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This article focuses on abstracts of papers presented at the 32nd annual meeting of the American Society of Dermatopathology at Intercontinental Hotel, New Orleans between February 1-3, 1995. The Kveim-Siltzbach Reactions (KSR) is an important model for investigating immunologic events in granuloma formation. It has been shown that T lymphocyte predominance with oligocionality of infiltrating cells in 4 week-old KSR. Verruciform xanthoma is a rare benign condition that commonly involves the oral mucosa. Cutaneous lesions are less often observed, predominantly occurring at anogenital sites. Despite anecdotal reports of its occurrence in a variety of disease states, the etiology of this condition remains unclear.

Background: Interleukin17 (IL17) is an important cytokine in host defense at mucosal surfaces and also mediates many autoimmune diseases, including rheumatoid arthritis (RA). In recent years, many types of research relevant to the structure and function of IL17 have been identified. However, there is no bibliometric analysis in this research field. This study aims to explore the history, research hotspots, and emerging trends of IL17 from the perspective of the structure and function dynamics. Methods: Articles relevant to IL17 in the last two decades were retrieved through the Web of Science Core Collection (WoSCC) database. The bibliometric analysis was performed by VOSview. Results: A total of 882 papers in this research were analyzed from 65 countries, and the rate of published articles has increased from 2008 annually, with the USA, China, and Germany leading the research effort. Frontiers in Immunology has significantly impacted research in this field and the University of Pittsburgh was the leading institution. Gaffen, Sarah L. from the University of Pittsburgh was the most productive researcher in this field and Papp Ka from the Probity Medical Research Incorporate of Canada is the most co-cited author. The analysis of keywords showed that inflammation, expression, Th17 cells, and cytokines were the main hotspots and frontier directions of IL17. The trend of clinical application in the future is the development of new therapy drugs based on the structure of IL17 or IL17 signaling pathway molecular. Conclusions: Our research summarized the developments and research trends of IL17 and would help researchers understand the research status of IL17 and provide a reference for future researchers as soon as possible. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) currently ranks as the third most common cancer in the United States, and its incidence is on the rise, especially among younger individuals. Despite the remarkable success of immune checkpoint inhibitors (ICIs) in various cancers, most CRC patients fail to respond due to intrinsic resistance mechanisms. While microsatellite instability-high phenotypes serve as a reliable positive predictive biomarker for ICI treatment, the majority of CRC patients with microsatellite-stable (MSS) tumors remain ineligible for this therapeutic approach. In this study, we investigated the role of centrosomal protein 55 (CEP55) in shaping the tumor immune microenvironment in CRC. CEP55 is overexpressed in multiple cancer types and was shown to promote tumorigenesis by upregulating the PI3K/AKT pathway. Our data revealed that elevated CEP55 expression in CRC was associated with reduced T cell infiltration, contributing to immune exclusion. As CRC tumors progressed, CEP55 expression increased alongside sequential mutations in crucial driver genes (APC, KRAS, TP53, and SMAD4), indicating its involvement in tumor progression. CEP55 knockout significantly impaired tumor growth in vitro and in vivo, suggesting that CEP55 plays a crucial role in tumorigenesis. Furthermore, the CEP55 knockout increased CD8+ T cell infiltration and granzyme B production, indicating improved anti-tumor immunity. Additionally, we observed reduced regulatory T cell infiltration in CEP55 knockout tumors, suggesting diminished immune suppression. Most significantly, CEP55 knockout tumors demonstrated enhanced responsiveness to immune checkpoint inhibition in a clinically relevant orthotopic CRC model. Treatment with anti-PD1 significantly reduced tumor growth in CEP55 knockout tumors compared to control tumors, suggesting that inhibiting CEP55 could improve the efficacy of ICIs. Collectively, our study underscores the crucial role of CEP55 in driving immune exclusion and resistance to ICIs in CRC. Targeting CEP55 emerges as a promising therapeutic strategy to sensitize CRC to immune checkpoint inhibition, thereby improving survival outcomes for CRC patients. [ABSTRACT FROM AUTHOR]

Examine prospective relationships between erectile dysfunction (ED) drugs and CD4 and CD8 T-cells, and immune markers among men who have sex with men (MSM). Data from Multicenter AIDS Cohort Study, an observational prospective cohort study, with semiannual follow-ups conducted in four U.S. centers from 1998 onwards was used. Marginal structural models using g-computation were fitted to estimate the mean differences for the effects of self-reported ED drug use on CD4 and CD8 T-cell outcomes and immune biomarkers. Total of 1,391 men with HIV (MWH) and 307 men without HIV (MWOH) was included. Baseline mean CD4 cell count among MWH and MWOH was 499.9 and 966.7 cells/μL, respectively. At baseline, 41.8% of MWH were virally suppressed. ED drug users reported a mean of 44.4 months of exposure to ED drugs. ED drug use was associated with increased CD4 cell outcomes among MWH but not MWOH. Mean differences in CD4 cell counts after 1 year of ED drug use was 57.6 cells/μL and increased to 117.7 after 10 years among MWH. CD8 counts were higher in ED drug users among MWH over 10 years than non-users; no consistent differences were found among MWOH. ED drug use appeared to reduce immune marker levels, such as IL-6 and increase markers, such as IL-10. We observed similar effects of ED drug use on biomarker levels among MWOH. Long-term use of ED drugs do not adversely affect immune function among MWH or MWOH. Future studies on the relationships between different types of ED drugs and effects on T-cell subtypes are warranted. [ABSTRACT FROM AUTHOR]

Congenital athymia is an ultra-rare pediatric condition characterized by the lack of thymus in utero and the naïve T cells critical for infection defense and immune regulation. Patients with congenital athymia receive supportive care to minimize and treat infections, autoimmune phenomena, and autologous graft-versus-host disease (aGVHD) manifestations, but historically, die within the first 3 years of life with supportive care only. We estimated the healthcare resource utilization and economic burden of supportive care over patients' first 3 years of life in the United States. A medical chart audit by the treating physician was used to collect patient data from birth to age 3 on clinical manifestations associated with congenital athymia (clinical manifestations due to underlying syndromic conditions excluded). Using costs and charges from publicly available sources, the total economic burden of direct medical costs and charges for the first 3 years of life (considered "lifetime" for patients receiving supportive care) and differences in economic burden between patients with higher and lower inpatient hospitalization durations were estimated. All patients (n = 10) experienced frequent infections and aGVHD manifestations; 40% experienced ≥1 episode of sepsis, and 20% had recurrent sepsis episodes annually. The estimated mean 3-year economic burden per patient was US$5,534,121 (2020 US dollars). The annual mean inpatient hospitalization duration was 150.6 days. Inpatient room charges accounted for 79% of the economic burden, reflecting the high costs of specialized care settings required to prevent infection, including isolation. Patients with high inpatient utilization (n = 5; annual mean inpatient hospitalization duration, 289.6 days) had an estimated 3-year economic burden of US$9,926,229. The total economic burden may not be adequately represented due to underestimation of some direct costs or overestimation of others. Current treatment of patients with congenital athymia (supportive care) presents a high economic burden to the healthcare system. [ABSTRACT FROM AUTHOR]

A scalable approach for quantifying intact HIV-1 proviruses is critical for basic research and clinical trials directed at HIV-1 cure. The intact proviral DNA assay (IPDA) is a novel approach to characterizing the HIV-1 reservoir, focusing on the genetic integrity of individual proviruses independent of transcriptional status. It uses multiplex digital droplet PCR to distinguish and separately quantify intact proviruses, defined by a lack of overt fatal defects such as large deletions and APOBEC3G-mediated hypermutation, from the majority of proviruses that have such defects. This distinction is important because only intact proviruses cause viral rebound on ART interruption. To evaluate IPDA performance and provide benchmark data to support its implementation, we analyzed peripheral blood samples from 400 HIV-1+ adults on ART from several diverse cohorts, representing a robust sample of treated HIV-1 infection in the United States. We provide direct quantitative evidence that defective proviruses greatly outnumber intact proviruses (by >12.5 fold). However, intact proviruses are present at substantially higher frequencies (median, 54/106 CD4+ T cells) than proviruses detected by the quantitative viral outgrowth assay, which requires induction and in vitro growth (~1/106 CD4+ T cells). IPDA amplicon signal issues resulting from sequence polymorphisms were observed in only 6.3% of individuals and were readily apparent and easily distinguished from low proviral frequency, an advantage of the IPDA over standard PCR assays which generate false-negative results in such situations. The large IPDA dataset provided here gives the clearest quantitative picture to date of HIV-1 proviral persistence on ART. [ABSTRACT FROM AUTHOR]

The butyrophilins (BTNs) represent a unique family of immunoglobulin. They were considered to be involved in milk lactation after their discovery in 1981. With the development of research, an increasing number of research revealed that BTNs play important roles in immune regulation [1992–2019]. Our research aimed to summarize the BTN research status and their relationship with lung cancers and breast cancers by bibliometrics and bioinformatics methods. Our results indicate that the researches on immune-regulatory functions of BTNs gradually developed from 1992 to 2006, whereas they increased quickly after 2007. There are international cooperations among 56 countries, of which the United States is the most active one with the highest number of studies as well as highest citations. By coauthorship and cocitation analysis, we showed that Adrian Hayday, who is active in γδ T-cell field, was an active author in BTN publications with average year of 2015 and led a subfield. By keywords co-occurrence analysis, we found that γδ T cell, which is an important cancer immune regulator, is one important hotspot. Finally, we found that several BTN members' expression levels were significantly correlated with prognosis of lung cancer and breast cancer patients. Thus, these BTNs might play immune regulatory effects and could serve as potential biomarkers for cancer. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a behaviorally defined disorder that is now thought to affect approximately 1 in 69 children in the United States. In most cases, the etiology is unknown, but several studies point to the interaction of genetic predisposition with environmental factors. The immune system is thought to have a causative role in ASD, and specific studies have implicated T lymphocytes, monocytes, natural killer (NK) cells, and certain cytokines. The human leukocyte antigen (HLA) system is involved in the underlying process for shaping an individual's immune system, and specific HLA alleles are associated with specific diseases as risk factors. In this study, we determine whether a specific HLA allele was associated with ASD in a large cohort of patients with ASD. Identifying such an association could help in the identification of immune system components which may have a causative role in specific cohorts of patients with ASD who share similar specific clinical features. Specimens from 143 patients with ASD were analyzed with respect to race and ethnicity. Overall, HLA-Cw7 was present in a much greater frequency than expected in individuals with ASD as compared to the general population. Further, the cohort of patients who express HLA-Cw7 shares specific immune system/inflammatory clinical features including being more likely to have allergies, food intolerances, and chronic sinusitis as compared to those with ASD who did not express HLA-Cw7. HLA-Cw7 has a role in stimulating NK cells. Thus, this finding may indicate that chronic over-activation of NK cells may have a role in the manifestation of ASD in a cohort of patients with increased immune system/inflammatory features. [ABSTRACT FROM AUTHOR]

Background: We investigated the correlation between pancreatic ductal adenocarcinoma patient prognosis and the presence of tumour infiltrating lymphocytes and expression of 521 immune system genes. Methods: Intratumoural CD3+, CD8+, and CD20+ lymphocytes were examined by immunohistochemistry in 12 PDAC patients with different outcomes who underwent pancreaticoduodenectomy. The results were correlated with gene expression profile using the digital multiplexed NanoString nCounter analysis system (NanoString Technologies, Seattle, WA, USA). Results: Twenty immune system genes were significantly differentially expressed in patients with a good prognosis relative to patients with a worse prognosis: TLR2 and TLR7 (Toll-like receptor superfamily); CD4, CD37, FOXP3, PTPRC (B cell and T cell signalling); IRF5, IRF8, STAT1, TFE3 (transcription factors); ANP32B, CCND3 (cell cycle); BTK (B cell development); TNF, TNFRF1A (TNF superfamily); HCK (leukocyte function); C1QA (complement system); BAX, PNMA1 (apoptosis); IKBKE (NFκB pathway). Differential expression was more than twice log 2 for TLR7, TNF, C1QA, FOXP3, and CD37. Discussion: Tumour infiltrating lymphocytes were present at higher levels in samples from patients with better prognosis. Our findings indicate that tumour infiltrating lymphocyte levels and expression level of the immune system genes listed above influence pancreatic ductal adenocarcinoma prognosis. This information could be used to improve selection of best responders to immune inhibitors. [ABSTRACT FROM AUTHOR]

Summary: Multiple sclerosis (MS) is the leading cause of non‐traumatic neurological disability in the United States in young adults, but current treatments are only partially effective, making it necessary to develop new, innovative therapeutic strategies. Myelin‐specific interleukin (IL)‐17‐producing T helper type 17 (Th17) cells are a major subset of CD4 T effector cells (Teff) that play a critical role in mediating the development and progression of MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), while regulatory T cells (Treg) CD4 T cells are beneficial for suppressing disease. The IL‐6/signal transducer and activator of transcription 3 (STAT‐3) signaling pathway is a key regulator of Th17 and Treg cells by promoting Th17 development and suppressing Treg development. Here we show that three novel small molecule IL‐6 inhibitors, madindoline‐5 (MDL‐5), MDL‐16 and MDL‐101, significantly suppress IL‐17 production in myelin‐specific CD4 T cells in a dose‐dependent manner in vitro. MDL‐101 showed superior potency in suppressing IL‐17 production compared to MDL‐5 and MDL‐16. Treatment of myelin‐specific CD4 T cells with MDL‐101 in vitro reduced their encephalitogenic potential following their subsequent adoptive transfer. Furthermore, MDL‐101 significantly suppressed proliferation and IL‐17 production of anti‐CD3‐activated effector/memory CD45RO+CD4+ human CD4 T cells and promoted human Treg development. Together, these data demonstrate that these novel small molecule IL‐6 inhibitors have the potential to shift the Teff : Treg balance, which may provide a novel therapeutic strategy for ameliorating disease progression in MS. [ABSTRACT FROM AUTHOR]

Questions: What are the mechanisms operating behind the plant community structure changes over time after lahars activity of Popocatépetl volcano? We hypothesize that functional diversity matters more than species richness and that, after major disturbances, the pioneer plant community will first show a ruderal composition, that subsequently changes into successional stages in which competitive and stress‐tolerating species become dominant life‐forms. We expect this process to be revealed by the community's functional signature. Location: Popocatépetl volcano in Mexico (19°1′0″N, 98°37′0″W) which has undergone large eruptive activity that has caused lahars formation. Methods: In 2002, survey plots were established in the bottom of the Huilóac gorge. Species composition and abundance data were thereafter collected for 10 years. In 2013, data on three functional traits leaf area (LA), leaf dry matter content and LA of 67 species were obtained and each species was assigned to a strategy according to the CSR (Competitive, Stress‐Tolerant or Ruderal) scheme. A community‐functional signature was calculated for each year. Also, a parallel ordination of plots strategies composition in time was performed to confirm functional shift trends. Results: Initial successional phases were dominated by ruderal and competitive species. Thereafter, the communities went through a phase of increasing heterogeneity of strategies, which was followed by dominance of competitive and stress‐tolerant strategists in the later years. Parallel ordination confirmed the gradient of functional differentiation through time. Conclusions: The change from ruderal/competitive to stress‐tolerant and competitive species with time suggests that the most recent lahar event played a major role in sorting species according to their tolerance for disturbances. Thereafter, a major trend has been the gradual shift from ruderal to stress‐tolerant species (conifers and alpine grasses). In 1997 and 2001, eruptive activity of Popocatépetl volcano in Mexico caused lahars formation that buried the vegetation at the bottom of Huilóac gorge on the volcano's eastern slope. Since 2002, plots were stablished to monitor vegetation recovery. Through Competitive/Stres‐Tolerator/Ruderal strategies scheme (CSR), it was possible to trace a functional shift from R to S strategists in the period 2002–2013. [ABSTRACT FROM AUTHOR]

The article presents data related to biotechnology research papers in the U.S. The US remains the most productive country in terms of biotech-related papers. But numbers of papers from the European Union surpassed the US last year (with Germany and the UK ahead of most EU countries); elsewhere, Korea, China and Japan also publish frequently. Some of the top cited papers, published in different journals, by field are: RNAi--Systematic functional analysis of the Caenorhabditis elegans genome using RNAi; Gene therapy--LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X2 and Nuclear transfer--Derivation of oocytes from mouse embryonic stem cells.

PD-1- and PD-L1-blocking monoclonal antibodies have shown significant promise in clinical settings and rekindled the hope for successful cancer immunotherapy. We recently demonstrated that interfering with PD-1/PD-L1 signaling selectively augments CD8+ T cell (TCD8) responses to subdominant determinants (SDDs) of a model tumor antigen. This was likely due to decreased lysis of SDD-specific TCD8 by neighboring immunodominant clones co-engaging the same antigen-presenting cells (APCs). We therefore proposed that PD-1-based checkpoint inhibitors widen the range of tumor determinants that can be effectively targeted by TCD8. Subsequently and using different tumor models, Chen et al. reported, in Proceedings of the National Academy of Sciences of the United States of America, that PD-L1 protects APCs from the lytic function of immunodominant TCD8 and that PD-L1 blockade narrows, rather than broadens, the overall anticancer T cell response. Here, we briefly compare and contrast the experimental systems employed by the two groups, which may account, at least partially, for the opposing conclusions drawn. We argue that the pathway(s) of tumor antigen presentation, direct presentation versus cross-presentation, and the intensity of PD-1 expression by immunodominant and subdominant TCD8 must be taken into consideration in rational design of anti-PD-1/PD-L1-adjuvanted tumor vaccines and therapies. [ABSTRACT FROM AUTHOR]

Background: The STTR treatment cascade provides a framework for research aimed at improving the delivery of services, care and outcomes of PLWH. The development of effective approaches to increase HIV diagnoses and engage PLWH in subsequent steps of the treatment cascade could lead to earlier and sustained ART treatment resulting in viral suppression. There is an unmet need for research applying the treatment cascade to improve outcomes for those with criminal justice involvement.Methods: The Seek, Test, Treat, and Retain (STTR) criminal justice (CJ) cohort combines data from 11 studies across the HIV treatment cascade that focused on persons involved in the criminal justice system, often but not exclusively for reasons related to substance use. The studies were conducted in a variety of CJ settings and collected information across 11 pre-selected domains: demographic characteristics, CJ involvement, HIV risk behaviors, HIV and/or Hepatitis C infections, laboratory measures of CD4 T-cell count (CD4) and HIV RNA viral load (VL), mental illness, health related quality of life (QoL), socioeconomic status, health care access, substance use, and social support.Results: The STTR CJ cohort includes data on 11,070 individuals with and without HIV infection who range in age from 18 to 77 years, with a median age at baseline of 37 years. The cohort reflects racial, ethnic and gender distributions in the U.S. CJ system, and 64% of participants are African-American, 12% are Hispanic and 83% are men. Cohort members reported a wide range of HIV risk behaviors including history of injection drug use and, among those who reported on pre-incarceration sexual behaviors, the prevalence of unprotected sexual intercourse ranged across studies from 4% to 79%. Across all studies, 53% percent of the STTR CJ cohort reported recent polysubstance use.Conclusions: The STTR CJ cohort is comprised of participants from a wide range of CJ settings including jail, prison, and community supervision who report considerable diversity in their characteristics and behavioral practices. We have developed harmonized measures, where feasible, to improve the integration of these studies together to answer questions that cannot otherwise be addressed. [ABSTRACT FROM AUTHOR]

Background: The possibility of incorporating generics into combination antiretroviral therapy and breaking apart once-daily single-tablet regimens (STRs), may result in less efficacious medications and/or more complex regimens with the expectation of marked monetary savings. A modeling approach that assesses the merits of such policies in terms of lifelong costs and health outcomes using adherence and effectiveness data from real-world U.S. settings. Methods: A comprehensive computer-based microsimulation model was developed to assess the lifetime health (life expectancy and quality adjusted life-years—QALYs) and economic outcomes in HIV-1 infected patients initiating STRs compared with multiple-table regimens including generic medications where possible (gMTRs). The STRs considered included tenofovir disoproxil fumarate/emtricitabine and efavirenz or rilpivirine or elvitegravir/cobicistat. gMTRs substitutions included each counterpart to STRs, including generic lamivudine for emtricitabine and generic versus branded efavirenz. Results: Life expectancy is estimated to be 1.301 years higher (discounted 0.619 QALY gain) in HIV-1 patients initiating a single-tablet regimen in comparison to a generic-based multiple-table regimen. STRs were associated with an average increment of $26,547.43 per patient in medication and $1,824.09 in other medical costs due to longer survival which were partially offset by higher inpatients costs ($12,035.61) with gMTRs treatment. Overall, STRs presented incremental lifetime costs of $16,335.91 compared with gMTRs, resulting in an incremental cost-effectiveness ratio of $26,383.82 per QALY gained. Conclusions: STRs continue to represent good value for money under contemporary cost-effectiveness thresholds despite substantial price reductions of generic medications in the U. S. [ABSTRACT FROM AUTHOR]

Seasonal epidemics of influenza virus result in ∼36,000 deaths annually in the United States. Current vaccines against influenza virus elicit an antibody response specific for the envelope glycoproteins. However, high mutation rates result in the emergence of new viral serotypes, which elude neutralization by preexisting antibodies. T lymphocytes have been reported to be capable of mediating heterosubtypic protection through recognition of internal, more conserved, influenza virus proteins. Here, we demonstrate using a recombinant influenza virus expressing the LCMV GP33-41 epitope that influenza virus-specific CD8+ T cells and virus-specific non-neutralizing antibodies each are relatively ineffective at conferring heterosubtypic protective immunity alone. However, when combined virus-specific CD8 T cells and nonneutralizing antibodies cooperatively elicit robust protective immunity. This synergistic improvement in protective immunity is dependent, at least in part, on alveolar macrophages and/or other lung phagocytes. Overall, our studies suggest that an influenza vaccine capable of eliciting both CD8+ T cells and antibodies specific for highly conserved influenza proteins may be able to provide heterosubtypic protection in humans, and act as the basis for a potential "universal" vaccine. [ABSTRACT FROM AUTHOR]

The article reports on the research on microRNAs in the U.S. The research revealed that microRNAs are needed to safeguard the function of regulatory T cells, and are required to maintain T cells activity, which befit their suggested role in buffering gene expression in conditions of environmental stress. It is concluded that this study highlights an essential role for microRNA-dependent regulation of gene expression in the maintenance of T cells homeostasis and suppressive function.

Background: This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection. Methods: Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining the long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in the absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria. Results: Questionnaires on 191 out of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and 6 clinical cases of HIVAN, and 7 biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, 3; IgA nephropathy, 2; membranous nephropathy, 2). Incidence rates for CKD associated with HIV in pre-highly active antiretroviral therapy (HAART) (1993-1997) and HAART (1998-2002, 2003-2006) eras were 0.43, 2.84, and 2.79 events per 1,000 person years respectively. In multivariate analysis, black race and viral load ≥100,000 copies/mL (rate ratios 3.28 and 5.05, p ≤ 0.02) were associated with CKD. Conclusions: A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV. [ABSTRACT FROM AUTHOR]

Background: We sought to determine the impact of naltrexone on hepatic enzymes and HIV biomarkers in HIV-infected patients. Methods: We used data from the Veterans Aging Cohort Study-Virtual Cohort, an electronic database of administrative, pharmacy, and laboratory data. We restricted our sample to HIV-infected patients who received an initial oral naltrexone prescription of at least 7 days duration. We examined aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and HIV biomarker (CD4 and HIV RNA) values for the 365 days prior to, during, and for the 365 days post-naltrexone prescription. We also examined cases of liver enzyme elevation (LEE; defined as >5 times baseline ALT or AST or >3.5 times baseline if baseline ALT or AST was >40 IU/l). Results: Of 114 HIV-infected individuals, 97% were men, 45% white, 57% Hepatitis C co-infected; median age was 49 years; 89% of the sample had a history of alcohol dependence and 32% had opioid dependence. Median duration of naltrexone prescription was 49 (interquartile range 30 to 83) days, representing 9,525 person-days of naltrexone use. Mean ALT and AST levels remained below the upper limit of normal. Two cases of LEE occurred. Mean CD4 count remained stable and mean HIV RNA decreased after naltrexone prescription. Conclusions: In HIV-infected patients, oral naltrexone is rarely associated with clinically significant ALT or AST changes and does not have a negative impact on biologic parameters. Therefore, HIV-infected patients with alcohol or opioid dependence can be treated with naltrexone. [ABSTRACT FROM AUTHOR]

Forty years have passed since our initial description of peculiar cases of adult-onset leukemia with abnormal cells having multi-convoluted nuclei and T cell properties, frequent in the southern regions of Japan in the early 1970s. Retrospectively, the study of adult T cell leukemia (ATL) and the related virus HTLV-I was a forerunner for all of human retrovirology, in which AIDS and the related retrovirus HIV were identified a few years later in the 1980s. Using the anti-TAC monoclonal antibody generated by the late Takashi Uchiyama during his stay in T. A. Waldmann's laboratory in NIH Bethesda, a cDNA encoding IL-2Rα chain was cloned by our group in Kyoto and by Waldmann's group in Bethesda. Abnormal IL-2Rα chain expression and the IL-2 dependency of ATL cell lines greatly contributed to the study of leukemogenesis of ATL. A new soluble factor named ADF/ATL-derived factor was also detected in ATL cell lines. After years of study, ADF proved to be a first human counterpart of thiol-related oxido-reductase thioredoxin/TRX, which opened the field of redox regulation of cell signaling involved in a variety of diseases. Close interaction among Drs. Kimishige Ishizaka, Kiyoshi Takastuki and T. A. Waldmanns before ATL and HTLV-I study was an essential base for our initiation of ATL research with Takashi Uchiyama and many other colleagues. [ABSTRACT FROM AUTHOR]

Background. Visiting a medical provider less frequently than clinical circumstances would suggest is appropriate has been reported to be associated with worse clinical outcomes for patients living with HIV infection. Patients with less frequent attendance to HIV care also may be systematically underrepresented in research or surveillance studies that enroll patients sequentially over a specified enrollment period - for example several months. For both reasons, understanding factors associated with time to care visit is important. Methods. We used data from the Adult and Adolescent Spectrum of HIV Disease (ASD) project, a multi-site clinical outcomes surveillance system that enrolled and followed patients in care for HIV prospectively from 1990 to 2004. For this analysis, we used data from all patients observed in ASD at least one time before 1 January 2003, and who had at least one HIV care visit in 2003. We documented time to first annual HIV care visit for each patient, and used Kaplan-Meier plots and proportional hazards regression to describe factors associated with longer time to care visit. Results. A total of 12,135 patients had ≥1 care visit during 2003 and were included in the analysis. Of these, 81%, 88%, and 95% had their first visit within three, four, and six months, respectively. In multivariate analysis, having a delayed (later) care visit was associated with not ever having had an AIDS diagnosis, having an HIV RNA concentration ≥10,000 copies/mL, having a current CD4 count <100 cells/µL, having no health insurance, and not being currently prescribed antiretroviral therapy. Having a delayed care visit was not associated with race/ethnicity or age. Conclusions. Having a delayed first annual HIV care visit was associated with higher viremia, lower CD4 cell count, and lack of health insurance. Interventions to address these factors are likely to ameliorate some of the consequences of HIV. For studies enrolling patients in care for HIV over a finite time period, an enrollment period of four-six months should sufficiently reflect the patient population seen in a one-year period, including those attending care infrequently. [ABSTRACT FROM AUTHOR]

Given the continued high incidence of HIV infection in the United States among racial/ethnic minority young men who have sex with men (YMSM), and an appreciation that antiretroviral therapy (ART) can provide personal and public health benefits, attention is needed to enhance the detection of HIV-infected youth and engage them in medical care and support services that encourage sustained HIV treatment and suppression of viremia. Poor retention in clinical care has been associated with higher mortality, an increase in HIV RNA, and decreased CD4 cell count. The goal of the current study was to evaluate the health care utilization and health outcomes of HIV-infected racial/ethnic minority YMSM enrolled in an outreach, linkage, and retention study funded by the Health Resources and Services Administration (HRSA) HIV/AIDS Bureau (HAB). We hypothesized that among racial/ethnic minority YMSM, baseline CD4 counts and usage of ART are influenced by age, race, drug and alcohol use, and mental health symptoms. Overall, 155 subjects had at least a baseline CD4 count recorded at study entry. There was a low rate of ART use in this population with only one-half of the cohort with CD4 counts ≤350 cells/mm3 being prescribed ART to treat their infection. However, of those youth who were started on ART, the majority (74%) did achieve undetectable viral loads (<400 copies). Given the continued increase in cases of HIV infection among racial/ethnic minority YMSM, efforts to increase both the provision of ART and support services that encourage adherence in this population are warranted. [ABSTRACT FROM AUTHOR]

The Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY) study is a prospective, multisite, longitudinal cohort of U.S. HIV-infected youth. This analysis was limited to perinatally HIV-infected youth ( n=197), 13 years and older, with selected variables completely abstracted from HIV diagnosis through 2006. We evaluated relationships between ever having one or more nonsubstance related medically documented psychiatric diagnoses and three risky health behaviors (substance abuse, preadult sexual activity, and treatment adherence problems) recorded between 2001 and 2006. Logistic regression was used for all binary outcomes and participant age was included as a covariate when possible. All 197 participants included in the analysis were prescribed antiretroviral therapy during the study period; 110 (56%) were female, 100 (51%) were black non-Hispanic, and 86 (44%) were Hispanic; mean age at the last visit was 16.8 years, ranging from 13 to 24 years. One hundred forty-six (74%) participants had a history of at least one risky health behavior. There were 108 (55%) participants with at least one medically documented psychiatric diagnosis, 17 (9%) with at least one record of substance abuse, 12 (6%) with documented preadult sexual activity, and 142 (72%) participants with reported adherence problems. In the final model, a history of at least one psychiatric diagnosis was associated with having at least one of the three risky behaviors (odds ratio [OR]=2.33, p=0.015). There is a need for a continued close partnership between HIV specialty care providers and mental health services treating perinatally HIV-infected youth with an added focus on improving treatment adherence. [ABSTRACT FROM AUTHOR]

Background: HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. Methodology/Principal Findings: In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%$25 were categorized as having no immune suppression (NS), and those with CD4%#15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLAB* 57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of nai&vuml;e CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. Conclusions/Significance: Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1- Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions. [ABSTRACT FROM AUTHOR]

Background: A post marketing surveillance study was conducted to evaluate safety and efficacy of natalizumab in Swedish multiple sclerosis (MS) patients since its introduction in August 2006 until March 2010.Methods: Patients were registered in the web-based Swedish MS-registry at 40 locations and evaluated every 6 months. Adverse events and clinical outcomes were recorded.Results: One thousand one hundred and fifty-two patients were included (71.4% female) and 149 patients stopped treatment; the main reason was planned pregnancy. Anti-natalizumab antibodies were found in 4.5% (52 patients) of which 1.6% displayed persistent antibodies. Serious adverse events were rare, but included three cases with progressive multifocal leukoencephalopathy (PML). There were seven fatal cases, probably unrelated to the natalizumab treatment. For relapsing–remitting MS patients (n = 901), mean Expanded Disability Status Scale (EDSS, −10.7%), Multiple Sclerosis Severity Scale (MSSS, −20.4%), Multiple Sclerosis Impact Scale (MSIS-29, physical −9.9%, psychological −13.3%) and Symbol Digit Modalities Test (SDMT, +10.7%) all showed significant improvements during 24 months of treatment with natalizumab. The Swedish web-based MS quality registry proved to function as a platform for post-marketing MS drug surveillance, providing long-term data regarding drug effects and adverse events beyond clinical trials.Conclusions: Our results indicate that natalizumab is generally well tolerated and has sustained efficacy for patients with active MS, though the risk of PML is still an important concern. [ABSTRACT FROM AUTHOR]

Many studies have chronicled the “epidemiologic synergy” between human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2). HIV adversely affects the natural history of HSV-2 and results in more frequent and severe HSV-2 reactivation. Few longitudinal studies, however, have examined whether HSV-2 is associated with increased HIV plasma viral loads or decreased CD4 counts. The authors estimated the effect of HSV-2 seropositivity on HIV RNA viral load and on CD4 count over time among 777 HIV-seropositive US women not receiving suppressive HSV-2 therapy in the HIV Epidemiology Research Study (1993–2000). Linear mixed models were used to assess the effect of HSV-2 on log HIV viral load and CD4 count/mm3 prior to widespread initiation of highly active antiretroviral therapy. Coinfection with HSV-2 was not associated with HIV RNA plasma viral loads during study follow-up. There was a statistically significant association between HSV-2 seropositivity and CD4 count over time, but this difference was small and counterintuitive at an increase of 8 cells/mm3 (95% confidence interval: 2, 14) per year among HSV-2-seropositive women compared with HSV-2-seronegative women. These data do not support a clinically meaningful effect of baseline HSV-2 seropositivity on the trajectories of HIV plasma viral loads or CD4 counts. [ABSTRACT FROM PUBLISHER]

Background: Regulatory T cells (Tregs) have an essential role in tolerance and immune regulation. However, few and controversial data have been published to date on the role and number of these cells in food allergic children. The forkhead/winged-helix transcription factor box protein 3 (FOXP3) is considered the most reliable marker for Tregs. Objective: This study aims to investigate the FOXP3, interleukin (IL)-10, and transforming growth factor (TGF-β) genes expression in children with IgE-dependent food allergy. Material and Methods: The study group consisted of 54 children with IgE-dependent food allergy (FA) and a control group of 26 non-atopic healthy children. The diagnosis of FA was established using questionnaires, clinical criteria, skin prick tests, serum sIgE antibodies (UniCAP 100 Pharmacia Upjohn), and a double-blind placebo control food challenge. In order to assess gene expression, the isolation of nucleated cells was performed using Histopaque-1077 (Sigma-Aldrich, Germany). The concentration of RNA obtained was measured using a super-sensitive NanoDrop ND1000 spectrophotometer (Thermo Scientific, USA). A reverse transcription reaction was performed using a commercially available set of High Capacity cDNA Archive Kit (Applied Biosystems, USA). Analysis have been carried out in the genetic analyzer 7900HT Real-Time PCR (Applied Biosystems, USA). Results: The average level of the FOXP3 gene expression in the studied group was 2.19 ± 1.16 and in the control group 2.88 ± 1.66 ( p = 0.03). The average level of IL10 mRNA expression in the study group was 13.6 ± 1.07 and was significantly lower than corresponding values in the control group 14.3 ± 1.1 ( p = 0.01). There were no significant differences in the average level of the TGF-β mRNA expression in the study group (3.4 ± 0.4) and controls (3.5 ± 0.3; p > 0.05). The FOXP3 gene expression was the highest in children who acquired tolerance to food (3.54 ± 0.75), lower in heated allergen-tolerant children (2.43 ± 0.81), and the lowest in heated allergen-reactive children (1.18 ± 0.5; p = 0.001 control vs heated allergen reactive; p = 0.005 heated allergen tolerant vs heated allergen reactive; p = 0.001 outgrown vs heated allergen reactive). The significant tendency toward lower total IgE levels with a higher FOXP3 mRNA expression was detected ( n = 54; Pearson r = −0.4393; p = 0.001). Conclusions: Children with FA showed statistically significant lower level of the FOXP3 and IL10 gene expression than healthy children. Children acquiring tolerance to the food show significantly higher levels of the FOXP3 gene expression than children with active FA. The correlation between the level of FOXP3 and total IgE was detected. [ABSTRACT FROM AUTHOR]

Background. Initiatives to improve early detection and access to human immunodeficiency virus (HIV) services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997 to 2007 in 13 US and Canadian clinical cohorts. Methods. We analyzed data from 44,491 HIV-infected patients enrolled in the North American-AIDS Cohort Collaboration on Research and Design. We identified first presentation for HIV care as the time of first CD4+ T lymphocyte (CD4) count and excluded patients who prior to this date had HIV RNA measurements, evidence of antiretroviral exposure, or a history of AIDS-defining illness. Trends in mean CD4 count (measured as cells/mm³) and 95% confidence intervals were determined using linear regression adjusted for age, sex, race/ethnicity, HIV transmission risk, and cohort. Results. Median age at first presentation for HIV care increased over time (range, 40-43 years; P < .01), whereas the percentage of patients with injection drug use HIV transmission risk decreased (from 26% to 14%; P < .01) and heterosexual transmission risk increased (from 16% to 23%; P < .01). Median CD4 count at presentation increased from 256 cells/mm³ (interquartile range, 96-455 cells/mm³) to 317 cells/mm³ (interquartile range, 135- 517 cells/mm3) from 1997 to 2007 (P < .01). The percentage of patients with a CD4 count _350 cells/mm³ at first presentation also increased from 1997 to 2007 (from 38% to 46%; P < .01). The estimated adjusted mean CD4 count increased at a rate of 6 cells/mm³ per year (95% confidence interval, 5-7 cells/mm3 per year). Conclusion. CD4 count at first presentation for HIV care has increased annually over the past 11 years but has remained <350 cells/mm³, which suggests the urgent need for earlier HIV diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Romidepsin has shown promise in the treatment of T-cell lymphomas, and so we evaluated molecular endpoints gathered from 61 patients enrolled on a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma at the National Institutes of Health. The endpoints included histone H3 acetylation and ABCB1 gene expression in peripheral blood mononuclear cells (PBMCs); ABCB1 gene expression in tumour biopsy samples; and blood fetal haemoglobin levels (HbF), all of which were increased following romidepsin treatment. The fold increase in histone acetylation in PBMCs at 24 h was weakly to moderately well correlated with the pharmacokinetic parameters Cmax and area under the curve (AUC)last (ρ = 0·37, P = 0·03 and ρ = 0·36, P = 0·03 respectively) and inversely associated with clearance (ρ = −0·44; P = 0·03). Histone acetylation in PBMCs at 24 h was associated with response ( P = 0·026) as was the increase in fetal haemoglobin ( P = 0·014); this latter association may be due to the longer on-study duration for patients with disease response. Together, these results suggest that pharmacokinetics may be an important determinant of response to histone deacetylase inhibitors (HDIs) – the association with histone acetylation in PBMCs at 24 h is consistent with a hypothesis that potent HDIs are needed for a critical threshold of drug exposure and durable activity. [ABSTRACT FROM AUTHOR]

Annual vaccination against seasonal influenza viruses is recommended for certain individuals that have a high risk for complications resulting from infection with these viruses. Recently it was recommended in a number of countries including the USA to vaccinate all healthy children between 6 and 59 months of age as well. However, vaccination of immunologically naïve subjects against seasonal influenza may prevent the induction of heterosubtypic immunity against potentially pandemic strains of an alternative subtype, otherwise induced by infection with the seasonal strains. Here we show in a mouse model that the induction of protective heterosubtypic immunity by infection with a human A/ H3N2 influenza virus is prevented by effective vaccination against the A/H3N2 strain. Consequently, vaccinated mice were no longer protected against a lethal infection with an avian A/H5N1 influenza virus. As a result H3N2-vaccinated mice continued to loose body weight after A/H5N1 infection, had 100-fold higher lung virus titers on day 7 post infection and more severe histopathological changes than mice that were not protected by vaccination against A/H3N2 influenza. The lack of protection correlated with reduced virus-specific CD8+ T cell responses after A/H5N1 virus challenge infection. These findings may have implications for the general recommendation to vaccinate all healthy children against seasonal influenza in the light of the current pandemic threat caused by highly pathogenic avian A/H5N1 influenza viruses. [ABSTRACT FROM AUTHOR]

A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans. Additionally, we offer that because the GWAS cohort was a subset of HIV-positive individuals, selected based in part on having a low viral load, the observed associations for viral load are magnified compared with those we detect in a large well-characterized prospective natural history cohort of HIV-1-infected persons. We also find that because of linkage disequilibrium (LD) patterns, the dominant viral load- and disease-influencing associations for the ZNRD1 or HLA-C and HCP5 alleles are apparent mainly when these alleles are present in HLA-A10- or HLA-B*57-containing haplotypes, respectively. ZNRD1 alleles lacking HLA-A10 did not confer disease protection whereas ZNRD1-A10 haplotypes did. When examined in isolation, the HCP5-G allele associates with a slow disease course and lower viral loads. However, in multivariate models, after partitioning out the protective effects of B*57, the HCP5-G allele associates with disease-acceleration and enhanced viral replication; these associations for HCP5-G are otherwise obscured because of the very strong LD between this allele and a subset of protective B*57 alleles. Furthermore, HCP5 and HLA-C alleles stratify B*57-containing genotypes into those that associate with either striking disease retardation or progressive disease, providing one explanation for the long-standing conundrum of why some HLA-B*57-carrying individuals are long-term non-progressors, whereas others exhibit progressive disease. Collectively, these data generally underscore the strong dependence of genotype-phenotype relationships upon cohort design, phenotype selection, LD patterns and populations studied. They specifically demonstrate that the influence of ZNRD1 alleles on disease progression rates are attributable to HLA-A10, help clarify the relationship between the HCP5, HLA-C and HLA-B*57 alleles, and reaffirm a critical role of HLA-B*57 alleles in HIV disease. Furthermore, as the protective B*57-containing genotypes convey striking salutary effects independent of their strong impact on viral control, it is conceivable that T cell-based therapeutic vaccine strategies aimed at reducing viral loads may be inadequate for limiting AIDS progression, raising the potential need for complementary strategies that target viral load-independent determinants of pathogenesis. [ABSTRACT FROM AUTHOR]

Work on one haplotype-mismatched transplants has been proceeding for over 20 years all over the world and novel transplant techniques have been developed. Some centres have focused on the conditioning regimens and post transplant immune suppression; others have concentrated on manipulating the graft. Haploidentical transplant modalities are based mainly on high-intensity conditioning regimen, but reduced intensity regimens have recently been introduced. The graft may be a megadose of extensively T cell-depleted or unmanipulated progenitor cells. Excellent engraftment rates are associated with a very low incidence of GVHD- and regimen-related mortality even in patients who are over 50 years old. Overall, event-free survival and transplant-related mortality compare favourably with reports on transplants from sources of stem cells other than the matched sibling. Improvements will come with successful implementation of strategies to accelerate and strengthen post transplant immune reconstitution as well as transplantation of patients in early stage disease.Bone Marrow Transplantation (2008) 41, 473–481; doi:10.1038/sj.bmt.1705966; published online 7 January 2008 [ABSTRACT FROM AUTHOR]

Background: Angiolymphoid hyperplasia with eosinophilia (ALHE) is a vasocentric process characterized by infiltrates of lymphocytes and eosinophils, usually affecting the muscular arteries of the head and neck. Currently it is unclear whether it is a reactive or neoplastic process. Report: We present a 61-year-old African American male with a twenty year history of superficial skin patches involving the head and neck region. An excisional biopsy of a right submental lymph node revealed an atypical T-cell lymphocytic process, diagnosed as peripheral T-cell lymphoma after immunophenotyping and molecular studies. Three months later the patient underwent a biopsy of a left temporal nodule that was diagnosed as ALHE. Subsequently, at two year follow-up, the patient was diagnosed with Mycosis Fungoides. Polymerase chain reaction for T cell receptor gamma showed the same T-cell receptor gene rearrangement in both the temporal mass and the right submental lymph node. Conclusion: ALHE with molecular evidence of monoclonality is extremely unusual, as is the association with nodal peripheral T-cell nodal lymphoma. The findings of this case support our hypothesis that ALHE might be an early form of T-cell lymphoma. [ABSTRACT FROM AUTHOR]

Cytotoxic lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activation, and may help to limit T cell response under conditions of inflammation. Genetic variability in CTLA-4 has been implicated in the development of several autoimmune diseases. Some studies have described associations between CTLA-4 polymorphisms and systemic lupus erythematosus (SLE), but findings have been inconsistent. We examined polymorphisms in the CTLA-4 gene promoter region ( - 1722T/C, - 1661A/G, 2 318C/T) and exon 1 (+49G/A) with respect to SLE in a populationbased case – control study in the southeastern US. Genotypes from 230 recently diagnosed cases and 276 controls were examined separately for African-Americans and whites. We observed no overall associations between SLE and the four CTLA-4 polymorphisms examined. Subgroup analyses revealed effect modification by age for the presence of the - 1661G allele, yielding a significant positive association with SLE in younger (≤ 35 years) African-Americans (OR = 3.3). CTLA-4 genotypes also interacted with HLA-DR2 and GM allotype to contribute to risk of SLE. These findings suggest allelic variation in this region of CTLA-4 is not a major independent risk factor for SLE, but may contribute to risk of disease in younger African-Americans or in the presence of certain immunogenetic markers. [ABSTRACT FROM AUTHOR]

SUMMARY The aetiology of chronic prostatitis is not understood. The aim of this study is to investigate an autoimmune hypothesis by looking for T cell proliferation in response to proteins of the seminal plasma. We studied peripheral blood mononuclear cell proliferation from 20 patients with chronic prostatitis and 20 aged-matched controls in response to serial dilutions of seminal plasma (SP) from themselves (autologous SP) and from a healthy individual without the disease (allo-SP). We found that the patients have a statistically greater lymphocyte proliferation to autologous SP at the 1/50 dilution on day 6 compared to controls (P = 0·01). They also have a greater proliferation to allo-SP on both day 5 (P = 0·001) and day 6 (P = 0·01) at the same dilution. Using a stimulation index (SI) of 9 to either autologous SP or allo-SP on day 6 at the 1/50 dilution as a definition of a proliferative response to SP, then 13/20 patients as compared to 3/20 controls showed a proliferative response to SP (P = 0·003, Fisher’s exact test). These data support an autoimmune hypothesis for chronic prostatitis. [ABSTRACT FROM AUTHOR]

Simple Summary: Cytokine release syndrome is a potentially life-threatening complication of therapy with T-cell engaging bispecific antibodies. Here we evaluated the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome who received weekly intravenous infusions of the CD3xCD123 bispecific antibody APVO436. Cytokine release syndrome was encountered in 10 of 46 patients (21.7%) treated with APVO436 with a cumulative Grade 3/4 cytokine release syndrome incidence of 8.7%. Cytokine profiling in patients who developed cytokine release syndrome after APVO436 infusion indicated that the predominant cytokine in this inflammatory cytokine response was IL-6. The findings from this research provide new insights regarding the biology and effective management of cytokine release syndrome in leukemia patients treated with T-cell redirecting bispecific antibodies. We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions. [ABSTRACT FROM AUTHOR]

Examines the role of salicylic acid in the treatment of psoriasis in the U.S. Characterization of the disease; Detection of T cell infiltration in epidermal plaques; Consideration on the degree of severity in the treatment.

The authors reflect on the activation of lymphocyte in the context of allo- and auto-immunity in the U.S. They note that on account of the increasingly sophisticated molecular and immunological tools, their knowledge of the complexities of cell-cell interaction continues to evolve. Moreover, examination of the molecular interaction that occurs when a lymphocyte encounters an antigen-presenting cell (APC) has revealed that T cells require multiple signals to become fully activated.

The article reports on the research in the U.S. on how to generate the variability of T-cell responses to antigenic stimulation within a clonal population. Accordingly, the researchers combine computer modelling and single-cell analysis for this research. Through this strategy, they were able to show that variability in the basal expression of CD8 and the phosphatase SHP1 within a clonal T-cell population provides phenotypic variability in a controlled manner.

The article reports on the research in the U.S. on the role of autophagy in T-cell selection. Accordingly, the researchers transplanted the autophagy-related gene 5 embryonic thymi under the renal capsule of a panel of T-cell receptor transgenic mice. After analyzing the gathered data, researchers concluded that autophagy in TECs shapes the selection of the T-cell repertoire in the thymus and is essential for the induction of central tolerance.

The article focuses on the research on different combinations of chemical modifications that affect the expression of almost 12,500 genes in CD4+T cells conducted by Keji Zhao of the U.S. National Institutes of Health in Bethesda, Maryland and his colleagues. It states that section of its DNA that a cell expresses lies in part on chemical modifications to the histone proteins around which DNA is wound. The authors discovered that a set of 17 chemical modifications is associated with a quarter of all promoters in human immune cells. However, acetylation does not directly determine whether a gene is "read," as had been surmised, but appears to prime the gene for activation.

The article reports on the study which shows that histone deacetylase inhibitors (HDACis) therapy increases the number and suppressor ability of regulatory T cells (Treg cells), which are key mediators of immune tolerance in the U.S. Using different mouse models, it showed that HDACi treatment enhances the production of Treg cells by either increasing thymic output of Treg cells or peripheral conversion of conventional T cells into Treg cells.