Diagnostic dilemmas in HLH: Can T‐cell phenotyping help?

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) can be a difficult one, and the distinction between primary versus secondary HLH can be particularly challenging during the early stages of diagnosis. This distinction is important to make as primary HLH requires allogeneic hematopoietic cell transplantation for a definitive cure. Flow cytometric screening tests for many of the genetic forms of HLH are available. However, not all patients with primary HLH are captured by these screening tests, due to the fact that no screening test is 100% sensitive, and additionally, some patients with “primary” forms of HLH may have mutations in genes which are yet to be discovered. In this issue of the European Journal of Immunology, Ammann et al. [Eur. J. Immunol. 2017. 47 : 364–373] compare T‐cell phenotype patterns among patients with primary and secondary HLH, and find that assessment of T‐cell activation and differentiation may assist with the diagnosis of HLH. Furthermore, this phenotypic analysis has the potential to help make the important distinction between primary and secondary HLH.     

Immediate moxifloxacin hypersensitivity: Is there more than currently meets the eye?

Immediate drug hypersensitivity reactions (IDHR) to moxifloxacin constitute a pathomechanistic conundrum and a diagnostic challenge. Our objective was to study whether simultaneous phenotyping and quantification of histamine release might add to our knowledge about the basophil activation properties of moxifloxacin and constitute a reliable diagnostic aid. Fifteen patients with an IDHR to moxifloxacin and nine moxifloxacin challenged controls were selected. All had a basophil activation test (BAT) with moxifloxacin. Flow cytometric analysis of basophil responses implied labeling for CD63, CD203c, and intracellular histamine. Unlike tolerant challenged controls, basophilic upregulation of CD203c in response to moxifloxacin was observed in seven of 15 patients. Only two of these seven patients demonstrated appearance of CD63 and release of histamine. In the remainder eight patients, no basophil responses were demonstrable. In conclusion, immediate hypersensitivity to moxifloxacin might involve mechanisms difficult to capture by traditional CD63‐/CD203c‐based BAT. Deciphering the complexity of quinolone IDHR seems mandatory.     

A good manufacturing practice method to ex vivo expand natural killer cells for clinical use

BackgroundGreat interest has been raised recently by the design of new adoptive immunotherapeutic strategies based on the in vivo infusion of ex vivo-expanded and activated natural killer (NK) cells. The development of good manufacturing practice (GMP) methods for the efficient production of fully functional NK cells is mandatory for clinical application.ResultsNK-cell populations expanded on average 15.7±4.7 fold by day 14, with a viability of 96% ±0.5. At the end of the incubation period, 97% ±1.1 of the expanded population was CD56⁺ NK cells; these effector cells showed significant up-regulation of the activating receptors NKG2D and DNAM-1. Functional tests demonstrated that expanded NK cells are fully functional with no difference whether tested before cryopreservation or after thawing.DiscussionThese data provide the basis for developing new NK-cell-based immunotherapeutic strategies for the treatment of patients with cancer.     

同型半胱氨酸与H型高血压患者血小板活化的相关性及依叶的干预研究

【摘要】 目的 研究H型高血压患者血同型半胱氨酸水平与其体内血小板活化因子（CD41、CD62P）关系,及依那普利叶酸片对H型高血压患者血同型半胱氨酸与血小板活化因子（CD41、CD62P）的影响。方法 选取轻中度H型高血压患者200例,将其随机分为试验组和对照组各100例。试验组给予口服依那普利叶酸片,对照组给予口服依那普利,疗程均为3个月。治疗前后分别测量患者血压、超敏C反应蛋白、同型半胱氨酸、血小板活化因子（CD41、CD62P）。结果 治疗3个月后,与对照组相比,试验组平均动脉压（80.2±6.6 VS 81.6±8.1 mmHg）、超敏C反应蛋白（3.1±1.3 VS 3.7±1.5 mg/L）、血同型半胱氨酸（14.1±3.1 VS 20.2±4.4 umol/L）、血小板活化因子 CD41（47.5±4.1 VS 54.5±3.9%）、CD62P（18.5±3. 1 VS 23.6±3.8%）均下降,差异有统计学意义（P<0.05或P<0.01）。相关分析显示,血同型半胱氨酸水平与H型高血压患体内血小板活化因子呈正相关（CD41 r=0.61,P<005;CD62P r=0.55,P<005）。结论 高同型半胱氨酸可增加H型高血压患者体内血小板活化,依那普利叶酸片在降血压和降血浆同型半胱氨酸浓度的同时还可降低H型高血压患者炎症与血小板活化。与单纯依那普利治疗相比,依那普利叶酸片可更有效减少H型高血压患者心血管发病风险。     

Cyclophosphamide enhances anti-tumor effects of a fibroblast activation protein α-based DNA vaccine in tumor-bearing mice with murine breast carcinoma

Cyclophosphamide (CY) is a DNA alkylating agent, which is widely used with other chemotherapy drugs in the treatment of various types of cancer. It can be used not only as a chemotherapeutic but also as an immunomodulatory agent to inhibit IL-10 expression and T regulatory cells (Tregs). Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts in the tumor microenvironment. Immunotherapy based on FAPα, as a tumor stromal antigen, typically induces specific immune response targeting the tumor microenvironment. This study evaluated the efficacy of a previously unreported CY combination strategy to enhance the limited anti-tumor effect of a DNA vaccine targeting FAPα. The results suggested CY administration could promote the percentage of splenic CD8^+?T cells and decrease the proportion of CD4?⁺?CD25?⁺?Foxp3^+?Tregs in spleen. In tumor tissues, levels of immunosuppressive cytokines including IL-10 and CXCL-12 were also reduced. Meanwhile, the CY combination did not impair the FAPα-specific immunity induced by the DNA vaccine and further reduced tumor stromal factors. Most importantly, FAP-vaccinated mice also treated with CY chemotherapy showed a marked suppression of tumor growth (inhibition ratio =80%) and a prolongation of survival time. Thus, the combination of FAPα immunotherapy and chemotherapy with CY offers new insights into improving cancer therapies.     

Preparation,Characterization, and Rheological Behaviors of Polysiloxanes Presenting Densely Simple and Well‐Defined Short‐Branched Chains

In this paper, a series of polysiloxanes, presenting different contents of densely simple and well‐defined short‐branched chains (G₁–G₅), are prepared by hydrosilylation of α,ω‐(dimethylvinylsiloxy)‐poly(dimethyl‐methylvinyl)siloxanes (P₁–P₅) with 1,1,1,3,5,5,5‐heptamethyltrisiloxane (MD^HM) and characterized by ¹H and ²⁹Si nuclear magnetic resonance, Fourier transform‐infrared spectroscopy, Abbe refractometry, gel permeation chromatography, and differential scanning calorimetry. The rheological behaviors of the G₁–G₅ products are investigated to study the influences of the short‐branched chains. The rheological parameters including non‐Newtonian index (n ) and the flow activation energy (ΔE_η ) are obtained and discussed. It is observed that the G₁–G₅ polymers belonged to pseudoplastic fluids and the ΔE_η values of the G₁–G₅ products are significantly influenced by the short‐chain branching degree of the polymers.

     

A disease‐associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity

Mutations in G protein‐coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C‐terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N‐terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild‐type BAI2 primarily couples to Gα_z, with the R1465W mutation conferring increased coupling to Gα_i. The R1465W mutation also increases the total and surface expression of BAI2. The mutation has no effect on receptor binding to β‐arrestins, but does perturb binding to the endocytic protein endophilin A1, identified here as a novel interacting partner for BAI2. These studies provide new insights into the signaling capabilities of the adhesion GPCR BAI2/ADGRB2 and shed light on how an apparent gain‐of‐function mutation to the receptor's C‐terminus may lead to human disease.     

Role for coronin 1 in mouse NK cell function

Coronin 1, a member of the evolutionary conserved WD repeat protein family of coronin proteins is expressed in all leukocytes, but a role for coronin 1 in natural killer (NK) cell homeostasis and function remains unclear. Here, we have analyzed the number and functionality of NK cells in the presence and absence of coronin 1. In coronin 1-deficient mice, absolute NK cell numbers and phenotype were comparable to wild type mice in blood, spleen and liver. Following in vitro stimulation of the activating NK cell receptors NK1.1, NKp46, Ly49D and NKG2D, coronin 1-deficient NK cells were functional with respect to interferon-γ production, degranulation and intracellular Ca²⁺ mobilization. Also, both wild type as well as coronin 1-deficient NK cells showed comparable cytotoxic activity. Furthermore, activation and functionality of NK cells following Vesicular Stomatitis Virus (VSV) infection was similar between wild type and coronin 1-deficient mice. Taken together these data suggest that coronin 1 is dispensable for mouse NK cell homeostasis and function.     

转录因子YY1在妇科肿瘤和妊娠疾病中的作用

转录因子Ying-Yang1(YY1)是正常细胞和癌组织中普遍表达的多功能转录调控蛋白,其参与调控多种细胞正常生理过程,如胚胎发育、细胞骨架蛋白结构和功能、染色体失活和修复、肿瘤发生和浸润转移等过程,在生物体内发挥着重要作用.已有大量证明YY1在多种肿瘤中有异常表达,并通过多种途径调控肿瘤的增殖过程,如宫颈癌、乳腺癌、卵巢癌等,在某些癌症类型中YY1的高表达可提高患者生存预后.并且,近年来YY1在妊娠中的作用也备受关注,以下将重点就YY1的作用机制和在妇科肿瘤方面和妊娠疾病中的研究进展作一综述.     

Neural signatures of fairness‐related normative decision making in the ultimatum game: A coordinate‐based meta‐analysis

The willingness to incur personal costs to enforce prosocial norms represents a hallmark of human civilization. Although recent neuroscience studies have used the ultimatum game to understand the neuropsychological mechanisms that underlie the enforcement of fairness norms; however, a precise characterization of the neural systems underlying fairness‐related norm enforcement remains elusive. In this study, we used a coordinate‐based meta‐analysis on functional magnetic resonance imaging (fMRI) studies using the ultimatum game with the goal to provide an additional level of evidence for the refinement of the underlying neural architecture of this human puzzling behavior. Our results demonstrated a convergence of reported activation foci in brain networks associated with psychological components of fairness‐related normative decision making, presumably reflecting a reflexive and intuitive system (System 1) and a reflective and deliberate system (System 2). System 1 (anterior insula, ventromedial prefrontal cortex [PFC]) may be associated with the reflexive and intuitive responses to norm violations, representing a motivation to punish norm violators. Those intuitive responses conflict with economic self‐interest, encoded in the dorsal anterior cingulate cortex (ACC), which may engage cognitive control from a reflective and deliberate System 2 to resolve the conflict by either suppressing (ventrolateral PFC, dorsomedial PFC, left dorsolateral PFC, and rostral ACC) the intuitive responses or over‐riding self‐interest (right dorsolateral PFC). Taken together, we suggest that fairness‐related norm enforcement recruits an intuitive system for rapid evaluation of norm violations and a deliberate system for integrating both social norms and self‐interest to regulate the intuitive system in favor of more flexible decision making. Hum Brain Mapp 36:591–602, 2015. © 2014 Wiley Periodicals, Inc .