Treatment strategies for hypertension in patients with type 1 diabetes

ABSTRACT

Introduction

Type 1 diabetes mellitus (T1DM) is a chronic, autoimmune disease that is characterized by total absence of insulin production. Hypertension is a common comorbidity in T1DM with complex pathophysiology, while it is also a well-recognized risk factor for the development of cardiovascular disease (CVD), as well as other microvascular diabetic complications.     

胸腔镜下心包厚壁囊肿切除术1例报告

面对来势汹汹的新型冠状病毒肺炎(COVID-19),如何能够正确、快速诊断和筛检出确诊病例显得尤为重要,国内诸多科技工作者都在积极开展相关的诊断试验研究。本文回顾了目前正在开展的十余项诊断试验的注册信息,针对其中存在的共性问题进行了讨论,重点阐述了如何使用PICOS原则构造COVID-19诊断试验的研究问题,还对金标准的设置、受试者的代表性、样本量计算和同步、独立、盲法的测定等诊断试验的设计要点进行了详细说明。旨在为广大研究者提供开展COVID-19诊断试验的设计建议,帮助研究者在顶层设计阶段减少、避免偏倚,完成高质量的临床研究,为临床诊疗提供循证医学证据。     

Low-dose all-trans retinoic acid enhances cytotoxicity of cisplatin and 5-fluorouracil on CD44+ cancer stem cells

Cis-diamminedichloridoplatinum(II)(CDDP)-based combination chemotherapy is frequently used in gastrointestinal cancer. The synergistic mechanism of all-trans retinoic acid (ATRA), cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear. Despite their potent antitumor properties, resistance to CDDP and 5-FU develops frequently in tumors. To clarify this mechanism, we determined the sensitivity to each drug and their combination in two gastrointestinal cancer stem cells (CSCs) subpopulation.Here, we report the identification and separation of CD44⁺ cells from human gastric carcinoma (AGS) and human esophageal squamous cell carcinoma (KYSE-30) cancer cell lines by magnetic activated cell sorting (MACS). We allowed the CD44^± cells to grow 6 days at a subtoxic concentration of ATRA and then treated with different concentration of CDDP and 5-FU for 24 h. The cytotoxicity was examined by cell proliferation MTT assay. Additionally, AO/EB staining was used for detection of apoptotic cells. In order to determine whether the growth inhibition was also associated with changes in cell cycle distribution, cell cycle analysis was performed using flow cytometry.Low concentration of ATRA (1 μM, 6days) followed by 5-FU and CDDP was found to be more effective than either drugs alone, thus resulting in synergistic cytotoxicity in Kyse-30 and AGSCD44^± cells. Furthermore, there was an indication that the combination of ATRA with 5FU and CDDP caused an increase in cell cycle arrest in G2/M and G0/G1.We conclude that low concentration of ATRA enhances the cytotoxicity of CDDP and 5FU by facilitating apoptosis and cell cycle arrest in gastrointestinal CSCs and provide a rational basis for the design of novel, well-tolerated CDDP- and 5FU-based chemotherapy in human gastrointestinal carcinoma.     

Pharmacotherapeutic strategies for critical asthma syndrome: a look at the state of the art

ABSTRACT

Introduction

‘Critical Asthma Syndrome’ (CAS) is an umbrella term proposed to include several forms of asthma, responsible for acute and life-threatening exacerbations. CAS requires urgent and adequate supportive and pharmacological treatments to prevent serious outcomes.     

体外转染Cyclin A2基因对原代大鼠心肌细胞增殖的影响

目的探讨体外转染细胞周期素A2(Cyclin A2)基因对原代大鼠心肌细胞增殖的影响,为心脏再生提供细胞学依据。方法 SD乳鼠12只,分离、培养、鉴定原代乳鼠心肌细胞并分为3组,实验组:转染带有强化绿色荧光蛋白(GFP)和Cyclin A2基因的重组腺病毒(Ad-Cyclin A2-GFP);空病毒组:转染不含目的基因带有GFP的重组腺病毒(Ad-Null-GFP);阴性对照组:未做转染处理,仅加入等量的培养基。利用GFP示踪技术,评估原代心肌细胞转染效率;转染后的细胞继续体外培养3~5d,利用免疫荧光技术分别检测Cyclin A2、磷酸化组蛋白H3(H3P)、心肌肌钙蛋白-T(c Tn T)。结果 1.荧光GFP示踪表明原代心肌细胞的转染效率高达(97±0.74)%;2.免疫荧光标记显示,空病毒组和对照组结果相似;心肌细胞特异性标记蛋白c Tn T分布于细胞质,原代心肌细胞纯度高达(95±0.62)%;心肌细胞Cyclin A2主要在胞核内聚集,少数分布于细胞质。H3P为核蛋白在细胞核内分布。3.转染Cyclin A2后,实验组H3P阳性率明显高于空病毒组和对照组,差异具有统计学意义(P0.05);实验组可见大量多核细胞,以双核为主,伴少量3核细胞。结论腺病毒作为转染载体对原代心肌细胞有很好的侵染效率;Cyclin A2超表达促进原代心肌细胞形成双核。     

低密度脂蛋白在2型糖尿病骨质疏松中的作用研究进展

2型糖尿病及骨质疏松已成为我国最主要的慢性代谢性疾病。2型糖尿病常伴有血脂紊乱，常表现为低密度脂蛋白升高，而越来越多的研究表明血脂通过不同的方式影响骨代谢，其机制可能是通过抑制骨髓间充质干细胞成骨分化，通过RANK/RNAKL/OPG信号通路及炎症反应调节破骨细胞等方式调节骨代谢。     

Dissecting the biological heterogeneity of HER2-positive breast cancer

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.     

Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils

Ceramide synthases (CerS) synthesise ceramides of defined acyl chain lengths, which are thought to mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed a significant elevation of CerS2 and its products, C24-ceramides, in CD11b⁺ cells (monocytes and neutrophils) isolated from blood. This result correlates with the clinical finding that CerS2 mRNA expression and C24-ceramide levels were significantly increased by 2.2- and 1.5-fold, respectively, in white blood cells of MS patients. The increased CerS2 mRNA/C24-ceramide expression in neutrophils/monocytes seems to mediate pro-inflammatory effects, since a specific genetic deletion of CerS2 in blood cells or a total genetic deletion of CerS2 significantly delayed the onset of clinical symptoms, due to a reduced infiltration of immune cells, in particular neutrophils, into the central nervous system. CXCR2 chemokine receptors, expressed on neutrophils, promote the migration of neutrophils into the central nervous system, which is a prerequisite for the recruitment of further immune cells and the inflammatory process that leads to the development of MS. Interestingly, neutrophils isolated from CerS2 null EAE mice, as opposed to WT EAE mice, were characterised by significantly lower CXCR2 receptor mRNA expression resulting in their reduced migratory capacity towards CXCL2. Most importantly, G-CSF-induced CXCR2 expression was significantly reduced in CerS2 null neutrophils and their migratory capacity was significantly impaired. In conclusion, our data strongly indicate that G-CSF-induced CXCR2 expression is regulated in a CerS2-dependent manner and that CerS2 thereby promotes the migration of neutrophils, thus, contributing to inflammation and the development of EAE and MS.