Echocardiographic determination of pulmonary arterial capacitance.

A growing body of evidence has demonstrated that pulmonary arterial capacitance (PAC) is the strongest hemodynamic predictor of clinical outcomes across a wide spectrum of cardiovascular disease, including pulmonary hypertension and heart failure. We hypothesized that a ratio of right ventricular stroke volume (RVOT VTI) to the associated peak arterial systolic pressure (PASP) could function as a reliable non-invasive surrogate for PAC. We performed a prospective study of patients undergoing simultaneous transthoracic echocardiography and right heart catheterization (RHC) for various clinical indications.

Seamless Designs: Current Practice and Considerations for Early-Phase Drug Development in Oncology.

Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns.

Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study.

Importance: Atezolizumab (anti-programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported.

Objective: To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC.

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial.

Background: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types.

Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: final results from a phase I study.

Introduction: Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, inhibits PD-L1:PD-1 and PD-L1:B7.1 interactions, restoring anticancer immunity. Here, we report final analyses from the non-small-cell lung cancer (NSCLC) cohort of the first atezolizumab phase I study.

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma.

Purpose: Glioblastoma is the most common primary malignant brain tumor. No standard treatment exists for recurrent disease. Glioblastoma is associated with an immunosuppressive tumor microenvironment.

Portrait of a leader in immunotherapeutics.

It's the question that every grade school kid has to answer at some point or another--"What do you want to be when you grow up?" My mom still has the second grade paper on which I first wrote down that I wanted to be a "physician scientist." I'm quite certain that I probably didn't know exactly what a physician scientist was at the time. I certainly didn't know any physician scientists personally, nor was I exposed to academic environments in the tiny Minnesota town in which I grew up.

Myocardial stress and hypertrophy: a complex interface between biophysics and cardiac remodeling.

Pressure and volume overload results in concentric and eccentric hypertrophy of cardiac ventricular chambers with, respectively, parallel and series replication of sarcomeres. These divergent patterns of hypertrophy were related 40 years ago to disparate wall stresses in both conditions, with systolic wall stress eliciting parallel replication of sarcomeres and diastolic wall stress, series replication. These observations are relevant to clinical practice, as they relate to the excessive hypertrophy and contractile dysfunction regularly observed in patients with aortic stenosis.

Validity of self-reported adult secondhand smoke exposure.

Objectives: Exposure of adults to secondhand smoke (SHS) has immediate adverse effects on the cardiovascular system and causes coronary heart disease. The current study evaluated brief self-report screening measures for accurately identifying adult cardiology patients with clinically significant levels of SHS exposure in need of intervention.

Design And Setting: A cross-sectional study conducted in a university-affiliated cardiology clinic and cardiology inpatient service.

Advanced Donor Age Impairs Bone Marrow Cell Therapeutic Efficacy for Cardiac Disease.

Therapeutic results of clinical autologous bone marrow cell (BMC) therapy trials for cardiac disease have been modest compared to results of BMC implantation into rodent hearts post-myocardial infarction (MI). In clinical trials, autologous BMCs are typically harvested from older patients who have recently suffered an MI. In contrast, experimental studies in rodent models typically utilize donor BMCs isolated from young, healthy, inbred mice that are not the recipients.

Sca-1+ cardiosphere-derived cells are enriched for Isl1-expressing cardiac precursors and improve cardiac function after myocardial injury.

Background: Endogenous cardiac progenitor cells are a promising option for cell-therapy for myocardial infarction (MI). However, obtaining adequate numbers of cardiac progenitors after MI remains a challenge. Cardiospheres (CSs) have been proposed to have cardiac regenerative properties; however, their cellular composition and how they may be influenced by the tissue milieu remains unclear.

Granzyme B regulates antiviral CD8+ T cell responses.

CTLs and NK cells use the perforin/granzyme cytotoxic pathway to kill virally infected cells and tumors. Human regulatory T cells also express functional granzymes and perforin and can induce autologous target cell death in vitro. Perforin-deficient mice die of excessive immune responses after viral challenges, implicating a potential role for this pathway in immune regulation.

Newborn screening for severe combined immunodeficiency; the Wisconsin experience (2008-2011).

Severe combined immunodeficiency is a life-threatening primary immune deficiency characterized by low numbers of naïve T cells. Early diagnosis and treatment of this disease decreases mortality. In 2008, Wisconsin began newborn screening of infants for severe combined immunodeficiency and other forms of T-cell lymphopenia by the T-cell receptor excision circle assay.

Cardiology Rx for Change: improving clinical attention to tobacco use and secondhand smoke exposure in cardiology.

Background: Heart disease is the leading cause of tobacco-related death in smokers and of deaths due to secondhand smoke (SHS) exposure in nonsmokers. This study centers on the development and evaluation of an evidence-based model curriculum for improving clinical attention to tobacco use and SHS exposure in cardiology.

Hypothesis: We hypothesized that the curriculum would be associated with improvements in clinician tobacco-related knowledge, attitudes, confidence, and counseling behaviors from pre-to post-training and at the 3-month follow-up.

Efficacy, safety, and pharmacokinetics of a 10% liquid immune globulin preparation (GAMMAGARD LIQUID, 10%) administered subcutaneously in subjects with primary immunodeficiency disease.

A multi-center, prospective, open-label study was conducted in primary immunodeficiency disease patients to determine the tolerability and pharmacokinetics of a 10% liquid IgG preparation administered subcutaneously. Forty-nine subjects (3-77 years old) were enrolled. Pharmacokinetic equivalence of subcutaneous treatment was achieved at a median dose of 137% of the intravenous dose, with a mean trough IgG level of 1,202 mg/dL at the end of the assessment period.

Language and literacy relate to lack of children's dental sealant use.

Objectives: This study aimed to determine the percent of California's third grade public school children lacking sealants by child and family factors and to measure social disparities for lacking sealants.

Methods: The study analyzed data from the California Oral Health Needs Assessment (COHNA) 2004-2005, a complex stratified cluster sample of children (n = 10,450) from 182 randomly selected public elementary schools in California. The dependent variable was absence of sealants in first permanent molars.

Cytokine combination therapy with erythropoietin and granulocyte colony stimulating factor in a porcine model of acute myocardial infarction.

Purpose: Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model.

Methods: MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery.

Nitric oxide synthase expression and functional response to nitric oxide are both important modulators of circulating angiogenic cell response to angiogenic stimuli.

Objective: Circulating angiogenic cells (CACs), also termed endothelial progenitor cells, play an integral role in vascular repair and are functionally impaired in coronary artery disease (CAD). The role of nitric oxide (NO) in CAC function is poorly understood. We hypothesized that CAC migration toward angiogenic signals is modulated by both NO synthase (NOS) expression and functional response to NO.

Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies.

Primary immunodeficiency disease (PIDD) associated with hypogammaglobulinemia is typically treated with immunoglobulin replacement therapy. When administered as intravenous immunoglobulin (IVIG), an IgG trough occurs prior to the next replacement dose. While frequently measured, IgG trough levels required to minimize infection risk are not established.

Cytokine combination therapy with long-acting erythropoietin and granulocyte colony stimulating factor improves cardiac function but is not superior than monotherapy in a mouse model of acute myocardial infarction.

Background: Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) are potential novel therapies after myocardial infarction (MI). We first established the optimal and clinically applicable dosages of these drugs in mobilizing hematopoietic stem cells (HSC), and then tested the efficacy of monotherapy and combination therapy post-MI.

Methods And Results: Optimal doses were established in enhanced green fluorescent protein (eGFP) + chimeric mice (n = 30).

Timing of bone marrow cell therapy is more important than repeated injections after myocardial infarction.

Background: Bone marrow cell treatment has been proposed as a therapy for myocardial infarction, but the optimal timing and number of injections remain unknown.

Methods: Myocardial infarction was induced in mice followed by ultrasound-guided injection of mouse bone marrow cells at different time points post myocardial infarction (Days 3, 7, and 14) as monotherapy and at Days 3+7 as "double" therapy and at Days 3+7+14 as "triple" therapy. Controls received saline injections at Day 3 and Days 3+7+14.

Improvement of endothelial function with dietary flavanols is associated with mobilization of circulating angiogenic cells in patients with coronary artery disease.

Objectives: In patients with coronary artery disease (CAD) medically managed according to currently accepted guidelines, we tested whether a 1-month dietary intervention with flavanol-containing cocoa leads to an improvement of endothelial dysfunction and whether this is associated with an enhanced number and function of circulating angiogenic cells (CACs).

Background: Dietary flavanols can improve endothelial dysfunction. The CACs, also termed endothelial progenitor cells, are critical for vascular repair and maintenance of endothelial function.

Prolonged therapy with erythropoietin is safe and prevents deterioration of left ventricular systolic function in a porcine model of myocardial infarction.

Background: Erythropoietin (EPO) has generated interest as a novel therapy after myocardial infarction (MI), but the safety and efficacy of prolonged therapy have not been studied in a large animal model of reperfused MI.

Methods And Results: MI was induced in pigs by a 90-minute balloon occlusion of the left anterior descending coronary artery. Sixteen animals were randomized to either EPO or saline (control group).