Association Between Urinary Phthalate Metabolites and Chronic Obstructive Pulmonary Disease: A Cross-Sectional Study.

Objective: To determine the association of urinary phthalate metabolites with chronic obstructive pulmonary disease (COPD), airflow obstruction, lung function and respiratory symptoms. Methods: Our study included a total of 2023 individuals aged ≥ 40 years old in the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression was conducted to explore the correlation of eleven urinary phthalate metabolites (MCNP, MCOP, MECPP, MnBP, MCPP, MEP, MEHHP, MEHP, MiBP, MEOHP, and MBzP) with COPD, airflow obstruction and respiratory symptoms. Linear regression analyses were used to evaluate the relationship between urinary phthalate metabolites and lung function. Results: When compared to the first tertile, the third tertile of MEHHP was associated with the risk of COPD [OR: 2.779; 95% confidence interval (CI): 1.129-6.840; P = 0.026]. Stratified analysis showed that MEHHP increased the risk of COPD by 7.080 times in male participants. Both MCPP and MBzP were positively correlated with the risk of airflow obstruction. The third tertile of MBzP increased the risk of cough by 1.545 (95% CI: 1.030-2.317; P = 0.035) times. Both FEV1 and FVC were negatively associated with MEHHP, MECPP, MnBP, MEP, MiBP and MEOHP. Conclusion: Higher levels of MEHHP are associated with increased risk of COPD, and lower measures of FEV1 and FVC. MBzP is positively related to airflow obstruction and cough.

Geographically and Temporally Weighted Regression in Assessing Dengue Fever Spread Factors in YunnanBorder Regions.

Objective: This study employs the Geographically and Temporally Weighted Regression (GTWR) model to assess the impact of meteorological elements and imported cases on dengue fever outbreaks, emphasizing the spatial-temporal variability of these factors in border regions. Methods: We conducted a descriptive analysis of dengue fever's temporal-spatial distribution in Yunnan border areas. Utilizing annual data from 2013 to 2019, with each county in the Yunnan border serving as a spatial unit, we constructed a GTWR model to investigate the determinants of dengue fever and their spatio-temporal heterogeneity in this region. Results: The GTWR model, proving more effective than Ordinary Least Squares (OLS) analysis, identified significant spatial and temporal heterogeneity in factors influencing dengue fever's spread along the Yunnan border. Notably, the GTWR model revealed a substantial variation in the relationship between indigenous dengue fever incidence, meteorological variables, and imported cases across different counties. Conclusion: In the Yunnan border areas, local dengue incidence is affected by temperature, humidity, precipitation, wind speed, and imported cases, with these factors' influence exhibiting notable spatial and temporal variation.

Application of Short T1 Inversion Recovery Sequence in Increased Signal Intensity Following Cervical Spondylotic Myelopathy.

OBJECTIVES: To compare magnetic resonance (MR) short T1 inversion recovery (STIR) sequence with MR T2-weighted (T2W) sequence for detecting increased signal intensity (ISI) and assessing outcomes of ISI in cervical spondylotic myelopathy (CSM). METHODS: Data of patients with CSM who showed ISI on MR imaging and had undergone cervical spine surgery were retrospectively reviewed. STIR and T2W images were examined to assess signal intensity ratio (SIR), length and grading of the ISI, maximal spinal cord compression, canal narrowing ratio, and ligamentum flavum hypertrophy. The patients were divided into good and poor groups based on their outcomes. χ2 tests and variance analysis were used to assess intergroup differences. Univariate and multivariate logistic regression analyses were performed to identify risk factors for poor outcomes, and receiver operating characteristic curves were plotted to detect prognostic effects. RESULTS: SIR and ISI lengths were significantly different between the STIR and T2 images. In the univariate logistic regression analysis, age, diabetes, SIRT2, SIRSTIR, and ISISTIR grading were significant factors. Accordingly, in the multivariate logistic regression analysis, age, diabetes, SIRT2, and SIRSTIR were included in the model. Among patients with diabetes, we observed a significant difference between SIRT2 and SIRSTIR. CONCLUSIONS: The STIR sequence demonstrated superior capability to the T2W sequence in detecting ISI; however, there was no obvious difference in predicted outcomes. STIR sequence has a better prognostic value than T2W sequence in patients with diabetes who have CSM. ISI grading based on the STIR sequence may be a clinically valuable indicator.

Comparison of allo-SCT, auto-SCT and chemotherapy for the treatment of patients with low- or intermediate-risk acute myeloid leukemia: a network meta-analysis.

BACKGROUND: The therapeutic status of allogeneic stem cell transplantation (allo-SCT) as a post-remission treatment for patients with high-risk acute myeloid leukemia (AML) was well-accepted. However, the optimal treatment for patients with low/favorable- or intermediate-risk AML who achieve complete remission has remained controversial. Therefore, we conducted a network meta-analysis to discuss this disputed problem. METHODS: We compared the effects of treatment strategies including allo-SCT, autologous stem cell transplantation (auto-SCT) and consolidation chemotherapy (CT) for patients with low/favorable- or intermediate-risk AML. The pooled HRs and 95% CIs for overall survival and disease-free survival were estimated with Stata12 and R software. Thirty clinical studies with 6682 patients were included in the meta-analysis. RESULTS: The results indicated that the treatment outcome of allo-SCT was the best, followed by auto-SCT, and CT was likely the worst in the total AML patients. In patients with low/favorable-risk AML, the treatment outcome of auto-SCT was likely ranked first, followed by allo-SCT, and CT was the worst. In patients with intermediate-risk AML, the treatment outcome of haploidentical stem cell transplantation (haplo-SCT) was the best, followed by allo-SCT (excluding haplo-SCT), and auto-SCT and CT were the worst. However, the median age of the haplo-SCT group was much younger than that of the control group, which may be one of the reasons for the better prognosis of the haplo-SCT group. CONCLUSIONS: Patients with low/favorable- and intermediate-risk (non-high-risk) AML should prioritize allo-SCT if they are eligible for transplantation, and auto-SCT is optional. However, in the subgroup analysis, auto-SCT was the optimal treatment choice for patients with low/favorable-risk AML, and allo-SCT was the priority selection for patients with intermediate-risk AML, especially young patients. These findings could provide references for clinical practice.

Deubiquitinase UCHL1 promotes angiogenesis and blood-spinal cord barrier function recovery after spinal cord injury by stabilizing Sox17.

Improving the function of the blood-spinal cord barrier (BSCB) benefits the functional recovery of mice following spinal cord injury (SCI). The death of endothelial cells and disruption of the BSCB at the injury site contribute to secondary damage, and the ubiquitin-proteasome system is involved in regulating protein function. However, little is known about the regulation of deubiquitinated enzymes in endothelial cells and their effect on BSCB function after SCI. We observed that Sox17 is predominantly localized in endothelial cells and is significantly upregulated after SCI and in LPS-treated brain microvascular endothelial cells. In vitro Sox17 knockdown attenuated endothelial cell proliferation, migration, and tube formation, while in vivo Sox17 knockdown inhibited endothelial regeneration and barrier recovery, leading to poor functional recovery after SCI. Conversely, in vivo overexpression of Sox17 promoted angiogenesis and functional recovery after injury. Additionally, immunoprecipitation-mass spectrometry revealed the interaction between the deubiquitinase UCHL1 and Sox17, which stabilized Sox17 and influenced angiogenesis and BSCB repair following injury. By generating UCHL1 conditional knockout mice and conducting rescue experiments, we further validated that the deubiquitinase UCHL1 promotes angiogenesis and restoration of BSCB function after injury by stabilizing Sox17. Collectively, our findings present a novel therapeutic target for treating SCI by revealing a potential mechanism for endothelial cell regeneration and BSCB repair after SCI.

Prognostic value of circulating plasma cells detected by flow cytometry in newly diagnosed multiple myeloma patients: a systematic review and meta-analysis.

OBJECTIVES: Multiple myeloma (MM) is a malignant plasma cell disorder. The most widely accepted staging system for MM is the revised International Staging System based on cytogenetic and clinical biomarkers. The circulating clonal plasma cells (CPCs) were reported to have potential prognostic impact on MM. Among various diagnostic approaches, multiparametric flow cytometry (FCM) offers heightened sensitivity, minimal invasiveness and reproducibility. We conducted a meta-analysis to evaluate the prognostic value of quantifying CPCs via FCM in newly diagnosed symptomatic MM (NDMM) patients. DESIGN: Systematic review and meta-analysis. DATA SOURCE: PubMed, Web of Science, Embase and references of included studies. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included observational studies that evaluated the prognostic value of CPCs detected by FCM in NDMM. DATA EXTRACTION AND SYNTHESIS: Data were screened and extracted independently by two investigators. The pooled results originated from random effects models. The primary endpoint was overall survival (OS). The secondary endpoint was progression-free survival (PFS). To evaluate the prognostic value of CPCs in NDMM, HRs and their 95% CI for both OS and PFS were derived using COX multivariable models. These values were then used to compute the pooled estimated effect. RESULTS: Our meta-analysis encompassed a total of 2704 NDMM patients from 11 studies up to 27 August 2022. The pooled HR for OS and PFS in CPC-positive (CPCs+) group and CPC-negative group were 1.95 (95% CI 1.24 to 3.07) and 2.07 (95% CI 1.79 to 2.39), respectively. The autologous stem cell transplantation (ASCT) failed to eliminate the adverse impact on OS and PFS. The heterogeneity may stem from the use of novel agents or traditional chemotherapy as initial treatment. CONCLUSION: This meta-analysis indicates CPCs+ had an adverse impact on the prognosis of NDMM patients in the total population, and the adverse impact could not be eliminated by ASCT. PROSPERO REGISTRATION NUMBER: CRD42021272381.

Assessing the utility of MRI-based vertebral bone quality (VBQ) for predicting lumbar pedicle screw loosening.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study is to assess the potential of utilizing the MRI-based vertebral bone quality (VBQ) score as a predictive tool for pedicle screw loosening (PSL) in patients who have undergone pedicle screw fixation and to identify risk factors associated with VBQ scores. METHODS: One hundred and sixteen patients who had undergone pedicle screw fixation between December 2019 and January 2021 and had more than a year of follow-up were divided into two groups of PSL and non-PSL. The radiological and clinical parameters investigated were age, gender, body mass index, the VBQ score, length of fusion and the DXA T-score. RESULTS: Of the 116 patients included in the study, 22 patients developed pedicle screw loosening after surgery (18.97%). VBQ score of PSL group was higher than the non-PSL group (3.61 ± 0.63 vs. 2. 86 ± 0.43, p < 0.001). According to logistic regression, PSL was independently linked with a higher VBQ score (OR = 3.555, 95% confidence interval [1.620-7.802], p < 0.005). The AUC of predicting screw loosening was 0.774 (p < 0.001) for VBQ score, and the best threshold was 3.055 (sensitivity, 81.8%; specificity, 71.3%). High VBQ score was associated with age (r (114) = 0.29, p = 0.002), while it was not negatively correlated with T-scores of each part. CONCLUSION: VBQ score is an independent predictor of pedicle screw loosening, with higher scores indicating a greater risk. Our results showed that older patients and women had higher VBQ scores.

[4D bioprinting technology and its application in cardiovascular tissue engineering].

3D bioprinting technology is a rapidly developing technique that employs bioinks containing biological materials and living cells to construct biomedical products. However, 3D-printed tissues are static, while human tissues are in real-time dynamic states that can change in morphology and performance. To improve the compatibility between in vitro and in vivo environments, an in vitro tissue engineering technique that simulates this dynamic process is required. The concept of 4D printing, which combines "3D printing + time" provides a new approach to achieving this complex technique. 4D printing involves applying one or more smart materials that respond to stimuli, enabling them to change their shape, performance, and function under the corresponding stimulus to meet various needs. This article focuses on the latest research progress and potential application areas of 4D printing technology in the cardiovascular system, providing a theoretical and practical reference for the development of this technology.

Diagnostic performance of metagenomic next-generation sequencing for Pneumocystis jirovecii pneumonia.

OBJECTIVE: Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection. We aimed to evaluate the diagnostic accuracy of metagenomic next-generation sequencing (mNGS) for PJP. METHODS: A comprehensive electronic literature search of Web of Knowledge, PubMed, Cochrane Library, CNKI and Wanfang data was performed. Bivariate analysis was conducted to calculate the pooled sensitivity, specificity, diagnostic odds ratio (DOR), the area under the summary receiver operator characteristic (SROC) curve and the Q-point value (Q*). RESULTS: The literature search resulted in 9 studies with a total of 1343 patients, including 418 cases diagnosed with PJP and 925 controls. The pooled sensitivity of mNGS for diagnosis of PJP was 0.974 [95% confidence interval (CI), 0.953-0.987]. The pooled specificity was 0.943 (95% CI, 0.926-0.957), the DOR was 431.58 (95% CI, 186.77-997.27), the area under the SROC curve was 0.987, and the Q* was 0.951. The I2 test indicated no heterogeneity between studies. The Deek funnel test suggested no potential publication bias. Subgroup analyses showed that the area under the SROC curve of mNGS for diagnosis of PJP in immunocompromised and non-HIV patients was 0.9852 and 0.979, respectively. CONCLUSIONS: Current evidence indicates that mNGS exhibits excellent accuracy for the diagnosis of PJP. The mNGS is a promising tool for assessment of PJP in both immunocompromised and non-HIV patients.

Do Cervical Parameters Increase the Risk of Thoracic Spinal Stenosis in Patients with Cervical Spinal Stenosis?

OBJECTIVES: The diagnosis and treatment of tandem stenosis have been widely discussed. However, studies on concurrent cervical and thoracic spinal stenosis are rare in the literature. This study was aimed to investigate the risk factors for thoracic spinal stenosis (TSS) in patients with cervical spinal stenosis (CSS). METHODS: This retrospective cohort study assessed the risk factors for TSS in 162 patients who were diagnosed with CSS. Patients were divided into TSS (n = 45) and non-TSS (n = 117) groups. We retrospectively analyzed clinical characteristics and radiographic parameters including age, gender, body mass index, ossification of the cervical posterior longitudinal ligament (OPLLc), hypertrophy of cervical ligamentum flavum (HLFc), cervical stenosis segments, and cervical sagittal parameters. Cervical sagittal parameters were measured on T2-weighted magnetic resonance imaging including C2-7 Cobb angle, cervical tilt, T1 slope, thoracic inlet angle (TIA), C2-C7 sagittal vertical axis (C2-C7), and cervical curvature. RESULTS: Two groups showed significant differences in ossification of the cervical posterior longitudinal ligament, HLFc, cervical stenosis segments, and TIA. The receiver operating characteristic curves demonstrated that the optimal threshold for TIA was 68.25. In multivariate logistic regression analysis, OPLLc (odds ratio [OR] = 4.403, 95% confidence interval [CI] = 1.782-10.880, P = 0.001), HLFc (OR = 4.849, 95% CI = 1.995-11.782, P < 0.001), and TIA >68.25 degrees (OR = 2.555, 95% CI = 1.044-6.251, P = 0.040) were independent risk factors for TSS. Moreover, the multiindex receiver operating characteristic curve demonstrated that the area under the curve for predicted probability was 0.799 (P < 0.001). CONCLUSIONS: Routine thoracic magnetic resonance imaging assessment is strongly recommended in CSS patients with OPLLc, HLFc, and enlarged TIA to screen for neglected but vital thoracic disease.

Qi-Dong-Huo-Xue-Yin balances the immune microenvironment to protect against LPS induced acute lung injury.

COVID-19 induces acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and leads to severe immunological changes that threatens the lives of COVID-19 victims. Studies have shown that both the regulatory T cells and macrophages were deranged in COVID-19-induced ALI. Herbal drugs have long been utilized to adjust the immune microenvironment in ALI. However, the underlying mechanisms of herbal drug mediated ALI protection are largely unknown. This study aims to understand the cellular mechanism of a traditional Chinese medicine, Qi-Dong-Huo-Xue-Yin (QD), in protecting against LPS induced acute lung injury in mouse models. Our data showed that QD intrinsically promotes Foxp3 transcription via promoting acetylation of the Foxp3 promoter in CD4+ T cells and consequently facilitates CD4+CD25+Foxp3+ Tregs development. Extrinsically, QD stabilized ß-catenin in macrophages to expedite CD4+CD25+Foxp3+ Tregs development and modulated peripheral blood cytokines. Taken together, our results illustrate that QD promotes CD4+CD25+Foxp3+ Tregs development via intrinsic and extrinsic pathways and balanced cytokines within the lungs to protect against LPS induced ALI. This study suggests a potential application of QD in ALI related diseases.

Exosomal USP13 derived from microvascular endothelial cells regulates immune microenvironment and improves functional recovery after spinal cord injury by stabilizing IκBα.

Spinal cord injury (SCI) can result in irreversible sensory and motor disability with no effective treatment currently. After SCI, infiltrated macrophages accumulate in epicenter through destructed blood-spinal cord barrier (BSCB). Further, great majority of macrophages are preferentially polarized to M1 phenotype, with only a few transient M2 phenotype. The purpose of this study was to explore roles of vascular endothelial cells in microglia/macrophages polarization and the underlying mechanism. Lipopolysaccharide (LPS) was used to pretreat BV2 microglia and RAW264.7 macrophages followed by administration of conditioned medium from microvascular endothelial cell line bEnd.3 cells (ECM). Analyses were then performed to determine the effects of exosomes on microglia/macrophages polarization and mitochondrial function. The findings demonstrated that administration of ECM shifted microglia/macrophages towards M2 polarization, ameliorated mitochondrial impairment, and reduced reactive oxygen species (ROS) production in vitro. Notably, administration of GW4869, an exosomal secretion inhibitor, significantly reversed these observed benefits. Further results revealed that exosomes derived from bEnd.3 cells (Exos) promote motor rehabilitation and M2 polarization of microglia/macrophages in vivo. Ubiquitin-specific protease 13 (USP13) was shown to be significantly enriched in BV2 microglia treated with Exos. USP13 binds to, deubiquitinates and stabilizes the NF-κB inhibitor alpha (IκBα), thus regulating microglia/macrophages polarization. Administration of the selective IκBα inhibitor betulinic acid (BA) inhibited the beneficial effect of Exos in vivo. These findings uncovered the potential mechanism underlying the communications between vascular endothelial cells and microglia/macrophages after SCI. In addition, this study indicates exosomes might be a promising therapeutic strategy for SCI treatment.

Prognostic significance of KMT2A-PTD in patients with acute myeloid leukaemia: a systematic review and meta-analysis.

OBJECTIVES: Whether KMT2A-PTD has a prognostic impact on patients with acute myeloid leukaemia (AML) is controversial. Therefore, we conducted a meta-analysis to assess the prognostic value of KMT2A-PTD in patients with AML. METHODS: Eligibility criteria: we included studies concerning the prognostic value of KMT2A-PTD in patients with AML. INFORMATION SOURCES: Eligible studies were identified from PubMed, Embase, Medline, Web of Science, Cochrane Library and Chinese Biomedical Database. The systematic search date was 19 December 2020.Risk of bias: Sensitivity analysis was used to evaluate the stability and reliability of the combined results. Begg's and Egger's tests were used to assess the publication biases of studies. SYNTHESIS OF RESULTS: We calculated the pooled HRs and their 95% CIs for overall survival (OS) and event-free survival (EFS) by Stata V.12 software. RESULTS: Included studies: 18 studies covering 6499 patients were included. SYNTHESIS OF RESULTS: KMT2A-PTD conferred shorter OS in total population (HR=1.30, 95% CI 1.09 to 1.51). In the subgroup analysis, KMT2A-PTD also resulted in shorter OS in karyotypically normal AML patients (HR=2.72, 95% CI 1.83 to 3.61) and old AML patients (HR=1.93, 95% CI 1.44 to 2.42). KMT2A-PTD indicated no prognostic impact on EFS in total population (HR=1.26, 95% CI 0.86 to 1.66). However, in the sensitivity analysis, KMT2A-PTD resulted in poor EFS (HR=1.34, 95% CI 1.04 to 1.64) when deleting the study with a relatively obvious effect on the combined HR. In the subgroup analysis, KMT2A-PTD was associated with poor EFS in old AML patients (HR=1.64, 95% CI 1.25 to 2.03). CONCLUSION: The findings indicated that KMT2A-PTD had an adverse impact on the prognosis of patients with AML in the total population, and the conclusion can also be applied to some subgroups including karyotypically normal AML and old AML patients. KMT2A-PTD may be a promising genetic biomarker in patients with AML in the future. TRIAL REGISTRATION NUMBER: CRD42021227185.

USP1/UAF1-Stabilized METTL3 Promotes Reactive Astrogliosis and Improves Functional Recovery after Spinal Cord Injury through m6A Modification of YAP1 mRNA.

RNA N6-methyladenosine (m6A) modification is involved in diverse biological processes. However, its role in spinal cord injury (SCI) is poorly understood. The m6A level increases in injured spinal cord, and METTL3, which is the core subunit of methyltransferase complex, is upregulated in reactive astrocytes and further stabilized by the USP1/UAF1 complex after SCI. The USP1/UAF1 complex specifically binds to and subsequently removes K48-linked ubiquitination of the METTL3 protein to maintain its stability after SCI. Moreover, conditional knockout of astrocytic METTL3 in both sexes of mice significantly suppressed reactive astrogliosis after SCI, thus resulting in widespread infiltration of inflammatory cells, aggravated neuronal loss, hampered axonal regeneration, and impaired functional recovery. Mechanistically, the YAP1 transcript was identified as a potential target of METTL3 in astrocytes. METTL3 could selectively methylate the 3'-UTR region of the YAP1 transcript, which subsequently maintains its stability in an IGF2BP2-dependent manner. In vivo, YAP1 overexpression by adeno-associated virus injection remarkably contributed to reactive astrogliosis and partly reversed the detrimental effects of METTL3 knockout on functional recovery after SCI. Furthermore, we found that the methyltransferase activity of METTL3 plays an essential role in reactive astrogliosis and motor repair, whereas METTL3 mutant without methyltransferase function failed to promote functional recovery after SCI. Our study reveals the previously unreported role of METTL3-mediated m6A modification in SCI and might provide a potential therapy for SCI.SIGNIFICANCE STATEMENT Spinal cord injury is a devastating trauma of the CNS involving motor and sensory impairments. However, epigenetic modification in spinal cord injury is still unclear. Here, we propose an m6A regulation effect of astrocytic METTL3 following spinal cord injury, and we further characterize its underlying mechanism, which might provide promising strategies for spinal cord injury treatment.

Characterizing in-cabin air quality and vehicular air filtering performance for passenger cars in China.

The rapidly growing vehicle population has become a crucial contributor to severe air-pollution and public health issues. In urban areas, vehicles have become one of the important sources of air pollutants such as nitrogen oxides and fine particulate matter (PM2.5). In particular, the on-road concentrations of traffic-related air pollutants (TRAPs) are typically many times higher than normal ambient concentrations, potentially leading to high in-vehicle exposure levels to TRAPs. Limited studies have focused on the variability in in-vehicle concentrations of TRAPs and linked the pollution level to both out-cabin conditions and the in-cabin filtration performance during real-world travels. Therefore, this study measured on-roadway, in-cabin concentrations of PM2.5 and carbon dioxide (CO2) by using well-calibrated low-cost sensors during various conditions. Our results indicate that, although in-cabin PM2.5 concentrations are correlated to out-cabin PM2.5 concentration levels, the control efficiency would be affected by the ventilation mode and the adoption of vehicular filtration device. The PM2.5 reduction efficiencies could achieve 45% and 77% for in-use and new filters made by vehicle manufacturers respectively, with the average CO2 concentration remained at a safe level (<800 ppm) under the in-vehicle outside air ventilation. The application of a high-efficiency cabin air (HECA) filter can further enhance the PM2.5 filtration efficiency up to 85-96%, indicating the significance of advanced cabin air filtration technology for improving in-cabin air quality and reducing health risk of Chinese drivers.

Engineered extracellular vesicles for delivery of siRNA promoting targeted repair of traumatic spinal cord injury.

Spinal cord injury (SCI) is a severe disease of the nervous system that causes irreparable damage and loss of function, for which no effective treatments are available to date. Engineered extracellular vesicles (EVs) carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy. In this study, we demonstrated the design of a drug delivery system of peptide CAQK-modified, siRNA-loaded EVs (C-EVs-siRNA) for SCI-targeted therapy. The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells (iNSCs). CCL2-siRNA was then loaded into the EVs through electroporation. The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo. C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells. C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA, thus enhancing the therapeutic effect against SCI. The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI, promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI. Thus, engineered EVs are a potentially feasible and efficacious treatment for SCI, and may also be used to develop targeted treatments for other diseases.

The proteolysis targeting chimera GMB-475 combined with dasatinib for the treatment of chronic myeloid leukemia with BCR::ABL1 mutants.

Patients with chronic myeloid leukemia (CML) show resistance to tyrosine kinase inhibitors (TKIs) targeting ABL1 due to the emergence of BCR::ABL1 mutants, especially compound mutants during the treatment, which brings great challenges to clinical practice. Combination therapy is an effective strategy for drug resistance. GMB-475, a proteolysis targeting chimera (PROTAC) targeting the myristoyl pocket of ABL1 in an allosteric manner, degrades the BCR::ABL1 through the ubiquitin-proteasome pathway. In this study, we combined GMB-475 with orthosteric TKIs targeting ABL1 to overcome resistance. We constructed Ba/F3 cells carrying BCR::ABL1 mutants by gene cloning technology and compared the effects of combination therapy with those of monotherapy on the biological characteristics and signaling pathways in CML cells. We found that the effects of ABL1 inhibitors, including imatinib, dasatinib, ponatinib, and ABL001, on growth inhibition and promoting apoptosis of Ba/F3 cells with BCR::ABL1 mutants, especially compound mutants, were weakened. GMB-475 combined with TKIs, especially dasatinib, synergistically inhibited growth, promoted apoptosis, and blocked the cell cycle of Ba/F3 cells carrying BCR::ABL1 mutants and synergistically blocked multiple molecules in the JAK-STAT pathway. In conclusion, dasatinib enhanced the antitumor effect of GMB-475; that is, the combination of PROTAC targeting ABL1 in an allosteric manner and orthosteric TKIs, especially dasatinib, provides a novel idea for the treatment of CML patients with BCR::ABL1 mutants in clinical practice.

Radiographic predictors for recurrence of lumbar symptoms after prioritized cervical surgery in patients with tandem spinal stenosis.

OBJECTIVES: The purpose of the current study was to explore radiographic predictors for recurrence of lumbar symptoms after prioritized cervical surgery in patients with tandem spinal stenosis (TSS). METHODS: The current retrospective cohort study included 74 patients with TSS, who underwent prioritized cervical surgery. Based on presence or absence of improvement in lower limb symptoms, patients were grouped into improved and non-improved groups. Medical records and radiological parameters including age, sex, body mass index, cervical and lumbar parameters were analyzed. In improved group, patients were divided into relapsed and non-relapsed groups based on recurrence in lower limb symptoms. RESULTS: Lumbar symptoms improved in 70.1% (n = 52) of patients. Comparison between the improved and non-improved group showed that there were no statistically significant differences in cervical parameters while comparisons between the relapsed and non-relapsed groups showed significant differences in redundant nerve roots (RNRs) (p = 0.029), narrow segment (p = 0.042) and lumbar stenosis index (LSI) (p = 0.003). In multivariate logistic regression analysis, LSI > 10 (p = 0.016) was independently associated with recurrence of lumbar symptoms. CONCLUSIONS: Finding of the current study indicated that LSI > 10 was associated with recurrence of lumbar symptoms in TSS patients following cervical surgery.

TSG-6 released from adipose stem cells-derived small extracellular vesicle protects against spinal cord ischemia reperfusion injury by inhibiting endoplasmic reticulum stress.

BACKGROUND: Spinal cord ischemia reperfusion injury (SCIRI) is a complication of aortic aneurysm repair or spinal cord surgery that is associated with permanent neurological deficits. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been shown to be potential therapeutic options for improving motor functions after SCIRI. Due to their easy access and multi-directional differentiation potential, adipose-derived stem cells (ADSCs) are preferable for this application. However, the effects of ADSC-derived sEVs (ADSC-sEVs) on SCIRI have not been reported. RESULTS: We found that ADSC-sEVs inhibited SCIRI-induced neuronal apoptosis, degradation of tight junction proteins and suppressed endoplasmic reticulum (ER) stress. However, in the presence of the ER stress inducer, tunicamycin, its anti-apoptotic and blood-spinal cord barrier (BSCB) protective effects were significantly reversed. We found that ADSC-sEVs contain tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) whose overexpression inhibited ER stress in vivo by modulating the PI3K/AKT pathway. CONCLUSIONS: ADSC-sEVs inhibit neuronal apoptosis and BSCB disruption in SCIRI by transmitting TSG-6, which suppresses ER stress by modulating the PI3K/AKT pathway.

TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling.

Osteosarcoma (OS) is a malignant bone tumor that mainly occurs in adolescents. It is accompanied by a high rate of lung metastasis, and high mortality. Recent studies have suggested the important roles of tripartite motif-containing (TRIM) family proteins in regulating various substrates and signaling pathways in different tumors. However, the detailed functional role of TRIM family proteins in the progression of OS is still unknown and requires further investigations. In this study, we found that tripartite motif-containing 22 (TRIM22) was downregulated in OS tissues and was hence associated with better prognosis. In vitro and in vivo functional analysis demonstrated that TRIM22 inhibits proliferation and metastasis of OS cells. Nuclear factor erythroid 2-related factor 2 (NRF2), a redox regulator, was identified as a novel target for TRIM22. TRIM22 interacts with and accelerates the degradation of NRF2 by inducing its ubiquitination dependent on its E3 ligase activity but independent of Kelch-like ECH-associated protein 1 (KEAP1). Further, a series of gain- and loss-of-function experiments showed that knockdown or overexpression of NRF2 reversed the functions of knockdown or overexpression of TRIM22 in OS. Mechanistically, TRIM22 inhibited OS progression through NRF2-mediated intracellular reactive oxygen species (ROS) imbalance. ROS production was significantly promoted and mitochondrial potential was remarkably inhibited when overexpressing TRIM22, thus activating AMPK/mTOR signaling. Moreover, TRIM22 was also found to inhibit Warburg effect in OS cells. Autophagy activation was found in OS cells which were overexpressed TRIM22, thus leading to autophagic cell death. Treatment with N-Acetylcysteine (NAC), a ROS scavenger or the autophagy inhibitor 3-Methyladenine (3-MA) abolished the decreased malignant phenotypes in TRIM22 overexpressing OS cells. In conclusion, our study indicated that TRIM22 inhibits OS progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating ROS/AMPK/mTOR/Autophagy signaling that leads to autophagic cell death in OS. Therefore, our findings indicated that targeting TRIM22/NRF2 could be a promising therapeutic target for treating OS.