tbuckley/cabot-search huggingface dataset:
Origin and Homing of Intestinal IgA Antibody-secreting Cells
Authors: Michael E. Lamm, Julia M. Phillips-Quagliata
Journal: The Journal of Experimental Medicine (2002)

The fact that IgA comprises the body's major isotype of antibody on a biosynthetic basis is not widely appreciated because IgG, not IgA, is the predominant isotype in serum. Nevertheless, the bulk of the body's Ig-producing cells reside in the various mucosal and exocrine sites, especially along the
Intravascular Ultrasound–Guided Percutaneous Coronary Interventions
Authors: Lorenz Räber, Stephan Windecker
Journal: Circulation (2013)

C oronary angiography falls short in accurately delineat- ing the anatomy of epicardial vessels because it provides only a 2-dimensional visualization of the lumen. 1 Moreover, angiographic lesion assessment is impeded in cases of diffuse disease of reference vessels, lesion foreshortening, and eccentricity, and the overlap of several arterial branches, as well.Conversely, intravascular ultrasound-a sound wave-based technology-provides superior spatial resolution of 80 to 150 μm and extends diagnostic information, enabling more precise assessment of lumen and vessel wall dimensions including atheroma burden and vessel remodeling.
New insight on the Xq28 association with systemic sclerosis
Authors: F David Carmona, M Carmen Cénit, Lina-Marcela Diaz-Gallo, Jasper C A Broen, Carmen P Simeón, Patricia E Carreira, José-Luis Callejas-Rubio, Vicente Fonollosa, Francisco J López-Longo, Miguel A González-Gay, Nicolas Hunzelmann, Gabriela Riemekasten, Torsten Witte, Alexander Kreuter, Jörg H W Distler, Rajan Madhok, Paul Shiels, Jacob M van Laar, Annemie J Schuerwegh, Madelon C Vonk, Alexandre E Voskuyl, Carmen Fonseca, Christopher P Denton, Ariane Herrick, Jane Worthington, Frank C Arnett, Filemon K Tan, Shervin Assassi, Timothy R D J Radstake, Maureen D Mayes, Javier Martín
Journal: Annals of the Rheumatic Diseases (2013)

Objective To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene ( MECP2 ). Methods We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc. Results IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (P FDR =4.12×10 −3 , OR=1.27, 95% CI 1.09 to 1.47, and P FDR =5.26×10 −4 , OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (P FDR =0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF− (p=0.025, OR=1.26, 95% CI 1.03 to 1.55). Conclusions Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.
Inhibition of <i>KRAS</i>-Driven Tumorigenicity by Interruption of an Autocrine Cytokine Circuit
Authors: Zehua Zhu, Amir R. Aref, Travis J. Cohoon, Thanh U. Barbie, Yu Imamura, Shenghong Yang, Susan E. Moody, Rhine R. Shen, Anna C. Schinzel, Tran C. Thai, Jacob B. Reibel, Pablo Tamayo, Jason T. Godfrey, Zhi Rong Qian, Asher N. Page, Karolina Maciag, Edmond M. Chan, Whitney Silkworth, Mary T. Labowsky, Lior Rozhansky, Jill P. Mesirov, William E. Gillanders, Shuji Ogino, Nir Hacohen, Suzanne Gaudet, Michael J. Eck, Jeffrey A. Engelman, Ryan B. Corcoran, Kwok-Kin Wong, William C. Hahn, David A. Barbie
Journal: Cancer Discovery (2014)

Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKKε promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKε inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKε promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKε, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.
MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis
Authors: Chi-Hong Chao, Chao-Ching Chang, Meng-Ju Wu, How-Wen Ko, Da Wang, Mien-Chie Hung, Jer-Yen Yang, Chun-Ju Chang
Journal: Journal of Clinical Investigation (2014)

Dysregulation of epigenetic controls is associated with tumorigenesis in response to microenvironmental stimuli; however, the regulatory pathways involved in epigenetic dysfunction are largely unclear. We have determined that a critical epigenetic regulator, microRNA-205 (miR-205), is repressed by the ligand jagged1, which is secreted from the tumor stroma to promote a cancer-associated stem cell phenotype. Knockdown of miR-205 in mammary epithelial cells promoted epithelial-mesenchymal transition (EMT), disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, miR-205-deficient mice spontaneously developed mammary lesions, while activation of miR-205 markedly diminished breast cancer stemness. These data provide evidence that links tumor microenvironment and microRNA-dependent regulation to disruption of epithelial polarity and aberrant mammary stem cell division, which in turn leads to an expansion of stem cell population and tumorigenesis. This study elucidates an important role for miR-205 in the regulation of mammary stem cell fate, suggesting a potential therapeutic target for limiting breast cancer genesis.
Virus-Induced Maturation and Activation of Autoreactive Memory B Cells
Authors: Amy J. Reed, Michael P. Riley, Andrew J. Caton
Journal: The Journal of Experimental Medicine (2000)

We have examined B cell populations that participate in distinct phases of the immune response to the influenza virus A/PR/8/34 hemagglutinin (HA) for their susceptibility to negative selection in mice that express the HA as a neo-self-antigen (HA104 mice). We demonstrated previously that specificity for the neo-self-HA causes a population of immunoglobulin G antibody-secreting cells, which dominate the primary response to virus immunization in BALB/c mice, to be negatively selected in HA104 mice. We find here that in contrast to these primary response B cells, HA-specific memory response B cells developed equivalently in HA104 and nontransgenic (BALB/c) mice. Indeed, there was no indication that HA-specific B cells were negatively selected during memory formation in influenza virus-immunized HA104 mice, even though the neo-self-HA can be recognized by memory B cells. Furthermore, HA-specific autoantibodies were induced in the absence of virus immunization by mating HA104 mice with mice transgenic for a CD4(+) HA-specific T cell receptor. These findings indicate that specificity for a self-antigen does not prevent the maturation of autoreactive B cells in the germinal center pathway. Rather, the availability of CD4(+) T cell help may play a crucial role in regulating autoantibody responses to the HA in HA104 mice.
Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial
Authors: Jaafar Bennouna, Javier Sastre, Dirk Arnold, Pia Österlund, Richard Greil, Eric Van Cutsem, Roger von Moos, Jose Maria Viéitez, Olivier Bouché, Christophe Borg, Claus-Christoph Steffens, Vicente Alonso-Orduña, Christoph Schlichting, Irmarie Reyes-Rivera, Belguendouz Bendahmane, Thierry André, Stefan Kubicka
Journal: The Lancet Oncology (2012)
High-Resolution Intravascular Magnetic Resonance Imaging
Authors: Gesine G. Zimmermann-Paul, Harald H. Quick, Peter Vogt, Gustav K. von Schulthess, Dorothee Kling, Jörg F. Debatin
Journal: Circulation (1999)

Background —The individual makeup of atherosclerotic plaque has been identified as a dominant prognostic factor. With the use of an intravascular magnetic resonance (MR) catheter coil, we evaluated the effectiveness of high-resolution MR in the study of the development of atherosclerotic lesions in heritable hyperlipidemic rabbits. Methods and Results —Sixteen hyperlipidemic rabbits were investigated at the ages of 6, 12, 24, and 36 months. The aorta was studied with digital subtraction angiography and high-resolution MR with the use of a surface coil and an intravascular coil that consisted of a single-loop copper wire integrated in a 5F balloon catheter. Images were correlated with histological sections regarding wall thickness, plaque area, and plaque components. Digital subtraction angiography revealed no abnormalities in the 6- and 12-month-old rabbits and only mild stenoses in the 24- and 36-month-old rabbits. High-resolution imaging with surface coils resulted in an in-plane resolution of 234×468 μm. Delineation of the vessel wall was not possible in younger rabbits and correlated only poorly with microscopic measurements in the 36-month-old rabbits. Intravascular images achieved an in-plane resolution of 117×156 μm. Increasing thickness of the aortic wall and plaque area was observed with increasing age. In the 24- and 36-month-old animals, calcification could be differentiated from fibrous and fatty tissue on the basis of the T2-fast spin echo images, as confirmed by histological correlation. Conclusions —Atherosclerotic evolution of hyperlipidemic rabbits can be monitored with high-resolution intravascular MR imaging. Image quality is sufficient to determine wall thickness and plaque area and to differentiate plaque components.
CD4+ T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation
Authors: Gesine Hansen, Jennifer J. McIntire, V. Peter Yeung, Gerald Berry, G. Jeanette Thorbecke, Lizhen Chen, Rosemarie H. DeKruyff, Dale T. Umetsu
Journal: Journal of Clinical Investigation (2000)

T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-β abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-β in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-β was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-β–secreting Th cells was antigen-specific and was reversed by neutralization of TGF-β. Our results demonstrate that T cells secreting TGF-β in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-β–producing T cells play an important regulatory role in asthma.
Improved Human β-globin Expression from Self-inactivating Lentiviral Vectors Carrying the Chicken Hypersensitive Site-4 (cHS4) Insulator Element
Authors: Paritha I Arumugam, Jessica Scholes, Natalya Perelman, Ping Xia, Jiing-Kuan Yee, Punam Malik
Journal: Molecular Therapy (2007)

Effective gene therapy for beta-thalassemia major (beta-TM) requires consistent, high expression of human beta-globin (hbeta-globin) in red blood cells (RBCs). Several groups have now shown that lentiviral (LV) vectors stably transmit the hbeta/hgamma-globin genes and large elements of the locus control region, resulting in correction of the murine thalassemia intermedia (TI) phenotype and survival of mice with the TM phenotype. However, current LVs show variable hbeta/hgamma-globin expression and require a high number of vector copies/cell for a therapeutic effect. To address this, we designed LVs flanked by the chicken hypersensitive site-4 (cHS4) chromatin insulator element and compared them with their "un-insulated" counterparts. We observed a consistent twofold-higher hbeta expression from insulated vectors in single-copy mouse erythroleukemia cell clones, an increase that resulted from reduced position effect variegation (PEV) and increased probability of expression from individual integrants. This effect was confirmed in vivo: an approximately twofold increase in hbeta expression was seen in the RBC progeny of murine hematopoietic stem cells, with significantly higher numbers of hbeta-expressing cells in individual secondary spleen colony-forming units. In summary, cHS4-insulated hbeta-globin LVs showed distinct chromatin barrier activity, resulting in higher, consistent hbeta expression. These studies have important implications for vector design for clinical trials for gene therapy for hemoglobinopathies.
Catatonia, motor neglect, and hysterical paralysis: Some similarities and differences
Authors: John C. Marshall, Jennifer M. Gurd, Gereon R. Fink
Journal: Behavioral and Brain Sciences (2002)

We outline some ways in which motor neglect (the underutilization of a limb despite adequate strength) and hysterical paralysis (failure to move a limb despite no relevant structural damage or disease) may throw light on the pathophysiology of catatonia. We also comment on the manifold inadequacies of distinguishing too firmly between symptoms of “neurologic origin” and of “psychiatric origin.”
Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis
Authors: Sharon M. Moe, Safa Abdalla, Glenn M. Chertow, Patrick S. Parfrey, Geoffrey A. Block, Ricardo Correa-Rotter, Jürgen Floege, Charles A. Herzog, Gerard M. London, Kenneth W. Mahaffey, David C. Wheeler, Bastian Dehmel, William G. Goodman, Tilman B. Drüeke
Journal: Journal of the American Society of Nephrology (2014)

Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.
Impact of Bariatric Surgery on Health Care Costs of Obese Persons
Authors: Jonathan P Weiner, Suzanne M Goodwin, Hsien-Yen Chang, Shari D Bolen, Thomas M Richards, Roger A Johns, Soyal R Momin, Jeanne M Clark
Journal: JAMA Surgery (2013)

Bariatric surgery is a well-documented treatment for obesity, but there are uncertainties about the degree to which such surgery is associated with health care cost reductions that are sustained over time.To provide a comprehensive, multiyear analysis of health care costs by type of procedure within a large cohort of privately insured persons who underwent bariatric surgery compared with a matched nonsurgical cohort.Longitudinal analysis of 2002-2008 claims data comparing a bariatric surgery cohort with a matched nonsurgical cohort.Seven BlueCross BlueShield health insurance plans with a total enrollment of more than 18 million persons.A total of 29 820 plan members who underwent bariatric surgery between January 1, 2002, and December 31, 2008, and a 1:1 matched comparison group of persons not undergoing surgery but with diagnoses closely associated with obesity.Standardized costs (overall and by type of care) and adjusted ratios of the surgical group's costs relative to those of the comparison group.Total costs were greater in the bariatric surgery group during the second and third years following surgery but were similar in the later years. However, the bariatric group's prescription and office visit costs were lower and their inpatient costs were higher. Those undergoing laparoscopic surgery had lower costs in the first few years after surgery, but these differences did not persist.Bariatric surgery does not reduce overall health care costs in the long term. Also, there is no evidence that any one type of surgery is more likely to reduce long-term health care costs. To assess the value of bariatric surgery, future studies should focus on the potential benefit of improved health and well-being of persons undergoing the procedure rather than on cost savings.
Spatial Clusters of Nontuberculous Mycobacterial Lung Disease in the United States
Authors: Jennifer Adjemian, Kenneth N. Olivier, Amy E. Seitz, Joseph O. Falkinham, Steven M. Holland, D. Rebecca Prevots
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Prevalence of pulmonary nontuberculous mycobacterial (PNTM) disease varies by geographic region, yet the factors driving these differences remain largely unknown.To identify spatial clusters of PNTM disease at the county level and to describe environmental and sociodemographic factors predictive of disease.PNTM cases identified from a nationally representative sample of Medicare Part B beneficiaries from 1997 to 2007 were geocoded by county and state of residence. County-level PNTM case counts and Medicare population data were then uploaded into SaTScan to identify significant spatial clusters and low-risk areas of disease. High-risk and low-risk counties were then compared to identify significant sociodemographic and environmental differences.We identified seven significant (P < 0.05) clusters of PNTM cases. These high-risk areas encompassed 55 counties in 8 states, including parts of California, Florida, Hawaii, Louisiana, New York, Oklahoma, Pennsylvania, and Wisconsin. Five low-risk areas were also identified, which encompassed 746 counties in 23 states, mostly in the Midwest. Counties in high-risk areas were significantly larger, had greater population densities, and higher education and income levels than low-risk counties. High-risk counties also had higher mean daily potential evapotranspiration levels and percentages covered by surface water, and were more likely to have greater copper and sodium levels in the soil, although lower manganese levels.Specific environmental factors related to soil and water exposure appear to increase the risk of PNTM infection. Still, given that environmental sources of NTM are ubiquitous and PNTM disease is rare, both host susceptibility and environmental factors must be considered in explaining disease development.
Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10
Authors: Joshua E. Allen, Varun V. Prabhu, Mala Talekar, A. Pieter J. van den Heuvel, Bora Lim, David T. Dicker, Jennifer L. Fritz, Adam Beck, Wafik S. El-Deiry
Journal: Cancer Research (2015)

Abstract ONC201/TIC10 is a small-molecule inducer of the TRAIL gene under current investigation as a novel anticancer agent. In this study, we identify critical molecular determinants of ONC201 sensitivity offering potential utility as pharmacodynamic or predictive response markers. By screening a library of kinase siRNAs in combination with a subcytotoxic dose of ONC201, we identified several kinases that ablated tumor cell sensitivity, including the MAPK pathway–inducer KSR1. Unexpectedly, KSR1 silencing did not affect MAPK signaling in the presence or absence of ONC201, but instead reduced expression of the antiapoptotic proteins FLIP, Mcl-1, Bcl-2, cIAP1, cIAP2, and survivin. In parallel to this work, we also conducted a synergy screen in which ONC201 was combined with approved small-molecule anticancer drugs. In multiple cancer cell populations, ONC201 synergized with diverse drug classes, including the multikinase inhibitor sorafenib. Notably, combining ONC201 and sorafenib led to synergistic induction of TRAIL and its receptor DR5 along with a potent induction of cell death. In a mouse xenograft model of hepatocellular carcinoma, we demonstrated that ONC201 and sorafenib cooperatively and safely triggered tumor regressions. Overall, our results established a set of determinants for ONC201 sensitivity that may predict therapeutic response, particularly in settings of sorafenib cotreatment to enhance anticancer responses. Cancer Res; 75(8); 1668–74. ©2015 AACR.
CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10–driven MARCH1-mediated ubiquitination and degradation
Authors: Lina E. Tze, Keisuke Horikawa, Heather Domaschenz, Debbie R. Howard, Carla M. Roots, Robert J. Rigby, David A. Way, Mari Ohmura-Hoshino, Satoshi Ishido, Christopher E. Andoniou, Mariapia A. Degli-Esposti, Christopher C. Goodnow
Journal: The Journal of Experimental Medicine (2011)

Effective vaccine adjuvants must induce expression of major histocompatibility (MHC) class II proteins and the costimulatory molecule CD86 on dendritic cells (DCs). However, some adjuvants elicit production of cytokines resulting in adverse inflammatory consequences. Development of agents that selectively increase MHC class II and CD86 expression without triggering unwanted cytokine production requires a better understanding of the molecular mechanisms influencing the production and degradation of MHC class II and CD86 in DCs. Here, we investigate how CD83, an immunoglobulin protein expressed on the surface of mature DCs, promotes MHC class II and CD86 expression. Using mice with an N-ethyl-N-nitrosourea-induced mutation eliminating the transmembrane (TM) region of CD83, we found that the TM domain of CD83 enhances MHC class II and CD86 expression by blocking MHC class II association with the ubiquitin ligase MARCH1. The TM region of CD83 blocks interleukin 10-driven, MARCH1-dependent ubiquitination and degradation of MHC class II and CD86 in DCs. Exploiting this posttranslational pathway for boosting MHC class II and CD86 expression on DCs may provide an opportunity to enhance the immunogenicity of vaccines.