The funders' perspective: Lessons learned from the National Institutes of Health Diversity Program Consortium evaluation.

Advancing diversity in the biomedical research workforce is critical to the ability of the National Institutes of Health (NIH) to achieve its mission. The NIH Diversity Program Consortium is a unique, 10-year program that builds upon longstanding training and research capacity-building activities to promote workforce diversity. It was designed to rigorously evaluate approaches to enhancing diversity in the biomedical research workforce at the student, faculty, and institutional level.

From pipettes to policy: Reflections on a decade working to expand opportunity and equity in science.

Science policy focuses on the allocation of resources within the scientific enterprise and the downstream impacts of these investments. Here, I describe my journey from being a curious kid, to becoming a signaling biologist, to my current role as a science policy professional focusing on the areas of biomedical research training, workforce diversity, and promoting basic research. I provide insights on skills important in this career track-collaboration, diplomacy, adaptability, and resilience.

Special Collection of Perspectives on Broadening Participation.

This is an introduction to a special collection of perspectives on Broadening Participation by leaders in the field on how the life sciences community can cultivate and harness the talents of people from all backgrounds.

Decoupling of the minority PhD talent pool and assistant professor hiring in medical school basic science departments in the US.

Faculty diversity is a longstanding challenge in the US. However, we lack a quantitative and systemic understanding of how the career transitions into assistant professor positions of PhD scientists from underrepresented minority (URM) and well-represented (WR) racial/ethnic backgrounds compare. Between 1980 and 2013, the number of PhD graduates from URM backgrounds increased by a factor of 9.

Broadening Participation in the Life Sciences: Current Landscape and Future Directions.

This lead editorial for the special issue on broadening participation defines terms, marks progress, and calls on the community to consider specific approaches going forward.

Career Development among American Biomedical Postdocs.

Recent biomedical workforce policy efforts have centered on enhancing career preparation for trainees, and increasing diversity in the research workforce. Postdoctoral scientists, or postdocs, are among those most directly impacted by such initiatives, yet their career development remains understudied. This study reports results from a 2012 national survey of 1002 American biomedical postdocs.

An Assessment of Hospital-Based Palliative Care in Maryland: Infrastructure, Barriers, and Opportunities.

Context: Maryland recently passed legislation mandating that hospitals with more than 50 beds have palliative care (PC) programs. Although the state's health agency can play a key role in ensuring successful implementation of this measure, there is little actionable information from which it can guide resource allocation for enhancing PC delivery statewide.

Objectives: To assess the PC infrastructure at Maryland's 46 community-based nonspecialty hospitals and to describe providers' perspectives on barriers to PC and supports that could enhance PC delivery.

Biomedical Science Ph.D. Career Interest Patterns by Race/Ethnicity and Gender.

Increasing biomedical workforce diversity remains a persistent challenge. Recent reports have shown that biomedical sciences (BMS) graduate students become less interested in faculty careers as training progresses; however, it is unclear whether or how the career preferences of women and underrepresented minority (URM) scientists change in manners distinct from their better-represented peers. We report results from a survey of 1500 recent American BMS Ph.

What do I want to be with my PhD? The roles of personal values and structural dynamics in shaping the career interests of recent biomedical science PhD graduates.

Interest in faculty careers decreases as graduate training progresses; however, the process underlying career-interest formation remains poorly defined. To better understand this process and whether/how it differs across social identity (i.e.

Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells.

Natural killer (NK) cells are potent anti-viral and antitumor "first responders" endowed with natural cytotoxicity and cytokine production capabilities. To date, attempts to translate these promising biologic functions through the adoptive transfer of NK cells for the treatment of cancer have been of limited benefit. Here we trace the fate of adoptively transferred murine NK cells and make the surprising observation that NK cells traffic to tumor sites yet fail to control tumor growth or improve survival.

Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-driven AML.

Increasing evidence suggests tumors are maintained by cancer stem cells; however, their nature remains controversial. In a HoxA9-Meis1 (H9M) model of acute myeloid leukemia (AML), we found that tumor-initiating activity existed in three, immunophenotypically distinct compartments, corresponding to disparate lineages on the normal hematopoietic hierarchy--stem/progenitor cells (Lin(-)kit(+)) and committed progenitors of the myeloid (Gr1(+)kit(+)) and lymphoid lineages (Lym(+)kit(+)). These distinct tumor-initiating cells (TICs) clonally recapitulated the immunophenotypic spectrum of the original tumor in vivo (including cells with a less-differentiated immunophenotype) and shared signaling networks, such that in vivo pharmacologic targeting of conserved TIC survival pathways (DNA methyltransferase and MEK phosphorylation) significantly increased survival.

Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE.

The ability to analyze multiple single-cell parameters is critical for understanding cellular heterogeneity. Despite recent advances in measurement technology, methods for analyzing high-dimensional single-cell data are often subjective, labor intensive and require prior knowledge of the biological system. To objectively uncover cellular heterogeneity from single-cell measurements, we present a versatile computational approach, spanning-tree progression analysis of density-normalized events (SPADE).

Single-cell phospho-specific flow cytometric analysis demonstrates biochemical and functional heterogeneity in human hematopoietic stem and progenitor compartments.

The low frequency of hematopoietic stem and progenitor cells (HSPCs) in human BM has precluded analysis of the direct biochemical effects elicited by cytokines in these populations, and their functional consequences. Here, single-cell phospho-specific flow cytometry was used to define the signaling networks active in 5 previously defined human HSPC subsets. This analysis revealed that the currently defined HSC compartment is composed of biochemically distinct subsets with the ability to respond rapidly and directly in vitro to a broader array of cytokines than previously appreciated, including G-CSF.

Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms.

Dysregulated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling due to activation of tyrosine kinases is a common feature of myeloid malignancies. Here we report the first human disease-related mutations in the adaptor protein LNK, a negative regulator of JAK-STAT signaling, in 2 patients with JAK2 V617F-negative myeloproliferative neoplasms (MPNs). One patient exhibited a 5 base-pair deletion and missense mutation leading to a premature stop codon and loss of the pleckstrin homology (PH) and Src homology 2 (SH2) domains.

CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells (LSC). We hypothesized that increased CD47 expression on human AML LSC contributes to pathogenesis by inhibiting their phagocytosis through the interaction of CD47 with an inhibitory receptor on phagocytes. We found that CD47 was more highly expressed on AML LSC than their normal counterparts, and that increased CD47 expression predicted worse overall survival in three independent cohorts of adult AML patients.

Dendritic cells cross-dressed with peptide MHC class I complexes prime CD8+ T cells.

The activation of naive CD8+ T cells has been attributed to two mechanisms: cross-priming and direct priming. Cross-priming and direct priming differ in the source of Ag and in the cell that presents the Ag to the responding CD8+ T cells. In cross-priming, exogenous Ag is acquired by professional APCs, such as dendritic cells (DC), which process the Ag into peptides that are subsequently presented.

Tumor-specific CD4+ T cells are activated by "cross-dressed" dendritic cells presenting peptide-MHC class II complexes acquired from cell-based cancer vaccines.

Tumor cells that constitutively express MHC class I molecules and are genetically modified to express MHC class II (MHC II) and costimulatory molecules are immunogenic and have therapeutic efficacy against established primary and metastatic cancers in syngeneic mice and activate tumor-specific human CD4+ T lymphocytes. Previous studies have indicated that these MHC II vaccines enhance immunity by directly activating tumor-specific CD4+ T cells during the immunization process. Because dendritic cells (DCs) are considered to be the most efficient APCs, we have now examined the role of DCs in CD4+ T cell activation by the MHC II vaccines.

Hereditary prostate cancer in Finland: fine-mapping validates 3p26 as a major predisposition locus.

In a recent genome-wide linkage (GWL) analysis of Finnish families at high risk for prostate cancer, we found two novel putative susceptibility loci at 3p25-p26 and 11q14. Here, we report the fine-mapping of these two critical regions at high resolution with 39 microsatellite markers in 16 families, including multiplex families that were not used in the GWL scan. The maximum multipoint HLOD was 3.

Genome-wide scan for linkage in finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25-26.

Background: In order to identify predisposition loci to hereditary prostate cancer (HPC), we performed a genome-wide linkage analysis using samples from a genetically homogeneous population, with 13 Finnish multiplex prostate cancer families.

Methods: Altogether 87 DNA samples were genotyped from 13 families. Logarithm-of-odds (LOD) scores were calculated for all autosomes using FASTLINK and GENEHUNTER designating all unaffected men and all women as unknown.