Anti-N-methyl-D-aspartate receptor-associated encephalitis: A review of clinicopathologic hallmarks and multimodal imaging manifestations

Anti-N-methyl-D-aspartate receptor-associated encephalitis(NMDARE)is a rare immune-mediated neuroinflammatory condition characterized by the rapid onset of neuropsychiatric symptoms and autonomic dysfunction.The mechanism of pathogenesis remains incompletely understood,but is thought to be related to antibodies targeting the GluN1 subunit of the NMDA receptor with resultant downstream dysregulation of dopaminergic pathways.Young adults are most frequently affected;the median age at diagnosis is 21 years.There is a strong female predilection with a female sex predominance of 4:1.NMDARE often develops as a paraneoplastic process and is most commonly associated with ovarian teratoma.However,NMDARE has also been described in patients with small cell lung cancer,clear cell renal carcinoma,and other benign and malignant neoplasms.Diagnosis is based on correlation of the clinical presentation,electro-encephalography,laboratory studies,and imaging.Computed tomography,positron emission tomography,and magnetic resonance imaging are essential to identify an underlying tumor,exclude clinicopathologic mimics,and predict the likelihood of long-term functional impairment.Nuclear imaging may be of value for prognostication and to assess the response to therapy.Treatment may involve high-dose corticosteroids,intravenous immunoglobulin,and plasma exchange.Herein,we review the hallmark clinicopathologic features and imaging findings of this rare but potentially devastating condition and summarize diagnostic criteria,treatment regimens,and proposed pathogenetic mechanisms.

Flexibility in the order of action and in the enzymology of the nuclease, polymerases, and ligase of vertebrate non-homologous DNA end joining： relevance to cancer, aging, and the immune system

加入的 Nonhomologous 脱氧核糖核酸结束(NHEJ ) 是为在人的房间并且在多细胞的优核质的双海滨脱氧核糖核酸裂缝的修理的主要小径。双海滨裂缝的原因经常碎裂在损坏的地点的脱氧核糖核酸，导致在那里的信息的损失。NHEJ 不恢复失去的信息并且可以将切除另外的核苷酸在修理过程期间。修理大量 overhang 并且损坏配置的能力反映 NHEJ 的核酸酶，聚合酶，和连接酶的灵活性。单个部件的灵活性也解释 NHEJ 能在修理脱氧核糖核酸结束的任何给定的对的方法的大数字。局部地，在 NHEJ 的地点，修理可以贡献癌症和老化的信息的损失，而是由 NHEJ 的行动保证染色体的全部片断没被失去。

Hepatic angiosarcoma with clinical and histological features of Kasabach-Merritt syndrome

Hepatic angiosarcoma is a mesenchymal tumor originating from liver sinusoidal endothelial cells. It is an extremely rare malignant neoplasm accounting for less than 1% of primary malignant liver tumors. The deregulated coagulopathy that can be seen in hepatic angiosarcoma fulfills the clinical diagnostic criteria of disseminated intravascular coagulation. However, the mechanism that governs this coagulopathy has been poorly understood. This case report provides histological evidence of the consumption of coagulation factors along with trapped platelets occurring within the tumor, which is the foundation for the concept of Kasabach-Merritt syndrome(KMS). KMS is characterized by thrombocytopenia and hyperconsumption of coagulation factors within a vascular tumor. However, KMS associated with angiosarcoma has not been well recognized. This case report describes, for the first time, the histological evidence of KMS that occurred in an extremely rare mesenchymal malignant tumor of the liver.

Thoracic epidural angiolipoma: A case report and review of the literature

Angiolipoma of the spine is a benign neoplasm consisting of both mature fatty tissue and abnormal vascular elements, and usually presents with a slow progressive clinical course. Our patient presented with bilateral lower extremity weakness and chest-back numbness. Physical examination revealed adipose elements superficial hypesthesia below the T5 level and analgesia below the T6 level. Magnetic resonance imaging (MRI) scan showed an avidly and heterogeneously enhancing mass which was located in the posterior epidural space. Compression of the thoracic cord by the fusiform mass was seen between T3-T4. During the operation, a flesh pink vascular mass (4.7 cm × 1.0 cm × 1.0 cm) with obscure margin and strong but pliable texture was found in the posterior epidural space extending from T3 to T4. There was no infiltration of the dura or the adjacent bony spine. Histopathological study of the surgical specimen showed a typical angiolipoma. We review the previously documented cases of spinal extradural angiolipomas performed with MRI.

Pathophysiology and treatment of Barrett's esophagus

Gastroesophageal reflux disease (GERD) affects an estimated 20% of the population in the United States. About 10%-15% of patients with GERD develop Barrett’s esophagus, which can progress to adenocarcinoma, currently the most prevalent type of esophageal cancer. The esophagus is normally lined by squamous mucosa, therefore, it is clear that for adenocarcinoma to develop, there must be a sequence of events that result in transformation of the normal squamous mucosa into columnar epithelium. This sequence begins with gastroesophageal reflux, and with continued injury metaplastic columnar epithelium develops. This article reviews the pathophysiology of Barrett’s esophagus and implications for its treatment. The effect of medical and surgical therapy of Barrett’s esophagus is compared.

Regulators of liver cancer stem cells

Hepatocellular carcinoma(HCC)is a leading cause of cancer deaths.It is often detected at a stage when there are few therapeutic options.Liver cancer stem cells(LCSCs)are highly tumorigenic and resistant to chemotherapy and radiation therapy.Their presence in HCC is a major reason why HCC is difficult to treat.The development of LCSCs is regulated by a variety of factors.This review summarizes recent advances on the factors that regulate the development of LCSCs.Due to the importance of LCSCs in the development of HCC,a better understanding of how LCSCs are regulated will help to improve the treatments for HCC patients.

Selective Laser Trabeculoplasty Complicated by Cystoid Macular Edema:Report of Two Cases

Purpose: Selective laser trabeculoplasty,a relatively novel treatment for open angle glaucoma,is frequently associated with mild post-operative intraocular inflammation. Methods: We report two uncommon cases of cystoid macular edema within a few weeks of routine selective laser trabeculoplasty. Results:Visual acuities and macular thicknesses of the two cases returned to baseline after medical treatment,but in one case, the cystoid macular edema persisted for months. Conclusion:Cystoid macular edema after selective laser trabeculoplasty is fortunately a rare complication, but it might be more common in patients with predisposing factors, and it can be resistant to treatment.

Investigating evolutionary perspective of carcinogenesis with single-cell transcriptome analysis

We developed phase-switch microfluidic devices for molecular profiling of a large number of single cells.Whole genome microarrays and RNA-sequencing are commonly used to determine the expression levels of genes in cell lysates(a physical mix of millions of cells)for inferring gene functions.However,cellular heterogeneity becomes an inherent noise in the measurement of gene expression.The unique molecular characteristics of individual cells,as well as the temporal and quantitative information of gene expression in cells,are lost when averaged among all cells in cell lysates.Our single-cell technology overcomes this limitation and enables us to obtain a large number of single-cell transcriptomes from a population of cells.A collection of single-cell molecular profiles allows us to study carcinogenesis from an evolutionary perspective by treating cancer as a diverse population of cells with abnormal molecular characteristics.Because a cancer cell population contains cells at various stages of development toward drug resistance,clustering similar single-cell molecular profiles could reveal how drug-resistant subclones evolve during cancer treatment.Here,we discuss how single-cell transcriptome analysis technology could enable the study of carcinogenesis from an evolutionary perspective and the development of drugresistance in leukemia.The single-cell transcriptome analysis reported here could have a direct and significant impact on current cancer treatments and future personalized cancer therapies.

Cardiac adverse events of immune checkpoint inhibitors in oncology patients:A systematic review and meta-analysis

BACKGROUND Immune checkpoint inhibitors(ICIs)are novel therapeutic agents used for various types of cancer.ICIs have revolutionized cancer treatment and improved clinical outcomes among cancer patients.However,immune-related adverse effects of ICI therapy are common.Cardiovascular immune-related adverse events(irAEs)are rare but potentially life-threatening complications.AIM To estimate the incidence of cardiovascular irAEs among patients undergoing ICI therapy for various malignancies.METHODS We conducted this systematic review and meta-analysis by searching PubMed,Cochrane CENTRAL,Web of Science,and SCOPUS databases for relevant interventional trials reporting cardiovascular irAEs.We performed a single-arm meta-analysis using OpenMeta[Analyst]software of the following outcomes:Myocarditis,pericardial effusion,heart failure,cardiomyopathy,atrial fibrillation,myocardial infarction,and cardiac arrest.We assessed the heterogeneity using the I2 test and managed to solve it with Cochrane’s leave-one-out method.The risk of bias was performed with the Cochrane’s risk of bias tool.RESULTS A total of 26 studies were included.The incidence of irAEs follows:Myocarditis:0.5%[95%confidence interval(CI):0.1%-0.9%];Pericardial effusion:0.5%(95%CI:0.1%-1.0%);Heart failure:0.3%(95%CI:0.0%-0.5%);Cardiomyopathy:0.3%(95%CI:-0.1%-0.6%);atrial fibrillation:4.6%(95%CI:1.0%-14.1%);Myocardial infarction:0.4%(95%CI:0.0%-0.7%);and Cardiac arrest:0.4%(95%CI:0.1%-0.8%).CONCLUSION The most common cardiovascular irAEs were atrial fibrillation,myocarditis,and pericardial effusion.Although rare,data from post market surveillance will provide estimates of the long-term prevalence and prognosis in patients with ICIassociated cardiovascular complications.

在与含酒精的肝疾病联系的肠的 microbiome 的细菌的 translocation 和变化

Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability and changes the bacterial microflora. Liver disease severity correlates with levels of systemic bacterial products in patients, and experimental alcoholic liver disease is dependent on gut derived bacterial products in mice. Supporting evidence for the importance of bacterial translocation comes from animal studies demonstrating that intestinal decontamination is associated with decreased liver fibrogenesis. In addition, mice with a gene mutation or deletion encoding receptors for either bacterial products or signaling molecules downstream from these receptors, are resistant to alcohol-induced liver disease. Despite this strong association, the exact molecular mechanism of bacterial translocation and of how changes in the intestinal microbiome contribute to liver disease progression remains largely unknown. In this review we will summarize evidence for bacterial translocation and enteric microbial changes in response to alcoholic liver injury and chronic alcoholic liver disease. We will further describe consequences of intestinal dysbiosis on host biology. We finally discuss how therapeutic interventions may modify the gastrointestinal microflora and prevent or reduce alcoholic liver disease progression.

基于抗原修复技术的定量免疫组化:从实验、假说到研究计划

在人类历史上,自然科学的发展总是和新技术的发明密不可分。以形态学为例,17世纪,光学显微镜的发明使人们认识到细胞的存在。随后一系列的组织固定、包埋以及切片染色技术的研发,导致组织病理学的产生。

The development and function of follicular helper T cells in immune responses

Follicular helper T cells （Tfh） have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset development, like other lineages, is dependent on microenvironment where a particular transcriptional program is initiated. It has been shown that Bcl-6 and IL-21 act as master regulators for the development and function of Tfh cells. Tfh dysregulation is involved in the development of autoimmune pathologies, such as systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases. The present review highlights the recent advances in the field of Tfh cells and focus on their development and function.

Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation

Regulatory T cells(Tregs)play a pivotal role in immune-tolerance,and loss of Treg function can lead to the development of autoimmunity.Natural Tregs generated in the thymus substantially contribute to the Treg pool in the periphery,where they suppress self-reactive effector T cells(Teff)responses.Recently,we showed that OX40L(TNFSF4)is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation(CAP-independent)in the presence of low-dose IL-2.Therefore,we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg(tTreg)development.Development of tTregs is a two-step process:Strong T-cell receptor(TCR)signals in combination with co-signals from the TNFRSF members facilitate tTreg precursor selection,followed by a TCR-independent phase of tTreg development in which their maturation is driven by IL-2.Therefore,we investigated whether OX40 signaling could also play a critical role in the TCR-independent phase of tTreg development.OX40−/−mice had significantly reduced numbers of CD25−Foxp3low tTreg precursors and CD25+Foxp3+mature tTregs,while OX40L treatment of WT mice induced significant proliferation of these cell subsets.Relative to tTeff cells,OX40 was expressed at higher levels in both murine and human tTreg precursors and mature tTregs.In ex vivo cultures,OX40L increased tTreg maturation and induced CAP-independent proliferation of both murine and human tTregs,which was mediated through the activation of AKT-mTOR signaling.These novel findings show an evolutionarily conserved role for OX40 signaling in tTreg development and proliferation,and might enable the development of novel strategies to increase Tregs and suppress autoimmunity.

Identification and targeting of CD22ΔE12 as a molecular RNAi target to overcome drug resistance in high-risk B-lineage leukemias and lymphomas

Aim:CD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia(BPL)cells.The purpose of the present study was to identify the CD22ΔE12-specific signature transcriptome in human BPL cells and evaluate the clinical potential of a nanoscale formulation of CD22ΔE12-siRNA as an RNAi therapeutic against drug-resistant BPL.CD22ΔE12-siRNA nanoparticles significantly improved the event-free survival(EFS)outcome of NOD/SCID(NS)mice challenged with human BPL xenograft cells.Methods:Gene expression and translational bioinformatics methods were applied to examine the expression of the CD22ΔE12-specific signature transcriptome in human BPL cells in subsets of BPL patients.Survival analysis for mice challenged with BPL cells and treated with CD22ΔE12 siRNA was performed using standard methods.Results:Leukemia cells from CD22ΔE12-Tg mice exhibit gene and protein expression profiles consistent with constitutive activation of multiple signaling networks,mimicking the profiles of relapsed BPL patients as well as newly diagnosed high-risk patients with BCR-ABL+/Philadelphia chromosome(Ph)+BPL as well as Ph-like BPL.A nanoscale formulation of CD22ΔE12-siRNA abrogated the in vivo clonogenicity of the leukemia-initiating leukemic cell fraction in xenograft specimens derived from patients with relapsed BPL and significantly improved the EFS outcome of NS mice challenged with drug-resistant human BPL xenograft cells.Conclusion:The CD22-RNAi technology is applicable to all BPL patients both high risk and standard risk.That is because CD22ΔE12 is a characteristic feature of drug-resistant leukemic clones that escape chemotherapy and cause relapse in both high risk and low risk subgroups of patients.The technology therefore has the potential(1)for prevention of relapses by selectively killing the clones that are most likely to escape chemotherapy and cause relapse as well(2)for treatment of relapses in BPL.This research project may also lead to innovative salvage regimens against other forms of CD22ΔE12-positive relapsed B-lineage leukemias and lymphomas.

Celebrating the work of Nobel Laureate Paul Modrich

On October 7,2015,the Nobel Prize Committee announced that the 2015 Nobel Prize in Chemistry had been awarded jointly to Professors Paul Modrich,Tomas Lindahl and Aziz Sancar(Figure 1),each of whom made ground-breaking discoveries about the molecular mechanisms of DNA Repair.In one of life’s unpredictable turns,Paul was among the last individuals in his entire personal,professional

Caseous mitral annular calcifications: Multimodality imaging characteristics

The authors report herein a series of 3 patients with caseous mitral annular calcifications (MAC). One of the patients presented with mass-like, caseous MAC as an incidental finding on a staging computed tomography (CT) for metastatic colorectal carcinoma. Another patient presented with a nodule on a chest radiograph, which was later found on CT to be due to caseous MAC. In the third patient, caseous MAC was initially detected on echocardiography, and was further evaluated with CT and cardiac magnetic resonance imag-ing. In all three patients, the appearances posed a diagnostic dilemma. The appearance of caseous MAC is dissimilar to non-caseous MAC and is usually seen as an ovoid, mass-like structure, with homogeneous hyperattenuation, representing a liquefied form of calcium and proteinaceous fluid. This homogeneous center is surrounded by peripheral, shell-like calcifications. Caseous MAC is likely an under-recognized entity and may present a diagnostic dilemma at CT, magnetic resonance imaging, or echocardiography.

Electronic cigarettes — myocardial infarction, hemodynamic compromise during pregnancy, and systolic and diastolic dysfunction: Minireview

The aim of this study was to review the most recent literature on the safety of electronic cigarettes(ECs)in the context of cardiovascular disease and in the context as a tool for smoking cessation and recreational purposes.The format of this review begins with relevant research from the basic sciences and follows through with a pertinent review of clinical trials.Daily use of ECs has implications in myocardial infarction(MI)with an odds ratio of 1.70 compared to healthy,nonsmokers and even worse risk for MI with dual use of combustible cigarettes together with EC with an odds ratio of 4.62.Studies measuring cardiac function with echocardiography reported both systolic and diastolic dysfunction along with reduced ejection fractions.Platelet aggregation,endothelial function,and hemodynamics during pregnancy were all but some of the pernicious cardiovascular implications of EC exposure.Though more studies need to be done on the topic of EC use and cardiovascular disease,the majority of studies considered in this review concluded some level of harm albeit in some instances less than that of traditional combustible cigarettes.ECs are toxic to human beings and their harmful effects cannot be overlooked.There is some favorable evidence of efficacy in smoking cessation though mixed with concern of chronic EC use.It will take decades to collect data for chronic EC use on long term sequelae,such as lung cancer.Though more and more reports of acute lung injury and hospitalizations related to EC use have been reported.Due to undergoing investigations of possible harm and life threatening complications of EC use,we cannot recommend ECs as safer or a more efficacious method of smoking cessation to traditional nicotine replacement therapies.A notable consideration for much of the literature reviewed are that standardization of EC use is difficult as device generation and battery voltage,frequency of use,and contents of ECliquid are just some of the vast complicating factors that limit the ability to effectively compare data.

有病理学的破裂的 humeri 的双边的主要黄瘤: 一份案例报告

Xanthomas are rare bone tumors that occur more often in the appendicular skeleton and typically appear radiographically benign,with a narrow zone of transition and a sclerotic rim.We report the case of a 57-year-old woman with hyperlipidemia presenting with bilateral shoulder pain after minor trauma.Radiographic and histopathologic investigation demonstrated intraosseous xanthoma with atypical features,including multifocality,a wide zone of transition and pathologic fractures-characteristics more commonly associated with aggressive lesions such as multiple myeloma or metastasis.The diagnosis,imaging,and histological appearance of xanthoma of bone are reviewed.

On the horizon:Hedgehog signaling to heal broken bones

Uncovering the molecular pathways that drive skeletal repair has been an ongoing challenge. Initial efforts have relied on in vitro assays to identify the key signaling pathways that drive cartilage and bone differentiation. While these assays can provide some clues, assessing specific pathways in animal models is critical. Furthermore, definitive proof that a pathway is required for skeletal repair is best provided using genetic tests. Stimulating the Hh(Hedgehog) pathway can promote cartilage and bone differentiation in cell culture assays. In addition, the application of HH protein or various pathway agonists in vivo has a positive influence on bone healing. Until recently, however, genetic proof that the Hh pathway is involved in bone repair has been lacking. Here, we consider both in vitro and in vivo studies that examine the role of Hh in repair and discuss some of the challenges inherent in their interpretation. We also identify needed areas of study considering a new appreciation for the role of cartilage during repair, the variety of cell types that may have differing roles in repair, and the recent availability of powerful lineage tracing techniques. We are optimistic that emerging genetic tools will make it possible to precisely define when and in which cells promoting Hh signaling can best promote skeletal repair, and thus, the clinical potential for targeting the Hh pathway can be realized.