Combination of EGFR-TKI and Chemotherapy Versus EGFR-TKI Monotherapy as Neoadjuvant Treatment of Stage III-N2 EGFR-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: The efficacy of neoadjuvant treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy in patients with stage III-N2 EGFR-mutant remains unsatisfactory. This study explored the potential benefits of combining first-generation EGFR-TKI with chemotherapy as a neoadjuvant treatment for patients with stage III-N2 EGFR-mutant non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The medical records of patients with III-N2 EGFR-mutant NSCLC who received neoadjuvant therapy with EGFR-TKI at Shanghai Chest Hospital from October 2011 to October 2022 were retrospectively reviewed. Patients with stage III-N2 EGFR-mutant NSCLC who received first-generation TKI combined with chemotherapy as neoadjuvant treatment were included in the combination group, and those who received EGFR-TKI monotherapy were included in the monotherapy group. The study assessed the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, disease-free survival (DFS), overall survival (OS), downstaging rates of pathologic lymph nodes (from stage N2 to N1 or N0), major pathologic response (MPR) rate, pathological complete response (PCR) rate, and safety. RESULTS: A total of 74 631 patients with EGFR-mutant NSCLC were screened, and 60 patients were included, 7 of whom did not undergo surgery after neoadjuvant targeted therapy. Of the remaining 53 patients, 15 received first-generation EGFR-TKI combined with chemotherapy as neoadjuvant treatment, and 38 received EGFR-TKI monotherapy. The median follow-up time was 44.12 months. The ORR was 50.0% (9/18) in the combination group and 40.5% (17/42) in the monotherapy group (P = .495). The MPR rate was 20.0% (3/15) and 10.5% (4/38) in the combination and monotherapy groups, respectively (P = .359). No patients achieved PCR in the combination group, while 3 (7.89%) attained PCR in the monotherapy group. The 2 groups did not differ in N2 downstaging rate (P = .459). The median DFS was not reached in the combination group, while it was 23.6 months (95% CI: 8.16-39.02) in the monotherapy group (P = .832). Adverse events observed were consistent with those commonly associated with the 2 treatments. CONCLUSION: Combination therapy with first-generation EGFR-TKI and chemotherapy could be considered a neoadjuvant treatment option for patients with stage III-N2 EGFR-mutant NSCLC, exhibiting acceptable toxicity. However, regarding short-term efficacy, combination therapy did not demonstrate superiority over EGFR-TKI monotherapy. Long-term follow-up is warranted for a more accurate assessment of the DFS and OS.

Optimizing drug combination and mechanism analysis based on risk pathway crosstalk in pan cancer.

Combination therapy can greatly improve the efficacy of cancer treatment, so identifying the most effective drug combination and interaction can accelerate the development of combination therapy. Here we developed a computational network biological approach to identify the effective drug which inhibition risk pathway crosstalk of cancer, and then filtrated and optimized the drug combination for cancer treatment. We integrated high-throughput data concerning pan-cancer and drugs to construct miRNA-mediated crosstalk networks among cancer pathways and further construct networks for therapeutic drug. Screening by drug combination method, we obtained 687 optimized drug combinations of 83 first-line anticancer drugs in pan-cancer. Next, we analyzed drug combination mechanism, and confirmed that the targets of cancer-specific crosstalk network in drug combination were closely related to cancer prognosis by survival analysis. Finally, we save all the results to a webpage for query ( http://bio-bigdata.hrbmu.edu.cn/oDrugCP/ ). In conclusion, our study provided an effective method for screening precise drug combinations for various cancer treatments, which may have important scientific significance and clinical application value for tumor treatment.

Endothelial extracellular vesicles induce acute lung injury via follistatin-like protein 1.

Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury (ALI), including acute respiratory distress syndrome (ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles (eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of eEVs after cardiopulmonary bypass, remains unclear. Plasma plasminogen-activated inhibitor-1 (PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice (C57BL/6, Toll-like receptor 4 knockout (TLR4-/-) and inducible nitric oxide synthase knockout (iNOS-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3 (JAK2/3)-signal transducer and activator of transcription 3 (STAT3)-interferon regulatory factor 1 (IRF-1) pathway, along with iNOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors (AG490 or S3I-201, respectively), and was relieved in TLR4-/- and iNOS-/- mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1 (FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/ARDS after cardiac surgery. Our findings provide new insight into the molecular mechanisms and therapeutic targets for ALI/ARDS after cardiac surgery.

Open a new epoch of arsenic trioxide investigation: ATOdb.

Arsenic trioxide (ATO) is a great discovery in the treatment of acute promyelocytic leukemia (APL), which has been used in an increasing number of malignant diseases. Systematic integrative analysis will help to precisely understand the mechanism of ATO and find new combined drugs. Therefore, we developed a one-stop comprehensive database of ATO named ATOdb by manually compiling a wealth of experimentally supported ATO-related data from 3479 articles, and integrated analysis tools. The current version of ATOdb contains 8373 associations among 2300 ATO targets, 80 conditions and 262 combined drugs. Each entry in ATOdb contains detailed information on ATO targets, therapeutic/side effects, systems, cell names, cell types, regulations, detection methods, brief descriptions, references, etc. Furthermore, ATOdb also provides data visualization and analysis results such as the drug similarities, protein-protein interactions, and miRNA-mRNA relationships. An easy-to-use web interface was deployed in ATOdb for users to easily browse, search and download the data. In conclusion, ATOdb will serve as a valuable resource for in-depth study of the mechanism of ATO, discovery of new drug combination strategies, promotion of rational drug use and individualized treatments. ATOdb is freely available at http://bio-bigdata.hrbmu.edu.cn/ATOdb/index.jsp.

The protective effect of an extract of Salvia miltiorrhiza Bunge (Danshen) on cerebral ischemic injury in animal models: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Cerebral ischemia is a common disease that seriously threatens the health of human beings. Tanshinone IIA (TSA) is a fat-soluble compound isolated from the traditional Chinese medicine Danshen. Recent studies have shown that TSA plays a significant protective role in the animal models of cerebral ischemic injury. AIM OF THE STUDY: The meta-analysis was to evaluate the protective effect of Danshen (Salvia miltiorrhiza Bunge) extract (TSA) in cerebral ischemic injury, aiming at providing scientific evidence for clinical application of TSA in the treatment of cerebral ischemia in patients. MATERIALS AND METHODS: All relevant studies published in PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Scientific Journals Database (VIP) and Chinese Biomedicine Database (CBM) before Jan 2023 were systematically retrieved. The methodological quality was assessed by SYRCLE's risk of bias tool for the animal studies. Data was analyzed using Rev Man 5.3 software. RESULTS: A total of 13 studies were included. Compared with the control group, TSA significantly reduced the expression of glial fibrillary acidic protein (GFAP) (mean difference [MD], -1.78; 95% CI, [-2.13, -1.44]; P < 0.00001) and high mobility group protein B1 (HMGB1) (MD, -0.69; 95% CI, [-0.87, -0.52]; P < 0.00001). TSA also inhibited the activation of brain nuclear factor κB (NF-κB) (MD, - 0.36; 95% CI, [-0.41, -0.32]; P < 0.00001), malondialdehyde (MDA) (MD, -0.90; 95% CI, [-1.66, -0.13]; P = 0.02), cysteine protease-3 (Caspase-3) (MD, -1.39; 95% CI, [-1.98, -0.81]; P < 0.00001), and reduced cerebral infarction volume(MD, -16.26; 95% CI, [-20.76, -11.77]; P < 0.00001), brain water content (MD, -4.89; 95% CI, [-7.06, -2.71]; P < 0.0001) and neurological deficit scores (MD, -1.19; 95% CI, [-1.48, -0.89]; P < 0.00001). Additionally, TSA increased the brain content of superoxide dismutase (SOD) (MD, 68.31; 95% CI, [10.41, 126.22]; P = 0.02). CONCLUSIONS: The result of this study showed that TSA had a protective effect on cerebral ischemic injury in animal models, and the mechanism is associated with the reduction of inflammation and oxidative stress, and the inhibition of cell apoptosis. However, the quality of included studies may affect the accuracy of positive results. Therefore, more high-quality randomized controlled animal experiments are need for meta-analysis in the future.

Loss of BLK expression as a potential predictor of poor prognosis and immune checkpoint blockade response in NSCLC and contribute to tumor progression.

BACKGROUND: Immune checkpoint blockade (ICB) has been proved to have significant anti-tumor effect in the clinical treatment of non-small cell lung cancer (NSCLC). Therefore, biomarkers predicting ICB response can provide better treatment for patients with NSCLC. METHODS: Differential expression genes (DEGs) were identified by ImmuCellAI database. Copy number alteration (CNA) was analyzed by cBioPortal. The predicted efficiency of 4 genes on cancer immunotherapy was assessed by ROC analysis. The survival value of BLK was analyzed by Kaplan-Meier plotter and Prognoscan analysis. Clinical significance of BLK IHC-TMA score in NSCLC was also explored. The CCK-8 assay, wound healing assay, western blot assay in vitro and subcutaneous xenograft experiments in vivo were used for investigating the functions of BLK. The RNA-sequencing were performed to screen BLK regulated genes and conducted for GO/KEGG enrichment analysis. The transcriptional regulatory factor of BLK promoter region was predicted by ChIP-seq analysis. RESULTS: 39 common DEGs between ICB Response (R) group and No Response (NR) group with NSCLC were identified, in which the CNA frequency of BLK deletion (> 6%) was found. The predicted efficiency of BLK on immunotherapy was performed best in NSCLC (AUC>0.7). Low expression of BLK was related to NSCLC with significantly poor prognosis. BLK overexpression can inhibit growth of NSCLC via activating apoptosis pathway, inhibiting the G2M checkpoint and Glycolysis pathway. The enrichment analysis indicated that BLK regulated genes related to oncogenic potential in NSCLC. Besides, BLK expression was inhibited via H3K27me3 modification in A549 and H1299 cells. BLK mRNA level was negatively correlated with methylation and positively correlated with the tumor purity in NSCLC. CONCLUSION: Our study provides strong evidence that low expression of BLK may serve as a biomarker for poor prognosis in NSCLC, while response to ICB therapy and contributes to NSCLC tumor progression.

Structural and regulatory insights into the glideosome-associated connector from Toxoplasma gondii.

The phylum of Apicomplexa groups intracellular parasites that employ substrate-dependent gliding motility to invade host cells, egress from the infected cells, and cross biological barriers. The glideosome-associated connector (GAC) is a conserved protein essential to this process. GAC facilitates the association of actin filaments with surface transmembrane adhesins and the efficient transmission of the force generated by myosin translocation of actin to the cell surface substrate. Here, we present the crystal structure of Toxoplasma gondii GAC and reveal a unique, supercoiled armadillo repeat region that adopts a closed ring conformation. Characterisation of the solution properties together with membrane and F-actin binding interfaces suggests that GAC adopts several conformations from closed to open and extended. A multi-conformational model for assembly and regulation of GAC within the glideosome is proposed.

Severe distress & denial among Asian patients with Type 2 Diabetes Mellitus in the primary care: A prospective, multicentre study.

AIMS: To determine the point-prevalence and distribution of diabetes distress among primary care Asians with Type 2 Diabetes Mellitus (T2DM) and evaluate its association with cardiovascular risk. METHODS: This was a prospective, multicentre study conducted in two outpatient clinics. Patients aged ≥ 21 years with uncontrolled T2DM (HbA1c > 7.0 % [53 mmol/mol]) and polypharmacy were stratified based on their Framingham Risk Score (FRS-high ≥ 10 %, low < 10 %) and matched in accordance to their baseline HbA1c. Cardiovascular risk was estimated using FRS while diabetes distress was measured using Problem Areas in Diabetes (PAID) scale (denial 0-10, severe distress ≥ 40). RESULTS: Of 1940 patients approached, 210 were recruited. A final 132 (62.9 %) participants were eligible for analysis. Median PAID score was 17.5 (IQR 6.25-41.56), with an even distribution in each distress category. There was no significant difference in PAID scores between the high and low FRS groups (20.00vs13.75, p = 0.446). Additionally, PAID score distribution within each group was similar (McNemar-Bowker test, p = 0.477). However, a high prevalence of severe distress (31.4 %) and denial (33.8 %) was detected. Among those in denial, 58.7 % had accompanying intermediate-high 10-year cardiovascular risk. CONCLUSION: In our sample of Asian primary care patients, a high prevalence of severe diabetes distress and denial was detected although no clear association between cardiovascular risk and diabetes distress was found. Future studies should assess the longitudinal changes and impact of other risk factors in diabetes distress. (Abstract: 199 words).

CellMarker 2.0: an updated database of manually curated cell markers in human/mouse and web tools based on scRNA-seq data.

CellMarker 2.0 (http://bio-bigdata.hrbmu.edu.cn/CellMarker or http://117.50.127.228/CellMarker/) is an updated database that provides a manually curated collection of experimentally supported markers of various cell types in different tissues of human and mouse. In addition, web tools for analyzing single cell sequencing data are described. We have updated CellMarker 2.0 with more data and several new features, including (i) Appending 36 300 tissue-cell type-maker entries, 474 tissues, 1901 cell types and 4566 markers over the previous version. The current release recruits 26 915 cell markers, 2578 cell types and 656 tissues, resulting in a total of 83 361 tissue-cell type-maker entries. (ii) There is new marker information from 48 sequencing technology sources, including 10X Chromium, Smart-Seq2 and Drop-seq, etc. (iii) Adding 29 types of cell markers, including protein-coding gene lncRNA and processed pseudogene, etc. Additionally, six flexible web tools, including cell annotation, cell clustering, cell malignancy, cell differentiation, cell feature and cell communication, were developed to analysis and visualization of single cell sequencing data. CellMarker 2.0 is a valuable resource for exploring markers of various cell types in different tissues of human and mouse.

The external jugular vein is a feasible and safe alternative access for retrieval of inferior vena cava filter.

PURPOSE: The purpose is to analyze whether the external jugular vein (EJV) is a feasible and safe alternative access for the retrieval IVCFs designed for the jugular approach. METHODS: This study was designed as a nonrandomized, controlled study. The patients were divided into two groups: the IJV or EJV access groups. All operations were performed by the vascular surgery team. The main outcome was the technical success rate. The secondary outcomes included (1) the IVCF retrieval rate; (2) the time required to puncture the access vein (min); (3) the number of punctures required for access, and other aspects. RESULTS: A total of 119 patients were recruited for IVCF retrieval. Seventeen patients refused to join this trial, leaving 58 patients in the IJV group and 44 patients in the EJV group. In the IJV group, technical success was not achieved in one patient who started in the EJV group and was transferred to the IJV group. There was no significant difference in age, comorbidities, or technical success rate between the two groups. Significant differences were observed in puncture time (min), number of punctures, and inadvertent puncture of the carotid artery. All of the patients were discharged 1 or 2 days after the operation. CONCLUSION: EJV is safe and feasible alternative access for the retrieval of IVCFs that are designed for jugular approaches.

Identifying and characterizing drug sensitivity-related lncRNA-TF-gene regulatory triplets.

Recently, many studies have shown that lncRNA can mediate the regulation of TF-gene in drug sensitivity. However, there is still a lack of systematic identification of lncRNA-TF-gene regulatory triplets for drug sensitivity. In this study, we propose a novel analytic approach to systematically identify the lncRNA-TF-gene regulatory triplets related to the drug sensitivity by integrating transcriptome data and drug sensitivity data. Totally, 1570 drug sensitivity-related lncRNA-TF-gene triplets were identified, and 16 307 relationships were formed between drugs and triplets. Then, a comprehensive characterization was performed. Drug sensitivity-related triplets affect a variety of biological functions including drug response-related pathways. Phenotypic similarity analysis showed that the drugs with many shared triplets had high similarity in their two-dimensional structures and indications. In addition, Network analysis revealed the diverse regulation mechanism of lncRNAs in different drugs. Also, survival analysis indicated that lncRNA-TF-gene triplets related to the drug sensitivity could be candidate prognostic biomarkers for clinical applications. Next, using the random walk algorithm, the results of which we screen therapeutic drugs for patients across three cancer types showed high accuracy in the drug-cell line heterogeneity network based on the identified triplets. Besides, we developed a user-friendly web interface-DrugSETs (http://bio-bigdata.hrbmu.edu.cn/DrugSETs/) available to explore 1570 lncRNA-TF-gene triplets relevant with 282 drugs. It can also submit a patient's expression profile to predict therapeutic drugs conveniently. In summary, our research may promote the study of lncRNAs in the drug resistance mechanism and improve the effectiveness of treatment.

Size Distribution of Microparticles: A New Parameter to Predict Acute Lung Injury After Cardiac Surgery With Cardiopulmonary Bypass.

Background: Acute lung injury (ALI) is a common complication after cardiac surgery with cardiopulmonary bypass (CPB). No precise way, however, is currently available to predict its occurrence. We and others have demonstrated that microparticles (MPs) can induce ALI and were increased in patients with ALI. However, whether MPs can be used to predict ALI after cardiac surgery with CPB remains unknown. Methods: In this prospective study, 103 patients undergoing cardiac surgery with CPB and 53 healthy subjects were enrolled. MPs were isolated from the plasma before, 12 h after, and 3 d after surgery. The size distributions of MPs were measured by the LitesizerTM 500 Particle Analyzer. The patients were divided into two subgroups (ALI and non-ALI) according to the diagnosis of ALI. Descriptive and correlational analyzes were conducted between the size distribution of MPs and clinical data. Results: Compared to the non-ALI group, the size at peak and interquartile range (IQR) of MPs in patients with ALI were smaller, but the peak intensity of MPs is higher. Multivariate logistic regression analysis indicated that the size at peak of MPs at postoperative 12 h was an independent risk factor for ALI. The area under the curve (AUC) of peak diameter at postoperative 12 h was 0.803. The best cutoff value of peak diameter to diagnose ALI was 223.05 nm with a sensitivity of 88.0% and a negative predictive value of 94.5%. The AUC of IQR at postoperative 12 h was 0.717. The best cutoff value of IQR to diagnose ALI was 132.65 nm with a sensitivity of 88.0% and a negative predictive value of 92.5%. Combining these two parameters, the sensitivity reached 92% and the negative predictive value was 96%. Conclusions: Our findings suggested that the size distribution of MPs could be a novel biomarker to predict and exclude ALI after cardiac surgery with CPB.

Identifying individualized risk subpathways reveals pan-cancer molecular classification based on multi-omics data.

Cancer is a highly heterogeneous disease with different functional disorders among individuals. The initiation and progression of cancer is usually related to dysregulation of local regions within pathways. Identification of individualized risk pathways is crucial for revealing the mechanisms of tumorigenesis and heterogeneity. However, approach that focused on mining patient-specific risk subpathway regions is still lacking. Here, we developed an individualized cancer risk subpathway identification method that was referred as InCRiS by integrating multi-omics data. Then, the method was applied to nearly 3000 samples across 9 TCGA cancer types and its robustness and reliability were evaluated. Dissecting dysregulated subpathways in these tumor samples revealed several key regions which may play oncogenic roles in cancer. The construction of risk subpathway dysregulation profile of pan-cancers revealed 11 pan-cancer molecular classification (InCRiS subtypes) with significantly different clinical outcomes. Moreover, subpathway regions that tend to be disordered in individuals of specific subtypes were examined for understanding the pathogenesis of tumor and some key genes such as CTNNB1, EP300 and PRKDC were nominated in different subtypes. In summary, the proposed method and resulting data presented useful resources to study the mechanism of tumor heterogeneity and to discovery novel therapeutic targets for precise treatment of cancer.

Long-term clinical and cost-effectiveness of collaborative care in people with uncontrolled type 2 diabetes mellitus and polypharmacy: A multicenter randomized controlled trial.

AIMS: This study examined the effectiveness of a collaborative care model on clinical and humanistic outcomes, medical cost, productivity loss, and its cost-effectiveness in managing uncontrolled Type 2 Diabetes Mellitus (T2DM). METHODS: A randomized controlled study was conducted in two outpatient health institutions in Singapore. Patients aged above 21 years with HbA1c > 7% and polypharmacy were included. Eligible patients were randomized into the intervention (collaborative care) and control (usual care) arms. RESULTS: A total of 255 patients were included in the analysis. Compared to the control arm, the intervention arm achieved significantly greater glycated hemoglobin (HbA1c) reduction (mean difference: 0.25, 95%CI: [0.001, 0.50], p = 0.049) and quality-adjusted life year (QALY) (+0.011, 95%CI: [0.003, 0.019], p = 0.011) at 12 months. The costs per additional HbA1c and QALY improvements over one year were $40.52 and $920.91 respectively. Activity impairment was lower in the intervention group both at 6 months (12.7% vs 19.0%; p = 0.022) and at 12 months (6.7% vs 14.0%; p = 0.008). CONCLUSIONS: The collaborative care model achieved earlier HbA1c reduction and reduced patients' activity impairment without decreasing work productivity or increasing medical costs. This intervention is cost-effective for improving glycemic control and quality of life in patients with T2DM.

Dissecting immune cell stat regulation network reveals biomarkers to predict ICB therapy responders in melanoma.

BACKGROUND: Immunotherapy is a revolutionary strategy in cancer therapy, but the resistance of which is one of the important challenges. Detecting the regulation of immune cells and biomarkers concerning immune checkpoint blockade (ICB) therapy is of great significance. METHODS: Here, we firstly constructed regulation networks for 11 immune cell clusters by integrating biological pathway data and single cell sequencing data in metastatic melanoma with or without ICB therapy. We then dissected these regulation networks and identified differently expressed genes between responders and non-responders. Finally, we trained and validated a logistic regression model based on ligands and receptors in the regulation network to predict ICB therapy response. RESULTS: We discovered the regulation of genes across eleven immune cell stats. Functional analysis indicated that these stat-specific networks consensually enriched in immune response corrected pathways and highlighted antigen processing and presentation as a core pathway in immune cell regulation. Furthermore, some famous ligands like SIRPA, ITGAM, CD247and receptors like CD14, IL2 and HLA-G were differently expressed between cells of responders and non-responders. A predictive model of gene sets containing ligands and receptors performed accuracy prediction with AUCs above 0.7 in a validation dataset suggesting that they may be server as biomarkers for predicting immunotherapy response. CONCLUSIONS: In summary, our study presented the gene-gene regulation landscape across 11 immune cell clusters and analysis of these networks revealed several important aspects and immunotherapy response biomarkers, which may provide novel insights into immune related mechanisms and immunotherapy response prediction.

Key Genes and Prognostic Analysis in HER2+ Breast Cancer.

Human epidermal growth factor 2 (HER2)+ breast cancer is considered the most dangerous type of breast cancers. Herein, we used bioinformatics methods to identify potential key genes in HER2+ breast cancer to enable its diagnosis, treatment, and prognosis prediction. Datasets of HER2+ breast cancer and normal tissue samples retrieved from Gene Expression Omnibus and The Cancer Genome Atlas databases were subjected to analysis for differentially expressed genes using R software. The identified differentially expressed genes were subjected to gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses followed by construction of protein-protein interaction networks using the STRING database to identify key genes. The genes were further validated via survival and differential gene expression analyses. We identified 97 upregulated and 106 downregulated genes that were primarily associated with processes such as mitosis, protein kinase activity, cell cycle, and the p53 signaling pathway. Visualization of the protein-protein interaction network identified 10 key genes (CCNA2, CDK1, CDC20, CCNB1, DLGAP5, AURKA, BUB1B, RRM2, TPX2, and MAD2L1), all of which were upregulated. Survival analysis using PROGgeneV2 showed that CDC20, CCNA2, DLGAP5, RRM2, and TPX2 are prognosis-related key genes in HER2+ breast cancer. A nomogram showed that high expression of RRM2, DLGAP5, and TPX2 was positively associated with the risk of death. TPX2, which has not previously been reported in HER2+ breast cancer, was associated with breast cancer development, progression, and prognosis and is therefore a potential key gene. It is hoped that this study can provide a new method for the diagnosis and treatment of HER2 + breast cancer.

IL-33 promotes the progression of vascular restenosis after carotid artery balloon injury by promoting carotid artery intimal hyperplasia and inflammatory response.

Interleukin (IL)-33 is associated with vascular restenosis after carotid artery balloon injury. This work aims to investigate the involvement of IL-33 in carotid artery balloon injury. We first constructed carotid artery balloon injury model in male Wistar rats. Then, we found that IL-33 was highly expressed in the rats with carotid artery balloon injury 3, 14 and 21 days after surgery. Furthermore, IL-33 treatment promoted inflammatory response and carotid artery intimal hyperplasia in the rats with carotid artery balloon injury, which was effectively improved by anti-IL-33 treatment. In addition, IL-33 treatment enhanced proliferation, migration, inflammatory response and tube formation of human umbilical vein endothelial cells in a concentration-dependent way. In summary, our study demonstrates that IL-33 treatment promotes the progression of vascular restenosis after carotid artery balloon injury by enhancing carotid artery intimal hyperplasia and inflammatory response. Thus, our findings suggest that IL-33 maybe a valuable target for carotid artery balloon injury therapies.

Mid-Term Outcome after Tricuspid Valve Replacement.

OBJECTIVE: To evaluate the mid-term survival rate after tricuspid valve replacement (TVR). METHODS: We retrospectively studied 110 consecutive patients who underwent TVR from January 2007 to November 2017. A survival analysis was performed with the Kaplan-Meier method and the log-rank test. RESULTS: The median survival was 65.81 months. Mean age was 50 (range 39 to 59) years. Forty-eight patients (43.6%) were male, and 62 patients (56.4%) were female. Most of the patients (78.5%) were categorized into the New York Heart Association (NYHA) functional classes III/IV. Seventy-two patients (65.5%) had isolated TVR. Six-three patients (57.3%) had previously undergone heart surgery. The Kaplan-Meier survival rates at one year, three years, and five years were 59.0%±5%, 52.0%±6%, and 48.0%±6%, respectively. A Cox regression analysis demonstrated that the risk factors for mid-term mortality were advanced NYHA class (hazard ratio [HR] 2.430, 95% confidence interval [CI] 1.099-5.375, P=0.028), need for continuous renal replacement therapy (CRRT) treatment (HR 3.121, 95% CI 1.610-6.050, P=0.001), and need for intra-aortic balloon pump (IABP) treatment (HR 3.356, 95% CI 1.072-10.504, P=0.038). CONCLUSION: In TVR, impaired cardiac function before the operation and a need for CRRT or IABP treatment after the operation is independently associated with increased mid-term mortality.

Mid-term outcome after tricuspid valve replacement

Abstract Objective: To evaluate the mid-term survival rate after tricuspid valve replacement (TVR). Methods: We retrospectively studied 110 consecutive patients who underwent TVR from January 2007 to November 2017. A survival analysis was performed with the Kaplan-Meier method and the log-rank test. Results: The median survival was 65.81 months. Mean age was 50 (range 39 to 59) years. Forty-eight patients (43.6%) were male, and 62 patients (56.4%) were female. Most of the patients (78.5%) were categorized into the New York Heart Association (NYHA) functional classes III/IV. Seventy-two patients (65.5%) had isolated TVR. Six-three patients (57.3%) had previously undergone heart surgery. The Kaplan-Meier survival rates at one year, three years, and five years were 59.0%±5%, 52.0%±6%, and 48.0%±6%, respectively. A Cox regression analysis demonstrated that the risk factors for mid-term mortality were advanced NYHA class (hazard ratio [HR] 2.430, 95% confidence interval [CI] 1.099-5.375, P=0.028), need for continuous renal replacement therapy (CRRT) treatment (HR 3.121, 95% CI 1.610-6.050, P=0.001), and need for intra-aortic balloon pump (IABP) treatment (HR 3.356, 95% CI 1.072-10.504, P=0.038). Conclusion: In TVR, impaired cardiac function before the operation and a need for CRRT or IABP treatment after the operation is independently associated with increased mid-term mortality.

Investigation on the association between diabetes distress and productivity among patients with uncontrolled type 2 diabetes mellitus in the primary healthcare institutions.

AIMS: To investigate associations between diabetes distress and productivity, and to identify the potential risk factors that could affect these particular associations. METHODS: This cross-sectional study was conducted in three outpatient healthcare institutions. Patients aged ≥21 years with uncontrolled T2DM and polypharmacy were included. The Problem Areas in Diabetes (PAID) measuring diabetes distress and Work Productivity and Activity Impairment General Health (WPAI-GH) measuring productivity were administered by trained interviewers. RESULTS: A total of 259 patients were analysed. Point prevalence of clinically severe diabetes distress, work productivity loss and life productivity loss were 7.7%, 45.0% and 35.1% respectively. Diabetes distress was positively associated with work productivity loss (p = 0.001) and life productivity loss (p < 0.001). Multiple linear regression analysis demonstrated that diabetes distress (p = 0.003), the total number of chronic medications (p = 0.012), insulin therapy (p = 0.027) and the presence of chronic kidney disease (p = 0.038) were significantly associated with work impairment. Diabetes distress (p = 0.001) and the presences of osteoarthritis (p = 0.039) were significantly associated with activity impairment. CONCLUSION: Healthcare professionals should screen patients for diabetes distress to prevent productivity losses, especially in patients with polypharmacy and/or on insulin and with coexisting osteoarthritis or chronic kidney disease.