tbuckley/cabot-search huggingface dataset:
Neonatal Bacille Calmette-Guerin Vaccination and Type 1 Diabetes
Authors: Marceline Huppmann, Andrea Baumgarten, Anette-G. Ziegler, Ezio Bonifacio
Journal: Diabetes Care (2005)

Type 1 diabetes is a genetic disorder that is associated with the early development of autoimmunity against islet β-cells (1). The a priori genetically determined risk for type 1 diabetes is modified by mostly unknown environmental factors that are thought to contribute to the increasing incidences of childhood diabetes in the last decade. Changes in exposure to environment are also discussed as a potential means to reduce the incidence of type 1 diabetes. Adjuvant therapy that includes vaccinations with agents such as Bacille Calmette-Guerin (BCG), for example, have been proposed as beneficial modifiers of the immune system that can reduce the incidence of autoimmune diabetes in animal models (2). In humans, there have also been sporadic reports of preserving β-cell function when BCG vaccination is administered soon after diabetes onset (3), and it has been suggested that BCG vaccination early in childhood could reduce the incidence of type 1 diabetes. Hence, there is substantial interest in whether immunostimulation with BCG could be used as a primary, secondary, or tertiary vaccination strategy for type 1 diabetes.

Vaccination with BCG in the first weeks after birth was practiced in Germany until 1998. Approximately 25% of children received vaccination, which was given as a single injection. Between 1989 and 2000, we recruited newborn children of parents with type 1 diabetes living in Germany into a prospective study (4) that examined the development of islet autoimmunity and type 1 diabetes. …
HMGB1 Is a Therapeutic Target for Sterile Inflammation and Infection
Authors: Ulf Andersson, Kevin J. Tracey
Journal: Annual Review of Immunology (2011)

A key question in immunology concerns how sterile injury activates innate immunity to mediate damaging inflammation in the absence of foreign invaders. The discovery that HMGB1, a ubiquitous nuclear protein, mediates the activation of innate immune responses led directly to the understanding that HMGB1 plays a critical role at the intersection of the host inflammatory response to sterile and infectious threat. HMGB1 is actively released by stimulation of the innate immune system with exogenous pathogen-derived molecules and is passively released by ischemia or cell injury in the absence of invasion. Established molecular mechanisms of HMGB1 binding and signaling through TLR4 reveal signaling pathways that mediate cytokine release and tissue damage. Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat.
The CXCL12 (SDF-1)/CXCR4 Axis Is Essential for the Development of Renal Vasculature
Authors: Yoshitsugu Takabatake, Tatsuki Sugiyama, Hiroshi Kohara, Taiji Matsusaka, Hidetake Kurihara, Pandelakis A. Koni, Yasuyuki Nagasawa, Takayuki Hamano, Isao Matsui, Noritaka Kawada, Enyu Imai, Takashi Nagasawa, Hiromi Rakugi, Yoshitaka Isaka
Journal: Journal of the American Society of Nephrology (2009)

CXC chemokine ligand 12 (CXCL12; stromal cell–derived factor 1) is a unique homeostatic chemokine that signals through its cognate receptor, CXCR4. CXCL12/CXCR4 signaling is essential for the formation of blood vessels in the gastrointestinal tract during development, but its contribution to renal development remains unclear. Here, we found that CXCL12-secreting stromal cells surround CXCR4-positive epithelial components of early nephrons and blood vessels in the embryonic kidney. In glomeruli, we observed CXCL12-secreting podocytes in close proximity to CXCR4-positive endothelial cells. Both CXCL12- and CXCR4-deficient kidneys exhibited identical phenotypes; there were no apparent abnormalities in early nephrogenesis or in differentiation of podocytes and tubules, but there was defective formation of blood vessels, including ballooning of the developing glomerular tuft and disorganized patterning of the renal vasculature. To clarify the relative importance of different cellular defects resulting from ablation of CXCL12 and CXCR4, we established endothelial cell–specific CXCR4-deficient mice, which recapitulated the renal phenotypes of conventional CXCR4-deficient mice. We conclude that CXCL12 secreted from stromal cells or podocytes acts on endothelial cells to regulate vascular development in the kidney. These findings suggest new potential therapeutic targets for remodeling the injured kidney.
Testing of Low-Risk Patients Presenting to the Emergency Department With Chest Pain
Authors: Ezra A. Amsterdam, J. Douglas Kirk, David A. Bluemke, Deborah Diercks, Michael E. Farkouh, J. Lee Garvey, Michael C. Kontos, James McCord, Todd D. Miller, Anthony Morise, L. Kristin Newby, Frederick L. Ruberg, Kristine Anne Scordo, Paul D. Thompson
Journal: Circulation (2010)

The management of low-risk patients presenting to emergency departments is a common and challenging clinical problem entailing 8 million emergency department visits annually. Although a majority of these patients do not have a life-threatening condition, the clinician must distinguish between those who require urgent treatment of a serious problem and those with more benign entities who do not require admission. Inadvertent discharge of patients with acute coronary syndrome from the emergency department is associated with increased mortality and liability, whereas inappropriate admission of patients without serious disease is neither indicated nor cost-effective. Clinical judgment and basic clinical tools (history, physical examination, and electrocardiogram) remain primary in meeting this challenge and affording early identification of low-risk patients with chest pain. Additionally, established and newer diagnostic methods have extended clinicians' diagnostic capacity in this setting. Low-risk patients presenting with chest pain are increasingly managed in chest pain units in which accelerated diagnostic protocols are performed, comprising serial electrocardiograms and cardiac injury markers to exclude acute coronary syndrome. Patients with negative findings usually complete the accelerated diagnostic protocol with a confirmatory test to exclude ischemia. This is typically an exercise treadmill test or a cardiac imaging study if the exercise treadmill test is not applicable. Rest myocardial perfusion imaging has assumed an important role in this setting. Computed tomography coronary angiography has also shown promise in this setting. A negative accelerated diagnostic protocol evaluation allows discharge, whereas patients with positive findings are admitted. This approach has been found to be safe, accurate, and cost-effective in low-risk patients presenting with chest pain.
shRNA Kinome Screen Identifies TBK1 as a Therapeutic Target for HER2+ Breast Cancer
Authors: Tao Deng, Jeff C. Liu, Philip E.D. Chung, David Uehling, Ahmed Aman, Babu Joseph, Troy Ketela, Zhe Jiang, Nathan F. Schachter, Robert Rottapel, Sean E. Egan, Rima Al-awar, Jason Moffat, Eldad Zacksenhaus
Journal: Cancer Research (2014)

Abstract HER2+ breast cancer is currently treated with chemotherapy plus anti-HER2 inhibitors. Many patients do not respond or relapse with aggressive metastatic disease. Therefore, there is an urgent need for new therapeutics that can target HER2+ breast cancer and potentiate the effect of anti-HER2 inhibitors, in particular those that can target tumor-initiating cells (TIC). Here, we show that MMTV-Her2/Neu mammary tumor cells cultured as nonadherent spheres or as adherent monolayer cells select for stabilizing mutations in p53 that “immortalize” the cultures and that, after serial passages, sphere conditions maintain TICs, whereas monolayer cells gradually lose these tumorigenic cells. Using tumorsphere formation as surrogate for TICs, we screened p53-mutant Her2/Neu+ tumorsphere versus monolayer cells with a lentivirus short hairpin RNA kinome library. We identified kinases such as the mitogen-activated protein kinase and the TGFβR protein family, previously implicated in HER2+ breast cancer, as well as autophagy factor ATG1/ULK1 and the noncanonical IκB kinase (IKK), TANK-binding kinase 1 (TBK1), which have not been previously linked to HER2+ breast cancer. Knockdown of TBK1 or pharmacologic inhibition of TBK1 and the related protein, IKKϵ, suppressed growth of both mouse and human HER2+ breast cancer cells. TBK1/IKKϵ inhibition promoted cellular senescence by suppressing p65–NF-κB and inducing p16Ink4a. In addition, TBK1/IKKϵ inhibition cooperated with lapatinib, a HER2/EGFR1–targeted drug, to accelerate apoptosis and kill HER2+ breast cancer cells both in culture and in xenografts. Our results suggest that patients with HER2+ breast cancer may benefit from anti-TBK1/IKKϵ plus anti-HER2 combination therapies and establish conditions that can be used to screen for additional TIC-specific inhibitors of HER2+ breast cancer. Cancer Res; 74(7); 2119–30. ©2014 AACR.
Pooled Analysis of the Prognostic and Predictive Effects of <i>KRAS</i> Mutation Status and <i>KRAS</i> Mutation Subtype in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy
Authors: Frances A. Shepherd, Caroline Domerg, Pierre Hainaut, Pasi A. Jänne, Jean-Pierre Pignon, Stephen Graziano, Jean-Yves Douillard, Elizabeth Brambilla, Thierry Le Chevalier, Lesley Seymour, Abderrahmane Bourredjem, Gwénaël Le Teuff, Robert Pirker, Martin Filipits, Rafael Rosell, Robert Kratzke, Bizhan Bandarchi, Xiaoli Ma, Marzia Capelletti, Jean-Charles Soria, Ming-Sound Tsao
Journal: Journal of Clinical Oncology (2013)

We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC).KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model.Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02).KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.
Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression
Authors: J. Jankowski, M. van der Giet, V. Jankowski, S. Schmidt, M. Hemeier, B. Mahn, G. Giebing, M. Tölle, H. Luftmann, H. Schlüter, W. Zidek, M. Tepel
Journal: Journal of Clinical Investigation (2003)

NO prevents atherogenesis and inflammation in vessel walls by inhibition of cell proliferation and cytokine-induced endothelial expression of adhesion molecules and proinflammatory cytokines. Reduced NO production due to inhibition of either eNOS or iNOS may therefore reinforce atherosclerosis. Patients with end-stage renal failure show markedly increased mortality due to atherosclerosis. In the present study we tested the hypothesis that uremic toxins are responsible for reduced iNOS expression. LPS-induced iNOS expression in mononuclear leukocytes was studied using real-time PCR. The iNOS expression was blocked by addition of plasma from patients with end-stage renal failure, whereas plasma from healthy controls had no effect. Hemofiltrate obtained from patients with end-stage renal failure was fractionated by chromatographic methods. The chromatographic procedures revealed a homogenous fraction that inhibits iNOS expression. Using gas chromatography/mass spectrometry, this inhibitor was identified as phenylacetic acid. Authentic phenylacetic acid inhibited iNOS expression in a dose-dependent manner. In healthy control subjects, plasma concentrations were below the detection level, whereas patients with end-stage renal failure had a phenylacetic acid concentration of 3.49 ± 0.33 mmol/l (n = 41). It is concluded that accumulation of phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression. That mechanism may contribute to increased atherosclerosis and cardiovascular morbidity in patients with end-stage renal failure.
Activation dependent apoptosis of peripheral blood mononuclear cells from patients with rheumatoid arthritis treated with methotrexate
Authors: J Swierkot
Journal: Annals of the Rheumatic Diseases (2004)

<h3>Introduction</h3> In clinical studies, delayed-release dimethyl fumarate (DMF) demonstrated a favorable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies enable char- acterization of risks that may emerge with long-term exposure in clinical practice. ESTEEM (NCT02047097) is an ongoing 5-year study characterizing real-world long-term safety and effectiveness of routinely pre- scribed DMF in MS patients. <h3>Methods</h3> Patients treated with DMF were recruited from ~380 sites. The primary objective was to determine incidence, type, and pattern of serious adverse events (SAEs), and AEs leading to DMF discontinuation. <h3>Results</h3> As of April 3, 2019, 5804 patients had ≥1 dose of DMF. SAEs were experienced by 245 (4.8%) patients, with infections (n=64; 1.3%) and nervous system disorders (n=35; &lt;1%) the most common. There were 1676 (33.0%) permanent treatment discontinuations. Annualized relapse rate over the period of up to 5 years was significantly lower than in the year prior to baseline (risk reduction 88.6% [95% confidence interval: 87.7–89.4]; P&lt;0.0001). <h3>Conclusions</h3> These results reveal low risk of SAE and beneficial therapeutic effects over up to 5 years of real-world DMF use. Updated safety and efficacy results for DMF patients in the United Kingdom will be presented. Support.Biogen. Disclosures: Included on the poster. Ben.newth@biogen.com
The Impact of Preconception Counseling on Pregnancy Outcomes: The experience of the Maine Diabetes in Pregnancy Program
Authors: M Beth Willhoite, Harry W Bennert, Glenn E Palomaki, Maryann M Zaremba, William H Herman, Josephine R Williams, Nona H Spear
Journal: Diabetes Care (1993)

To determine if a noncentralized, statewide program could be established to educate health-care providers and women with pregestational diabetes on available strategies to prevent adverse outcomes in pregnancies complicated by diabetes. Characteristics of women who participated in the program and the outcomes of their pregnancies are evaluated.A network of regional providers caring for pregnant women with diabetes was developed. Continuing education sessions were delivered to both providers and women with existing diabetes on the importance of preconception counseling.Maine health-care providers collaborated on the development and adoption of three patient-care guidelines that address preconception counseling, prenatal care, and contraception for women with established diabetes. A total of 185 pregnancies among 160 women with pregestational diabetes reporting estimated delivery dates between 1 January 1987 and 31 December 1990 were identified. Of the total pregnancies, 62 (34%) occurred in women who received preconception counseling: among these 62 pregnancies were one major congenital defect (1.6%) and four fetal or neonatal deaths (6.4%). Among the 123 (66%) pregnancies occurring in women that had not received preconception counseling, 8 (6.5%) infants were born with congenital abnormalities, and 26 (21.1%) fetal or neonatal deaths were documented.A program promoting preconception counseling can be implemented on a statewide basis by using various health-care providers to deliver the program. Participation in such a program appears to be related to improved pregnancy outcomes among women with pregestational diabetes.
Some of the 2009 American Joint Committee on Cancer Melanoma Staging and Classification Is Not Evidence Based
Authors: J. Meirion Thomas, Dirk C. Strauss, Andrew J. Hayes
Journal: Journal of Clinical Oncology (2010)

TO THE EDITOR: The recent publication of the 2009 American Joint Committee on Cancer melanoma staging and classification system 1 is a missed opportunity to define and link the role of micometastatic nodal disease, specifically tumor burden, to the biology and prognosis of patients with melanoma. Micrometastatic disease in this classificationsystemreferstoclinicallyoccult,nonpalpablemetastatic nodal disease diagnosed at sentinel node biopsy; therefore, by definition, this includes a wide spectrum of tumor burden. At one extreme arepatientswhohavesolitarymelanomacellsinthesubcapsularsinus of the sentinel node (which may be of no adverse prognostic significance); at the other extreme (and especially in obese patients), there may be one or two enlarged metastatic lymph nodes that measure 1
IDENTIFICATION OF HUMAN B AND T LYMPHOCYTES BY SCANNING ELECTRON MICROSCOPY
Authors: A. Polliack, N. Lampen, B. D. Clarkson, E. de Harven, Z. Bentwich, F. P. Siegal, H. G. Kunkel
Journal: The Journal of Experimental Medicine (1973)

In this study a variety of human lymphocytes of known B or T cell type, obtained from multiple sources, were prepared for scanning electron microscopy (SEM) by the critical point drying method. Distinction between normal B and T lymphocytes was relatively easy in most instances, on the basis of their surface architecture. Using immunological methods, between 20 and 30% of normal peripheral blood lymphocytes (PBL) were identified as B cells and from 69 to 82% as T cells. SEM results showed that 20% of the PBL had a complex villous surface and approximately 80% of cells were smaller and had a relatively smooth surface. Comparison of the above data and enrichment of B cells from PBL, by centrifugation after T cell rosettes had formed, indicated that the "villous" cells were B lymphocytes and the "relatively smooth" cells were T lymphocytes. T cells obtained from two human thymuses were also of the generally smooth cell type. Further evidence for the distinction of B and T lymphocytes, on the basis of surface morphology, was obtained from the examination of cultured lymphoid cell lines of known B or T cell derivation. Cells from cases of chronic lymphocytic leukemia also provided support for the above interpretations. Five of six untreated cases were clearly of B cell type by immunologic and SEM criteria. One unusual case showed the presence of T and B lymphocytes in almost equal numbers by SEM and a mixture of B and T cells by immunologic markers. An additional case that had received chemotherapy showed numerous atypical cells that were difficult to classify by SEM. Detailed examination of the smoother T cells showed that at least half of them had a moderate number of surface digitations and a small proportion had an intermediate surface morphology with a relatively large number of surface digitations. The latter presented difficulties in classification and may correspond to different stages of differentiation and represent subpopulations of lymphocytes. The distinction between human B and T lymphocytes on the basis of their surface architecture can be made by SEM of critical point dried samples, with relative ease in most but not all instances. The effects of stimulation, cell cycle, differentiation, intercellular contact, and density of cell population, on the surface architecture of lymphoid cells, remain to be determined.
Stat5b Is Essential for Natural Killer Cell–mediated Proliferation and Cytolytic Activity
Authors: Kazunori Imada, Eda T. Bloom, Hiroshi Nakajima, Judith A. Horvath-Arcidiacono, Garry B. Udy, Helen W. Davey, Warren J. Leonard
Journal: The Journal of Experimental Medicine (1998)

We have analyzed the immune system in Stat5-deficient mice. Although Stat5a−/− splenocytes have a partial defect in anti-CD3-induced proliferation that can be overcome by high dose interleukin (IL)-2, we now demonstrate that defective proliferation in Stat5b−/− splenocytes cannot be corrected by this treatment. Interestingly, this finding may be at least partially explained by diminished expression of the IL-2 receptor β chain (IL-2Rβ), which is a component of the receptors for both IL-2 and IL-15, although other defects may also exist. Similar to the defect in proliferation in activated splenocytes, freshly isolated splenocytes from Stat5b−/− mice exhibited greatly diminished proliferation in response to IL-2 and IL-15. This results from both a decrease in the number and responsiveness of natural killer (NK) cells. Corresponding to the diminished proliferation, basal as well as IL-2– and IL-15–mediated boosting of NK cytolytic activity was also greatly diminished. These data indicate an essential nonredundant role for Stat5b for potent NK cell–mediated proliferation and cytolytic activity.
A Micro-Colony-Inhibition Method for Quantitation of Tumor Immunity 2
Authors: J. Stephen Haskill
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article A Micro-Colony-Inhibition Method for Quantitation of Tumor Immunity Get access J. Stephen Haskill J. Stephen Haskill Department of Pathology, Queen's University, Kingston, Ontario Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 51, Issue 5, November 1973, Pages 1581–1588, https://doi.org/10.1093/jnci/51.5.1581 Published: 01 November 1973 Article history Received: 25 April 1973 Accepted: 05 July 1973 Published: 01 November 1973
L-triiodothyronine stimulates growth by means of an autocrine factor in a cultured growth-hormone-producing cell line.
Authors: M J Miller, E C Fels, L E Shapiro, M I Surks
Journal: Journal of Clinical Investigation (1987)

L-Triiodothyronine (T3) stimulates DNA synthesis and replication of cultured GC cells, a T3-responsive growth hormone (GH)-secreting cell line. To determine whether T3 stimulates secretion of an autocrine growth factor, we compared the growth-promoting activity of medium conditioned by T3-stimulated and T3-depleted cells to that of unconditioned medium. Addition of polyclonal rabbit anti-T3 serum to T3-containing media decreased cellular T3 content by 50-70%. In unconditioned medium, anti-T3 serum decreased T3-induced cell growth and GH production by 40-70%. In conditioned medium, anti-T3 serum also effected a 45-70% decrease in induction of GH secretion but did not attenuate the growth-promoting activity. Growth-promoting activity was not detected in medium conditioned by T3-depleted cells. Thus, conditioned medium from T3-containing GC cell cultures contains growth-promoting activity that is independent of T3. Further, the induction of GC cel growth by T3 may occur, at least in part, by induction of an autocrine growth factor.