tbuckley/cabot-search huggingface dataset:
Maintaining Normal Hemoglobin Levels With Epoetin Alfa in Mainly Nonanemic Patients With Metastatic Breast Cancer Receiving First-Line Chemotherapy: A Survival Study
Authors: Brian Leyland-Jones, Vladimir Semiglazov, Marek Pawlicki, Tadeusz Pienkowski, Sergei Tjulandin, George Manikhas, Antoly Makhson, Anton Roth, David Dodwell, Jose Baselga, Mikhail Biakhov, Konstantinas Valuckas, Edouard Voznyi, Xiangyang Liu, Els Vercammen
Journal: Journal of Clinical Oncology (2005)

Purpose To evaluate the effect on survival and quality of life of maintaining hemoglobin (Hb) in the range of 12 to 14 g/dL with epoetin alfa versus placebo in women with metastatic breast cancer (MBC) receiving first-line chemotherapy. Patients and Methods Eligible patients were randomly assigned to receive epoetin alfa 40,000 U once weekly or placebo for 12 months. Study drug was initiated if baseline Hb was ≤ 13 g/dL or when Hb decreased to ≤ 13g/dL during the study. The primary end point was 12-month overall survival (OS). Results The study drug administration was stopped early in accordance with a recommendation from the Independent Data Monitoring Committee because of higher mortality in the group treated with epoetin alfa. Enrollment had been completed, with 939 patients enrolled (epoetin alfa, n = 469; placebo, n = 470). Most patients had Hb more than 12 g/dL at baseline (median Hb, 12.8 g/dL) or during the study. From the final analysis, 12-month OS was 70% for epoetin alfa recipients and 76% for placebo recipients (P = .01). Optimal tumor response and time to disease progression were similar between groups. The reason for the difference in mortality between groups could not be determined from additional subsequent analyses involving both study data and chart review. Conclusion In this trial, the use of epoetin alfa to maintain high Hb targets in women with MBC, most of whom did not have anemia at the start of treatment, was associated with decreased survival. Additional research is required to clarify the potential impact of erythropoietic agents on survival when the Hb target range is 10 to 12 g/dL.
Dependency of Renal Blood Flow on Prostaglandin Synthesis in the Dog
Authors: ANDREW J. LONIGRO, HAROLD D. ITSKOVITZ, KEITH CROWSHAW, JOHN C. MCGIFF
Journal: Circulation Research (1973)

Inhibition of prostaglandin synthesis in chloralose-anesthetized dogs reduced renal blood flow, and this reduction closely correlated (r=0.92, P &lt;0.01) with a decline in the renal efflux of a substance having the properties of PGE 2 . We used solvent extraction and thin-layer chromatography coupled with parallel bioassay to identify and assay the PGE- and PGF-like substances (expressed as PGE 2 and PGF 2α equivalents). Either of two antiinflammatory acids, indomethacin or meclofenamate, that inhibited conversion of 14 C-arachidonic acid to prostaglandins in renal homogenates decreased the basal concentration of a PGE-like substance in renal venous blood to 0.06 ± 0.02 ng/ml from a mean control value of 0.34 ± 0.10 ng/ml ( P &lt;0.01). This change was associated with a mean reduction in renal blood flow of 45% in spite of increased renal perfusion pressure. Femoral blood flow and cardiac output were variably and insignificantly affected. Changes in the renal efflux of a PGF-like substance induced by indomethacin were unrelated to the decline in renal blood flow. Changes in the efflux of a PGE-like substance from the femoral vascular bed were unrelated to the small and variable changes in femoral blood flow. Extrarenal factors, i.e., humoral, nervous, or cardiopulmonary factors, did not account for the decline in renal blood flow produced by the inhibitors of prostaglandin synthesis, since the inhibitors produced identical effects in the isolated blood-perfused canine kidney. We concluded that PGE 2 participates in maintaining renal vascular tone which heretofore has been ascribed to autonomous, intrinsic renal arteriolar activity.
Home respiratory polygraphy for diagnosis of sleep-disordered breathing in heart failure
Authors: E. Quintana-Gallego
Journal: European Respiratory Journal (2004)

The present study assessed the usefulness of home cardiorespiratory polygraphy as an alternative to overnight polysomnography for the diagnosis of sleep-disordered breathing in heart failure. A total of 75 patients with chronic stable heart failure due to systolic dysfunction (left ventricular ejection fraction ≤45%) underwent polysomnography at the Virgen del Rocio Hospital and cardiorespiratory polygraphy at home. The two studies were performed in random order and within 30 days. The accuracy of polygraphical findings was determined by sensitivity and specificity obtained by area under the receiver operating characteristics (ROC) curves for apnoea-hypopnoea index (AHI) thresholds of ≥5, ≥10 and ≥15 in the polysomnography. The area under the ROC curve for AHI ≥5, ≥10 and ≥15 was 0.896, 0.907 and 0.862, respectively. The diagnostic accuracy of polygraphy compared with polysomnography ranged 78.6–84%, with sensitivities of 68.4–82.5%, and specificities of 88.6–97.8% for the different AHI thresholds. Altogether, 29 patients had an AHI ≥10 (central pattern 24, obstructive pattern 5). Sensitivity and specificity of home polygraphy for identifying the sleep-disordered breathing pattern was 100%. These data show that home cardiorespiratory polygraphy has a high sensitivity and specificity for the diagnosis of sleep-disordered breathing associated with heart failure.
<i>KRAS</i> Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Authors: Astrid Lièvre, Jean-Baptiste Bachet, Delphine Le Corre, Valérie Boige, Bruno Landi, Jean-François Emile, Jean-François Côté, Gorana Tomasic, Christophe Penna, Michel Ducreux, Philippe Rougier, Frédérique Penault-Llorca, Pierre Laurent-Puig
Journal: Cancer Research (2006)

Abstract The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment. (Cancer Res 2006; 66(8): 3992-5)
Diastolic Function Is Reduced in Adolescents With Type 1 Diabetes in Response to Exercise
Authors: Silmara Gusso, Teresa E. Pinto, James C. Baldi, Elizabeth Robinson, Wayne S. Cutfield, Paul L. Hofman
Journal: Diabetes Care (2012)

To determine whether adolescents with type 1 diabetes have left ventricular functional changes at rest and during acute exercise and whether these changes are affected by metabolic control and diabetes duration.The study evaluated 53 adolescents with type 1 diabetes and 22 control adolescents. Baseline data included peak exercise capacity and body composition by dual-energy X-ray absorptiometry. Left ventricular functional parameters were obtained at rest and during acute exercise using magnetic resonance imaging.Compared with nondiabetic control subjects, adolescents with type 1 diabetes had lower exercise capacity (44.7 ± 09 vs. 48.5 ± 1.4 mL/kg fat-free mass [FFM]/min; P < 0.05). Stroke volume was reduced in the diabetes group at rest (1.86 ± 0.04 vs. 2.05 ± 0.07 mL/kg FFM; P = 0.02) and during acute exercise (1.89 ± 0.04 vs. 2.17 ± 0.06 mL/kg FFM; P = 0.01). Diabetic adolescents also had reduced end-diastolic volume at rest (2.94 ± 0.06 vs. 3.26 ± 0.09 mL/kg FFM; P = 0.01) and during acute exercise (2.78 ± 0.05 vs. 3.09 ± 0.08 mL/kg FFM; P = 0.01). End-systolic volume was lower in the diabetic group at rest (1.08 ± 0.03 vs. 1.21 ± 0.04 mL/kg FFM; P = 0.01) but not during acute exercise. Exercise capacity and resting and exercise stroke volumes were correlated with glycemic control but not with diabetes duration.Adolescents with type 1 diabetes have reduced exercise capacity and display alterations in cardiac function compared with nondiabetic control subjects, associated with reduced stroke volume during exercise.
Ultrastructural distribution of vasodilator and constrictor nerves in cat cerebral arteries.
Authors: T J Lee
Journal: Circulation Research (1981)

This study examined the ultrastructural distribution of agranular vesicle-containing nerve (AVN) and granular vesicle-containing nerve (GVN) in cat cerebral blood vessels fixed in KMnO4. The percentages of the AVN and GVN throughout the adventitial layer in the basilar, middle cerebral, and anterior cerebral arteries were 63.4 and 36.7, 53.9 and 46.1, and 60.2 and 39.8, respectively. The AVN in the cat basilar artery is approximately 37 times denser than that in the rabbit basilar artery. This morphological result, in correlation with the previous pharmacological findings, provides indirect evidence that the AVN are the dilator nerves. The lack of neurogenic vasoconstriction in the cat basilar, middle cerebral, and anterior cerebral arteries may be attributable in part to a combination of denser dilator than constrictor nerves, a possible closer synaptic cleft distance for dilator than for constrictor nerves, and the reported insensitivity of the postsynaptic alpha-receptors. The small pial vessels (branches of the middle cerebral arteries), on the other hand, contain predominantly GVN (88%), suggesting that dilator nerves relative to constrictor nerves decrease as the size of the cerebral blood vessels becomes smaller. Furthermore, the synaptic cleft distance is found not parallel to the outer diameter of the artery. Thus, the results of this study indicate that the neurogenic control of brain circulation varies with brain region, lending further support to the theory that the dual cerebral innervation varies among species.
Noninvasive recovery of epicardial potentials in a realistic heart-torso geometry. Normal sinus rhythm.
Authors: B J Messinger-Rapport, Y Rudy
Journal: Circulation Research (1990)

The inverse problem in electrocardiography implies the reconstruction of electrical events within the heart from information measured noninvasively on the body surface. Deduction of these electrical events is possible from measured epicardial potentials, and, thus, a noninvasive method of recovering epicardial potentials from body surface data is useful in experimental and clinical studies. In the present study, an inverse method that uses Tikhonov regularization was shown to reconstruct, with good accuracy, important events in cardiac excitation. The inverse procedure was employed on data obtained from a human-torso tank in which a beating canine heart was placed in the correct anatomical position. Comparison with the actual, measured epicardial potentials indicates that positions and shapes of potential features (maxima, minima, zero potential line, saddles, etc.) are recovered with good accuracy throughout the QRS. An error in position of up to 1 cm is typical, while amplitudes are slightly diminished. In addition, application was extended from the above setting, in which the geometry was precisely known and potentials at a large number of leads were measured accurately, to a situation that is more representative of clinical and experimental settings. Effects of inaccuracy in location of the position of the heart were examined. A stylized torso that approximates the actual geometry was designed, and its performance in the inverse computations was evaluated. A systematic method of reduction of the number of leads on the body surface was proposed, and the resulting lead configurations were evaluated in terms of the accuracy of inverse solutions. The results indicate that the inverse problem can be stabilized with respect to different types of uncertainties in measured data and offer promise in the use of the inverse procedure in clinical and experimental situations.
Opportunistic infections in patients treated with immunotherapy for cancer
Authors: Chrisann Kyi, Matthew D Hellmann, Jedd D Wolchok, Paul B Chapman, Michael A Postow
Journal: Journal for ImmunoTherapy of Cancer (2014)

Immunomodulatory antibodies that enhance the immune system to fight cancer are revolutionizing the treatment of patients with an expanding variety of malignancies. There is a unique spectrum of side effects associated with immunomodulatory antibodies, termed immune-related adverse events (irAEs), which include colitis and hepatitis among others. The treatment of refractory or severe irAEs can occasionally require significant immunosuppression, involving steroids or tumor necrosis factor-alpha antagonists, placing these patients at risk for infections. We present the first reported case to our knowledge of an opportunistic infection in a patient treated with an immunomodulatory antibody. As the use of immunomodulatory antibodies expands and more patients develop irAEs that require treatment with immunosuppression, recognition of the potential for opportunistic infections in this emerging patient population will be critical. Prospective trials are needed to define the optimal immunosuppressive management of irAEs and determine whether prophylactic antiviral, antibacterial, or antifungal therapies are beneficial in this unique population.
Prevention of Peripheral Tolerance by a Dendritic Cell Growth Factor: Flt3 Ligand as an Adjuvant
Authors: Bali Pulendran, J.L. Smith, M. Jenkins, M. Schoenborn, E. Maraskovsky, C.R. Maliszewski
Journal: The Journal of Experimental Medicine (1998)

Injections of soluble proteins are poorly immunogenic, and often elicit antigen-specific tolerance. The mechanism of this phenomenon has been an enduring puzzle, but it has been speculated that tolerance induction may be due to antigen presentation by poorly stimulatory, resting B cells, which lack specific immunoglobulin receptors for the protein. In contrast, adjuvants, or infectious agents, which cause the release of proinflammatory cytokines such as tumor necrosis factor α and interleukin 1β in vivo are believed to recruit and activate professional antigen-presenting cells to the site(s) of infection, thereby eliciting immunity. Here we show that administration of Flt3 ligand (FL), a cytokine capable of inducing large numbers of dendritic cells (DCs) in vivo, (a) dramatically enhances the sensitivity of antigen-specific B and T cell responses to systemic injection of a soluble protein, through a CD40–CD40 ligand–dependent mechanism; (b) influences the class of antibody produced; and (c) enables productive immune responses to otherwise tolerogenic protocols. These data support the hypothesis that the delicate balance between immunity and tolerance in vivo is pivotally controlled by DCs, and underscore the potential of FL as a vaccine adjuvant for immunotherapy in infectious disease and other clinical settings.
Translational bioinformatics in the cloud: an affordable alternative
Authors: Joel T Dudley, Yannick Pouliot, Rong Chen, Alexander A Morgan, Atul J Butte
Journal: Genome Medicine (2010)

With the continued exponential expansion of publicly available genomic data and access to low-cost, high-throughput molecular technologies for profiling patient populations, computational technologies and informatics are becoming vital considerations in genomic medicine. Although cloud computing technology is being heralded as a key enabling technology for the future of genomic research, available case studies are limited to applications in the domain of high-throughput sequence data analysis. The goal of this study was to evaluate the computational and economic characteristics of cloud computing in performing a large-scale data integration and analysis representative of research problems in genomic medicine. We find that the cloud-based analysis compares favorably in both performance and cost in comparison to a local computational cluster, suggesting that cloud computing technologies might be a viable resource for facilitating large-scale translational research in genomic medicine.
Ki67 Expression and Docetaxel Efficacy in Patients With Estrogen Receptor–Positive Breast Cancer
Authors: Frédérique Penault-Llorca, Fabrice André, Christine Sagan, Magali Lacroix-Triki, Yves Denoux, Veronique Verriele, Jocelyne Jacquemier, Marie Christine Baranzelli, Frederic Bibeau, Martine Antoine, Nicole Lagarde, Anne-Laure Martin, Bernard Asselain, Henri Roché
Journal: Journal of Clinical Oncology (2009)

Purpose The indications of adjuvant chemotherapy for patients with estrogen receptor (ER) –positive breast cancer are controversial. We analyzed the predictive value of Ki67, HER2, and progesterone receptor (PR) expression for the efficacy of docetaxel in patients with ER-positive, node-positive breast cancer. Patients and Methods Expression of Ki67, HER2, and PR was measured by immunohistochemistry in tumor samples from 798 patients with ER-positive breast cancer who participated in PACS01, a randomized trial that evaluated the efficacy of docetaxel. Risk reduction was evaluated using a Cox model adjusted for age, tumor size, nodal involvement, treatment arm, and biomarkers. The predictive value of biomarkers was assessed by an interaction test. Disease-free survival (DFS) was the primary end point. Results Ki67, HER2, and PR were expressed in 21%, 9%, and 62% of samples, respectively. Hazard ratios for relapse associated with docetaxel were 0.51 (95% CI, 0.26 to 1.01) in ER-positive/Ki67-positive tumors and 1.03 (95% CI, 0.69 to 1.55) in ER-positive/Ki67-negative tumors (ratio for interaction: 0.53; 95% CI, 0.24 to 1.16; P = .11). Five-year DFS rates were 81% (95% CI, 76% to 86%) and 84% (95% CI, 75% to 93%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with docetaxel and 81% (95% CI, 76% to 86%) and 62% (95% CI, 52% to 72%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with fluorouracil, epirubicin, and cisplatin. No trend for interaction was observed between docetaxel and HER2 (ratio for interaction: 0.83; 95% CI, 0.35 to 1.94; P = .66), nor between docetaxel and PR (ratio for interaction: 0.89; 95% CI, 0.47 to 1.66; P = .71). Conclusion Ki67 expression identifies a subset of patients with ER-positive breast cancer who could be sensitive to docetaxel treatment in the adjuvant setting.
Insomnia and the Risk of Acute Myocardial Infarction
Authors: Lars E. Laugsand, Lars J. Vatten, Carl Platou, Imre Janszky
Journal: Circulation (2011)

Few prospective studies have investigated insomnia in relation to risk for coronary heart disease. We assessed insomnia symptoms and risk of acute myocardial infarction (AMI) in a large, population-based study.A total of 52 610 men and women were followed up for a first AMI, and 2368 incident AMIs occurred during 11.4 years of follow-up, either identified at hospitals or by the National Cause of Death Registry. In our analyses, we adjusted for age, sex, marital status, education, shift work, blood pressure, lipids, diabetes mellitus, body mass index, physical activity, smoking, and alcohol consumption. Difficulties initiating and maintaining sleep and having a feeling of nonrestorative sleep were associated with a moderate increase in AMI risk. The multiadjusted hazard ratios for AMI were 1.45 (95% confidence interval 1.18-1.80) for people with difficulties initiating sleep almost every night, 1.30 (1.01-1.68) for those with difficulties maintaining sleep almost every night, and 1.27 (1.03-1.57) for those with a feeling of nonrestorative sleep more than once a week compared with people who never experienced these sleep difficulties. When we combined the symptoms, a dose-dependent association was seen between the number of insomnia symptoms and AMI risk (P for trend 0.003). Alternative multivariable models and different sensitivity analyses suggest that the results were robust, especially concerning difficulties initiating sleep.Insomnia is associated with a moderately increased risk for AMI.
Six-Minute-Walk Test in Chronic Obstructive Pulmonary Disease
Authors: Michael I. Polkey, Martijn A. Spruit, Lisa D. Edwards, Michael L. Watkins, Victor Pinto-Plata, Jørgen Vestbo, Peter M. A. Calverley, Ruth Tal-Singer, Alvar Agustí, Per S. Bakke, Harvey O. Coxson, David A. Lomas, William MacNee, Stephen Rennard, Edwin K. Silverman, Bruce E. Miller, Courtney Crim, Julie Yates, Emiel F. M. Wouters, Bartolome Celli
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Outcomes other than spirometry are required to assess nonbronchodilator therapies for chronic obstructive pulmonary disease. Estimates of the minimal clinically important difference for the 6-minute-walk distance (6MWD) have been derived from narrow cohorts using nonblinded intervention.To determine minimum clinically important difference for change in 6MWD over 1 year as a function of mortality and first hospitalization in an observational cohort of patients with COPD.Data from the ECLIPSE cohort were used (n = 2,112). Death or first hospitalization were index events; we measured change in 6MWD in the 12-month period before the event and related change in 6MWD to lung function and St. George's Respiratory Questionnaire (health status).Of subjects with change in the 6MWD data, 94 died, and 323 were hospitalized. 6MWD fell by 29.7 m (SD, 82.9 m) more among those who died than among survivors (P < 0.001). A reduction in distance of more than 30 m conferred a hazard ratio of 1.93 (95% confidence interval, 1.29-2.90; P = 0.001) for death. No significant difference was observed for first hospitalization. Weak relationships only were observed with change in lung function or health status.A reduction in the 6MWD of 30 m or more is associated with increased risk of death but not hospitalization due to exacerbation in patients with chronic obstructive pulmonary disease and represents a clinically significant minimally important difference.
Antigenic Changes in Cultured Murine Lymphomas After Retransplantation Into Syngeneic Hosts2
Authors: Matko Cikes
Journal: JNCI Journal of the National Cancer Institute (1975)

When cultured murine lymphomas were retransplanted into syngeneic hosts, the quantitative representation of H-2 antigens and Moloney leukemia virus-determined cell-surface antigens tended to revert to the antigenic pattern characteristic of the corresponding lines propagated in vivo. In some instances, a complete reversion of both the virus-specific and H-2 antigens was observed after a single passage of cultured lymphoma cells in syngeneic hosts.
Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis
Authors: Emma Guttman-Yassky, Michelle A. Lowes, Judilyn Fuentes-Duculan, Julia Whynot, Inna Novitskaya, Irma Cardinale, Asifa Haider, Artemis Khatcherian, John A. Carucci, Reuven Bergman, James G. Krueger
Journal: Journal of Allergy and Clinical Immunology (2007)