tbuckley/cabot-search huggingface dataset:
<i>BRCA1</i> Promoter Methylation in Sporadic Breast Cancer Is Associated with Reduced <i>BRCA1</i> Copy Number and Chromosome 17 Aneusomy
Authors: Minjie Wei, Tatyana A. Grushko, James Dignam, Fitsum Hagos, Rita Nanda, Lise Sveen, Jinhua Xu, James Fackenthal, Maria Tretiakova, Soma Das, Olufunmilayo I. Olopade
Journal: Cancer Research (2005)

Abstract To explore the molecular mechanisms for the similarities between inherited and noninherited forms of breast cancer, we tested the hypothesis that inactivation of BRCA1 by promoter hypermethylation is associated with reduced gene copy number and chromosome 17 aneusomy as observed in tumors from BRCA1 mutation carriers. Using a combination of methylation-specific PCR analysis and fluorescence in situ hybridization, we observed varying degrees of promoter methylation in 39 of 131 (29.8%) primary tumors. Despite significant tumor heterogeneity, mean copy numbers of BRCA1 and CEP17 per cell were lower in methylated cases compared with unmethylated cases [1.78 versus 2.30 (P = 0.001) and 1.85 versus 2.29 (P = 0.005), respectively]. Methylation was more frequently observed in younger women (P = 0.05) with high-grade (P = 0.001), estrogen receptor–negative (P = 0.04), and progesterone receptor–negative (P = 0.01) tumors. Moreover, methylation was associated with reduced or absent BRCA1 transcripts, which was reversible in the heavily BRCA1-methylated cell line UACC3199 following treatment with 5-aza-2′-deoxycytidine and trichostatin A. We identified five CpGs at positions −533, −355, −173, −21, and +44 as critical in the reexpression of BRCA1. We conclude that BRCA1 methylation contributes to a subset of sporadic breast cancers with the resulting molecular and clinicopathologic phenotype similar to that of hereditary BRCA1-associated breast cancers. Our data support a model of carcinogenesis in which BRCA1 promoter methylation may serve as a “first hit,” much like an inherited germ line mutation, and promote tumor progression down a restricted set of molecular pathways.
ABVD Versus Modified Stanford V Versus MOPPEBVCAD With Optional and Limited Radiotherapy in Intermediate- and Advanced-Stage Hodgkin's Lymphoma: Final Results of a Multicenter Randomized Trial by the Intergruppo Italiano Linfomi
Authors: Paolo G. Gobbi, Alessandro Levis, Teodoro Chisesi, Chiara Broglia, Umberto Vitolo, Caterina Stelitano, Vincenzo Pavone, Luigi Cavanna, Gino Santini, Francesco Merli, Marina Liberati, Luca Baldini, Giorgio Lambertenghi Deliliers, Emanuele Angelucci, Roberto Bordonaro, Massimo Federico
Journal: Journal of Clinical Oncology (2005)

In this multicenter, prospective, randomized clinical trial on advanced Hodgkin's lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to < or = two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program).Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively.The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses.When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.
Sarcopenia in an Overweight or Obese Patient Is an Adverse Prognostic Factor in Pancreatic Cancer
Authors: Benjamin H.L. Tan, Laura A. Birdsell, Lisa Martin, Vickie E. Baracos, Kenneth C.H. Fearon
Journal: Clinical Cancer Research (2009)

The average weight-losing pancreatic cancer patient undergoing palliative therapy is frequently overweight rather than underweight, and this can confound conventional measures used for risk stratification. The aim of this study was to evaluate if weight and body composition, specifically sarcopenia, assessed from diagnostic computed tomography (CT) scans, is of prognostic value in patients with pancreatic cancer. The nature and extent of tissue loss over subsequent months was also evaluated.A total of 111 patients entering a palliative therapy program, who had CT images and had undergone nutritional screening, were studied. In patients for whom follow-up scans were available (n = 44), longitudinal changes in body composition were studied at a mean of 230 +/- 62 and 95 +/- 60 days prior to demise.Sixty-two patients (55.9%) were sarcopenic, 44 (39.6%) were overweight/obese, and 18 (16.2%) were both. Age > or =59 years (hazard ratio, 1.71; 95% confidence interval, 1.10-2.66; P = 0.018), and overweight/obese sarcopenia (hazard ratio, 2.07; 95% confidence interval, 1.23-3.50; P = 0.006) were identified as independent predictors of survival on multivariate analysis. Longitudinal analysis revealed that total fat-free mass index decreased from 15.5 +/- 2.5 kg/m(2) to 14.5 +/- 2.0 kg/m2 (P = 0.002), and total fat mass index decreased from 7.5 +/- 2.0kg/m2 to 6.0 +/- 1.5kg/m2 (P < 0.0001) over 135 days.Sarcopenia in overweight/obese patients with advanced pancreatic cancer is an occult condition but can be identified using CT scans. This condition is an independent adverse prognostic indicator that should be considered for stratification of patients' entering clinical trials, systemic therapy, or support care programs.
Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer
Authors: Michael E. Feigin, S. Dipikaa Akshinthala, Kiyomi Araki, Avi Z. Rosenberg, Lakshmi B. Muthuswamy, Bernard Martin, Brian D. Lehmann, Hal K. Berman, Jennifer A. Pietenpol, Robert D. Cardiff, Senthil K. Muthuswamy
Journal: Cancer Research (2014)

Scribble (SCRIB) localizes to cell-cell junctions and regulates establishment of epithelial cell polarity. Loss of expression of SCRIB functions as a tumor suppressor in Drosophila and mammals; conversely, overexpression of SCRIB promotes epithelial differentiation in mammals. Here, we report that SCRIB is frequently amplified, mRNA overexpressed, and protein is mislocalized from cell-cell junctions in human breast cancers. High levels of SCRIB mRNA are associated with poor clinical prognosis, identifying an unexpected role for SCRIB in breast cancer. We find that transgenic mice expressing a SCRIB mutant [Pro 305 to Leu (P305L)] that fails to localize to cell-cell junctions, under the control of the mouse mammary tumor virus long terminal repeat promoter, develop multifocal hyperplasia that progresses to highly pleomorphic and poorly differentiated tumors with basal characteristics. SCRIB interacts with phosphatase and tensin homolog (PTEN) and the expression of P305L, but not wild-type SCRIB, promotes an increase in PTEN levels in the cytosol. Overexpression of P305L, but not wild-type SCRIB, activates the Akt/mTOR/S6K signaling pathway. Human breast tumors overexpressing SCRIB have high levels of S6K but do not harbor mutations in PTEN or PIK3CA, identifying SCRIB amplification as a mechanism of activating PI3K signaling in tumors without mutations in PIK3CA or PTEN. Thus, we demonstrate that high levels of mislocalized SCRIB functions as a neomorph to promote mammary tumorigenesis by affecting subcellular localization of PTEN and activating an Akt/mTOR/S6kinase signaling pathway.
Gemcitabine and Erlotinib in Patients with Advanced Pancreatic Cancer: Retrospective Single Institution Experience
Authors: D. Sakai, T. Satoh, T. Kudo, N. Hama, H. Wada, S. Kobayashi, H. Eguchi, H. Nagano, Y. Doki, M. Mori
Journal: Annals of Oncology (2013)
LOGIC-Insulin Algorithm–Guided Versus Nurse-Directed Blood Glucose Control During Critical Illness
Authors: Tom Van Herpe, Dieter Mesotten, Pieter J. Wouters, Jeroen Herbots, Evy Voets, Jo Buyens, Bart De Moor, Greet Van den Berghe
Journal: Diabetes Care (2012)

Tight blood glucose control (TGC) in critically ill patients is difficult and labor intensive, resulting in poor efficacy of glycemic control and increased hypoglycemia rate. The LOGIC-Insulin computerized algorithm has been developed to assist nurses in titrating insulin to maintain blood glucose levels at 80-110 mg/dL (normoglycemia) and to avoid severe hypoglycemia (<40 mg/dL). The objective was to validate clinically LOGIC-Insulin relative to TGC by experienced nurses.The investigator-initiated LOGIC-1 study was a prospective, parallel-group, randomized, controlled clinical trial in a single tertiary referral center. A heterogeneous mix of 300 critically ill patients were randomized, by concealed computer allocation, to either nurse-directed glycemic control (Nurse-C) or algorithm-guided glycemic control (LOGIC-C). Glycemic penalty index (GPI), a measure that penalizes both hypoglycemic and hyperglycemic deviations from normoglycemia, was the efficacy outcome measure, and incidence of severe hypoglycemia (<40 mg/dL) was the safety outcome measure.Baseline characteristics of 151 Nurse-C patients and 149 LOGIC-C patients and study times did not differ. The GPI decreased from 12.4 (interquartile range 8.2-18.5) in Nurse-C to 9.8 (6.0-14.5) in LOGIC-C (P < 0.0001). The proportion of study time in target range was 68.6 ± 16.7% for LOGIC-C patients versus 60.1 ± 18.8% for Nurse-C patients (P = 0.00016). The proportion of severe hypoglycemic events was decreased in the LOGIC-C group (Nurse-C 0.13%, LOGIC-C 0%; P = 0.015) but not when considered as a proportion of patients (Nurse-C 3.3%, LOGIC-C 0%; P = 0.060). Sampling interval was 2.2 ± 0.4 h in the LOGIC-C group versus 2.5 ± 0.5 h in the Nurse-C group (P < 0.0001).Compared with expert nurses, LOGIC-Insulin improved efficacy of TGC without increasing rate of hypoglycemia.
Effect of a Multifaceted Intervention on Use of Evidence-Based Therapies in Patients With Acute Coronary Syndromes in Brazil
Authors: Otávio Berwanger, Hélio P. Guimarães, Ligia N. Laranjeira, Alexandre B. Cavalcanti, Alessandra A. Kodama, Ana Denise Zazula, Eliana V. Santucci, Elivane Victor, Marcos Tenuta, Vitor Carvalho, Vera Lucia Mira, Karen S. Pieper, Bernardete Weber, Luiz Henrique Mota, Eric D. Peterson, Renato D. Lopes, for the BRIDGE-ACS Investigators
Journal: JAMA (2012)

Studies have found that patients with acute coronary syndromes (ACS) often do not receive evidence-based therapies in community practice. This is particularly true in low- and middle-income countries.To evaluate whether a multifaceted quality improvement (QI) intervention can improve the use of evidence-based therapies and reduce the incidence of major cardiovascular events among patients with ACS in a middle-income country.The BRIDGE-ACS (Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndromes) trial, a cluster-randomized (concealed allocation) trial conducted among 34 clusters (public hospitals) in Brazil and enrolling a total of 1150 patients with ACS from March 15, 2011, through November 2, 2011, with follow-up through January 27, 2012.Multifaceted QI intervention including educational materials for clinicians, reminders, algorithms, and case manager training, vs routine practice (control).Primary end point was the percentage of eligible patients who received all evidence-based therapies (aspirin, clopidogrel, anticoagulants, and statins) during the first 24 hours in patients without contraindications.Mean age of the patients enrolled was 62 (SD, 13) years; 68.6% were men, and 40% presented with ST-segment elevation myocardial infarction, 35.6% with non-ST-segment elevation myocardial infarction, and 23.6% with unstable angina. The randomized clusters included 79.5% teaching hospitals, all from major urban areas and 41.2% with 24-hour percutaneous coronary intervention capabilities. Among eligible patients (923/1150 [80.3%]), 67.9% in the intervention vs 49.5% in the control group received all eligible acute therapies (population average odds ratio [OR(PA)], 2.64 [95% CI, 1.28-5.45]). Similarly, among eligible patients (801/1150 [69.7%]), those in the intervention group were more likely to receive all eligible acute and discharge medications (50.9% vs 31.9%; OR(PA),, 2.49 [95% CI, 1.08-5.74]). Overall composite adherence scores were higher in the intervention clusters (89% vs 81.4%; mean difference, 8.6% [95% CI, 2.2%-15.0%]). In-hospital cardiovascular event rates were 5.5% in the intervention group vs 7.0% in the control group (OR(PA), 0.72 [95% CI, 0.36-1.43]); 30-day all-cause mortality was 7.0% vs 8.4% (ORPA, 0.79 [95% CI, 0.46-1.34]).Among patients with ACS treated in Brazil, a multifaceted educational intervention resulted in significant improvement in the use of evidence-based therapies.clinicaltrials.gov Identifier: NCT00958958.
Endorepellin In Vivo: Targeting the Tumor Vasculature and Retarding Cancer Growth and Metabolism
Authors: Gregory Bix, Remedios Castello, Michelle Burrows, Jason J. Zoeller, Michelle Weech, Rex A. Iozzo, Christopher Cardi, Mathew L. Thakur, Christopher A. Barker, Kevin Camphausen, Renato V. Iozzo
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: The antiangiogenic approach to controlling cancer requires a better understanding of angiogenesis and the discovery of new compounds that modulate this key biological process. Here we investigated the role of endorepellin, an angiostatic protein fragment that is derived from the C-terminus of perlecan, a heparan sulfate proteoglycan, in controlling tumor angiogenesis in vivo. Methods: We administered human recombinant endorepellin systemically to mice bearing orthotopic squamous carcinoma xenografts or syngeneic Lewis lung carcinoma tumors. We monitored tumor growth, angiogenesis, metabolism, hypoxia, and mitotic index by using quantitative immunohistochemistry and positron emission tomography scan imaging. In addition, we determined the localization of injected endorepellin using near-infrared labeling and immunohistochemistry of frozen tumor sections. Finally, we isolated tumor-derived endothelial cells and tested whether endorepellin could interact with these cells and disrupt in vitro capillary morphogenesis. All statistical tests were two-sided. Results: Endorepellin specifically targeted the tumor vasculature as determined by immunohistochemical analysis and accumulated in the tumor perivascular zones where it persisted for several days as discrete deposits. This led to inhibition of tumor angiogenesis (as measured by decreased CD31-positive cells, mean control = 1902 CD31-positive pixels, mean endorepellin treated = 343.9, difference between means = 1558, 95% confidence interval [CI] = 1296 to 1820, P <.001), enhanced tumor hypoxia, and a statistically significant decrease in tumor metabolism and mitotic index (as measured by decreased Ki67-positive cells, mean control Ki67 pixels = 5970, mean endorepellin-treated Ki67 pixels = 3644, difference between means = 2326, 95% CI = 1904 to 2749, P <.001) compared to untreated controls. Endorepellin was actively internalized by tumor-derived endothelial cells causing a redistribution of α2β1 integrin such that both proteins colocalized to punctate deposits in the perivascular region. Endorepellin treatment inhibited in vitro capillary morphogenesis of both normal and tumor-derived endothelia. Conclusions: Our results provide support for the hypothesis that endorepellin is an effective antitumor vasculature agent that could be used as a therapeutic modality to combat cancer.
Home or hospital: choices at the end of life
Authors: M. Irwin
Journal: Journal of the Royal Society of Medicine (2004)

I wonder whether Barbara Gomes and Irene Higginson, who wrote the excellent editorial on place of death (September 2004 JRSM 1 ), would consider that a poll of RSM Fellows might provide useful data?I have seen only two formal papers, both from the USA, regarding the medical technology health workers would want for themselves at the end of life.One disclosed that the great majority of doctors in North Carolina would refuse cardiopulmonary resuscitation and tube feeding if terminally ill. 2 The other concluded that physicians and nurses who have extensive exposure to hospitals and sick patients are unlikely to wish aggressive treatment if they become terminally ill, demented, or in a persistent vegetative state. 3 I suspect that most British health professionals would be similarly reluctant to have much medical technology applied to them at the end of life, and, by what seems an obvious extension, would rather die at home than in hospital.Personally, if I do not die suddenly, I want to die at home, in very familiar surroundings, with my beloved cat and partner next to me, and with the music of Shirley Bassey as loud as possible.
Neuroimaging studies of language should connect with (psycho)linguistic theories
Authors: David Poeppel, Susan Johnson
Journal: Behavioral and Brain Sciences (1995)

Abstract PET studies in domains like vision and attention have been successful because the experiments are the product of highly articulated theories. In contrast, the results of PET studies investigating language processing are difficult to interpret. We suggest that this difficulty is due to the more tentative connection of these experiments with the insights of psycholinguistics and linguistic theory.
Low plasma protein nitrotyrosine levels distinguish primary Raynaud's phenomenon from scleroderma
Authors: E J Kingdon
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To investigate the hypothesis that increased formation of reactive nitrogen species may contribute to the vascular pathology that develops in patients with connective tissue disease such as scleroderma. <b>Patients and methods:</b> The level of protein-bound nitrotyrosine in plasma was measured by stable isotope dilution gas chromatography/negative ion chemical ionisation mass spectrometry in 11 patients with primary Raynaud's phenomenon, 37 with scleroderma, 13 with chronic renal impairment, and in 23 healthy controls. <b>Results:</b> Plasma protein-bound nitrotyrosine was markedly decreased in patients with primary Raynaud's phenomenon (mean (SEM) 0.60 (0.06) ng/mg dry protein) compared with patients with scleroderma (1.78 (0.21) ng/mg protein), chronic renal impairment (1.42 (0.17) ng/mg protein) or healthy controls (1.63±0.15 ng/mg protein, ANOVA p&lt;0.001). <b>Conclusion:</b> These data suggest that there is decreased nitration of plasma proteins, or increased degradation of nitrated proteins from the circulation of patients with primary but not secondary Raynaud's phenomenon.
Circulating Inflammation Markers and Prospective Risk for Lung Cancer
Authors: Meredith S. Shiels, Ruth M. Pfeiffer, Allan Hildesheim, Eric A. Engels, Troy J. Kemp, Ju-Hyun Park, Hormuzd A. Katki, Jill Koshiol, Gloriana Shelton, Neil E. Caporaso, Ligia A. Pinto, Anil K. Chaturvedi
Journal: JNCI Journal of the National Cancer Institute (2013)

Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating inflammation markers with lung cancer. We conducted a nested case–control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively. Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk ( Ptrend across marker categories < .05), including acute-phase proteins (C-reactive protein [CRP], serum amyloid A [SAA]), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 [sTNFRII]), anti-inflammatory cytokines (interleukin 1 receptor antagonist [IL-1RA]), lymphoid differentiation cytokines (interleukin 7 [IL-7]), growth factors (transforming growth factor alpha [TGF-A]), and chemokines (epithelial neutrophil-activating peptide 78 [ENA 78/CXCL5], monokine induced by gamma interferon [MIG/CXCL9], B cell–attracting chemokine 1 [BCA-1/CXCL13], thymus activation regulated chemokine [TARC/CCL17], macrophage-derived chemokine [MDC/CCL22]). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile [Q] 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking. Some circulating inflammation marker levels are associated with prospective lung cancer risk.
Nilima Choudhury, nee Kundu Philip Ross Harben Monica Cynthia Lewin Rosemarie Dorothy Lincoln Merlin Marshall George Leonard Plester John Albert Rich Douglas William Cumming Smith Geoffrey Harvey Martin Stanley-Jones Valentine Andrew James Swain Szeming Sze William Waugh
Authors: P. Choudhury, B W Maitland, L. Chippindale, W. Jeffcoate, R M Kalbag, W F Hendry, A. J Rich, I. M Duguid, J Thorley, A N Chakraborty, J. Lister, D. S. Wei, N. J Barton, W A. Wallace
Journal: BMJ (1999)

Calcutta 1937; q Calcutta 1962), died suddenly while on holiday in India on 12 March 1998 three weeks before her retirement.The third of six daughters of a jute merchant, my mother was encouraged to pursue a career in medicine.After arriving in Britain in 1968 she initially trained in obstetrics and gynaecology before joining her husband in general practice.She continued to work despite several major illnesses.She always dressed exquisitely and was an accomplished dressmaker.She had a passion for gardening, including the cultivation of bonsai, and was interested in Bengali literature and classical music.She leaves a husband, Sadhan, and me, her daughter (both doctors).