Molecular mechanisms of HER2-targeted therapy and strategies to overcome the drug resistance in colorectal cancer.

HER2 amplification is one of the mechanisms that induce drug resistance to anti-EGFR therapy in colorectal cancer. In recent years, data from several randomized clinical trials show that anti-HER2 therapies improved the prognosis of patients with HER2-positive colorectal cancer. These results indicate that HER2 is a promising therapeutic target in advanced colorectal cancer. Despite the anti-HER2 therapies including monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates improving the outcomes, less than 30 % of the patients achieve objective response and eventually have drug resistance. It is necessary to explore the primary and secondary mechanisms for the resistance to anti-HER2 therapies, which will pave the way to overcome the drug resistance. Several studies have reported the potential mechanisms for the resistance to anti-HER2 therapies. In this review, we present a comprehensive overview of the recent advances in clinical research, mechanisms of treatment resistance, and strategies for reversing resistance in HER2-positive colorectal cancer patients.

B-cell targeted therapies in autoimmune encephalitis: mechanisms, clinical applications, and therapeutic potential.

Autoimmune encephalitis (AE) broadly refers to inflammation of the brain parenchyma mediated by autoimmune mechanisms. In most patients with AE, autoantibodies against neuronal cell surface antigens are produced by B-cells and induce neuronal dysfunction through various mechanisms, ultimately leading to disease progression. In recent years, B-cell targeted therapies, including monoclonal antibody (mAb) therapy and chimeric antigen receptor T-cell (CAR-T) therapy, have been widely used in autoimmune diseases. These therapies decrease autoantibody levels in patients and have shown favorable results. This review summarizes the mechanisms underlying these two B-cell targeted therapies and discusses their clinical applications and therapeutic potential in AE. Our research provides clinicians with more treatment options for AE patients whose conventional treatments are not effective.

Citations of microRNA Biomarker Articles That Were Retracted: A Systematic Review.

Importance: Retraction is a tool that journals can use to deter research misconduct and alert their audience to erroneous content published in the journals. However, retracted articles may continue to damage science if they are still cited as legitimate articles. Objective: To characterize patterns of postretraction citations, particularly in microRNA biomarker research, a field with one of the highest rates of retraction. Evidence Review: Retracted scientific articles on microRNAs were retrieved from PubMed, Web of Science, and Retraction Watch between database inception and July 17, 2021, according to preestablished search strategies. Control articles with characteristics in common with retracted articles (ie, published in the same journals in the same years and months and with the same number of authors) were matched and retrieved from PubMed. Citation metrics of retractions and control articles were collected from Web of Science. PubPeer was referenced to examine the public response or comments on included retractions. Data were analyzed from September 2021 through March 2023. Findings: A total of 10 461 articles were analyzed, with 887 retractions and 9574 articles as controls. Among retracted articles, which were published from 1999 to 2021, there were 756 articles (85.23%) written by researchers affiliated with Chinese institutions. Retracted articles were cited 6327 times after retraction. Of 792 retracted articles that were cited, 621 articles (78.41%) were cited at least once after retraction and 238 articles (30.05%) were cited more often after retraction than before retraction. Overall citations (comprising citations before and after retraction) and postretraction citations accumulated over time (eg, the median [IQR] number of postretraction citations was 1 [1-2] and 23 [9-44] citations at the first 6 and 66 months, respectively, between retraction and citation retrieval). A random sample of 87 retracted articles (9.81%) recorded 478 citations after retraction, with 208 citations (43.51%) in articles published 12 months or longer after retraction. Of these citing articles, 19 articles (3.97%) mentioned the retractions. Compared with the control group of 1620 nonretracted articles, no significant differences were found in overall number of citations or citations after retraction. Among 478 articles citing retracted articles, 414 articles were found on PubMed and had matched control articles; these articles had higher odds of being subsequently retracted than 7954 matched control articles (odds ratio, 6.57; 95% CI, 3.39-12.72). Conclusions and Relevance: In this study, retraction was not associated with a reduction in citations of retracted articles, but articles that cited retracted publications had higher odds of later retraction. These findings suggest that journals may need to implement mechanisms for detection of postretraction citations.

The efficacy of Chinese herbal drugs for adults with angina pectoris: Bayesian network meta-analysis of 331 RCTs involving 36,467 individuals.

ETHNOPHARMACOLOGICAL RELEVANCE: Hundreds of randomized controlled trials (RCT) on Chinese herbal drugs (CHDs) including Shexiang baoxin pill (BXP), compound Danshen dripping pill (DSP), compound Danshen tablet (DST), Suxiao jiuxin pill (JXP), Naoxintong capsule (NXT), Tongxinluo capsule (TXL), and Di'ao xinxuekang capsule (XXK) and conventional chemical drugs, such as isosorbide dinitrate (ISDN), for angina pectoris are available but have not been evaluated by a PRISMA-compliant network meta-analysis (NMA). AIM OF THE STUDY: This study aimed to compare the efficacy of nine anti-anginal drugs through NMA on RCTs. METHODS: RCTs of drug treatment for adult patients with angina pectoris for improvements in symptoms and electrocardiography were retrieved. Odds ratios and 95% credible intervals were computed to measure effect sizes. RCT quality was evaluated with the Cochrane risk of bias tool. Evidence synthesis was performed with Bayesian NMA. Essential analyses including subgroup analysis, sensitivity analysis, meta-regression analysis, publication bias analysis, and ranking analysis were conducted to assess the robustness of efficacies. Evidence strength was assessed with the GRADE approach. RESULTS: A total of 331 RCTs with 36,467 participants were eligible. The overall quality of all included RCTs was low. Overall efficacy estimates from different approaches of evidential synthesis found that BXP, TXL, and DSP were more efficacious than DST and ISDN. Essential analyses indicated consistent efficacy estimates, insignificant publication bias, and corroborative ranking results. The overall GRADE evidence strength was low. CONCLUSION: This comprehensive Bayesian NMA found BXP, TXL, and DSP to be the top three candidates among the seven tested CHDs for treating adults suffering from angina pectoris. However, the quality and the evidence strength of eligible RCTs were low. Further high-quality RCTs with more outcome measures and their NMAs are warranted. REGISTRATION: PROSPERO CRD42014007035.

The efficacy and safety of compound kushen injection for adults with esophageal cancer: A meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Kushen injection (CKI), derived from the traditional Chinese medicine Sophora flavescens, has been widely prescribed to treat a variety of cancers including esophageal cancer (ESCA) in China. AIM OF THE STUDY: This study aimed to evaluate the efficacy and safety of CKI for ESCA systematically. METHODS: The protocol was registered in the PROSPERO database with No. CRD42022320503. PubMed, Embase, the Cochrane Library, Web of Science, CNKI, Wanfang Database, Clinicaltrials, and Chi-CTR were searched to select RCTs that compared CKI with other interventions for ESCA with outcome measures including clinical efficacy, complete response, quality of life (QoL), adverse events (AEs), and serious AEs (SAEs). The Cochrane Risk of Bias 2 (RoB2) tool was used to assess the quality of RCT. The overall effect sizes were estimated with odds ratios (ORs) and 95% confidence intervals (CIs) on binary outcome data. Meta-analyses were conducted to estimate effect sizes. Subgroup and sensitivity analyses on characteristics of RCTs were performed to test the robustness. Publication bias was also detected with different methods. The evidence strength was assessed with the Grading of Recommendation, Assessment, Development, and Evaluation method. RESULTS: This study finally included 35 RCTs with 2491 ESCA patients. The RoB of RCTs was some concern. The effect size of OR was 2.92 (95% CI [2.39, 3.57]) on clinical efficacy, 2.27 (95% CI [1.84, 2.81]) on complete response, 3.71 (95% CI [2.86, 4.80]) on QoL, 0.39 (95% CI [0.30, 0.50]) on AEs, and 0.13 (95% CI [0.07, 0.27]) on SAEs where the statistical significances (P < 0.00001) were found for all outcome measures. These overall effect sizes showed that CKI was more efficacious and safety for ESCA. Moreover, subgroup and sensitivity analyses found consistent results. Most publication bias analyses showed insignificant differences. The evidence strengths were moderate. CONCLUSION: The moderate evidence from this comprehensive PRISMA-compliant meta-analysis suggested that CKI may be a valuable alternative for adult patients with ESCA on its significant efficacy and safety. However, more RCTs of high quality with low RoB, large sample sizes, and long follow-up periods are still warranted to update the ESCA clinical guideline for physicians and policymakers in further study.

Critical quality appraisal of randomized controlled trials with traditional Chinese medicines for the coronavirus disease 2019.

OBJECTIVE: Traditional Chinese medicines (TCM) play an indispensable role during the pandemic of coronavirus disease 2019 (COVID-19), with an increasing number of randomized controlled trials (RCTs) designed and performed to evaluate the efficacy and safety of TCM for COVID-19. This study aimed to critically appraise the quality of currently available RCTs of TCM for COVID-19. METHODS: RCTs of TCM for COVID-19 were searched from three databases by two investigators and selected according to pre-established inclusion and exclusion criteria. General information of included studies was presented by applying descriptive statistics. The methodological and reporting quality of eligible RCTs was critically evaluated based on the risk of bias assessment tool 2 (RoB2) and CONSORT Extension for TCM (CONSORT-CHM Formulas 2017), respectively. The differences of risks and main general information were compared between RCTs published in English and Chinese journals. Microsoft Excel 2019 and SPSS were used for the statistical analysis. A result with p < 0.05 was considered statistically significant. RESULTS: This study finally included 64 RCTs with a total of 10858 participants investigating TCM for COVID-19. All 64 RCTs were evaluated as moderate-to-low RoB including 27 RCTs with high bias, 26 RCTs with some concerns, and 11 with low bias. Results of reporting quality appraisal by CONSORT-CHM Formulas 2017 showed that 61 (95%) RCTs reported more than 18 (50%) items, and 14 (22%) RCTs reported more than 26 (70%) items among all 38 items. Forty-two RCTs were approved by ethics committees and 47 RCTs reported the informed consent information. Twenty-five RCTs and 39 RCTs provided information on trial registration and funding resources, respectively. The quality of 44 RCTs published in Chinese was significantly worse than that of 20 RCTs published in English, especially in the following considerations including the overall RoB, ethics approved, informed consent, trial register, and reporting quality with CONSORT-CHM Formulas 2017. CONCLUSION: The overall quality of RCTs investigating TCM for COVID-19 was appraised as moderate-to-high that was substandard and needs to be continuously improved, especially for RCTs published in Chinese, in the future.

Effects of 101BHG-D01, a novel M receptor antagonism, on allergic rhinitis in animal models and its mechanism.

Allergic rhinitis (AR) is a nasal mucosal disease with sneezing and nasal itching as the main symptoms. Although AR treatment continues to improve, there remains a lack of effective drugs. There are still controversies regarding whether anticholinergic drugs can effectively and safely relieve the symptoms of AR and reduce inflammation in the nasal mucosa. Here, we synthesized 101BHG-D01, which is a novel anticholinergic drug that mainly targets the M3 receptor and may reduce the adverse effects of other anticholinergic drugs on the heart. We evaluated the effects of 101BHG-D01 on AR and investigated the potential molecular mechanism of anticholinergic therapy for AR. We found that 101BHG-D01 effectively alleviated AR symptoms, reduced the infiltration of inflammatory cells and attenuated the expression of inflammatory factors (IL-4, IL-5, IL-13, etc.) in various AR animal models. In addition, 101BHG-D01 reduced the activation of mast cells and the release of histamine from rat peritoneal mesothelial cells (RPMCs) challenged by IgE. Moreover, 101BHG-D01 reduced the expression of MUC5AC in IL-13-challenged rat nasal epithelial cells (RNECs) and human nasal epithelial cells (HNEpCs). Furthermore, IL-13 stimulation significantly increased JAK1 and STAT6 phosphorylation, which was suppressed by 101BHG-D01. We demonstrated that 101BHG-D01 reduced mucus secretion and inflammatory cell infiltration in the nasal mucosa, which may occur through a reduction in activation of the JAK1-STAT6 signaling pathway, indicating that 101BHG-D01 is a potent and safe anticholinergic therapy for AR.

Preparation and characterization of a biocompatible glucose-sensitive electrospun nanofibers scaffolds containing dexamethasone with enhanced osteogenic propertiesin vitrohigh glucose environment.

Diabetes has made it challenging to repair alveolar bone defects. A successful method for bone repair utilizes a glucose-sensitive osteogenic drug delivery. This study created a new glucose-sensitive nanofiber scaffold with controlled dexamethasone (DEX) release. DEX-loaded polycaprolactone/chitosan nanofibers scaffolds were created using electrospinning. The nanofibers had high porosity (>90%) and proper drug loading efficiency (85.51 ± 1.21%). Then, glucose oxidase (GOD) was immobilized on the obtained scaffolds by a natural biological cross-linking agent, genipin (GnP), after soaking in the mixture solution containing GOD and GnP. The enzyme properties and glucose sensitivity of the nanofibers were investigated. The results showed that GOD was immobilized on the nanofibers and exhibited good enzyme activity and stability. Meanwhile, the nanofibers expanded gradually in response to the increase in glucose concentration, followed by the release of DEX increased. The phenomena indicated that the nanofibers could sense glucose fluctuation and possess favorable glucose sensitivity. In addition, the GnP nanofibers group showed lower cytotoxicity in the biocompatibility test compared with a traditional chemical cross-linking agent. Lastly, the associated osteogenesis evaluation found that the scaffolds effectively promoted MC3T3-E1 cells' osteogenic differentiation in high-glucose environments. As a result, the glucose-sensitive nanofibers scaffolds offer a viable treatment option for people with diabetes with alveolar bone defects.

How efficacious are traditional Chinese medicine injections in treating angina pectoris? A network meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Over 50 million adults in China suffer from angina pectoris, which are often treated with traditional Chinese medicine injections (TCMIs). However, the efficacies of TCMIs and conventional drugs as determined by randomized controlled trials (RCTs) were not rigorously compared with one another by network meta-analysis (NMA). This PRISMA-compliant NMA aimed to compare the efficacy and assess the evidence strengths of 24 TCMIs in treating adults with angina pectoris of RCTs. MATERIALS AND METHODS: Following the protocol (PROSPERO registration number CRD42018117720), the RCTs that compared any TCMI with another TCMI or conventional drug on outcome measures including symptomatic and electrocardiography improvements were included. The quality of included RCTs was assessed with the Cochrane's risk of bias 2 tool. Frequentist statistical analyses were performed, including NMA, pairwise meta-analysis (PMA), subgroup analysis, sensitivity analysis, meta-regression, and publication bias analysis. The certainty of evidence was assessed with the GRADE approach. RESULTS: Totally, 556 eligible RCTs with 57015 participants were identified while the quality of all but five included RCTs was poor. The significant efficacy estimates and insignificant heterogeneity assessment from PMA and NMA indicated that nearly all TCMIs were more efficacious than conventional treatments for angina pectoris. Adequate subgroup and sensitivity analyses found the robust and consistent results. However, the evidence strengths of meta-analyses were assessed as very low to low due to the high risk of RCTs. The comprehensive efficacy estimates suggested that 4 TCMIs (HH, Honghua injection; HHH, Honghua Huangsesu injection; GLP, Gualoupi injection; and SM, Shenmai injection) was the best anti-anginal drugs for adults with angina pectoris. CONCLUSION: TCMIs appear to be efficacious for angina pectoris, although evidence evaluation of high-quality RCTs of TCMIs would be necessary. In particular, randomization and blinding procedures of the RCTs should be explicated to meet the CONSORT requirements.

Distinct clinical pattern of colorectal cancer patients with POLE mutations: A retrospective study on real-world data.

Objective: Studies have demonstrated an association between somatic POLE exonuclease domain mutations (EDMs) and the prognosis of colorectal cancer (CRC). However, the prognostic value of POLE non-EDMs remains unclear. This retrospective study aimed to explore the possible relationships between POLE mutation subtypes and CRC prognosis. Methods: The 272 CRC patients from the First Affiliated Hospital of Zhengzhou University (ZZ cohort) and 499 CRC patients from The Cancer Genome Atlas database (TCGA cohort) were retrospectively collected. The cases were divided into subgroups based on POLE mutation sites and microsatellite instability (MSI) status. The continuous variables were compared among three subgroups with Kruskal-Wallis tests. Pairwise comparisons between three groups were performed by Bonferroni correction method, and adjusted p < 0.05 was considered statistically significant. The categorical variables were compared with Chi-square test and Fisher's exact test. The Kaplan-Meier curves and Cox regression models were conducted to evaluate prognostic values of POLE mutations. Results: In the ZZ cohort, POLE EDMs (2.6%) were significantly associated with younger age (p = 0.018) and localized in the left colon (p = 0.001). POLE non-EDMs were significantly associated with MSI-high status (p < 0.001) and localization in the right colon (p = 0.001). In the TCGA cohort, the tumor mutation burden (TMB) of both POLE EDM tumors (p < 0.001) and POLE non-EDM tumors (p < 0.001) was significantly higher than that of POLE wild-type (WT) tumors. A similar trend was observed in the ZZ cohort, although there were no significant differences. In the ZZ cohort, the POLE EDM group had higher progression-free survival (PFS) (p = 0.002) and overall survival (OS) (p = 0.042) than the POLE non-EDM group and POLE WT group. We also report one CRC patient harboring a germline POLE mutation who received camrelizumab and exhibited long-term stable disease. Conclusion: Both POLE-EDMs and POLE non-EDMs were associated with significantly increased TMB in CRC and may be biomarkers for CRC treatment and prognosis. Current evidence does not support an effect of POLE non-EDMs on PFS and OS. A significant association between POLE EDMs and improved PFS and OS may exist, but future studies with larger sample sizes are needed. Entire coding region of the POLE gene should be screened.

Pharmacokinetics and Tissue Distribution of Nasal Spray of a Novel Muscarinic Receptor Blocker, 101BHG-D01, in Dogs and Rats.

BACKGROUND: 101BHG-D01 is a novel selective anti-muscarinic (M) 3 receptor-blocking drug. 101BHG-D01 nasal spray is intended to be used to relieve sneezing and runny nose symptoms caused by allergic rhinitis. METHODS: In this study, we examined the plasma pharmacokinetics, tissue distribution, and major excretion mode of 101BHG-D01 in Beagle dogs and rats following nasal spray and intranasal administration, respectively, using HPLC-MS/MS. RESULTS/DISCUSSION: We found that the pharmacokinetics of 101BHG-D01 was linear in dogs. 101BHG-D01 entered the bloodstream rapidly following nasal spray. Its plasma half-life was approximately 6 h and resided at least 24 h in the body. Moreover, 101BHG-D01 retained a significant amount in the nasal cavity. Finally, we found that 101BHG-D01 was eliminated mainly in the form of stools in rats. CONCLUSION: In conclusion, we provided pertinent reference information regarding the design and optimization of drug delivery regimens for clinical trials.

Notable efficacy of Shugan Jieyu capsule in treating adult with post-stroke depression: A PRISMA-compliant meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Post stroke depression (PSD), which happens in 40%-60% stroke patients, is one of the most common complications after cerebrovascular accident. Shugan Jieyu Capsule (SGJYC), a traditional Chinese medicine, has been widely prescribed for PSD in China. AIM OF THE STUDY: This study designed and conducted a PRISMA compliant meta-analysis to evaluate the efficacy of SGJYC in treating adults with PSD of randomized controlled trials (RCTs) under the condition that none PRISMA-compliant systematic evaluation or meta-analysis was conducted to fully evaluate the efficacy of SGJYC. METHODS: The study protocol has been registered in PROSPERO with registration number CRD42021250162. PubMed, ScienceDirect, CNKI, and Wanfang Databases were systematically searched to include eligible RCTs which used SGJYC and other antidepressants or placebo for the treatment of PSD adults with the Hamilton Depression Scale (HAMD). The Cochrane Risk of Bias 2 (RoB2) tool was used to evaluate the quality of included RCTs. Outcome measures including HAMD continuous data, efficacy data, and remission data were extracted for meta-analysis on a random-effects model. Adequate essential analyses including subgroup analysis, sensitivity analysis, and meta-regression analysis were performed according to the characteristics of RCTs to test the reliability and robustness of the overall effect sizes. Publication bias was detected with funnel plot, Egger's test, and Begg's test. The evidence strength of this meta-analysis was assessed with the GRADE method. RESULTS: A total of 63 eligible RCTs and 6036 participants were included. The RoB2 found that the overall risk of included RCTs was high. The MD of continuous data was 3.59 (95% CI: [2.63, 4.55]) with statistical significance (P < 0.00001) and significant heterogeneity (Chi2 = 2083.77, I2 = 97%, p < 0.00001). The OR of efficacy data was 2.12 (95% CI: [1.82, 2.47]) with statistical significance (P < 0.00001) and insignificant heterogeneity (Chi2 = 60.52, I2 = 22%, P = 0.09). The OR of remission data was 1.66 (95% CI: [1.45, 1.91]) with statistical significance (P < 0.00001) and insignificant heterogeneity (Chi2 = 26.45, I2 = 0%, P = 0.96). Adequate essential analyses found consistent results of overall effect sizes and most publication bias analyses found insignificant results. The overall evidence strength was assessed as moderate. CONCLUSION: The moderate evidence strength from this PRISMA-compliant meta-analysis found that SGJYC has notable efficacy in treating adults with PSD, although the quality of included RCT was low. The high-quality RCTs with large-sample, multi-centers, and long follow-up periods are still warranted to improve the evidence quality of SGJYC for PSD in further study.

Corrigendum: Diplatin, a Novel and Low-Toxicity Anti-Lung Cancer Platinum Complex, Activation of Cell Death in Tumors via a ROS/JNK/p53-Dependent Pathway, and a Low Rate of Acquired Treatment Resistance.

[This corrects the article DOI: 10.3389/fphar.2019.00982.].

Glucose-sensitive delivery of tannic acid by a photo-crosslinked chitosan hydrogel film for antibacterial and anti-inflammatory therapy.

A glucose-sensitive antibacterial and anti-inflammatory hydrogel film with controlled release of tannic acid (TA) was synthesized using chitosan (CS). Specifically, the photo-crosslinked CS hydrogel was first obtained and then immersed in TA solution to generate composite hydrogel film with enhanced mechanical properties. Subsequently, N-hydroxysuccinimide/1-ethyl-3-(3-dimethylaminopropyl) carbodiimide based coupling chemistry was used to covalently crosslink glucose oxidase (GOx) to CS to obtain glucose sensitivity. The physicochemical properties, including chemical composition, enzyme-related characteristics, glucose responsiveness, and mechanical strength, were thoroughly investigated, followed by the cytotoxicity, antibacterial and anti-inflammatory tests. The results showed that the GOx immobilized on the film surface by covalent bonding gave better stability than those that were physically adsorbed. In addition, it could quickly and correspondingly modify its inner pore structure in response to the glucose stimulus and then control the loaded TA release. Meanwhile, the TA addition could enhance the film's mechanical properties. The composite hydrogel film demonstrated adequate biocompatibility and can inhibit NO, IL-6, and TNF-α production in stimulated macrophages, as well as Porphyromonas gingivalis growth, demonstrating effective antibacterial and anti-inflammatory activity.

Big Data Reality Check (BDRC) for public health: to what extent the environmental health and health services research did meet the 'V' criteria for big data? A study protocol.

INTRODUCTION: Big data technologies have been talked up in the fields of science and medicine. The V-criteria (volume, variety, velocity and veracity, etc) for defining big data have been well-known and even quoted in most research articles; however, big data research into public health is often misrepresented due to certain common misconceptions. Such misrepresentations and misconceptions would mislead study designs, research findings and healthcare decision-making. This study aims to identify the V-eligibility of big data studies and their technologies applied to environmental health and health services research that explicitly claim to be big data studies. METHODS AND ANALYSIS: Our protocol follows Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Scoping review and/or systematic review will be conducted. The results will be reported using PRISMA for Scoping Reviews (PRISMA-ScR), or PRISMA 2020 and Synthesis Without Meta-analysis guideline. Web of Science, PubMed, Medline and ProQuest Central will be searched for the articles from the database inception to 2021. Two reviewers will independently select eligible studies and extract specified data. The numeric data will be analysed with R statistical software. The text data will be analysed with NVivo wherever applicable. ETHICS AND DISSEMINATION: This study will review the literature of big data research related to both environmental health and health services. Ethics approval is not required as all data are publicly available and involves confidential personal data. We will disseminate our findings in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021202306.

Prediction of differentially expressed microRNAs in blood as potential biomarkers for Alzheimer's disease by meta-analysis and adaptive boosting ensemble learning.

BACKGROUND: Blood circulating microRNAs that are specific for Alzheimer's disease (AD) can be identified from differentially expressed microRNAs (DEmiRNAs). However, non-reproducible and inconsistent reports of DEmiRNAs hinder biomarker development. The most reliable DEmiRNAs can be identified by meta-analysis. To enrich the pool of DEmiRNAs for potential AD biomarkers, we used a machine learning method called adaptive boosting for miRNA disease association (ABMDA) to identify eligible candidates that share similar characteristics with the DEmiRNAs identified from meta-analysis. This study aimed to identify blood circulating DEmiRNAs as potential AD biomarkers by augmenting meta-analysis with the ABMDA ensemble learning method. METHODS: Studies on DEmiRNAs and their dysregulation states were corroborated with one another by meta-analysis based on a random-effects model. DEmiRNAs identified by meta-analysis were collected as positive examples of miRNA-AD pairs for ABMDA ensemble learning. ABMDA identified similar DEmiRNAs according to a set of predefined criteria. The biological significance of all resulting DEmiRNAs was determined by their target genes according to pathway enrichment analyses. The target genes common to both meta-analysis- and ABMDA-identified DEmiRNAs were collected to construct a network to investigate their biological functions. RESULTS: A systematic database search found 7841 studies for an extensive meta-analysis, covering 54 independent comparisons of 47 differential miRNA expression studies, and identified 18 reliable DEmiRNAs. ABMDA ensemble learning was conducted based on the meta-analysis results and the Human MicroRNA Disease Database, which identified 10 additional AD-related DEmiRNAs. These 28 DEmiRNAs and their dysregulated pathways were related to neuroinflammation. The dysregulated pathway related to neuronal cell cycle re-entry (CCR) was the only statistically significant pathway of the ABMDA-identified DEmiRNAs. In the biological network constructed from 1865 common target genes of the identified DEmiRNAs, the multiple core ubiquitin-proteasome system, that is involved in neuroinflammation and CCR, was highly connected. CONCLUSION: This study identified 28 DEmiRNAs as potential AD biomarkers in blood, by meta-analysis and ABMDA ensemble learning in tandem. The DEmiRNAs identified by meta-analysis and ABMDA were significantly related to neuroinflammation, and the ABMDA-identified DEmiRNAs were related to neuronal CCR.

Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production.

Cigarette smoke (CS) is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) commonly coexists in lung cancer and COPD. CS triggers many factors including matrix metalloproteinases (MMPs) production, contributing to EMT progression in the lungs. Here, how Shp2 signaling regulates the CS-induced MMP-9 production and EMT progression were investigated in mouse lungs and in pulmonary epithelial cell cultures (NCI-H292) found CS induced MMP-9 production, EMT progression (increased vimentin and α-SMA; decreased E-cadherin) and collagen deposition in lung tissues; cigarette smoke extract (CSE) induced MMP-9 production and EMT-related phenotypes in NCI-H292 cells, which were partially prevented by Shp2 KO/KD or Shp2 inhibition. The CSE exposure induced EMT phenotypes were suppressed by MMP-9 inhibition. Recombinant MMP-9 induced EMT, which was prevented by MMP-9 inhibition or Shp2 KD/inhibition. Mechanistically, CS and CSE exposure resulted in ERK1/2, JNK and Smad2/3 phosphorylation, which were suppressed by Shp2 KO/KD/inhibition. Consequentially, the CSE exposure-induced MMP-9 production and EMT progression were suppressed by ERK1/2, JNK and Smad2/3 inhibitors. Thus, CS induced MMP-9 production and EMT resulted from activation of Shp2/ERK1/2/JNK/Smad2/3 signaling pathways. Our study contributes to the underlying mechanisms of pulmonary epithelial structural changes in response to CS, which may provide novel therapeutic solutions for treating associated diseases, such as COPD and lung cancer.