tbuckley/cabot-search huggingface dataset:
ScaffViz: visualizing metagenome assemblies
Authors: Sergey Koren, Todd Treangen, Mihai Pop
Journal: Genome biology (2011)

Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health.
ENERGY INTAKE, MEAL FREQUENCY, AND HEALTH: A Neurobiological Perspective
Authors: Mark P. Mattson
Journal: Annual Review of Nutrition (2005)

▪ Abstract The size and frequency of meals are fundamental aspects of nutrition that can have profound effects on the health and longevity of laboratory animals. In humans, excessive energy intake is associated with increased incidence of cardiovascular disease, diabetes, and certain cancers and is a major cause of disability and death in industrialized countries. On the other hand, the influence of meal frequency on human health and longevity is unclear. Both caloric (energy) restriction (CR) and reduced meal frequency/intermittent fasting can suppress the development of various diseases and can increase life span in rodents by mechanisms involving reduced oxidative damage and increased stress resistance. Many of the beneficial effects of CR and fasting appear to be mediated by the nervous system. For example, intermittent fasting results in increased production of brain-derived neurotrophic factor (BDNF), which increases the resistance of neurons in the brain to dysfunction and degeneration in animal models of neurodegenerative disorders; BDNF signaling may also mediate beneficial effects of intermittent fasting on glucose regulation and cardiovascular function. A better understanding of the neurobiological mechanisms by which meal size and frequency affect human health may lead to novel approaches for disease prevention and treatment.
Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys
Authors: Norman L. Letvin, Srinivas S. Rao, David C. Montefiori, Michael S. Seaman, Yue Sun, So-Yon Lim, Wendy W. Yeh, Mohammed Asmal, Rebecca S. Gelman, Ling Shen, James B. Whitney, Cathal Seoighe, Miguel Lacerda, Sheila Keating, Philip J. Norris, Michael G. Hudgens, Peter B. Gilbert, Adam P. Buzby, Linh V. Mach, Jinrong Zhang, Harikrishnan Balachandran, George M. Shaw, Stephen D. Schmidt, John-Paul Todd, Alan Dodson, John R. Mascola, Gary J. Nabel
Journal: Science Translational Medicine (2011)

A vaccine protecting monkeys against mucosal infection by simian immunodeficiency virus sheds light on immune and genetic correlates of protection.
Relapse-Free Survival in Breast Cancer Patients Is Associated with a Gene Expression Signature Characteristic for Inflammatory Breast Cancer
Authors: Steven Van Laere, Tim Beissbarth, Ilse Van der Auwera, Gert Van den Eynden, Xuan Bich Trinh, Hilde Elst, Paul Van Hummelen, Peter van Dam, Eric Van Marck, Peter Vermeulen, Luc Dirix
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We hypothesize that a gene expression profile characteristic for inflammatory breast cancer (IBC), an aggressive form of breast cancer associated with rapid cancer dissemination and poor survival, might be related to tumor aggressiveness in non-IBC (nIBC). Experimental Design: RNA from 17 IBC samples and 40 nIBC samples was hybridized onto Affymetrix chips. A gene signature predictive of IBC was identified and applied onto 1,157 nIBC samples with survival data of 881 nIBC samples. Samples were classified as IBC-like or nIBC-like. The IBC signature classification was compared with the classifications according to other prognostically relevant gene signatures and clinicopathologic variables. In addition, relapse-free survival (RFS) was compared by the Kaplan-Meyer method. Results: Classification according to the IBC signature is significantly (P &amp;lt; 0.05) associated with the cell-of-origin subtypes, the wound healing response, the invasive gene signature, the genomic grade index, the fibroblastic neoplasm signature, and the 70-gene prognostic signature. Significant associations (P &amp;lt; 0.01) were found between the IBC signature and tumor grade, estrogen receptor status, ErbB2 status, and patient age at diagnosis. Patients with an IBC-like phenotype show a significantly shorter RFS interval (P &amp;lt; 0.05). Oncomine analysis identified cell motility as an important concept linked with the IBC signature. Conclusions: We show that nIBC carcinomas having an IBC-like phenotype have a reduced RFS interval. This suggests that IBC and nIBC show comparable phenotypic traits, for example augmented cell motility, with respect to aggressive tumor cell behavior. This observation lends credit to the use of IBC to study aggressive tumor cell behavior.
Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia
Authors: Charles L Bennett, Samuel M Silver, Benjamin Djulbegovic, Athena T Samaras, C Anthony Blau, Kara J Gleason, Sara E Barnato, Kathleen M Elverman, D Mark Courtney, June M McKoy, Beatrice J Edwards, Cara C Tigue, Dennis W Raisch, Paul R Yarnold, David A Dorr, Timothy M Kuzel, Martin S Tallman, Steven M Trifilio, Dennis P West, Stephen Y Lai, Michael Henke
Journal: JAMA (2008)

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs.To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer.A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008).Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE.Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20).Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.
Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania
Authors: Wafaie W Fawzi, Gernard I Msamanga, Donna Spiegelman, Ernest JN Urassa, Nuala McGrath, Davis Mwakagile, Gretchen Antelman, Roger Mbise, Saidi Kapiga, Walter Willett, David J Hunter, Guillermo Herrera
Journal: The Lancet (1998)
Hepatic oxidative stress activates the<i>Gadd45b</i>gene by way of degradation of the transcriptional repressor STAT3
Authors: Jung-Hwan Kim, Aijuan Qu, Janardan K. Reddy, Bin Gao, Frank J. Gonzalez
Journal: Hepatology (2013)

Growth arrest and DNA damage-inducible beta (GADD45b) plays an important role in many intracellular events, such as cell cycle arrest, DNA repair, cell survival, apoptosis, and senescence. However, its mechanism of transcriptional regulation remains unclear. In this study the mechanism of peroxisome proliferator-activated receptor α (PPARα) ligand induction of the Gadd45b gene in mouse liver was investigated. Gadd45b messenger RNA (mRNA) was markedly induced by the PPARα agonist Wy-14,643 in wild-type mice but not in Ppara -null mice. Signal transducer and activator of transcription 3 (STAT3) was found to be a repressor of the Gadd45b gene through binding to upstream regulatory elements. The role of STAT3 in control of Gadd45b was confirmed using liver-specific Stat3 -null mice. Wy-14,643 treatment stimulated STAT3 ubiquitination leading to activation of the Gadd45b gene as a result of loss of Gadd45b repression by STAT3. STAT3 degradation was induced by forced overexpression of the PPARα target gene-encoded enzyme ACOX1, which produces increased H2O2 as a byproduct of fatty acid β-oxidation. H2O2 also stimulated expression of Gadd45b in cultured cells. Conclusion : PPARα indirectly induces the Gadd45b gene in liver through promoting degradation of the repressor STAT3 as a result of elevated oxidative stress. (Hepatology 2014;59:695–704)
First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip
Authors: Robert Farra, Norman F. Sheppard, Laura McCabe, Robert M. Neer, James M. Anderson, John T. Santini, Michael J. Cima, Robert Langer
Journal: Science Translational Medicine (2012)

The first clinical trial of an implantable microchip-based drug delivery device is discussed. Human parathyroid hormone fragment (1-34) [hPTH(1-34)] was delivered from the device in vivo. hPTH(1-34) is the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products. The microchip-based devices, containing discrete doses of lyophilized hPTH(1-34), were implanted in eight osteoporotic postmenopausal women for 4 months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses. The pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed. Device dosing produced similar pharmacokinetics to multiple injections and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not affect quality of life.
Nasal two-level positive-pressure ventilation in normal subjects. Effects of the glottis and ventilation.
Authors: V F Parreira, V Jounieaux, G Aubert, M Dury, P E Delguste, D O Rodenstein
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

The purpose of this study was to examine the behavior of the glottis during intermittent positive-pressure ventilation (nIPPV) using a two-level positive-pressure ventilator and to compare the glottic adaptation to this ventilatory mode with the one observed using volumetric ventilators, recently reported by us. Six healthy subjects were studied during both wakefulness and sleep. Their glottis was continuously monitored through a fiberoptic bronchoscope. We measured breath by breath the widest inspiratory angle formed by the vocal cords at the anterior commissure, the corresponding tidal volume, and other indices. We used the controlled ventilatory mode. The expiratory pressure was kept at 4 cm H2O, and the inspiratory pressure was increased by steps from 10 to 15 to 20 cm H2O. Increases in inspiratory pressure did not always lead to increases in effective ventilation reaching the lungs. This was due to a significant narrowing of the glottis by adduction of the vocal cords in all subjects. Periodic breathing with or without apneas were common during wakefulness, but especially during sleep, representing 10.5 +/- 11% (SD) of total sleep time. We conclude that effective ventilation during nIPPV using a two-level positive-pressure ventilator in the controlled mode is less predictable and less stable than during nIPPV using volumetric ventilators.
EXPERIMENTAL STUDIES WITH A SPIRAL ORGANISM FOUND IN A WILD RAT
Authors: H. Mooser
Journal: The Journal of Experimental Medicine (1924)

1. Two cases of rat-bite fever with a typical fever course and a maculopapular exanthem came under my observation in Mexico. 2. A spiral organism morphologically identical with one known in Japan as the causative agent of Sodoku was found in a Mus decumanus caught in Mexico City. 3. The organism was found to be pathogenic for white rats and guinea pigs, the infection being fatal for guinea pigs. 4. The bite of an infected guinea pig led in one of two instances to infection and death of the animal bitten. 5. The microscopical findings in the guinea pigs infected with this microorganism closely resemble in many respects the findings in Blake's case and in Kaneko and Okuda's first case, the only ones of human rat-bite fever which have been closely studied at post mortem. 6. Eye lesions were found in all the infected guinea pigs and the spiral organisms were demonstrated in the discharge from the eyes and also within the cornea. 7. Similar eye lesions were found in most of the infected rats and the secretion from the eyes of one of them was demonstrated to be infectious for guinea pigs. 8. The eye lesions constitute an evident source for the spiral organisms transmitted by biting, and not improbably the only one. My experiments may give an explanation for the transmission of some other spirochetal diseases besides rat-bite fever. Cases of Weil's diseases are reported to be caused by the bite of a rat and it is noteworthy that eye lesions occur in spirochaetosis icterohaemorrhagica (Manson).
Characterization of Naturally Occurring HPV16 Integration Sites Isolated from Cervical Keratinocytes under Noncompetitive Conditions
Authors: Keltie L. Dall, Cinzia G. Scarpini, Ian Roberts, David M. Winder, Margaret A. Stanley, Balaji Muralidhar, M. Trent Herdman, Mark R. Pett, Nicholas Coleman
Journal: Cancer Research (2008)

Abstract As the high-risk human papillomavirus (HPV) integrants seen in anogenital carcinomas represent the end-point of a clonal selection process, we used the W12 model to study the naturally occurring integration events that exist in HPV16-infected cervical keratinocytes before integrant selection. We performed limiting dilution cloning to identify integrants present in cells that also maintain episomes. Such integrants arise in a natural context and exist in a noncompetitive environment, as they are transcriptionally repressed by episome-derived E2. We found that integration can occur at any time during episome maintenance, providing biological support for epidemiologic observations that persistent HPV infection is a major risk factor in cervical carcinogenesis. Of 24 different integration sites isolated from a single nonclonal population of W12, 12 (50%) occurred within chromosome bands containing a common fragile site (CFS), similar to observations for selected integrants in vivo. This suggests that such regions represent relatively accessible sites for insertion of foreign DNA, rather than conferring a selective advantage when disrupted. Interestingly, however, integrants and CFSs did not accurately colocalize. We further observed that local DNA rearrangements occur frequently and rapidly after the integration event. The majority of integrants were in chromosome bands containing a cancer-associated coding gene or microRNA, indicating that integration occurs commonly in these regions, regardless of selective pressure. The cancer-associated genes were generally a considerable distance from the integration site, and there was no evidence for altered expression of nine strong candidate genes. These latter observations do not support an important role for HPV16 integration in causing insertional mutagenesis. [Cancer Res 2008;68(20):8249–59]
Colorectal Cancer: Looking for Answers in the Microbiota
Authors: Christian Jobin
Journal: Cancer Discovery (2013)

Abstract Summary: At a simplistic level, colorectal cancer arises from mutations in various proto-oncogenes and tumor suppressor genes. Aside from genetically inherited factors, environmental, lifestyle, and dietary habits have all been identified as risk agents promoting mutational events leading to the development of colorectal cancer. This “In Focus” presents evidence that the intestinal endogenous bacterial community represents a risk factor for the development of colorectal cancer. Cancer Discov; 3(4); 384–7. ©2013 AACR.
P252 Residual drowsiness and CPAP compliance in OSAS patients and the DVLA- on behalf of the British Thoracic Society Sleep Apnoea SAG
Authors: A Dwarakanath, D Ghosh, SL Jamson, PD Baxter, M Twiddy, MW Elliott
Journal: Thorax (2013)

<h3>Introduction</h3> Clinicians are often asked to complete forms about patients with OSAS by the DVLA. We evaluated the current practice of assessing residual drowsiness, CPAP compliance and whether objective testing is undertaken by clinicians to assess an individual’s fitness for driving. <h3>Methods</h3> Clinicians who complete the DVLA medical forms (SL1 and SL1V) were invited to participate in a web-based survey. Respondents were presented with five vignettes of patients with OSAS offered CPAP and to answer the questions posed by the DVLA about residual drowsiness (“excessive” (SL1) or “irresistible” (SL1V)) and adequacy of CPAP compliance. They were also asked about their use of objective tests. <h3>Results</h3> 178 respondents completed the survey. There was poor agreement among clinicians regarding the presence of residual drowsiness (McNemar9s test, figure-1). In response to the DVLA question about “excessive” drowsiness, the patient had a 1 in 2.57 (range-1.12 to 5.66), and about “irresistible” drowsiness, a 1 in 1.32 (range- 1.04 to 2.84), chance of being given a different answer depending on the clinician seen. Furthermore in each vignette the same clinician was more likely to say “yes” to “excessive” than to “irresistible” (71 +/-12% v/s 42 +/-10%, P-0.0045).There was also a lack of consensus as to what constitutes “adequate CPAP compliance”. Across the vignettes there was minimum of 1 in 1.7 and a maximum of 1 in 6.7 chance of disagreement amongst the clinicians (median- 3, range 1.7 to 6.7). 1% of clinicians always and 4% frequently use objective tests to help in their assessment. They are more likely to use in professional drivers as compared to non professional drivers (52% v/s 38%, P- 0.0002, OR-1.75). Tests used were MSLT (34%), OSLER (29%), MWT (28%) and divided attention driving simulator (9%). <h3>Conclusions</h3> The information that the DVLA is given may vary markedly depending upon which clinician completes the form. Furthermore the same clinician may give a different impression to the DVLA depending on which form they are asked to complete. Objective testing is not undertaken routinely. Better guidance and better objective tests are needed to ensure consistency of the information that the DVLA is given.
Invasion and Metastasis of Oral Cancer Cells Require Methylation of E-Cadherin and/or Degradation of Membranous β-Catenin
Authors: Yasusei Kudo, Shojiro Kitajima, Ikuko Ogawa, Masae Hiraoka, Soodabeh Sargolzaei, Mohammad Reza Keikhaee, Sunao Sato, Mutsumi Miyauchi, Takashi Takata
Journal: Clinical Cancer Research (2004)

Abstract The extent of lymph node metastasis is a major determinant in the prognosis of oral squamous cell carcinoma (OSCC). Abnormalities of cell adhesion molecules are known to play an important role in invasion and metastasis of cancer cells through the loss of cell-to-cell adhesion. In this study, we isolated highly invasive clones from an OSCC cell line established from a lymph node metastasis by using an in vitro invasion assay method and compared the abnormalities of cell adhesion molecule E-cadherin and β-catenin in these cells. The isolated, highly invasive clones showed significant invasive capacity and reduction of E-cadherin and membranous β-catenin protein in comparison with parent cells. We found that reduced expression of E-cadherin was due to methylation of its promoter region. In fact, most invasive and metastatic area of OSCCs showed reduced expression and methylation of E-cadherin. Moreover, we found that reduced expression of membranous β-catenin was due to its protein degradation. Reduced expression of membranous β-catenin was also found frequently in invasive and metastatic areas of OSCCs. In summary, invasion and metastasis of OSCC cells require methylation of E-cadherin and/or degradation of membranous β-catenin. In addition, we suggest that the method of isolation of highly invasive clones may be useful for studies aimed at discovering novel genes involved in invasion and metastasis.