This letter report is the first in a series of five reports. The committee will provide an independent review of the more than 30 evidence reports that NASA has compiled on human health risks for long-duration and exploration spaceflights. In 2008, NASA asked the IOM to assess the process for developing the evidence reports.1 The resulting report, Review of NASAs Human Research Program Evidence Books: A Letter Report, provided an initial and brief review of the evidence reports. This letter report builds on the work of the 2008 IOM report and examines three evidence reports: 1. Risk of Injury from Dynamic Loads; 2. Risk of Clinically Relevant Unpredicted Effects of Medication; and 3. Risk of Spaceflight-Induced Intracranial Hypertension and Visual Alterations.

关键词：职业安全与健康；健康风险；伤害

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To examine set shifting in a group of women previously diagnosed with anorexia nervosa (AN) who are now weight-restored (AN-WR) and a control group and then apply a biologically-based computational model (Competition between Verbal and Implicit Systems; COVIS) to simulate the pattern of category learning and set shifting performances observed in the AN-CW group. Method: Nineteen AN-WR women and 35 control women (CW) were administered an explicit category learning task that required the initial acquisition of a rule, and after a certain number of trials, a set shift following a rule change. COVIS was first fit to the behavioral results of the controls and then parameters of the model theoretically relevant to AN were altered to mimic the behavioral results. Results: Relative to CW, the AN-WR group displayed steeper learning curves (i.e., hyper learning) prior to the rule shift, but greater difficulty in learning the new categories after the rule shift (i.e., a deficit in set shifting). Hyper learning and set shifting deficits in the AN-CW group were not associated and demonstrated a different pattern of correlations with clinical measures. Hyper learning in the AN-WR group was simulated by increasing the model parameter that represents sensitivity to negative feedback (parameter), whereas the deficit in set shifting was simulated by altering the parameters that represent changes in rule selection and flexibility (and parameters, respectively), processes dependent on dopamine levels. Conclusions: These simulations suggest that multiple factors can impact category learning and set shifting in AN-WR individuals (e.g., alterations in sensitivity to negative feedback, rule selection deficits, and inflexibility) and provide an important starting point to further investigate this pervasive deficit in adult AN.

关键词：厌食；行为；临床医学；计算

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The overall objective of this work is to create novel chromatin engines , named Designed Epigenetic Remodeling Factors (DERFs). These factors will be designed to recognize 18-base pairs (bp) specific sequences in self- renewal gene promoters (found up-regulated in CSCs). These proteins will then incorporate specific silencing marks, which will trigger endogenous self- renewal gene silencing. Thus, the IDEA is to direct the chromatin editing of the breast cancer stem genome, by altering the collection of the epigenetic marks at specific histone tails ( histone code or histone grammar ) in CSCs. As a proof of principle, we will focus on the gene promoter SOX2, which plays a critical role controlling self-renewal of CSCs (10). Our specific hypothesis is that the delivery of sequence-specific ZF domains (engineered to bind the SOX2 promoter) tethered to specific silencing enzymes will result on forced epigenetic silencing of SOX2, inhibition of CSC self-renewal and inhibition of tumorigenicity in a mouse model of breast cancer.

关键词：乳腺癌；遗传学；组蛋白转录（遗传学）

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We examined whether chronic exposure to combinations of two neurotoxicants (chlorpyrifos and permethrin) with pyridostigmine bromide (PB) could produce a delayed neuropathic pain condition in rats; and whether corroccur in nociceptive neurons coding for pain in skin, muscle or vasculature. Following a 60 day exposure to neurotoxicants/PB esponding molecular changes would (NTPB), we observed molecular dysfunctions in membrane Kv (Kv7) and Nav (Nav1.8, Nav1.9) proteins that persisted 8 weeks after exposure had ended. Functional changes (spontaneous activity, action potential duration) were also documented. Most of the maladaptations were present in vascular nociceptors. The physical location of vascular nociceptive neurons renders them most exposed to concentrations of circulating neurotoxicants/PB as well as to any blood borne secondary influences (endocrine, immune) these agents might induce. As a result, vascular nociceptors could be the first nervous system component damaged by neurotoxicants/PB. An imbalance between Kv7 and other Na+ channel proteins (Nav1.9) could prove to be a basis for a chronic pain condition sourced from a vulnerable subset of vascular nociceptors. A resulting neurovascular reflex dysfunction could cause widespread pain and also contribute to the development of CNS symptoms that have been identified in Gulf War veterans.

关键词：乳腺癌；毒死蜱和氯菊酯；诊断（医学）

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Mammary gland samples were isolated from wild type, vitamin D receptor knockout (VDRKO) and 1alphahydroxylase knockout (1 KO) female mice for whole mounts and paraffin embedding (inguinal) and for RNA and protein isolation (thoracic). Time points collected included 6-10wk old nulliparous, 9 and 16 days pregnancy, 5 and 10 days lactation and 3 and 6 days involution. All whole mounts were completed and showed increased branching during pregnancy in the VDRKO glands relative to wild type and 1 KO glands. Paraffin embedded involution samples were stained with hematoxylin and eosin and showed an apparent decrease in alveolar breakdown in the first few days of involution in VDRKO and 1 KO glands compared to wild type controls. Organ culture studies show that treatment of wild type and 1 KO glands with 1,25 dihydroxyvitamin D retards tertiary branching. This appears not to be the case in VDRKO glands. Gene expression analysis via microarray and qPCR provides only a glimpse into the complexities of the signaling involved in this process and is being complimented by ongoing protein analysis. These results suggest that 1 KO mammary glands do not develop exclusively similar to VDRKO or wild type glands which verifies our need to complete the remainder of our studies to determine if the VDR is acting to control mammary gland development through the vitamin D pathway or through some other ligand or possibly without a ligand.

关键词：烷烃；乳腺癌；文化；基因；腺体

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The overarching goal of this proposal is to use massively parallel sequencing to detect somatic genomic alterations in breast cancer tumor samples in order to identify genetic determinants of tumor behavior that may inform clinical decision-making. To date, we have developed a targeted sequencing platform that interrogates approximately 450 genes that are known to be altered in breast cancer and other cancers. We now plan to utilize this platform to study 150 tumor samples from women with ER+ breast cancer who have had early-, late- or no relapse following endocrine therapy. We have also begun to sequence tumor samples from patients with advanced breast cancer. To date, we have performed whole exome sequencing on 8 patients. In 4 patients, we identified somatic genomic alterations with potential clinical impact. In 5 of the 8 patients, we also obtained and sequenced tumor samples at the time of resistance to targeted therapies. In some cases, known mechanisms of resistance (i.e., ligand-binding domain mutations in ESR1) were identified. Analysis is currently underway to further elucidate causes of resistance in those cases where the mechanism is unclear.

关键词：乳腺癌；遗传学；基因组学；肿瘤

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Research demonstrates that providing patients or their caregivers with access to clinical information empowers them to better manage their health. Recognizing the importance of patient access to clinical information, the Department of Health and Human Services (HHS) has amended the Clinical Laboratory Improvement Amendments of 1998 (CLIA) and the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule to increase patients direct access to their test results from laboratories. Using data from a survey commissioned by the Office of the National Coordinator for Health IT, this brief describes the levels of direct patient access to test results allowed by clinical laboratories in 2012.

关键词：病人；临床信息；检验结果；实验室

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Human papillomaviruses (HPV) cause most cases of cervical cancer and large proportions of vaginal, vulvar, anal, penile, and oropharyngeal cancers. HPV also causes genital warts and recurrent respiratory papillomatosis. HPV vaccines could dramatically reduce the incidence of HPV-associated cancers and other conditions among both females and males, but uptake of the vaccines has fallen short of target levels. The Presidents Cancer Panel finds underuse of HPV vaccines a serious but correctable threat to progress against cancer. In this report, the Panel presents four goals to increase HPV vaccine uptake: three of these focus on the United States and the fourth addresses ways the United States can help to increase global uptake of the vaccines. Several high-priority research questions related to HPV and HPV vaccines also are identified. The Presidents Cancer Panel finds underuse of HPV vaccines a serious but correctable threat to progress against cancer. Organized, mutually reinforcing efforts could have synergistic impact on HPV vaccine uptake. The Panel presents four goals to increase HPV vaccine uptake; three goals focus on increasing uptake in the United States (Part 3), and the fourth addresses ways the United States can help increase global uptake of the vaccines (Part 4). Several high-priority research areas also are identified (Part 5). All recommendations and some of the stakeholders responsible for implementing them are summarized in Appendix B.

关键词：医学研究；社区；医学研究；公共卫生

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We proposed that alterations in histone methylation regulate MSC fate commitment and predispose these progeny to malignant transformation. Transformed ER+ epithelial cells deregulate proliferation of MSC and luminal progenitors contributing to transformation of ER-luminal and basal cells and development of treatment resistant breast cancer. We previously reported that transformed MSC with reduced DNA repair contribute to more aggressive mammary tumors. Transformed luminal progenitor cells with altered histone methylation produced aggressive mammary tumors after long latency. The fractions of progenitor and differentiated cells in these tumors also were altered. ER+ tumor cells promoted proliferation and metastasis of tumor derived MSC. H3K27me3 levels were increased in JMJD3 depleted ER+tumor cells. Tumors derived from MMTV-Wnt1 MSC co-transplanted with JMJD3 shRNA transduced ER+ cells demonstrated increased latency with decreased tumor number, volume, and metastasis. Tumors derived from MMTV-Wnt1 MSC co-transplanted with JMJD3 shRNA transduced ER+ cells were classified as poorly differentiated adenocarcinoma by histopathologic analysis. The MSC fraction was reduced in tumors containing JMJD3 shRNA transduced ER+ cells compared to control transduced tumors. The implications of the results presented in this report suggest that while tumor suppressor pathways can inhibit mammary tumorigenesis when DNA damage repair is inhibited, more aggressive clones may eventually evolve via genomic instability with the ability to proliferate and metastasize. Decreased DNA damage repair or altered epigenetic marks can dramatically affect the cellular composition of these tumors, thereby regulating phenotype and outcomes. Paracrine factors secreted by ER+ tumor cells can induce proliferation of tumorigenic MSC, leading to increased genomic instability and metastasis. Epigenetic marks in specific tumor cell populations (MSC vs. ER+) can dramatically alter tumor phenotype and outcome.

关键词：乳腺癌；脱氧核糖核酸；上皮细胞

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The canonical TGFb/Smad signaling axis promotes breast cancer metastasis, as blocking this pathway could slow down metastasis in animal models. Since Smad2 and Smad3 are transcription factors, they are not ideal drug targets. As such, investigating intracellular signaling mechanisms that regulate Smad activity is highly meaningful not only for understanding TGFb s pro-invasive functions in breast cancer but also for identifying new leads to design therapies that block TGFb signaling in metastatic breast cancer. We identify two of such mechanisms, mediated through cell signaling molecules GRK2 and BCAR3, which could antagonize TGFb signaling in human breast cancer cells. During the tenure of the traineeship, we performed biochemical studies to elucidate how these signaling molecules could block TGFb/Smad signaling; and performed cell-based functional analysis to determine whether these molecules could modulate TGFb s pro-invasive functions. We found that both GRK2 and BCAR3 were potent inhibitory molecules of Smad activation. They both antagonize TGFb- mediated gene transcription and TGFb-induced breast cancer cell invasion. High expression of GRK2, or BCAR3, associates with lower chance of relapse and distant metastasis among breast cancer patients. As such, mimicking GRK2 or BCAR3 s function in breast cancer cells could likely decrease the invasive properties of these cells.

关键词：生物化学；乳腺癌；加拿大细胞（生物学）

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