tbuckley/cabot-search huggingface dataset:
Re: CYP2D6 Genotyping and the Use of Tamoxifen in Breast Cancer
Authors: M. A. Province, T. E. Klein
Journal: JNCI Journal of the National Cancer Institute (2014)

Donald Berry in his recent editorial (1) regarding the role of CYP2D6 and tamoxifen highlights several controversies that exist in the clinical and biomarker field for women with breast cancer. The International Tamoxifen Pharmacogenomics Consortium (ITPC) was formed with the intent to aggregate, curate, and analyze the data available in published breast cancer studies with the hope of answering the question, “Should CYP2D6 genotyping guide the use of tamoxifen in breast cancer?” The ITPC analyzed nearly 5000 patients regarding the association between CYP2D6 and clinical outcomes (2). These data demonstrated that CYP2D6 genotype was associated with the risk of recurrence or death in those patients who received tamoxifen monotherapy for 5 years but not in patients who received different doses or duration of tamoxifen or those who received chemotherapy along with tamoxifen. We are in agreement with Berry that further research is required to understand these complex relationships, and our intent has always been that others will be able to use the ITPC dataset to understand the data as fully as possible in conjunction with their own research efforts. The complete dataset of genotypes and clinical variables, the analysis code, and the full analyses are transparently available at PharmGKB (http://www.pharmgkb.org). Although we disagree with Berry about his conclusion in answering the all-important question of whether CYP2D6-guided genotype therapy is appropriate, we invite other researchers and practitioners to examine the data from their own perspectives and engage in ongoing efforts to use these data to the benefit of patients with breast cancer.
No longer lost in translation: the art and science of sports injury prevention implementation research
Authors: Caroline F Finch
Journal: British Journal of Sports Medicine (2011)

It is now understood that sports injury interventions will not have significant public health impact if they are not widely accepted and adopted by target sports participants. Although there has been increasing recognition of the need for intervention studies conducted within the real-world context of sports delivery, very few studies have been conducted in this important area. A major reason for this is that there are significant challenges in conducting implementation research; the more traditional sports medicine approaches may not be fully appropriate and new ways of thinking about how to design, conduct and report such research is needed. Moreover, real-world implementation of sports injury interventions and evaluation of their effectiveness needs to start to take into account the broad ecological context in which they are introduced, as well as considering the best way to translate this knowledge to reach the audiences who most need to benefit from such research. This overview paper provides perspectives and guidance on the design, conduct and evaluation of sports injury intervention implementation studies, including better understanding of the complexity of the ecological settings for intervention delivery. Some conceptual approaches that could be adopted in future implementation studies are discussed; particular emphasis is given to Intervention Mapping as a tool to assist intervention development, Diffusion of Innovations Theory to guide the planning of intervention strategies and the RE-AIM (reach, effectiveness, adoption, implementation and maintenance) framework for programme evaluation and programme design. Finally, a broad agenda for this emerging important field of sports medicine research is outlined.
Prevalence and clinical relevance of 52-kDa and 60-kDa Ro/SS-A autoantibodies in Japanese patients with systemic sclerosis
Authors: M Fujimoto, M Shimozuma, N Yazawa, M Kubo, H Ihn, S Sato, T Tamaki, K Kikuchi, K Tamaki
Journal: Annals of the Rheumatic Diseases (1997)

To determine the prevalence of 52-Kda and 60-Kda Ro/SS-A autoantibodies in serum samples from Japanese patients with systemic sclerosis (SSc).Serum samples from 263 Japanese patients with SSc were examined by double immunodiffusion and enzyme linked immunosorbent assay (ELISA).By double immunodiffusion, 29 serum samples from patients with SSc were found to possess anti-Ro/SS-A antibodies. By ELISA, 31 serum samples were positive for anti-Ro52 and/or anti-Ro60. Of 27 serum samples that were positive by both methods, 15 reacted with both Ro52 and Ro60, five with Ro52 alone, and seven with Ro60 alone. Eleven of 12 patients with both anti-Ro52 and anti-Ro60 and all five patients with anti-Ro52 alone had Sjögren's syndrome, while only one of six patients with anti-Ro60 alone had this disorder.Anti-Ro52 may be a serological marker for the presence of Sjögren's syndrome in anti-Ro/SS-A-positive patients with SSc.
A new cause for CA19.9 elevation: heavy tea consumption
Authors: M Howaizi
Journal: Gut (2003)

Serum carbohydrate associated antigen (CA19.9) is a reliable tumour marker of biliopancreatic malignancies. A number of benign diseases are also known to be related to CA19.9 elevation. Here we report a case of markedly raised levels of CA19.9 associated with heavy tea consumption.

A 52 year old woman was referred to our unit for epigastric pain and anorexia of two months’ duration. She also complained of nausea and a 2 kg weight loss. Her past medical history was unremarkable. She was a non-smoker and denied alcohol abuse or medication intake but remarked on overconsumption of warm black tea for several months (1.5–2 litres/day). Physical examination was normal.

Laboratory data demonstrated normal ranges for electrolytes, liver function tests, blood count, urea, creatinin, C reactive protein, amylase, and lipase. Fasting blood glucose, triglycerides, cholesterol, …
Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age.
Authors: M S Spach, P C Dolber
Journal: Circulation Research (1986)

Elucidation of the mechanisms of cardiac conduction disturbances leading to reentry will require resolution of the details of multidimensional propagation at a microscopic size scale (less than 200 micron). In practice, this will necessitate the combined analysis of extracellular and transmembrane action potentials. The purpose of this paper is to demonstrate the relationships between the time derivatives of the extracellular waveforms and the underlying action potentials in the experimental analysis of anisotropic propagation at this small size scale, and apply these relationships to human atrial muscle at different ages. The extracellular waveforms and their derivatives changed from a smooth contour during transverse propagation in young preparations to complex polyphasic waveforms in the older preparations. The major problem was to estimate the size and location of small groups of fibers that generated the complex waveforms in the older preparations. We found dissimilarities in the derivatives that distinguished source (bundle) size from the distance of the source to the measurement site. The differences in the extracellular waveforms and their derivatives indicated that there was electrical uncoupling of the side-to-side connections between small groups of fibers with aging. These changes produced a prominent zigzag course of transverse propagation at a microscopic level which, in turn, accounted for the increased complexity of the waveforms. The waveform differences also correlated with the development of extensive collagenous septa that separated small groups of fibers. The electrophysiological consequence was an age-related decrease in the "effective" transverse conduction velocities to the range of the very slow conduction (less than 0.08 m/sec) which makes it possible for reentry to occur in small regions of cardiac muscle with normal cellular electrophysiological properties.
Bcr-Abl Expression Levels Determine the Rate of Development of Resistance to Imatinib Mesylate in Chronic Myeloid Leukemia
Authors: David J. Barnes, Danai Palaiologou, Eleni Panousopoulou, Beate Schultheis, Agnes S.M. Yong, Alice Wong, Laura Pattacini, John M. Goldman, Junia V. Melo
Journal: Cancer Research (2005)

Abstract Chronic myeloid leukemia (CML) starts with the acquisition of a BCR-ABL fusion gene in a single hematopoietic stem cell, but the time to progression is unpredictable. Although the tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML, its continuous administration is associated with development of resistance, particularly in advanced phase or blast crisis. We investigate here whether a feature of disease progression (i.e., elevated expression of Bcr-Abl in CD34+ progenitor cells from CML patients in blast crisis) has any bearing on the kinetics of resistance to imatinib. By studying cell lines that exogenously express Bcr-Abl over the range found from chronic phase to blast crisis of CML, we show that cells expressing high amounts of Bcr-Abl, as in blast crisis, are much less sensitive to imatinib and, more significantly, take a substantially shorter time for yielding a mutant subclone resistant to the inhibitor than cells with low expression levels, as in chronic phase. Our data suggest that the differential levels of the Bcr-Abl oncoprotein expressed by CD34+ CML cells may reflect the extent and duration of their response to imatinib; the relatively high levels of oncoprotein in advanced-phase disease may underlie the observed rapid development of resistance.
THE SURGICAL TREATMENT OF GASTRIC ULCER
Authors: C. M. Moullin
Journal: BMJ (1903)

SURGIOCL TRE&TMENr GISTRrO ULCER.[ t, 9536.That some cases, thought at the time to be cancer, too extensive for removal, may after gastro-enterostomy clear up completely and get quite well.7.That in cases of disease of the cardiac end oi the stomach too extensive for removal, the operation of gastrostomy may considerably prolong life and prove of great comfort to the patient by preventing death from starvation.8. That even where the disease is too extensive either for removal or for a gastro-enterostomy being performed with a fair chance of success, the operation of jejunostomy may occasionally prove of service to the patient.9.That where a radical operation can be performed the thorough removal of the disease may bring about as much relief to the patient as does the operation for the removal of cancer in the breast, uterus, and other organs of the body, and that in some cases a complete cure may follow.
Does Aggressive Surgery Improve Outcomes? Interaction Between Preoperative Disease Burden and Complex Surgery in Patients With Advanced-Stage Ovarian Cancer: An Analysis of GOG 182
Authors: Neil S. Horowitz, Austin Miller, Bunja Rungruang, Scott D. Richard, Noah Rodriguez, Michael A. Bookman, Chad A. Hamilton, Thomas C. Krivak, G. Larry Maxwell
Journal: Journal of Clinical Oncology (2015)

To examine the effects of disease burden, complex surgery, and residual disease (RD) status on progression-free (PFS) and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and complete surgical resection (R0) or < 1 cm of RD (MR) after surgical cytoreduction.
Lymph node topology dictates T cell migration behavior
Authors: Joost B. Beltman, Athanasius F.M. Marée, Jennifer N. Lynch, Mark J. Miller, Rob J. de Boer
Journal: The Journal of Experimental Medicine (2007)

Adaptive immunity is initiated by T cell recognition of foreign peptides presented on dendritic cells (DCs) by major histocompatibility molecules. These interactions take place in secondary lymphoid tissues, such as lymph nodes (LNs) and spleen, and hence the anatomical structure of these tissues plays a crucial role in the development of immune responses. Two-photon microscopy (2PM) imaging in LNs suggests that T cells walk in a consistent direction for several minutes, pause briefly with a regular period, and then take off in a new, random direction. Here, we construct a spatially explicit model of T cell and DC migration in LNs and show that all dynamical properties of T cells could be a consequence of the densely packed LN environment. By means of 2PM experiments, we confirm that the large velocity fluctuations of T cells are indeed environmentally determined rather than resulting from an intrinsic motility program. Our simulations further predict that T cells self-organize into microscopically small, highly dynamic streams. We present experimental evidence for the presence of such turbulent streams in LNs. Finally, the model allows us to estimate the scanning rates of DCs (2,000 different T cells per hour) and T cells (100 different DCs per hour).
Neurobiology of Sensory Overresponsivity in Youth With Autism Spectrum Disorders
Authors: Shulamite A. Green, Leanna Hernandez, Nim Tottenham, Kate Krasileva, Susan Y. Bookheimer, Mirella Dapretto
Journal: JAMA Psychiatry (2015)

More than half of youth with autism spectrum disorders (ASDs) have sensory overresponsivity (SOR), an extreme negative reaction to sensory stimuli. However, little is known about the neurobiological basis of SOR, and there are few effective treatments. Understanding whether SOR is due to an initial heightened sensory response or to deficits in regulating emotional reactions to stimuli has important implications for intervention.To determine differences in brain responses, habituation, and connectivity during exposure to mildly aversive sensory stimuli in youth with ASDs and SOR compared with youth with ASDs without SOR and compared with typically developing control subjects.Functional magnetic resonance imaging was used to examine brain responses and habituation to mildly aversive auditory and tactile stimuli in 19 high-functioning youths with ASDs and 19 age- and IQ-matched, typically developing youths (age range, 9-17 years). Brain activity was related to parents' ratings of children's SOR symptoms. Functional connectivity between the amygdala and orbitofrontal cortex was compared between ASDs subgroups with and without SOR and typically developing controls without SOR. The study dates were March 2012 through February 2014.Relative increases in blood oxygen level-dependent signal response across the whole brain and within the amygdala during exposure to sensory stimuli compared with fixation, as well as correlation between blood oxygen level-dependent signal change in the amygdala and orbitofrontal cortex.The mean age in both groups was 14 years and the majority in both groups (16 of 19 each) were male. Compared with neurotypical control participants, participants with ASDs displayed stronger activation in primary sensory cortices and the amygdala (P < .05, corrected). This activity was positively correlated with SOR symptoms after controlling for anxiety. The ASDs with SOR subgroup had decreased neural habituation to stimuli in sensory cortices and the amygdala compared with groups without SOR. Youth with ASDs without SOR showed a pattern of amygdala downregulation, with negative connectivity between the amygdala and orbitofrontal cortex (thresholded at z > 1.70, P < .05).Results demonstrate that youth with ASDs and SOR show sensorilimbic hyperresponsivity to mildly aversive tactile and auditory stimuli, particularly to multiple modalities presented simultaneously, and show that this hyperresponsivity is due to failure to habituate. In addition, findings suggest that a subset of youth with ASDs can regulate their responses through prefrontal downregulation of amygdala activity. Implications for intervention include minimizing exposure to multiple sensory modalities and building coping strategies for regulating emotional response to stimuli.
Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment
Authors: Nathalie T. Joncker, Nataliya Shifrin, Frédéric Delebecque, David H. Raulet
Journal: The Journal of Experimental Medicine (2010)

Some mature natural killer (NK) cells cannot be inhibited by major histocompatibility complex (MHC) I molecules, either because they lack corresponding inhibitory receptors or because the host lacks the corresponding MHC I ligands for the receptors. Such NK cells nevertheless remain self-tolerant and exhibit a generalized hyporesponsiveness to stimulation through activating receptors. To address whether NK cell responsiveness is set only during the NK cell differentiation process, we transferred mature NK cells from wild-type (WT) to MHC I–deficient hosts or vice versa. Remarkably, mature responsive NK cells from WT mice became hyporesponsive after transfer to MHC I–deficient mice, whereas mature hyporesponsive NK cells from MHC I–deficient mice became responsive after transfer to WT mice. Altered responsiveness was evident among mature NK cells that had not divided in the recipient animals, indicating that the cells were mature before transfer and that alterations in activity did not require cell division. Furthermore, the percentages of NK cells expressing KLRG1, CD11b, CD27, and Ly49 receptors specific for H-2b were not markedly altered after transfer. Thus, the functional activity of mature NK cells can be reset when the cells are exposed to a changed MHC environment. These findings have important implications for how NK cell functions may be curtailed or enhanced in the context of disease.
Vitamin D in Pregnancy and Lactation in Humans
Authors: Patsy M. Brannon, Mary Frances Picciano
Journal: Annual Review of Nutrition (2011)

Concerns exist about the adequacy of vitamin D in pregnant and lactating women. This review assesses the evidence that maternal vitamin D status influences maternal, fetal, and breast-fed infant bone health; maternal adverse outcomes (preeclampsia, gestational diabetes, obstructed labor, and infectious disease); fetal adverse outcomes (growth, gestational age, and developmental programming); and infant adverse outcomes. The evidence for all of these outcomes is contradictory (except for maternal infectious disease) and lacking causality; thus, it is inconclusive. The 2011 Dietary Reference Intakes for vitamin D and their implications for assessing vitamin D status are discussed. An estimated 5% to 29% of American pregnant women may have inadequate vitamin D status, with the higher prevalence in African Americans. Little is known about the prevalence of inadequacy in American lactating women. Research needs are also identified, especially the need for rigorous and well-designed randomized clinical trials to determine the role of vitamin D in nonbone health outcomes in pregnancy and lactation.
Attitudes towards exercise and physical activity behaviours in Greek schoolchildren after a year long health education intervention
Authors: A D Christodoulos, H T Douda, M Polykratis, S P Tokmakidis
Journal: British Journal of Sports Medicine (2006)

To examine the short term effects of a health education programme on Greek primary schoolchildrenThe school based intervention programme was applied to 29 children in the 6th grade of the 2nd Primary School of Agios Stefanos (approximately 12,000 inhabitants); 49 pupils from the 1st Primary School constituted the control group. To assess the effectiveness of the intervention, attitude and behavioural variables were measured before and after the intervention.After adjustment for initial differences in the assessed variables, pupils who took part in the intervention had more positive attitudes towards physical activity than the control group and scored significantly more highly on their intention to participate in physical activity. Moreover, pupils in the intervention group reported more hours/week spent in organised physical activities than pupils in the control group (mean (SD) 3.54 (0.32) v 2.54 (0.26), p<0.020). Finally, a higher proportion of pupils in the intervention classes matched the recommendations of 60 minutes of moderate to vigorous physical activity daily (77.4% v 55.1%, p<0.043).Within the limitations of the study, the data show that school health education programmes have the potential to slow the age related decline in physical activity and help pupils establish lifelong, healthy physical activity patterns. Promoting healthy habits and physical activity behaviours during childhood may prevent some of the leading causes of morbidity and mortality in the Greek population, and also decrease direct healthcare costs and improve quality of life.
Transcriptional regulation of left ventricular beta-adrenergic receptors during chronic hypoxia.
Authors: D Bernstein, R Doshi, S Huang, E Strandness, J R Jasper
Journal: Circulation Research (1992)

beta-Adrenergic receptor downregulation is the end result of cellular adaptation to prolonged agonist exposure. The factors mediating receptor downregulation include receptor phosphorylation, receptor movement from the plasma membrane to intracellular sites, and alterations in nascent receptor synthesis. We have previously demonstrated a downregulation of the left ventricular beta-receptor during chronic hypoxia in vivo. To determine the mechanism of this downregulation, we produced chronic hypoxia in seven newborn lambs by creating right ventricular outflow obstruction and an atrial septal defect. Oxygen saturation was reduced to 65-74% for 2 weeks. Six lambs served as normoxic controls. Sarcolemmal membrane and cytosolic fractions were prepared from left ventricular free wall samples. beta-Receptor density in each fraction was determined with the radioligand [125I]iodocyanopindolol. Steady-state levels of beta-receptor mRNA were determined by Northern blot analysis using a beta 1-adrenergic receptor cDNA probe. During chronic hypoxia, left ventricular membrane beta-adrenergic receptor density decreased by 55% (153 +/- 28 fmol/mg for hypoxic lambs versus 342 +/- 79 fmol/mg for control lambs, p &lt; 0.05). There was no corresponding increase in beta-receptor density in the cytosolic fraction (23 +/- 3 fmol/mg for hypoxic lambs versus 33 +/- 9 fmol/mg for control lambs, p = NS), nor was there a significant change in the ratio of beta 1-receptor/beta 2-receptor subtypes as assessed by radioligand binding (beta 1 subtype, 84.1 +/- 10.1% for hypoxic lambs versus 93.2 +/- 8.8% for control lambs; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacogene regulatory elements: from discovery to applications
Authors: Robin P Smith, Ernest T Lam, Svetlana Markova, Sook Yee, Nadav Ahituv
Journal: Genome Medicine (2012)

Regulatory elements play an important role in the variability of individual responses to drug treatment. This has been established through studies on three classes of elements that regulate RNA and protein abundance: promoters, enhancers and microRNAs. Each of these elements, and genetic variants within them, are being characterized at an exponential pace by next-generation sequencing (NGS) technologies. In this review, we outline examples of how each class of element affects drug response via regulation of drug targets, transporters and enzymes. We also discuss the impact of NGS technologies such as chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq), and the ramifications of new techniques such as high-throughput chromosome capture (Hi-C), chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) and massively parallel reporter assays (MPRA). NGS approaches are generating data faster than they can be analyzed, and new methods will be required to prioritize laboratory results before they are ready for the clinic. However, there is no doubt that these approaches will bring about a systems-level understanding of the interplay between genetic variants and drug response. An understanding of the importance of regulatory variants in pharmacogenomics will facilitate the identification of responders versus non-responders, the prevention of adverse effects and the optimization of therapies for individual patients.