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

Nonhomologous DNA end joining （NHEJ） is the primary pathway for repair of double-strand DNA breaks in human cells and in multicellular eukaryotes. The causes of double-strand breaks often fragment the DNA at the site of damage, resulting in the loss of information there. NHEJ does not restore the lost information and may resect additional nucleotides during the repair process. The ability to repair a wide range of overhang and damage configurations reflects the flexibility of the nuclease, polymerases, and ligase of NHEJ. The flexibility of the individual components also explains the large number of ways in which NHEJ can repair any given pair of DNA ends. The loss of information locally at sites of NHEJ repair may contribute to cancer and aging, but the action by NHEJ ensures that entire segments of chromosomes are not lost.

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.

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.

Use of a naturally occurring codon bias for identifying topoisomerase mutations in ciprofloxacin resistant <i>Escherichia coli</i>using PCR and future prospects with other bacterial genera: A pilot study

We developed a novel PCR method aimed at identi- fying and amplifying native codon sequences of muta- tion-prone amino acids in DNA gyrase implicated in quinolone resistance using a naturally occurring co- don bias in E. coli DNA gyrase A.

Childhood opportunity and appropriate use of child safety restraints in motor vehicle collisions

Objectives Safety restraints reduce injuries from motor vehicle collisions(MVCs)but are often improperly applied or not used.The Childhood Opportunity Index(COI)reflects social determinants of health and its study in pediatric trauma is limited.We hypothesized that MVC patients from low-opportunity neighborhoods are less likely to be appropriately restrained.Methods A retrospective cross-sectional study was performed on children/adolescents≤18 years old in MVCs between January 1,2011 and December 31,2021.Patients were identified from the Children's Hospital Los Angeles trauma registry.The outcome was safety restraint use(appropriately restrained,not appropriately restrained).COI levels by home zip codes were stratified as very low,low,moderate,high,and very high.Multivariable regression controlling for age identified factors associated with safety restraint use.Results Of 337 patients,73.9%were appropriately restrained and 26.1%were not appropriately restrained.Compared with appropriately restrained patients,more not appropriately restrained patients were from low-COI(26.1%vs 20.9%),high-COI(14.8%vs 10.8%)and very high-COI(10.2%vs 3.6%)neighborhoods.Multivariable analysis demonstrated no significant associations in appropriate restraint use and COI.There was a non-significant trend that children/adolescents from moderate-COI neighborhoods were more likely than those from very low-COI neighborhoods to be appropriately restrained(OR=1.82,95%CI 0.78,4.28).Conclusion Injury prevention initiatives focused on safety restraints should target families of children from all neighborhood types.

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。

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.

410例核间性眼肌麻痹患者中114例的罕见病因

Internuclear ophthalmoplegia (INO) is a sign of exquisite localizing value, of ten due to either multiple sclerosis or infarction. To demonstrate that unusual causes of INO are more common than the 11%reported in previous series, this rev iew considers a case series of 410 inpatients whom I personally examined during a 33-year period. In this series, the cause of INO was infarction in 157 patien ts (38%), multiple sclerosis in 139 (34%), and unusual causes in 114 (28%). U nusual causes included trauma (20 cases), tentorial herniation (20 cases), infec tion (17 cases), tumor (17 cases), iatrogenic injury (12 cases), hemorrhage (13 cases), vasculitis (7 cases), and miscellaneous (8 cases). Internuclear ophthalm oplegia was unilateral in 136 of the infarct cases (87%), 38 of those with mult iple sclerosis (27%), and 48 of the unusual cases (42%). Because unusual cause s compose more than one quarter of the cases, the differential diagnosis of INO should be tripartite: multiple sclerosis, stroke, and other causes.

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 Re- pair. In one of life＇s unpredictable turns, Paul was among the last individuals in his entire personal, professional and social network to learn of the Committee＇s decision, be- cause Paul was very far ＂off-the-grid＂ at the time of the announcement. The news that he had been selected as a 2015 Nobel Laureate may have taken Paul by surprise, but it certainly was not a surprise to most, if not all, of Paul＇s colleagues, students, family and friends.

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.

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.

Factors Leading to a Dramatic Fall in Coronary Heart Disease Death Rates in Los Angeles County

This paper provides commentary on some of the factors leading to a dramatic fall in heart disease death rates and the 42-year period (1968-2010) documented on the accompanying table.

腹腔镜下附件手术使用Oxiplex/AP凝胶减少术后粘连的初步研究

Objective: To determine whether Oxiplex/AP Gel (FzioMed, San Luis Obispo, CA) was safe and preliminarily effective in reducing postsurgical adhesions after adnexal surgery by laparoscopy. Design: Prospective, multicenter, double-blind, randomized, U.S. Food and Drug Administration-monitored feasibility study. Setting: University and private clinics. Patient (s): Patients undergoing laparoscopic surgery with pelvic adhesions, tubal occlusion, endometriosis, and/or dermoids were randomized to receive Oxiplex/AP Gel or no further treatment after surgery. Intervention(s): A blinded, parallelgroup design was conducted at six centers. Patients (aged 18-46 years) underwent laparoscopic surgery, with secondlook surgery 6-10 weeks later. Surgeries were videotaped. Oxiplex/AP Gel was used to cover adnexa and adjacent tissue. Main Outcome Measure(s): Blinded reviews of videotapes were quantitated with the American Fertility Society adhesion score (AFS score). Result(s): In 18 treatment patients, surgery was performed on 29 adnexa. Application of Oxiplex/AP Gel required approximately 90 seconds. In 10 control patients, surgery was performed on 18 adnexa. The mean baseline AFS score for each group was 8.0. At second look, treated adnexa had the same score (8.1), whereas in control adnexa the score increased (from 8.0 to 11.6). Thirty-four percent of treated adnexa increased in adhesion score, in contrast to 67%of control adnexa. There were no device-related adverse events. Conclusion(s): In this pilot study, Oxiplex/AP Gel was safe, easy to use with laparoscopy, and produced a reduction in the increase of adnexal adhesion scores.

免疫组织化学展望

尽管免疫组织化学技术发明于20世纪40年代，但用于甲醛固定石蜡包埋组织切片的历史仅有30余年。一系列的技术发明，包括在酶标记抗体的基础上开发各种高敏感性检测系统（如PAP，ABC等），单克隆抗体的问世以及蛋白酶消化修复部分抗原等，为免疫组织化学技术用于石蜡切片提供了有利条件。在1991年以前，免疫组织化学技术已部分用于病理诊断，并展现了充满希望的远景。

抗原修复技术研究进展

自从应用抗原修复技术的文章于1991年发表后，抗原修复技术（煮沸石蜡切片于水溶液中）迅速、广泛应用于常规甲醛固定、石蜡包埋组织切片的免疫组织化学染色，从而打开了从传统形态学迈向分子形态学的大门。抗原修复技术被誉为免疫组织化学技术的革命性突破旧。Gown在评价抗原修复技术所取得的成就时，指出“在过去十多年里，抗原修复技术在诊断性免疫组织化学分析方面造成了如此深远的影响，使得这方面的文献分为2个时代：抗原修复技术前与抗原修复技术后时代。20世纪90年代初抗原修复技术的问世就是这两个阶段的分水岭”。

Genetic and epigenetic alterations in hepatitis B virus-associated hepatocellular carcinoma

Hepatitis B virus(HBV) is a major cause of hepatocellular carcinoma(HCC). Its chronic infection can lead to chronic liver inflammation and the accumulation of genetic alterations to result in the oncogenic transformation of hepatocytes. HBV can also sensitize hepatocytes to oncogenic transformation by causing genetic and epigenetic changes of the host chromosomes. HBV DNA can insert into host chromosomes and recent large-scale whole-genome sequencing studies revealed recurrent HBV DNA integrations sites that may play important roles in the initiation of hepatocellular carcinogenesis. HBV can also cause epigenetic changes by altering the methylation status of cellular DNA, the post-translational modification of histones, and the expression of micro RNAs. These changes can also lead to the eventual hepatocellular transformation. These recent findings on the genetic and epigenetic alterations of the host chromosomes induced by HBV opened a new avenue for the development of novel diagnosis and treatments for HBV-induced HCC.

Clinical Updates in Primary Biliary Cholangitis:Trends,Epidemiology, Diagnostics, and New Therapeutic Approaches

Primary biliary cholangitis,formerly known as primary biliary cirrhosis,is a chronic,autoimmune,and cholestatic disease ameliorating the biliary epithelial system causing fibrosis and end-stage liver disease,over time.Patients range from an asymptomatic phase early in the disease course,to symp-toms of decompensated cirrhosis later in its course.This review focuses on the current consensus on the epidemiology,diagnosis,and management of patients with primary biliary cholangitis.We also discuss established medical manage-ment as well as novel and investigational therapeutics in the pipeline for management of PBC.

Oncogenic viruses and cancer

This special issue of the journal is dedicated to the important topic of oncogenic viruses and cancer.It contains seven review articles covering all known oncogenic viruses except for human T-lymphotropic virus type1(HTLV-1).These review articles are contributed by experts on specific viruses and their associated human cancers.Viruses account for about 20%of total human cancer cases.Although many viruses can cause various tumors in animals,only seven of them

抗原修复技术研究发展的新起点

7年多前，我们曾经受贵刊编辑部之邀发表过“抗原修复技术研究进展”一文。在那篇文章里，尽管已经有片言只语提到可以应用抗原修复技术原则从石蜡切片中提取蛋白质和核酸。但是，全文的主题与绝大部分内容还是局限在免疫组织化学染色的问题方面。转瞬过去的7年在后基因组时代的舞台上大放异彩，高通量检测数以千计的蛋白质组学分析技术的开发以及各种形形色色的蛋白质质谱分析技术的开发，在探讨人类疾病的多种相关生物标志物及其在诊断治疗上，正在扮演着先锋作用的重要角色。

DNA mismatch repair in trinucleotide repeat instability

Trinucleotide repeat expansions cause over 30 severe neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy type 1, and fragile X syndrome. Although previous studies have substantially advanced the understanding of the disease biology, many key features remain unknown. DNA mismatch repair(MMR) plays a critical role in genome maintenance by removing DNA mismatches generated during DNA replication. However, MMR components,particularly mismatch recognition protein MutSβ and its interacting factors MutLα and MutLγ, have been implicated in trinucleotide repeat instability. In this review, we will discuss the roles of these key MMR proteins in promoting trinucleotide repeat instability.