Return of Research-Related Genetic Test Results and Genetic Discrimination Concerns: Facilitators and Barriers of Genetic Research Participation in Diverse Groups.

Background: Most genetics studies lack the diversity necessary to ensure that all groups benefit from genetic research.

Objectives: To explore facilitators and barriers to genetic research participation.

Methods: We conducted a survey on genetics in research and healthcare from November 15, 2017 to February 28, 2018 among adult Kaiser Permanente (KP) members who had been invited to participate in the KP biobank (KP Research Bank).

Demographic differences in the utilization of clinical and direct-to-consumer genetic testing.

Genetic testing has increased over the last decade due to growth in the number of clinical and direct-to-consumer (DTC) tests. However, there is uncertainty about how increased DTC genetic testing affects disparities. Between November 2017 and February 2018, a nationwide electronic survey on experiences with genetic testing was conducted among adult Kaiser Permanente members.

Physician Experience with Direct-To-Consumer Genetic Testing in Kaiser Permanente.

Health systems and physicians nationwide aspire to consistently and reliably apply genetic and genomic information to guide disease prevention, management, and treatment. However, clinical information, including genetics/genomics data from within and outside of the care delivery system, is expanding rapidly. Between November 2017 and April 2018, we surveyed 1502 Permanente Medical Group primary care and specialist physicians to assess the degree to which direct-to-consumer genetic test results were being presented to physicians and identify genetics educational needs among physicians (response rate 15%).

Correction: A collaborative translational research framework for evaluating and implementing the appropriate use of human genome sequencing to improve health.

[This corrects the article DOI: 10.1371/journal.pmed.

A collaborative translational research framework for evaluating and implementing the appropriate use of human genome sequencing to improve health.

In a Policy Forum, Muin Khoury and colleagues discuss research on the clinical application of genome sequencing data.

Principles and Recommendations for Standardizing the Use of the Next-Generation Sequencing Variant File in Clinical Settings.

A national workgroup convened by the Centers for Disease Control and Prevention identified principles and made recommendations for standardizing the description of sequence data contained within the variant file generated during the course of clinical next-generation sequence analysis for diagnosing human heritable conditions. The specifications for variant files were initially developed to be flexible with regard to content representation to support a variety of research applications. This flexibility permits variation with regard to how sequence findings are described and this depends, in part, on the conventions used.

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes, and epigenetic assays for genetic disorders.

College of American Pathologists' laboratory standards for next-generation sequencing clinical tests.

Context: The higher throughput and lower per-base cost of next-generation sequencing (NGS) as compared to Sanger sequencing has led to its rapid adoption in clinical testing. The number of laboratories offering NGS-based tests has also grown considerably in the past few years, despite the fact that specific Clinical Laboratory Improvement Amendments of 1988/College of American Pathologists (CAP) laboratory standards had not yet been developed to regulate this technology.

Objective: To develop a checklist for clinical testing using NGS technology that sets standards for the analytic wet bench process and for bioinformatics or "dry bench" analyses.

Methods-based proficiency testing in molecular genetic pathology.

This Perspectives article describes methods-based proficiency testing (MBPT), the benefits and limitations of MBPT, why the time is right for MBPT in molecular diagnostics, and how MBPT for next-generation sequencing is being developed by the College of American Pathologists.

Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.

This report of the Whole Genome Analysis group of the Association for Molecular Pathology illuminates the opportunities and challenges associated with clinical diagnostic genome sequencing. With the reality of clinical application of next-generation sequencing, technical aspects of molecular testing can be accomplished at greater speed and with higher volume, while much information is obtained. Although this testing is a next logical step for molecular pathology laboratories, the potential impact on the diagnostic process and clinical correlations is extraordinary and clinical interpretation will be challenging.

Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions.

Fibroblast activation protein-α (FAP) is a cell surface, serine protease of the post-prolyl peptidase family that is expressed in human breast cancer but not in normal tissues. Previously, we showed that FAP expression increased tumor growth rates in a mouse model of human breast cancer. Here the role of the proteolytic activities of FAP in promoting tumor growth, matrix degradation and invasion was investigated.

Structural markers in prostate cancer serum imaged ex vivo using cryogenic transmission electron microscopy.

We used cryogenic transmission electron microscopy (cryo-TEM) to identify differences in macromolecular structures present in the serum from healthy individuals (HI) and prostate cancer (PCa) patients and show that these differences are potential markers for disease. Using a murine orthotopic model of human PCa, we determined that some of these structural markers in serum are associated with the tumour burden. These findings signify the potential of this nanoscale ex vivo imaging technology of body fluids as a platform for discovering early markers of PCa and other diseases.

Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations.

Background: A lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs.

Objective: To determine whether inflammatory genetic markers could stratify patients with knee OA into high and low risk for destructive disease.

Methods: Genotype associations with knee OA severity were assessed in two Caucasian populations.

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice.

Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As the cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors, we set out to investigate the role of FAP in mouse models of epithelial-derived solid tumors.

Inhibitor of DASH proteases affects expression of adhesion molecules in osteoclasts and reduces myeloma growth and bone disease.

Dipeptidyl peptidase (DPP) IV activity and/or structure homologues (DASH) are serine proteases implicated in tumourigenesis. We previously found that a DASH protease, fibroblast activation protein (FAP), was involved in osteoclast-induced myeloma growth. Here we further demonstrated expression of various adhesion molecules in osteoclasts cultured alone or cocultured with myeloma cells, and tested the effects of DASH inhibitor, PT-100, on myeloma cell growth, bone disease, osteoclast differentiation and activity, and expression of adhesion molecules in osteoclasts.

HIV-1 Env vaccine comprised of electroporated DNA and protein co-administered with Talabostat.

Selection of potent yet low reactogenic adjuvants for protein immunization is important for HIV-1 vaccine development. Immunogenicity of electroporated DNA (HIV env) and recombinant gp120, administered with either QS-21 or the orally administered immunomodulator, Talabostat, was evaluated in BALB/c mice. Electroporation of low dose DNA elicited Th1 cytokines and anti-envelope antibodies.

Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context.

We questioned the significance of haplotype structure in gene regulation by testing whether individual single nucleotide polymorphisms (SNPs) within a gene promoter region [interleukin-1-beta (IL1B)] might affect promoter function and, if so, whether function was dependent on haplotype context. We sequenced genomic DNA from 25 individuals of diverse ethnicity, focusing on exons and upstream flanking regions of genes of the cluster. We identified four IL1B promoter region SNPs that were active in transient transfection reporter gene assays.

Inhibition of NF-kappaB activity by plasmid expressed alphaMSH peptide.

Alpha-Melanocyte Stimulating Hormone (alphaMSH) is a neuroimmunomodulatory peptide with remarkable anti-inflammatory properties. Daily or twice daily administration of the peptide reduces the symptoms of several inflammatory animal disease models and the peptide has demonstrated safety in human trials. Unfortunately, the pharmacokinetics of peptide delivery are not favorable from the pharmaceutical perspective.