Genetic Counseling and Testing for Breast Cancer Risk in African Americans

Genetic testing for susceptibility to breast and ovarian cancer (BRCA1/2 testing) has been available in clinical settings since 1996. Increasingly, such testing is helping women at increased risk make decisions about breast cancer screening and prevention. African American women have participated in genetic counseling and testing programs less than white women, despite greater rates of early onset disease and higher breast cancer mortality. The barriers and motivations for genetic testing among African American women are not well understood. This Issue Brief summarizes a series of studies that systematically explore African American women’s beliefs and intentions about BRCA1/2 testing. The findings have been used to tailor genetic counseling programs to better serve this population

Conducting Precision Medicine Research with African Americans

Importance Precision medicine is an approach to detecting, treating, and managing disease that is based on individual variation in genetic, environmental, and lifestyle factors. Precision medicine is expected to reduce health disparities, but this will be possible only if studies have adequate representation of racial minorities. Objective It is critical to anticipate the rates at which individuals from diverse populations are likely to participate in precision medicine studies as research initiatives are being developed. We evaluated the likelihood of participating in a clinical study for precision medicine. Design, Setting, Participants Observational study conducted between October 2010 and February 2011 in a national sample of African Americans. Main Outcome Measure Intentions to participate in a government sponsored study that involves providing a biospecimen and generates data that could be shared with other researchers to conduct future studies. Results One third of respondents would participate in a clinical study for precision medicine. Only gender had a significant independent association with participation intentions. Men had a 1.86 (95% CI = 1.11, 3.12, p = 0.02) increased likelihood of participating in a precision medicine study compared to women in the model that included overall barriers and facilitators. In the model with specific participation barriers, distrust was associated with a reduced likelihood of participating in the research described in the vignette (OR = 0.57, 95% CI = 0.34, 0.96, p = 0.04). Conclusion and Relevance African Americans may have low enrollment in PMI research. As PMI research is implemented, extensive efforts will be needed to ensure adequate representation. Additional research is needed to identify optimal ways of ethically describing precision medicine studies to ensure sufficient recruitment of racial minorities

Uptake of synthetic low density lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy

Chronic Myeloid Leukemia (CML) stem/progenitor cells, which over-express Bcr-Abl, respond to imatinib by a reversible block in proliferation without significant apoptosis. As a result, patients are unlikely to be cured owing to the persistence of leukemic quiescent stem cells (QSC) capable of initiating relapse. Previously, we have reported that intracellular levels of imatinib in primary primitive CML cells (CD34<sup>+</sup>38<sup>lo/−</sup>), are significantly lower than in CML progenitor cells (total CD34<sup>+</sup>) and leukemic cell lines. The aim of this study was to determine if potentially sub-therapeutic intracellular drug concentrations in persistent leukemic QSC may be overcome by targeted drug delivery using synthetic Low Density Lipoprotein (sLDL) particles. As a first step towards this goal, however, the extent of uptake of sLDL by leukemic cell lines and CML patient stem/progenitor cells was investigated. Results with non-drug loaded particles have shown an increased and preferential uptake of sLDL by Bcr-Abl positive cell lines in comparison to Bcr-Abl negative. Furthermore, CML CD34<sup>+</sup> and primitive CD34<sup>+</sup>38<sup>lo/−</sup> cells accumulated significantly higher levels of sLDL when compared with non-CML CD34<sup>+</sup> cells. Thus, drug-loading the sLDL nanoparticles could potentially enhance intracellular drug concentrations in primitive CML cells and thus aid their eradication

Direct N-glycosylation profiling of urine and prostatic fluid glycoproteins and extracellular vesicles

Expressed prostatic secretions (EPS), also called post digital rectal exam urines, are proximal fluids of the prostate that are widely used for diagnostic and prognostic assays for prostate cancer. These fluids contain an abundant number of glycoproteins and extracellular vesicles secreted by the prostate gland, and the ability to detect changes in their N-glycans composition as a reflection of disease state represents potential new biomarker candidates. Methods to characterize these N-glycan constituents directly from clinical samples in a timely manner and with minimal sample processing requirements are not currently available. In this report, an approach is described to directly profile the N-glycan constituents of EPS urine samples, prostatic fluids and urine using imaging mass spectrometry for detection. An amine reactive slide is used to immobilize glycoproteins from a few microliters of spotted samples, followed by peptide N-glycosidase digestion. Over 100 N-glycan compositions can be detected with this method, and it works with urine, urine EPS, prostatic fluids, and urine EPS-derived extracellular vesicles. A comparison of the N-glycans detected from the fluids with tissue N-glycans from prostate cancer tissues was done, indicating a subset of N-glycans present in fluids derived from the gland lumens. The developed N-glycan profiling is amenable to analysis of larger clinical cohorts and adaptable to other biofluids

Smoking and Chronic Obstructive Pulmonary Disease (COPD). Parallel Epidemics of the 21st Century

One hundred million deaths were caused by tobacco in the 20th century, and it is estimated that there will be up to one billion deaths attributed to tobacco use in the 21st century. Chronic obstructive pulmonary disease (COPD) is rapidly becoming a global public health crisis with smoking being recognized as its most important causative factor. The most effective available treatment for COPD is smoking cessation. There is mounting evidence that the rate of progression of COPD can be reduced when patients at risk of developing the disease stop smoking, while lifelong smokers have a 50% probability of developing COPD during their lifetime. More significantly, there is also evidence that the risk of developing COPD falls by about half with smoking cessation. Several pharmacological interventions now exist to aid smokers in cessation; these include nicotine replacement therapy, bupropion, and varenicline. All pharmacotherapies for smoking cessation are more efficacious than placebo, with odds ratios of about 2. Pharmacologic therapy should be combined with nonpharmacologic (behavioral) therapy. Unfortunately, despite the documented efficacy of these agents, the absolute number of patients who are abstinent from smoking at 12 months of follow-up is low

Regional differences in awareness and attitudes regarding genetic testing for disease risk and ancestry

Little is known about the lay public’s awareness and attitudes concerning genetic testing and what factors influence their perspectives. The existing literature focuses mainly on ethnic and socioeconomic differences; however, here we focus on how awareness and attitudes regarding genetic testing differ by geographical regions in the US. We compared awareness and attitudes concerning genetic testing for disease risk and ancestry among 452 adults (41% Black and 67% female) in four major US cities, Norman, OK; Cincinnati, OH; Harlem, NY; and Washington, DC; prior to their participation in genetic ancestry testing. The OK participants reported more detail about their personal ancestries (p = 0.02) and valued ancestry testing over disease testing more than all other sites (p < 0.01). The NY participants were more likely than other sites to seek genetic testing for disease (p = 0.01) and to see benefit in finding out more about one’s ancestry (p = 0.02), while the DC participants reported reading and hearing more about genetic testing for African ancestry than all other sites (p < 0.01). These site differences were not better accounted for by sex, age, education, self-reported ethnicity, religion, or previous experience with genetic testing/counseling. Regional differences in awareness and attitudes transcend traditional demographic predictors, such as ethnicity, age and education. Local sociocultural factors, more than ethnicity and socioeconomic status, may influence the public’s awareness and belief systems, particularly with respect to genetics

Implementation of child-centred outcome measures in routine paediatric healthcare practice: a systematic review

Background: Person-centred outcome measures (PCOMs) are commonly used in routine adult healthcare to measure and improve outcomes, but less attention has been paid to PCOMs in children’s services. The aim of this systematic review is to identify and synthesise existing evidence of the determinants, strategies, and mechanisms that influence the implementation of PCOMs into paediatric healthcare practice. Methods: The review was conducted and reported in accordance with PRISMA guidelines. Databased searched included CINAHL, Embase, Medline, and PsycInfo. Google scholar was also searched for grey literature on 25th March 2022. Studies were included if the setting was a children’s healthcare service, investigating the implementation or use of an outcome measure or screening tool in healthcare practice, and reported outcomes relating to use of a measure. Data were tabulated and thematically analysed through deductive coding to the constructs of the adapted-Consolidated Framework for Implementation Research (CFIR). Results were presented as a narrative synthesis, and a logic model developed. Results: We retained 69 studies, conducted across primary (n = 14), secondary (n = 13), tertiary (n = 37), and community (n = 8) healthcare settings, including both child self-report (n = 46) and parent-proxy (n = 47) measures. The most frequently reported barriers to measure implementation included staff lack of knowledge about how the measure may improve care and outcomes; the complexity of using and implementing the measure; and a lack of resources to support implementation and its continued use including funding and staff. The most frequently reported facilitators of implementation and continued use include educating and training staff and families on: how to implement and use the measure; the advantages of using PCOMs over current practice; and the benefit their use has on patient care and outcomes. The resulting logic model presents the mechanisms through which strategies can reduce the barriers to implementation and support the use of PCOMs in practice. Conclusions: These findings can be used to support the development of context-specific implementation plans through a combination of existing strategies. This will enable the implementation of PCOMs into routine paediatric healthcare practice to empower settings to better identify and improve child-centred outcomes. Trial registration: Prospero CRD 42022330013

A Systems Approach to Interrogate Gene Expression Patterns in African American Men Presenting with Clinically Localized Prostate Cancer

An emerging theory about racial differences in cancer risk and outcomes is that psychological and social stressors influence cellular stress responses; however, limited empirical data are available on racial differences in cellular stress responses among men who are at risk for adverse prostate cancer outcomes. In this study, we undertook a systems approach to examine molecular profiles and cellular stress responses in an important segment of African American (AA) and European American (EA) men: men undergoing prostate biopsy. We assessed the prostate transcriptome with a single biopsy core via high throughput RNA sequencing (RNA-Seq). Transcriptomic analyses uncovered impacted biological pathways including PI3K-Akt signaling pathway, Neuroactive ligand-receptor interaction pathway, and ECM-receptor interaction. Additionally, 187 genes mapping to the Gene Ontology (GO) terms RNA binding, structural constituent of ribosome, SRP-dependent co-translational protein targeting to membrane and the biological pathways, translation, L13a-mediated translational silencing of Ceruloplasmin expression were differentially expressed (DE) between EA and AA. This signature allowed separation of AA and EA patients, and AA patients with the most severe clinical characteristics. AA patients with elevated expression levels of this genomic signature presented with higher Gleason scores, a greater number of positive core biopsies, elevated dehydroepiandrosterone sulfate levels and serum vitamin D deficiency. Protein-protein interaction (PPI) network analysis revealed a high degree of connectivity between these 187 proteins