Reflections on the Cost of Low-Cost Whole Genome Sequencing: Framing the Health Policy Debate

The cost of whole genome sequencing is dropping rapidly. There has been a great deal of enthusiasm about the potential for this technological advance to transform clinical care. Given the interest and significant investment in genomics, this seems an ideal time to consider what the evidence tells us about potential benefits and harms, particularly in the context of health care policy. The scale and pace of adoption of this powerful new technology should be driven by clinical need, clinical evidence, and a commitment to put patients at the centre of health care policy

SAMHD1 promotes DNA end resection to facilitate DNA repair by homologous recombination

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV- 1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity

Women's health care teams and the future of obstetrics and gynecology

Health care delivery is in a stage of transformation and a meaningful change in provision of care must also be accompanied by changes in the educational process of health care professionals. This article lays out a roadmap to better prepare obstetrician-gynecologists (ob-gyns) to succeed in interdisciplinary women's health care teams. Just as our current educational programs emphasize the development of competent surgical skills, our future programs must encourage and support the development of communication, teamwork, and leadership skills for ob-gyns. Formal integration of these fundamentals at all levels of the health care training continuum will create an educational system designed to equip all practitioners with a basic level of knowledge and provide opportunities to acquire additional knowledge and skills as needs and interest dictate. Integral to the implementation will be the evaluation of the effects of the contributions of interprofessional education on patient, practice, and health system outcomes. Successful demonstration of value will lead to the sustainability of the educational programs through recognition by physicians, health care teams, academia, health care systems, and payers

Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage

After intrathymic development, T cells exit the thymus and join the peripheral T-cell pool. Such recent thymic emigrants (RTEs) undergo both phenotypic and functional maturation during the first 3 weeks they reside in the periphery. Using a well-controlled in vitro polarization scheme, we now show that CD4+ RTEs are defective in T-helper (Th) type 0 (Th0), Th1, Th17, and regulatory T-cell lineage commitment, with dampened cytokine production and transcription factor expression. In contrast, CD4+ RTES are biased toward the Th2 lineage both in vitro and in vivo, with more robust interleukin-4, interleukin-5, and interleukin-13 production than their mature naive counterparts. Coculture experiments demonstrate that mature naive T cells influence neighboring RTEs in their Th responses. In adoptive hosts, CD4+ RTEs drive production of the Th2-associated antibody isotype immunoglobulin G1 and mediate airway inflammatory disease. This bias in RTEs likely results from dampened negative regulation of the Th2 lineage by diminished levels of T-bet, a key Th1 transcription factor. CD4+ RTEs thus represent a transitional population with a distinct interpretation of, and response to, immunologic cues. These characteristics may be beneficial during the postthymic maturation period by leading to the avoidance of inappropriate immune responses, particularly in lymphopenic neonates and adults

Reflections on the cost of "low-cost" whole genome sequencing: framing the health policy debate

The future clinical applications of whole genome sequencing come with speculation and enthusiasm but require careful consideration of the true system costs and health benefits of the clinical uses of this exciting technology.status: publishe

A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome

BACKGROUND The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G -> A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.

"Eu não preciso falar que eu sou branca, cara, eu sou Latina!" Ou a complexidade da identificação racial na ideologia de ativistas jovens (não)brancas "I do not have to say that I am white, man, I am Latina!" Or the complexity of racial identification in the ideology of (non)white, young, female activists

Neste artigo procuro explorar a complexidade do processo de formação da identidade racial de mulheres, jovens ativistas (não)brancas em São Paulo. Levando em conta a interação do indivíduo com o mundo social, distingue-se a identidade racial apropriada da atribuída e a identidade racial individual da coletiva. Isso requer atenção para o papel da posição social racial, com as subsequentes vantagens raciais, para os sentimentos da ativista neste processo e para a influência mútua da heterogeneidade de identidade racial, do deslocamento da identidade racial e, por conseguinte, do papel da formação de identidade como estratégia de ideologia e práxis ativista.<br>In this article, I explore the complexity of racial identity formation of (non)white, young, female activists in São Paulo. Taking into account the interaction of the individual with the social world, one must distinguish between appropriated and attributed racial identities, as well as individual and collective identities. This requires attention to the role of racial social position and its subsequent racial advantages, to the feelings of activists about this process, and to the mutual influence of the heterogeneity of racial identity, the displacement of racial identity and, consequently, the role of identity formation as a strategy of activist ideology and praxis