Maximizing intelligence obtained from higher-order DNA mixtures from volume crime samples

ABSTRACT

This work collates data from the analysis of complex mixtures analysed in STRmix during routine no-suspect volume crime work. It interrogates the upload rate for these types of mixtures and which component of the profile has been able to be interpreted for upload. The number of profiles giving multiple uploads and the amount of replicate PCR analysis has been collated.     

TLR9在不同胎龄新生儿脐血中的表达变化

目的 通过观察早产儿不同胎龄Toll样受体9（TLR9）的表达，探讨早产儿免疫功能低下的机制。方法 采集2010年7月至2014年6月在上海市嘉定区妇幼保健院产科出生的活产新生儿的脐血229份，按胎龄分为4组，28~31周组，31~34周组，34~37周组，≥37周组，采用流式细胞术和实时荧光定量PCR方法，分别检测其TLR9的蛋白和mRNA表达情况，了解其与胎龄之间的关系，并分析mRNA和蛋白表达间的相关性。结果 TLR9阳性细胞率在28~31周组，31~34周组，34~37周组，≥37周组分别为（15.93±6.23）%，（11.63±6.70）%，（13.66±6.88）%，（20.51±12.06）%；其在胎龄28~31周较高，至31~34周逐渐下降至最低，两组差异有统计学意义（P<0.05）；34~37周后TLR9阳性细胞率表达逐渐升高，至≥37周达最高，两胎龄组比较，差异具有统计学意义（P<0.05）。31~37周间新生儿脐血TLR9阳性细胞率与胎龄呈正相关（r=0.273，P=0.006）。TLR9 mRNA表达在28~31周组，31~34周组，34~37周组，≥37周组分别为（4.95±3.44）%，（8.89±8.49）%，（13.91±10.92）%，（7.19±7.11）%；其在28~36周逐渐升高，与胎龄呈正相关（r=0.355，P< 0.001）。≥37周TLR9 mRNA表达量下降，该值虽高于28~31周，但差异无统计学意义（P>0.05）。相关性分析表明，同胎龄时期同样本新生儿的TLR9 mRNA和TLR9阳性细胞率之间存在负相关（r=-0.227，P=0.011）。结论 TLR9阳性细胞率和TLR9 mRNA表达在不同胎龄组新生儿间有差异，TLR9阳性细胞率表达在31~37周间随着胎龄的增加而增加，TLR9 mRNA在28~36周间随着胎龄的增加而增加。     

Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters

Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CL_h) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CL_h involving OATP1B-mediated hepatic uptake. CL_h can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CL_h and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction.     

Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

普通变异型免疫缺陷病合并肝硬化1例并文献复习

目的:讨论普通变异型免疫缺陷病(common variable immunodeficiency disease,CVID)的发病机制、临床表现及治疗方法。方法:报道1例普通变异型免疫缺陷病合并肝硬化患者并复习相关文献。结果:普通变异型免疫缺陷病是临床少见病,易误诊,病因不清,临床表现复杂,部分患者病程中可出现肝功能异常,甚至并发肝硬化。结论:临床反复感染的患者应考虑CVID的可能,须进一步作血浆免疫球蛋白的检测确诊。对已经确诊患者定期补充静脉丙种球蛋白,同时还应定期检查肝功能。     

Vaccination inhibits the human adenoviral transduction in a mouse keratoconjunctivitis model

Adenovirus infections are a major cause of epidemic keratoconjunctivitis (EKC), which can lead to corneal subepithelial infiltrates and multifocal corneal opacity. In the current study, we investigated the use of an E1/E3-deleted adenovirus serotype 5 (Ad5) vector as a vaccine administered intramuscularly (IM) or intranasally (IN) against subsequent challenges with a luciferase-expressing Ad5 (Ad5-Luci) vector via eyedrop. We evaluated the adaptive immune response to Ad5 vector vaccination and confirmed a robust polyfunctional CD8 T cell response in splenic cells. Neutralizing Ad5 antibodies were also measured in the sera of vaccinated mice as well as Ad5 antibody in the eye wash solutions. Upon challenge with Ad5-Luci vector 8 weeks post the primary immunization, transduction was significantly reduced by > 70% in the vaccinated mice, which was slightly better in IM- vs. that in IN-vaccinated animals. Resistance to subsequent challenge was observed 10 months post primary IM vaccination, with sustained reduction up to 60% in the Ad5-Luci vector transduction. Passive immunization of naive mice with antisera from IM to vaccinated mice subsequently challenged with the Ad5-Luci vector resulted in approximately 40% loss in transduction efficiency. Furthermore, the mice that received IM immunization with or without CD8 T cell depletion showed > 40% and 70% reductions, respectively, in Ad8 genomic copies after Ad8 topical challenge. We conclude that Ad-vector vaccination successfully induced an adaptive immune response that prevented subsequent Ad transduction in the cornea and conjunctiva-associated tissues in a mouse model of adenovirus keratoconjunctivitis, and that both cellular and humoral immunity play an important role in preventing Ad transduction.