tbuckley/cabot-search huggingface dataset:
Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness
Authors: Paul R. Mittelstadt, João P. Monteiro, Jonathan D. Ashwell
Journal: Journal of Clinical Investigation (2012)

Generation of a self-tolerant but antigen-responsive T cell repertoire occurs in the thymus. Although glucocorticoids are usually considered immunosuppressive, there is also evidence that they play a positive role in thymocyte selection. To address the question of how endogenous glucocorticoids might influence the adaptive immune response, we generated GRlck-Cre mice, in which the glucocorticoid receptor gene (GR) is deleted in thymocytes prior to selection. These mice were immunocompromised, with reduced polyclonal T cell proliferative responses to alloantigen, defined peptide antigens, and viral infection. This was not due to an intrinsic proliferation defect, because GR-deficient T cells responded normally when the TCR was cross-linked with antibodies or when the T cell repertoire was "fixed" with αβ TCR transgenes. Varying the affinity of self ligands in αβ TCR transgenic mice showed that affinities that would normally lead to thymocyte-positive selection caused negative selection, and alterations in the TCR repertoire of polyclonal T cells were confirmed by analysis of TCR Vβ CDR3 regions. Thus, endogenous glucocorticoids are required for a robust adaptive immune response because of their promotion of the selection of T cells that have sufficient affinity for self, and the absence of thymocyte glucocorticoid signaling results in an immunocompromised state.
Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung
Authors: Emily E. Thornton, Mark R. Looney, Oishee Bose, Debasish Sen, Dean Sheppard, Richard Locksley, Xiaozhu Huang, Matthew F. Krummel
Journal: The Journal of Experimental Medicine (2012)

Asthma pathogenesis is focused around conducting airways. The reasons for this focus have been unclear because it has not been possible to track the sites and timing of antigen uptake or subsequent antigen presentation to effector T cells. In this study, we use two-photon microscopy of the lung parenchyma and note accumulation of CD11b+ dendritic cells (DCs) around the airway after allergen challenge but very limited access of these airway-adjacent DCs to the contents of the airspace. In contrast, we observed prevalent transepithelial uptake of particulate antigens by alveolar DCs. These distinct sites are temporally linked, as early antigen uptake in alveoli gives rise to DC and antigen retention in the airway-adjacent region. Antigen-specific T cells also accumulate in the airway-adjacent region after allergen challenge and are activated by the accumulated DCs. Thus, we propose that later airway hyperreactivity results from selective retention of allergen-presenting DCs and antigen-specific T cells in airway-adjacent interaction zones, not from variation in the abilities of individual DCs to survey the lung.
A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American Brain Tumor Consortium study1
Authors: Michael D. Prados, Kathleen Lamborn, W.K.A. Yung, Kurt Jaeckle, H. Ian Robins, Minesh Mehta, Howard A. Fine, Patrick Y. Wen, Timothy Cloughesy, Susan Chang, M. Kelly Nicholas, David Schiff, Harry Greenberg, Larry Junck, Karen Fink, Ken Hess, John Kuhn
Journal: Neuro-Oncology (2006)

The purpose of this study was to determine the response to CPT-11 administered every three weeks to adults with progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m2 i.v. every three weeks in patients not on EIAED and 750 mg/m2 in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42 years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07-0.31) for the GBM patients and 23% (95% CI, 0.07-0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population.
A Combined Epigenetic Therapy Equals the Efficacy of Conventional Chemotherapy in Refractory Advanced Non–Small Cell Lung Cancer
Authors: Manuel Rodríguez-Paredes, Manel Esteller
Journal: Cancer Discovery (2011)

A new study by Juergens and colleagues provides the first successful example of a combined epigenetic therapy capable of achieving results similar to those of conventional chemotherapy in refractory metastatic non-small cell lung cancer. Furthermore, the authors describe interesting blood-based DNA methylation biomarkers that may be useful in predicting clinical response.
Immunocytochemical localization of sodium-calcium exchanger in canine nephron.
Authors: J E Bourdeau, A N Taylor, A M Iacopino
Journal: Journal of the American Society of Nephrology (1993)

The sodium-calcium exchanger was localized in tissue sections of canine kidneys with two different polyclonal antisera raised against purified sodium-calcium exchanger protein derived from dog cardiac sarcolemma. The sodium-calcium exchanger was prominent in the basolateral plasmalemma of the majority of cells in all connecting tubules. In contrast, it was observed rarely and inconspicuously over the basolateral aspects of proximal tubular cells. The sodium-calcium exchanger was undetectable in all other portions of the nephron.
No Racial Differences in the Association of Glycated Hemoglobin With Kidney Disease and Cardiovascular Outcomes
Authors: Elizabeth Selvin, Andreea M. Rawlings, Richard M. Bergenstal, Josef Coresh, Frederick L. Brancati
Journal: Diabetes Care (2013)

There is debate regarding the clinical significance of well-established racial differences in HbA1c. We compared the associations of diabetes diagnostic categories for HbA1c and fasting glucose with clinical outcomes in black and white persons in the community.We conducted a prospective cohort analysis of participants without diabetes or cardiovascular disease from the Atherosclerosis Risk in Communities study. We examined the associations of clinical categories of HbA1c (<5.7%, 5.7-6.4%, ≥6.5%) and fasting glucose (<100, 100-125, ≥126 mg/dL) with outcomes separately among 2,484 black and 8,593 white participants and tested for race interactions.Baseline characteristics differed significantly in blacks compared with whites, including HbA1c (5.8 vs. 5.4%; P<0.001). During 18 years of follow-up, there were trends of increased risk of kidney disease, fatal and nonfatal coronary heart disease, and stroke across categories of HbA1c in both blacks and whites. The adjusted hazard ratios for each outcome across categories of HbA1c were similar in blacks and whites (P for interaction>0.05) except for all-cause mortality. Patterns of association were similar, but weaker, for fasting glucose. HbA1c and fasting glucose both were more strongly associated with all-cause mortality in whites compared with blacks, largely explained by racial differences in the rate of cardiovascular deaths.HbA1c is a risk factor for vascular outcomes and mortality in both black and white adults. Patterns of association for HbA1c were similar to or stronger than those for fasting glucose. With respect to long-term outcomes, our findings support a similar interpretation of HbA1c in blacks and whites for diagnosis and treatment of diabetes mellitus.
Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1β Inhibition
Authors: Raphaela Goldbach-Mansky, Natalie J. Dailey, Scott W. Canna, Ana Gelabert, Janet Jones, Benjamin I. Rubin, H. Jeffrey Kim, Carmen Brewer, Christopher Zalewski, Edythe Wiggs, Suvimol Hill, Maria L. Turner, Barbara I. Karp, Ivona Aksentijevich, Frank Pucino, Scott R. Penzak, Margje H. Haverkamp, Leonard Stein, Barbara S. Adams, Terry L. Moore, Robert C. Fuhlbrigge, Bracha Shaham, James N. Jarvis, Kathleen O'Neil, Richard K. Vehe, Laurie O. Beitz, Gregory Gardner, William P. Hannan, Robert W. Warren, William Horn, Joe L. Cole, Scott M. Paul, Philip N. Hawkins, Tuyet Hang Pham, Christopher Snyder, Robert A. Wesley, Steven C. Hoffmann, Steven M. Holland, John A. Butman, Daniel L. Kastner
Journal: New England Journal of Medicine (2006)

Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.
Factors of improvement of dyspnoea, exercise capacity, and quality of life in COPD patients undergoing an outpatient pulmonary rehabilitation
Authors: Marie-Cécile Fournier, Thomas Lesuffleur, Alexandre Touvron, Michel Cabillic, Arnaud Cavailles, Jean-Benoit Hardouin, Arnaud Chambellan
Journal: European Respiratory Journal (2013)

Pulmonary rehabilitation (PR) represents the optimal way to improve COPD patients, but inclusion criteria of success remain challenging.  Aim: to identify factors of improvement of patients at the beginning of an outpatient PR.  Methods: 94 consecutive COPD patients were included. After complete assessment, they underwent a 3 week’s physical training and therapeutic education at the hospital. This was followed by 20 physical sessions supervised by the patient’s physiotherapist. The patients were evaluated at 6 months and one year. The logistic regression was used to identify the independent predictors of success to PR, defined by the MCID for dyspnoea (mMRC scale), the 6 minute walk distance (6MWD), and the Saint George’s Respiratory Questionnaire (SGRQ) total score at baseline.  Results: Patients who improve the mMRC scale had a higher level of dyspnoea (OR=4.92, 2.35 to 10.32 CI 95%), were treated by tiotropium (OR=6.43, 1.71 to 24.10), were not frequent exacerbators (OR=4.04, 1.27 to 12.88), and reached a higher VO2max (OR=1.09, 1.04 to 1.15). The only variable identified for 6MWD improvement was not to live alone (OR=9.19, 1.16 to 73.02). Patients who improve the SGRQ score had a higher FEV1 (OR=1.06, 1.01 to 1.11), a higher level of dyspnoea (OR=2.12, 1.05 to 4.28), a worse SGRQ score (OR=1.11, 1.04 to 1.18), a lower CRP (OR=4.07, 1.15 to 14.39), and were more prone to have a 6MWD>350 m (OR=9.72, 1.92 to 49.24).  Conclusion: Predictors of improvement in COPD patients undergoing an outpatient PR differ from each dimension. They should be evaluated separately with the patient9s perspectives to better define the components of success to PR.
Humanized Anti-Trop-2 IgG-SN-38 Conjugate for Effective Treatment of Diverse Epithelial Cancers: Preclinical Studies in Human Cancer Xenograft Models and Monkeys
Authors: Thomas M. Cardillo, Serengulam V. Govindan, Robert M. Sharkey, Preeti Trisal, David M. Goldenberg
Journal: Clinical Cancer Research (2011)

Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans.
OBSERVATIONS ON TWENTY-THREE CASES OF CARCINOMA OF THE BLADDER TREATED BY RADIUM
Authors: A. C. Morson
Journal: BMJ (1929)

TEDl. rTos wlhetlher these niecrotic foci are really due to a mixed in- fecotion withl the tubercle bacillus, or whether there is in lynsj)hadenoma a type of " caseation " similar in certain aspects bu-t differing in others.This latter view is of iml)ortance since, if this is so, the anialogy with other in- fective granulonata like syphilis, tubercle, and actino- mycosis becomes, more str ikiing, for ini all these conditions we have alteration of the normal structures by endothelial and lymphoid tissuie with the presence of giant cells, followed later on by " caseatioI " and by sclerosis.The followinig case of coexistent Hodgkin's disease and tuber culosis is of intelrest since these necrotic foci were presenit in the glanids.A man, aged 30, was admitted under the care of one of us ii4 the General Hospital, Madras, on August 28th, 1927, with a history of enlargement of the glands in the neck, pectoral region, and axilla of five months' duration.He was sent to the surgical
Depression, Self-Care, and Medication Adherence in Type 2 Diabetes
Authors: Jeffrey S. Gonzalez, Steven A. Safren, Enrico Cagliero, Deborah J. Wexler, Linda Delahanty, Eve Wittenberg, Mark A. Blais, James B. Meigs, Richard W. Grant
Journal: Diabetes Care (2007)

We examined the association between depression, measured as either a continuous symptom severity score or a clinical disorder variable, with self-care behaviors in type 2 diabetes.We surveyed 879 type 2 diabetic patients from two primary care clinics using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), the Summary of Diabetes Self-Care Activities, and self-reported medication adherence.Of the patients, 19% met the criteria for probable major depression (HANDS score >or=9), and an additional 66.5% reported at least some depressive symptoms. After controlling for covariates, patients with probable major depression reported significantly fewer days' adherent to diet, exercise, and glucose self-monitoring regimens (P < 0.01) and 2.3-fold increased odds of missing medication doses in the previous week (95% CI 1.5-3.6, P < 0.001) compared with all other respondents. Continuous depressive symptom severity scores were better predictors of nonadherence to diet, exercise, and medications than categorically defined probable major depression. Major depression was a better predictor of glucose monitoring. Among the two-thirds of patients not meeting the criteria for major depression (HANDS score <9, n = 709), increasing HANDS scores were incrementally associated with poorer self-care behaviors (P < 0.01).These findings challenge the conceptualization of depression as a categorical risk factor for nonadherence and suggest that even low levels of depressive symptomatology are associated with nonadherence to important aspects of diabetes self-care. Interventions aimed at alleviating depressive symptoms, which are quite common, could result in significant improvements in diabetes self-care.
Beyond the Signal Sequence: Protein Routing in Health and Disease
Authors: Cecilia Castro-Fernández, Guadalupe Maya-Núñez, P. Michael Conn
Journal: Endocrine Reviews (2004)

Receptors, hormones, enzymes, ion channels, and structural components of the cell are created by the act of protein synthesis. Synthesis alone is insufficient for proper function, of course; for a cell to operate effectively, its components must be correctly compartmentalized. The mechanism by which proteins maintain the fidelity of localization warrants attention in light of the large number of different molecules that must be routed to distinct subcellular loci, the potential for error, and resultant disease. This review summarizes diseases known to have etiologies based on defective protein folding or failure of the cell's quality control apparatus and presents approaches for therapeutic intervention.
The Role of the WNT inhibitor sclerostin in rheumatoid arthritis
Authors: C Wehmeyer, A Stratis, T Pap, B Dankbar
Journal: Annals of the Rheumatic Diseases (2010)

Joints affected by rheumatoid arthritis (RA) display signs of bone resorption and usually lack signs of repair which contributes to rapid and progressive loss of joint structures. Sclerostin is a potent inhibitor of osteoblast development by antagonising the Wnt/β-catenin signalling pathway, a key regulator of bone turnover. Since it has been shown that sclerostin is expressed under inflammatory conditions, we analysed the …
New Strategies in Breast Cancer: The Significance of Molecular Subtypes in Systemic Adjuvant Treatment for Small T1a,bN0M0 Tumors
Authors: Amir Sonnenblick, Debora Fumagalli, Hatem A. Azim, Christos Sotiriou, Martine Piccart
Journal: Clinical Cancer Research (2014)

Awareness of breast cancer heterogeneity has strikingly increased in the past decade in parallel with the development of high-throughput molecular tests. Beyond the clear usefulness of antiestrogen treatment in luminal tumors and trastuzumab in HER2-positive tumors, breast cancer subtypes may have additional clinical and predictive roles that can be relevant to clinical practice. In this article, we discuss the significance of molecular subtypes in the systemic treatment of early-stage breast tumors smaller than 1 cm (T1a,bN0M0) and suggest new strategies for future treatment recommendations for these patients.
P963 SINGLE HCC ≤3cm IN LEFT LATERAL SEGMENT: LIVER RESECTION OR RADIOFREQUENCY ABLATION?
Authors: J.M. Kim, T.W. Kang, J.Y. Choi, S. Lee, W. Cho, C.H.D. Kwon, H. Rhim, J.H. Lee, S.W. Paik, J.-W. Joh
Journal: Journal of Hepatology (2014)
Comparison of bronchial challenge with ultrasonic nebulized distilled water and hypertonic saline in children with mild-to-moderate asthma
Authors: C Wojnarowski, K Storm Van's Gravesande, J Riedler, I Eichler, C Gartner, T Frischer
Journal: European Respiratory Journal (1996)

There is still controversy about the most suitable method to measure bronchial hyperresponsiveness in children. In epidemiological surveys, nonisotonic aerosols are being used increasingly for bronchial provocation testing. Our aim was to study the acceptability, safety and correlation between two published bronchial challenge tests. Two standardized protocols--the inhalation of hypertonic saline (HS) and ultrasonically-nebulized distilled water (UNDW)--were performed in 36 children: 19 patients with the clinical diagnosis of mild-to-moderate asthma (7-12 yrs of age), and 17 control subjects (8-18 yrs of age). HS challenge involved stepwise inhalation of 4.5% saline (for 0.5, 1, 2, 4 and 8 min), whereas challenge with UNDW was performed as a single step protocol with 10 min inhalation of cold UNDW. Asthma medication was withheld prior to challenge testing. Thirty five subjects completed both challenge tests (one asthmatic patient did not return after UNDW challenge) in random order within a 7 day time interval. For HS a &gt; or = 15% reduction in forced expiratory volume in one second (FEV1) from baseline was considered a positive response, and for UNDW a &gt; or = 10% decrease. In 13 of the 19 asthmatic patients, but in none of the controls, a positive response was observed for UNDW. Fifteen out of 18 patients and one control subject had a positive response to HS. Twelve out of 18 asthmatic children responded to both challenges, three responded only to HS and three had no response to either challenge. There was a negative correlation between log provocative dose causing a 15% reduction in FEV1 (PD15) after HS and the maximum fall in FEV1 after UNDW (rs = -0.63; p &lt; 0.005). The HS challenge had a lower acceptability than challenge with UNDW due to the unpleasant salty taste of HS. However, this did not inhibit the completion of the tests in any subject. The results of this study suggest a good correlation between response to hypertonic saline and ultrasonically-nebulized distilled water in children with mild-to-moderate asthma. A multiple step protocol might be safer when applied in field studies involving children.
ERS is founding member of a new Alliance for Biomedical Research in Europe
Authors: L.P. Nicod, N. Kamel, B. Ward, M. Decramer, Y. Sibille, B. Lambrecht, C. Dive, U. Smith, K.R. Sipido
Journal: European Respiratory Journal (2011)

The Alliance for Biomedical Research in Europe (BioMed Alliance) was founded on December 9, 2010 by the four leading European medical academic societies: the European Association for the Study of Diabetes (EASD), the European Society of Cardiology (ESC), the European Respiratory Society (ERS) and the European CanCer Organisation (ECCO)...
Nodular localized cutaneous amyloidosis: detection of monoclonality of infiltrating plasma cells by polymerase chain reaction
Authors: Y. HAGARI, M. MIHARA, S. HAGARI
Journal: British Journal of Dermatology (1996)

We report nodular localized cutaneous amyloidosis arising in a 74-year-old woman as a single nodule at the left angle of the mouth. Histological examination revealed eosinophilic material deposited in the dermis, identified as amyloid by staining with Dylon stain, and antiamyloid P component, and by electron microscopy. The amyloid material was further determined immunohistochemically to be of AL fibril protein type derived from lambda light chains. Infiltrating plasma cells, around blood vessels in the dermis, stained monotypically with anti-lambda antibody, suggesting plasma cell monoclonality. Semi-nested polymerase chain reaction (PCR), for rearrangement of immunoglobulin heavy chain gene using paraffin-embedded sections, yielded two distinct amplified bands, indicating monoclonality of the infiltrating plasma cells. These findings support the hypothesis that primary localized nodular amyloidosis involves local accumulation of monoclonal plasma cells and their secreted products. The two amplified bands observed on PCR may, in the present case, reflect abnormal secretion of immunoglobulin light chains.
Insulin-Like Growth Factor Binding Protein-2 Is a Novel Therapeutic Target Associated with Breast Cancer
Authors: Alan I. So, Randy J. Levitt, Bernhard Eigl, Ladan Fazli, Motosugu Muramaki, Sam Leung, Maggie C.U. Cheang, Torsten O. Nielsen, Martin Gleave, Michael Pollak
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Insulin-like growth factor (IGF) binding proteins (IGFBP) modulate interactions of IGF ligands with the IGF-I receptor. The role of IGFBPs, and specifically IGFBP-2, in breast cancer progression has been poorly defined. This study assesses the effect of IGFBP-2 on the behavior of human breast cancer using clinical specimens as well as in vitro and in vivo experimental systems. Experimental Design: 4,181 primary invasive breast cancers and 120 benign breast tissue samples were identified for tumor tissue microarray construction and immunostained with IGFBP-2 antibody. Estrogen receptor-negative MDA-MB-231 cells constitutively overexpressing IGFBP-2 (MDA-MB-231BP-2) were created to assess the effect of IGFBP-2 gain-of-function. MDA-MB-468 cells, naturally expressing IGFBP-2, were used to determine the effect of IGFBP-2 loss-of-function using OGX-225, an antisense oligonucleotide drug candidate. Results: IGFBP-2 expression was significantly higher in breast cancer tissue compared with benign breast tissue. MDA-MB-231BP-2 cells grew more rapidly and were more resistant to paclitaxel both in vitro and in vivo compared with parental cells. OGX-225 decreased IGFBP-2 expression and attenuated the associated aggressive phenotype of MDA-MB-231BP-2 cells both in vitro and in vivo. Furthermore, OGX-225 inhibited the in vitro and in vivo growth of MDA-MB-468 cells. Conclusions: This study provides evidence that IGFBP-2 expression is associated with breast cancer. Novel therapeutics targeting IGFBP-2, such as OGX-225, merit further evaluation.