tbuckley/cabot-search huggingface dataset:
Expression of Vascular Endothelial Growth Factor Receptor-3 by Lymphatic Endothelial Cells Is Associated with Lymph Node Metastasis in Prostate Cancer
Authors: Yiping Zeng, Kenneth Opeskin, Megan E. Baldwin, Lisa G. Horvath, Marc G. Achen, Steven A. Stacker, Robert L. Sutherland, Elizabeth D. Williams
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The molecular mechanisms underlying lymph node metastasis are poorly understood, despite the well-established clinical importance of lymph node status in many human cancers. Recently, vascular endothelial growth factor (VEGF)-C and VEGF-D have been implicated in the regulation of tumor lymphangiogenesis and enhancement of lymphatic invasion via activation of VEGF receptor-3. The purpose of this study was to determine the expression pattern of the VEGF-C/VEGF-D/VEGF receptor-3 axis in prostate cancer and its relationship with lymph node metastasis. Experimental Design: The expression pattern of VEGF-C, VEGF-D, and VEGF receptor-3 in localized prostate cancer specimens (n = 37) was determined using immunohistochemistry. Results: Widespread, heterogeneous staining for VEGF-C and VEGF-D was observed in all cancer specimens. Intensity of VEGF-C staining was lower in benign prostate epithelium than in adjacent carcinoma, whereas no difference between benign epithelium and carcinoma was observed for VEGF-D staining. VEGF receptor-3 immunostaining was detected in endothelial cells of lymphatic vessels in 18 of 37 tissue samples. The presence of VEGF receptor-3-positive vessels was associated with lymph node metastasis (P = 0.0002), Gleason grade (P &amp;lt; 0.0001), extracapsular extension (P = 0.0382), and surgical margin status (P = 0.0069). In addition, VEGF receptor-3 staining highlighted lymphatic invasion by VEGF-C-positive/VEGF-D-positive carcinoma cells. Conclusions: Together, these results suggest that paracrine activation of lymphatic endothelial cell VEGF receptor-3 by VEGF-C and/or VEGF-D may be involved in lymphatic metastasis. Thus the VEGF-C/VEGF-D/VEGF receptor-3 signaling pathway may provide a target for antilymphangiogenic therapy in prostate cancer.
Potentiation of Ca <sup>2+</sup> Release by cADP-Ribose in the Heart Is Mediated by Enhanced SR Ca <sup>2+</sup> Uptake Into the Sarcoplasmic Reticulum
Authors: Valeriy Lukyanenko, Inna Györke, Theodore F. Wiesner, Sandor Györke
Journal: Circulation Research (2001)

Abstract— cADP-Ribose (cADPR) is a novel endogenous messenger that is believed to mobilize Ca 2+ from ryanodine-sensitive Ca 2+ stores. Despite intense research, the precise mechanism of action of cADPR remains uncertain, and experimental findings are contradictory. To elucidate the mechanism of cADPR action, we performed confocal Ca 2+ imaging in saponin-permeabilized rat ventricular myocytes. Exposure of the cells to cADPR resulted in a slow (&gt;2 minutes) and steady increase in the frequency of Ca 2+ sparks. These effects on local release events were accompanied by a significant increase in sarcoplasmic reticulum (SR) Ca 2+ content. In comparison, sensitization of ryanodine receptors (RyRs) by caffeine, a true RyR agonist, caused a rapid (&lt;1 second) and transient potentiation of Ca 2+ sparks followed by a decrease in SR Ca 2+ content. When the increase in the SR load was prevented by partial inhibition of the SR Ca 2+ with thapsigargin, cADPR failed to produce any increase in sparking activity. cADPR had no significant impact on activity of single cardiac RyRs incorporated into lipid bilayers. However, it caused a significant increase in the rate of Ca 2+ uptake by cardiac SR microsomes. Our results suggest that the primary target of cADPR is the SR Ca 2+ uptake mechanism. Potentiation of Ca 2+ release by cADPR is mediated by increased accumulation of Ca 2+ in the SR and subsequent luminal Ca 2+ -dependent activation of RyRs.
The frequency of non-radiographic axial spondyloarthritis in relation to symptom duration in patients referred because of chronic back pain: results from the Berlin early spondyloarthritis clinic
Authors: Denis Poddubnyy, Henning Brandt, Janis Vahldiek, Inge Spiller, In-Ho Song, Martin Rudwaleit, Joachim Sieper
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> This study was aimed at investigating the frequencies of non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) diagnoses and their ratios in relation to symptom duration in patients referred because of chronic back pain and suspicion of axial SpA. <h3>Methods</h3> In this monocentre study, orthopaedists and primary care physicians were requested to refer patients with chronic low back pain (duration &gt;3 months) and onset of back pain before 45 years of age to a SpA-specialised rheumatology outpatient clinic for further diagnostic investigation, if proposed screening parameters were present. The ratio of nr-axSpA to AS was analysed in relation to the duration of symptoms. <h3>Results</h3> A diagnosis of definite axial SpA was made in 43.7% of the referred patients (n=522). Axial SpA was diagnosed in a similar percentage of about 50% if back pain duration was &lt;9 years but decreased to 36% if symptom duration was &gt;9 years. Nr-axSpA represented the majority of patients (67.3%) only if duration of back pain was 1 year and less at the time of referral. Between 1 and 6 years of back pain duration the probability of nr-axSpA and AS was nearly equal (1–3 years: 52.5% and 47.5%, respectively; 3–6 years: 53.7% and 46.3%, respectively). In patients with back pain duration of 6–9 years, AS was more likely (61.1%) to be diagnosed than nr-axSpA (38.9%), and this increased further over time. <h3>Conclusions</h3> Non-radiographic axial SpA represents an important differential diagnosis of back pain, especially in patients with recent symptom onset.
Immunogenetics of Spontaneous Control of HIV
Authors: Mary Carrington, Bruce D. Walker
Journal: Annual Review of Medicine (2010)

Host genetic variation is presently estimated to account for about one-fourth of the observed differences in control of HIV across infected individuals. Genome-wide association studies have confirmed that polymorphism within the HLA class I locus is the primary host genetic contributor to determining outcome after infection. Here we progress beyond the genetic associations alone to consider the functional explanations for these correlations. In this process, the complex and multidimensional effects of HLA molecules in viral disease become apparent.
Broad metabolic sensitivity profiling of a prototrophic yeast deletion collection
Authors: Benjamin VanderSluis, David C Hess, Colin Pesyna, Elias W Krumholz, Tahin Syed, Balázs Szappanos, Corey Nislow, Balázs Papp, Olga G Troyanskaya, Chad L Myers, Amy A Caudy
Journal: Genome biology (2014)

Genome-wide sensitivity screens in yeast have been immensely popular following the construction of a collection of deletion mutants of non-essential genes. However, the auxotrophic markers in this collection preclude experiments on minimal growth medium, one of the most informative metabolic environments. Here we present quantitative growth analysis for mutants in all 4,772 non-essential genes from our prototrophic deletion collection across a large set of metabolic conditions.The complete collection was grown in environments consisting of one of four possible carbon sources paired with one of seven nitrogen sources, for a total of 28 different well-defined metabolic environments. The relative contributions to mutants' fitness of each carbon and nitrogen source were determined using multivariate statistical methods. The mutant profiling recovered known and novel genes specific to the processing of nutrients and accurately predicted functional relationships, especially for metabolic functions. A benchmark of genome-scale metabolic network modeling is also given to demonstrate the level of agreement between current in silico predictions and hitherto unavailable experimental data.These data address a fundamental deficiency in our understanding of the model eukaryote Saccharomyces cerevisiae and its response to the most basic of environments. While choice of carbon source has the greatest impact on cell growth, specific effects due to nitrogen source and interactions between the nutrients are frequent. We demonstrate utility in characterizing genes of unknown function and illustrate how these data can be integrated with other whole-genome screens to interpret similarities between seemingly diverse perturbation types.
Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level
Authors: Olivier Harismendy, Vikas Bansal, Gaurav Bhatia, Masakazu Nakano, Michael Scott, Xiaoyun Wang, Colette Dib, Edouard Turlotte, Jack C Sipe, Sarah S Murray, Jean Deleuze, Vineet Bafna, Eric J Topol, Kelly A Frazer
Journal: Genome biology (2010)

Targeted re-sequencing of candidate genes in individuals at the extremes of a quantitative phenotype distribution is a method of choice to gain information on the contribution of rare variants to disease susceptibility. The endocannabinoid system mediates signaling in the brain and peripheral tissues involved in the regulation of energy balance, is highly active in obese patients, and represents a strong candidate pathway to examine for genetic association with body mass index (BMI). We sequenced two intervals (covering 188 kb) encoding the endocannabinoid metabolic enzymes fatty-acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal controls and 142 extremely obese cases. After applying quality filters, we called 1,393 high quality single nucleotide variants, 55% of which are rare, and 143 indels. Using single marker tests and collapsed marker tests, we identified four intervals associated with BMI: the FAAH promoter, the MGLL promoter, MGLL intron 2, and MGLL intron 3. Two of these intervals are composed of rare variants and the majority of the associated variants are located in promoter sequences or in predicted transcriptional enhancers, suggesting a regulatory role. The set of rare variants in the FAAH promoter associated with BMI is also associated with increased level of FAAH substrate anandamide, further implicating a functional role in obesity. Our study, which is one of the first reports of a sequence-based association study using next-generation sequencing of candidate genes, provides insights into study design and analysis approaches and demonstrates the importance of examining regulatory elements rather than exclusively focusing on exon sequences.
A down-regulatable E-selectin ligand is functionally important for PSGL-1–independent leukocyte–endothelial cell interactions
Authors: Renata C. O. Zanardo, Claudine S. Bonder, John M. Hwang, Graciela Andonegui, Lixin Liu, Dietmar Vestweber, Lori Zbytnuik, Paul Kubes
Journal: Blood (2004)
THE ORIGIN OF ALVEOLAR MACROPHAGES IN MOUSE RADIATION CHIMERAS
Authors: John J. Godleski, Joseph D. Brain
Journal: The Journal of Experimental Medicine (1972)

This investigation attempted to determine whether the primary source of alveolar macrophages is pulmonary or hematopoietic. We have utilized an antigenic marker to identify cells of hematopoietic origin. Mouse chimeras were produced by irradiating C57B6/AF1 mice (900 R) and then injecting them intravenously with B10D2/AF1 bone marrow. The donor animal has an antigenic specificity on the H-2 locus, not shared by the recipient. Alveolar macrophages were obtained by repeated lung washings with physiologic saline at 37°C. Cytotoxic tests were done on bone marrow and alveolar macrophages using anti-31 mouse antibody, absorbed rabbit serum as complement, and trypan blue exclusion as a test for viability. Animals were studied at 7, 14, 21, 28, and 35–50 days and 4, 5, 8, and 11 months after irradiation and bone marrow replacement. By 21 days after irradiation, 90% of the animals had greater than 80% replacement of marrow with donor tissue; and white blood cell and alveolar macrophage counts approached normal. At this time and at later intervals the per cent of donor cells in the lung free cell population was not significantly different from the per cent of donor cells in the bone marrow. Similarly, after aerosol particulate exposure, the percentage of marrow cells and alveolar macrophages of donor origin were not significantly different. This immunologic approach suggests that alveolar macrophages in radiation chimeras are entirely of hematopoietic origin.
Letter from America: the political economics of US healthcare reform
Authors: Rubin Minhas, Claus Wendt
Journal: Journal of the Royal Society of Medicine (2009)

Obama's proposals are incremental and reflect the lesson learned by Hilary Clinton: that small steps are required to address big problems and the fact that there are no simple ‘magic bullet’ solutions to improving its performance. Lack of universal coverage and uncontained costs lie at the heart of the ‘broken’ American healthcare system and the current reforms do not offer an easy or assured approach to reducing both in the near term. Despite high expectations, the proposed investments are likely to be inflationary and any cost savings are likely to be longer term. Aspiring to universal coverage is more feasible than reducing costs that require some stakeholders to lose in order for the government to achieve its savings. The economic price attached to the current reforms is considerable and so controversy is inevitable. Nevertheless, Obama's election and his proposed reforms mark a significant political milestone.

It was small step from the free market ideology of Friedman, Hayek and others to the assertion by President Gerald Ford that ‘a government big enough to give you everything you want is a government big enough to take from you everything you have’ and President Ronald Reagan's later claim that ‘government is the problem not the solution’. So long was the shadow cast by this stance that President Bill Clinton subsequently felt obligated to maintain that ‘the era of big government is over’. In his November 2008 victory speech President Obama told Americans that ‘we have never just been a collection of individuals’, signalling that the political pendulum might be swinging away from the dominant conservative ideology of recent decades that has emphasized the self-interested individual. During his inauguration he went further, to declare that the ‘stale political arguments … no longer apply’ and in respect of healthcare that, ‘the question today is not whether our government is too big or too small, but whether it works, whether it helps families … find care they can afford’.

There is increasing consensus that the need for government regulation of the financial markets is a matter of degree. This was given voice by Obama during his inauguration speech when he stated that despite its strengths, ‘without a watchful eye, the market can spin out of control’. Though it is not clear how far-reaching health reforms will eventually be, it is reasonable to assume they involve stronger state involvement and the time when the US healthcare system has been an open playing field for free market ideology may now be passing.
TCT-737 BIOFLOW-III an all comers registry with a Sirolimus Eluting Stent, Presentation of Five Year Target Lesion Failure Data
Authors: Johannes Waltenberger, Stefan Hoffmann, Johannes Brachmann, Jan van der Heyden, Gert Richardt, Ole Frobert, Andrejs Erglis
Journal: Journal of the American College of Cardiology (2017)
Populations and determinants of airborne fungi in large office buildings.
Authors: H Jasmine Chao, Joel Schwartz, Donald K Milton, Harriet A Burge
Journal: Environmental Health Perspectives (2002)

Bioaerosol concentrations in office environments and their roles in causing building-related symptoms have drawn much attention in recent years. Most bioaerosol studies have been cross-sectional. We conducted a longitudinal study to examine the characteristics of airborne fungal populations and correlations with other environmental parameters in office environments. We investigated four office buildings in Boston, Massachusetts, during 1 year beginning May 1997, recruiting 21 offices with open workstations. We conducted intensive bioaerosol sampling every 6 weeks resulting in 10 sets of measurement events at each workstation, and recorded relative humidity, temperature, and CO2 concentrations continuously. We used principal component analysis (PCA) to identify groups of culturable fungal taxa that covaried in air. Four major groupings (PCA factors) were derived where the fungal taxa in the same groupings shared similar ecological requirements. Total airborne fungal concentrations varied significantly by season (highest in summer, lowest in winter) and were positively correlated with relative humidity and negatively related to CO2 concentrations. The first and second PCA factors had similar correlations with environmental variables compared with total fungi. The results of this study provide essential information on the variability within airborne fungal populations in office environments over time. These data also provide background against which cross-sectional data can be compared to facilitate interpretation. More studies are needed to correlate airborne fungi and occupants' health, controlling for seasonal effects and other important environmental factors.
Evaluation of a System for Automatic Detection of Diabetic Retinopathy From Color Fundus Photographs in a Large Population of Patients With Diabetes
Authors: Michael D. Abràmoff, Meindert Niemeijer, Maria S.A. Suttorp-Schulten, Max A. Viergever, Stephen R. Russell, Bram van Ginneken
Journal: Diabetes Care (2008)

To evaluate the performance of a system for automated detection of diabetic retinopathy in digital retinal photographs, built from published algorithms, in a large, representative, screening population.We conducted a retrospective analysis of 10,000 consecutive patient visits, specifically exams (four retinal photographs, two left and two right) from 5,692 unique patients from the EyeCheck diabetic retinopathy screening project imaged with three types of cameras at 10 centers. Inclusion criteria included no previous diagnosis of diabetic retinopathy, no previous visit to ophthalmologist for dilated eye exam, and both eyes photographed. One of three retinal specialists evaluated each exam as unacceptable quality, no referable retinopathy, or referable retinopathy. We then selected exams with sufficient image quality and determined presence or absence of referable retinopathy. Outcome measures included area under the receiver operating characteristic curve (number needed to miss one case [NNM]) and type of false negative.Total area under the receiver operating characteristic curve was 0.84, and NNM was 80 at a sensitivity of 0.84 and a specificity of 0.64. At this point, 7,689 of 10,000 exams had sufficient image quality, 4,648 of 7,689 (60%) were true negatives, 59 of 7,689 (0.8%) were false negatives, 319 of 7,689 (4%) were true positives, and 2,581 of 7,689 (33%) were false positives. Twenty-seven percent of false negatives contained large hemorrhages and/or neovascularizations.Automated detection of diabetic retinopathy using published algorithms cannot yet be recommended for clinical practice. However, performance is such that evaluation on validated, publicly available datasets should be pursued. If algorithms can be improved, such a system may in the future lead to improved prevention of blindness and vision loss in patients with diabetes.
Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study—CALGB 30504 (Alliance)
Authors: Neal E. Ready, Herbert H. Pang, Lin Gu, Gregory A. Otterson, Sachdev P. Thomas, Antonius A. Miller, Maria Baggstrom, Gregory A. Masters, Stephen L. Graziano, Jeffrey Crawford, Jeffrey Bogart, Everett E. Vokes
Journal: Journal of Clinical Oncology (2015)

To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC).The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m(2) or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m(2) per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67.One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on sunitinib (6 to 27 weeks).Maintenance sunitinib was safe and improved PFS in extensive-stage SCLC.
PharmGKB Update: I. Genetic Variants of the Organic Cation Transporter 2 (OCT2, SLC22A2)
Authors: Maya K. Leabman, Conrad C. Huang, Doug Stryke, Susan J. Johns, Michiko Kawamoto, Thomas E. Ferrin, Joseph DeYoung, Travis R. Taylor, Melanie De La Cruz, Ira Herskowitz, Kathleen M. Giacomini
Journal: Pharmacological Reviews (2003)

Category: genotype PharmGKB Submission Number: PS202784 <http://www.pharmgkb.org/do/serve?objId=PA331&objCls=Gene> Project: Pharmacogenetics of Membrane Transporters HGNC Symbol: SLC22A2 HGNC Name: solute carrier family 22 (organic cation transporter), member 2 Synonyms: OCT2 Gene Ontology