tbuckley/cabot-search huggingface dataset:
Genomic Architecture Characterizes Tumor Progression Paths and Fate in Breast Cancer Patients
Authors: Hege G. Russnes, Hans Kristian Moen Vollan, Ole Christian Lingjærde, Alexander Krasnitz, Pär Lundin, Bjørn Naume, Therese Sørlie, Elin Borgen, Inga H. Rye, Anita Langerød, Suet-Feung Chin, Andrew E. Teschendorff, Philip J. Stephens, Susanne Månér, Ellen Schlichting, Lars O. Baumbusch, Rolf Kåresen, Michael P. Stratton, Michael Wigler, Carlos Caldas, Anders Zetterberg, James Hicks, Anne-Lise Børresen-Dale
Journal: Science Translational Medicine (2010)

This study demonstrates the relation among structural genomic alterations, molecular subtype, and clinical behavior and shows that an objective score of genomic complexity can provide independent prognostic information in breast cancer.
The Making of Rehabilitation: A Political Economy of Medical Specialization, 1890-1980
Authors: D. Cantor
Journal: Annals of the Rheumatic Diseases (1990)

at the Cite des Sciences et de l'Industrie de la Villette.On the first morning there will be a plenary session on patellofemoral osteoarthritis and in the afternoon parallel sessions on bone and calcium metabolism, pharmacology and therapeutics, and medical social aspects.On the second morning there will be a combined meeting with the British Society for Rheumatology, followed in the afternoon by parallel sessions on immunology ofinflammatoryarthritis, epidemiology, and free subjects.A plenary session on multiple myeloma will be held on the third morning.
HLA-G in human reproduction: aspects of genetics, function and pregnancy complications
Authors: Thomas Vauvert F. Hviid
Journal: Human Reproduction Update (2005)

The non-classical human leukocyte antigen (HLA) class Ib genes, HLA-E, -G and -F, are located on chromosome 6 in the human major histocompatibility complex (MHC). HLA class Ib antigens resemble the HLA class Ia antigens in many ways, but several major differences have been described. This review will, in particular, discuss HLA-G and its role in human reproduction and in the human MHC. HLA-G seems to be important in the modulation of the maternal immune system during pregnancy and thereby the maternal acceptance of the semiallogenic fetus. Recent findings regarding aspects of HLA-G polymorphism, the possible significance of this polymorphism in respect to HLA-G function and certain complications of pregnancy (such as pre-eclampsia and recurrent spontaneous abortions (RSA)) are discussed together with possible importance to IVF. Finally, aspects of a possible role of HLA-G in organ transplantation and in inflammatory or autoimmune disease, and of HLA-G in an evolutionary context, are also briefly examined.
FGFR-Mediated Reactivation of MAPK Signaling Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal Tumors
Authors: Fang Li, Hung Huynh, Xiaoyan Li, David A. Ruddy, Youzhen Wang, Richard Ong, Pierce Chow, Shumei Qiu, Angela Tam, Daniel P. Rakiec, Robert Schlegel, John E. Monahan, Alan Huang
Journal: Cancer Discovery (2015)

Abstract Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GIST). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines and improved efficacy in patient-derived GIST xenografts. In addition, inhibition of MAPK signaling by imatinib was not sustained in GIST cells. An ERK rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregulation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells. Significance: We here show that FGFR-mediated reactivation of the MAPK pathway attenuates the antiproliferation effects of imatinib in GISTs. The imatinib-induced ERK rebound can be repressed by the FGFR inhibitor BGJ398, and combined KIT and FGFR inhibition leads to increased efficacy in vitro and in patient-derived xenografts. Cancer Discov; 5(4); 438–51. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 333
Reply to L.C. Panasci and D.S.-W. Tan et al
Authors: Bente Holm, Anders Mellemgaard, Torsten Skov, Birgit Guldhammer Skov
Journal: Journal of Clinical Oncology (2010)

We would like to thank Panasci 1 and Tan 2 for their interest in our article measuring ERCC1 by immunohistochemistry in patients with non-small-cell lung cancer treated with carboplatin and gemcitabine. 3The points raised in the comments are all well taken.We agree that predictive markers in non-small-cell lung cancer are much needed and that validation of the biomarkers is a key issue before clinical application.We are also well aware of the limitations of retrospective studies.Regarding the possible confounding effect of stage, a multivariate analysis including stage showed almost identical parameter estimates for H-score and the interaction between H-score and gender.Thus the reported effects were not confounded by stage.Concerning the comment on treatments, the material used for detection of ERCC1 was diagnostic material.None of the patients had any concurrent chemoradiotherapy. 3n order to make a comparable study, we designed our study exactly as Olaussen et al. 4 We used the same antibody, well aware that Zeng et al 5 were unable to show that ERCC1 mRNA expression and ERCC1 protein expression was correlated in tumor specimens.This work did not validate the 8F1 monoclonal antibody.Because of the concerns about the antibody by Niederhofer et al, 6 Olaussen et al 7 later examined the specificity of the 8F1 monoclonal antibody and found that the 8F1 monoclonal antibody detects ERCC1 in a specific manner.The protein expression of ERCC1 was assessed semiquantitatively using the same scoring system as Olaussen et al 4 to overcome the issue that different scoring systems are not comparable.At the time the study was done, there were few papers and comments concerning the 8F1 monoclonal antibody.We agree that it is challenging to equate levels of expression of a single protein with repair capacity.Antibodies usually staining the nucleus can occasionally be seen staining the cytoplasm. 8The biologic consequence of the occasional staining of ERCC1 in the cytoplasm has not yet been clarified. 9As for now, measuring ERCC1 as mRNA or protein expression is not applicable for standard use in the everyday clinic. 10
Second Malignant Neoplasms Among Long-Term Survivors of Hodgkin’s Disease: A Population-Based Evaluation Over 25 Years
Authors: Graça M. Dores, Catherine Metayer, Rochelle E. Curtis, Charles F. Lynch, E. Aileen Clarke, Bengt Glimelius, Hans Storm, Eero Pukkala, Flora E. van Leeuwen, Eric J. Holowaty, Michael Andersson, Tom Wiklund, Timo Joensuu, Mars B. van’t Veer, Marilyn Stovall, Mary Gospodarowicz, Lois B. Travis
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To quantify the relative and absolute excess risks (AER) of site-specific second cancers, in particular solid tumors, among long-term survivors of Hodgkin’s disease (HD) and to assess risks according to age at HD diagnosis, attained age, and time since initial treatment. PATIENTS AND METHODS: Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed. RESULTS: Two thousand one hundred fifty-three second cancers (observed-to-expected ratio [O/E] = 2.3; 95% confidence interval [CI] = 2.2 to 2.4), including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) were reported. Cancers of the lung (observed [Obs] = 377; O/E = 2.9), digestive tract (Obs = 376; O/E = 1.7), and female breast (Obs = 234; O/E = 2.0) accounted for the largest number of subsequent malignancies. Twenty-five years after HD diagnosis, the actuarial risk of developing a solid tumor was 21.9%. The relative risk of solid neoplasms decreased with increasing age at HD diagnosis, however, patients aged 51 to 60 years at HD diagnosis sustained the highest cancer burden (AER = 79.2/10,000 patients/year). After a progressive rise in relative risk and AER of all solid tumors over time, there was an apparent downturn in risk at 25 years. Temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, female breast, bladder, thyroid, and bone/connective tissue were suggestive of a radiogenic effect. CONCLUSION: Significantly increased risks of second cancers were observed in all HD age groups. Although significantly elevated risks of stomach, female breast, and uterine cervix cancers persisted for 25 years, an apparent decrease in relative risk and AER of solid tumors at other sites is suggested.
Activation of mTORC1 in Collecting Ducts Causes Hyperkalemia
Authors: Zhenguo Chen, Heling Dong, Chunhong Jia, Qiancheng Song, Juan Chen, Yue Zhang, Pinglin Lai, Xiaorong Fan, Xuan Zhou, Miao Liu, Jun Lin, Cuilan Yang, Ming Li, Tianming Gao, Xiaochun Bai
Journal: Journal of the American Society of Nephrology (2013)

Mutation of TSC (encoding tuberous sclerosis complex protein) and activation of mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of several renal diseases, such as diabetic nephropathy and polycystic kidney disease. However, the role of mTOR in renal potassium excretion and hyperkalemia is not known. We showed that mice with collecting-duct (CD)–specific ablation of TSC1 (CDTsc1KO) had greater mTOR complex 1 (mTORC1) activation in the CD and demonstrated features of pseudohypoaldosteronism, including hyperkalemia, hyperaldosteronism, and metabolic acidosis. mTORC1 activation caused endoplasmic reticulum stress, columnar cell lesions, and dedifferentiation of CD cells with loss of aquaporin-2 and epithelial-mesenchymal transition-like phenotypes. Of note, mTORC1 activation also reduced the expression of serum- and glucocorticoid-inducible kinase 1, a crucial regulator of potassium homeostasis in the kidney, and decreased the expression and/or activity of epithelial sodium channel-α, renal outer medullary potassium channel, and Na+, K+-ATPase in the CD, which probably contributed to the aldosterone resistance and hyperkalemia in these mice. Rapamycin restored these phenotypic changes. Overall, this study identifies a novel function of mTORC1 in regulating potassium homeostasis and demonstrates that loss of TSC1 and activation of mTORC1 results in dedifferentiation and dysfunction of the CD and causes hyperkalemia. The CDTsc1KO mice provide a novel model for hyperkalemia induced exclusively by dysfunction of the CD.
Gene expression profiles of primary colorectal carcinomas, liver metastases, and carcinomatoses
Authors: Kristine Kleivi, Guro E Lind, Chieu B Diep, Gunn I Meling, Lin T Brandal, Jahn M Nesland, Ola Myklebost, Torleiv O Rognum, Karl-Erik Giercksky, Rolf I Skotheim, Ragnhild A Lothe
Journal: Molecular Cancer (2007)

Despite the fact that metastases are the leading cause of colorectal cancer deaths, little is known about the underlying molecular changes in these advanced disease stages. Few have studied the overall gene expression levels in metastases from colorectal carcinomas, and so far, none has investigated the peritoneal carcinomatoses by use of DNA microarrays. Therefore, the aim of the present study is to investigate and compare the gene expression patterns of primary carcinomas (n = 18), liver metastases (n = 4), and carcinomatoses (n = 4), relative to normal samples from the large bowel.Transcriptome profiles of colorectal cancer metastases independent of tumor site, as well as separate profiles associated with primary carcinomas, liver metastases, or peritoneal carcinomatoses, were assessed by use of Bayesian statistics. Gains of chromosome arm 5p are common in peritoneal carcinomatoses and several candidate genes (including PTGER4, SKP2, and ZNF622) mapping to this region were overexpressed in the tumors. Expression signatures stratified on TP53 mutation status were identified across all tumors regardless of stage. Furthermore, the gene expression levels for the in vivo tumors were compared with an in vitro model consisting of cell lines representing all three tumor stages established from one patient.By statistical analysis of gene expression data from primary colorectal carcinomas, liver metastases, and carcinomatoses, we are able to identify genetic patterns associated with the different stages of tumorigenesis.
Small brains and minimalist emulation: When is an internal model no longer a model?
Authors: Barbara Webb
Journal: Behavioral and Brain Sciences (2004)

Many of Grush's arguments should apply equally to animals with small brains, for which the capacity to internally model the body and environment must be limited. The dilemma may be solved by making only very approximate predictions, or only attempting to derive a “high-level” prediction from “high-level” output. At the extreme, in either case, the “emulation” step becomes trivial.
Pemetrexed Safety and Pharmacokinetics in Patients with Third-Space Fluid
Authors: Nicolas J. Dickgreber, Jens Benn Sorensen, Luis G. Paz-Ares, Tine Kjestrup Schytte, Jane E. Latz, Karen B. Schneck, Zheng Yuan, José Miguel Sanchez-Torres
Journal: Clinical Cancer Research (2010)

Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated.Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF.Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF.No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.
Effect of Age on Excess Mortality in Obesity
Authors: Ralf Bender
Journal: JAMA (1999)

ContextThe effect of age on excess mortality from all causes associated with obesity is controversial.Few studies have investigated the association between body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), age, and mortality, with sufficient numbers of subjects at all levels of obesity.Objective To assess the effect of age on the excess mortality associated with all degrees of obesity.Design Prospective cohort study.Setting and Participants A total of 6193 obese patients with mean (SD) BMI of 36.6 (6.1) kg/m 2 and mean (SD) age of 40.4 (12.9) years who had been referred to the obesity clinic of Heinrich-Heine University, Du ¨sseldorf, Germany, between 1961 and 1994.Median follow-up time was 14.8 years.Main Outcome Measure All-cause mortality through 1994 among 6053 patients for whom follow-up data were available (1028 deaths) analyzed as standardized mortality ratios (SMRs) using the male-female population of the geographic region (North Rhine Westphalia) as reference. ResultsThe cohort was grouped into approximate quartiles according to age (18-29, 30-39, 40-49, and 50-74 years) and BMI (25 to Ͻ32, 32 to Ͻ36, 36 to Ͻ40, and Ն40 kg/m 2 ) at baseline.The SMRs showed a significant excess mortality with an SMR for men of 1.67 (95% confidence interval, 1.51-1.85;PϽ.001) and an SMR for women of 1.45 (95% confidence interval, 1.34-1.57;PϽ.001).The excess mortality associated with obesity declined with age.For men, the SMRs of the 4 age groups were 2.46, 2.30, 1.99, and 1.31, respectively; for women, they were 1.81, 2.10, 1.70, and 1.26, respectively (Poisson trend test, PϽ.001).The SMRs increased with BMI but, within each BMI group, the SMRs decreased with age.The lowest SMRs (for men, 1.01; for women, 0.91) were obtained for patients older than 50 years with BMIs of 25 to less than 32 kg/m 2 .Thus, older men and women at a BMI range of 25 to less than 32 kg/m 2 had no excess mortality.The highest SMRs (for men, 4.22; for women, 3.79) were calculated for the patients aged 18 to 29 years with a BMI of 40 kg/m 2 or higher. ConclusionsIn this large cohort of obese persons, risk of death increased with body weight, but obesity-related excess mortality declined with age at all levels of obesity.
What proportion of youth are physically active? Measurement issues, levels and recent time trends
Authors: Ulf Ekelund, Grant Tomkinson, Neil Armstrong
Journal: British Journal of Sports Medicine (2011)

The aim of this review is to summarise issues surrounding the measurement of physical activity (PA) by self-report and accelerometry in youth (2-18 years old). Current levels and temporal trends in PA and sport participation and the effect of assessment method on data interpretation will be summarised.Relevant papers were extracted from a computerised literature search of MEDLINE and personal databases. Additional papers were extracted from reference lists of recently published reviews.The criterion validity (direct comparison with an objective method) of self-reported instruments is low to moderate, with correlation coefficients generally between 0.3 and 0.4. Self-report instruments overestimate the intensity and duration of PA and sport participation. The interpretation of PA data from accelerometry is a challenge, and specific issues include the definition of intensity thresholds and the influence of age on intensity thresholds. Recent data on self-reported PA in youth suggest that between 30% and 40% are sufficiently active. Prevalence values for sufficiently active youth measured by accelerometry range between 1% and 100%, depending on the intensity thresholds used. Sport participation is likely to contribute to higher levels of PA. The available evidence does not support the notion that PA levels and sport participation in youth have declined in recent decades.The number of youth meeting current PA guidelines varies by assessment method and the intensity thresholds used when PA is measured by accelerometry. The available evidence does not firmly support the notion that PA in young people has declined during the last decades. It is unlikely that any self-report method is sufficiently accurate for examining cross-cultural differences and temporal trends in young people's PA and sport participation over time. Surveillance systems therefore need to strive for an international standardisation using objective measurements of PA to complement existing self-report instruments.
Long-term treatment with continuous positive airway pressure improves quality of life in obstructive sleep apnoea syndrome
Authors: B.M. Sanner, J Klewer, A. Trumm, W Randerath, I. Kreuzer, W. Zidek
Journal: European Respiratory Journal (2000)

Continuous positive airway pressure (CPAP) is an established treatment of obstructive sleep apnoea syndrome (OSAS). While it is known that CPAP reverses the pathological breathing pattern and improves daytime sleepiness, there are no sufficient data on the long-term influence of CPAP on quality of life in patients with OSAS. Thirty-nine patients with polysomnographically verified OSAS (apnoea/hypopnoea index (AHI): (mean+/-SD) 46.8+/-21.8 events x h(-1)) were prospectively studied. All patients answered three quality of life measures (Complaint List, Nottingham Health Profile Part 1 (NHP), and Verbal Analogue-Scale "quality of life") prior to the initiation of CPAP therapy. After a mean of 9 months they were re-evaluated by polysomnography, and completed the questionnaires once again. As expected, CPAP was effective in treating the sleep-related breathing disorder. AHI decreased significantly from (mean+/-SD) 46.8+/-21.8 events x h(-1) to 3.3+/-6.3 events x h(-1), and minimum oxygen saturation increased from 77.1+/-9.3% to 89.9+/-3.4%, while body mass index did not change significantly (31.3+/-5.4 versus 30.8+/-4.8 kg x m(-2)). During long-term treatment with CPAP the Complaint List revealed a significant improvement of the extent of subjective impairment due to physical and general complaints (26.4+/-9.9 versus 20.4+/-11.1), and NHP a significant improvement of emotional reactions (19.8+/-21.7 versus 11.1+/-14.0) and energy (50.8+/-36.6 versus 32.1+/-36.7), but not of pain, physical mobility, sleep, social isolation, and quality of life as assessed by the It is concluded that long-term continuous positive airway pressure therapy is effective in improving not only pathological breathing patterns but also parameters that estimate quality of life in patients with obstructive sleep apnoea syndrome.
Prospective Study of Survival Outcomes in Non-Hodgkin's Lymphoma Patients With Rheumatoid Arthritis
Authors: Ted R. Mikuls, Justin O. Endo, Susan E. Puumala, Patricia A. Aoun, Natalie A. Black, James R. O'Dell, Julie A. Stoner, Eugene C. Boilesen, Martin A. Bast, Debra A. Bergman, Kay M. Ristow, Melissa Ooi, James O. Armitage, Thomas M. Habermann
Journal: Journal of Clinical Oncology (2006)

Although preliminary studies suggest that non-Hodgkin's lymphoma (NHL) complicating rheumatoid arthritis (RA) may be a clinically distinct entity compared with that occurring in the general population, studies examining the impact of antecedent RA on survival are limited. In this prospective study, we examined the association of RA with survival in patients with NHL.Using two large lymphoma registries, we identified patients with evidence of RA preceding NHL. Survival in RA patients was compared with that of controls using proportional hazards regression, adjusting for the effects of age, sex, lymphoma diagnosis-to-treatment lag time, calendar year, International Prognostic Index score, and NHL grade.The frequency of NHL subtypes was similar in RA patients (n = 65) and controls (n = 1,530). Compared with controls, RA patients with NHL had similar overall survival (hazard ratio [HR] = 0.95; 95% CI, 0.70 to 1.30) but were at lower risk of lymphoma progression or relapse (HR = 0.41; 95% CI, 0.25 to 0.68) or death related to lymphoma or its treatment (HR = 0.60; 95% CI, 0.37 to 0.98), but were more than twice as likely to die from causes unrelated to lymphoma (HR = 2.16; 95% CI, 1.33 to 3.50).RA is associated with improved NHL-related outcomes, including a 40% reduced risk of death occurring as a result of lymphoma or its treatment and approximately a 60% lower risk of lymphoma relapse or progression compared with non-RA controls. However, the survival advantage gained in RA from the acquisition of lymphomas with favorable prognoses is negated through an increased mortality from other comorbid conditions.