Evaluation of Technology-Enabled Monitoring of Patient-Reported Outcomes to Detect and Treat Toxic Effects Linked to Immune Checkpoint Inhibitors.

Importance: Immune checkpoint inhibitors can produce distinct toxic effects that require prompt recognition and timely management.

Objective: To develop a technology-enabled, dynamically adaptive protocol that can provide the accurate information needed to inform specific remedies for immune toxic effects in patients treated with immune checkpoint inhibitors.

Design, Setting, And Participants: An open-label cohort study was conducted at a single tertiary referral center from September 6, 2019, to September 3, 2020.

A Bronchial Genomic Classifier for the Diagnostic Evaluation of Lung Cancer.

Background: Bronchoscopy is frequently nondiagnostic in patients with pulmonary lesions suspected to be lung cancer. This often results in additional invasive testing, although many lesions are benign. We sought to validate a bronchial-airway gene-expression classifier that could improve the diagnostic performance of bronchoscopy.

Derivation of a bronchial genomic classifier for lung cancer in a prospective study of patients undergoing diagnostic bronchoscopy.

Background: The gene expression profile of cytologically-normal bronchial airway epithelial cells has previously been shown to be altered in patients with lung cancer. Although bronchoscopy is often used for the diagnosis of lung cancer, its sensitivity is imperfect, especially for small and peripheral suspicious lesions. In this study, we derived a gene expression classifier from airway epithelial cells that detects the presence of cancer in current and former smokers undergoing bronchoscopy for suspect lung cancer and evaluated its sensitivity to detect lung cancer among patients from an independent cohort.

Mcl-1 dependence predicts response to vorinostat and gemtuzumab ozogamicin in acute myeloid leukemia.

Older adults with acute myeloid leukemia (AML) are commonly considered for investigational therapies, which often only benefit subsets of patients. In this study, we assessed whether BH3 profiling of apoptotic functionality could predict outcomes following treatment with vorinostat (histone deacetylase inhibitor) and gemtuzumab ozogamicin (GO; CD33-targeted immunoconjugate). Flow cytometry of BH3 peptide priming with Noxa (anti-apoptotic protein Mcl-1 modulator) correlated with remission induction (p=.

A peripheral blood gene expression score is associated with atherosclerotic Plaque Burden and Stenosis by cardiovascular CT-angiography: results from the PREDICT and COMPASS studies.

Objective: We previously validated a gene expression score (GES) based on age, sex and peripheral blood cell expression levels of 23 genes measured by quantitative real-time PCR (qRT-PCR) for diagnosis of obstructive coronary artery disease (CAD) (≥ 50% luminal diameter stenosis). In this study we sought to determine the association between the GES and coronary arterial Plaque Burden and Stenosis by CT-angiography.

Methods: A total of 610 patients (mean age: 57 ± 11; 50% male) from the PREDICT and COMPASS studies from 59 centers were analyzed.

Personalized reproductive medicine on the brink: progress, opportunities and challenges ahead.

Significant progress has been made in several fields of medicine towards personalizing treatment recommendations based on individual patient genotype. As the number of clinical and genetic biomarkers available to physicians has increased, predictive models able to integrate the contributions of multiple variables simultaneously have become valuable tools for medical decision making. Leveraging genotype information and multivariate predictive models holds the promise of bringing greater efficiency to, and reducing the costs of, fertility treatments.

Clinical implications of referral bias in the diagnostic performance of exercise testing for coronary artery disease.

Background: Exercise testing with echocardiography or myocardial perfusion imaging is widely used to risk-stratify patients with suspected coronary artery disease. However, reports of diagnostic performance rarely adjust for referral bias, and this practice may adversely influence patient care. Therefore, we evaluated the potential impact of referral bias on diagnostic effectiveness and clinical decision-making.

A peripheral blood gene expression score is associated with plaque volume and phenotype by intravascular ultrasound with radiofrequency backscatter analysis: results from the ATLANTA study.

Background: A composite, peripheral gene expression score based on quantitative RNA-measurements has been validated for detecting stenosis against invasive coronary X-ray angiography. IVUS/VH has been validated for quantitative measurements of coronary plaque volume and composition and has been shown to be predictive of outcomes and treatment effects. The correlation between peripheral gene expression and coronary plaque composition by intravascular ultrasound with radiofrequency backscatter (IVUS/VH) is unknown.

Apoprotein B, small-dense LDL and impaired HDL remodeling is associated with larger plaque burden and more noncalcified plaque as assessed by coronary CT angiography and intravascular ultrasound with radiofrequency backscatter: results from the ATLANTA I study.

Background: Apoprotein B-containing lipoproteins are atherogenic, but atheroprotective functions of apoprotein A-containing high-density lipoprotein (HDL) particles are poorly understood. The association between lipoproteins and plaque components by coronary computed tomography angiography (CTA) and intravascular ultrasound with radiofrequency backscatter (IVUS/VH) has not been evaluated.

Methods And Results: Quantitative, 3-dimensional plaque measurements were performed in 60 patients with CTA and IVUS/VH.

BH3 profiling discriminates response to cytarabine-based treatment of acute myelogenous leukemia.

As acute myelogenous leukemia (AML) patient response to cytarabine-based standard-of-care treatment is variable, stratification into subgroups by biomarker-predicted response may lead to improved clinical outcomes. Here, we assess cell mitochondrial depolarization to proapoptotic signaling BH3-only peptides as a surrogate for the function of Bcl-2 family proteins to address clinical response to cytarabine-based therapy in patients with AML (N = 62). Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate specimens were obtained from newly diagnosed patients with AML, viably preserved, and assayed by flow cytometry following BH3 profile assay with individual BH3 peptides.

A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe?

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia.

A blood-based gene expression test for obstructive coronary artery disease tested in symptomatic nondiabetic patients referred for myocardial perfusion imaging the COMPASS study.

BACKGROUND- Obstructive coronary artery disease diagnosis in symptomatic patients often involves noninvasive testing before invasive coronary angiography. A blood-based gene expression score (GES) was previously validated in nondiabetic patients referred for invasive coronary angiography but not in symptomatic patients referred for myocardial perfusion imaging (MPI). METHODS AND RESULTS- This prospective, multicenter study obtained peripheral blood samples for GES before MPI in 537 consecutive patients.

A whole blood gene expression-based signature for smoking status.

Background: Smoking is the leading cause of preventable death worldwide and has been shown to increase the risk of multiple diseases including coronary artery disease (CAD). We sought to identify genes whose levels of expression in whole blood correlate with self-reported smoking status.

Methods: Microarrays were used to identify gene expression changes in whole blood which correlated with self-reported smoking status; a set of significant genes from the microarray analysis were validated by qRT-PCR in an independent set of subjects.

A gender-specific blood-based gene expression score for assessing obstructive coronary artery disease in nondiabetic patients: results of the Personalized Risk Evaluation and Diagnosis in the Coronary Tree (PREDICT) trial.

Background: Currently available noninvasive tests to risk stratify patients for obstructive coronary disease result in many unnecessary cardiac catheterizations, especially in women. We sought to compare the diagnostic accuracy of presenting symptoms, noninvasive test results, and a gene expression score (GES) in identifying obstructive coronary artery disease (CAD) according to gender, using quantitative coronary angiography as the criterion standard.

Methods: The PREDICT trial is a prospective multicenter observational study designed to develop and validate gene expression algorithms to assess obstructive CAD, defined as at least one ≥50% diameter stenosis measured by quantitative coronary angiography.

Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab.

Objective: To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA).

Methods: GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14.

Identification of factors contributing to variability in a blood-based gene expression test.

Background: Corus CAD is a clinically validated test based on age, sex, and expression levels of 23 genes in whole blood that provides a score (1-40 points) proportional to the likelihood of obstructive coronary disease. Clinical laboratory process variability was examined using whole blood controls across a 24 month period: Intra-batch variability was assessed using sample replicates; inter-batch variability examined as a function of laboratory personnel, equipment, and reagent lots.

Methods/results: To assess intra-batch variability, five batches of 132 whole blood controls were processed; inter-batch variability was estimated using 895 whole blood control samples.

Whole blood gene expression testing for coronary artery disease in nondiabetic patients: major adverse cardiovascular events and interventions in the PREDICT trial.

The majority of first-time angiography patients are without obstructive coronary artery disease (CAD). A blood gene expression score (GES) for obstructive CAD likelihood was validated in the PREDICT study, but its relation to major adverse cardiovascular events (MACE) and revascularization was not assessed. Patients (N = 1,160) were followed up for MACE and revascularization 1 year post-index angiography and GES, with 1,116 completing follow-up.

Serum markers associated with clinical improvement in patients with ankylosing spondylitis treated with golimumab.

Objective: Identify serum biomarkers modulated by golimumab treatment and associated with clinical response in patients with ankylosing spondylitis (AS).

Methods: Sera were collected at weeks 0, 4 and 14 from 100 patients with active AS in the GO-RAISE study. Patients were randomly assigned subcutaneous injections of placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks.

Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients.

Background: Alterations in gene expression in peripheral blood cells have been shown to be sensitive to the presence and extent of coronary artery disease (CAD). A non-invasive blood test that could reliably assess obstructive CAD likelihood would have diagnostic utility.

Results: Microarray analysis of RNA samples from a 195 patient Duke CATHGEN registry case:control cohort yielded 2,438 genes with significant CAD association (p < 0.

Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.

Background & Aims: Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.

Methods: We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls.

Association of serum markers with improvement in clinical response measures after treatment with golimumab in patients with active rheumatoid arthritis despite receiving methotrexate: results from the GO-FORWARD study.

Introduction: The goal of this study was to identify serum markers that are modulated by treatment with golimumab with or without methotrexate (MTX) and are associated with clinical response.

Methods: Sera were collected at weeks 0 and 4 from a total of 336 patients (training dataset, n = 100; test dataset, n = 236) from the GO-FORWARD study of patients with active rheumatoid arthritis despite MTX. Patients were randomly assigned to receive placebo plus MTX; golimumab, 100 mg plus placebo; golimumab, 50 mg plus MTX; or golimumab, 100 mg plus MTX.

Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia.

Objective: The onset of schizophrenia symptoms in late adolescence implies a neurodevelopmental trajectory for the disease. Indeed, the γ-aminobutyric acid (GABA) inhibitory system shows protracted development, and GABA-ergic deficits are widely replicated in postmortem schizophrenia studies. The authors examined expression of several interneuron markers across postnatal human development and in schizophrenia to assess whether protracted development of certain interneuron subpopulations may be associated with a particular vulnerability in schizophrenia.

Multicenter validation of the diagnostic accuracy of a blood-based gene expression test for assessing obstructive coronary artery disease in nondiabetic patients.

Background: Diagnosing obstructive coronary artery disease (CAD) in at-risk patients can be challenging and typically requires both noninvasive imaging methods and coronary angiography, the gold standard. Previous studies have suggested that peripheral blood gene expression can indicate the presence of CAD.

Objective: To validate a previously developed 23-gene, expression-based classification test for diagnosis of obstructive CAD in nondiabetic patients.

Molecular evidence that cortical synaptic growth predominates during the first decade of life in humans.

Theories concerning the pathology of human neurodevelopmental disorders that emerge in adolescence, such as schizophrenia, often hypothesize that there may be a failure of normal cortical synaptic loss or pruning. However, direct evidence that synaptic regression is a major developmental event in the adolescent human cortex is limited. Furthermore, developmental work in rodents suggested that synaptic regression in adolescence is not a major feature of cortical development.

Developmental co-regulation of the beta and gamma GABAA receptor subunits with distinct alpha subunits in the human dorsolateral prefrontal cortex.

The GABA(A) receptor (GABA(A)R) is a pentameric chloride ion channel that mediates neuronal inhibition and is commonly comprised of 2alpha, 2beta and 1gamma subunits. These subunits have distinct characteristics that critically impact receptor function. In this study, we sought to determine if developmental expression of the beta and gamma subunit mRNAs in the prefrontal cortex would show complementary or opposing patterns of change as compared to the alpha subunits.