated advanced NSCLC in previous clinical studies and is further analyzed here. METHODS: Eligible patients from the previous phase I and phase IIb studies of rezivertinib were included for pooled analysis. Post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily were included in full analysis set (FAS), while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in CNS full analysis set (cFAS). Patients with measurable CNS lesions were included in CNS evaluable for response set (cEFR). BICR-assessed CNS objective response rate (CNS-ORR), CNS disease control rate (CNS-DCR), CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR) were evaluated. RESULTS: 355 patients were included in FAS, among whom 150 and 45 patients were included in cFAS and cEFR. This pooled analysis showed the CNS-ORR was 32.0% (48/150; 95% CI: 24.6-40.1%) and the CNS-DCR was 42.0% (63/150; 95% CI: 34.0-50.3%) in cFAS, while that in cEFR were 68.9% (31/45; 95% CI: 53.4-81.8%) and 100% (45/45; 95% CI: 92.1-100.0%). In cEFR, the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range: -100.0 to 16.1%) and -46.8% (95% CI: -55.5 to -38.1%). In cFAS, the median CNS-DoR and CNS-PFS were 13.8 (95% CI: 9.6-not calculable [NC]) and 16.5 (95% CI: 13.7-NC) months. CONCLUSIONS: Rezivertinib demonstrated encouraging clinical CNS efficacy among advanced NSCLC patients with EGFR T790M mutation and CNS metastases.

MiR-942-5p inhibits tumor migration and invasion through targeting CST1 in esophageal squamous cell carcinoma.

INTRODUCTION: Cysteine Protease Inhibitor 1 (CST1), a cystatin superfamily protein with the effect on the inhibition of cysteine protease activity, is reported to be involved in the development of many malignancies. MiR-942-5p has been demonstrated its regulatory effects on some malignancies. However, the roles of CST1 and miR-942-5p on esophageal squamous cell carcinoma (ESCC) are still unknown up to now. METHODS: The expression of CST1 in ESCC tissues was analyzed by TCGA database, immunohistochemistry, and RT-qPCR, respectively. Matrigel-uncoated or-coated transwell assay was used to determine the effect of CST1 on migration and invasion of ESCC cells. Regulatory effect of miR-942-5p on CST1 was detected by dual luciferase assay. RESULTS: CST1 was ectopically highly expressed in ESCC tissues, and had the effect on promoting the migration and invasion of ESCC cells by upregulating phosphorylated levels of key effectors including MEK1/2, ERK1/2, and CREB in MEK/ERK/CREB pathway. Dual-luciferase assay results showed that miR-942-5p had a regulatory effect on targeting CST1. CONCLUSIONS: CST1 plays a carcinogenic role on ESCC, and miR-942-5p can regulate the migration and invasion of ESCC cells by targeting CST1 to downregulate MEK/ERK/CREB signaling pathway, suggesting that miR-942-5p/CST1 axis might be a promising target for diagnosis and treatment of ESCC.

Efficacy and safety of iruplinalkib (WX-0593) in ALK-positive crizotinib-resistant advanced non-small cell lung cancer patients: a single-arm, multicenter phase II study (INTELLECT).

BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.

Results of the phase IIa study to evaluate the efficacy and safety of rezivertinib (BPI-7711) for the first-line treatment of locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation from a phase I/IIa study.

BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This phase IIa study was part of a phase I/IIa study (NCT03386955), aimed to evaluate the efficacy and safety of rezivertinib as the first-line treatment for patients with locally advanced or metastatic/recurrent EGFR mutated non-small cell lung cancer (NSCLC). METHODS: Patients received the first-line treatment of 180 mg rezivertinib orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: From Jun 12, 2019, to Oct 17, 2019, 43 patients were enrolled. At the data cutoff date on Dec 23, 2021, the ORR by BICR was 83.7% (95% CI: 69.3-93.2%). The median DoR was 19.3 (95% CI: 15.8-25.0) months. The median PFS by BICR was 20.7 (95% CI: 13.8-24.8) months and 22.0 (95% CI: 16.8-26.3) months by investigators. Data on OS was immature. Totally, 40 (93.0%) patients had at least one treatment-related adverse event while 4 (9.3%) of them were grade ≥ 3. CONCLUSIONS: Rezivertinib (BPI-7711) showed promising efficacy and a favorable safety profile for the treatment among the locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation in the first-line setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03386955.

Aberrant NSG1 Expression Promotes Esophageal Squamous Cell Carcinoma Cell EMT by the Activation of ERK Signaling Pathway.

BACKGROUND: Neuron-specific gene family member 1 (NSG1) is a 21 kDa endosomal protein that is specifically expressed in neurons. AIMS: This study was to explore the expression of NSG1 and possible mechanism in Esophageal Squamous Cell Carcinoma (ESCC). METHODS: The Cancer Genome Atlas (TCGA) database was consulted to analyze the expression of NSG1 in ESCC. Immunohistochemistry (IHC) staining was used to evaluate NSG1 expression in ESCC cancerous tissues and matched paracancerous tissues. The CCK-8 assay, wound-healing assay, and transwell assay were used to detect the cell viability, migration, and invasion of ESCC cells. Western blot was used to assay epithelial-mesenchymal transition (EMT)-related proteins and ERK signaling pathway protein expression. RESULTS: The results showed that the expression of NSG1 in ESCC cancerous tissues was higher than noncancerous tissues. Compared with negative control (NC) group, cell viability, migration. and invasion significantly increased, the expression of p-ERK in ERK signaling pathway was significantly upregulated, the expressions of mesenchymal marker Vimentin and EMT-related transcription factors including snail and slug were significantly upregulated, and the expression of epithelial marker E-cadherin was significantly downregulated in KYSE-150 cells with NSG1 overexpression. However, these effects were reversed by the ERK signaling pathway inhibitor U0126. On the other hand, TE-1 cells with NSG1 knockdown had the changes contrary to that in KYSE-150 cells with NSG1 overexpression. CONCLUSION: NSG1 plays a potential carcinogenic role on the occurrence and progression of ESCC, and aberrant NSG1 expression might promote ESCC cell EMT by the activation of ERK signaling pathway.