tbuckley/cabot-search huggingface dataset:
Identification of HLA-DR alpha chain residues critical for binding of the toxic shock syndrome toxin superantigen.
Authors: P Panina-Bordignon, X T Fu, A Lanzavecchia, R W Karr
Journal: The Journal of Experimental Medicine (1992)

Staphylococcal toxic shock syndrome toxin 1 (TSST-1) binds to major histocompatibility complex class II molecules, and the toxin-class II complexes induce proliferation of T cells expressing V beta 2 sequences. To define the residues involved in TSST-1 binding, a set of transfectants expressing 21 HLA-DR alpha chain mutants were analyzed for their abilities to bind and present TSST-1 and to present an antigenic peptide. Mutations at DR alpha positions 36 and 39 markedly decreased the ability of the DR7 molecule to bind and present TSST-1 but did not affect the ability to present an antigenic peptide. These data indicate that DR alpha residues 36 and 39, predicted to be located on an outer loop, are important in the formation of the TSST-1 binding site on DR molecules.
Updated BSG guidelines for cancer surveillance in IBD - improving consensus and changing practice?
Authors: B. Hudson, J. T. Green, M. Lockett
Journal: Gut (2011)

<h3>Introduction</h3> BSG guidelines for screening and surveillance in IBD have been recently updated to account for changes in consensus opinion and evidence since their initial publication in 2002.12 Changes include use of pancolonic dye spray, suggested intervals between colonoscopies, and use of therapeutic endoscopy. The current work aims to assess contemporary practice, opinion and understanding among gastroenterologists in relation to the updated guidelines. <h3>Methods</h3> A questionnaire survey was electronically distributed to gastroenterology consultants and trainees within Severn and Wales deaneries. A 31.4% (37/118) response rate was achieved across 14 NHS trusts. Guidelines were available to all respondents. <h3>Results</h3> Variations in local protocols included the choice of bowel preparation, the number of ‘points’ allocated per colonoscopy (range 1–4), and in the targeting of colonoscopies to endoscopists with a special interest (35% of institutions). Pancolonic dye spray was used routinely by only 30% of respondents, with the majority (60%) employing the previously recommended strategy of taking two to four random biopsies at 10 cm intervals.2 The average number of biopsies taken during routine surveillance colonoscopy ranged from 4 to 50 (mean=18.83). A general consensus with guidelines in respect to the timing of initial screening colonoscopy, and of the surveillance intervals necessary in proctitis and pancolitis was demonstrated. Nonetheless, widespread confusion regarding optimum surveillance intervals in high risk groups (eg, PSC, family history) and in cases where definition of disease extent was unclear (eg, UC extending to sigmoid – classified as left sided disease by Montreal criteria3) was evident. With the notable exception of low grade dysplasia, lesion management was broadly consistent and in keeping with BSG guidelines. Responses were similar in both consultant (n=25) and trainee (n=12) groups. <h3>Conclusion</h3> A similar study undertaken in relation to the 2002 BSG guidelines highlighted widespread controversy and uncertainty surrounding IBD surveillance.4 Analysis of results from the current work suggest that, although the updated guidelines clarify some areas, notable variations in local and individual practice remain, and areas of confusion persist. In particular a reluctance to use pancolonic dye spray, uncertainty regarding surveillance intervals in high risk groups, a lack of clarity in classification of disease extent, and disparity in management of low grade dysplasia are demonstrated. If these findings are representative of opinion and understanding nationally, it would seem that uniform, quality surveillance in IBD is not yet accepted standard practice.
PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome
Authors: Ashley Pandolfi, Robert F. Stanley, Yiting Yu, Boris Bartholdy, Gopichand Pendurti, Kira Gritsman, Jacqueline Boultwood, Jonathan Chernoff, Amit Verma, Ulrich Steidl
Journal: Blood (2015)
Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells
Authors: A. Rasim Barutcu, Bryan R. Lajoie, Rachel P. McCord, Coralee E. Tye, Deli Hong, Terri L. Messier, Gillian Browne, Andre J. van Wijnen, Jane B. Lian, Janet L. Stein, Job Dekker, Anthony N. Imbalzano, Gary S. Stein
Journal: Genome biology (2015)

Higher-order chromatin structure is often perturbed in cancer and other pathological states. Although several genetic and epigenetic differences have been charted between normal and breast cancer tissues, changes in higher-order chromatin organization during tumorigenesis have not been fully explored. To probe the differences in higher-order chromatin structure between mammary epithelial and breast cancer cells, we performed Hi-C analysis on MCF-10A mammary epithelial and MCF-7 breast cancer cell lines. Our studies reveal that the small, gene-rich chromosomes chr16 through chr22 in the MCF-7 breast cancer genome display decreased interaction frequency with each other compared to the inter-chromosomal interaction frequency in the MCF-10A epithelial cells. Interestingly, this finding is associated with a higher occurrence of open compartments on chr16–22 in MCF-7 cells. Pathway analysis of the MCF-7 up-regulated genes located in altered compartment regions on chr16–22 reveals pathways related to repression of WNT signaling. There are also differences in intra-chromosomal interactions between the cell lines; telomeric and sub-telomeric regions in the MCF-10A cells display more frequent interactions than are observed in the MCF-7 cells. We show evidence of an intricate relationship between chromosomal organization and gene expression between epithelial and breast cancer cells. Importantly, this work provides a genome-wide view of higher-order chromatin dynamics and a resource for studying higher-order chromatin interactions in two cell lines commonly used to study the progression of breast cancer.
Funding for Reproductive Health in Conflict and Post-Conflict Countries: A Familiar Story of Inequity and Insufficient Data
Authors: Paul B. Spiegel, Nadine Cornier, Marian Schilperoord
Journal: PLoS Medicine (2009)

This article discusses a new study that addresses the knowledge gap of the actual reproductive health (RH) funding required to meet the sexual and reproductive health needs in conflict-affected countries. The study attempts to quantify the direct and indirect  RH disbursements to conflict-affected countries compared with overall official development assistance (ODA) by country donor and different RH activities. It states that in order to meet the Millennium Development Goals RH issues related to conflict and post-conflict settings must be better understood and addressed in a more reasonable manner than the current situation.
Statement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quit
Authors: Carlos A. Jiménez-Ruiz, Stefan Andreas, Keir E. Lewis, Philip Tonnesen, C.P. van Schayck, Peter Hajek, Serena Tonstad, Bertrand Dautzenberg, Monica Fletcher, Sarah Masefield, Pippa Powell, Thomas Hering, Stefano Nardini, Thomy Tonia, Christina Gratziou
Journal: European Respiratory Journal (2015)

Chronic obstructive pulmonary disease (COPD), lung cancer, asthma and pulmonary tuberculosis are common pulmonary diseases that are caused or worsened by tobacco smoking. Growing observational evidence suggests that symptoms and prognosis of these conditions improve upon smoking cessation. Despite increasing numbers of (small) randomised controlled trials suggesting intensive smoking cessation treatments work in people with pulmonary diseases many patients are not given specific advice on the benefits or referred for intensive cessation treatments and, therefore, continue smoking. This is a qualitative review regarding smoking cessation in patients with COPD and other pulmonary disorders, written by a group of European Respiratory Society experts. We describe the epidemiological links between smoking and pulmonary disorders, the evidence for benefits of stopping smoking, how best to assess tobacco dependence and what interventions currently work best to help pulmonary patients quit. Finally, we describe characteristics and management of any “hardcore” smoker who finds it difficult to quit with standard approaches.
Steroid sulfatase of human leukocytes and epidermis and the diagnosis of recessive X-linked ichthyosis.
Authors: E H Epstein, M E Leventhal
Journal: Journal of Clinical Investigation (1981)

Patients with recessive X-linked ichthyosis, one of the inherited types of excessive stratum corneum cohesion, have deficient steroid sulfatase in fibroblasts grown from their dermis. Because of the expense and long period required to grow such cells, we have assayed this enzyme in peripheral blood leukocytes and found it to be undetectable in those from patients with this type of ichthyosis, but normal in those from patients with other hereditary or acquired types of ichthyosis. In addition, steroid sulfatase activity is less in leukocytes from women who are carriers of this disease than normal women, and this assay can be used to detect such carriers. Despite previous studies demonstrating that the gene for this enzyme escapes the inactivation of other x-chromosome genes, normal women have leukocyte steroid sulfatase activity only 1.3 times that of normal men, suggesting that some gene dosage compensation occurs. Normal human epidermis, the tissue most affected clinically, also expresses steroid sulfatase activity. The epidermal enzyme is similar in its subcellular localization, its molecular size, and kinetically to that of placenta, leukocytes, and fibroblasts.
A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors
Authors: K. Mross, H. Richly, N. Schleucher, S. Korfee, M. Tewes, M.E. Scheulen, S. Seeber, T. Beinert, M. Schweigert, U. Sauer, C. Unger, D. Behringer, E. Brendel, C.G. Haase, D. Voliotis, D. Strumberg
Journal: Annals of Oncology (2004)
Nitric Oxide Primes Pancreatic β Cells for Fas-mediated Destruction in Insulin-dependent Diabetes Mellitus
Authors: Giorgio Stassi, Ruggero De Maria, Giuliana Trucco, William Rudert, Roberto Testi, Aldo Galluzzo, Carla Giordano, Massimo Trucco
Journal: The Journal of Experimental Medicine (1997)

Fas is an apoptosis-inducing surface receptor involved in controlling tissue homeostasis and function at multiple sites. Here we show that β cells from the pancreata of newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients express Fas and show extensive apoptosis among those cells located in proximity to Fas ligand–expressing T lymphocytes infiltrating the IDDM islets. Normal human pancreatic β cells that do not constitutively express Fas, become strongly Fas positive after interleuken (IL)-1β exposure, and are then susceptible to Fas-mediated apoptosis. NG-monomethyl-l-arginine, an inhibitor of nitric oxide (NO) synthase, prevents IL-1β–induced Fas expression, whereas the NO donors sodium nitroprusside and nitric oxide releasing compound (NOC)-18, induce functional Fas expression in normal pancreatic β cells. These findings suggest that NO-mediated upregulation of Fas contributes to pancreatic β cell damage in IDDM.
Coronary Heart Disease Mortality and Adjuvant Tamoxifen Therapy
Authors: J. P. Costantino, J. Dignam, L. H. Kuller, D. G. Ives, B. Fisher
Journal: JNCI Journal of the National Cancer Institute (1997)

Background and Purpose: Data from randomized clinical trials in Scotland and Sweden testing the efficacy of tamoxifen therapy in patients with breast cancer have suggested that the drug may also reduce the risk of coronary heart disease. In view of these findings, we examined mortality from coronary heart disease among patients with early stage breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project B-14 trial of tamoxifen therapy. Methods: Deaths occurring among women who were randomly assigned to 5 years of either tamoxifen or placebo in the first phase of the B-14 trial were reviewed to determine the cause. Three categories of heart disease-related death were defined: 1) death from a definite fatal myocardial infarction, 2) death from definite fatal coronary heart disease/ possible myocardial infarction, and 3) death from possible fatal coronary heart disease. Comparisons of the findings by treatment group were made on the basis of average annual hazard (i.e., death) rates and the corresponding relative hazard of death. Results: The average annual death rate from coronary heart disease was lower for patients who received tamoxifen than for patients who received placebo, but the difference was not statistically significant. There were eight definite heart-related deaths (i.e., definite fatal myocardial infarction or definite fatal coronary heart disease/possible myocardial infarction) among the patients who received tamoxifen, yielding an average annual rate of 0.62 per 1000 patients. There were 12 definite heart-related deaths among the patients who received placebo, yielding an average annual rate of 0.94 per 1000. The corresponding relative hazard of death from definite fatal heart disease (tamoxifen versus placebo) was 0.66 (95% confidence interval = 0.27- 1.61). Eleven deaths in the tamoxifen group and 10 deaths in the placebo group were classified as possible cases of fatal coronary heart disease. When these cases and the definite cases were considered together, the average annual death rate for the patients who received tamoxifen was 1.48 per 1000, and the rate for the patients who received placebo was 1.73 per 1000. The corresponding relative hazard of death was 0.85 (95% confidence interval = 0.46-1.58). Conclusions: The findings from the B-14 trial are consistent with the findings from the Scottish and the Swedish trials, suggesting that tamoxifen treatment reduces coronary heart disease among patients with breast cancer. Continued follow-up of the patients in these trials and in ongoing prevention trials is needed to accumulate enough data so that reliable conclusions can be drawn about the benefits of tamoxifen in preventing heart disease.
Diagnosing axial spondyloarthropathy. The new Assessment in SpondyloArthritis international Society criteria: MRI entering centre stage
Authors: A N Bennett, H Marzo-Ortega, P Emery, D McGonagle
Journal: Annals of the Rheumatic Diseases (2009)

In this issue of the Annals of Rheumatic Disease the Assessment in SpondyloArthritis international Society (ASAS) have published three interrelated papers (see pages 770, 777 and 784) 1–3 that could contribute to a new era in the diagnosis and classification of axial spondyloathritis (SpA). The first paper focuses on a new definition of inflammatory back pain (IBP), the “expert” criteria, followed by two reports on the development of new classification criteria for axial SpA and their validation in a large multicentre study. These criteria for axial SpA will be welcomed by the spondyloarthropathy community, since the currently available criteria4–6 do not allow for the diagnosis of preradiographic axial SpA. The proposed new set of criteria includes early (preradiographic) and established ankylosing spondylitis (AS), recognising them as a continuum of disease. This is of major importance as it is now clear that the burden of early AS is comparable to that of the later stages.7 The benefit of MRI in the diagnosis of early axial SpA is recognised by the authors and included in the new classification criteria. Indeed, the inclusion of MRI is the most significant change compared to previous criteria4–6 and is in line with clinical experience where MRI is of recognised value as a diagnostic and outcome tool.8 9 14 Furthermore, with the emerging data on the efficacy of tumour necrosis factor (TNF)α blocking therapies in early disease10 11 a new horizon has opened whereby AS sufferers can be identified and treated in the early stages of their disease process before structural damage has occurred.

In the first report Sieper et al 1 propose new clinical criteria for IBP. The study adopted a novel approach in which the “experts” were blinded to patient diagnosis, and …
Differential Expression of Cell Cycle Regulators in Phenotypic Variants of Transgenically Induced Bladder Tumors: Implications for Tumor Behavior
Authors: Antonio Garcia-España, Edgard Salazar, Tung-Tien Sun, Xue-Ru Wu, Angel Pellicer
Journal: Cancer Research (2005)

Abstract Proteins controlling cell growth, differentiation, apoptosis, and oncogenic stress are often deregulated in tumor cells. However, whether such deregulations affect tumor behavior remains poorly understood in many tumor types. We recently showed that the urothelium-specific expression of activated H-ras and SV40 T antigen in transgenic mice produced two distinctive types of tumors strongly resembling the human superficial papillary tumors and carcinoma in situ of the bladder, respectively. Here we assessed the expression of a key set of cell cycle regulators in these mouse tumors and in a new transgenic line expressing a cyclin D1 oncogene in the urothelium. We found that urothelia of the wild-type and cyclin D1 transgenic mice exhibited a profile of cell cycle regulators found in quiescent (G0) cells, indicating that urothelium overexpressing the cyclin D1 (an 8-fold increase) is reminiscent of normal urothelium and remains slow-cycling. Low-grade superficial papillary tumors induced by activated H-ras had no detectable Rb family proteins (Rb, p107, and p130) and late cell cycle cyclins and kinases (cyclin A, E, and CDK1), but had increased level of p16, p53, and MDM2. These data suggest that the inactivation of the Rb pathway plays an important role in H-ras-induced superficial papillary tumors and that oncogenic H-ras can induce a compensatory activation of alternative tumor suppressor pathways. In contrast, carcinoma in situ of the bladder induced by SV40 T antigen had increased expression of cell cycle regulators mainly active in post-G1 phases. The fact that phenotypically different bladder tumors exhibit different patterns of cell cycle regulators may explain why these tumors have different propensity to progress to invasive tumors. Our results indicate that the transgenic mouse models can be used not only for studying tumorigenesis but also for evaluating therapeutic strategies that target specific cell cycle regulators.
Mapping of ESE-1 subdomains required to initiate mammary epithelial cell transformation via a cytoplasmic mechanism
Authors: Jason D Prescott, Joanna M Poczobutt, John J Tentler, Darius M Walker, Arthur Gutierrez-Hartmann
Journal: Molecular Cancer (2011)

Abstract Background The ETS family transcription factor ESE-1 is often overexpressed in human breast cancer. ESE-1 initiates transformation of MCF-12A cells via a non-transcriptional, cytoplasmic process that is mediated by a unique 40-amino acid serine and aspartic acid rich (SAR) subdomain, whereas, ESE-1's nuclear transcriptional property is required to maintain the transformed phenotype of MCF7, ZR-75-1 and T47D breast cancer cells. Results To map the minimal functional nuclear localization (NLS) and nuclear export (NES) signals, we fused in-frame putative NLS and NES motifs between GFP and the SAR domain. Using these GFP constructs as reporters of subcellular localization, we mapped a single NLS to six basic amino acids ( 242 HGKRRR 247 ) in the AT-hook and two CRM1-dependent NES motifs, one to the pointed domain (NES1: 102 LCNCALEELRL 112 ) and another to the DNA binding domain (DBD), (NES2: 275 LWEFIRDILI 284 ). Moreover, analysis of a putative NLS located in the DBD ( 316 GQKKKNSN 323 ) by a similar GFP-SAR reporter or by internal deletion of the DBD, revealed this sequence to lack NLS activity. To assess the role of NES2 in regulating ESE-1 subcellular localization and subsequent transformation potency, we site-specifically mutagenized NES2, within full-length GFP-ESE-1 and GFP-NES2-SAR reporter constructs. These studies show that site-specific mutation of NES2 completely abrogates ESE-1 transforming activity. Furthermore, we show that exclusive cytoplasmic targeting of the SAR domain is sufficient to initiate transformation, and we report that an intact SAR domain is required, since block mutagenesis reveals that an intact SAR domain is necessary to maintain its full transforming potency. Finally, using a monoclonal antibody targeting the SAR domain, we demonstrate that the SAR domain contains a region accessible for protein - protein interactions. Conclusions These data highlight that ESE-1 contains NLS and NES signals that play a critical role in regulating its subcellular localization and function, and that an intact SAR domain mediates MEC transformation exclusively in the cytoplasm, via a novel nontranscriptional mechanism, whereby the SAR motif is accessible for ligand and/or protein interactions. These findings are significant, since they provide novel molecular insights into the functions of ETS transcription factors in mammary cell transformation.
Discrepancies Between Nitroglycerin and NO-Releasing Drugs on Mitochondrial Oxygen Consumption, Vasoactivity, and the Release of NO
Authors: Cristina Núñez, Víctor M. Víctor, Remedios Tur, Alberto Alvarez-Barrientos, Salvador Moncada, Juan V. Esplugues, Pilar D’Ocón
Journal: Circulation Research (2005)

It has been generally acknowledged that the actions of glyceryl trinitrate (GTN) are a result of its bioconversion into NO. However, recent observations have thrown this idea into doubt, with many studies demonstrating that NO is present only when there are high concentrations of GTN. We have explored this discrepancy by developing a new approach that uses confocal microscopy to directly detect NO. Intracellular levels of NO in the rat aortic vascular wall have been compared with those present after incubation with 3 different NO donors (DETA-NO, 3-morpholinosydnonimine, and S-nitroso-N-acetylpenicillamine), endothelial activation with acetylcholine, or administration of GTN. We have also evaluated the relaxant effects of these treatments on isolated rings of aorta following activation of the enzyme soluble guanylyl cyclase and their inhibitory action on mitochondrial respiration, which is an index of the interaction of NO with the enzyme of the electron transport chain cytochrome C oxidase. In the case of the various NO donors and acetylcholine, we detected a concentration-dependent relationship in the intensity of vascular relaxation and degree of NO fluorescence and an increase in the Michaelis constant (Km) for O2. GTN did not produce similar effects, and although clinically relevant concentrations of this compound caused clear, concentration-related relaxations, there was neither any increase in NO-related fluorescence nor an augmented Km for O2. The nature of these differences suggests that these concentrations of GTN do not release free NO but probably a different species that, although it interacts with soluble guanylyl cyclase in vascular smooth muscle, does not inhibit O2 consumption by vascular mitochondria.
THE HORRORS OF WITTENBERG CAMP
Authors: W. Milligan
Journal: BMJ (1916)

When unexpected results are obtained with standard image collection, the nuclear medicine physician must consider many technical factors that may have contributed. When image quality is poor, prior radiotracer administration, among other things, should always be considered. Our case demonstrates how knowledge of patient history and basic principles of nuclear medicine physics allows recognition of the septal penetration artifact. This allows the nuclear medicine physician to tailor the exam to an individual patient and obtain the most useful diagnostic information for the clinician.