Locationally activated PRP via an injectable dual-network hydrogel for endometrial regeneration.

Enhancing the effectiveness of platelet-rich plasma (PRP) for endometrial regeneration is challenging, due to its limited mechanical properties and burst release of growth factors. Here, we proposed an injectable interpenetrating dual-network hydrogel that can locationally activate PRP within the uterine cavity, sustained release growth factors and further address the insufficient therapeutic efficacy. Locational activation of PRP is achieved using the dual-network hydrogel. The phenylboronic acid (PBA) modified methacrylated hyaluronic acid (HAMA) dispersion chelates Ca2+ by carboxy groups and polyphenol groups, and in situ crosslinked with PRP-loaded polyvinyl alcohol (PVA) dispersion by dynamic borate ester bonds thus establishing the soft hydrogel. Subsequently, in situ photo-crosslinking technology is employed to enhance the mechanical performance of hydrogels by initiating free radical polymerization of carbon-carbon double bonds to form a dense network. The PRP-hydrogel significantly promoted the endometrial cell proliferation, exhibited strong pro-angiogenic effects, and down-regulated the expression of collagen deposition genes by inhibiting the TGF-ß1-SMAD2/3 pathway in vitro. In vivo experiments using a rat intrauterine adhesion (IUA) model showed that the PRP-hydrogel significantly promoted endometrial regeneration and restored uterine functionality. Furthermore, rats treated with the PRP-hydrogel displayed an increase in the number of embryos, litter size, and birth rate, which was similar to normal rats. Overall, this injectable interpenetrating dual-network hydrogel, capable of locational activation of PRP, suggests a new therapeutic approach for endometrial repair.

Injectable "Homing-Like" Bioactive Short-Fibers for Endometrial Repair and Efficient Live Births.

The prevalence of infertility caused by endometrial defects is steadily increasing, posing a significant challenge to women's reproductive health. In this study, injectable "homing-like" bioactive decellularized extracellular matrix short-fibers (DEFs) of porcine skin origin are innovatively designed for endometrial and fertility restoration. The DEFs can effectively bind to endometrial cells through noncovalent dipole interactions and release bioactive growth factors in situ. In vitro, the DEFs effectively attracted endometrial cells through the "homing-like" effect, enabling cell adhesion, spreading, and proliferation on their surface. Furthermore, the DEFs effectively facilitated the proliferation and angiogenesis of human primary endometrial stromal cells (HESCs) and human umbilical vein endothelial cells (HUVECs), and inhibited fibrosis of pretreated HESCs. In vivo, the DEFs significantly accelerated endometrial restoration, angiogenesis, and receptivity. Notably, the deposition of endometrial collagen decreased from 41.19 ± 2.16% to 14.15 ± 1.70% with DEFs treatment. Most importantly, in endometrium-injured rats, the use of DEFs increased the live birth rate from 30% to an impressive 90%, and the number and development of live births close to normal rats. The injectable "homing-like" bioactive DEFs system can achieve efficient live births and intrauterine injection of DEFs provides a new promising clinical strategy for endometrial factor infertility.

The association of long-term trajectories of BMI, its variability, and metabolic syndrome: a 30-year prospective cohort study.

Background: Limited data exists on how early-life weight changes relate to metabolic syndrome (MetS) risk in midlife. This study examines the association between long-term trajectories of body mass index (BMI), its variability, and MetS risk in Chinese individuals. Methods: In the Hanzhong Adolescent Hypertension study (March 10, 1987-June 3, 2017), 1824 participants with at least five BMI measurements from 1987 to 2017 were included. Using group-based trajectory modeling, different BMI trajectories were identified. BMI variability was assessed through standard deviation (SD), variability independent of the mean (VIM), and average real variability (ARV). Logistic regression analyzed the relationship between BMI trajectory, BMI variability, and MetS occurrence in midlife (URL: https://www.clinicaltrials.gov; Unique identifier: NCT02734472). Findings: BMI trajectories were categorized as low-increasing (34.4%), moderate-increasing (51.8%), and high-increasing (13.8%). Compared to the low-increasing group, the odds ratios (ORs) [95% CIs] for MetS were significantly higher in moderate (4.27 [2.63-6.91]) and high-increasing groups (13.11 [6.30-27.31]) in fully adjusted models. Additionally, higher BMI variabilities were associated with increased MetS odds (ORs for SDBMI, VIMBMI, and ARVBMI: 2.30 [2.02-2.62], 1.22 [1.19-1.26], and 4.29 [3.38-5.45]). Furthermore, BMI trajectories from childhood to adolescence were predictive of midlife MetS, with ORs in moderate (1.49 [1.00-2.23]) and high-increasing groups (2.45 [1.22-4.91]). Lastly, elevated BMI variability in this period was also linked to higher MetS odds (ORs for SDBMI, VIMBMI, and ARVBMI: 1.24 [1.08-1.42], 1.00 [1.00-1.01], and 1.21 [1.05-1.38]). Interpretation: Our study suggests that both early-life BMI trajectories and BMI variability could be predictive of incident MetS in midlife. Funding: This work was supported by the National Natural Science Foundation of China No. 82070437 (J.-J.M.), the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University of China (No. XJTU1AF-CRF-2022-002, XJTU1AF2021CRF-021, and XJTU1AF-CRF-2023-004), the Key R&D Projects in Shaanxi Province (Grant No. 2023-ZDLSF-50), the Chinese Academy of Medical Sciences & Peking Union Medical College (2017-CXGC03-2), and the International Joint Research Centre for Cardiovascular Precision Medicine of Shaanxi Province (2020GHJD-14).

Screening of potential key ferroptosis-related genes in Chronic Obstructive Pulmonary Disease.

Purpose: Ferroptosis plays essential roles in the development of COPD. We aim to identify the potential ferroptosis-related genes of COPD through bioinformatics analysis. Methods: The RNA expression profile dataset GSE148004 was obtained from the GEO database. The ferroptosis-related genes were obtained from the FerrDb database. The potential differentially expressed ferroptosis-related genes of COPD were screened by R software. Then, protein-protein interactions (PPI), correlation analysis, gene-ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were applied for the differentially expressed ferroptosis-related genes. Finally, hub gene-microRNA(miRNA), hug gene-transcription factor interaction networks were constructed by miRTarBase v8.0 and JASPAR respectively, and hub gene drugs were predicted by the Enrichr database. Results: A total of 41 differentially expressed ferroptosis-related genes (22 up-regulated genes and 19 down-regulated genes) were identified between 7 COPD patients and 9 healthy controls. The PPI results demonstrated that these ferroptosis-related genes interacted with each other. The GO and KEGG enrichment analyses of differentially expressed ferroptosis-related genes indicated several enriched terms related to ferroptosis, central carbon metabolism in cancer, and the HIF-1 signaling pathway. The crucial miRNAs and drugs associated with the top genes were identified. Conclusion: We identified 41 potential ferroptosis-related genes in COPD through bioinformatics analysis. HIF1A, PPARG, and KRAS may affect the development of COPD by regulating ferroptosis. These results may expand our understanding of COPD and might be useful in the treatment of COPD.

Ferrostatin-1 Ameliorated Oxidative Lipid Damage in LPS-induced Acute Lung Injury.

INTRODUCTION: Ferroptosis is a new type of regulated cell death that is characterized by the overwhelming iron-dependent accumulation of lethal lipid reactive oxygen species and is involved in various diseases. However, the relationship between ferroptosis and lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains largely unknown. METHODS: In this study, iron metabolism and ferroptosis-related gene mRNA levels in the lung tissues of LPS-induced ALI mice at different time points were detected. Then, the histological, cytokines production, and iron levels of LPS-induced ALI mice with or without the pretreatment of the ferroptosis inhibitor ferrostatin-1 (Fer-1) were measured after mice received the ferroptosis inhibitor ferrostatin-1 (Fer-1) intraperitoneally before LPS administration. Ferroptosis-related protein (GPX4, NRF2, and DPP4) expression was measured in the in vivo and in vitro ALI model. Finally, ROS accumulation and lipid peroxidation was measured in in vivo and in vitro study. RESULTS: Our results showed that iron metabolism and ferroptosis-related gene mRNA demonstrated significant variation in LPS-treated pulmonary tissues. The ferroptosis inhibitor Fer-1 markedly attenuated the histologic injuries of the lung tissue and suppressed the production of cytokines in bronchoalveolar lavage fluid (BALF). Fer-1 administration reduced the levels of NRF2 and DPP4 protein induced by the LPS challenge. Furthermore, Fer-1 reversed the tendency of iron metabolism, MDA, SOD, and GSH levels induced by LPS administration in in vivo and in vitro. CONCLUSIONS: Taken together, ferroptosis inhibition by ferrostatin-1 alleviated acute lung injury through modulating oxidative lipid damages induced by the LPS challenge.

CoLAMP: CRISPR-based one-pot loop-mediated isothermal amplification enables at-home diagnosis of SARS-CoV-2 RNA with nearly eliminated contamination utilizing amplicons depletion strategy.

Rapid point-of-care diagnostics, essential in settings such as airport on-site testing and home-based screening, displayed important implications for infectious disease control during the SARS-CoV-2 outbreak. However, the deployment of simple and sensitive assays in real-life scenarios still faces the concern of aerosol contamination. Here, we report an amplicon-depleting CRISPR-based one-pot loop-mediated isothermal amplification (CoLAMP) assay for point-of-care diagnosis of SARS-CoV-2 RNA. In this work, AapCas12b sgRNA is designed to recognize the activator sequence sited in the loop region of the LAMP product, which is crucial for exponential amplification. By destroying the aerosol-prone amplifiable products at the end of each amplification reaction, our design can significantly reduce the amplicons contamination that causes false positive results in point-of-care diagnostics. For at-home self-testing, we designed a low-cost sample-to-result device for fluorescence-based visual interpretation. As well, a commercial portable electrochemical platform was deployed as a proof-of-concept of ready-to-use point-of-care diagnostic systems. The field deployable CoLAMP assay can detect as low as 0.5 copies/µL of SARS-CoV-2 RNA in clinical nasopharyngeal swab samples within 40 min without the need for specialists for its operation.

A prognostic risk model, tumor immune environment modulation, and drug prediction of ferroptosis and amino acid metabolism-related genes in hepatocellular carcinoma.

The prognosis of hepatocellular carcinoma (HCC) is challenging due to its heterogeneity. Ferroptosis and amino acid metabolism have been shown to be closely related to HCC. We obtained HCC-related expression data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. We then crossed differentially expressed genes (DEGs), amino acid metabolism genes, and ferroptosis-related genes (FRGs) to obtain amino acid metabolism-ferroptosis-related differentially expressed genes (AAM-FR DEGs). Moreover, we developed a prognostic model using Cox analysis, followed by a correlation analysis of risk scores with clinical characteristics. We also performed an immune microenvironment analysis and drug sensitivity analysis. Finally, the expression levels of model genes were verified by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical assays. We found that the 18 AAM-FR DEGs were mainly enriched to the alpha-amino acid metabolic process and amino acid biosynthesis pathways. Cox analysis identified CBS, GPT2, SUV39H1, and TXNRD1 as prognostic biomarkers for the risk model construction. Our results showed that the risk scores differed between pathology stage, pathology T stage, and HBV, and the number of HCC patients in the two groups. In addition, the expression of PD-L1 and CTLA-4 was high in the high-risk group, and the half-maximal inhibitory concentration (IC50) of sorafenib also differed between the two groups. Finally, the experimental validation demonstrated that the expression of biomarkers was consistent with the study analysis. Therefore, in this study, we constructed and validated a prognostic model (CBS, GPT2, SUV39H1, and TXNRD1) related to ferroptosis and amino acid metabolism and examined their prognostic value for HCC.

Management of dermatomyositis patients amidst the COVID-19 pandemic: Two case reports.

RATIONALE: In December 2019, a new epidemic of coronavirus disease 2019 (COVID-19) appeared in Wuhan, Hubei Province, and spread rapidly to other parts of China and worldwide. Although established methods exist for the diagnosis and treatment of COVID-19 infection, the management of dermatomyositis (DM) patients with COVID-19 is unknown. PATIENT CONCERNS: In this article, we describe case reports of 2 patients with DM. The first case was a 67-year-old patient with DM and infected with COVID-19 who was admitted to Leishenshan Hospital for a 1-month history of fever, cough, and expectoration. The second case was a 51-year-old male patient who was admitted to Leishenshan Hospital due to fever with cough, expectoration and shortness of breath for 1 month. DIAGNOSES: The first patient was diagnosed with COVID-19 secondary to DM based on repeated SARS-CoV-2 real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) test, detailed medical history and chest computed tomography; The second patient was diagnosed with interstitial lung disease associated with anti-MDA5 DM based on the results of antirheumatic and anti-inflammatory therapy and the above 3 methods. INTERVENTIONS AND OUTCOMES: The first patient received supportive and empirical treatment, including antiviral treatment, anti-inflammatory treatment, oxygen therapy and prophylactic anticoagulation therapy. The symptoms and laboratory results got improved after the treatments. He was discharged with thrice negative PCR tests for the SARS-CoV-2 virus. The second patient received a comprehensive treatment, including glucocorticoid and plasma exchange; his symptoms were relieved and improved. LESSONS: These cases suggest that repeated new pathogenic test results for the coronavirus and a detailed diagnosis of the medical history are important means to distinguish these diseases. Increased attention to the individual characteristics of different cases may allow for more effective diagnosis and treatment.

Platelet P2Y12 Inhibitor in the Treatment and Prevention of Migraine: A Systematic Review and Meta-Analysis.

There have been speculation and research linking migraine with abnormalities of platelet aggregation and activation. The role of the P2Y12 platelet inhibitor in the treatment of migraine has not been established. We aim to evaluate the efficacy of the platelet P2Y12 inhibitor in the treatment of migraine and prevention of new-onset migraine headache (MHA) following transcatheter atrial septal defect closure (ASDC). We searched the PubMed, Web of Science, and Cochrane Library databases for relevant studies. The primary outcomes were the headache responder rate and the rate of new-onset migraine attacks following ASDC. Four studies for a total of 262 migraine patients with or without patent foramen ovale (PFO) and three studies involving 539 patients with antiplatelet treatment in the prevention of new-onset migraine following ASDC were included. The pooled responder rate of the P2Y12 inhibitor for migraine was 0.64 (95% CI: 0.43 to 0.81). For patients who underwent ASDC, the use of antiplatelet regimens including the P2Y12 inhibitor, compared with regimens excluding P2Y12 inhibitor, resulted in a lower rate of new-onset migraine (OR: 0.41, 95% CI: 0.22 to 0.77, P = 0.005). We concluded that the P2Y12 platelet inhibitor may have a primary prophylactic role in migraine patients with or without PFO and prevent new-onset MHA after ASDC. The responsiveness of the P2Y12 inhibitor could help select candidates who would benefit from PFO closure. It warrants further large-scale research to explore the role of the P2Y12 inhibitor, particularly in a proportion of migraine patients.

Effect of MAP3K8 on Prognosis and Tumor-Related Inflammation in Renal Clear Cell Carcinoma.

Background: MAPK kinase kinase 8 (MAP3K8) is involved in the regulation of MAPK cascades and immune responses. Differential expression of MAP3K8 is closely correlated with tumorigenesis. In this study, we used bioinformatics tools to explore expression level, prognostic values, and interactive networks of MAP3K8 in renal clear cell carcinoma (ccRCC). Methods: Differential expression of MAP3K8 was determined by TIMER2.0, UALCAN, and Oncomine Platform. For exploration of MAP3K8 mutation profile, TIMER2.0, DriverDBv3, and cBioPortal were used. The survival module of GEPIA, UALCAN, and DriverDBv3 was used to examine the prognostic value of MAP3K8. Immune infiltration was estimated by TIMER, TIDE, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, XCELL, MCPCOUNTER, and EPIC algorithms. PPI networks and functional enrichment analysis were constructed using GeneMANIA, Cytoscape, and Metascape. The co-expression module in cBioPortal was used to find genes that are correlated with MAP3K8 in mRNA expression. Results: Compared to normal renal samples, ccRCC (3.08-fold change, P = 1.50E-7; 1.10-fold change, P = 3.00E-3), papillary RCC (2.24-fold change, P = 1.86E-4), and hereditary ccRCC (1.98-fold change, P = 1.69E-9) have significantly higher levels of MAP3K8 expression. Compared to Grade 1 ccRCC samples, Grade 2 (P = 1.28E-3) and Grade 3 (P = 7.41E-4) cases have higher levels of MAP3K8 methylation. Percentage of patients harboring MAP3K8 mutation is 0.3% from TIMER2.0 and 0.2 to 11.5% from cBioPortal. High levels of MAP3K8 expression were associated with poorer overall survival (OS) in ccRCC (GEPIA: Log-rank P = 0.60E-2, HR = 1.5; DriverDBv3: Log-rank P = 1.68E-7, HR = 2.21; UALCAN: P = 0.20E-2). MAP3K8 was positively correlated with the presence of T cell regulatory (Tregs) (QUANTISEQ: Rho = 0.33, P = 1.59E-13). PPI network and functional enrichment analyses revealed that MAP3K8 correlated with NFKBIZ, MIAT, PARP15, CHFR, MKNK1, and ERMN, which was mainly involved in I-kappaB kinase/NF-kappaB and toll-like receptor signaling pathways. Conclusion: MAP3K8 overexpression was correlated with damaged survival in ccRC and may play a crucial role in cancer-related inflammation via I-kappaB kinase/NF-kappaB and toll-like receptor signaling pathways.

Detection of rare variant alleles using the AsCas12a double-stranded DNA trans-cleavage activity.

The sensitive and accurate detection of rare mutations has profound clinical implications; however, current methods require expensive instrumentation and are laborious and time-consuming. Thus, there is a need for a probe-based alternative that can effectively discriminate single-base mutations. Recently, several groups have shown the potential of the CRISPR/Cas12a system for sensitive and selective DNA detection but its application on single nucleotide variants (SNVs) detection is limited by the requirement of a protospacer adjacent motif (PAM) directly upstream to the SNV site and the amplification of non-specific signals due to the rapid and indiscriminate trans cleavage activity. Here, we report an ultra-selective Cas12a-based system that eliminates the need for the PAM sequence in the target with lower noise from the wild-type sequence by using its non-canonical double-stranded trans-cleavage activity. We show that our strategy can allow the detection of an EGFR gene mutation in sub-femtomolar concentrations up to 0.1% variant allele frequency using either fluorescence or electrochemical readouts.

Maternal RNF114-mediated target substrate degradation regulates zygotic genome activation in mouse embryos.

Zygotic genomic activation (ZGA) is a landmark event in the maternal-to-zygotic transition (MZT), and the regulation of ZGA by maternal factors remains to be elucidated. In this study, the depletion of maternal ring finger protein 114 (RNF114), a ubiquitin E3 ligase, led to developmental arrest of two-cell mouse embryos. Using immunofluorescence and transcriptome analysis, RNF114 was proven to play a crucial role in major ZGA. To study the underlying mechanism, we performed protein profiling in mature oocytes and found a potential substrate for RNF114, chromobox 5 (CBX5), ubiquitylation and degradation of which was regulated by RNF114. The overexpression of CBX5 prevented embryonic development and impeded major ZGA. Furthermore, TAB1 was abnormally accumulated in mutant two-cell embryos, which was consistent with the result of in vitro knockdown of Rnf114. Knockdown of Cbx5 or Tab1 in maternal RNF114-depleted embryos partially rescued developmental arrest and the defect of major ZGA. In summary, our study reveals that maternal RNF114 plays a precise role in degrading some important substrates during the MZT, the misregulation of which may impede the appropriate activation of major ZGA in mouse embryos.

A novel framework of collaborative early warning for COVID-19 based on blockchain and smart contracts.

Early warning is a vital component of emergency response systems for infectious diseases. However, most early warning systems are centralized and isolated, thus there are potential risks of single evidence bias and decision-making errors. In this paper, we tackle this issue via proposing a novel framework of collaborative early warning for COVID-19 based on blockchain and smart contracts, aiming to crowdsource early warning tasks to distributed channels including medical institutions, social organizations, and even individuals. Our framework supports two surveillance modes, namely, medical federation surveillance based on federated learning and social collaboration surveillance based on the learning markets approach, and fuses their monitoring results on emerging cases to alert. By using our framework, medical institutions are expected to obtain better federated surveillance models with privacy protection, and social participants without mutual trusts can also share verified surveillance resources such as data and models, and fuse their surveillance solutions. We implemented our proposed framework based on the Ethereum and IPFS platforms. Experimental results show that our framework has advantages of decentralized decision-making, fairness, auditability, and universality. It also has potential guidance and reference value for the early warning and prevention of unknown infectious diseases.

Unbiased RNA-Seq-driven identification and validation of reference genes for quantitative RT-PCR analyses of pooled cancer exosomes.

BACKGROUND: Exosomes are extracellular vesicles (EVs) derived from endocytic compartments of eukaryotic cells which contain various biomolecules like mRNAs or miRNAs. Exosomes influence the biologic behaviour and progression of malignancies and are promising candidates as non-invasive diagnostic biomarkers or as targets for therapeutic interventions. Usually, quantitative real-time polymerase chain reaction (qRT-PCR) is used to assess gene expression in cancer exosomes, however, the ideal reference genes for normalization yet remain to be identified. RESULTS: In this study, we performed an unbiased analysis of high-throughput mRNA and miRNA-sequencing data from exosomes of patients with various cancer types and identify candidate reference genes and miRNAs in cancer exosomes. The expression stability of these candidate reference genes was evaluated by the coefficient of variation "CV" and the average expression stability value "M". We subsequently validated these candidate reference genes in exosomes from an independent cohort of ovarian cancer patients and healthy control individuals by qRT-PCR. CONCLUSIONS: Our study identifies OAZ1 and hsa-miR-6835-3p as the most reliable individual reference genes for mRNA and miRNA quantification, respectively. For superior accuracy, we recommend the use of a combination of reference genes - OAZ1/SERF2/MPP1 for mRNA and hsa-miR-6835-3p/hsa-miR-4468-3p for miRNA analyses.

PIM1 inhibition attenuated endotoxin-induced acute lung injury through modulating ELK3/ICAM1 axis on pulmonary microvascular endothelial cells.

OBJECTIVE: The dysfunction of pulmonary microvascular endothelial cells (PMVECs) is one of the critical characteristics of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) induced by severe infection. PIM1 is a constitutively active serine/threonine kinase that is involved in multiple biological processes. However, the underlying correlation between PIM1 and PMVECs injury remains unclear. The main purpose of this study was to reveal roles of PIM1 and explore the potential mechanisms during the development of endotoxin-induced ALI induced by intraperitoneal LPS administration. MATERIALS AND METHODS: PIM1 level in the lung tissues of endotoxin-induced ALI mice or plasma derived from cardiopulmonary bypass (CPB)-induced ALI patients were measured. The protective roles of PIM1 specific inhibitor SMI-4a on endotoxin-induced lung injuries were evaluated through histological, permeability, neutrophil infiltration and survival assessment. The relationship between PIM1 and ELK3/ICAM-1 axis was validated in vivo and vitro. The correlation between plasma PIM1 and indicative vascular endothelium injury biomarkers (PaO2/FiO2 ratio, Ang-II, E-selectin and PAI-1) levels derived from CPB-induced ALI patient were analyzed. RESULTS: PIM1 expression in the lung tissues was increased in the mice of endotoxin-induced ALI. The PIM1 specific inhibitor SMI-4a administration relieved the severity of endotoxin-induced ALI. More importantly, PIM1 modulates ICAM1 expression through regulating transcription factor ELK3 expression in vitro. Eventually, plasma PIM1 level was positively correlated with Ang-II and PAI-1 levels but negatively correlated with SpO2/FiO2 ratio among CPB induced ALI patients. CONCLUSION: Our results indicated that PIM1 inhibition carried a protective role against endotoxin-induced ALI by modulating the ELK3/ICAM1 axis on PMVECs. PIM1 may be a potential therapeutic target for endotoxin-induced ALI.

Intravenous sodium valproate for acute migraine in the emergency department: A meta-analysis.

The role of intravenous sodium valproate (iVPA) in acute migraine attack has not been completely established. The aim of this updated review was to evaluate the efficacy and safety of iVPA in patients with acute migraine in the emergency department. We searched the PubMed, Web of Science, and Cochrane Library databases for relevant randomized controlled trials (RCTs). The primary outcome was improvement of headache intensity and headache relief. The need for rescue therapy, recurrence of headache, and number of adverse events was also assessed. Seven double-blinded RCTs involving 682 patients were analyzed. Overall, patients receiving iVPA had less improvement of headache intensity (SMD: -0.39, 95% CI: -0.73 to -0.06, P = .02) and lower rate of headache relief (OR: 0.51, 95% CI: 0.33 to 0.77, P = .002) than those receiving other active comparators. In addition, iVPA increased the odds of rescue therapy compared with other active drugs (OR: 3.76; 95% CI: 1.96 to 7.20, P < .0001). Subgroup analysis showed that iVPA was comparable to dexamethasone, with similar improvement of headache intensity, and recurrence of headache. For migraine without aura, we found no significant difference in headache intensity improvement when iVPA was compared with active comparators (SMD: -0.00, 95% CI: -0.54 to 0.54, P = 1.00). iVPA was inferior to the studied comparators and was comparable to dexamethasone for aborting migraine attack. Based on the available evidence, iVPA may be a reasonable alternative or salvage therapy. In particular, iVPA might be a promising agent for migraine with aura and migraine status.

Inhibition of PIM1 kinase attenuates bleomycin-induced pulmonary fibrosis in mice by modulating the ZEB1/E-cadherin pathway in alveolar epithelial cells.

PIM1 is serine/threonine protein kinase that is involved in numerous biological processes. Pulmonary fibrosis (PF) is a chronic pathological result of the dysfunctional repair of lung injury without effective therapeutic treatments. In the current study, we investigated whether PIM1 inhibition would improve bleomycin (BLM)-induced pulmonary fibrosis. In a BLM-induced pulmonary fibrosis model, PIM1 was persistently upregulated in fibrotic lung tissues. Furthermore, PIM1 inhibition by the PIM1-specific inhibitor SMI-4a showed protective effects against BLM-induced mortality. Furthermore, SMI-4a suppressed hydroxyproline deposition and reversed epithelial-mesenchymal transition (EMT) formation, which was characterized by E-cadherin and α-SMA expression in vivo. More importantly, the ZEB1/E-cadherin pathway was found to be closely associated with BLM-induced pulmonary fibrosis. After the in vitro treatment of A549 cells, PIM1 regulated E-cadherin expression by dependently modulating the activity of the transcription factor ZEB1. These findings were verified in vivo after SMI-4a administration. Finally, an shPIM1-expressing adeno-associated virus was delivered via intratracheal injection to induce a long-term PIM1 deficiency in the alveolar epithelium. AAV-mediated PIM1 knockdown in the lung tissues alleviated BLM-induced pulmonary fibrosis, as indicated by collagen accumulation reduction, pulmonary histopathological mitigation and EMT reversion. These findings enhance our understanding of the roles of PIM1 in BLM-induced pulmonary fibrosis and suggest PIM1 inhibition as a potential therapeutic strategy in chronic pulmonary injuries.

Serotonin-norepinephrine reuptake inhibitors for the prevention of migraine and vestibular migraine: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: The role of serotonin-norepinephrine reuptake inhibitors (SNRIs) in migraine prophylaxis has not been completely established. Current treatments for vestibular migraine (VM) are based on scarce evidence. We aimed to perform an updated review focusing on the efficacy and tolerability of SNRIs for migraine and VM prevention. METHODS: We searched the PubMed, Web of Science, and Cochrane Library databases for relevant studies. The primary outcome was migraine frequency. In the case of VM, the Dizziness Handicap Inventory (DHI) scores and Vertigo Severity Scores (VSSs) were extracted. RESULTS: Six randomized controlled trials involving 418 patients were analyzed. Patients receiving SNRIs had fewer migraine days than those receiving a placebo (standardized mean difference -0.38, 95% CI -0.76 to -0.01, p=0.04). The effects of SNRIs and other active drugs were comparable. In patients with VM, venlafaxine had a significant advantage over other active drugs in decreasing the VSS (weighted mean difference (MD) -1.45, 95% CI -2.11 to -0.78, p<0.0001) and the emotional domain score of the DHI (MD -2.64, 95% CI -4.97 to -0.31, p=0.03). We found no significant difference in the rate of withdrawals due to any reason or withdrawals due to side effects between SNRIs and active drugs and between SNRIs and a placebo. CONCLUSIONS: SNRIs were clinically safe and effective for migraine and VM prophylaxis, were better than a placebo, and not inferior to other active drugs. SNRIs may be a preferable choice for patients with VM with psychiatric disorders.