tbuckley/cabot-search huggingface dataset:
Obesity and the gastroenterologist
Authors: E. Mathus-Vliegen
Journal: Endoscopy (2009)

Obesity (body mass index [BMI] ≥ 30 kg/m2) is a chronic, incurable and life-threatening disease of excess fat storage. The absolute and relative excess of adipose tissue and the visceral distribution of fat place the individual at risk of premature death and obesity-associated co-morbidities. A considerable decrease in life expectancy is associated with obesity. A very recent analysis of 57 prospective studies has assessed the associations of BMI with overall and cause-specific mortality [1]. In both sexes, mortality was lowest at about 22.5 – 25 kg/m2. After adjustment for age, sex, smoking status, and after correction for reverse causality, the median survival at BMI 30 – 35 kg/m2 was reduced by 2 – 4 years and at BMI 40 – 45 kg/m2 by 8 – 10 years. Each 5 kg/m2 higher BMI was associated with about 30 % higher overall mortality: 40 % for vascular mortality, 120 % for diabetic, 60 % for renal and 82 % for hepatic mortality, 10 % for neoplastic mortality, and 20 % for respiratory mortality. In the EPIC study (European Prospective Investigation into Cancer and Nutrition) both general adiposity and abdominal adiposity were associated with significant increased risks of death [2].
A Novel Therapeutic Regimen to Eradicate Established Solid Tumors with an Effective Induction of Tumor-Specific Immunity
Authors: James R. Tysome, Xiaozhu Li, Shengdian Wang, Pengju Wang, Dongling Gao, Pan Du, Dong Chen, Rathi Gangeswaran, Louisa S. Chard, Ming Yuan, Ghassan Alusi, Nicholas R. Lemoine, Yaohe Wang
Journal: Clinical Cancer Research (2012)

The efficacy of oncolytic viruses depends on multiple actions including direct tumor lysis, modulation of tumor perfusion, and stimulation of tumor-directed immune responses. In this study, we investigated whether a sequential combination of immunologically distinct viruses might enhance antitumor efficacy through the induction of tumor-specific immunity and circumvention or mitigation of antiviral immune responses.The Syrian hamster as an immune-competent model that supports replication of both adenovirus and vaccinia virus was evaluated in vitro and in vivo. The antitumor efficacy of either virus alone or sequential combination of the two viruses was examined in pancreatic and kidney cancer models. The functional mechanism of the regimen developed here was investigated by histopathology, immunohistochemistry staining, CTL assay, and T-cell depletion.The Syrian hamster is a suitable model for assessment of oncolytic adenovirus and vaccinia virus. Three low doses of adenovirus followed by three low doses of vaccinia virus resulted in a superior antitumor efficacy to the reverse combination, or six doses of either virus alone, against pancreatic and kidney tumors in Syrian hamsters. A total of 62.5% of animals bearing either tumor type treated with the sequential combination became tumor-free, accompanied by the induction of effective tumor-specific immunity. This enhanced efficacy was ablated by CD3+ T-cell depletion but was not associated with humoral immunity against the viruses.These findings show that sequential treatment of tumors with oncolytic adenovirus and vaccinia virus is a promising approach for cancer therapy and that T-cell responses play a critical role.
Effects of ambient air pollution on symptoms of asthma in Seattle-area children enrolled in the CAMP study.
Authors: O Yu, L Sheppard, T Lumley, J Q Koenig, G G Shapiro
Journal: Environmental Health Perspectives (2000)

We observed a panel of 133 children (5-13 years of age) with asthma residing in the greater Seattle, Washington, area for an average of 58 days (range 28-112 days) during screening for enrollment in the Childhood Asthma Management Program (CAMP) study. Daily self-reports of asthma symptoms were obtained from study diaries and compared with ambient air pollution levels in marginal repeated measures logistic regression models. We defined days with asthma symptoms as any day a child reported at least one mild asthma episode. All analyses were controlled for subject-specific variables [age, race, sex, baseline height, and FEV(1) PC(20) concentration (methacholine provocative concentration required to produce a 20% decrease in forced expiratory volume in 1 sec)] and potential time-dependent confounders (day of week, season, and temperature). Because of variable observation periods for participants, we estimated both between- and within-subject air pollutant effects. Our primary interest was in the within-subject effects: the effect of air pollutant excursions from typical levels in each child's observation period on the odds of asthma symptoms. In single-pollutant models, the population average estimates indicated a 30% [95% confidence interval (CI), 11-52%] increase for a 1-ppm increment in carbon monoxide lagged 1 day, an 18% (95% CI, 5-33%) increase for a 10-microg/m(3) increment in same-day particulate matter < 1.0 microm (PM(1.0)), and an 11% (95% CI, 3-20%) increase for a 10-microg/m(3) increment in particulate matter < 10 microm (PM(10)) lagged 1 day. Conditional on the previous day's asthma symptoms, we estimated 25% (95% CI, 10-42%), 14% (95% CI, 4-26%), and 10% (95% CI, 3-16%) increases in the odds of asthma symptoms associated with increases in CO, PM(1.0), and PM(10), respectively. We did not find any association between sulfur dioxide (SO(2)) and the odds of asthma symptoms. In multipollutant models, the separate pollutant effects were smaller. The overall effect of an increase in both CO and PM(1. 0) was a 31% (95% CI, 11-55%) increase in the odds of symptoms of asthma. We conclude that there is an association between change in short-term air pollution levels, as indexed by PM and CO, and the occurrence of asthma symptoms among children in Seattle. Although PM effects on asthma have been found in other studies, it is likely that CO is a marker for vehicle exhaust and other combustion by-products that aggravate asthma.
Carboplatin-Associated Ototoxicity in Children With Retinoblastoma
Authors: Ibrahim Qaddoumi, Johnnie K. Bass, Jianrong Wu, Catherine A. Billups, Amy W. Wozniak, Thomas E. Merchant, Barrett G. Haik, Matthew W. Wilson, Carlos Rodriguez-Galindo
Journal: Journal of Clinical Oncology (2012)

Carboplatin-induced ototoxicity remains poorly defined but is of potential great consequence in children with retinoblastoma. We retrospectively assessed the incidence of ototoxicity and its risk factors in children with retinoblastoma who were treated with carboplatin.
Up-Regulation of PD-L1, IDO, and T <sub>regs</sub> in the Melanoma Tumor Microenvironment Is Driven by CD8 <sup>+</sup> T Cells
Authors: Stefani Spranger, Robbert M. Spaapen, Yuanyuan Zha, Jason Williams, Yuru Meng, Thanh T. Ha, Thomas F. Gajewski
Journal: Science Translational Medicine (2013)

Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8(+) T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell-inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3(+) regulatory T cells (T(regs)), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8(+) T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of T(regs), in the tumor microenvironment depended on the presence of CD8(+) T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell-inflamed tumor microenvironment.
Anti-Inflammatory Actions of Intravenous Immunoglobulin
Authors: Falk Nimmerjahn, Jeffrey V. Ravetch
Journal: Annual Review of Immunology (2008)

The remarkable success story of the therapeutic application of pooled immunoglobulin G (IgG) preparations from thousands of donors, the so-called intravenous IgG (IVIG) therapy, to patients with a variety of hematological and immunological disorders began more than half a century ago. Since then, the use of this primary blood product has increased constantly, resulting in the serious danger of shortages in supply. Despite its widespread use and therapeutic success, the mechanisms of action, especially of the anti-inflammatory activity, are only beginning to be understood. In this review, we summarize the clinical use of IVIG for different diseases and discuss recent data on the molecular mechanisms that might explain how this potent drug mediates its activity in vivo.
Inhibition of Prolyl Hydroxylases Increases Erythropoietin Production in ESRD
Authors: Wanja M. Bernhardt, Michael S. Wiesener, Paul Scigalla, James Chou, Roland E. Schmieder, Volkmar Günzler, Kai-Uwe Eckardt
Journal: Journal of the American Society of Nephrology (2010)

The reasons for inadequate production of erythropoietin (EPO) in patients with ESRD are poorly understood. A better understanding of EPO regulation, namely oxygen-dependent hydroxylation of the hypoxia-inducible transcription factor (HIF), may enable targeted pharmacological intervention. Here, we tested the ability of fibrotic kidneys and extrarenal tissues to produce EPO. In this phase 1 study, we used an orally active prolyl-hydroxylase inhibitor, FG-2216, to stabilize HIF independent of oxygen availability in 12 hemodialysis (HD) patients, six of whom were anephric, and in six healthy volunteers. FG-2216 increased plasma EPO levels 30.8-fold in HD patients with kidneys, 14.5-fold in anephric HD patients, and 12.7-fold in healthy volunteers. These data demonstrate that pharmacologic manipulation of the HIF system can stimulate endogenous EPO production. Furthermore, the data indicate that deranged oxygen sensing--not a loss of EPO production capacity--causes renal anemia.
716 PROGNOSTIC GENE-EXPRESSION SIGNATURE FOR HEPATITIS C-RELATED EARLY-STAGE LIVER CIRRHOSIS
Authors: Y. Hoshida, A. Villanueva, A. Sangiovanni, M. Solé, C. Hur, K.L. Andersson, R.T. Chung, J. Gould, K. Kojima, S. Gupta, B. Taylor, A. Crenshaw, S. Gabriel, B. Minguez, M. Iavarone, S.L. Friedman, M. Colombo, J.M. Llovet, T. Golub
Journal: Journal of Hepatology (2012)
Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy
Authors: K. Blackwell, V. Semiglazov, D. Krasnozhon, I. Davidenko, L. Nelyubina, R. Nakov, G. Stiegler, P. Singh, A. Schwebig, S. Kramer, N. Harbeck
Journal: Annals of Oncology (2015)

Biosimilars of filgrastim are in widespread clinical use in Europe. This phase III study compares biosimilar filgrastim (EP2006), with the US-licensed reference product, Neupogen(®), in breast cancer patients receiving (neo)adjuvant myelosuppressive chemotherapy (TAC).A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomized 1:1:1:1 into four arms. Two arms received only one product (nonalternating), biosimilar or reference, and two arms (alternating) received alternating treatments during each cycle (biosimilar then reference or vice versa). The primary end point was duration of severe neutropenia (DSN) during cycle 1.The baseline characteristics were balanced between the four treatment arms. Noninferiority of biosimilar versus the reference was demonstrated: DSN (days) in cycle 1 was 1.17 ± 1.11 (biosimilar, N = 101) and 1.20 ± 1.02 (reference, N = 103), 97.5% confidence interval lower boundary for the difference was -0.26 days (above the predefined limit of -1 day). No clinically meaningful differences were observed regarding any other efficacy parameter: incidence of febrile neutropenia (FN); hospitalization due to FN; incidence of infections; depth and time of absolute neutrophil count (ANC) nadir and time to ANC recovery during cycle 1 and across all cycles. The pattern and frequency of adverse events were similar across all treatments.This study demonstrates that biosimilar and the reference filgrastim are similar with no clinically meaningful differences regarding efficacy and safety in prevention of severe neutropenia. Biosimilar filgrastim could represent an important alternative to the reference product, potentially benefiting public health by increasing access to filgrastim treatment.NCT01519700.
Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer
Authors: S. Vincent Rajkumar, Paul G. Richardson, Teru Hideshima, Kenneth C. Anderson
Journal: Journal of Clinical Oncology (2005)

The 26S proteasome is a large intracellular adenosine 5'-triphosphate-dependent protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib.
A Concordance Study of Three Electrophysiological Measures in Schizophrenia
Authors: Sandrine Louchart-de la Chapelle, Irène Nkam, Emmanuelle Houy, Angélique Belmont, Jean-François Ménard, Anne-Claire Roussignol, Ophélie Siwek, Mustapha Mezerai, Marion Guillermou, Gaël Fouldrin, Daniel Levillain, Sonia Dollfus, Dominique Campion, Florence Thibaut
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The authors evaluated concordance rates among three electrophysiological measures in patients with schizophrenia, nonschizophrenic first-degree relatives of schizophrenia patients, and healthy comparison subjects. The purpose of the study was to provide data for defining a common endophenotype for genetic studies of schizophrenia and for improving the criteria for diagnosis. METHOD: P50 event-related potential inhibition, antisaccade, and smooth pursuit eye tracking paradigms were measured. Data for all three paradigms were available for 81 patients with schizophrenia, 25 parents of patients with schizophrenia, and 60 healthy comparison subjects. RESULTS: The schizophrenia patients and the patients’ parents showed a high rate of inhibitory deficits measured by the P50 inhibition and antisaccade paradigms. Both groups had a high prevalence of eye tracking dysfunction. Smooth pursuit gain and the error rate in the antisaccade paradigm were significantly correlated in the schizophrenia patients and the parents, whereas P50 inhibition showed no correlation with smooth pursuit gain or antisaccade paradigm measurements. CONCLUSIONS: Despite superficial similarities, two paradigms designed to measure central inhibition processes (antisaccade and P50 inhibition) do not appear to reflect the same neurobiological substrates. In contrast, the convergence in performance data for the antisaccade and eye tracking paradigms suggests that the neural circuitry underlying these tasks may overlap. P50 inhibition and antisaccade errors were the optimal paradigms for discrimination between comparison subjects, patients with schizophrenia, and the parents of patients with schizophrenia.
Cutaneous polyarteritis nodosa in patients presenting with atrophie blanche
Authors: D. Mimouni, P.P. Ng, A. Rencic, O.V. Nikolskaia, B.D. Bernstein, H.C. Nousari
Journal: British Journal of Dermatology (2003)

The term 'atrophie blanche' is used both as a descriptive term denoting ivory-white stellate scars on the lower limbs as well as a diagnostic label synonymous with livedoid vasculitis, an ill-defined entity. Medium-sized vasculitides, such as polyarteritis nodosa (PAN), occasionally present with ulceration resulting in ivory-white stellate scarring on the lower limbs and may potentially be misdiagnosed as livedoid vasculitis.To assess the occurrence, clinical and immunopathological features of medium-sized vasculitis in patients presenting with atrophie blanche without clinical and/or compression duplex ultrasonographic evidence of venous insufficiency.We retrospectively evaluated patients presenting with atrophie blanche at the Department of Dermatology of Johns Hopkins Medical Institutions, from April 1996 until April 2002, following the diagnostic guidelines for leg ulcers of the Division of Immunodermatology. Deep and multiple skin biopsies were performed for histology. Investigations for underlying vasculitis, thrombophilia, nerve conduction studies and compression duplex ultrasonography of the lower extremities were performed in all patients.Of 29 consecutive patients presenting with atrophie blanche, six had underlying medium-sized vasculitis consistent with PAN, three of whom had previously been diagnosed to have segmental hyalinizing vasculitis/vasculopathy (livedoid vasculitis/vasculopathy) on superficial biopsies. All six patients with cutaneous PAN were women with a median age of 36.5 years (range 34-46) and with a median duration of the disease prior to diagnosis of 18 years (range 3-30). Of the six cutaneous PAN patients, four had neurological involvement evidenced by clinical symptoms and nerve conduction studies. No evidence of any other extracutaneous involvement was found. Erythrocyte sedimentation rate and tests for vasculitis and thrombophilic were normal in all six patients. None had evidence of venous insufficiency. Immunosuppressive therapy was effective in controlling PAN-associated cutaneous and neurological disease. Of the remaining 23 patients, two had antiphospholipid syndrome and one had homocystineaemia; all three also had evidence of venous insufficiency. One patient had multiple myeloma-associated type I cryoglobulinaemia and 19 patients had venous insufficiency alone. None of the non-PAN patients had abnormalities in the nerve conduction studies.In patients presenting with atrophie blanche without evidence of venous insufficiency and thrombophilia, PAN should be excluded, particularly in the presence of mononeuritis multiplex. Repeated and deep biopsies are often necessary to reveal the accurate underlying pathology of necrotizing medium-sized vasculitis in the reticular dermis and the subcutis, especially in the setting of atrophie blanche lesions. Immunosuppressive therapy was effective in controlling the PAN-associated clinical manifestations.
Changes in Lung Cancer Incidence and Mortality Rates Among Americans: 1969–78
Authors: J W Horm, A J Asire
Journal: JNCI Journal of the National Cancer Institute (1982)

Cancer incidence data from two large cancer surveys and cancer mortality data for the entire United States were used to estimate trends in lung cancer incidence and mortality rates among whites for specific age groups during the 10 years 1969–78. Data for the Third National Cancer Survey were from 1969 to 1971; data for the Surveillance, Epidemiology, and End Results Program were from 1973 to 1978. For both incidence and mortality, the rates for women increased much more rapidly than the rates for men, except in the oldest age group (≥85). For both men and women, there was a striking similarity between the average annual percent changes for age-specific incidence rates and those for age-specific mortality rates. For the first time women and men had a similar incidence rate for the youngest (35–44) age group in 1978. If these trends continue, the data suggest that the total incidence rates for men and women will be equal by the year 2000.
Reversal of Ouabain and Acetyl Strophanthidin Effects in Normal and Failing Cardiac Muscle by Specific Antibody
Authors: Herman K. Gold, Thomas W. Smith
Journal: Journal of Clinical Investigation (1974)

Isolated cat right ventricular papillary muscles were used to study the effects of antibodies with high affinity for ouabain and acetyl strophanthidin on myocardium exposed to these cardioactive steroids. Antibodies with average intrinsic affinity constants for ouabain and acetyl strophanthidin of the order of 108 M-1 were raised in rabbits challenged by repeated injection of a conjugate of ouabain covalently linked to a poly D,L-alanyl derivative of human serum albumin. Effects were assessed in terms of time-course and extent of inotropy reversal, influence of experimentally induced ventricular failure, digitalis-antibody concentration relations, influence of digitalis-antibody complex on response to additionally added digitalis, and relation of antibody effects on digitalis-induced automaticity and contracture to reversal of inotropy. Specific antibody (but not control antibody) in 1.1-1.5-fold molar excess over cardioactive steroid concentrations blocked positive inotropic effects of ouabain and acetyl strophanthidin, and gradually reversed established contractile effects of these agents with a mean time for half-reversal of ouabain-induced inotropy of 124±6 (SEM) min and 37±3 min for half-reversal of acetyl strophanthidin-induced inotropy. Papillary muscles from cats with right ventricular failure induced by chronic pulmonary artery constriction responded similarly. Both normal and failing muscles returned to but not below levels of contractility existing before cardioactive steroid exposure, and time for half-reversal of inotropy by antibody was significantly shorter than time for half-reversal after removal of ouabain or acetyl strophanthidin by muscle bath washout alone. Presence of ouabain- or acetyl strophanthidin-antibody complex did not alter the myocardial contractile response to subsequently added cardioactive steroids.
Unusual cause of pseudomonal infection
Authors: R Levy, D T Hindley, R Burman, S A Haider, J Blease
Journal: BMJ (1995)

health care and its evaluation have led to the expectation that studies of use of health services will become prominent.It would be deplorable if unreasonable procedures regarding access to data were to hinder practical applications of health record linkage.Some people will undoubtedly argue that the consent of each subject should be obtained for any procedure that links records.We believe that governments, as custodians of health care data- bases, have a duty to allow scientific investigators access to them in view of the benefits that have resulted from previous studies based on these databases.A requirement for individual consent would lead to the extinction of useful research using health care databases.