代谢综合征相关基因多态性与蒙古族寻常型银屑病的相关性及与HLA-C*06：02交互作用研究

【摘要】 目的 探讨代谢综合征相关基因多态性与蒙古族寻常型银屑病（PsV）的相关性及其与HLA-C*06：02的交互作用。方法 内蒙古医科大学附属医院2012年12月至2018年3月住院的379例蒙古族PsV患者及518例蒙古族健康对照。选择16个既往报道的与代谢综合征及其包含疾病相关的单核苷酸多态性（SNP）及HLA-C*06：02，利用二代测序法和聚合酶链反应-序列特异性引物（PCR-SSP）对受试者进行基因分型。计算蒙古族PsV组及对照组16个变异位点及HLA-C*06：02的最小等位基因频率，χ2检验比较两组各SNP位点的最小等位基因频率差异。结果 蒙古族PsV患者中16个代谢综合征易感SNP位点最小等位基因频率与健康对照比较，差异无统计学意义（均P > 0.05），而HLA-C*06：02位点的最小等位基因频率差异有统计学意义（P = 4.09 × 10-35，OR = 3.41）。HLA-C* 06：02阳性受试者中，252例PsV患者的rs7593730_T和rs6931514_G最小等位基因频率与191例健康对照相比差异有统计学意义（P = 0.016，OR = 0.64；P = 0.041，OR = 1.33）；而在HLA-C*06：02阴性受试者中，两组间16个SNP位点的最小等位基因频率差异均无统计学意义（P > 0.05）。结论 rs7593730和rs6931514与内蒙古地区蒙古族寻常型银屑病可能相关，与HLA-C*06：02可能存在交互作用。     

Endogenous contrast MRI of cardiac fibrosis: Beyond late gadolinium enhancement

The aim of this review is to provide an overview of detection of cardiac fibrosis with MRI using current standards and novel endogenous MRI techniques. Assessment of cardiac fibrosis is important for diagnosis, prediction of prognosis and follow‐up after therapy. During the past years, progress has been made in fibrosis detection using MRI. Cardiac infarct size can be assessed noninvasively with late gadolinium enhancement. Several methods for fibrosis detection using endogenous contrast have been developed, such as native T₁‐mapping, T_1ρ‐mapping, Magnetization transfer imaging, and T₂*‐mapping. Each of these methods will be described, providing the basic methodology, showing potential applications from applied studies, and discussing the potential and challenges or pitfalls. We will also identify future steps and developments that are needed for bringing these methods to the clinical practice. J. Magn. Reson. Imaging 2015;41:1181–1189. © 2014 Wiley Periodicals, Inc.     

Of men and mice: Human X-linked retinoschisis and fidelity in mouse modeling

X-linked Retinoschisis (XLRS) is an early-onset transretinal dystrophy, often with a prominent macular component, that affects males and generally spares heterozygous females because of X-linked recessive inheritance. It results from loss-of-function RS1 gene mutations on the X-chromosome. XLRS causes bilateral reduced acuities from young age, and on clinical exam and by ocular coherence tomography (OCT) the neurosensory retina shows foveo-macular cystic schisis cavities in the outer plexiform (OPL) and inner nuclear layers (INL). XLRS manifests between infancy and school-age with variable phenotypic presentation and without reliable genotype-phenotype correlations. INL disorganization disrupts synaptic signal transmission from photoreceptors to ON-bipolar cells, and this reduces the electroretinogram (ERG) bipolar b-wave disproportionately to photoreceptor a-wave changes. RS1 gene expression is localized mainly to photoreceptors and INL bipolar neurons, and RS1 protein is thought to play a critical cell adhesion role during normal retinal development and later for maintenance of retinal structure. Several independent XLRS mouse models with mutant RS1 were created that recapitulate features of human XLRS disease, with OPL-INL schisis cavities, early onset and variable phenotype across mutant models, and reduced ERG b-wave to a-wave amplitude ratio. The faithful phenotype of the XLRS mouse has assisted in delineating the disease pathophysiology. Delivery to XLRS mouse retina of an AAV8-RS1 construct under control of the RS1 promoter restores the retinal structure and synaptic function (with increase of b-wave amplitude). It also ameliorates the schisis-induced inflammatory microglia phenotype toward a state of immune quiescence. The results imply that XLRS gene therapy could yield therapeutic benefit to preserve morphological and functional retina particularly when intervention is conducted at earlier ages before retinal degeneration becomes irreversible. A phase I/IIa single-center, open-label, three-dose-escalation clinical trial reported a suitable safety and tolerability profile of intravitreally administered AAV8-RS1 gene replacement therapy for XLRS participants. Dose-related ocular inflammation occurred after dosing, but this resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in dose-dependent fashion, but no antibodies were observed against the RS1 protein. Retinal cavities closed transiently in one participant. Technological innovations in methods of gene delivery and strategies to further reduce immune responses are expected to enhance the therapeutic efficacy of the vector and ultimate success of a gene therapy approach.     

CCL3, CCL5, IL-15, IL-1Ra and VEGF compose a reliable algorithm to discriminate classes of adverse events following 17DD-YF primary vaccination according to cause-specific definitions

In the present study, a range of serum biomarkers were quantified in suspected cases of adverse events following YF immunization (YEL-AEFI) to propose a reliable laboratorial algorithm to discriminate confirmed YEL-AEFI (“A1” class) from cases with other illnesses (“C” class). Our findings demonstrated that increased levels of CXCL8, CCL2, CXCL10, IL-1β, IL-6 and TNF-α were observed in YEL-AEFI (“A1” and “C” classes) as compared to primary vaccines without YEL-AEFI [PV(day 3–28)] and reference range (RR) controls. Notably, increased levels of CCL3, CCL4, CCL2, CCL5, IL-1β, IL-15, IL-1Ra and G-CSF were found in “A1” as compared to “C” class. Venn diagrams analysis allowed the pre-selection of biomarkers for further analysis of performance indices. Data demonstrated that CCL3, CCL5, IL-15 and IL-1Ra presented high global accuracy (AUC = 1.00) to discriminate “A1” from “C”. Decision tree was proposed with a reliable algorithm to discriminate YEL-AEFI cases according to cause-specific definitions with outstanding overall accuracy (91%). CCL3, CCL5, IL-15 and IL-1Ra appears as root attributes to identify “A1” followed by VEGF as branch nodes to discriminate Wild Type YFV infection (“C(WT-YFV)”) from cases with other illnesses (“C*”). Together, these results demonstrated the applicability of serum biomarker measurements as putative parameters towards the establishment of accurate laboratorial tools for complementary differential diagnosis of YEL-AEFI cases.     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metformin Hydrochloride

Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin's Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transporter-mediated drug and is highly soluble, but only 50% of an orally administered dose is absorbed from the gut. Therefore, metformin is a BCS Class III substance. A BCS-based approval approach for major changes to marketed products and new generics is admissible if test and reference dosage forms have the identical active pharmaceutical ingredient and if in vitro dissolution from both are very rapid (i.e. at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Recent International Council for Harmonisation BCS guidance indicates all excipients for Class III biowaivers are recommended to be qualitatively the same and quantitatively similar (except for preservatives, flavor agents, colorant, or capsule shell or film coating excipients). However, despite metformin being a prototypical transporter-mediated drug, there is no evidence that commonly used excipients impact metformin absorption, such that this restriction on excipients for BCS III drugs merits regulatory relief. Commonly used excipients in usual amounts are not likely to impact metformin absorption.     

The role of nuclear factors as “Find-Me”/alarmin signals and immunostimulation in defective efferocytosis and related disorders

Efferocytosis as an apoptotic cell (AC) clearance mechanism facilitates the removal of dangerous and damaged cells, an important process in regulating normal homeostasis. Failure to correctly execute apoptosis and efferocytosis is associated with atherosclerosis, as well as chronic inflammatory and autoimmune disorders such as systemic lupus erythematosus (SLE). Effective and timely efferocytosis involves various molecules that act as “Find-Me” signals or as alarmins to quickly allow identification by phagocytic cells. In recent years, most of these molecules have been investigated, but less attention has been paid to the nuclear molecules associated with efferocytosis of ACs and necrotic cells (NCs). These molecules have several functions including acting as alarmin signals for faster recognition of ACs, facilitating the cleanup of ACs and for maintaining self-tolerance. The same group of molecules is also implicated in several inflammatory and autoimmune diseases. Previous studies have shown that these molecules also serve as targets for pharmacological agents such as necrostatins, recombinant Fcnb, anti-histone, neutralizing antibodies, calbiochem, aminophylline, activated protein C, CD24IgG recombinant fission protein, and recombinant thrombomodulin. Thus, greater understanding of these molecules/pathways will enable developments in the treatment and/or prevention of various disorders, especially autoimmune diseases. Here, we review current knowledge about the mechanisms by which nucleic acids, histones, nucleosomes and monosodium urate microcrystals (MSU) can act as alarmins/“Find-Me” signals, how they might be stimulated in defective efferocytosis and their function and importance as biomarkers for prognosis and treatment of atherosclerosis, inflammatory disorders and autoimmune diseases.     

Crosstalk among colon cancer-derived exosomes,fibroblast-derived exosomes,and macrophage phenotypes in colon cancer metastasis

Cellular crosstalk is an important mechanism in the pathogenesis of inflammatory disorders and cancers. One significant means by which cells communicate with each other is through the release of exosomes. Exosomes are extracellular vesicles formed by the outward budding of plasma membranes, which are then released from cells into the extracellular space. Many studies have suggested that microvesicles released by colon cancer cells initiate crosstalk and modulate the fibroblast activities and macrophage phenotypes. Interestingly, crosstalk among colon cancer cells, macrophages and cancer-associated fibroblasts maximizes the mechanical composition of the stromal extracellular matrix (ECM). Exosomes contribute to cancer cell migration and invasion, which are critical for colon cancer progression to metastasis. The majority of the studies on colorectal cancers (CRCs) have focused on developing exosomal biomarkers for the early detection and prediction of CRC prognosis. This study highlights the crosstalk among colon cancer-derived exosomes, macrophage phenotypes and fibroblasts during colon cancer metastasis.