Affirming NIH's commitment to addressing structural racism in the biomedical research enterprise.

NIH has acknowledged and committed to ending structural racism. The framework for NIH's approach, summarized here, includes understanding barriers; developing robust health disparities/equity research; improving its internal culture; being transparent and accountable; and changing the extramural ecosystem so that diversity, equity, and inclusion are reflected in funded research and the biomedical workforce.

Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer.

To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. VIDEO ABSTRACT.

Proteogenomic characterization of human colon and rectal cancer.

Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.

Comprehensive quantitative analysis of ovarian and breast cancer tumor peptidomes.

Aberrant degradation of proteins is associated with many pathological states, including cancers. Mass spectrometric analysis of tumor peptidomes, the intracellular and intercellular products of protein degradation, has the potential to provide biological insights on proteolytic processing in cancer. However, attempts to use the information on these smaller protein degradation products from tumors for biomarker discovery and cancer biology studies have been fairly limited to date, largely due to the lack of effective approaches for robust peptidomics identification and quantification and the prevalence of confounding factors and biases associated with sample handling and processing. Herein, we have developed an effective and robust analytical platform for comprehensive analyses of tissue peptidomes, which is suitable for high-throughput quantitative studies. The reproducibility and coverage of the platform, as well as the suitability of clinical ovarian tumor and patient-derived breast tumor xenograft samples with postexcision delay of up to 60 min before freezing for peptidomics analysis, have been demonstrated. Moreover, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. Peptidomics complements results obtainable from conventional bottom-up proteomics and provides insights not readily obtainable from such approaches.

Linking cancer genome to proteome: NCI's investment into proteogenomics.

Advances in both targeted and unbiased MS-based proteomics are now at a mature stage for comprehensively and reproducibly characterizing a large part of the cancer proteome. These developments combined with the extensive genomic characterization of several cancer types by large-scale initiatives such as the International Cancer Genome Consortium and Cancer Genome Atlas Project have paved the way for proteogenomic analysis of omics datasets and integration methods. The advances serve as the basis for the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium and this article highlights its current work and future steps in the area of proteogenomics.

A relationship between the transient structure in the monomeric state and the aggregation propensities of α-synuclein and ß-synuclein.

α-Synuclein is an intrinsically disordered protein whose aggregation is implicated in Parkinson's disease. A second member of the synuclein family, ß-synuclein, shares significant sequence similarity with α-synuclein but is much more resistant to aggregation. ß-Synuclein is missing an 11-residue stretch in the central non-ß-amyloid component region that forms the core of α-synuclein amyloid fibrils, yet insertion of these residues into ß-synuclein to produce the ßSHC construct does not markedly increase the aggregation propensity. To investigate the structural basis of these different behaviors, quantitative nuclear magnetic resonance data, in the form of paramagnetic relaxation enhancement-derived interatomic distances, are combined with molecular dynamics simulations to generate ensembles of structures representative of the solution states of α-synuclein, ß-synuclein, and ßSHC. Comparison of these ensembles reveals that the differing aggregation propensities of α-synuclein and ß-synuclein are associated with differences in the degree of residual structure in the C-terminus coupled to the shorter separation between the N- and C-termini in ß-synuclein and ßSHC, making protective intramolecular contacts more likely.

Virtual BUILD Research Collaboratory: A biomedical data science training using innovative pedagogy to address structures of racism and inequitable stress for undergraduates of color.

OBJECTIVE: The unprecedented events of 2020 required a pivot in scientific training to better prepare the biomedical research workforce to address global pandemics, structural racism, and social inequities that devastate human health individually and erode it collectively. Furthermore, this pivot had to be accomplished in the virtual environment given the nation-wide lockdown. METHODS: These needs and context led to leveraging of the San Francisco Building Infrastructure Leading to Diversity (SF BUILD) theories of change to innovate a Virtual BUILD Research Collaboratory (VBRC). The purpose of VBRC was to train Black, Indigenous, and people of color (BIPOC) students to apply their unique perspectives to biomedical research. These training activities were evaluated using a pre-post survey design that included both validated and new psychosocial scales. A new scale was piloted to measure culturally relevant pedagogy. RESULTS: VBRC scholars increased science identity on two items: thinking of myself as a scientist (+1point, p = 0.006) and belonging to a community of scientists (+1point, p = 0.069). Overall, scholars perceived stress also decreased over VBRC (-2.35 points, p = 0.02). Post VBRC, scholars had high agency scores (µ = 11.02, Md = 12, range = 6-12, σ = 1.62) and cultural humility scores (µ = 22.11, Md = 23, range = 12-24, σ = 2.71). No notable race/ethnic differences were found in any measures. CONCLUSIONS: Taken together, our innovative approach to data science training for BIPOC in unprecedented times shows promise for better preparing the workforce critically needed to address the fundamental gaps in knowledge at the intersection of public health, structural racism, and biomedical sciences.

Recommendations for mass spectrometry data quality metrics for open access data (corollary to the Amsterdam Principles).

Policies supporting the rapid and open sharing of proteomic data are being implemented by the leading journals in the field. The proteomics community is taking steps to ensure that data are made publicly accessible and are of high quality, a challenging task that requires the development and deployment of methods for measuring and documenting data quality metrics. On September 18, 2010, the United States National Cancer Institute convened the "International Workshop on Proteomic Data Quality Metrics" in Sydney, Australia, to identify and address issues facing the development and use of such methods for open access proteomics data. The stakeholders at the workshop enumerated the key principles underlying a framework for data quality assessment in mass spectrometry data that will meet the needs of the research community, journals, funding agencies, and data repositories. Attendees discussed and agreed up on two primary needs for the wide use of quality metrics: 1) an evolving list of comprehensive quality metrics and 2) standards accompanied by software analytics. Attendees stressed the importance of increased education and training programs to promote reliable protocols in proteomics. This workshop report explores the historic precedents, key discussions, and necessary next steps to enhance the quality of open access data. By agreement, this article is published simultaneously in the Journal of Proteome Research, Molecular and Cellular Proteomics, Proteomics, and Proteomics Clinical Applications as a public service to the research community. The peer review process was a coordinated effort conducted by a panel of referees selected by the journals.

Competing Discourses about Youth Sexual Exploitation in Canadian News Media.

Media holds the power to create, maintain, or break down stigmatizing attitudes, which affect policies, funding, and services. To understand how Canadian news media depicts the commercial sexual exploitation of children and youth, we examined 835 Canadian newspaper articles from 1989-2008 using a mixed methods critical discourse analysis approach, comparing representations to existing research about sexually exploited youth. Despite research evidence that equal rates of boys and girls experience exploitation, Canadian news media depicted exploited youth predominantly as heterosexual girls, and described them alternately as victims or workers in a trade, often both in the same story. News media mentioned exploiters far less often than victims, and portrayed them almost exclusively as male, most often called 'customers' or 'consumers,' and occasionally 'predators'; in contrast, research has documented the majority of sexually exploited boys report female exploiters. Few news stories over the past two decades portrayed the diversity of victims, perpetrators, and venues of exploitation reported in research. The focus on victims but not exploiters helps perpetuate stereotypes of sexual exploitation as business or a 'victimless crime,' maintains the status quo, and blurs responsibility for protecting youth under the UN Convention on the Rights of the Child. Health care providers and researchers can be advocates for accuracy in media coverage about sexual exploitation; news reporters and editors should focus on exploiters more than victims, draw on existing research evidence to avoid perpetuating stereotypes, and use accurate terms, such as commercial sexual exploitation, rather than terms related to business or trade.

Advancing socioecological mental health promotion intervention: A mixed methods exploration of Phase 1 Agenda Gap findings.

Introduction: Protecting and promoting the mental health of youth under 30 years of age is a priority, globally. Yet investment in mental health promotion, which seeks to strengthen the determinants of positive mental health and wellbeing, remains limited relative to prevention, treatment, and recovery. The aim of this paper is to contribute empirical evidence to guide innovation in youth mental health promotion, detailing the early outcomes of Agenda Gap, an intervention centering youth-led policy advocacy to influence positive mental health for individuals, families, communities and society. Methods: Leveraging a convergent mixed methods design, this study draws on data from n = 18 youth (ages 15 to 17) in British Columbia, Canada, who contributed to pre- and post-intervention surveys and post-intervention qualitative interviews following their participation in Agenda Gap from 2020-2021. These data are supplemented by qualitative interviews with n = 4 policy and other adult allies. Quantitative and qualitative data were analyzed in parallel, using descriptive statistics and reflexive thematic analysis, and then merged for interpretation. Results: Quantitative findings suggest Agenda Gap contributes to improvements in mental health promotion literacy as well as several core positive mental health constructs, such as peer and adult attachment and critical consciousness. However, these findings also point to the need for further scale development, as many of the available measures lack sensitivity to change and are unable to distinguish between higher and lower levels of the underlying construct. Qualitative findings provided nuanced insights into the shifts that resulted from Agenda Gap at the individual, family, and community level, including reconceptualization of mental health, expanded social awareness and agency, and increased capacity for influencing systems change to promote positive mental health and wellbeing. Discussion: Together, these findings illustrate the promise and utility of mental health promotion for generating positive mental health impacts across socioecological domains. Using Agenda Gap as an exemplar, this study underscores that mental health promotion programming can contribute to gains in positive mental health for individual intervention participants whilst also enhancing collective capacity to advance mental health and equity, particularly through policy advocacy and responsive action on the social and structural determinants of mental health.

Recommendations for mass spectrometry data quality metrics for open access data (corollary to the Amsterdam principles).

Policies supporting the rapid and open sharing of proteomic data are being implemented by the leading journals in the field. The proteomics community is taking steps to ensure that data are made publicly accessible and are of high quality, a challenging task that requires the development and deployment of methods for measuring and documenting data quality metrics. On September 18, 2010, the U.S. National Cancer Institute (NCI) convened the "International Workshop on Proteomic Data Quality Metrics" in Sydney, Australia, to identify and address issues facing the development and use of such methods for open access proteomics data. The stakeholders at the workshop enumerated the key principles underlying a framework for data quality assessment in mass spectrometry data that will meet the needs of the research community, journals, funding agencies, and data repositories. Attendees discussed and agreed upon two primary needs for the wide use of quality metrics: (i) an evolving list of comprehensive quality metrics and (ii) standards accompanied by software analytics. Attendees stressed the importance of increased education and training programs to promote reliable protocols in proteomics. This workshop report explores the historic precedents, key discussions, and necessary next steps to enhance the quality of open access data. By agreement, this article is published simultaneously in Proteomics, Proteomics Clinical Applications, Journal of Proteome Research, and Molecular and Cellular Proteomics, as a public service to the research community. The peer review process was a coordinated effort conducted by a panel of referees selected by the journals.

Recommendations for mass spectrometry data quality metrics for open access data (corollary to the Amsterdam Principles).

Policies supporting the rapid and open sharing of proteomic data are being implemented by the leading journals in the field. The proteomics community is taking steps to ensure that data are made publicly accessible and are of high quality, a challenging task that requires the development and deployment of methods for measuring and documenting data quality metrics. On September 18, 2010, the U.S. National Cancer Institute (NCI) convened the "International Workshop on Proteomic Data Quality Metrics" in Sydney, Australia, to identify and address issues facing the development and use of such methods for open access proteomics data. The stakeholders at the workshop enumerated the key principles underlying a framework for data quality assessment in mass spectrometry data that will meet the needs of the research community, journals, funding agencies, and data repositories. Attendees discussed and agreed up on two primary needs for the wide use of quality metrics: (1) an evolving list of comprehensive quality metrics and (2) standards accompanied by software analytics. Attendees stressed the importance of increased education and training programs to promote reliable protocols in proteomics. This workshop report explores the historic precedents, key discussions, and necessary next steps to enhance the quality of open access data. By agreement, this article is published simultaneously in the Journal of Proteome Research, Molecular and Cellular Proteomics, Proteomics, and Proteomics Clinical Applications as a public service to the research community. The peer review process was a coordinated effort conducted by a panel of referees selected by the journals.

Evolution of clinical proteomics and its role in medicine.

Significant progress has been made in characterizing and sequencing genomic alterations of biospecimens from several types of cancer. Understanding the functional changes in the human proteome that arise from the genomic alterations or other factors is the next logical step in the development of high-value protein biomarkers that can be transitioned to clinical studies for biomarker qualification. Linking advances in genomic analysis to proteomic analysis will provide a pathway for qualified biomarkers which can drive the rational development of new diagnostics and therapies. The availability of these multidimensional data to the scientific community sets the stage for the development of new molecularly targeted cancer interventions.

The journey to regulation of protein-based multiplex quantitative assays.

BACKGROUND: Clinical proteomics presents great promise in biology and medicine because of its potential for improving our understanding of diseases at the molecular level and for detecting disease-related biomarkers for diagnosis, prognosis, and prediction of therapeutic responses. To realize its full potential to improve clinical outcome for patients, proteomic studies have to be well designed, from biosample cohorts to data and statistical analyses. One key component in the biomarker development pipeline is the understanding of the regulatory science that evaluates diagnostic assay performance through rigorous analytical and clinical review criteria. CONTENT: The National Cancer Institute's Clinical Proteomic Technologies for Cancer (CPTC) initiative has proposed an intermediate preclinical "verification" step to close the gap between protein-based biomarker discovery and clinical qualification. In collaboration with the US Food and Drug Administration (FDA), the CPTC network investigators recently published 2 mock submission review documents, first-of-their-kind educational materials that may help the scientific community interested in developing products for the clinic in understanding the likely analytical evaluation requirements for multiplex protein technology-based diagnostic tests. CONCLUSIONS: Building on this momentum, the CPTC continues with this report its collaboration with the FDA, as well as its interactions with the AACC and the Centers for Medicare and Medicaid Services, to further the understanding of regulatory requirements for approving multiplex proteomic platform-based tests and analytically validating multiple analytes.

A synopsis of the 3rd annual Cancer Proteomics Conference.

The 3rd annual 'Cancer Proteomics Conference', organized by Select Biosciences (Sudbury, UK), was held in Berlin, Germany, 8-9 June 2010. With the aim of strengthening the links between scientists from Europe, as well as international investigators worldwide, more than 200 delegates attended, representing various countries. The Conference covered many topics in proteomics, including the use of proteomics for cancer therapeutic development, diagnostic applications, biomarker discovery, post-translational modifications and clinical proteomics, as well as new proteomic technologies, which may facilitate future progress. One distinct feature of this meeting was that the Conference was co-located with the 'Advances in Antibody and Peptide Therapeutics' meeting. Delegates had access to both meetings, allowing for enhanced interaction among investigators from the closely linked fields of research.

Assessing the impacts of the Agenda Gap intervention for youth mental health promotion through policy engagement: a study protocol.

BACKGROUND: Mental health challenges are a leading health concern for youth globally, requiring a comprehensive approach incorporating promotion, prevention and treatment within a healthy public policy framework. However, the broad enactment of this vision has yet to be realized. Further, mental health promotion evidence specific to youth is still emerging and has not yet focused at a policy level. This is a critical gap, as policy is a key mental health promotion lever that can alter the social and structural conditions that contribute to shaping youth mental health outcomes for all youth, across the full spectrum of need. Responsive to this research and intervention priority, our prototype study intervention-the Agenda Gap-is comprised of an innovative, multi-media engagement intervention, developed in collaboration with youth. This intervention aims to equip youth and build capacity for them to lead meaningful policy change reflective of the mental health needs of diverse communities of youth, including those who experience structural vulnerability and who would not typically have had their voice represented in policymaking processes. METHODS: This study will use a multiple case study design and mixed methods grounded in a realist approach and will be conducted in three sites across two Canadian provinces (British Columbia and Alberta). In an earlier phase of this research, we collaboratively designed the prototype intervention with youth, community and policy partners. In this phase of the study, the intervention will be implemented and further tested with new groups of youth collaborators (n = 10-15/site). Outcome data will be collected through realist qualitative interviews, validated questionnaires [i.e., Child and Youth Resilience Measure (CYRM-12), General Self-Efficacy (GSE) Scale, and the Critical Consiousness Scale (CCS)] and additional survey items developed by our study team. Analysis will focus on identification of key context-mechanism-outcome configurations to provide comprehensive insights into how this intervention works, for whom, and in what context. DISCUSSION: This study is unique in its "upstream" focus on youth-engaged policymaking as a tool for improving the social and structural conditions that influence youth mental health across socioecological levels. Through the implementation and testing of the Agenda Gap intervention with diverse youth, this study will contribute to the evidence base on youth-engaged policymaking as a novel and innovative, mental health promotion strategy.

The NIDDK High School Short-Term Research Experience for Underrepresented Persons.

Background: Increasing the pipeline of aspiring minority biomedical/health professionals is a crucial component to diversifying the health science workforce. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) created the High School Short-Term Research Experience for Underrepresented Persons (HS-STEP-UP) to provide introductory biomedical/biobehavioral research experiences to promising high school students, who are traditionally underrepresented in the biomedical/biobehavioral sciences. The program reaches out to African American and Lationo/Hispanic students, as well as Native American students and students from the United States Territories. Methods: HS-STEP-UP provides a stimulating, rigorous 8- to 10-week summer research experience for a national cohort of ~100 high school students each year; the experience is organized through four National Institutes of Health (NIH)-funded coordinating centers. Typically, the program receives about 300 applications a year and about 100 students are accepted. Applicants are reviewed and selected based upon their online application that includes: a high school transcript, list of classes and extracurricular activities, two recommendation letters and a personal statement. The program culminates with a symposium at the NIH where students present their research and attend workshops and seminars. Results: For the 2017 and 2018 HS-STEP-UP programs, the classes included 193 students; 67% were females and 82% were underrepresented minorities. Forty eight percent of students reported a family income <$37,000/year, and 23% were from first generation college families. Ninety percent were very satisfied or satisfied with their research topic and 94% rated the end of the year symposium at NIH as excellent or very good. Only 65% were very satisfied or satisfied with their mentor matching, and 21% stated they were dissatisfied or very dissatisfied with their mentor. All the students successfully completed their summer research projects and presented their research abstracts at the symposium. All participating seniors reported attending college. Conclusion: HS-STEP-UP has been highly successful in recruiting traditionally underrepresented students and supporting underrepresented HS students with a rewarding introductory experience to research. Students are overall satisfied with the program, but mentor matching needs more attention. Longer-term follow-up is needed to determine how participating in STEP UP impacts their decisions to participate in the biomedical workforce in the future.

Using the CPTAC Assay Portal to Identify and Implement Highly Characterized Targeted Proteomics Assays.

The Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute (NCI) has launched an Assay Portal (http://assays.cancer.gov) to serve as an open-source repository of well-characterized targeted proteomic assays. The portal is designed to curate and disseminate highly characterized, targeted mass spectrometry (MS)-based assays by providing detailed assay performance characterization data, standard operating procedures, and access to reagents. Assay content is accessed via the portal through queries to find assays targeting proteins associated with specific cellular pathways, protein complexes, or specific chromosomal regions. The position of the peptide analytes for which there are available assays are mapped relative to other features of interest in the protein, such as sequence domains, isoforms, single nucleotide polymorphisms, and posttranslational modifications. The overarching goals are to enable robust quantification of all human proteins and to standardize the quantification of targeted MS-based assays to ultimately enable harmonization of results over time and across laboratories.