tbuckley/cabot-search huggingface dataset:
Association of HER2/ErbB2 Expression and Gene Amplification with Pathologic Features and Prognosis in Esophageal Adenocarcinomas
Authors: Harry H. Yoon, Qian Shi, William R. Sukov, Anne E. Wiktor, Maliha Khan, Christopher A. Sattler, Axel Grothey, Tsung-Teh Wu, Robert B. Diasio, Robert B. Jenkins, Frank A. Sinicrope
Journal: Clinical Cancer Research (2012)

Abstract Purpose: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). Experimental Design: HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3–4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Results: Overall, 17% of EACs were HER2 positive (i.e., IHC3+ or IHC2+ with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1–2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (Pinteraction = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35–0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. Conclusions: HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival. Clin Cancer Res; 18(2); 546–54. ©2012 AACR.
Mobile Phone Use and Brain Tumors in Children and Adolescents: A Multicenter Case-Control Study
Authors: D. Aydin, M. Feychting, J. Schuz, T. Tynes, T. V. Andersen, L. S. Schmidt, A. H. Poulsen, C. Johansen, M. Prochazka, B. Lannering, L. Klaeboe, T. Eggen, D. Jenni, M. Grotzer, N. Von der Weid, C. E. Kuehni, M. Roosli
Journal: JNCI Journal of the National Cancer Institute (2011)

BackgroundIt has been hypothesized that children and adolescents might be more vulnerable to possible health effects from mobile phone exposure than adults. We investigated whether mobile phone use is associated with brain tumor risk among children and adolescents.
Glycosylation of fibroblast growth factor receptor 4 is a key regulator of fibroblast growth factor 19-mediated down-regulation of cytochrome P450 7A1
Authors: Vassilis Triantis, Eirikur Saeland, Nora Bijl, Ronald P. Oude‐Elferink, Peter L. M. Jansen
Journal: Hepatology (2010)

De novo bile acid synthesis in the liver needs to be tightly regulated in order to maintain optimal bile flow and prevent cholestasis. In the liver, fibroblast growth factor 19 (FGF19) regulates bile acid synthesis by down-regulating messenger RNA levels of cytochrome P450 7A1 (CYP7A1). FGF19 acts through fibroblast growth factor receptor 4 (FGFR4), and β-Klotho has recently been recognized as a modulator of FGFR4 activity. However, its precise mechanism of action has not been thoroughly described. We show here that β-Klotho is an endoplasmic reticulum–resident protein that affects the cellular abundance of different FGFR4 glycoforms. β-Klotho binds and directs the core glycoform of FGFR4 to the proteasome, and it allows only a terminal glycoform to reach the plasma membrane. Only the terminal FGFR4 glycoform is phosphorylated upon FGF19 treatment of HepG2 cells, and this shows that only fully glycosylated FGFR4 is active in CYP7A1 down-regulation. Conclusion: β-Klotho enhances FGF19 signaling by binding the inactive, core-glycosylated FGFR4 and preventing it from reaching the surface. These results indicate that β-Klotho is an indirect regulator of FGFR4, whereas glycosylation is the master switch for FGF19 activity and regulation of bile acid synthesis. (HEPATOLOGY 2010)
Osteoporosis in rheumatological practice: questions to be answered.
Authors: C Cooper
Journal: Annals of the Rheumatic Diseases (1995)

Osteoporosis in rheumatological practice: questions to be answered Osteoporosis, the most common metabolic bone disorder in western populations, is now firmly positioned on the agenda of clinical rheumatologists in Britain and the United States.While this has been the order of the day throughout mainland Europe for decades, our own com- mitment to the management of osteoporosis is more recent.The change has much to do with altered per- ceptions of the disorder: we see a lot of it; we can measure it; and we can do something about it.While there is truth in each of these observations (and support, in the rapidly growing numbers of papers, congresses, and journals devoted to osteoporosis), the challenge of translating much of this recent knowledge into coherent, effective preventive and therapeutic strategies remains.To meet this challenge, we must have a clear idea of what we do, and do not, know.This editorial addresses this problem, with regard to two issues relevant to all rheumatologists-the clinical uses of bone densitometry, and the prevention of steroid induced osteoporosis.Although several techniques have been developed in recent years for the non-invasive measurement of bone density,' the most precise and widely used method is dual energy x ray absorptiometry (DXA).Initially developed to
Anti-immunoglobulin antibodies. I. Expression of cross-reactive idiotypes and Ir gene control of the response to IgG2a of the b allotype.
Authors: C Bona, P K Mongini, K E Stein, W E Paul
Journal: The Journal of Experimental Medicine (1980)

The anti-allotype antibody response to the b allotypic form of IgG2a is regulated by major histocompatibility complex (MHC)-encoded immune response (Ir) genes. Mice of d, b, p, q, r, and s haplotypes make a strong anti-allotype response on immunization with the CBPC101 myeloma protein (IgG2ab), whereas mice of the k, m, a, a1, u, and z haplotypes made no, or a very poor, response. All responder strains produce anti-IgG2ab antibodies which share common idiotypes (Id) without relation to the allelic forms of the Ig heavy-chain-constant region genes that the responding mice possess. Isoelectric focusing analysis of the anti-allotype antibodies produced in various strains of mice showed that they are of limited heterogeneity and quite similar from strain to strain. Five out of six hybridoma products with specificity for CBPC101 allotype expressed cross-reactive idiotypes (IdX). Two of hybridoma products expressing IdX identify CH3-domain determinants, and one has been assigned a CH2-domain specificity.
Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism
Authors: Gabriel Frampton, Pietro Invernizzi, Francesca Bernuzzi, Hae Yong Pae, Matthew Quinn, Darijana Horvat, Cheryl Galindo, Li Huang, Matthew McMillin, Brandon Cooper, Lorenza Rimassa, Sharon DeMorrow
Journal: Gut (2011)

Background and objectives Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. The growth factor, progranulin, is overexpressed in a number of tumours. The study aims were to assess the expression of progranulin in cholangiocarcinoma and to determine its effects on tumour growth. Methods The expression and secretion of progranulin were evaluated in multiple cholangiocarcinoma cell lines and in clinical samples from patients with cholangiocarcinoma. The role of interleukin 6 (IL-6)-mediated signalling in the expression of progranulin was assessed using a combination of specific inhibitors and shRNA knockdown techniques. The effect of progranulin on proliferation and Akt activation and subsequent effects of FOXO1 phosphorylation were assessed in vitro. Progranulin knockdown cell lines were established, and the effects on cholangiocarcinoma growth were determined. Results Progranulin expression and secretion were upregulated in cholangiocarcinoma cell lines and tissue, which were in part via IL-6-mediated activation of the ERK1/2/RSK1/C/EBPβ pathway. Blocking any of these signalling molecules, by either pharmacological inhibitors or shRNA, prevented the IL-6-dependent activation of progranulin expression. Treatment of cholangiocarcinoma cells with recombinant progranulin increased cell proliferation in vitro by a mechanism involving Akt phosphorylation leading to phosphorylation and nuclear extrusion of FOXO1. Knockdown of progranulin expression in cholangiocarcinoma cells decreased the expression of proliferating cellular nuclear antigen, a marker of proliferative capacity, and slowed tumour growth in vivo. Conclusions Evidence is presented for a role for progranulin as a novel growth factor regulating cholangiocarcinoma growth. Specific targeting of progranulin may represent an alternative for the development of therapeutic strategies.
Cortical Control of Arm Movements: A Dynamical Systems Perspective
Authors: Krishna V. Shenoy, Maneesh Sahani, Mark M. Churchland
Journal: Annual Review of Neuroscience (2013)

Our ability to move is central to everyday life. Investigating the neural control of movement in general, and the cortical control of volitional arm movements in particular, has been a major research focus in recent decades. Studies have involved primarily either attempts to account for single-neuron responses in terms of tuning for movement parameters or attempts to decode movement parameters from populations of tuned neurons. Even though this focus on encoding and decoding has led to many seminal advances, it has not produced an agreed-upon conceptual framework. Interest in understanding the underlying neural dynamics has recently increased, leading to questions such as how does the current population response determine the future population response, and to what purpose? We review how a dynamical systems perspective may help us understand why neural activity evolves the way it does, how neural activity relates to movement parameters, and how a unified conceptual framework may result.
Proteasome inhibition and stress compromise the heart in chemotherapy
Authors: Y. E.A. Appelman, P. A. Doevendans
Journal: Cardiovascular Research (2008)

Several new therapeutic options are opening up for the treatment of haematological and solid malignancies. Although the effects on the malignancies can be dramatic, the collateral damage can be devastating as well. The concept of gene therapy was to develop cell-type-specific techniques, and similar expectations were raised with the concept of targeting cells specifically by binding selected receptors or other proteins. Yet, most therapies that have reached the clinic are not specific and will therefore influence all tissues and organs. This will make the heart a vulnerable organ, as it has limited or no regenerative capacity.

The best known and most frequently used therapy in cancer are drugs from the anthracycline family, including doxorubicin. The exact mechanism of cardiotoxicity is still not completely clear, but one prevailing hypothesis involves oxidative stress and the production of free radicals, interference with the sodium–potassium pump of the sarcolemma, and interference with the mitochondrial electron-transport chain. This latter may explain the severe cardiotoxic effect of doxorubicin as the heart is a mitochondria-rich organ.1 Of patients treated with anthracyclines, nearly 17% develop cardiomyopathy, as reported for a group of sarcoma patients.2

An unexpected surprise came with the introduction of monoclonal antibodies … 

*Corresponding author. +31 88 755 9801; fax: +31 30 254 2155. E-mail address: p.doevendans{at}umcutrecht.nl
Developing a Clinically Feasible Personalized Medicine Approach to Pediatric Septic Shock
Authors: Hector R. Wong, Natalie Z. Cvijanovich, Nick Anas, Geoffrey L. Allen, Neal J. Thomas, Michael T. Bigham, Scott L. Weiss, Julie Fitzgerald, Paul A. Checchia, Keith Meyer, Thomas P. Shanley, Michael Quasney, Mark Hall, Rainer Gedeit, Robert J. Freishtat, Jeffrey Nowak, Raj S. Shekhar, Shira Gertz, Emily Dawson, Kelli Howard, Kelli Harmon, Eileen Beckman, Erin Frank, Christopher J. Lindsell
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Using microarray data, we previously identified gene expression-based subclasses of septic shock with important phenotypic differences. The subclass-defining genes correspond to adaptive immunity and glucocorticoid receptor signaling. Identifying the subclasses in real time has theranostic implications, given the potential for immune-enhancing therapies and controversies surrounding adjunctive corticosteroids for septic shock.To develop and validate a real-time subclassification method for septic shock.Gene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (NanoString nCounter) and visualized using gene expression mosaics. Study subjects (n = 168) were allocated to the subclasses using computer-assisted image analysis and microarray-based reference mosaics. A gene expression score was calculated to reduce the gene expression patterns to a single metric. The method was tested prospectively in a separate cohort (n = 132).The NanoString-based data reproduced two septic shock subclasses. As previously, one subclass had decreased expression of the subclass-defining genes. The gene expression score identified this subclass with an area under the curve of 0.98 (95% confidence interval [CI95] = 0.96-0.99). Prospective testing of the subclassification method corroborated these findings. Allocation to this subclass was independently associated with mortality (odds ratio = 2.7; CI95 = 1.2-6.0; P = 0.016), and adjunctive corticosteroids prescribed at physician discretion were independently associated with mortality in this subclass (odds ratio = 4.1; CI95 = 1.4-12.0; P = 0.011).We developed and tested a gene expression-based classification method for pediatric septic shock that meets the time constraints of the critical care environment, and can potentially inform therapeutic decisions.
EXPERIMENTAL STUDIES OF THE NASOPHARYNGEAL SECRETIONS FROM INFLUENZA PATIENTS
Authors: Peter K. Olitsky, Frederick L. Gates
Journal: The Journal of Experimental Medicine (1923)

Thirteen volunteers were injected subcutaneously with a vaccine prepared from two strains of Bacterium pneumosintes. Three doses were given corresponding, by opacity tests, to 1,000, 2,000, and 2,000 million staphylococci. The intervals between the several injections were 5 and 8 days. Local reactions of mild and transitory character only were noted. Constitutional reactions, also mild and transitory, consisting of headache, depression, and generalized muscular pains, were infrequently observed. None of the men was prevented by the vaccine from pursuing his ordinary duties. The vaccinations induce a transitory leucocytosis and lead to the appearance of specific agglutinins in the blood serum.
Complex Selection on Intron Size in Cryptococcus neoformans
Authors: S. S. Hughes, C. O. Buckley, D. E. Neafsey
Journal: Molecular Biology and Evolution (2008)

We conducted a genome-wide analysis of the roles of mutation and selection in sculpting intron size in the fungal pathogen Cryptococcus neoformans. We find that deletion rate is positively associated with intron length and that insertion rate exhibits a weak negative association with intron length. These patterns suggest that long introns as well as extremely short introns in this unusually intron-rich fungal genome are in mutation–selection disequilibrium and that the proportion of constrained functional sequence in introns does not scale linearly with size. We find that untranslated region introns are longer than coding-region introns and that first introns are substantially longer than subsequent introns, suggesting heterogeneous distribution of constrained functional sequence and/or selective pressures on intron size within genes. In contrast to Drosophila, we find a positive correlation between dN and first intron or last intron length and a negative correlation between dN and internal intron length. This contrasting pattern may indicate that terminal introns and internal introns are differentially subject to hypothesized selection pressures modulating intron size and provides further evidence of widespread selective constraints on noncoding sequences.
Increased Angiogenesis and Lymphangiogenesis in Inflammatory <b> <i>versus</i> </b> Noninflammatory Breast Cancer by Real-Time Reverse Transcriptase-PCR Gene Expression Quantification
Authors: Ilse Van der Auwera, Steven J. Van Laere, Gert G. Van den Eynden, Ina Benoy, Peter van Dam, Cecile G. Colpaert, Stephen B. Fox, Helen Turley, Adrian L. Harris, Eric A. Van Marck, Peter B. Vermeulen, Luc Y. Dirix
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Inflammatory breast cancer is a distinct and aggressive form of locally advanced breast cancer with unique clinical and pathological features. Recently, histologic evidence of intense angiogenesis was found in inflammatory breast cancer specimens. The aim of this study was to confirm the angiogenic phenotype of inflammatory breast cancer and to investigate its potential to induce lymphangiogenesis. Experimental Design: Real-time quantitative reverse transcriptase-PCR was used to measure levels of mRNA of tumor angiogenesis and lymphangiogenesis-related factors [vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, Flt-1, KDR, Flt-4, Ang-1, Ang-2, Tie-1, Tie-2, cyclooxygenase-2, fibroblast growth factor-2 (FGF-2), Egr-1, Prox-1, and LYVE-1] in tumor specimens of 16 inflammatory breast cancer and 20 noninflammatory breast cancer patients. Tissue microarray technology and immunohistochemistry were used to study differential protein expression of some of the angiogenic factors in inflammatory breast cancer and noninflammatory breast cancer. Active lymphangiogenesis was further assessed by measuring lymphatic endothelial cell proliferation. Results: Inflammatory breast cancer specimens had significantly higher mRNA expression levels than noninflammatory breast cancer specimens of the following genes: KDR (P = 0.033), Ang-1, (P = 0.0001), Tie-1 (P = 0.001), Tie-2 (P = 0.001), FGF-2 (P = 0.002), VEGF-C (P = 0.001), VEGF-D (P = 0.012), Flt-4 (P = 0.001), Prox-1 (P = 0.005), and LYVE-1 (P = 0.013). High mRNA levels of FGF-2 and cyclooxygenase-2 corresponded to increased protein expression by immunohistochemistry. Inflammatory breast cancer specimens contained significantly higher fractions of proliferating lymphatic endothelial cells than noninflammatory breast cancer specimens (P = 0.033). Conclusions: Using real-time quantitative reverse transcriptase-PCR and immunohistochemistry, we confirmed the intense angiogenic activity in inflammatory breast cancer and demonstrated the presence of active lymphangiogenesis in inflammatory breast cancer. This may help explain the high metastatic potential of inflammatory breast cancer by lymphatic and hematogenous route. Both pathways are potential targets for the treatment of inflammatory breast cancer.
Childhood Cancer Survivor Study Participants' Perceptions and Understanding of the Affordable Care Act
Authors: Elyse R. Park, Anne C. Kirchhoff, Giselle K. Perez, Wendy Leisenring, Joel S. Weissman, Karen Donelan, Ann C. Mertens, James D. Reschovsky, Gregory T. Armstrong, Leslie L. Robison, Mariel Franklin, Kelly A. Hyland, Lisa R. Diller, Christopher J. Recklitis, Karen A. Kuhlthau
Journal: Journal of Clinical Oncology (2015)

The Patient Protection and Affordable Care Act (ACA) established provisions intended to increase access to affordable health insurance and thus increase access to medical care and long-term surveillance for populations with pre-existing conditions. However, childhood cancer survivors' coverage priorities and familiarity with the ACA are unknown.
The Median Informs the Message: Accuracy of Individualized Scenarios for Survival Time Based on Oncologists' Estimates
Authors: Belinda E. Kiely, Andrew J. Martin, Martin H.N. Tattersall, Anna K. Nowak, David Goldstein, Nicholas R.C. Wilcken, David K. Wyld, Ehtesham A. Abdi, Amanda Glasgow, Philip J. Beale, Michael Jefford, Paul A. Glare, Martin R. Stockler
Journal: Journal of Clinical Oncology (2013)

Purpose To determine the accuracy and usefulness of oncologists' estimates of survival time in individual patients with advanced cancer. Patients and Methods Twenty-one oncologists estimated the “median survival of a group of identical patients” for each of 114 patients with advanced cancer. Accuracy was defined by the proportions of patients with an observed survival time bounded by prespecified multiples of their estimated survival time. We expected 50% to live longer (or shorter) than their oncologist's estimate (calibration), 50% to live from half to double their estimate (typical scenario), 5% to 10% to live ≤ one quarter of their estimate (worst-case scenario), and 5% to 10% to live three or more times their estimate (best-case scenario). Estimates within 0.67 to 1.33 times observed survival were deemed precise. Discriminative value was assessed with Harrell's C-statistic and prognostic significance with proportional hazards regression. Results Median survival time was 11 months. Oncologists' estimates were relatively well-calibrated (61% shorter than observed), imprecise (29% from 0.67 to 1.33 times observed), and moderately discriminative (Harrell C-statistic 0.63; P = .001). The proportion of patients with an observed survival half to double their oncologist's estimate was 63%, ≤ one quarter of their oncologist's estimate was 6%, and three or more times their oncologist's estimate was 14%. Independent predictors of observed survival were oncologist's estimate (hazard ratio [HR] = 0.92; P = .004), dry mouth (HR = 5.1; P &lt; .0001), alkaline phosphatase more than 101U/L (HR = 2.8; P = .0002), Karnofsky performance status ≤ 70 (HR = 2.3; P = .007), prostate primary (HR = 0.23; P = .002), and steroid use (HR = 2.4; P = .02). Conclusion Oncologists' estimates of survival time were relatively well-calibrated, moderately discriminative, independently associated with observed survival, and a reasonable basis for estimating worst-case, typical, and best-case scenarios for survival.