tbuckley/cabot-search huggingface dataset:
Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for <i>IL2, REL</i> , and <i>CARD9</i>
Authors: Marcel Janse, Laetitia E. Lamberts, Lude Franke, Soumya Raychaudhuri, Eva Ellinghaus, Kirsten Muri Boberg, Espen Melum, Trine Folseraas, Erik Schrumpf, Annika Bergquist, Einar Björnsson, Jingyuan Fu, Harm Jan Westra, Harry J.M. Groen, Rudolf S.N. Fehrmann, Joanna Smolonska, Leonard H. van den Berg, Roel A. Ophoff, Robert J. Porte, Tobias J. Weismüller, Jochen Wedemeyer, Christoph Schramm, Martina Sterneck, Rainer Günther, Felix Braun, Severine Vermeire, Liesbet Henckaerts, Cisca Wijmenga, Cyriel Y. Ponsioen, Stefan Schreiber, Tom H. Karlsen, Andre Franke, Rinse K. Weersma
Journal: Hepatology (2011)

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 ( P-value 4.12 × 10−4), 4q27 ( P-value 4.10 × 10−5), and 9q34 ( P-value 8.41 × 10−4) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated ( P &lt; 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. Conclusion: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors. (HEPATOLOGY 2011;)
Small Cell Lung Cancer
Authors: Gregory P. Kalemkerian, Wallace Akerley, Robert J. Downey, David S. Ettinger, Frank V Fossella, John C. Grecula, Thierry Jahan, Bruce E. Johnson, Anne Kessinger, Marianna Koczywas, Corey J. Langer, Renato Martins, Harvey B. Niell, Charles C. Pan, Nithya Ramnath, Neal Ready, Francisco Robert, Charles C. Williams
Journal: Journal of the National Comprehensive Cancer Network (2013)

Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted.
ABL Mutations in Late Chronic Phase Chronic Myeloid Leukemia Patients With Up-Front Cytogenetic Resistance to Imatinib Are Associated With a Greater Likelihood of Progression to Blast Crisis and Shorter Survival: A Study by the GIMEMA Working Party on Chronic Myeloid Leukemia
Authors: Simona Soverini, Giovanni Martinelli, Gianantonio Rosti, Simona Bassi, Marilina Amabile, Angela Poerio, Barbara Giannini, Elena Trabacchi, Fausto Castagnetti, Nicoletta Testoni, Simona Luatti, Antonio de Vivo, Daniela Cilloni, Barbara Izzo, Milena Fava, Elisabetta Abruzzese, Daniele Alberti, Fabrizio Pane, Giuseppe Saglio, Michele Baccarani
Journal: Journal of Clinical Oncology (2005)

Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib.Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months.Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045).Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.
BIOPSY-PROVEN ACTIVE MYOCARDITIS IN SYSTEMIC SCLEROSIS PATIENTS WITH RECENT-ONSET CARDIAC INVOLVEMENT
Authors: Costantino Smaldone, Maurizio Pieroni, Maria De Santis, Gaetano Zizzo, Mara Campioni, Antonella Ventrone, Antonia Camporeale, Andrea Macchione, Anna Severino, Fulvio Bellocci, Gianfranco Ferraccioli, Filippo Crea
Journal: Journal of the American College of Cardiology (2010)
Prediagnosis Body Mass Index, Physical Activity, and Mortality in Endometrial Cancer Patients
Authors: Hannah Arem, Yikyung Park, Colleen Pelser, Rachel Ballard-Barbash, Melinda L. Irwin, Albert Hollenbeck, Gretchen L. Gierach, Louise A. Brinton, Ruth M. Pfeiffer, Charles E. Matthews
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundHigher body mass index (BMI) and inactivity have been associated with a higher risk of developing endometrial cancer, but the impact on endometrial cancer survival is unclear.
Limitation of immune tolerance–inducing thymic epithelial cell development by Spi-B–mediated negative feedback regulation
Authors: Nobuko Akiyama, Miho Shinzawa, Maki Miyauchi, Hiromi Yanai, Ryosuke Tateishi, Yusuke Shimo, Daisuke Ohshima, Koichi Matsuo, Izumi Sasaki, Katsuaki Hoshino, Guoying Wu, Shintaro Yagi, Jun-ichiro Inoue, Tsuneyasu Kaisho, Taishin Akiyama
Journal: The Journal of Experimental Medicine (2014)

Medullary thymic epithelial cells (mTECs) expressing the autoimmune regulator AIRE and various tissue-specific antigens (TSAs) are critical for preventing the onset of autoimmunity and may attenuate tumor immunity. However, molecular mechanisms controlling mTEC development remain elusive. Here, we describe the roles of the transcription factor Spi-B in mTEC development. Spi-B is rapidly up-regulated by receptor activator of NF-κB ligand (RANKL) cytokine signaling, which triggers mTEC differentiation, and in turn up-regulates CD80, CD86, some TSAs, and the natural inhibitor of RANKL signaling, osteoprotegerin (OPG). Spi-B–mediated OPG expression limits mTEC development in neonates but not in embryos, suggesting developmental stage–specific negative feedback regulation. OPG-mediated negative regulation attenuates cellularity of thymic regulatory T cells and tumor development in vivo. Hence, these data suggest that this negative RANKL–Spi-B–OPG feedback mechanism finely tunes mTEC development and function and may optimize the trade-off between prevention of autoimmunity and induction of antitumor immunity.
ET-33 * PLACENTA-DERIVED MESENCHYMAL STEM CELLS AND THEIR SECRETED EXOSOMES INHIBIT THE SELF-RENEWAL AND STEMNESS OF GLIOMA STEM CELLS IN VITRO AND IN VIVO
Authors: H. K. Lee, E. Buchris, S. Finniss, S. Cazacu, C. Xiang, L. Poisson, C. Brodie
Journal: Neuro-Oncology (2014)

Mesenchymal stromal cells (MSCs) are multipotent stem cells that can be obtained from bone marrow and adipose tissues or from other sources such as placenta and umbilical cord. The latter allow the potential use of universal, allogeneic cell therapy because to reduced antigenicity due to low expression of MHC class II molecules. MSCs can be easily expanded in vitro for therapeutic applications and their safety and therapeutic impact have been demonstrated in various pre-clinical and clinical studies. MSCs have been shown to cross the blood brain barrier and migrate to sites of experimental GBM and can deliver cytotoxic compounds that exert anti-tumor effects. In this study we examined the effects of placenta-derived MSCs and their secreted exosomes on GSCs in vitro and in vivo. Conditioned medium of placenta MSCs or their derived exosomes decreased the self-renewal, stemness markers, Sox2 and Oct4 and the migration of these cells. Similarly, intracranial administration of the MSCs decreased the tumor volume of GSC-derived xenografts and prolonged animal survival. miRNA sequencing analysis of placenta MSC-derived exosomes revealed a set of specific miRNAs that were downregulated in GSCs and that acted as tumor suppressor in these cells. We demonstrated delivery of some of these miRNAs to GSCs following treatments with MSC-derived exosomes. We further demonstrated that MSCs or exosomes that were loaded with exogenous miR-124 delivered high levels of this miRNA into glioma cells as detected by a novel quantitative miRNA reporter. Moreover, administration of placenta MSCs loaded with exogenous miR-124 exerted a strong inhibitory effect on GSC-derived xenograft growth. These results demonstrate that placenta-derived MSCs may have important clinical applications in stem cell-based glioma therapeutics. Moreover, these studies provide a novel approach for the targeted delivery of endogenous and exogenous anti-tumor miRNAs to glioma cells as a miRNA replacement therapy for GBM.
“To B(MP-2) or Not To B(MP-2)” or “Much Ado About Nothing”: Are Orthobiologics in Tumor Surgery Worth the Risks?
Authors: Kurt R. Weiss
Journal: Clinical Cancer Research (2015)

Geller and colleagues report that adjuvant chemotherapy affected the adequacy of osteosarcoma local surgical control. Exogenous bone morphogenetic protein-2 (BMP-2) did not increase local recurrence, but the limited theoretical benefits of BMP-2 for a subset of patients with osteosarcoma may not justify the systemic and long-term risks.
Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients
Authors: L. Morales, D. Timmerman, P. Neven, M.L. Konstantinovic, A. Carbonez, S. Van Huffel, L. Ameye, C. Weltens, M.-R. Christiaens, I. Vergote, R. Paridaens
Journal: Annals of Oncology (2004)
Interspersed DNA Repeats bcr1-bcr18 of Bacillus cereus Group Bacteria Form Three Distinct Groups with Different Evolutionary and Functional Patterns
Authors: S. M. Kristoffersen, N. J. Tourasse, A.-B. Kolsto, O. A. Okstad
Journal: Molecular Biology and Evolution (2010)

Many short (<400 bp) interspersed sequence repeats exist in bacteria, yet little is known about their origins, mode of generation, or possible function. Here, we present a comprehensive analysis of 18 different previously identified repeated DNA elements, bcr1-bcr18 (Økstad OA, Hegna I, Lindback T, Rishovd AL, Kolstø AB. 1999. Genome organization is not conserved between Bacillus cereus and Bacillus subtilis. Microbiology. 145:621–631.; Tourasse NJ, Helgason E, Økstad OA, Hegna IK, Kolstø AB. 2006. The Bacillus cereus group: novel aspects of population structure and genome dynamics. J Appl Microbiol. 101:579–593.), in 36 sequenced genomes from the Bacillus cereus group of bacteria. This group consists of genetically closely related species with variable pathogenic specificity toward different hosts and includes among others B. anthracis, B. cereus, and B. thuringiensis. The B. cereus group repeat elements could be classified into three categories with different properties: Group A elements (bcr1–bcr3) exhibited highly variable copy numbers ranging from 4 to 116 copies per strain, showed a nonconserved chromosomal distribution pattern between strains, and displayed several features characteristic of mobile elements. Group B repeats (bcr4–bcr6) were present in 0–10 copies per strain and were associated with strain-specific genes and disruptions of genome synteny, implying a possible contribution to genome rearrangements and/or horizontal gene transfer events. bcr5, in particular, was associated with large gene clusters showing resemblance to integrons. In agreement with their potentially mobile nature or involvement in horizontal transfers, the sequences of the repeats from Groups A and B (bcr1–bcr6) followed a phylogeny different from that of the host strains. Conversely, repeats from Group C (bcr7–bcr18) had a conserved chromosomal location and orthologous gene neighbors in the investigated B. cereus group genomes, and their phylogeny matched that of the host chromosome. Several of the group C repeats exhibited a conserved secondary structure or had parts of the structure conserved, possibly indicating functional RNAs. Accordingly, five of the repeats in group C overlapped regions encoding previously characterized riboswitches. Similarly, other group C repeats could represent novel riboswitches, encode small RNAs, and/or constitute other types of regulatory elements with specific biological functions. The current analysis suggests that the multitude of repeat elements identified in the B. cereus group promote genome dynamics and plasticity and could contribute to the flexible and adaptive life style of these bacteria.
Inactivation of specific β cell transcription factors in type 2 diabetes
Authors: Shuangli Guo, Chunhua Dai, Min Guo, Brandon Taylor, Jamie S. Harmon, Maike Sander, R. Paul Robertson, Alvin C. Powers, Roland Stein
Journal: Journal of Clinical Investigation (2013)

Type 2 diabetes (T2DM) commonly arises from islet β cell failure and insulin resistance. Here, we examined the sensitivity of key islet-enriched transcription factors to oxidative stress, a condition associated with β cell dysfunction in both type 1 diabetes (T1DM) and T2DM. Hydrogen peroxide treatment of β cell lines induced cytoplasmic translocation of MAFA and NKX6.1. In parallel, the ability of nuclear PDX1 to bind endogenous target gene promoters was also dramatically reduced, whereas the activity of other key β cell transcriptional regulators was unaffected. MAFA levels were reduced, followed by a reduction in NKX6.1 upon development of hyperglycemia in db/db mice, a T2DM model. Transgenic expression of the glutathione peroxidase-1 antioxidant enzyme (GPX1) in db/db islet β cells restored nuclear MAFA, nuclear NKX6.1, and β cell function in vivo. Notably, the selective decrease in MAFA, NKX6.1, and PDX1 expression was found in human T2DM islets. MAFB, a MAFA-related transcription factor expressed in human β cells, was also severely compromised. We propose that MAFA, MAFB, NKX6.1, and PDX1 activity provides a gauge of islet β cell function, with loss of MAFA (and/or MAFB) representing an early indicator of β cell inactivity and the subsequent deficit of more impactful NKX6.1 (and/or PDX1) resulting in overt dysfunction associated with T2DM.
Safety and Efficacy of Liposomal Amphotericin B Compared with Conventional Amphotericin B for Induction Therapy of Histoplasmosis in Patients with AIDS
Authors: Philip C. Johnson
Journal: Annals of Internal Medicine (2002)

Background: In patients with moderate to severe histoplasmosis associated with AIDS, the preferred treatment has been the deoxycholate formulation of amphotericin B. However, serious side effects are associated with use of amphotericin B. Objective: To compare amphotericin B with liposomal amphotericin B for induction therapy of moderate to severe disseminated histoplasmosis in patients with AIDS. Design: Randomized, double-blind, multicenter clinical trial. Setting: 21 sites of the U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Patients: 81 patients with AIDS and moderate to severe disseminated histoplasmosis. Measurements: Clinical success, conversion of baseline blood cultures to negative, and acute toxicities that necessitated discontinuation of treatment. Results: Clinical success was achieved in 14 of 22 patients (64%) treated with amphotericin B compared with 45 of 51 patients (88%) receiving liposomal amphotericin B (difference, 24 percentage points [95% CI, 1 to 52 percentage points]). Culture conversion rates were similar. Three patients treated with amphotericin B and one treated with liposomal amphotericin B died during induction (P = 0.04). Infusion-related side effects were greater with amphotericin B (63%) than with liposomal amphotericin B (25%) (P = 0.002). Nephrotoxicity occurred in 37% of patients treated with amphotericin B and 9% of patients treated with liposomal amphotericin B (P = 0.003). Conclusion: Liposomal amphotericin B seems to be a less toxic alternative to amphotericin B and is associated with improved survival. *For a list of study investigators and numbers of patients enrolled, see Appendix.
Persistence of symptoms after gall bladder clearance with cholecystolithotripsy.
Authors: S H Lee, H J Burhenne
Journal: Gut (1991)

Forty six patients rendered stone and fragment free with successful cholecystolithotripsy without the use of oral chemolitholysis were followed by serial ultrasound for a period of two to 25 months (mean 11 months, median 10 months). Seven patients (15%), six of whom remain asymptomatic, developed recurrent calculi. Of the 39 gall stone free patients, 26 were asymptomatic. Six patients complained of persistent abdominal pain similar to that before treatment. One of these had a bile duct stone. Seven patients complained of a variety of non-biliary symptoms. The patient with recurrent gall stones and recurrent symptoms is eligible for further lithotripsy treatment. The overall 30% incidence of persistent abdominal symptoms is similar to that reported after elective cholecystectomy.
Perceptions of Psychosocial Factors and the Insulin Pump
Authors: Marilyn D. Ritholz, Arlene Smaldone, Jarim Lee, Astrid Castillo, Howard Wolpert, Katie Weinger
Journal: Diabetes Care (2007)

The purpose of this study was to identify psychosocial issues related to diabetes, approaches to self-care, self-perceptions, and social interactions among insulin pump users with type 1 diabetes.Adult insulin pump users participated in focus groups loosely formed on the basis of A1C level. Transcripts of focus group meetings were coded into themes by five reviewers using NVivo2 qualitative software.Thirty adults with long-term diabetes participated in five focus groups: two with low mean +/-SD A1C (6.8 +/- 0.4%), one with mid A1C (7.80 +/- 0.3%), and two with high A1C (9.1 +/- 0.5%). Three major themes were identified: impact on diabetes self-care, emotional reactions to the insulin pump, body image, and social acceptance. Participants who described the pump as a tool to meet glycemic goals also described a more active approach to diabetes and had better glycemic control; those who discussed the pump as a panacea described more passive self-care and had poorer glycemic control. Low A1C groups reported that starting the insulin pump reminded them of feelings they experienced at their initial diabetes diagnosis, whereas the high A1C groups did not report these feelings. Women were more concerned than men about body image and social acceptance with pump use.Active participation in self-care, realistic expectations of pump use, and emotional recall of diabetes diagnosis were associated with better glycemic control. Interventions to improve diabetes management with pump use should include evaluation and discussion of active versus passive approaches to self-care, recall of diabetes diagnosis, expectations of the pump, and pump-related self-consciousness and body image concerns. The roles of these factors in optimal diabetes management warrant further investigation.
Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension
Authors: P. Egermayer, G I. Town, A. J Peacock
Journal: Thorax (1999)

The causes of pulmonary hypertension fall into four broad categories: (1) passive increases in pulmonary artery pressure secondary to increased left atrial pressure and left ventricular dysfunction, (2) veno-occlusive disorders, (3) conditions in which the blood flow through the pulmonary arteries is increased beyond the ability of the pulmonary circulation to compensate, and (4) conditions associated with vasospasm or occlusion, resulting in a diminished effective cross sectional area of the pulmonary vascular bed.1 2 In many cases several factors are present simultaneously. Regardless of the initiating cause, severe prolonged pulmonary hypertension appears to result in largely irreversible changes which involve vascular remodelling and often thrombosis.3-5 

Because the signs and symptoms of pulmonary hypertension are often very non-specific, patients commonly present late and, until recently, invasive tests were required to establish the diagnosis. Consequently pulmonary hypertension was frequently an important but unrecognised component of other disease states, many of which will be the subject of this discussion.

The main importance of severe pulmonary hypertension is that it may cause right ventricular dysfunction and ultimately death from right heart failure. Pulmonary heart disease, usually associated with pulmonary hypertension, has been estimated to account for at least 10% of all cases of heart disease in the USA.6 The significance of milder pulmonary hypertension is less clear, but it is probably important. A study in Chicago of 1118 subjects who were undergoing coronary angiography for suspected heart disease showed that the finding of pulmonary hypertension, independent of left ventricular dysfunction, was the single most important predictor of the likelihood of death over the subsequent two years.7 Pulmonary hypertension also has important prognostic implications in critically ill surgical patients8 and in those with chronic obstructive pulmonary disease (COPD).9 

The changes which take place in pulmonary arteries as a result …
SUCROSE TAKEN DURING MIXED MEAL HAS NO ADDITIONAL HYPERGLYCAEMIC ACTION OVER ISOCALORIC AMOUNTS OF STARCH IN WELL-CONTROLLED DIABETICS
Authors: G. Slama, P. Jean-Joseph, I. Goicolea, F. Elgrably, M.J. Haardt, D. Costagliola, F. Bornet, G. Tchobroutsky
Journal: The Lancet (1984)