Single Cell Droplet-Based Efficacy and Transcriptomic Analysis of a Novel Anti-KLRG1 Antibody for Elimination of Autoreactive T Cells.

Progress in developing improvements in the treatment of autoimmune disease has been gradual, due to challenges presented by the nature of these conditions. Namely, the need to suppress a patient's immune response while maintaining the essential activity of the immune system in controlling disease. Targeted treatments to eliminate the autoreactive immune cells driving disease symptoms present a promising new option for major improvements in treatment efficacy and side effect management.

PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models.

Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFNγ exposure confers resistance to immunotherapy targeting PD-1 (α-PD-1) in immunocompetent female mice.

PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity.

PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. Here, we identify PARP7 as a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 restores type I interferon (IFN) signaling responses to nucleic acids in tumor models.

Targeting Calcium Release-activated Calcium Channel Is Not Sufficient to Prevent Rejection in Nonhuman Primate Kidney Transplantation.

Background: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity.

Methods: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3).

A Pilot Observational Study of an Acupressure/Acupuncture Intervention in Children with Autism Spectrum Disorder.

Objectives: To determine whether children with autism spectrum disorder (ASD) would tolerate an acupressure/acupuncture intervention and whether parents would adhere to a twice-weekly, 8-week intervention protocol. Second, to further understand best measures to use to capture impact of intervention on behavioral and regulatory functions.

Design: This is an observational pilot study with pre-, mid-, and postintervention measures.

Autism Screening With Online Decision Support by Primary Care Pediatricians Aided by M-CHAT/F.

Background And Objective: Autism spectrum disorders (ASDs) often go undetected in toddlers. The Modified Checklist for Autism in Toddlers (M-CHAT) With Follow-up Interview (M-CHAT/F) has been shown to improve detection and reduce over-referral. However, there is little evidence supporting the administration of the interview by a primary care pediatrician (PCP) during typical checkups.

The HSP90 Inhibitor Ganetespib Alleviates Disease Progression and Augments Intermittent Cyclophosphamide Therapy in the MRL/lpr Mouse Model of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex, systemic autoimmune disease with a diverse range of immunological and clinical manifestations. The introduction of broad spectrum immunosuppressive therapies and better management of acute disease exacerbations have improved outcomes for lupus patients over recent years. However, these regimens are burdened by substantial toxicities and confer significantly higher risks of infection, thus there remains a significant and unmet medical need for alternative treatment options, particularly those with improved safety profiles.

The impact of social skills training for social anxiety disorder: a randomized controlled trial.

Objective: Social anxiety disorder (SAD) impacts social, occupational and academic functioning. Although many interventions report change in social distress, improvement in social behavior remains under-addressed. This investigation examined the additive impact of social skills training (SST) for the treatment of SAD.

Association between severity of behavioral phenotype and comorbid attention deficit hyperactivity disorder symptoms in children with autism spectrum disorders.

Autism spectrum disorder and attention deficit hyperactivity disorder are neurodevelopmental disorders that cannot be codiagnosed under existing diagnostic guidelines (Diagnostic and Statistical Manual of the American Psychiatric Association, 4th ed., text rev.).

Characterization of a novel CRAC inhibitor that potently blocks human T cell activation and effector functions.

Store operated calcium entry (SOCE) downstream of T cell receptor (TCR) activation in T lymphocytes has been shown to be mediated mainly through the Calcium Release Activated Calcium (CRAC) channel. Here, we compared the effects of a novel, potent and selective CRAC current inhibitor, 2,6-Difluoro-N-{5-[4-methyl-1-(5-methyl-thiazol-2-yl)-1,2,5,6-tetrahydro-pyridin-3-yl]-pyrazin-2-yl}-benzamide (RO2959), on T cell effector functions with that of a previously reported CRAC channel inhibitor, YM-58483, and a calcineurin inhibitor Cyclosporin A (CsA). Using both electrophysiological and calcium-based fluorescence measurements, we showed that RO2959 is a potent SOCE inhibitor that blocked an IP3-dependent current in CRAC-expressing RBL-2H3 cells and CHO cells stably expressing human Orai1 and Stim1, as well as SOCE in human primary CD4(+) T cells triggered by either TCR stimulation or thapsigargin treatment.

Mitochondrial electron transport is the cellular target of the oncology drug elesclomol.

Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined.

Social skills and social phobia: an investigation of DSM-IV subtypes.

Social phobia is characterized as pervasive social timidity in social settings. Although much is known about this disorder, aspects of its clinical presentation remain unexplored, in particular characteristics that distinguish the generalized and non-generalized subtypes. For example, it remains unclear whether patients with the non-generalized subtype display social skills deficits in social interactions, and if so, are these deficits clinically, as well as statistically, significant? In this study, adults with either the non-generalized (NGSP; n=60) or generalized (GSP; n=119) subtype of social phobia and adults with no psychological disorder (n=200) completed an extensive behavioral assessment of social skill and social anxiety.

The impact of children with high-functioning autism on parental stress, sibling adjustment, and family functioning.

The article discusses a study conducted to investigate the impact of children with high-functioning autism (HFA) on parental stress, sibling adjustment, and family functioning; the study involves a sample of parents of 15 children with HFA and parents of 15 matched control children who completed questionnaires measuring the dependent variables. The results indicate parents of children with HFA experience significantly more parenting stress than parents of children with no psychological disorder, which was found to be directly related to characteristics of the children. The study further shows that the higher intellectual functioning in children with HFA does not compensate for the stress associated with parenting children with autism spectrum disorders.

Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels.

CRACM1 (also called Orai1) constitutes the pore subunit of store-operated calcium release-activated calcium channels. A point mutation in the gene encoding CRACM1 is associated with severe combined immunodeficiency disease in humans. Here we generated CRACM1-deficient mice in which beta-galactosidase activity 'reported' CRACM1 expression.

Social skills interventions for children with Asperger's syndrome or high-functioning autism: a review and recommendations.

This paper reviews the literature examining social skills training (SST) programs for youth with AS/HFA, with an emphasis on critically evaluating efficacy and highlighting areas of future research. The review highlights the disparity between SST programs described in the extant literature, including lack of a universal definition of social skills, various levels of intensity and duration of treatment, divergent theoretical backgrounds, and variety in services provided in clinic or classroom settings. Overall, it is clear that, despite their widespread clinical use, empirical support for SST programs for children with AS/HFA is minimal at this time.

Social anxiety disorder in childhood and adolescence: descriptive psychopathology.

Although the presentation of social anxiety disorder (SAD) in adults is well documented, less is known about its clinical manifestation in children and adolescents. To date, most studies have included combined samples of children and adolescents despite the fact that this age range represents an extensive period of growth and development. This study compares and contrasts the clinical presentation of SAD among children (ages 7-12) and adolescents (ages 13-17).

Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF-{beta}.

T cells with immunoregulatory function have been described in human and mouse systems. In both systems these cells can be differentiated either in the thymus or from peripheral T cells. To date, more progress has been made in the study of murine regulatory T cells, because it has been very difficult to isolate human regulatory T cells of sufficient purity and in sufficient numbers to permit detailed examinations of their biochemistry.

Computerized screening of substance abuse problems in a primary care setting: older vs. younger adults.

The purpose of the current study was to examine differences in responses of older adults (age 55 and above) and younger adults (ages 18 to 54) to the Drug Abuse Problem Assessment for Primary Care (DAPA-PC), a computerized drug and alcohol abuse screening instrument developed for primary care settings. Data were collected from a diverse population of 327 adults presenting for care at The George Washington University Medical Faculty Associates clinic in downtown Washington, DC. Results indicated that rates of drug and alcohol abuse were similar in both groups.

Induction of immunological tolerance/hyporesponsiveness in baboons with a nondepleting CD4 antibody.

Tolerance induction with anti-CD4 Abs is well established in rodent transplant and autoimmune disease models, but has yet to be demonstrated in non-human primates or in clinical studies. In retrospect, failure of anti-CD4 Abs to induce tolerance in primates may be technical, a consequence of insufficient dosing and Ab properties influencing immunogenicity and cell depletion. To circumvent these possible limitations, we constructed a novel anti-CD4 mAb, TRX1, humanized to reduce immunogenicity and Fc-modified to prevent cell depletion.

Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted.

A central role for leukocytes in neointimal hyperplasia after arterial injury is suspected. However, the relative importance of neutrophils and monocytes in balloon or stent-induced injury are not well understood, and mechanistic targeting of leukocyte recruitment or function is crude. We determined the temporal and spatial distribution of different leukocytes after balloon and stent-induced injury in primate iliac arteries.