tbuckley/cabot-search huggingface dataset:
Insulins, Growth Hormone, and Recombinant DNA Technology
Authors: Walter L. Miller
Journal: JAMA (1982)

This book derives from a conference entitled "Insulins and Growth Hormone" convened by the Food and Drug Administration last winter. As such, it suffers from the inconsistency of style, quality, and scholarship inherent to all summaries of symposia. Taken within that context, the volume contains some tantalizing insights into a new field—tantalizing for what is omitted rather than the information provided. The first 108 pages contain eight presentations on insulins. This section begins well enough with a brief, scholarly, and well-referenced review by Agiris Efstratiadis describing the structure, evolution, and bacterial expression of insulin genes. This is followed by two very general chapters by Giuseppe Miozzari and Michael Ross concerning mechanisms by which bacteria are used to produce polypeptide hormones. These two chapters provide the general reader with a clear understanding of some of the principles and devices used to produce useful proteins by recombinant DNA, but they are limited
Microevolution of Cryptococcus neoformans Driven by Massive Tandem Gene Amplification
Authors: E. W. L. Chow, C. A. Morrow, J. T. Djordjevic, I. A. Wood, J. A. Fraser
Journal: Molecular Biology and Evolution (2012)

The subtelomeric regions of organisms ranging from protists to fungi undergo a much higher rate of rearrangement than is observed in the rest of the genome. While characterizing these ~40-kb regions of the human fungal pathogen Cryptococcus neoformans, we have identified a recent gene amplification event near the right telomere of chromosome 3 that involves a gene encoding an arsenite efflux transporter (ARR3). The 3,177-bp amplicon exists in a tandem array of 2-15 copies and is present exclusively in strains with the C. neoformans var. grubii subclade VNI A5 MLST profile. Strains bearing the amplification display dramatically enhanced resistance to arsenite that correlates with the copy number of the repeat; the origin of increased resistance was verified as transport-related by functional complementation of an arsenite transporter mutant of Saccharomyces cerevisiae. Subsequent experimental evolution in the presence of increasing concentrations of arsenite yielded highly resistant strains with the ARR3 amplicon further amplified to over 50 copies, accounting for up to ~1% of the whole genome and making the copy number of this repeat as high as that seen for the ribosomal DNA. The example described here therefore represents a rare evolutionary intermediate-an array that is currently in a state of dynamic flux, in dramatic contrast to relatively common, static relics of past tandem duplications that are unable to further amplify due to nucleotide divergence. Beyond identifying and engineering fungal isolates that are highly resistant to arsenite and describing the first reported instance of microevolution via massive gene amplification in C. neoformans, these results suggest that adaptation through gene amplification may be an important mechanism that C. neoformans employs in response to environmental stresses, perhaps including those encountered during infection. More importantly, the ARR3 array will serve as an ideal model for further molecular genetic analyses of how tandem gene duplications arise and expand.
Concordance, disease progression, and heritability of coeliac disease in Italian twins
Authors: L Nistico
Journal: Gut (2005)

<b>Background and aims:</b> We adopted the twin method to disentangle the genetic and environmental components of susceptibility to coeliac disease (CD). We estimated disease concordance rate by zygosity and HLA genotypes, discordance times, progression rates to disease, and heritability. <b>Methods:</b> We crosslinked the Italian Twin Registry with the membership lists of the Italian Coeliac Disease Association and recruited 23 monozygotic (MZ) and 50 dizygotic (DZ) twin pairs with at least one affected member. Zygosity was assigned by DNA fingerprinting, and HLA-DQ and DR alleles were genotyped. Disease status was ascertained by antiendomysial, anti-human tissue transglutaminase antibodies, and bowel biopsy. <b>Results:</b> Concordance was significantly higher in MZ (83.3% probandwise, 71.4% pairwise) than in DZ (16.7% probandwise, 9.1% pairwise) pairs. Concordance was not affected by sex or HLA genotype of the co-twin and being MZ was significantly associated with the occurrence of CD (Cox adjusted hazard ratio 14.3 (95% confidence interval 4.0–50.3)). In 90% of concordant pairs the discordance time was ⩽2 years. MZ and DZ co-twins had 70% and 9% cumulative probability of having symptomatic or silent forms of CD, respectively, within five years. Under ACE (additive genetic, common, and unshared environmental factors) models, with CD population prevalences of 1/91 and 1/1000, heritability estimates were 87% and 57%, respectively. <b>Conclusion:</b> MZ pairs have a high probability of being concordant, regardless of sex or HLA genotype. Most of the affected co-twins receive a diagnosis within two years. A remarkable proportion of phenotypic variance is due to genetic factors.
Biomarkers for Cetuximab-Based Neoadjuvant Radiochemotherapy in Locally Advanced Rectal Cancer
Authors: Peter P. Grimminger, Peter Danenberg, Kathrin Dellas, Dirk Arnold, Claus Rödel, Jean-Pascal Machiels, Karin Haustermans, Annelies Debucquoy, Vaneja Velenik, Christine Sempoux, Matej Bracko, Arnulf H. Hölscher, Robert Semrau, Dongyun Yang, Kathleen Danenberg, Heinz-Josef Lenz, Daniel Vallböhmer
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Phase II trials in locally advanced rectal cancer have shown that cetuximab-based neoadjuvant radiochemotherapy is feasible but without an improvement in complete pathologic response rates. Our goal was to identify patients who would benefit from cetuximab-based neoadjuvant chemoradiation measuring gene expression levels of proteins involved in tumor growth [endothelial growth factor receptor (EGFR)], angiogenesis [VEGF, VEGF receptors 1 and 2 (VEGFR1, VEGFR2)], DNA repair [excision repair cross-complementing 1 (ERCC1)], and drug metabolism [thymidylate synthetase (TS)]. We also determined mutation status of KRAS and BRAF. Experimental Design: This study was carried out on 130 patients with locally advanced rectal cancer who were enrolled in 4 different phase II clinical trials, using cetuximab-based chemoradiation. Tumor tissues were obtained before neoadjuvant and at surgical therapy. After microdissection, intratumoral gene expression levels and KRAS/BRAF mutation status were analyzed. Results: A significant decrease of TS, VEGFR1, and VEGFR2 gene expression was seen following neoadjuvant therapy (P &amp;lt; 0.03). High pretreatment VEGF gene expression levels were associated with nonresponse (P = 0.070). KRAS mutations were found in 42% and mutant KRAS (KRAS mt) was significantly associated with pathologic nonresponse (P = 0.037). In patients with wild-type KRAS (KRAS wt), low EGFR was significantly associated with higher nonresponse and VEGF mRNA expressions were associated with complete pathologic response (P = 0.012; P = 0.06). KRAS transversion (KRAS tv) was associated with tumor regression: nonresponse was more common in patients with KRAS tv than with KRAS wt (P = 0.007). BRAF V600E mutations were not detected in any of the patients. Conclusion: This study suggests that pretreatment intratumoral EGFR and VEGF mRNA expression levels as well as KRAS mutation status are predictive markers of pathologic response to neoadjuvant cetuximab-based chemoradiation in locally advanced rectal cancer. Clin Cancer Res; 17(10); 3469–77. ©2011 AACR.
Delayed endoscopy increases re-bleeding and mortality in patients with hematemesis and active esophageal variceal bleeding: A cohort study
Authors: Ping-Hsien Chen, Wen-Chi Chen, Ming-Chih Hou, Tsu-Te Liu, Chen-Jung Chang, Wei-Chih Liao, Chien-Wei Su, Huay-Min Wang, Han-Chieh Lin, Fa-Yauh Lee, Shou-Dong Lee
Journal: Journal of Hepatology (2012)
A Functional Variant of Tandem Repeats in Human Telomerase Gene Was Associated with Survival of Patients with Early Stages of Non–Small Cell Lung Cancer
Authors: Luo Wang, Li-E Wang, Li Mao, Margaret R. Spitz, Qingyi Wei
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Elevated levels of human telomerase (hTERT) mRNA in tumors is a marker for poorer survival in patients with stage I non–small cell lung cancer (NSCLC). A functional variant of MNS16A-short tandem repeats in hTERT (S allele) is associated with higher expression levels of hTERT mRNA compared with the MNS16A-long (L) allele. It is unknown, however, whether or not the hTERT MNS16A variant genotype predicts survival of NSCLC patients. Experimental Design: The hTERT genotypes of 808 patients with NSCLC were determined by direct PCR with genomic DNA. Overall median survival times were estimated by the life-table method, and the log-rank test was used to test for homogeneity of the survival curves. Both univariate and multivariate Cox proportional hazards models were used to assess the associations between survival time and the hTERT genotype as well as other known risk factors. Results: The hTERT variant genotype was not associated with overall survival among the 808 patients. However, among 221 patients with stage I or II NSCLC, the S allele was associated with shorter survival time (P = 0.027, by log-rank test). The adjusted hazard ratios were 1.30 (95% confidence interval, 0.79-2.14; P = 0.310) for the SL-genotype and 2.34 (95% confidence interval, 1.20-4.56, P = 0.012) for the SS-genotype compared with the LL-genotype (P = 0.021 for trend test). These findings were not evident in 587 patients with stage III or IV NSCLC. Conclusion: The functional MNS16A-SS genotype may be a marker for poorer survival in early-stage NSCLC. Clin Cancer Res; 16(14); 3779–85. ©2010 AACR.
Medical Mystery — The Answer
Authors: Willy-Anne Nieuwlaat, Gerlach Pieters
Journal: New England Journal of Medicine (2004)

The medical mystery in the July 1 issue 1 involved 50-year-old identical twins (Fig. 1A).The patient is the twin on the left side of the photograph.He has acromegaly caused by a growth hormone-hypersecreting pituitary macroadenoma.He presented with visual-field impairment, and magnetic resonance imaging showed a pituitary macroadenoma with extrasellar extension (Fig. 1B shows a coronal section, and Fig. 1C a sagittal section).A few months earlier, obstructive sleep apnea had been diagnosed.The history also included headache, enlargement of the feet, increased sweating, and joint stiffness.The patient's serum insulin-like growth factor level was elevated, at 56.5 nmol per liter (mean for age, 17.0 nmol per liter), and an oral glucose-tolerance test showed a failure to suppress growth hormone (5 mU per liter; normal value, <2 mU per liter).The patient's coarse facial features were evident in comparison with the facial features of his identical twin.The acral enlargement (nose and lips) and enlargement of the facial soft tissue (skin folds and infraorbital puffiness) are striking.Few patients with acromegaly seek care owing to the very slow progression.The patient underwent transsphenoidal surgery, with visual-field improvement.Complete relief from symptoms was not attained, and treatment with a somatostatin analogue was started, which reduced the patient's headache, fatigue, and sweating.
Influence of Pre- and Postdiagnosis Physical Activity on Mortality in Breast Cancer Survivors: The Health, Eating, Activity, and Lifestyle Study
Authors: Melinda L. Irwin, Ashley Wilder Smith, Anne McTiernan, Rachel Ballard-Barbash, Kathy Cronin, Frank D. Gilliland, Richard N. Baumgartner, Kathy B. Baumgartner, Leslie Bernstein
Journal: Journal of Clinical Oncology (2008)

To investigate the association between pre- and postdiagnosis physical activity (as well as change in prediagnosis to postdiagnosis physical activity) and mortality among women with breast cancer.This was a prospective observational study of 933 women enrolled onto the Health, Eating, Activity, and Lifestyle Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or September 2004, whichever came first. The primary outcomes measured were total deaths and breast cancer deaths. The primary exposures were physical activity in the year before and 2 years after diagnosis and the pre- to postdiagnosis change in physical activity.Compared with inactive women, the multivariable hazard ratios (HRs) for total deaths for women expending at least 9 metabolic equivalent hours per week (approximately 2 to 3 h/wk of brisk walking) were 0.69 (95% CI, 0.45 to 1.06; P = .045) for those active in the year before diagnosis and 0.33 (95% CI, 0.15 to 0.73; P = .046) for those active 2 years after diagnosis. Compared with women who were inactive both before and after diagnosis, women who increased physical activity after diagnosis had a 45% lower risk of death (HR = 0.55; 95% CI, 0.22 to 1.38), and women who decreased physical activity after diagnosis had a four-fold greater risk of death (HR = 3.95; 95% CI, 1.45 to 10.50).Moderate-intensity physical activity after a diagnosis of breast cancer may improve prognosis.
Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis
Authors: M.W. Ziegenhagen, M.E. Rothe, M. Schlaak, J. Müller-Quernheim
Journal: European Respiratory Journal (2003)

The aim of the present study was to determine which bronchoalveolar lavage fluid (BALF) and serological parameters reflect the severity of newly diagnosed pulmonary sarcoidosis. Seventy-four previously untreated sarcoid patients were categorised into three groups: 10 patients with Löfgren's syndrome, 51 patients with stable disease and 13 patients with progressing disease requiring systemic steroid treatment. Total BALF cell count, percentage of alveolar lymphocytes and lymphocyte CD4/CD8 ratio were not associated with severity of disease. Interestingly, a significant increase in percentages of BALF neutrophils (5.2±1.1%) and eosinophils (1.7±0.6%) was observed in sarcoid patients with progressing disease. Elevated percentages of these two cell types were the only BALF parameters associated with a more frequent necessity for systemic steroid therapy. This association between an elevated percentage of BALF neutrophils and the necessity for steroid treatment was observed in advanced as well as early sarcoidosis (radiological types I and II). Serum levels of soluble interleukin‐2 receptor and neopterin were significantly elevated in progressing disease compared to stable disease or Löfgren's syndrome. The present results demonstrate that increased percentages of neutrophils (&gt;3.0%) and eosinophils (&gt;1%) in bronchoalveolar lavage fluid from newly diagnosed pulmonary sarcoidosis is associated with a significantly higher risk of necessity for steroid therapy and may be helpful markers of progressive disease. Furthermore, of the serological parameters investigated, only serum levels of soluble interleukin‐2 receptor and neopterin were associated with disease severity.
HEART-LIVER TRANSPLANTATION IN A PATIENT WITH FAMILIAL HYPERCHOLESTEROLAEMIA
Authors: T.E. Starzl, H.T. Bahnson, R.L. Hardesty, S. Iwatsuki, J.C. Gartner, D.W. Bilheimer, B.W. Shaw, B.P. Griffith, B.J. Zitelli, J.J. Malatack, A.H. Urbach
Journal: The Lancet (1984)
2000 Update of American Society of Clinical Oncology Colorectal Cancer Surveillance Guidelines
Authors: Al B. Benson, Christopher E. Desch, Patrick J. Flynn, Carol Krause, Charles L. Loprinzi, Bruce D. Minsky, Nicholas J. Petrelli, David G. Pfister, Thomas J. Smith, Mark R. Somerfield
Journal: Journal of Clinical Oncology (2000)

Article Tools ASCO SPECIAL ARTICLE Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.20.3586 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11032600 2000 Update of American Society of Clinical Oncology Colorectal Cancer Surveillance Guidelines Al B. Benson IIIxAl B. Benson IIISearch for articles by this author , Christopher E. DeschxChristopher E. DeschSearch for articles by this author , Patrick J. FlynnxPatrick J. FlynnSearch for articles by this author , Carol KrausexCarol KrauseSearch for articles by this author , Charles L. LoprinzixCharles L. LoprinziSearch for articles by this author , Bruce D. MinskyxBruce D. MinskySearch for articles by this author , Nicholas J. PetrellixNicholas J. PetrelliSearch for articles by this author , David G. PfisterxDavid G. PfisterSearch for articles by this author , Thomas J. SmithxThomas J. SmithSearch for articles by this author , Mark R. SomerfieldxMark R. SomerfieldSearch for articles by this author , for the American Society of Clinical OncologyxSearch for articles by this author Show More From the American Society of Clinical Oncology, Alexandria, VA. https://doi.org/10.1200/JCO.2000.18.20.3586 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical Oncology
Asthma admissions, smoking bans and administrative databases: author’s response
Authors: Michelle Sims, Roy Maxwell, Anna Gilmore
Journal: Thorax (2013)

The issue of the potential misclassification within Hospital Episode Statistics (HES) data of asthma for another condition such as COPD, or vice versa, raised by Kent et al 1 is an important one and any impact that this may have should be considered. Misclassification with resultant bias is a potential risk of many studies. However, the extent, or direction, to which bias may be introduced to a study that uses the recorded primary diagnosis from nationally collected data to ascertain trends in admissions is difficult to estimate.

Kent et al ’ claim that asthma is misclassified in 9–14% of cases is based on a single study2 using data, which is now at …
Separable portions of the CD2 cytoplasmic domain involved in signaling and ligand avidity regulation.
Authors: W C Hahn, B E Bierer
Journal: The Journal of Experimental Medicine (1993)

Effective T cell immune responses require the molecular interplay between adhesive and signaling events mediated by the T cell receptor for antigen (TCR) and other cell surface coreceptor molecules. In this report, we have distinguished between the role of regulated adhesion and transmembrane signaling in coreceptor function using the T cell glycoprotein CD2. By binding its ligands on antigen-presenting cell (APC), CD2 serves both to initiate signal transduction events and to promote cellular adhesion. Furthermore, the avidity of CD2 for one ligand, CD58 (LFA-3), is regulated by TCR signaling. We have expressed wild type CD2 and a series of mutated CD2 molecules in an antigen-specific murine T cell hybridoma. Structure-function studies using these stably transfected cell lines identify two structurally and functionally distinct regions of the 116 amino acid (aa) cytoplasmic domain. One region is required for CD2-mediated signal transduction, and a separate COOH-terminal 21 aa portion is required for CD2 activity regulation. Cell lines expressing CD2 molecules lacking the cytoplasmic segment required for CD2-initiated IL-2 production retain the ability to upregulate CD2 avidity. Conversely, cell lines expressing CD2 mutants lacking the cytoplasmic segment required for avidity regulation retain the ability to initiate CD2-specific signaling. In antigen-specific T cell responses, basal binding of CD2 to its ligands enhances antigen responsiveness only minimally, whereas regulated avidity and transmembrane signaling are both required for optimal coreceptor function. Taken together, these studies demonstrate the independent contributions of regulated adhesion and intracellular signaling in CD2 coreceptor function.
Oxygen therapy is equivalent to room air for alleviating refractory dyspnoea
Authors: J. R. Y. Chew
Journal: Thorax (2010)

Palliative oxygen is commonly used for the treatment of dyspnoea in individuals with life-limiting illness who are ineligible for long-term oxygen therapy despite insufficient evidence for symptomatic benefit. This multicentre study investigated the effectiveness of oxygen compared with room air in this population group.

Between 2006 and 2008, 239 patients …
Insulin Sensitivity and the Risk of Incident Hypertension
Authors: David C. Goff, Daniel J. Zaccaro, Steven M. Haffner, Mohammed F. Saad
Journal: Diabetes Care (2003)

The insulin resistance syndrome has been described as including hypertension. Previous studies have documented cross-sectional associations between insulin sensitivity (S(I)) and blood pressure or prevalent hypertension. Prospective data have been sparse.The Insulin Resistance Atherosclerosis Study (IRAS) is a prospective study of the associations of S(I) with atherosclerosis and other risk factors for cardiovascular disease. We examined the association between S(I), measured using the frequently sampled intravenous glucose tolerance test with minimal model analysis, and incident hypertension (defined as per the Joint National Committee), at the 5-year examination in 840 IRAS participants who were free of hypertension at the baseline examination.Adjusted for age, sex, ethnicity, and smoking status, for each unit greater S(I), the risk of hypertension was 10% lower (95% CI 2-19, P < 0.05).These findings, from a prospective study, support the presence of a modest protective association between greater S(I) and lower risk of hypertension. These findings support the contention that interventions that improve S(I) may be beneficial with respect to the development of hypertension and cardiovascular disease. This contention should be tested in randomized clinical trials.