tbuckley/cabot-search huggingface dataset:
Low avidity antibodies to dsDNA as a diagnostic tool.
Authors: J.C Nossent, V Huysen, R.J Smeenk, A.J Swaak
Journal: Annals of the Rheumatic Diseases (1989)

An evaluation of the diagnostic value of low avidity antibodies to double stranded DNA (dsDNA) measured by the polyethylene glycol (PEG) assay was undertaken. By routine screening low avidity anti-dsDNA were detected in the serum samples of 106 hitherto unknown patients. Clinical data of these patients were collected and when only low avidity anti-dsDNA was present (n = 92) a varied disease spectrum was observed. A diagnosis of systemic lupus erythematosus (SLE) was established in 48/92 (52%), lupus-like disease in 21/92 (23%), autoimmune hepatitis in 9/92 (10%), rheumatoid arthritis in 8/92 (9%), and mixed connective tissue disease in 2/92 (2%) of all patients. Patients with definite SLE were all older than 45 years and predominantly female (46/48, 96%). They showed a remarkably low incidence of renal disease (2/69, 3%). When high avidity antibodies to dsDNA as measured by the Farr assay were present as well (n = 14) a diagnosis of SLE could be established in 12/14 (86%) of all patients, indicating the secondary importance of low avidity anti-dsDNA in these patients.
Epigenetics Meets Genetics in Acute Myeloid Leukemia: Clinical Impact of a Novel Seven-Gene Score
Authors: Guido Marcucci, Pearlly Yan, Kati Maharry, David Frankhouser, Deedra Nicolet, Klaus H. Metzeler, Jessica Kohlschmidt, Krzysztof Mrózek, Yue-Zhong Wu, Donna Bucci, John P. Curfman, Susan P. Whitman, Ann-Kathrin Eisfeld, Jason H. Mendler, Sebastian Schwind, Heiko Becker, Constance Bär, Andrew J. Carroll, Maria R. Baer, Meir Wetzler, Thomas H. Carter, Bayard L. Powell, Jonathan E. Kolitz, John C. Byrd, Christoph Plass, Ramiro Garzon, Michael A. Caligiuri, Richard M. Stone, Stefano Volinia, Ralf Bundschuh, Clara D. Bloomfield
Journal: Journal of Clinical Oncology (2013)

Molecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML.Next-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older (≥ 60 years) cytogenetically normal (CN) patients with AML (n = 134). Genes with promoter DMRs and expression levels significantly associated with outcome were used to compute a prognostic gene expression weighted summary score that was tested and validated in four independent patient sets (n = 355).In the training set, we identified seven genes (CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8) with promoter DMRs and expression associated with overall survival (OS; P ≤ .001). Each gene had high DMR methylation and lower expression, which were associated with better outcome. A weighted summary expression score of the seven gene expression levels was computed. A low score was associated with a higher complete remission (CR) rate and longer disease-free survival and OS (P < .001 for all end points). This was validated in multivariable models and in two younger (< 60 years) and two older independent sets of patients with CN-AML. Considering the seven genes individually, the fewer the genes with high expression, the better the outcome. Younger and older patients with no genes or one gene with high expression had the best outcomes (CR rate, 94% and 87%, respectively; 3-year OS, 80% and 42%, respectively).A seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance.
Psychological Stress May Induce Diabetes-Related Autoimmunity in Infancy
Authors: Anneli Sepa, Jeanette Wahlberg, Outi Vaarala, Ann Frodi, Johnny Ludvigsson
Journal: Diabetes Care (2005)

OBJECTIVE— In retrospective studies, a number of disparate environmental factors (including experiences of serious life events) have been proposed as trigger mechanisms for type 1 diabetes or the autoimmune process behind the disease. Psychosocial stress in families may affect children negatively due to a link to hormonal levels and nervous signals that in turn influence both insulin sensitivity/insulin need and the immune system. Our aim was to investigate whether psychological stress, measured as psychosocial strain in families, is associated with diabetes-related autoimmunity during infancy. RESEARCH DESIGN AND METHODS— The first 4,400 consecutive 1-year-old children from a large prospective population-based project participated in the study. Parents completed questionnaires at birth and at 1 year, including various measures of psychosocial stress (e.g., parenting stress) and sociodemographic background. Blood samples drawn from the children at 1 year were analyzed for type 1 diabetes–associated autoantibodies toward tyrosine phosphatase and GAD. Antibodies toward tetanus toxoid were used as non–diabetes-related control antibodies. RESULTS— Psychosocial factors, i.e., high parenting stress (odds ratio 1.8 [95% CI 1.2–2.9], P &amp;lt; 0.01), experiences of a serious life event (2.3 [1.3–4.0], P &amp;lt; 0.01), foreign origin of the mother (2.1 [1.3–3.3], P &amp;lt; 0.001), and low paternal education (1.6 [1.1–2.3], P &amp;lt; 0.01) were associated with diabetes-related autoimmunity in the child, independent of family history of diabetes. CONCLUSIONS— Psychological stress, measured as psychosocial strain in the family, seems to be involved in the induction, or progression, of diabetes-related autoimmunity in the child during the 1st year of life.
Effect of bortezomib on human neuroblastoma: analysis of molecular mechanisms involved in cytotoxicity
Authors: Valérie Combaret, Sandrine Boyault, Isabelle Iacono, Stéphanie Brejon, Raphaël Rousseau, Alain Puisieux
Journal: Molecular Cancer (2008)

Bortezomib, a specific and selective inhibitor of the 26S proteasome with antitumor activity against a wide range of malignancies, has been approved for the treatment of relapsed or refractory multiple myeloma and other cancers. Recently, bortezomib has been identified as an effective inhibitor of neuroblastoma cell growth and angiogenesis. In the present study, we demonstrate that some neuroblastoma cell lines are actually resistant to bortezomib. We have sought to characterize the main pathway by which proteasome inhibition leads to apoptosis, and to define the mechanism responsible for resistance to bortezomib in neuroblastoma cells. Our results show that SB202190, an inhibitor of mitogen-activated protein kinase (MAPK) p38, enhances the ability of bortezomib to induce apoptosis by preventing the phosphorylation of the heat shock protein (HSP) 27. This study opens the way to further clinical investigations and suggests a potential benefit of using a combination of bortezomib with an inhibitor of p38 MAPK for the treatment of neuroblastoma relapse.
Parotid lipomatosis in HIV positive patients: a new clinical disorder associated with protease inhibitors
Authors: A. OLIVE, A. SALAVERT, M. MANRIQUEZ, B. CLOTET, A. MORAGAS
Journal: Annals of the Rheumatic Diseases (1998)

Protease inhibitors (PI) are a major advance in the treatment of HIV-1 infection. However, side effects of these drugs occur frequently.1 Abnormal fat accumulation in patients infected with HIV-1 has been described after starting treatment with PI.2 There might be several clinical disorders associated with fat deposition, namely increasing abdominal girth, abnormal dorsal cervical fat (“buffalo hump”), and hypertrophy of the breast.2-4 We report two cases of parotid fatty deposition associated with with retroviral treatment.

case 1 A 54 year old heterosexual man with asymptomatic HIV infection of seven years duration was referred with a two year history of painless growing bilateral parotid swelling. He complained of dry mouth but not dry eyes. In June 1995 he was taking zidovudine (1200 mg twice daily). From January 1996 he …
IL-33 is a mediator rather than a trigger of the acute allergic response in humans
Authors: M. Fux, T. Pecaric-Petkovic, A. Odermatt, O. V. Hausmann, A. Lorentz, S. C. Bischoff, J. C. Virchow, C. A. Dahinden
Journal: Allergy (2013)

Background IL-33 enhances FcεRI-induced mediator release in human basophils without inducing degranulation itself. In contrast, studies in mice suggested that in the presence of high IgE levels, IL-33 triggers degranulation and anaphylaxis of similar severity as specific allergen. Consistent with this view, sera of atopic patients contain elevated levels of IL-33 after anaphylaxis. In this study, we determined whether IL-33 is potentially anaphylactogenic in humans with high IgE levels by regulating exocytosis independent of FcεRI cross-linking. Furthermore, we investigated whether IL-33 is released upon allergen provocation in vivo. Methods In subjects with high serum IgE levels, we measured IL-33-induced histamine/LTC4 in vitro, CD63 translocation ex vivo, and responsiveness of mast cells in vivo by skin prick test (SPT). In asthma patients, release of IL-33 and its correlation with early (tryptase)- and late-phase markers (IL-13 levels, eosinophil numbers) of the allergic response were assessed in bronchoalveolar lavage fluids (BALFs) after allergen challenge. Results IL-33 itself does not trigger basophil degranulation in vitro and ex vivo, even in subjects with high serum IgE levels, and negative SPTs demonstrate that skin mast cells do not degranulate in response to IL-33. However, in response to allergen challenge, IL-33 is rapidly released into BALFs at levels that do not correlate with other immediate- and late-phase parameters. Conclusion IL-33 is unlikely an independent trigger of anaphylaxis even in subjects with high IgE levels. However, the rapid release of IL-33 upon allergen provocation in vivo supports its role as a mediator of immediate allergic responses.
Type III IFN Interleukin-28 Mediates the Antitumor Efficacy of Oncolytic Virus VSV in Immune-Competent Mouse Models of Cancer
Authors: Phonphimon Wongthida, Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Jill Thompson, Jose Pulido, Kevin Pavelko, Larry Pease, Alan Melcher, Richard Vile
Journal: Cancer Research (2010)

Abstract Innate immune effector mechanisms triggered by oncolytic viruses may contribute to the clearance of both infected and uninfected tumor cells in immunocompetent murine hosts. Here, we developed an in vitro tumor cell/bone marrow coculture assay and used it to dissect innate immune sensor and effector responses to intratumoral vesicular stomatitis virus (VSV). We found that the type III IFN interleukin-28 (IL-28) was induced by viral activation of innate immune-sensing cells, acting as a key mediator of VSV-mediated virotherapy of B16ova melanomas. Using tumor variants which differentially express the IL-28 receptor, we showed that IL-28 induced by VSV within the tumor microenvironment sensitizes tumor cells to natural killer cell recognition and activation. These results revealed new insights into the immunovirological mechanisms associated with oncolytic virotherapy in immune-competent hosts. Moreover, they defined a new class of tumor-associated mutation, such as acquired loss of responsiveness to IL-28 signaling, which confers insensitivity to oncolytic virotherapy through a mechanism independent of viral replication in vitro. Lastly, the findings suggested new strategies to manipulate immune signals that may enhance viral replication, along with antitumor immune activation, and improve the efficacy of oncolytic virotherapies. Cancer Res; 70(11); 4539–49. ©2010 AACR.
Western Equine Encephalitis Mimicking Herpes Simplex Encephalitis
Authors: Frank J. Bia
Journal: JAMA (1980)

A patient with severe encephalitis had focal findings suggesting herpes simplex encephalitis. After brain biopsy and administration of vidarabine, the patient's condition improved but was ultimately diagnosed as a case of western equine encephalitis. Further complicating laboratory diagnosis, an endogenous murine coronavirus was isolated from newborn mice inoculated with the patient's brain biopsy tissue. This case illustrates the need for caution in attributing therapeutic responses to antiviral agents or in attributing human illness to viruses that are actually endogenous to animals and tissue culture used in diagnostic virology.
Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance
Authors: Ping-Hui Tseng, Ho-Pi Lin, Jiuxiang Zhu, Kuen-Feng Chen, Erinn M. Hade, Donn C. Young, John C. Byrd, Michael Grever, Kara Johnson, Brian J. Druker, Ching-Shih Chen
Journal: Blood (2005)
Influence of Deoxycholic acid and its metal complexes on viability and proliferation of human tumor cell lines
Authors: L. Dyakova, T. Zhivkova, A. Abudalleh, D.-C. Culita, G. Marinescu, L. Patron, M. Georgieva, G. Miloshev, R. Kalfin, R. Alexandrova
Journal: Annals of Oncology (2015)
Endoplasmic Reticulum Ca<sup>2+</sup>Handling in Excitable Cells in Health and Disease
Authors: Grace E. Stutzmann, Mark P. Mattson
Journal: Pharmacological Reviews (2011)

The endoplasmic reticulum (ER) is a morphologically and functionally diverse organelle capable of integrating multiple extracellular and internal signals and generating adaptive cellular responses. It plays fundamental roles in protein synthesis and folding and in cellular responses to metabolic and proteotoxic stress. In addition, the ER stores and releases Ca<sup>2+</sup> in sophisticated scenarios that regulate a range of processes in excitable cells throughout the body, including muscle contraction and relaxation, endocrine regulation of metabolism, learning and memory, and cell death. One or more Ca<sup>2+</sup> ATPases and two types of ER membrane Ca<sup>2+</sup> channels (inositol trisphosphate and ryanodine receptors) are the major proteins involved in ER Ca<sup>2+</sup> uptake and release, respectively. There are also direct and indirect interactions of ER Ca<sup>2+</sup> stores with plasma membrane and mitochondrial Ca<sup>2+</sup>-regulating systems. Pharmacological agents that selectively modify ER Ca<sup>2+</sup> release or uptake have enabled studies that revealed many different physiological roles for ER Ca<sup>2+</sup> signaling. Several inherited diseases are caused by mutations in ER Ca<sup>2+</sup>-regulating proteins, and perturbed ER Ca<sup>2+</sup> homeostasis is implicated in a range of acquired disorders. Preclinical investigations suggest a therapeutic potential for use of agents that target ER Ca<sup>2+</sup> handling systems of excitable cells in disorders ranging from cardiac arrhythmias and skeletal muscle myopathies to Alzheimer disease.
Dose Escalation Studies of Cytarabine, Daunorubicin, and Etoposide With and Without Multidrug Resistance Modulation With PSC-833 in Untreated Adults With Acute Myeloid Leukemia Younger Than 60 Years: Final Induction Results of Cancer and Leukemia Group B Study 9621
Authors: Jonathan E. Kolitz, Stephen L. George, Richard K. Dodge, David D. Hurd, Bayard L. Powell, Steven L. Allen, Enrique Velez-Garcia, Joseph O. Moore, Thomas C. Shea, Eva Hoke, Michael A. Caligiuri, James W. Vardiman, Clara D. Bloomfield, Richard A. Larson
Journal: Journal of Clinical Oncology (2004)

P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses.A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833.Doses selected for phase III testing were DNR 90 mg/m(2) and ETOP 100 mg/m(2) in ADE, and DNR and ETOP each 40 mg/m(2) in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients < or = 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE.A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients < or = 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.
Authors’ response to Almirall<i>et al</i>
Authors: Robert D Sanders
Journal: Thorax (2013)

Almirall et al have reanalysed their previously published data 1 (that we have previously critiqued 2 ) and shown that benzodiazepine exposure is associated with a reduced risk of pneumonia in younger patients. 3They report both bivariate and multivariate analyses 3 but, by contrast with our analysis 4 have only adjusted for a few comorbidities.For example, it is unclear why they have adjusted for temperature change, that is presumably a consequence of the outcome of interest: pneumonia.The biological rationale for their finding is also unclear, the authors justify their data by suggesting that REM sleep depression may reduce the incidence of bronchial aspiration.Critically, they ignore data that REM sleep deprivation leads to disordered thermogenesis and increased mortality 5 ; in addition to data showing direct impairments of immune function by benzodiazepines. 6While we acknowledge the limitations of our data 4 that depend on the clinical diagnosis of lower respiratory tract infection, this may lend generalisability to clinicians as a readily diagnosed endpoint. 4If present, misclassification of benzodiazepine exposure would likely shift the data towards unity; however, we observed a clinically important risk of both pneumonia and death from
Combined Loss of <i>Hey1</i> and <i>HeyL</i> Causes Congenital Heart Defects Because of Impaired Epithelial to Mesenchymal Transition
Authors: Andreas Fischer, Christian Steidl, Toni U. Wagner, Esra Lang, Peter M. Jakob, Peter Friedl, Klaus-Peter Knobeloch, Manfred Gessler
Journal: Circulation Research (2007)

Congenital heart defects affect almost 1% of human newborns. Recently, mutations in Notch ligands and receptors have been found to cause a variety of heart defects in rodents and humans. However, the molecular effects downstream of Notch are still poorly understood. Here we report that combined inactivation of Hey1 and HeyL , two primary target genes of Notch, causes severe heart malformations, including membranous ventricular septal defects and dysplastic atrioventricular and pulmonary valves. These defects lead to congestive cardiac failure with high lethality. We found both genes to be coexpressed with Notch1 , Notch2 and the Notch ligand Jagged1 in the endocardium of the atrioventricular canal, representing the primary source of mesenchymal cells forming membraneous septum and valves. Atrioventricular explants from Hey1 / HeyL deficient mice exhibited impaired epithelial to mesenchymal transition. Although epithelial to mesenchymal transition was initiated regularly, full transformation into mesenchymal cells failed. This was accompanied by reduced levels of matrix metalloproteinase-2 expression and reduced cell density in endocardial cushions in vivo. We further show that loss of Hey2 leads to very similar deficiencies, whereas a Notch1 null mutation completely abolishes epithelial to mesenchymal transition. Thus, the Hey gene family shows overlap in controlling Notch induced endocardial epithelial to mesenchymal transition, a process critical for valve and septum formation.
Clinical Reminders Attached to Echocardiography Reports of Patients With Reduced Left Ventricular Ejection Fraction Increase Use of β-Blockers
Authors: Paul A. Heidenreich, Parisa Gholami, Anju Sahay, Barry Massie, Mary K. Goldstein
Journal: Circulation (2007)

Although beta-blockers are known to prolong survival for patients with reduced left ventricular ejection fraction, they are often underused. We hypothesized that a reminder attached to the echocardiography report would increase the use of beta-blockers for patients with reduced left ventricular ejection fraction.We randomized 1546 consecutive patients with a left ventricular ejection fraction <45% found on echocardiography at 1 of 3 laboratories to a reminder for use of beta-blockers or no reminder. Patients were excluded from analysis if they died within 30 days of randomization (n=89), did not receive medications through the Veterans Affairs system after 30 days (n=180), or underwent echocardiography at >1 laboratory (n=6). The primary outcome was a prescription for an oral beta-blocker between 1 and 9 months after randomization. The mean age of the 1271 included patients was 69 years; 60% had a history of heart failure, and 51% were receiving treatment with beta-blockers at the time of echocardiography. More patients randomized to the reminder had a subsequent beta-blocker prescription (74%, 458 of 621) compared with those randomized to no reminder (66%, 428 of 650; P=0.002). The effect of the reminder was not significantly different for subgroups based on patient location (inpatient versus outpatient) or prior use of beta-blockers.A reminder attached to the echocardiography report increased the use of beta-blockers in patients with depressed left ventricular systolic function.
Comparative Analysis of Extract-based Skin Test and IgE detection, Singleplexed Molecule-based IgE Detection and a Molecule-based Microarray System
Authors: A. Mari, P. Palazzo, D. Pomponi, M. Helmer-Citterich, D. Zennaro, M. Giani, E. Scala
Journal: Journal of Allergy and Clinical Immunology (2007)