tbuckley/cabot-search huggingface dataset:
Secondary Attack Rate of Type 1 Diabetes in Colorado Families
Authors: Andrea K. Steck, Katherine J. Barriga, Lisa M. Emery, Rosanna V. Fiallo-Scharer, Peter A. Gottlieb, Marian J. Rewers
Journal: Diabetes Care (2005)

OBJECTIVE—Families of children diagnosed with type 1 diabetes require counseling concerning type 1 diabetes risk in nondiabetic siblings and parents. No U.S. population–specific life-table risk estimates are currently available for parents, and those for siblings (2–6% by age 20 years) are based on family studies completed before 1987. RESEARCH DESIGN AND METHODS—We analyzed family histories of 1,586 patients in Colorado with type 1 diabetes (83% non-Hispanic white, 10% Hispanic, and 7% other) diagnosed before 16 years of age and interviewed during 1999–2002. Families of probands with type 2, undetermined, or secondary diabetes (n = 53) or those with incomplete data (n = 137) were excluded. The median age at onset of the proband was 7.1 years and the median diabetes duration 3.5 years. Cumulative risk estimates were calculated using survival analysis for 2,081 full siblings and 3,016 biological parents. RESULTS—In siblings, the overall risk of type 1 diabetes by age 20 years was 4.4%, but it was significantly (P &amp;lt; 0.0001) higher in siblings of probands diagnosed under age 7 years than in those diagnosed later. In parents, the overall risk by age 40 years was 2.6% and higher in fathers (3.6%) than in mothers (1.7%) of probands (P &amp;lt; 0.001). Similar to siblings, the risk was also higher (P = 0.006) in parents of probands diagnosed &amp;lt;7 years of age than in those diagnosed later. CONCLUSIONS—Current risks of type 1 diabetes in Colorado siblings and parents of type 1 diabetic probands are higher than in the 1982 Pittsburgh study but similar to contemporary European rates. Recurrence risk of type 1 diabetes is significantly higher in first-degree relatives of probands diagnosed at a young age.
The Angola HIV epidemic, 2004–11: a case of change or stability?
Authors: E Catumbela, A Freitas, D Serrano, M L Furtado, M Gomes, R W Shiraishi, P Young, N Naffga, D Love Hall, M C T Mendoza, C Costa, A Sarmento, A Costa-Pereira
Journal: The Lancet (2013)
COPD-related morbidity and mortality after smoking cessation: status of the evidence
Authors: N. S. Godtfredsen, T. H. Lam, T. T. Hansel, M. E. Leon, N. Gray, C. Dresler, D. M. Burns, E. Prescott, J. Vestbo
Journal: European Respiratory Journal (2008)

The evidence base for the benefit of quitting smoking as regards morbidity and mortality outcomes in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) is limited. The present article is a review of the existing literature. A systematic literature search in medical databases was performed until March 2006, and subsequently until September 1, 2007. The outcomes examined were COPD-related morbidity and mortality (including all-cause mortality) in COPD patients in connection with smoking cessation. A total of 21 and 27 published articles on morbidity and mortality, respectively, were identified and reviewed. For both outcomes, only a few of the studies included patients with severe COPD. Most of the studies reported a beneficial effect of smoking cessation compared with continued smoking, whereas a few found no improvement. Methodological problems, including small study sizes, poor data quality, possibility of reverse causality and incomplete ascertainment of cause of death, limit interpretation of some of the studies. The evidence as a whole supports the conclusion that, even in severe chronic obstructive pulmonary disease, smoking cessation slows the accelerated rate of lung function decline and improves survival compared with continued smoking.
Effect of the CYP3A4 inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of AZD5069, an oral CXCR2 antagonist
Authors: Marie Cullberg, Heather Wray, Bengt Larsson
Journal: European Respiratory Journal (2014)

Background: AZD5069 is an oral C-X-C chemokine receptor 2 (CXCR2) antagonist targeting neutrophil-driven inflammation and is in clinical evaluation for the treatment of inadequately controlled asthma. AZD5069 is primarily metabolised by CYP3A isoenzymes,1 but the impact of CYP3A inhibition on systemic AZD5069 exposure in humans is not known.

Aims: To evaluate the effect of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics and effect on blood neutrophil counts of AZD5069.

Methods: Fifteen healthy male volunteers received single oral doses of AZD5069 15mg, alone and after pre-treatment with ketoconazole 400 mg once daily for 4 days. In addition to standard safety and laboratory evaluations, serial blood samples for assessment of pharmacokinetics and blood neutrophil counts were drawn up to 72 hours post-dose.

Results: Compared with AZD5069 alone, co-administration of AZD5069 and ketoconazole increased the geometric mean AUC 2.11-fold (90% CI: 1.92–2.32) and Cmax 1.65-fold (90% CI: 1.45–1.87). Blood neutrophil counts decreased when AZD5069 was administered alone and were further decreased following the combination of AZD5069 and ketoconazole. This correlated with the increase in AZD5069 exposure. The neutrophil counts returned to baseline within 48 h after dosing.

Conclusions: Co-administration of AZD5069 and ketoconazole resulted in a 2-fold increase in systemic exposure of AZD5069 and a greater reduction in blood neutrophil counts than AZD5069 alone. The clinical relevance of this has yet to be determined.

1. Gardiner P, et al. The mechanisms and routes of clearance of the CXCR2 antagonist AZD5069 in human. AAPS 2013, TX, USA. W4280

Funding: AstraZeneca.
THE DISTRIBUTION AND CHEMICAL COMPOSITION OF ULTRACENTRIFUGALLY SEPARATED LIPOPROTEINS IN HUMAN SERUM
Authors: Richard J. Havel, Howard A. Eder, Joseph H. Bragdon
Journal: Journal of Clinical Investigation (1955)

In the past few years several methods have been developed for the analysis of serum lipoproteins.Lindgren, Elliott, and Gofman (1) have utilized the relatively low density of the lipoproteins to separate them from the other serum proteins by ultracentrifugal flotation.Quantitation was sub- sequently performed by refractometric methods in the analytical ultracentrifuge.Separations of lipoproteins have also been made by Cohn frac- tionation in cold ethanol, and the quantities of lipoprotein have been estimated from the lipid.content of the fractions (2, 3).Widely used at the present time is the method of zone electrophoresis with quantitation either by staining (4) or by chemical analysis of eluates from the support- ing medium (5, 6).Each of these methods has serious limitations.Analytical ultracentrifugal techniques (7, 8) require the possession of expensive equipment.The quantitation of data is subject to considerable error and gives no information regarding the chemi- cal composition of the lipoproteins.Cohn frac- tionation requires facilities for operation at -5°C.It permits accurate determination of the lipid com- ponents of the alpha and beta lipoproteins, but with this technique it is impossible to subfractionate these groups.With certain abnormal sera the method is unreliable (9).Determination of electrophoretically separated fractions by stain- ing techniques or by chemical analysis of eluates is subject to appreciable error.Both Cohn frac- tionation and electrophoretic techniques fail to separate lipoproteins from other serum pro- teins, thus making impossible the study of the protein moiety.The combination of preparative ultracentrifu- gation with chemical analysis of the separated fractions would seem to be a procedure by which both the distribution and composition of lipo- proteins could be determined simply and accu- rately.
Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models
Authors: James G. Taylor VI, Adam T. Cheuk, Patricia S. Tsang, Joon-Yong Chung, Young K. Song, Krupa Desai, Yanlin Yu, Qing-Rong Chen, Kushal Shah, Victoria Youngblood, Jun Fang, Su Young Kim, Choh Yeung, Lee J. Helman, Arnulfo Mendoza, Vu Ngo, Louis M. Staudt, Jun S. Wei, Chand Khanna, Daniel Catchpoole, Stephen J. Qualman, Stephen M. Hewitt, Glenn Merlino, Stephen J. Chanock, Javed Khan
Journal: Journal of Clinical Investigation (2009)

Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined. Here, we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation and present evidence that it functions as an oncogene in RMS. Higher FGFR4 expression in RMS tumors was associated with advanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth and experimental lung metastases when the cells were transplanted into mice. Moreover, 6 FGFR4 tyrosine kinase domain mutations were found among 7 of 94 (7.5%) primary human RMS tumors. The mutants K535 and E550 increased autophosphorylation, Stat3 signaling, tumor proliferation, and metastatic potential when expressed in a murine RMS cell line. These mutants also transformed NIH 3T3 cells and led to an enhanced metastatic phenotype. Finally, murine RMS cell lines expressing the K535 and E550 FGFR4 mutants were substantially more susceptible to apoptosis in the presence of a pharmacologic FGFR inhibitor than the control cell lines expressing the empty vector or wild-type FGFR4. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncogene, and these are what we believe to be the first known mutations in a receptor tyrosine kinase in RMS. These findings support the potential therapeutic targeting of FGFR4 in RMS.
Blame It on the Chimps: Researchers Resolve Evolutionary Origins of Human Herpes Viruses
Authors: J. Caspermeyer
Journal: Molecular Biology and Evolution (2014)

A leading sexually transmitted disease, the herpes virus, infects more than two-thirds of all people. An evolutionary question for scientists has been why humans are the only primate species that harbor two forms of the herpes simplex virus (HSV): HSV-1 (causing cold sores) and HSV-2 (genital herpes). Wertheim et al. (2014) used a novel model of molecular evolution to demonstrate that HSV-1 likely infected the last common, ancient ancestor of chimpanzees and humans at estimates of 6 Ma. Although HSV-2, which leads to more severe complications for people, arose by an entirely different means, jumping from species to a species when, around 1.6 Ma, an ancestor of modern chimpanzees first passed on HSV-2 to an early hominid species. “Before we were human, there was still cross-species transmission into our evolutionary lineage,” study author Joel O. Wertheim. Since that time, when the ancient split first introduced HSV-2 into ancient hominids, the herpes virus has remained a scourge that has been passed down all the way to modern humans.
A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in theneo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial
Authors: I.E. Smith, R.P. A’Hern, G.A. Coombes, A. Howell, S.R. Ebbs, T.F. Hickish, M.E.R. O’Brien, J.L. Mansi, C.B. Wilson, A.C. Robinson, P.A. Murray, C.G.A. Price, T.J. Perren, R.W. Laing, J.M. Bliss
Journal: Annals of Oncology (2004)
Cross-presentation of Disialoganglioside GD3 to Natural Killer T Cells
Authors: Dianna Y. Wu, Neil H. Segal, Stephane Sidobre, Mitchell Kronenberg, Paul B. Chapman
Journal: The Journal of Experimental Medicine (2003)

GD3, a ganglioside expressed on human melanoma, can be recognized by the humoral immune system. In this paper, we demonstrate that immunizing mice with the human melanoma cell line SK-MEL-28 (GD3+ GM2− CD1−) or with syngeneic APCs loaded with GD3 can induce a GD3-reactive natural killer T (NKT) cell response. GD3-reactive NKT cells were detected among splenocytes of immunized mice at frequencies of ∼1:2,000 both by ELISPOT and GD3-loaded mouse CD1d tetramer analysis. GD3-reactive NKT cells did not react with GM2, a closely related ganglioside, and were not detectable in unimmunized mice. GD3-reactive NKT cells initially produced IL-4 and IFN-γ followed by IL-10. They were CD1d restricted in that reactivity was abrogated when APCs were blocked with anti-CD1d monoclonal antibody before being loaded with GD3 or when APCs from CD1d knockout mice were used. Because SK-MEL-28 does not express any isoform of human CD1, GD3 must be cross-presented by murine APCs in vivo. This is the first analysis of a natural ligand for mouse NKT cells and the first definitive paper of cross-presentation to NKT cells. This could be a mechanism for NKT cell recognition of tumor gangliosides in CD1− tumors.
Uncoupling Protein 2 Deficiency Mimics the Effects of Hypoxia and Endoplasmic Reticulum Stress on Mitochondria and Triggers Pseudohypoxic Pulmonary Vascular Remodeling and Pulmonary Hypertension
Authors: Peter Dromparis, Roxane Paulin, Gopinath Sutendra, Andrew C. Qi, Sébastien Bonnet, Evangelos D. Michelakis
Journal: Circulation Research (2013)

Mitochondrial signaling regulates both the acute and the chronic response of the pulmonary circulation to hypoxia, and suppressed mitochondrial glucose oxidation contributes to the apoptosis-resistance and proliferative diathesis in the vascular remodeling in pulmonary hypertension. Hypoxia directly inhibits glucose oxidation, whereas endoplasmic reticulum (ER)-stress can indirectly inhibit glucose oxidation by decreasing mitochondrial calcium (Ca²⁺m levels). Both hypoxia and ER stress promote proliferative pulmonary vascular remodeling. Uncoupling protein 2 (UCP2) has been shown to conduct calcium from the ER to mitochondria and suppress mitochondrial function.We hypothesized that UCP2 deficiency reduces Ca²⁺m in pulmonary artery smooth muscle cells (PASMCs), mimicking the effects of hypoxia and ER stress on mitochondria in vitro and in vivo, promoting normoxic hypoxia inducible factor-1α activation and pulmonary hypertension.Ucp2 knockout (KO)-PASMCs had lower mitochondrial calcium than Ucp2 wildtype (WT)-PASMCs at baseline and during histamine-stimulated ER-Ca²⁺ release. Normoxic Ucp2KO-PASMCs had mitochondrial hyperpolarization, lower Ca²⁺-sensitive mitochondrial enzyme activity, reduced levels of mitochondrial reactive oxygen species and Krebs' cycle intermediates, and increased resistance to apoptosis, mimicking the hypoxia-induced changes in Ucp2WT-PASMC. Ucp2KO mice spontaneously developed pulmonary vascular remodeling and pulmonary hypertension and exhibited a pseudohypoxic state with pulmonary vascular and systemic hypoxia inducible factor-1α activation (increased hematocrit), not exacerbated further by chronic hypoxia.This first description of the role of UCP2 in oxygen sensing and in pulmonary hypertension vascular remodeling may open a new window in biomarker and therapeutic strategies.
Stent Thrombosis and Bleeding Complications After Implantation of Sirolimus-Eluting Coronary Stents in an Unselected Worldwide Population
Authors: Philip Urban, Alexandre Abizaid, Adrian Banning, Antonio L. Bartorelli, Ana Cebrian Baux, Vladimír Džavík, Stephen Ellis, Runlin Gao, David Holmes, Myung Ho Jeong, Victor Legrand, Franz-Josef Neumann, Maria Nyakern, Christian Spaulding, Stephen Worthley
Journal: Journal of the American College of Cardiology (2011)
Sequencing and characterization of the FVB/NJ mouse genome
Authors: Kim Wong, Suzannah Bumpstead, Louise Van Der Weyden, Laura G Reinholdt, Laurens G Wilming, David J Adams, Thomas M Keane
Journal: Genome biology (2012)

The FVB/NJ mouse strain has its origins in a colony of outbred Swiss mice established in 1935 at the National Institutes of Health. Mice derived from this source were selectively bred for sensitivity to histamine diphosphate and the B strain of Friend leukemia virus. This led to the establishment of the FVB/N inbred strain, which was subsequently imported to the Jackson Laboratory and designated FVB/NJ. The FVB/NJ mouse has several distinct characteristics, such as large pronuclear morphology, vigorous reproductive performance, and consistently large litters that make it highly desirable for transgenic strain production and general purpose use.Using next-generation sequencing technology, we have sequenced the genome of FVB/NJ to approximately 50-fold coverage, and have generated a comprehensive catalog of single nucleotide polymorphisms, small insertion/deletion polymorphisms, and structural variants, relative to the reference C57BL/6J genome. We have examined a previously identified quantitative trait locus for atherosclerosis susceptibility on chromosome 10 and identify several previously unknown candidate causal variants.The sequencing of the FVB/NJ genome and generation of this catalog has increased the number of known variant sites in FVB/NJ by a factor of four, and will help accelerate the identification of the precise molecular variants that are responsible for phenotypes observed in this widely used strain.
HEREDITARY DISTAL FORELEG CURVATURE IN THE RABBIT
Authors: Louise Pearce
Journal: The Journal of Experimental Medicine (1960)

An inwardly directed curvature of the distal segment of both forelegs of the rabbit has been described. The condition was detected at 2 to 3 weeks of age, developed rapidly, and reached its final and permanent stage at 2 to 3 months of age. Only the distal epiphysis of the ulna was primarily affected and this in the form of a massive chondrodystrophic lesion accompanied by a progressive curvature of the shaft. The curvature of the growing radius was a secondary effect due to the firm, immovable, anatomical connection of the ulna and radius. The positional changes of the wrist and paw were likewise effects secondary to the changed form of the ulna and radius. The bowing abnormality occurred only in certain families of pure bred Beveren, Belgian, French Silver, and Dutch rabbits and was found to be inherited. The mode of inheritance was on the basis of a single recessive unit factor (5).
Interferon-γ, a Th1 Cytokine, Regulates Fat Inflammation
Authors: Viviane Zorzanelli Rocha, Eduardo J. Folco, Galina Sukhova, Koichi Shimizu, Israel Gotsman, Ashley H. Vernon, Peter Libby
Journal: Circulation Research (2008)

Adipose tissue (AT) can accumulate macrophages and secrete several inflammatory mediators. Despite its pivotal role in the progression of chronic inflammatory processes such as atherosclerosis, the adaptive role of immunity in obesity remains poorly explored. Visceral AT of diet-induced obese C57BL/6 mice had higher numbers of both CD4(+) and CD8(+) T cells than lean controls, monitored by flow cytometry. When stimulated in vitro, T cells from obese AT produced more interferon (IFN)gamma than those from controls. AT from obese animals also had more cells expressing I-A(b), a mouse class II histocompatibility marker implicated in antigen presentation, as determined by immunostaining. Differentiated 3T3-L1 cells stimulated with recombinant IFNgamma or T-helper 1-derived supernatant produced several chemokines and their mRNAs. Obese IFNgamma-deficient animals had significantly reduced AT expression of mRNA-encoding inflammatory genes such as tumor necrosis factor-alpha and monocyte chemoattractant protein-1, decreased AT inflammatory cell accumulation, and better glucose tolerance than control animals consuming the same diet. Obese mice doubly deficient for IFNgamma receptor and apolipoprotein (Apo)E on a mixed 129SvEv/C57BL/6 (129/B6) genetic background, despite exhibiting similar AT mRNA levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 as 129/B6-ApoE(-/-) controls, had decreased expression of important T cell-related genes, such as IFNgamma-inducible protein-10 and I-A(b), and lower plasma triglycerides and glucose. These results indicate a role for T cells and IFNgamma, a prototypical T-helper 1 cytokine, in regulation of the inflammatory response that accompanies obesity.
Selected Anatomists
Authors: Dillon Arango, Patrick Greiffenstein, James Patrick O’Leary
Journal: JAMA Surgery (2013)

Fascination with the interworkings of the human body has permeated scientific discovery for eons. Materials for dissection proved problematic for anatomists. Andreas Vesalius solved his dilemma by visiting local gallows where criminals had been executed. Eduard Pernkopf has been alleged to have taken some of his materials from victims of the Holocaust. Even today, executed criminals have served as subjects for anatomical educational purposes. These circumstances are explored and the contemporary ethics of each are compared.
Sugar Industry Influence on the Scientific Agenda of the National Institute of Dental Research’s 1971 National Caries Program: A Historical Analysis of Internal Documents
Authors: Cristin E. Kearns, Stanton A. Glantz, Laura A. Schmidt
Journal: PLoS Medicine (2015)

Background In 1966, the National Institute of Dental Research (NIDR) began planning a targeted research program to identify interventions for widespread application to eradicate dental caries (tooth decay) within a decade. In 1971, the NIDR launched the National Caries Program (NCP). The objective of this paper is to explore the sugar industry's interaction with the NIDR to alter the research priorities of the NIDR NCP. Methods and Findings We used internal cane and beet sugar industry documents from 1959 to 1971 to analyze industry actions related to setting research priorities for the NCP. The sugar industry could not deny the role of sucrose in dental caries given the scientific evidence. They therefore adopted a strategy to deflect attention to public health interventions that would reduce the harms of sugar consumption rather than restricting intake. Industry tactics included the following: funding research in collaboration with allied food industries on enzymes to break up dental plaque and a vaccine against tooth decay with questionable potential for widespread application, cultivation of relationships with the NIDR leadership, consulting of members on an NIDR expert panel, and submission of a report to the NIDR that became the foundation of the first request for proposals issued for the NCP. Seventy-eight percent of the sugar industry submission was incorporated into the NIDR's call for research applications. Research that could have been harmful to sugar industry interests was omitted from priorities identified at the launch of the NCP. Limitations are that this analysis relies on one source of sugar industry documents and that we could not interview key actors. Conclusions The NCP was a missed opportunity to develop a scientific understanding of how to restrict sugar consumption to prevent tooth decay. A key factor was the alignment of research agendas between the NIDR and the sugar industry. This historical example illustrates how industry protects itself from potentially damaging research, which can inform policy makers today. Industry opposition to current policy proposals—including a World Health Organization guideline on sugars proposed in 2014 and changes to the nutrition facts panel on packaged food in the US proposed in 2014 by the US Food and Drug Administration—should be carefully scrutinized to ensure that industry interests do not supersede public health goals.