Changes in self-confidence in professional, personal, and scientific skills by gender during physician-scientist training at the University of Pittsburgh.

Introduction: Persistence in physician-scientist careers has been suboptimal, particularly among women. There is a gender gap in self-confidence in medicine. We measured the impact of our physician-scientist training programs on trainee's confidence in professional, personal, and scientific competencies, using a survey measuring self-rated confidence in 36 competencies across two timepoints.

Alterations in visible light exposure modulate platelet function and regulate thrombus formation.

Background: Variations in light exposure are associated with changes in inflammation and coagulation. The impact of light spectra on venous thrombosis (VT) and arterial thrombosis is largely unexplored.

Objectives: To investigate the impact of altering light spectrum on platelet function in thrombosis.

Career trajectories of MD-PhD physician scientists: The loss of women investigators.

Advances in biomedical research require a robust physician scientist workforce. Despite being equally successful at securing early career awards from the NIH as men, women MD-PhD physician scientists are less likely to serve as principal investigators on mid- and later careers awards. Here, we discuss the causes of gender disparities in academic medicine, the implications of losing highly trained women physician scientists, and the institutional and systemic changes needed to sustain this pool of talented investigators.

MACROPHAGE SWITCHING: POLARIZATION AND MOBILIZATION AFTER TRAUMA.

Introduction: Trauma alters the immune response in numerous ways, affecting both the innate and adaptive responses. Macrophages play an important role in inflammation and wound healing following injury. We hypothesize that macrophages mobilize from the circulation to the site of injury and secondary sites after trauma, with a transition from proinflammatory (M1) shortly after trauma to anti-inflammatory (M2) at later time points.

An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain.

Background: Aicardi-Goutières syndrome (AGS) is a severe neurodegenerative disease with clinical features of early-onset encephalopathy and progressive loss of intellectual abilities and motor control. Gene mutations in seven protein-coding genes have been found to be associated with AGS. However, the causative role of these mutations in the early-onset neuropathogenesis has not been demonstrated in animal models, and the mechanism of neurodegeneration of AGS remains ambiguous.

Innate immune activation without immune cell infiltration in brains of murine models of Aicardi-Goutières Syndrome.

Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi-Goutières Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1).

Predoctoral MD-PhD grants as indicators of future NIH funding success.

MD-PhD trainees constitute an important source of physician-scientists. Persistence on this challenging path is facilitated by success in garnering independent (R grant) support from the NIH. Published research tracks academic appointments and global R01 success for MD-PhD trainees but has not included information on future funding success of individual MD-PhD predoctoral grant holders.

Aicardi-Goutières syndrome-associated mutation at ADAR1 gene locus activates innate immune response in mouse brain.

Background: Aicardi-Goutières syndrome (AGS) is a severe infant or juvenile-onset autoimmune disease characterized by inflammatory encephalopathy with an elevated type 1 interferon-stimulated gene (ISG) expression signature in the brain. Mutations in seven different protein-coding genes, all linked to DNA/RNA metabolism or sensing, have been identified in AGS patients, but none of them has been demonstrated to activate the IFN pathway in the brain of an animal. The molecular mechanism of inflammatory encephalopathy in AGS has not been well defined.

Syngeneic tobacco carcinogen-induced mouse lung adenocarcinoma model exhibits PD-L1 expression and high tumor mutational burden.

Human lung adenocarcinoma (LUAD) in current or former smokers exhibits a high tumor mutational burden (TMB) and distinct mutational signatures. Syngeneic mouse models of clinically relevant smoking-related LUAD are lacking. We established and characterized a tobacco-associated, transplantable murine LUAD cell line, designated FVBW-17, from a LUAD induced by the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone in the FVB/N mouse strain.

The Highly Structured Physician Scientist Training Program (PSTP) for Medical Students at the University of Pittsburgh.

The University of Pittsburgh School of Medicine Physician Scientist Training Program (PSTP) is a 5-year medical student training program designed to prepare the next generation of MD-only physician-scientists engaging in preclinical research. This article provides an overview of the program, including the novel longitudinal structure and competency goals, which facilitate success and persistence in a laboratory-based physician-scientist career. The authors present data on 81 medical students accepted to the program from academic year 2007-2008 through 2018-2019.

Foveation dynamics in congenital nystagmus IV: vergence.

Purpose: To evaluate foveation dynamics and characteristics of vergence eye movements during fixation of static targets at different distances and while tracking a target moving in depth in a subject with congenital nystagmus (CN).

Method: Eye movements of a well-studied subject with CN were recorded using the magnetic search coil technique and analyzed using the OMtools software, including the eXpanded Nystagmus Acuity Function (NAFX).

Results: Both the phase planes and NAFX values during fixation of targets at various near distances were equivalent to those during fixation of a far target.

Anti-CTLA-4 synergizes with dendritic cell-targeted vaccine to promote IL-3-dependent CD4 effector T cell infiltration into murine pancreatic tumors.

One successful class of cancer immunotherapies, immune checkpoint inhibitory antibodies, disrupts key pathways that regulate immune checkpoints, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These agents unleash the potency of antigen-experienced T cells that have already been induced as a consequence of the existing tumor. But only 20% of cancers naturally induce T cells.

Implantable cardioverter-defibrillators in heart failure patients with reduced ejection fraction and diabetes.

Aim: There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes.

Gestational Diabetes Mellitus: Post-partum Risk and Follow Up.

Background: Women with gestational diabetes mellitus (GDM) are at an increased risk for developing metabolic syndrome, type 2 diabetes mellitus (T2DM), and cardiovascular disease. In this review, we will discuss postpartum cardiovascular and diabetes risk in women with a history of GDM and different ways to improve postpartum screening.

Methods: This review involves a comprehensive literature review on gestational diabetes and postpartum risk for cardiovascular disease and diabetes mellitus as well as post-partum screening methods.

New York Heart Association class and the survival benefit from primary prevention implantable cardioverter defibrillators: A pooled analysis of 4 randomized controlled trials.

Background: Primary prevention implantable cardioverter defibrillator (ICD) reduce all-cause mortality by reducing sudden cardiac death. There are conflicting data regarding whether patients with more advanced heart failure derive ICD benefit owing to the competing risk of nonsudden death.

Methods: We performed a patient-level meta-analysis of New York Heart Association (NYHA) class II/III heart failure patients (left ventricular ejection fraction ≤35%) from 4 primary prevention ICD trials (MADIT-I, MADIT-II, DEFINITE, SCD-HeFT).

In vivo targeting of protein antigens to dendritic cells using anti-DEC-205 single chain antibody improves HIV Gag specific CD4 T cell responses protecting from airway challenge with recombinant vaccinia-gag virus.

Introduction: Targeting antigens to dendritic cells (DCs) in vivo via a DC-restricted endocytic receptor, DEC205, has been validated to enhance immunity in several vaccine platforms. Particularly atttractive is selected delivery of proteins to DCs in vivo because it enables proteins to be more immunogenic and provides a cheaper and effective way for repeated immunizations.

Methods: In this study, we tested the efficacy of a single chain antibody to DEC205 (scDEC) to deliver protein antigens selectively to DCs in vivo and to induce protective immunity.

Downregulation of estrogen receptor and modulation of growth of breast cancer cell lines mediated by paracrine stromal cell signals.

Purpose: Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. We explored the ability of marrow-derived stromal cell lines to arrest co-cultured breast cancer cells and suppress estrogen receptor alpha (ER) expression during arrest, facilitating the emergence of estrogen-independent breast cancer clones.

Dendritic Cells Induce a Subpopulation of IL-12Rβ2-Expressing Treg that Specifically Consumes IL-12 to Control Th1 Responses.

Cytokines secreted from dendritic cells (DCs) play an important role in the regulation of T helper (Th) cell differentiation and activation into effector cells. Therefore, controlling cytokine secretion from DCs may potentially regulate Th differentiation/activation. DCs also induce de-novo generation of regulatory T cells (Treg) that modulate the immune response.

ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis.

Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen's naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonary mycobacterial load).

Outcomes of implantable cardioverter-defibrillator use in patients with comorbidities: results from a combined analysis of 4 randomized clinical trials.

Objectives: The aim of this study was to determine if the benefit of implantable cardioverter-defibrillators (ICDs) is modulated by medical comorbidity.

Background: Primary prevention ICDs improve survival in patients at risk for sudden cardiac death. Their benefit in patients with significant comorbid illness has not been demonstrated.

Classical Flt3L-dependent dendritic cells control immunity to protein vaccine.

DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent.

Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross-tolerance.

Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C-type lectin Langerin/CD207 are cross-presented to CD8(+) T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin(+) dermal DCs (dDCs) in different vaccination settings.