tbuckley/cabot-search huggingface dataset:
The NCBI dbGaP database of genotypes and phenotypes
Authors: Matthew D Mailman, Michael Feolo, Yumi Jin, Masato Kimura, Kimberly Tryka, Rinat Bagoutdinov, Luning Hao, Anne Kiang, Justin Paschall, Lon Phan, Natalia Popova, Stephanie Pretel, Lora Ziyabari, Moira Lee, Yu Shao, Zhen Y Wang, Karl Sirotkin, Minghong Ward, Michael Kholodov, Kerry Zbicz, Jeffrey Beck, Michael Kimelman, Sergey Shevelev, Don Preuss, Eugene Yaschenko, Alan Graeff, James Ostell, Stephen T Sherry
Journal: Nature Genetics (2007)
Roles of Sema4D and Plexin-B1 in tumor progression
Authors: Ewe Seng Ch'ng, Atsushi Kumanogoh
Journal: Molecular Cancer (2010)

Sema4D, also known as CD100, is a protein belonging to class IV semaphorin. Its physiologic roles in the immune and nervous systems have been extensively explored. However, the roles of Sema4D have extended beyond these traditionally studied territories. Via interaction with its high affinity receptor Plexin-B1, Sema4D-Plexin-B1 involvement in tumor progression is strongly implied. Here, we critically review and delineate the Sema4D-Plexin-B1 interaction in many facets of tumor progression: tumor angiogenesis, regulation of tumor-associated macrophages and control of invasive growth. We correlate the in vitro and in vivo experimental data with the clinical study outcomes, and present a molecular mechanistic basis accounting for the intriguingly contradicting results from these recent studies.
Increased circulating levels of interleukin 33 in systemic sclerosis correlate with early disease stage and microvascular involvement
Authors: Mirko Manetti, Serena Guiducci, Claudia Ceccarelli, Eloisa Romano, Silvia Bellando-Randone, Maria Letizia Conforti, Lidia Ibba-Manneschi, Marco Matucci-Cerinic
Journal: Annals of the Rheumatic Diseases (2011)

Early activation/damage of endothelial cells and multiple profibrotic T helper type 2 (Th2)-associated cytokines play an important role in the pathogenesis of systemic sclerosis (SSc).1

Interleukin 33 (IL-33) was recently identified as a member of the IL-1 family and a ligand for the orphan receptor ST2L, which mediates the action of IL-33 on polarised Th2 lymphocytes and other leucocyte subsets, and tissue-resident cells, such as vascular endothelial cells and fibroblasts/myofibroblasts.2 IL-33 has been shown to induce IL-13-dependent cutaneous fibrosis and stimulate angiogenesis and vascular permeability.3 4 In healthy human tissues IL-33 protein is constitutively highly expressed in the nuclei of resting endothelial cells, but rapidly lost upon angiogenic or proinflammatory activation.2 Indeed, IL-33 is thought to function as an endogenous ‘alarmin’ that is rapidly released after endothelial cell damage to alert the cells of the innate and adaptive immune system.2

Recently, we have shown that microvascular endothelial cells in inflamed skin from patients with early-stage SSc lacked or had decreased nuclear IL-33 protein expression.5 Instead, IL-33 transcript levels were even upregulated suggesting that, …
NOVEL ANTITHROMBOTIC THERAPEUTICS TARGETED AGAINST PLATELET GLYCOPROTEIN IIb/IIIa
Authors: Steven Coutré, M.D, Lawrence Leung, M.D
Journal: Annual Review of Medicine (1995)

▪ Abstract Platelet aggregation is one of the best understood examples of adhesive cell-cell interactions. The platelet glycoprotein IIb/IIIa membrane receptor plays a pivotal role in platelet aggregation through its binding of fibrinogen. It is intimately involved in the pathogenesis of platelet-rich arterial thromboses. The IIb/IIIa receptor is an important target for recently described novel antiplatelet therapeutics. The development and clinical evaluation of this class of antiplatelet therapeutics are reviewed in this article.
Small bowel biopsies in patients with iron deficiency anaemia Reply
Authors: C B PEARCE
Journal: Gut (2001)

<h3>ABSTRACT</h3> <h3>Background</h3> Rates of suicidal ideation, attempts and completions are increasing and identifying causal risk factors continues to be a public health priority. Observational literature has shown that educational attainment (EA) and cognitive performance (CP) can influence suicide attempt risk; however, due to residual confounding and reverse causation, the causal nature of these relationships is unknown. <h3>Methods</h3> We perform a multivariable two-sample Mendelian randomization (MR) analysis to disentangle the effects of EA and CP on suicide attempt risk. We use summary statistics from recent genome-wide association studies (GWAS) of EA, CP, household income versus suicide attempt risk in individuals with and without mental disorders, with more than 815,000 combined study participants. <h3>Results</h3> We found evidence that both EA and CP significantly reduced the risk of suicide attempt when considered separately in single variable MR (SVMR) (Model 1 EA odds ratio (OR), 0.524, 95% CI, 0.412-0.666, <i>P</i> = 1.07⨯10<sup>−7</sup>; CP OR, 0.714, 95% CI, 0.577-0.885, <i>P</i> = 0.002). When simultaneously analyzing EA,CA, and adjusting for household income but not comorbid mental disorders (Model 1), we found evidence that the direct effect of EA, independent of CP, on suicide attempt risk was greater than the total effect estimated by SVMR, with EA, independent of CP, significantly reducing the risk of suicide attempt by almost 66% (95% CI, 43%-79%); however, the effect of CP was no longer significant independent of EA (Model 1 EA OR, 0.342, 95% CI, 0.206-0.568, <i>P</i> = 1.61×10<sup>−4</sup>; CP OR, 1.182, 95% CI, 0.842-1.659, <i>P</i> = 0.333). Further, when accounting for comorbid mental disorders (Model 2), these results did not significantly change: we found EA significantly reduced the risk of suicide attempt by 55% (35%-68%), a lower point estimate but still within the 95% confidence interval of Model 1; the effect of CP was still not significant (Model 2 EA OR, 0.450, 95% CI, 0.314-0.644, <i>P</i> &lt; 1.00×10<sup>−4</sup>; CP OR, 1.143, 95% CI, 0.803-1.627, <i>P</i> = 0.475). <h3>Conclusions</h3> Our results show that even after accounting for comorbid mental disorders and adjusting for household income, EA, but not CP, is a causal risk factor in suicide attempt. These findings could have important implications for health policy and prevention programs aimed at reducing the increasing rates of suicide.
Jules Gavarret's <i>Principes Généraux de Statistique Médicale</i>
Authors: Edward Huth
Journal: Journal of the Royal Society of Medicine (2008)

The burgeoning support for evidence-based medicine in the 21st century has made clear why physicians must depend on quantitative data generated by clinical trials for decisions about treatment. The value to them of data reported from trials depends in part on the adequacy of a trial’s design and how carefully the trial carried out an appropriate design. In addition, if the conclusions reached in a trial are to be reliable, they must be justified by appropriate statistical assessment of the data reported. Today’s ubiquity of statistical analysis of data from clinical trials developed mainly during the second-half of the 20th century. But the concept of needing numerical data to justify conclusions about treatments goes back at least three centuries. An early major attempt to assess with quantitative data the validity of a medical treatment came in the first half of the 18th century, when James Jurin and other English physicians gathered data on differences in mortality from smallpox inoculation as a preventive treatment compared with mortality from naturally-acquired smallpox. Jurin’s judgments, however, came simply from inspecting those mortality data and not from critical statistical analysis of the validity of conclusions that might be drawn from them; such statistical methods had not surfaced for applications in medicine. His use of such mortality data can be described as descriptive statistics – crudely put, ‘simply eyeballing the data’. Jurin’s simple statistical assessment of quantitative data was only one of an increasing number of such assessments in 18th century Britain. But these judgments relied, in essence, on comparing mortality or morbidity proportions in groups of treated and untreated persons. Even the concept of considering the value of data for judgments began to be entertained. For example, in 1785 Gilbert Blane noted that: ‘There is . a great difficulty attending all practical inquiries in medicine; for in order to ascertain truth, in a manner that is satisfactory to a mind habituated to chaste investigation, there must be a series of patient and attentive observations upon a great number of cases, and the different trials must be varied, weighed, and compared, in order to form a proper estimate of the real efficacy of different remedies and modes of treatment.’
A patient with the inability to maintain in vivo levels of bound cobalamin (Cbl) and manifestations of tissue deficiency of Cbl
Authors: James A. Begley, Peter T. Burkart, Charles A. Hall
Journal: American Journal of Hematology (1986)

Abstract A 39‐year‐old woman presented with mild anemia, glossitis, an increased MCV, a low serum cobalamin (Cbl) (vitamin B 12 ), mild tissue deficiency of Cbl, but with neither malabsorption of Cbl, impaired intake, nor deficiency of or inactivity of transcobalamin II (TC II). Because of a persistently low holo‐TC II (TC II carrying Cbl as the circulating complex of TC II‐Cbl), much of the evaluation was focused on the patient's TC II. Her TC II promoted the uptake of Cbl, reacted with anti‐TC II, and bound Cbl in vitro. A test dose of 200 μg of cyanocobalamin (CN‐Cbl) i.m. increased her holo TC II to levels higher than those in healthy persons, but with a much more abrupt fall to a subnormal level. Two milligrams of CN‐Cbl i.m. followed by 100 μg i.m. monthly failed to maintain normal amounts of circulating TC II‐Cbl or to overcome the tissue deficiency of Cbl. One milligram i.m. weekly or daily p.o. corrected both. The low holo TC II was considered to be responsible for the clinical expression and may have been primary to the reduced amounts of total and holo R binder of Cbl in the circulation. This study of a newly recognized defect points out the need for circulating holo TC II, a rational use of pharmacologic amounts of Cbl, and a possible interrelationship between TC II and the R binder of Cbl.
Differential niche and Wnt requirements during acute myeloid leukemia progression
Authors: Steven W. Lane, Yingzi J. Wang, Cristina Lo Celso, Christine Ragu, Lars Bullinger, Stephen M. Sykes, Francesca Ferraro, Sebastian Shterental, Charles P. Lin, D. Gary Gilliland, David T. Scadden, Scott A. Armstrong, David A. Williams
Journal: Blood (2011)
Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T Cells
Authors: Anne Krug, Ravi Veeraswamy, Andrew Pekosz, Osami Kanagawa, Emil R. Unanue, Marco Colonna, Marina Cella
Journal: The Journal of Experimental Medicine (2003)

Interferon-producing cells (IPCs) secrete high levels of type I interferon in response to certain viruses. The lack of lineage markers, the expression of major histocompatibility complex (MHC) class II and the capacity to stimulate allogeneic T cells have led these cells to be classified as a subset of dendritic cells (DCs), called plasmacytoid DCs (PDCs). However, the role of IPCs/PDCs in initiating primary immune responses remains elusive. Here we examined the antigen presenting capacity of murine IPCs in antigen specific systems. While CD8α+ and CD11b+ DCs induced logarithmic expansion of naive CD4 and CD8 T cells, without conferring T helper commitment at a first encounter, primary IPCs lacked the ability to stimulate naive T cells. However, when antigen-experienced, nonpolarized T cells expanded by classical DC subsets, were restimulated by IPCs, they proliferated and produced high amounts of IFN-γ. These data indicate that IPCs can effectively stimulate preactivated or memory-type T cells and exert an immune-regulatory role. They also suggest that expansion of naive T cells and acquisition of effector function during antigen-specific T cell responses may involve different antigen-presenting cell (APC) types. Independent and coordinated control of T cell proliferation and differentiation would provide the immune system with greater flexibility in regulating immune responses.
Inflammatory lymphangiogenesis in postpartum breast tissue remodeling
Authors: Melody A. Swartz
Journal: Journal of Clinical Investigation (2014)

Like many cancers, mammary carcinomas use lymphatic vessels to disseminate, and numerous clinical and experimental studies have documented a strong correlation between peritumoral lymphangiogenesis and tumor dissemination. At the same time, many other factors can affect the incidence, invasiveness, and mortality of breast cancer, including lactation history. Although lactation reduces overall cancer risk, patients diagnosed within 5 years of pregnancy have an increased incidence of metastatic disease. In this issue of the JCI, Lyons and colleagues demonstrate that postpartum breast tissue remodeling during involution coincides with inflammatory lymphangiogenesis. In mouse models, cyclooxygenase-2 (COX-2) inhibition during involution reduced the risk of cancer metastasis and correlated with decreased lymphangiogenesis. In addition to lymphangiogenesis, COX-2 inhibition reduces many of the immune-suppressive features of the tumor microenvironment, including development of myeloid-derived suppressor cells and regulatory T cells; therefore, these results support the notion that inhibiting COX-2 during lactation weaning may lessen the incidence of breast cancer metastasis.
Effect of in vitro and in vivo administration of dexamethasone on rat macrophage functions: comparison between alveolar and peritoneal macrophages
Authors: Y Nakamura, T Murai, Y Ogawa
Journal: European Respiratory Journal (1996)

Resident alveolar macrophages (AMs) and peritoneal macrophages (PMs), though they originate from common precursor cells, differ morphologically and functionally. The two types of macrophages residing in different tissues may respond differently to glucocorticoids. In the present study, we compared the effects of a synthetic glucocorticoid, dexamethasone (Dex), on rat AMs and PMs with regard to their phagocytic activity and tumour necrosis factor-alpha (TNF-alpha) releasability. In vitro exposure of the macrophages to Dex caused the depression of phagocytic activity of AMs but not of PMs. In contrast, TNF-alpha releasability was depressed in the both types of macrophages, and no difference was found between AMs and PMs in their susceptibility to TNF-alpha regulation by Dex. When Dex was administered subcutaneously into rats, phagocytic activity was severely depressed in AMs but not in PMs. On the other hand, TNF-alpha releasability was depressed both in AMs and PMs by the in vivo Dex administration. The depression in PMs, however, was transitory and less severe than that in AMs. These results suggest that alveolar macrophages and peritoneal macrophages differ intrinsically in responses to glucocorticoid, and that the cell location and the cell's microenvironment can also modulate the effects of glucocorticoid on macrophage functions.
Clinical Significance of Immunocytochemical Detection of Tumor Cells Using Digital Microscopy in Peripheral Blood and Bone Marrow of Breast Cancer Patients
Authors: Jean-Yves Pierga, Charlyne Bonneton, Anne Vincent-Salomon, Patricia de Cremoux, Claude Nos, Nathalie Blin, Pierre Pouillart, Jean-Paul Thiery, Henri Magdelénat
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The presence of tumor cells in bone marrow has been reported to represent an important prognostic indicator in breast cancer, but the clinical significance of circulating cells in peripheral blood is less well known. The aim of this study was to evaluate the feasibility of identifying cytokeratin (CK)-expressing cells in peripheral blood with an automat-assisted immunohistochemical detection system and to compare it with detection of tumor cells in bone marrow samples. Experimental Design: Cytospun Ficoll fractions of peripheral blood and bone marrow were obtained simultaneously in 114 breast cancer patients at different stages of the disease (I to IV) before treatment with chemotherapy. The pancytokeratin (CK) monoclonal antibody A45-B/B3 (anti-CKs 8, 18, and 19) was used for epithelial cell detection. Immunostained cells were detected by an automated cellular imaging system (ChromaVision Medical System). Results: CK+ cells were detected in 28 (24.5%) patients in blood and in 67 (59%) patients in bone marrow. Twenty-six (93%) patients with CK-positive cells in blood also had positive bone marrow (P &amp;lt; 0.001). Positive cells were detected in peripheral blood in 3/39 (7.5%) operable breast cancers (stage I/II), 9 of 36 (25%) locally advanced breast cancers (stage III), and 16 of 39 (41%) patients with metastatic disease (stage IV; P = 0.017). In the subgroup of nonmetastatic patients (n = 75), prognostic factors for poor disease-free survival were: absence of estrogen receptor; presence of CK+ cells in bone marrow (P = 0.012); clinical nodal involvement; large tumor size (T4); and presence of tumor emboli. Presence of circulating CK+ cells in the peripheral blood was not statistically correlated with disease-free survival. On multivariate analysis, independent indicators for disease-free survival were: absence of estrogen receptor (P = 0.043) and presence of CK+ cells in bone marrow (P = 0.076). Conclusions: The clinical relevance of circulating epithelial cells as a prognostic factor is not supported by the present data, especially in comparison with tumor cells in the bone marrow. However, this method of detection may be useful to monitor the efficacy of treatment in advanced or metastatic breast cancer.
Attributing psychopathology to systemic lupus erythematosus: some methodological considerations.
Authors: G L Iverson, L M McCracken
Journal: Annals of the Rheumatic Diseases (1992)

Limitations are listed below:1 Random sample not obtained-for example, sample obtained from a single hospital or specialty consultancy such as psychiatry or dermatology, or composed of only inpatients or outpatients. 2Psychiatric diagnostic system not specified. 3Psychiatric assessment methods not clearly defined. 4Psychiatric assessment procedures lack adequate standardisation, reliability, or validitv. 5Diagnosis not made by a qualified professional or not based on clearly defined data. 6Use of archival data allows inadequate control of data collection and may be unreliable.7 No comparison group. 8Cross validation procedures not used. 9Base rates for psychiatric disorders in normal or other medical populations not considered. 10Inappropriate generalisations based on limited sample. 11Causal statements based on correlational data are inappropriate. 12Improper or inaccurate use or interpretation of statistics.tlndeterminable.lNine per cent of the patients in this study showed psychopathology attributable to causes other than SLE.
Effects of Phosphate Binders in Moderate CKD
Authors: Geoffrey A. Block, David C. Wheeler, Martha S. Persky, Bryan Kestenbaum, Markus Ketteler, David M. Spiegel, Matthew A. Allison, John Asplin, Gerard Smits, Andrew N. Hoofnagle, Laura Kooienga, Ravi Thadhani, Michael Mannstadt, Myles Wolf, Glenn M. Chertow
Journal: Journal of the American Society of Nephrology (2012)

Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.
First trimester maternal tobacco smoking habits and fetal growth
Authors: N. Prabhu, N. Smith, D. Campbell, L. C Craig, A. Seaton, P. J Helms, G. Devereux, S. W Turner
Journal: Thorax (2010)

<h3>Rationale</h3> Maternal smoking in pregnancy is associated with reduced birth weight and childhood lung function. This study determined when maternal smoking first influences fetal growth and how this relates to childhood respiratory outcomes. <h3>Methods</h3> A longitudinal cohort of 1924 pregnant women was recruited. Fetal ultrasound measurements at 11 weeks (crown–rump length, CRL) and at 20 weeks gestation (femur length, FL, and biparietal diameter, BPD) and birth measurements were recorded. Childhood respiratory symptoms and spirometry were ascertained. <h3>Results</h3> Of the 1924 original study participants, fetal size was determined in 903 in the first trimester, 1544 in the second trimester and at term in 1737 infants. Maternal smoking when first pregnant was reported in 593 (31%) and was not associated with reduced CRL. There was an inverse exposure-response relationship between cigarette consumption and FL (mean reduction in lowest compared with highest tertile 0.91 cm, p=0.033). Birth weight and length of those born to mothers who did (n=331) and did not (n=56) reduce cigarette consumption were similar and reduced compared with 186 infants whose mothers quit during the first trimester (p≤0.020). Children of mothers who continued smoking had increased wheeze at age 2 years (OR 1.58, p=0.017) and GP visits with wheeze at age 5 years (OR 2.18, p=0.030) and mean reduction in forced expiratory volume in 1 s of 62 ml (p=0.014) compared with controls. <h3>Conclusions</h3> Maternal smoking is associated with reduced fetal measurements in the second and third trimesters but not in the first trimester. Mothers who do not quit smoking during the first trimester deliver smaller infants who go on to have adverse respiratory outcomes in childhood.