tbuckley/cabot-search huggingface dataset:
Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with <i>BRCA1/2</i> Inactivation
Authors: Tatiana Popova, Elodie Manié, Guillaume Rieunier, Virginie Caux-Moncoutier, Carole Tirapo, Thierry Dubois, Olivier Delattre, Brigitte Sigal-Zafrani, Marc Bollet, Michel Longy, Claude Houdayer, Xavier Sastre-Garau, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Marc-Henri Stern
Journal: Cancer Research (2012)

Abstract BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer. Cancer Res; 72(21); 5454–62. ©2012 AACR.
Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients
Authors: Helena Colom, Núria Lloberas, Franc Andreu, Ana Caldés, Joan Torras, Federico Oppenheimer, Jaime Sanchez-Plumed, Miguel A. Gentil, Dirk R. Kuypers, Mercè Brunet, Henrik Ekberg, Josep M. Grinyó
Journal: Kidney International (2014)
Combining Targeted Therapy With Immunotherapy in <i>BRAF</i>-Mutant Melanoma: Promise and Challenges
Authors: Siwen Hu-Lieskovan, Lidia Robert, Blanca Homet Moreno, Antoni Ribas
Journal: Journal of Clinical Oncology (2014)

Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAF V600 -mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAF V600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.
Is there a difference between the results of the standard six minutes walking test (S6MWT) and the test with ventilation monitoring (V6MWT)
Authors: Carmen Columbia Stroescu, Alina Croitoru, Diana Ionita
Journal: European Respiratory Journal (2011)

Background:  6MWT is a validated test for the evaluation and monitoring of patients with cardiovascular and respiratory conditions. The standard test evaluates the initial and final heart rate (HR) and oxygen saturation (SaO2), and does not measure ventilation.   Aim:  To assess (a) the similarities of the main parameters between S6MWT and V6MWT and (b) the mask-related discomfort during V6MWT.   Subjects and method:  23 patients (P) with respiratory diseases (15 COPD cases) and 5 healthy subjects (H) performed two S6MWT and one V6MWT, at 1 hour intervals. 6MWT distance (6MWD), initial and final HR, SaO2 and symptoms, and the mask–related discomfort were recorded.   Results:  The mean 6MWD was 9 meters longer in S6MWT than in V6MWT (range -65, +135 m). In 7P (30%) the 6MWD was significantly different (>50 m) between the tests, with 5 P (22%) walking less and 2P walking more at the V6MWT.  The mean initial and final symptom scores were similar between the tests (difference   The mean desaturation was similar between the tests, but 7P (30%) desaturated more at V6MWT (difference >4%).  The mean initial and final HR was similar, but 7P had higher initial HR and 9P higher final HR at V6MWT.  Mask-related discomfort was minor in 20P and 4H (86% tests), moderate in 2P and 1H, and major in 1P.   Conclusions:  The mean results of the measured parameters were similar in V6MWT and S6MWT, but the 6MWD was significantly different in 30% of patients. The mask needed for the V6MWT was generally well tolerated.
Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells
Authors: Yanyan Li, Tao Zhang, Hasan Korkaya, Suling Liu, Hsiu-Fang Lee, Bryan Newman, Yanke Yu, Shawn G. Clouthier, Steven J. Schwartz, Max S. Wicha, Duxin Sun
Journal: Clinical Cancer Research (2010)

The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. In this study, we evaluated sulforaphane, a natural compound derived from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs and its potential mechanism.Aldefluor assay and mammosphere formation assay were used to evaluate the effect of sulforaphane on breast CSCs in vitro. A nonobese diabetic/severe combined immunodeficient xenograft model was used to determine whether sulforaphane could target breast CSCs in vivo, as assessed by Aldefluor assay, and tumor growth upon cell reimplantation in secondary mice. The potential mechanism was investigated using Western blotting analysis and beta-catenin reporter assay.Sulforaphane (1-5 micromol/L) decreased aldehyde dehydrogenase-positive cell population by 65% to 80% in human breast cancer cells (P < 0.01) and reduced the size and number of primary mammospheres by 8- to 125-fold and 45% to 75% (P < 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for 2 weeks reduced aldehyde dehydrogenase-positive cells by >50% in nonobese diabetic/severe combined immunodeficient xenograft tumors (P = 0.003). Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor growth after the reimplantation of primary tumor cells into the secondary mice (P < 0.01). Western blotting analysis and beta-catenin reporter assay showed that sulforaphane downregulated the Wnt/beta-catenin self-renewal pathway.Sulforaphane inhibits breast CSCs and downregulates the Wnt/beta-catenin self-renewal pathway. These findings support the use of sulforaphane for the chemoprevention of breast cancer stem cells and warrant further clinical evaluation.
Individual variation in the erythropoietic response to altitude training in elite junior swimmers
Authors: B Friedmann, F Frese, E Menold, F Kauper, J Jost, P Bärtsch
Journal: British Journal of Sports Medicine (2005)

Objectives: Inter-individual variations in sea level performance after altitude training have been attributed, at least in part, to an inter-individual variability in hypoxia induced erythropoiesis. The aim of the present study was to examine whether the variability in the increase in total haemoglobin mass after training at moderate altitude could be predicted by the erythropoietin response after 4 h exposure to normobaric hypoxia at an ambient Po 2 corresponding to the training altitude. Methods: Erythropoietin levels were measured in 16 elite junior swimmers before and after 4 h exposure to normobaric hypoxia (Fio 2 0.15, ∼2500 m) as well as repeatedly during 3 week altitude training (2100–2300 m). Before and after the altitude training, total haemoglobin mass (CO rebreathing) and performance in a stepwise increasing swimming test were determined. Results: The erythropoietin increase (10–185%) after 4 h exposure to normobaric hypoxia showed considerable inter-individual variation and was significantly (p&lt;0.001) correlated with the acute erythropoietin increase during altitude training but not with the change in total haemoglobin mass (significant increase of ∼6% on average). The change in sea level performance after altitude training was not related to the change in total haemoglobin mass. Conclusions: The results of the present prospective study confirmed the wide inter-individual variability in erythropoietic response to altitude training in elite athletes. However, their erythropoietin response to acute altitude exposure might not identify those athletes who respond to altitude training with an increase in total haemoglobin mass.
Quantifying the Impoverishing Effects of Purchasing Medicines: A Cross-Country Comparison of the Affordability of Medicines in the Developing World
Authors: Laurens M. Niëns, Alexandra Cameron, Ellen Van de Poel, Margaret Ewen, Werner B. F. Brouwer, Richard Laing
Journal: PLoS Medicine (2010)

Laurens Niëns and colleagues estimate the impoverishing effects of four medicines in 16 low- and middle-income countries using the impoverishment method as a metric of affordability and show that medicine purchases could impoverish large numbers of people.
Multistage Carcinogenesis: Population-Based Model for Colon Cancer
Authors: S H Moolgavkar, E G Luebeck
Journal: JNCI Journal of the National Cancer Institute (1992)

Recent laboratory work and previous models suggest that multiple mutations are associated with the development of colon cancer.To estimate the number of mutations required for colon carcinogenesis, we used likelihood analysis to obtain the best fit between mathematical models postulating different numbers of rate-limiting events and data on incidence rates of colon cancer in two human populations--the general population of Birmingham, England, from 1968 to 1972 and patients with familial adenomatous polyposis (FAP) diagnosed at Saint Mark's Hospital, London, England, between 1925 and 1965. The Armitage-Doll model and two- and three-mutation models that explicitly incorporated cell proliferation kinetics were used.When cell kinetics were considered, models postulating either two or three rate-limiting events described the incidence rates of colon cancer equally well in both human populations. A comparison of the incidence rate of colon cancer in the general population with that in patients with polyposis suggests that a mutation at the FAP gene locus is not one of the rate-limiting events in colon carcinogenesis.Compared with the two-mutation model, the three-mutation model was more consistent with the number of mutations reported to date in colon cancer and with mutation rates measured in the laboratory.A mutation at the FAP locus may not be a rate-limiting step but may act indirectly by stimulating the proliferation of stem cells. Thus, the development of colon cancer in patients with FAP does not appear to fit the retinoblastoma paradigm.
Skin Progenitor Cells Contribute to Bleomycin‐Induced Skin Fibrosis
Authors: Shangxi Liu, Yann Herault, Guillaume Pavlovic, Andrew Leask
Journal: Arthritis & Rheumatology (2013)

The origin of the cells that contribute to skin fibrosis is unclear. We undertook the present study to assess the contribution of Sox2-expressing skin progenitor cells to bleomycin-induced scleroderma.Scleroderma was induced, by bleomycin administration, in wild-type mice and in mice in which CCN2 was deleted from Sox2-expressing cells. Lineage tracing analysis was performed to assess whether cells expressing Sox2 are recruited to fibrotic lesions in response to bleomycin-induced scleroderma.In response to bleomycin, Sox2-positive/α-smooth muscle actin-positive cells were recruited to fibrotic tissue. CCN2-conditional knockout mice in which CCN2 was deleted from Sox2-expressing cells exhibited resistance to bleomycin-induced skin fibrosis. Collectively, these results indicate that CCN2 is required for the recruitment of progenitor cells and that CCN2-expressing progenitor cells are essential for bleomycin-induced skin fibrosis. Lineage tracing analysis using mice in which a tamoxifen-dependent Cre recombinase was expressed under the control of the Sox2 promoter confirmed that progenitor cells were recruited to the fibrotic lesion in response to bleomycin, and that this did not occur in CCN2-knockout mice. The ability of serum to induce α-smooth muscle actin expression in skin progenitor cells required the presence of CCN2.Sox2-positive skin progenitor cells are required in order for bleomycin-induced skin fibrosis to occur, and CCN2 is required for the recruitment of these cells to the fibrotic lesion. Targeting stem cell recruitment or CCN2 may therefore represent a useful therapeutic approach in combating fibrotic skin disease.
Insulin secretion and plasma levels of glucose-dependent insulinotropic peptide and glucagon-like peptide 1 [7-36 amide] after oral glucose in cirrhosis
Authors: Yolanta T. Kruszynska, Mohammad A. Ghatei, Stephen R. Bloom, Neil McIntyre
Journal: Hepatology (1995)

A blunted initial insulin secretory response may contribute to oral glucose intolerance in cirrhosis. Oral glucose is a better stimulant to insulin secretion than intravenous (IV) glucose in part because of release of gut peptides, notably glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 [7-36 amide] (GLP-1 [7-36 amide]). Because impaired release of or resistance to these gut peptides could explain impaired insulin secretion after oral glucose, we measured insulin secretion, plasma GIP, and GLP-1 [7-36 amide] levels, basally and after 75 g oral glucose, in 10 cirrhotics and 10 controls. Insulin secretion was calculated from a two-compartment analysis of serum C-peptide levels using kinetic parameters derived from IV injection of recombinant human C-peptide. C-peptide metabolic clearance rate, and the fractional rate constants for C-peptide (using the two-compartment model) were not significantly different, but the volume of the central compartment was 15% greater in cirrhotics (P < .01). Fasting blood glucose levels were similar (cirrhotics, 4.9 +/- 0.2; controls, 4.6 +/- 0.1 mmol/L) but serum insulin was six times higher in cirrhotics (P < .001). Cirrhotics had higher fasting GIP (215 +/- 72 vs. 42 +/- 18 pmol/L) and GLP-1 [7-36 amide] levels (25 +/- 3 vs. 16 +/- 1 pmol/L) (both P < .05). After oral glucose, blood glucose levels were significantly higher in cirrhotics. The timing of the gut peptide response to oral glucose was similar in the two groups, but peak levels of both peptides were approximately x2 higher in the cirrhotics.(ABSTRACT TRUNCATED AT 250 WORDS)
Methods for Detection of Antibody to the Mammary Tumor Virus
Authors: Mary Alexander Fink, William F. Feller, Louis R. Sibal
Journal: JNCI Journal of the National Cancer Institute (1968)

Antiserums to the mammary tumor virus were prepared in rhesus monkeys, rabbits, and two strains of mice, C3H and BALB/c. One in vivo test—neutralization—and two in vitro serological tests—immunodiffusion and passive hemagglutination—were used to identify specific antiviral antibody in these serums.
Small-Molecule Allosteric Activators of Sirtuins
Authors: David A. Sinclair, Leonard Guarente
Journal: The Annual Review of Pharmacology and Toxicology (2011)

The mammalian sirtuins (SIRT1-7) are NAD(+)-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans.
Screening of Silent Myocardial Ischemia in Type 2 Diabetic Patients
Authors: Sophie Jacqueminet, Olivier Barthélémy, Claude Le Feuvre
Journal: Diabetes Care (2010)

The prevalence of silent myocardial ischemia (SMI) is more frequent in diabetic patients and is associated with a worse prognosis (1). In order to prevent adverse cardiac events, current guidelines recommend detection of asymptomatic coronary artery disease (CAD) in type 2 diabetic patients with high cardiovascular (CV) risk (2,3). The ECG stress test is recommended but frequently inconclusive in type 2 diabetic patients.

This study aimed to compare stress thallium-201 single photon emission computed tomography (SPECT) with dobutamine echocardiography (DE) for the screening of SMI and CAD in type 2 diabetic patients.

The study was designed with 55 and 30% anticipated rates of positive SPECT and DE, …
Cohort Study of Insulin Glargine and Risk of Breast, Prostate, and Colorectal Cancer Among Patients With Diabetes
Authors: Laurel A. Habel, Kim N. Danforth, Charles P. Quesenberry, Angela Capra, Stephen K. Van Den Eeden, Noel S. Weiss, Assiamira Ferrara
Journal: Diabetes Care (2013)

OBJECTIVE To examine whether use of insulin glargine, compared with another long-acting insulin, is associated with risk of breast, prostate, colorectal cancer, or all cancers combined. RESEARCH DESIGN AND METHODS Computerized health records from Kaiser Permanente Northern and Southern California regions starting in 2001 and ending in 2009 were used to conduct a population-based cohort study among patients with diabetes aged ≥18 years. With use of Cox regression modeling, cancer risk in users of insulin glargine (n = 27,418) was compared with cancer risk in users of NPH (n = 100,757). RESULTS The cohort had a median follow-up of 3.3 years during which there was a median of 1.2 years of glargine use and 1.4 years of NPH use. Among users of NPH at baseline, there was no clear increase in risk of breast, prostate, colorectal, or all cancers combined associated with switching to glargine. Among those initiating insulin, ever use or ≥2 years of glargine was not associated with increased risk of prostate or colorectal cancer or all cancers combined. Among initiators, the hazard ratio (HR) for breast cancer associated with ever use of glargine was 1.3 (95% CI 1.0–1.8); the HR for breast cancer associated with use of glargine for ≥2 years was 1.6 or 1.7 depending on whether glargine users had also used NPH. CONCLUSIONS Results of this study should be viewed cautiously, given the relatively short duration of glargine use to date and the large number of potential associations examined.
Optimal Morphologic Response to Preoperative Chemotherapy: An Alternate Outcome End Point Before Resection of Hepatic Colorectal Metastases
Authors: Junichi Shindoh, Evelyne M. Loyer, Scott Kopetz, Piyaporn Boonsirikamchai, Dipen M. Maru, Yun Shin Chun, Giuseppe Zimmitti, Steven A. Curley, Chusilp Charnsangavej, Thomas A. Aloia, Jean-Nicolas Vauthey
Journal: Journal of Clinical Oncology (2012)

Purpose The purposes of this study were to confirm the prognostic value of an optimal morphologic response to preoperative chemotherapy in patients undergoing chemotherapy with or without bevacizumab before resection of colorectal liver metastases (CLM) and to identify predictors of the optimal morphologic response. Patients and Methods The study included 209 patients who underwent resection of CLM after preoperative chemotherapy with oxaliplatin- or irinotecan-based regimens with or without bevacizumab. Radiologic responses were classified as optimal or suboptimal according to the morphologic response criteria. Overall survival (OS) was determined, and prognostic factors associated with an optimal response were identified in multivariate analysis. Results An optimal morphologic response was observed in 47% of patients treated with bevacizumab and 12% of patients treated without bevacizumab (P &lt; .001). The 3- and 5-year OS rates were higher in the optimal response group (82% and 74%, respectively) compared with the suboptimal response group (60% and 45%, respectively; P &lt; .001). On multivariate analysis, suboptimal morphologic response was an independent predictor of worse OS (hazard ratio, 2.09; P = .007). Receipt of bevacizumab (odds ratio, 6.71; P &lt; .001) and largest metastasis before chemotherapy of ≤ 3 cm (odds ratio, 2.12; P = .025) were significantly associated with optimal morphologic response. The morphologic response showed no specific correlation with conventional size-based RECIST criteria, and it was superior to RECIST in predicting major pathologic response. Conclusion Independent of preoperative chemotherapy regimen, optimal morphologic response is sufficiently correlated with OS to be considered a surrogate therapeutic end point for patients with CLM.
Disorders of Childhood and Adolescence: Gender and Psychopathology
Authors: Carolyn Zahn-Waxler, Elizabeth A. Shirtcliff, Kristine Marceau
Journal: Annual Review of Clinical Psychology (2008)

Early-onset disorders (e.g., conduct problems, autism) show a marked male preponderance, whereas adolescent-onset disorders (e.g., depression, anxiety) show a marked female preponderance. A developmental psychopathology framework provides a means to investigate complex gender-related etiologies of these different disorders. This review focuses on biological and environmental factors implicated in the development of conduct problems and depression in boys and girls. Boys and girls showed certain differences in types, rates, comorbidities, antecedents, correlates, and trajectories of these problems. Origins of male and female preponderant problems are likely to be rooted, in part, in biological, physical, cognitive, and social-emotional differences in boys and girls that can precede the expression of clinical problems. These male-like and female-like characteristics are considered regarding conduct problems and depression to explore how they inform biological and environmental theories about gender and psychopathology. At the same time, because boys and girls also show many similarities, it is important to avoid sex-stereotyping mental health problems.
British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011
Authors: M. Harris, J. Clark, N. Coote, P. Fletcher, A. Harnden, M. McKean, A. Thomson
Journal: Thorax (2011)

The British Thoracic Society first published management guidelines for community acquired pneumonia in children in 2002 and covered available evidence to early 2000. These updated guidelines represent a review of new evidence since then and consensus clinical opinion where evidence was not found. This document incorporates material from the 2002 guidelines and supersedes the previous guideline document.