Discovery medicine最新文献

{"title":"Establishing a Predictive Model to Predict Survival of de Novo Metastatic HER2-Low Breast Cancer: A National Cancer Database Analysis.","authors":"Mingying Li,&nbsp;Miao Liu,&nbsp;Ling Zhu,&nbsp;Hongjiang Lu,&nbsp;An Mao,&nbsp;Huihui Liu,&nbsp;Kun Yu,&nbsp;Liyun Dong","doi":"10.24976/Discov.Med.202335176.29","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335176.29","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer with low human epidermal growth factor receptor (HER2) expression is increasingly considered as a distinct subtype which consists of types of HER2 immunohistochemistry (IHC) 1+ and HER2 IHC 2+/<i>in-situ</i> hybridization (ISH)-negative. We aim to assess the survival difference between HER2 IHC 1+ and HER2 IHC 2+/ISH-negative breast cancer patients with metastasis at presentation and construct a prognostic nomogram for HER2-low patients.</p><p><strong>Method: </strong>Patients diagnosed with de novo metastatic HER2-low breast cancer from 2010 to 2015 were included and analyzed using the National Cancer Database (NCDB). Cox proportional hazards regression model and Kaplan-Meier (KM) method were used for survival analysis. Nomograms were built to predict survival.</p><p><strong>Result: </strong>A total of 7897 patients were included in the final analysis, among which 5458 (69.1%) patients were HER2 IHC 1+ and 2439 (30.9%) were HER2 IHC 2+/ISH-negative. Although the Kaplan-Meier survival analysis showed difference in survival, this survival difference was lost in the multivariate Cox analysis (multivariate: HR (hazard ratio) = 0.97; 95% CI (confidence interval) [0.92-1.03]). A prognostic nomogram was successfully constructed for individually predicting the long-term survival rate of HER2-low patients, which exhibited an acceptable predictive capability in training (C index: 0.719) and validation cohort (C index: 0.706). This nomogram could easily divide patients into high and low-risk subgroups with distinct prognoses.</p><p><strong>Conclusions: </strong>Our data suggest no statistical survival differences between HER2 1+ and HER2 2+ breast cancer. Additionally, a nomogram was constructed with an acceptable capacity to individually predict the long-term outcome of HER2-low metastatic breast cancer patients.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 176","pages":"283-292"},"PeriodicalIF":1.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9980800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of PD-1 Inhibitors Combined with Anti-Angiogenic Therapy in Driver Gene Mutation Negative Non-Small-Cell Lung Cancer with Brain Metastases.","authors":"Jia-Qi Song,&nbsp;Xia Wang,&nbsp;Zhi-Min Zeng,&nbsp;Ping-An Liang,&nbsp;Cong-Ying Zhong,&nbsp;An-Wen Liu","doi":"10.24976/Discov.Med.202335176.33","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335176.33","url":null,"abstract":"<p><strong>Objective: </strong>Anti-angiogenic therapy has proven effective in non-small-cell lung cancer (NSCLC) patients. The purpose of this study was to evaluate the efficacy of programmed cell death protein 1 (PD-1) inhibitors combined with anti-angiogenic therapy in patients with driver gene mutation negative NSCLC and brain metastases (BMs).</p><p><strong>Methods: </strong>A retrospective analysis was performed on NSCLC BMs in patients without driver gene mutations who received PD-1 inhibitors. Two groups, receiving either PD-1 inhibitor monotherapy or PD-1 inhibitor plus anti-angiogenesis therapy, were identified. The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). The secondary endpoints were safety, intracranial objective response rate (iORR) and intracranial disease control rate (iDCR).</p><p><strong>Results: </strong>113 NSCLC patients were included, 51 (45.1%) in the PD-1 inhibitor monotherapy group and 62 (54.9%) in the PD-1 inhibitor plus anti-angiogenesis therapy group. The median follow-up time was 26.2 months. OS was higher in the combination therapy cohort than in the monotherapy cohort (OS: 21.4 <i>vs</i>. 11.8 months; <i>p</i> = 0.004), with no significant difference in iPFS (<i>p</i> = 0.088). Moreover, the PD-1 inhibitor + anti-angiogenic therapeutic regimen exhibited the preferred iDCR (<i>p</i> = 0.005) but not the iORR (<i>p</i> = 0.121). There was no significant difference in the incidence of grade 3-4 adverse events between the two groups. In multivariate Cox regression analysis, PD-1 inhibitor therapy combined with anti-angiogenic treatment (<i>p</i> = 0.003) was an independent prognostic indicator of OS.</p><p><strong>Conclusions: </strong>Combining PD-1 inhibitor therapy with anti-angiogenic treatment significantly improves the OS of driver gene mutation negative NSCLC patients with BMs.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 176","pages":"321-331"},"PeriodicalIF":1.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9980803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Action and Mechanism of Trehalose on GATA4 Autophagy Degradation and Ventricular Remodeling.","authors":"Qiaoying Chai,&nbsp;Wei Zhang,&nbsp;Lijuan Gao,&nbsp;Yingtao Yang,&nbsp;Mengdan Miao,&nbsp;Da Liu,&nbsp;Lixia Chen,&nbsp;Mingqi Zheng,&nbsp;Shuanli Xin","doi":"10.24976/Discov.Med.202335176.40","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335176.40","url":null,"abstract":"<p><strong>Objective: </strong>To probe the effect of trehalose on myocardial hypertrophy and its specific molecular mechanism.</p><p><strong>Methods: </strong>C57BL/6J male mice were divided into four subgroups: Sham operation subgroup (Sham), negative sham subgroup (Sham+Trehalose), transverse aortic constriction (TAC), and trehalose treatment subgroup (TAC+Trehalose). Immediately after the TAC operation, trehalose at a dose of 10 mg/kg was given daily via gavage. After four weeks, changes in cardiac function were evaluated using ultrasound to measure EF (ejection fraction), FS (fractional shortening), IVRT (isovolumic relaxation time), MPI (myocardial performance index), Tau (isovolumic relaxation time constant), LVESP (left ventricular end-systolic pressure), and EDPVR (end-diastolic pressure-volume relationship). The profiles of autophagy-associated proteins (p62, LC3II/I, and Beclin-1) and GATA4 protein in mice myocardial tissues were assessed by Western blotting (WB). Myocardial cells were classified from TAC mice into five groups: Control, Trehalose, Phenylephrine (PE), PE+Trehalose, and PE+Trehalose+autophagy inhibitor chloroquine groups. In the PE group, cardiomyocytes were treated with 50 μmol/L PE. Then, the cells were treated with trehalose (100 μmol/L), trehalose (100 μmol/L)+autophagy (20 μmol/L) for 24 hours respectively. The Control group was treated with the same amount of normal saline. Flow cytometry was utilized to detect myocardial cell apoptosis in each subgroup. The alterations in apoptosis and autophagy-correlated proteins (p62, LC3II/I, and Beclin-1) were assessed by WB. Additionally, the level of GATA4 protein upstream of autophagy was estimated. Furthermore, the expression levels of pro-apoptotic proteins Bad, BAX, Cleaved-caspase-3, and anti-apoptotic protein Bcl-2 were examined by WB.</p><p><strong>Results: </strong>The TAC operation significantly augmented myocardial hypertrophy, heart weight-to-body weight ratio, and myocardial cell apoptosis in mice (<i>p</i> < 0.05). Trehalose significantly improved cardiac hypertrophy, cardiomyocyte apoptosis, and cardiac function decline in mice. Additionally, it also significantly enhanced autophagy in mouse cardiac tissues (<i>p</i> < 0.05). At the cellular level, trehalose significantly decreased PE-elicited apoptosis and promoted the protein expressions of Beclin-1 and LC3 II/I in cardiomyocytes while significantly dampening the profiles of p62 and GATA4 in cells. The effect of trehalose and chloroquine treatment was significantly greater than that of the trehalose group.</p><p><strong>Conclusions: </strong>Trehalose significantly abates myocardial hypertrophy and pressure overload-induced cardiomyocyte apoptosis in mice. The cardioprotective effect of trehalose on enhanced autophagy is attributed, at least in part, to the promotion of autophagic degradation of GATA4.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 176","pages":"394-404"},"PeriodicalIF":1.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9599850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can Cytokine Detection Predict the Occurrence and Outcome of aGVHD after Allo-HCT? A Retrospective Study.","authors":"Qian Gao,&nbsp;Weijie Zhang,&nbsp;Di Zhang,&nbsp;Qi Hao,&nbsp;Yu An,&nbsp;Guowei Liang","doi":"10.24976/Discov.Med.202335176.25","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335176.25","url":null,"abstract":"<p><strong>Background: </strong>Many cytokines play essential roles in the occurrence and development of acute graft-versus-host-disease (aGVHD). This study aims to validate whether 11 proinflammatory and anti-inflammatory cytokines can be a candidate for aGVHD biomarkers to predict its occurrence and outcome.</p><p><strong>Methods: </strong>Out of 178 patients who underwent allogeneic hematopoietic stem cell transplantation, we retrospectively enrolled 32 cases into the pre-transplant cohort and 45 cases into the post-transplant cohort. The serum cytokine concentrations were determined by flow cytometry. The control and experimental groups were non-aGVHD, I-II aGVHD and III-IV aGVHD groups, respectively. Risk factors and overall survival (OS) were also evaluated.</p><p><strong>Results: </strong>In the pre-transplant cohort, interleukin (IL)-2 decreased in patients with aGVHD, and IL-4 only reduced in patients with III-IV aGVHD. In the post-transplant cohort, only IL-4 increased 1.79 times more in patients with III-IV aGVHD than in the other two groups. Patients with gastrointestinal (GI) aGVHD had lower IL-2, IL-4 and IL-17F levels pre-transplant and lower IL-2 post-transplant. None of the other cytokines was significantly different. Logistic regression analysis showed that no cytokine could predict the occurrence and outcome of aGVHD. Diarrhea within 15 days post-transplant is an independent risk factor for the occurrence of aGVHD and a risk factor for a fatal outcome. Patients without diarrhea had longer survival time of 672 (586-757) days vs 444 (229-548) days and better 2-year OS (85.7% vs 46.4%) than those with diarrhea. Compared to patients with aGVHD, patients without aGVHD had a longer survival time of 618 (530-706) days vs 449 (353-545) days and better 2-year OS (76.2% vs 47.1%).</p><p><strong>Conclusions: </strong>Proinflammatory and anti-inflammatory cytokines can provide specific indications for the occurrence and progression of aGVHD. However, to truly guide the diagnosis and prognosis, cytokines with larger sample sizes, more detection time points and more accurate diagnostic efficacy need to be further studied.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 176","pages":"242-250"},"PeriodicalIF":1.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9607570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Clinical Application and Accuracy Evaluation of Noninvasive Prenatal Testing for Common Trisomy and Sex Chromosome Aneuploidy.","authors":"Yichao Wang,&nbsp;Yanhong Shao,&nbsp;Juan Yu","doi":"10.24976/Discov.Med.202335176.36","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335176.36","url":null,"abstract":"<p><strong>Background: </strong>Noninvasive prenatal testing (NIPT) has been widely adopted in prenatal examination for fetal chromosomal aneuploidy. The present study aimed to evaluate the clinical features of NIPT for both common trisomy and sex chromosome aneuploidy (SCA).</p><p><strong>Methods: </strong>A total of 24,164 pregnant women with NIPT testing from July 2020 to June 2022 were recruited at the Linping Maternity and Child Health Care Hospital.</p><p><strong>Results: </strong>Ninety cases showed high risk of trisomy 21/18/13 with karyotype results available, and the sensitivity, specificity, and positive predictive value (PPV) were 98.41%, 99.88% and 68.89%, respectively. The three most important reasons for screening were advanced maternal age (AMA, 28.06%), intermediate risk of prenatal screening (20.34%) and Multiple of medium (MoM) abnormality of prenatal screening (17.38%). High risk of NIPT results with Z-score ≥15 have a higher PPV when compared to those with 3 ≤ Z-score < 10, and 10 ≤ Z-score < 15. Meanwhile, 97 pregnant women received positive results for fetal sex chromosome aneuploidy (SCA) in NIPT. In addition, the rate for further diagnostics of SCA was 64.95% and the PPV of SCA was 50.79%.</p><p><strong>Conclusions: </strong>Our data show that NIPT has a promising future in prenatal screening for genetic abnormalities of the fetus, and that the accuracy of NIPT is closely related to Z-score.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 176","pages":"353-360"},"PeriodicalIF":1.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9607577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrochemical Sensor Based on Nanomaterials and Its Application in the Detection of Alpha Fetoprotein.","authors":"Rongping Huang,&nbsp;Zhikun Zhang,&nbsp;Lu Gan,&nbsp;Dianfa Fan,&nbsp;Zhangbo Qian,&nbsp;Xinjun Sun,&nbsp;Yong Huang","doi":"10.24976/Discov.Med.202335175.10","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335175.10","url":null,"abstract":"<p><p>Hepatocellular carcinoma development and many other tumors are closely related to alpha-fetoprotein (AFP), its determination can be used as a positive test for tumors. It is mainly used clinically as a serum marker to diagnose and monitor the efficacy of primary hepatocellular carcinoma. Therefore, a variety of biosensors have been developed to detect AFP. Electrochemical sensors integrate a variety of detection methods. They have inherent advantages over other types of sensors, they are fast, portable, simple, and highly sensitive. Some meaningful electrochemical biosensors work with nanomaterials acting as signal amplification elements or as signal amplification catalysts. This review introduced the field of biosensors and discuss about the use of nanomaterials in electrochemical sensing, specificity electrochemical biosensing of AFP. The study ends with a discussion about the prospects for nanomaterial-based signal amplification and future research directions.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 175","pages":"95-103"},"PeriodicalIF":1.4,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9449798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High Red Blood Cell Distribution Width to Platelet Ratio is an Independent Poor Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.","authors":"Mengyi Li,&nbsp;Yanliang Bai,&nbsp;Xiaobai Sun,&nbsp;Haoyan Wang,&nbsp;Weiya Li,&nbsp;Xingjun Xiao,&nbsp;Yuqing Chen,&nbsp;Kai Sun","doi":"10.24976/Discov.Med.202335175.16","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335175.16","url":null,"abstract":"<p><strong>Background: </strong>The red blood cell distribution width to platelet ratio (RPR) is an inflammatory marker that is a convenient and reliable prognostic indicator for several solid malignancies. However, the correlation between RPR and myeloma prognosis has not been reported. Therefore, this study aims to explore the correlation between RPR level and the prognosis of multiple myeloma (MM) patients.</p><p><strong>Methods: </strong>We retrospectively analyzed 145 newly diagnosed patients with MM. The receiver operating characteristic curve (ROC) method was used to determine the RPR cut-off value. In addition, we studied the correlation between pre-treatment RPR levels and clinical characteristics, immunophenotype, cytogenetics, and its impact on the disease prognosis.</p><p><strong>Results: </strong>The optimal cut-off value for RPR was 0.12 and was divided into high RPR and low RPR groups. Patients in the high RPR group are more likely to have anemia, thrombocytopenia, high β2-macroglobulinemia, a high percentage of bone marrow plasma cells, late-stage status by Dury-Salmon (DS) and international staging system (ISS) (<i>p</i> < 0.05). More notably, between the high RPR and low RPR groups, the incidence rates of CD56-positive, D13S319-positive, RB1-positive, and 1q21 amplification were statistically significant (<i>p</i> < 0.05). Additionally, survival analysis revealed that compared with patients in the low RPR group, the median progression-free survival (PFS) and overall survival (OS) of patients in the high RPR group were substantially shortened (<i>p</i> < 0.05). Multivariate analysis confirmed that RPR ≥0.12, D13S319-positive, and 1q21 amplification were independent risk factors for poor PFS and OS.</p><p><strong>Conclusions: </strong>RPR is a practical and effective prognostic marker in newly diagnosed patients with MM, and a high RPR is an independent poor prognostic factor.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 175","pages":"157-167"},"PeriodicalIF":1.4,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9442982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-Analysis of the Efficacy of Low Molecular Weight Heparin and Aspirin in the Treatment of Thrombosis During Pregnancy and Effects on Coagulation Function.","authors":"Meng Yin,&nbsp;Xiaosong Qin","doi":"10.24976/Discov.Med.202335175.11","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335175.11","url":null,"abstract":"<p><strong>Background: </strong>At present, there is no comprehensive evaluation of the efficacy and safety of low molecular weight heparin (LMWH) for the treatment of thrombophilia during pregnancy in clinical practice. This study aimed to systematically evaluate the efficacy of LMWH in the treatment of patients and its effects on coagulation function, thereby providing a reference for the clinical treatment and prognosis evaluation of thrombophilia during pregnancy.</p><p><strong>Methods: </strong>Database PubMed, Web of Science and Embase as well as China National Knowledge Infrastructure and Wanfang Database were applied for the search of data. A comparative study on the efficacy of LMWH in the treatment of gestational thrombophilia was enrolled. Stata 16.0 software (Stata, College Station, TX, USA) was utilized to conduct the meta-analysis.</p><p><strong>Results: </strong>A total of 487 relevant articles were retrieved and 14 studies were finally included. Patients in the LMWH combined with the low-dose aspirin group had a significantly higher live birth rate than those in the aspirin or LMWH treat group (OR (odds ratio) = 4.54, 95% CI (confidence interval): 2.76, 7.45). The adverse effects rate was lower in the LMWH combined with the low-dose aspirin group than in the aspirin or LMWH treatment group (OR = 0.40, 95% CI: 0.29, 0.56). After treatment, patients in the LMWH combined with the low-dose aspirin group had significantly lower D-dimer (SMD (standardized mean differences) = -1.50, 95% CI: -2.19, 0.80) and platelet count (PLT; SMD = -0.13, 95% CI: -0.35, 0.09) than those in the aspirin or LMWH treatment group. However, activated partial thromboplastin time (APTT; SMD = 0.16, 95% CI: -0.10, 0.42), thrombin time (TT; SMD = 0.60, 95% CI: -0.14, 1.34), plasma prothrombin time (PT; SMD = 0.42, 95% CI: -0.71, 1.56), and fibrin values (FIB; SMD = -0.92, 95% CI: -2.12, 0.28) were significantly higher in the LMWH combined with low-dose aspirin group than those in the aspirin or LMWH treatment group.</p><p><strong>Conclusions: </strong>LMWH heparin combined with low-dose aspirin can effectively correct coagulation function in pregnant women, improve prothrombotic state and increase the live birth rate, which has high clinical value.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 175","pages":"104-115"},"PeriodicalIF":1.4,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9449801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proprotein Convertase Furin Regulates Melanogenesis via the Notch Signaling Pathway.","authors":"Lingling Luo,&nbsp;Weixue Jia,&nbsp;Yuanyuan Zhang,&nbsp;Youming Guo,&nbsp;Jing Zhu,&nbsp;Chengrang Li","doi":"10.24976/Discov.Med.202335175.15","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335175.15","url":null,"abstract":"<p><strong>Background: </strong>Furin is a calcium-dependent serine protease found in almost all mammals. It plays an important role in embryogenesis, tissue homeostasis, tumors pathogenesis, viral infectious diseases, and neurodegenerative diseases. However, whether furin directly regulates melanin synthesis and transport has rarely been evaluated yet. The present study aimed to investigate furin potential function and mechanisms in melanogenesis.</p><p><strong>Methods: </strong>Short hairpin RNAs targeting <i>furin</i> gene (sh-furin RNAs) were used to inhibit <i>furin</i> gene expression in human melanoma cell line MNT-1 cells. Then, intracellular melanin content was measured using a sodium hydroxide method. Extracellular melanin content was measured determining cell culture medium absorbance at 450 nm. Levodopa (L-DOPA) oxidation rate was measured to assess the tyrosinase activity. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were performed to measure melanogenesis-related genes and Notch pathway-related genes expression levels. Human primary melanocytes (MCs) were extracted from foreskin tissues and were stimulated with a furin inhibitor. Then, the extracellular and intracellular melanin content, tyrosinase activity and molecules related to melanogenesis and the Notch pathway expression were measured in MCs with or without a furin inhibitor. Additionally, morpholino technology was used to inhibit furin in zebrafish. Zebrafish pigmentary phenotypes in the control group and furin inhibition group were observed with a stereo microscope. Then, MCs number in the tail and head of the zebrafish were counted using Image J software (version 1.53t, National Institute of Health, Bethesda, MD, USA). Meanwhile, melanin content, tyrosinase activity, and molecules related to melanogenesis and the Notch pathway expression levels were measured. Subsequently, valproic acid (VPA), a Notch pathway agonist, was used in MNT-1 melanoma cells treated with or without sh-furin lentiviral vectors for rescue experiments.</p><p><strong>Results: </strong>Furin inhibition enhanced intracellular and extracellular melanin content, and cellular tyrosinase activity in MNT-1 cells and MCs. Additionally, furin inhibition increased melanin synthesis-associated and transport-associated proteins expression levels while inhibiting Notch pathway-relevant proteins. After using VPA to activate the Notch pathway in MNT-1 cells transfected with a sh-furin RNA, the biological effects resulting from furin knockdown were reversed. In addition, the results of <i>in vivo</i> experiments using morpholino to knock down <i>furin</i> gene in zebrafish further confirmed that furin knockdown regulated melanogenesis and impaired the Notch pathway.</p><p><strong>Conclusions: </strong>This study clarified that furin affected the synthesis and transport of melanin via Notch pathway. Notch pathway may be a potential therapeutic target for pigmented skin diseases.","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 175","pages":"144-156"},"PeriodicalIF":1.4,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9442978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and Prognosis of Adjuvant Argatroban Treatment in Acute Ischemic Stroke Patients with Early Neurological Deterioration.","authors":"Shu Xu,&nbsp;Wenjun Zhang,&nbsp;Yan Zhang,&nbsp;Zhou Xu,&nbsp;Ting Wu","doi":"10.24976/Discov.Med.202335175.19","DOIUrl":"https://doi.org/10.24976/Discov.Med.202335175.19","url":null,"abstract":"<p><strong>Background: </strong>The therapeutic outcomes for acute ischemic stroke (AIS) with early neurological deterioration (END) are adverse. Argatroban is a novel direct thrombin inhibitor, which is safe in the treatment of AIS, but its efficacy is controversial. This study sought to assess the therapeutic effect of argatroban as an adjunct to aspirin in the treatment of AIS patients with END. Patients' prognosis for the presence of END was also evaluated.</p><p><strong>Methods: </strong>Overall, 166 AIS patients with END were included in the study from June 2018 to June 2021 in The Affiliated Zhangjiagang Hospital of Soochow University. Patients were divided in the control group (aspirin alone) and the study group (aspirin combined with argatroban). General data of the patients were collected. Clinical indexes such as the modified Edinburgh-Scandinavian stroke scale (MESSS), and the serum fibrinogen (FIB) and neuropeptide Y (NPY) levels before and after treatment were also collected. Correlations between prognosis and general data, and FIB and NPY levels in AIS patients with END were analyzed by multivariate logistic regression. The performance of FIB and NPY levels in predicting patients' prognosis was further analyzed using receiver operating characteristic (ROC) curves.</p><p><strong>Results: </strong>There was no significant difference in the general data, such as sex, age, course of disease and basic diseases between the 2 groups. After treatment, the MESSS score (13.08 ± 3.24 vs. 16.48 ± 3.32, <i>p</i> < 0.001), serum FIB level (2.72 ± 0.81 vs. 3.52 ± 0.71, <i>p</i> < 0.001), and NPY level (121.28 ± 17.34 vs. 152.09 ± 18.25, <i>p</i> < 0.001) of the study group was significantly lower than that of the control group. A further analysis revealed that the serum FIB (OR, odds ratio = 2.296, 95% confidence interval, CI: 1.437-3.669, <i>p</i> = 0.001) and NPY (OR = 1.020, 95% CI: 1.002-1.039, <i>p</i> = 0.031) levels were independent risk factors of patients' prognosis for the presence of END.</p><p><strong>Conclusions: </strong>Aspirin combined with argatroban significantly improved neurological impairment of AIS patients with END, which is worthy of clinical application.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":"35 175","pages":"185-192"},"PeriodicalIF":1.4,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9442981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}