Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice

TALL-1/Blys/BAFF is a member of the tumor necrosis factor (TNF) ligand superfamily that is functionally involved in B cell proliferation. Here, we describe B cell hyperplasia and autoimmune lupus-like changes in transgenic mice expressing TALL-1 under the control of a beta-actin promoter. The TALL-1 transgenic mice showed severe enlargement of spleen, lymph nodes, and Peyer's patches because of an increased number of B220+ cells. The transgenic mice also had hypergammaglobulinemia contributed by elevations of serum IgM, IgG, IgA, and IgE. In addition, a phenotype similar to autoimmune lupus-like disease was also seen in TALL-1 transgenic mice, characterized by the presence of autoantibodies to nuclear antigens and immune complex deposits in the kidney. Prolonged survival and hyperactivity of transgenic B cells may contribute to the autoimmune lupus-like phenotype in these animals. Our studies further confirm TALL-1 as a stimulator of B cells that affect Ig production. Thus, TALL-1 may be a primary mediator in B cell-associated autoimmune diseases.     

In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells

Background

Brain tumor-initiating cells (BTICs) are stem-like cells hypothesized to form a disease reservoir that mediates tumor recurrence in high-grade gliomas. Oncolytic virotherapy uses replication-competent viruses to target and kill malignant cells and has been evaluated in clinic for glioma therapy with limited results. Myxoma virus (MyxV) is a safe and highly effective oncolytic virus (OV) in conventional glioma models but, as seen with other OVs, is only modestly effective for patient-derived BTICs. The objective of this study was to determine whether MyxV treatment against human BTICs could be improved by combining chemotherapeutics and virotherapy.

Methods

A 73-compound library of drug candidates in clinical use or preclinical development was screened to identify compounds that sensitize human BTICs to MyxV treatment in vitro, and synergy was evaluated mathematically in lead compounds using Chou-Talalay analyses. The effects of combination therapy on viral gene expression and viral replication were also assessed.

Results

Eleven compounds that enhance MyxV efficacy were identified, and 6 were shown to synergize with the virus using Chou-Talalay analyses. Four of the synergistic compounds were shown to significantly increase viral gene expression, indicating a potential mechanism for synergy. Three highly synergistic compounds (axitinib, a VEGFR inhibitor; rofecoxib, a cyclooxygenase-2 inhibitor; and pemetrexed, a folate anti-metabolite) belong to classes of compounds that have not been previously shown to synergize with oncolytic viruses in vitro.

Conclusions

This study has identified multiple novel drug candidates that synergistically improve MyxV efficacy in a preclinical BTIC glioma model.     

Efficacy and safety of bosentan in adults with simple and complex Eisenmenger's syndrome

Background. Eisenmenger's syndrome (ES) is associated with decreased longevity and reduced functional capacity. Targeted pharmacologic therapies improve functional capacity and survival in these patients. We sought to compare the response of patients with simple vs. complex ES following initiation of bosentan. Methods. ES patients with a history of bosentan use were identified by chart review. Simple ES was defined as ES associated with atrial septal defect, ventricular septal defect, or patent ductus arteriosus. Complex ES consisted of patients with truncus arteriosus and single ventricle congenital heart disease. Six‐minute walking distance (6MWD), maximal oxygen consumption (VO₂ max), brain natriuretic peptide (BNP), and resting oxygen saturation were compared between simple and complex ES patients before and after bosentan treatment. Results. Twenty‐four patients were included (11 simple, 13 complex). Resting oxygen saturation, 6MWD, VO₂ max, and BNP were not significantly different between the two groups prior to bosentan initiation. Ten patients received bosentan monotherapy, and bosentan was used in combination with sildenafil in 13 (five simple, eight complex). One patient received bosentan with iloprost. Mean duration of therapy was 38 ± 14 months in the simple group and 40 ± 8.1 months in the complex group (P= NS). Posttreatment, 6MWD increased from 274 ± 135 m to 326 ± 106 m in simple ES patients (P= .32). 6MWD in patients with complex ES increased from 332 ± 51 m to 364 ± 109 (P= .028). VO₂ max improved from 13.4 ± 3.8 to 17 ± 6 (P= .54) in the simple group, while VO₂ max in the complex group improved from 12.7 ± 2.3 to 15.5 ± 2.2 (P= .17). There was minimal change in BNP or resting oxygen saturation between the groups. Conclusions. Treatment with bosentan is both safe and effective in patients with both simple and complex forms of ES.     

Gender Differences in Acute and Chronic Pain in the Emergency Department: Results of the 2014 Academic Emergency Medicine Consensus Conference Pain Section

Pain is a leading public health problem in the United States, with an annual economic burden of more than $630 billion, and is one of the most common reasons that individuals seek emergency department (ED) care. There is a paucity of data regarding sex differences in the assessment and treatment of acute and chronic pain conditions in the ED. The Academic Emergency Medicine consensus conference convened in Dallas, Texas, in May 2014 to develop a research agenda to address this issue among others related to sex differences in the ED. Prior to the conference, experts and stakeholders from emergency medicine and the pain research field reviewed the current literature and identified eight candidate priority areas. At the conference, these eight areas were reviewed and all eight were ratified using a nominal group technique to build consensus. These priority areas were: 1) gender differences in the pharmacological and nonpharmacological interventions for pain, including differences in opioid tolerance, side effects, or misuse; 2) gender differences in pain severity perceptions, clinically meaningful differences in acute pain, and pain treatment preferences; 3) gender differences in pain outcomes of ED patients across the life span; 4) gender differences in the relationship between acute pain and acute psychological responses; 5) the influence of physician–patient gender differences and characteristics on the assessment and treatment of pain; 6) gender differences in the influence of acute stress and chronic stress on acute pain responses; 7) gender differences in biological mechanisms and molecular pathways mediating acute pain in ED populations; and 8) gender differences in biological mechanisms and molecular pathways mediating chronic pain development after trauma, stress, or acute illness exposure. These areas represent priority areas for future scientific inquiry, and gaining understanding in these will be essential to improving our understanding of sex and gender differences in the assessment and treatment of pain conditions in emergency care settings.     

Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection

Spontaneous resolution of hepatitis C virus (HCV) infection is a relatively infrequent event, and these individuals provide a unique opportunity to characterize correlates of protective immunity as an important first step in the development of vaccine candidates. The aim of this study was to directly and comprehensively enumerate HCV-nonstructural protein 3 (NS3) specific CD4(+) and CD8(+) T cells ex vivo from HLA diverse individuals who had been successful in spontaneously resolving HCV infection. We measured interferon gamma (IFN-gamma) production with an ELISPOT assay using magnetic bead-separated CD4(+) or CD8(+) T cells in response to autologous DCs that had been pulsed with 15mer per peptides overlapping by 11 amino acids and spanning all of the NS3 protein (150 total peptides). All subjects with spontaneously recovered HCV infection demonstrated vigorous and multispecific CD4(+) T-cell responses to NS3 peptides, and 6 of 10 subjects demonstrated CD8(+) T-cell responses. More importantly, we identified novel, previously unpredicted antigenic regions, which in most cases elicited high frequencies within a given individual. In conclusion, subjects who have spontaneously eradicated HCV infection up to 35 years earlier demonstrate persistent CD4(+) and CD8(+) T-cell responses specific to NS3. By providing a comprehensive screening of all potential T-cell epitopes contained in the NS3 region, our strategy defines the breadth of the T-cell response and identifies novel, unpredicted specificities.