tbuckley/cabot-search huggingface dataset:
Obesity and asthma: location, location, location
Authors: Stephanie A. Shore
Journal: European Respiratory Journal (2013)

here is a worldwide epidemic of obesity.In the USA, the prevalence of obesity, defined as a body mass index (BMI) o30 kg?m -2 , has increased among adults aged 20-74 yrs from ,15% in the late 1970s to ,35% in 2010.Another third of the population is overweight (BMI o25 to ,30 kg?m -2 ).The obesity epidemic has impacted both developed and developing nations throughout the world.The World Health Organization estimates that worldwide, ,2 billion people are either obese or overweight.
Diagnosis of portopulmonary hypertension in candidates for liver transplantation: A prospective study
Authors: Isabelle O. Colle, Richard Moreau, Erica Godinho, Jacques Belghiti, Florence Ettori, Alain Cohen-Solal, Hervé Mal, Jacques Bernuau, Jean Marty, Didier Lebrec, Dominique Valla, François Durand
Journal: Hepatology (2003)

Portopulmonary hypertension represents a major risk factor for transplantation; therefore, preoperative detection is crucial. The aims of this study were to determine (1) whether Doppler echocardiography performed at evaluation is a reliable tool for detecting portopulmonary hypertension and (2) the incidence of acquired portopulmonary hypertension profile after evaluation. One hundred sixty-five patients had Doppler echocardiography and right heart catheterization at evaluation over a 9-year period. All patients had a prospective follow-up, and the results of catheterization at evaluation were compared with those obtained at the time of transplantation. Seventeen of 165 patients met the criteria for portopulmonary hypertension on Doppler echocardiography. Portopulmonary hypertension was confirmed by catheterization in 10 patients and ruled out in 7. There were no false negatives for echocardiography. Mean pulmonary artery pressure was significantly higher during the initial phase of transplantation than at evaluation (17.8 +/- 4.3 vs. 20.3 +/- 5.5 mm Hg, respectively, P <.0001), and there was no significant correlation between values obtained at these 2 time points. Three patients showed to have acquired portopulmonary hypertension profile while waiting for a graft within time intervals ranging from 2.5 to 5 months. In conclusion, Doppler echocardiography is a highly sensitive tool for detecting portopulmonary hypertension. However, because this technique has a poor positive predictive value, right heart catheterization is recommended for confirming portopulmonary hypertension. In addition, the absence of portopulmonary hypertension at evaluation does not exclude the occasional occurrence of acquired portopulmonary hypertension profile after listing.
Antigen-Independent Appearance of Recombination Activating Gene (Rag)-Positive Bone Marrow B Cells in the Spleens of Immunized Mice
Authors: Frank Gärtner, Frederick W. Alt, Robert J. Monroe, Katherine J. Seidl
Journal: The Journal of Experimental Medicine (2000)

Splenic B lineage cells expressing recombination activation genes (RAG+) in mice immunized with 4-hydroxy-3-nitrophenyl-acetyl coupled to chicken γ-globulin (NP-CGG) and the adjuvant aluminum-hydroxide (alum) have been proposed to be mature B cells that reexpress RAG after an antigen encounter in the germinal center (GC), a notion supported by findings of RAG expression in peripheral B lymphocyte populations activated in vitro. However, recent studies indicate that these cells might be immature B cells that have not yet extinguished RAG expression. Here, we employ RAG2–green fluorescent protein (GFP) fusion gene knock-in mice to show that RAG+ B lineage cells do appear in the spleen after the administration of alum alone, and that their appearance is independent of T cell interactions via the CD40 pathway. Moreover, splenic RAG+ B lineage cells were detectable in immunized RAG2-deficient mice adoptively transferred with bone marrow (BM) cells, but not with spleen cells from RAG+ mice. Although splenic RAG+ B cells express surface markers associated with GC B cells, we also find the same basic markers on progenitor/precursor BM B cells. Finally, we did not detect RAG gene expression after the in vitro stimulation of splenic RAG− mature B cells with mitogens (lipopolysaccharide and anti-CD40) and cytokines (interleukin [IL]-4 and IL-7). Together, our studies indicate that RAG+ B lineage cells from BM accumulate in the spleen after immunization, and that this accumulation is not the result of an antigen-specific response.
Vasculogenesis: a new piece of the endometriosis puzzle
Authors: M.W. Laschke, C. Giebels, M.D. Menger
Journal: Human Reproduction Update (2011)

Endometriosis is a complex disease with a multifactorial pathogenesis, which is crucially dependent on the development of new blood vessels. Based on the current literature, the present review highlights the fact that the neovascularization of endometriotic lesions is not only driven by angiogenesis, but also involves de novo formation of microvessels from circulating endothelial progenitor cells (EPCs). This process, termed post-natal vasculogenesis, is a characteristic of various pathogenic conditions, such as tumour growth and atherosclerosis, and typically comprises the activation, mobilization and recruitment of bone marrow-derived EPCs to the sites of tissue hypoxia. Literature searches were performed in PubMed, MEDLINE and ISI Web of Knowledge for publications focusing on vasculogenesis in the endometrium and endometriotic lesions. Recent studies indicate that up to 37% of the microvascular endothelium of ectopic endometrial tissue originates from EPCs, partly controlled by the stromal-cell-derived factor-1/chemokine receptor type 4 axis. Accordingly, blockade of EPC recruitment effectively inhibits the formation of microvascular networks in developing endometriotic lesions, indicating that vasculogenesis represents an integral part of the pathogenesis of endometriosis. The involvement of vasculogenesis in endometriosis may offer the exciting opportunity for the future establishment of novel diagnostic and therapeutic strategies for this frequent gynaecological disease.
Photodynamic Therapy Generates a Matrix Barrier to Invasive Vascular Cell Migration
Authors: Marcus Overhaus, Joerg Heckenkamp, Sylvie Kossodo, Dariusz Leszczynski, Glenn M. LaMuraglia
Journal: Circulation Research (2000)

Abstract —Photodynamic therapy (PDT) inhibits experimental intimal hyperplasia. PDT results in complete vascular wall cell eradication with subsequent adventitia but minimal media repopulation. This study was designed to test the hypothesis that PDT alters the vascular wall matrix thereby inhibiting invasive cell migration, and as such, provides an important barrier mechanism to favorably alter the vascular injury response. Untreated smooth muscle cells (SMCs) and fibroblasts were seeded on control and PDT-treated (100 J/cm 2 ; photosensitizer was chloroaluminum-sulfonated phthalocyanine, 5 μg/mL) 3-dimensional collagen matrix gels. Invasive cell migration was temporally quantified by calibrated microscopy. Zymography and ELISA assessed SMC matrix metalloproteinase levels. Molecular changes of gel proteins and their susceptibility to collagenase were analyzed by SDS-PAGE and Western blot. Limited pepsin digestion and histology were used to assess the in vivo relevance of the model, using an established rat carotid artery model at 1 and 4 weeks after balloon injury and PDT. PDT of 3-dimensional matrix of gels led to a 52% reduction of invasive SMCs and to a 59% reduction of fibroblast migration ( P &lt;0.001) but did not significantly affect secretion of matrix metalloproteinases. PDT induced collagen matrix changes, including cross-linking, which resulted in resistance to protease digestion. PDT led to a durable 45% reduction in pepsin digestion susceptibility of treated arteries ( P &lt;0.001) and inhibition of periadventitial cell migration into the media. These data suggest that PDT of matrix gels generates a barrier to invasive cellular migration. This newly identified effect on matrix proteins underscores its pleiotropic actions on the vessel wall, and as such, PDT may be of considerable potential therapeutic value to inhibit restenosis.
On the T cell hyperreactivity of NZB mice against H-2-identical cells. Evidence for primary response characteristics and an increased helper potential.
Authors: B Stockinger, U Botzenhardt
Journal: The Journal of Experimental Medicine (1980)

Experimental evidence presented in this paper suggests that the T cell hyperreactivity of NZB mice against H-2 identical target cells is a true primary response and not the consequence of an in vivo T cell autoimmune priming event. Based on additional data, we believe an elevated potential of T cell help to be present in NZB mice, which facilitates the observed hyperreactivity F1 hybrids of NZB and normal strains of mice inherited the capacity to hyperreact against H-2 identical cells in an H-2-unrestricted fashion. Because the hybrids tested possess both Qa-1 alleles--Qa-1b and Qa-1a--our experiments either indicate the existence of heterogeneity within the Qa-1b system or of an H-2-unrestricted response against additional target antigens. The T cell hyperreactivity might prove to be a valuable tool in further investigations of the pathomechanism of autoimmune disease.
Adoptive Transfer of Autologous Natural Killer Cells Leads to High Levels of Circulating Natural Killer Cells but Does Not Mediate Tumor Regression
Authors: Maria R. Parkhurst, John P. Riley, Mark E. Dudley, Steven A. Rosenberg
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Adoptive transfer of tumor-infiltrating lymphocytes (TIL) can mediate regression of metastatic melanoma. However, many patients with cancer are ineligible for such treatment because their TIL do not expand sufficiently or because their tumors have lost expression of antigens and/or MHC molecules. Natural killer (NK) cells are large granular lymphocytes that lyse tumor cells in a non–MHC-restricted manner. Therefore, we initiated in a clinical trial to evaluate the efficacy of adoptively transferred autologous NK cells to treat patients with cancers who were ineligible for treatment with TIL. Experimental Design: Patients with metastatic melanoma or renal cell carcinoma were treated with adoptively transferred in vitro activated autologous NK cells after the patients received a lymphodepleting but nonmyeloablative chemotherapy regimen. Clinical responses and persistence of the adoptively transferred cells were evaluated. Results: Eight patients were treated with an average of 4.7 × 1010 (± 2.1 × 1010) NK cells. The infused cells exhibited high levels of lytic activity in vitro. Although no clinical responses were observed, the adoptively transferred NK cells seemed to persist in the peripheral circulation of patients for at least one week posttransfer and, in some patients, for several months. However, the persistent NK cells in the circulation expressed significantly lower levels of the key activating receptor NKG2D and could not lyse tumor cell targets in vitro unless reactivated with IL-2. Conclusions: The persistent NK cells could mediate antibody-dependent cell-mediated cytotoxicity without cytokine reactivation in vitro, which suggests that coupling adoptive NK cell transfer with monoclonal antibody administration deserves evaluation. Clin Cancer Res; 17(19); 6287–97. ©2011 AACR.
Minding the gaps to promote thrombus growth and stability
Authors: L. F. Brass
Journal: Journal of Clinical Investigation (2005)

Efforts to understand the role of platelets in hemostasis and thrombosis have largely focused on the earliest events of platelet activation, those that lead to aggregation. Although much remains to be learned about those early events, this Review examines a later series of events: the interactions between platelets that can only occur once aggregation has begun, bringing platelets into close contact with each other, creating a protected environment in the gaps between aggregated platelets, and fostering the continued growth and stability of the hemostatic plug.
Comparative Genomics as a Time Machine: How Relative Gene Dosage and Metabolic Requirements Shaped the Time-dependent Resolution of Yeast Polyploidy
Authors: Gavin C. Conant
Journal: Molecular Biology and Evolution (2014)

Using a phylogenetic model of evolution after genome duplication (i.e., polyploidy) and 12 yeast genomes with a shared genome duplication, I show that the loss of duplicate genes after that duplication occurred in three phases. First, losses that occurred immediately after the event were biased toward genes functioning in DNA repair and organellar functions. Then, the main group of duplicate losses appear to have been shaped by a requirement to maintain balance in protein levels: There is a strong statistical association between the number of protein interactions a gene's product is involved in and its propensity to have remained in duplicate. Moreover, when duplicated genes with interactions were lost, it was more common than expected for both members of an interaction pair to have been lost on the same branch of the phylogeny. Finally, in the third phase of the resolution process, overretention of duplicated enzymes carrying high flux and of duplicated genes involved in transcriptional regulation became dominant. I speculate that initial retention of such genes by a requirement to maintain gene dosage set the stage for the later functional changes that then maintained these duplicates for long periods.
The Nlrp3 inflammasome regulates acute graft-versus-host disease
Authors: Dragana Jankovic, Jayanthi Ganesan, Michael Bscheider, Natalie Stickel, Felix C. Weber, Greta Guarda, Marie Follo, Dietmar Pfeifer, Aubry Tardivel, Kristina Ludigs, Abdellatif Bouazzaoui, Katrin Kerl, Julius C. Fischer, Tobias Haas, Annette Schmitt-Gräff, Anand Manoharan, Leonard Müller, Jürgen Finke, Stefan F. Martin, Oliver Gorka, Christian Peschel, Jürgen Ruland, Marco Idzko, Justus Duyster, Ernst Holler, Lars E. French, Hendrik Poeck, Emmanuel Contassot, Robert Zeiser
Journal: The Journal of Experimental Medicine (2013)

The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome–mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro–IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication.
Tracking the culprit: HIV-1 evolution and immune selection revealed by single-genome amplification
Authors: Zabrina L. Brumme, Bruce D. Walker
Journal: The Journal of Experimental Medicine (2009)

Early control of HIV-1 infection is determined by a balance between the host immune response and the ability of the virus to escape this response. Studies using single-genome amplification now reveal new details about the kinetics and specificity of the CD8+ T cell response and the evolution of the virus during early HIV infection.
Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B
Authors: Elinor K Karlsson, Snaevar Sigurdsson, Emma Ivansson, Rachael Thomas, Ingegerd Elvers, Jason Wright, Cedric Howald, Noriko Tonomura, Michele Perloski, Ross Swofford, Tara Biagi, Sarah Fryc, Nathan Anderson, Celine Courtay-Cahen, Lisa Youell, Sally L Ricketts, Sarah Mandlebaum, Patricio Rivera, Henrik von Euler, William C Kisseberth, Cheryl A London, Eric S Lander, Guillermo Couto, Kenine Comstock, Mike P Starkey, Jaime F Modiano, Matthew Breen, Kerstin Lindblad-Toh
Journal: Genome biology (2013)

Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors.Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.
Dietary Interventions to Prevent Disease
Authors: Deborah J. Bowen, Shirley A. A. Beresford
Journal: Annual Review of Public Health (2002)

▪ Abstract Changing dietary behaviors to prevent chronic disease has been an important research focus for the last 25 years. Here we present a review of published articles on the results of research to identify methods to change key dietary habits: fat intake, fiber intake, and consumption of fruits and vegetables. We divided the research reviewed into sections, based on the channel through which the intervention activities were delivered. We conclude that the field is making progress in identifying successful dietary change strategies, but that more can be learned. Particularly, we need to transfer some of the knowledge from the individual-based trials to community-level interventions. Also, more research with rigorous methodology must be done to test current and future intervention options.
Aldolase B inhibits metastasis through Ten–Eleven Translocation 1 and serves as a prognostic biomarker in hepatocellular carcinoma
Authors: Qi-fei Tao, Sheng-xian Yuan, Fu Yang, Sen Yang, Yuan Yang, Ji-hang Yuan, Zhen-guang Wang, Qing-guo Xu, Kong-ying Lin, Jie Cai, Jian Yu, Wei-long Huang, Xiao-lei Teng, Chuan-chuan Zhou, Fang Wang, Shu-han Sun, Wei-ping Zhou
Journal: Molecular Cancer (2015)

Downregulation of Aldolase B (ALDOB) has been reported in hepatocellular carcinoma. However, its clinical significance and its role in pathogenesis of HCC remain largely unknown.We analyzed the expression of ALDOB and its clinical features in a large cohort of 313 HCC patients using tissue microarray and immunohistochemistry. Moreover, the function of stably overexpressed ALDOB in HCC cells was explored in vitro and in vivo. Gene expression microarray analysis was performed on ALDOB-overexpressing SMMC7721 cells to elucidate its mechanism of action.ALDOB downregulation in HCC was significantly correlated with aggressive characteristics including absence of encapsulation, increased tumor size (>5 cm) and early recurrence. ALDOB downregulation was indicative of a shorter recurrence-free survival (RFS) and overall survival (OS) for all HCC patients and early-stage HCC patients (BCLC 0-A and TNM I stage patients). Multiple analyses revealed that ALDOB downregulation was an independent risk factor of RFS and OS. Stable expression of ALDOB in HCC cell lines reduced cell migration in vitro and inhibited lung metastasis, intrahepatic metastasis, and reduced circulating tumor cells in vivo. Mechanistically, we found that cells stably expressing ALDOB show elevated Ten-Eleven Translocation 1 (TET1) expression. Moreover, ALDOB expressing cells have higher levels of methylglyoxal than do control cells, which can upregulate TET1 expression.The downregulation of ALDOB could indicate a poor prognosis for HCC patients, and therefore, ALDOB might be considered a prognostic biomarker for HCC, especially at the early stage. In addition, ALDOB inhibits the invasive features of cell lines partly through TET1 expression.
STUDIES OF THE Vi (γ2c) SUBGROUP OF γ-GLOBULIN
Authors: William J. Yount, Henry G. Kunkel, Stephen D. Litwin
Journal: The Journal of Experimental Medicine (1967)

Further delineation of the antigens characteristic of the Vi or γ2c subgroup of γ-globulin was carried out utilizing a number of rabbit and primate antisera. Two genetic antigens characteristic of this subgroup, Gm(b) and Gm(g), were also detected by precipitation techniques with certain of the antisera. These were clearly differentiated from antigens common to all proteins of this subgroup. The concentration, of Vi protein in normal and pathological sera from several population groups was measured quantitatively utilizing a variety of immunological procedures. All sera studied showed measurable levels. The mean value for Caucasian sera was 1.06 mg/ml, representing approximately 8% of γG-globulin. This agreed closely with a figure of 8.4% for the incidence of myeloma proteins of the Vi subgroup among all γG-myeloma proteins in Caucasians. A relationship was found between the Vi subgroup concentration and the specific genetic type of a given individual. Measurements of the Gm(b) genetic determinants, which are found solely in Vi-type proteins, brought forward this relationship. Gm(b+) individuals showed higher concentrations of Vi-type γ-globulin than those who were Gm(b-), and this difference was statistically significant for both the homozygous and heterozygous states. It appeared that the structural genes for Gm(b+) polypeptide chains showed a greater synthetic capacity than those for Gm(b-) types. The possible significance of such effects in governing the relative composition of the antibody population in a given individual is discussed.
Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways
Authors: Meredith A. Morgan, Theodore S. Lawrence
Journal: Clinical Cancer Research (2015)

Abstract DNA double-strand breaks are the critical lesions responsible for the majority of ionizing radiation–induced cell killing. Thus, the ability of tumor cells to elicit a DNA damage response following radiation, via activation of DNA repair and cell-cycle checkpoints, promotes radiation resistance and tumor cell survival. Consequently, agents that target these DNA damage response pathways are being developed to overcome radiation resistance. Overall, these agents are effective radiosensitizers; however, their mechanisms of tumor cell selectivity are not fully elucidated. In this review, we focus on the crucial radiation-induced DNA damage responses as well as clinical and translational advances with agents designed to inhibit these responses. Importantly, we describe how synthetic lethality can provide tumor cell–selective radiosensitization by these agents and expand the therapeutic window for DNA damage response–targeted agents used in combination with radiotherapy. Clin Cancer Res; 21(13); 2898–904. ©2015 AACR.