tbuckley/cabot-search huggingface dataset:
Palliative Chemotherapy or Watchful Waiting? A Vignettes Study Among Oncologists
Authors: C.G. Koedoot, J.C.J.M. de Haes, S.H. Heisterkamp, P.J.M. Bakker, A. de Graeff, R.J. de Haan
Journal: Journal of Clinical Oncology (2002)

To determine the preferences of oncologists for palliative chemotherapy or watchful waiting and the factors considered important to that preference.Sixteen vignettes (paper case descriptions), varying on eight patient and treatment characteristics, were designed to assess the oncologists' preferences. Their strength of preference was rated on a 7-point scale. An orthogonal main effects design provided a subset of all possible combinations of the characteristics, allowing estimations of the relative weights of the presented characteristics. A written questionnaire was sent to a random sample of oncologists (N = 1,235).The response rate was 67%, and 697 questionnaires were available for analysis. Eighty-one percent of the respondents were male. The mean age was 46 years. We found considerable variation among the oncologists. No major associations between physician characteristics and preferences were found. Of the patient and treatment characteristics affecting treatment preference, age was the strongest predictor, followed by the patient's wish to be treated and the expected survival gain. Other patient and treatment characteristics had a limited effect on preferences, except for psychologic distress, which had no independent impact.Patients will encounter different decisions depending on their oncologists' preferences and their own personal background. Therefore, to ensure adequate information for decision-making processes, decision aids are proposed.
DNA Repair, Dysplastic Nevi, and Sunlight Sensitivity in the Development of Cutaneous Malignant Melanoma
Authors: M. T. Landi, A. Baccarelli, R. E. Tarone, A. Pesatori, M. A. Tucker, M. Hedayati, L. Grossman
Journal: JNCI Journal of the National Cancer Institute (2002)

Exposure to UV radiation is associated with cutaneous malignant melanoma (CMM). In mammalian cells, UV radiation induces DNA damage that can be repaired by the nucleotide excision repair system. We designed this case-control study to determine whether DNA repair capacity (DRC) is associated with the risk of CMM and to identify risk factors that may interact biologically with DRC in the development of melanoma.Global DRC was measured in lymphocytes with the host-cell reactivation assay. Data were analyzed by use of multiple regression models. All statistical tests were two-sided.DRC could be determined for 132 case patients with incident melanoma and for 145 age- and sex-matched control subjects. No statistically significant association between melanoma risk and DRC by itself was found (odds ratio [OR] = 1.0; 95% confidence interval [CI] = 0.6 to 1.7, adjusted for age, sex, lymphocyte viability, and sample storage time). DRC, however, strongly influenced CMM risk in individuals with a low tanning ability or dysplastic nevi. Individuals with a low tanning ability and a low DRC had a higher risk for CMM (OR = 8.6; 95% CI = 2.7 to 27.5) than individuals with a higher tanning ability and a high DRC. Likewise, individuals with dysplastic nevi and a low DRC had a higher relative risk (OR = 6.7; 95% CI = 2.4 to 18.6) than those lacking dysplastic nevi and having a high DRC. Subjects with dysplastic nevi and a high DRC had an intermediate risk. A likelihood-ratio test gave statistically significant interactions between DRC and tanning response (P =.001) and between DRC and dysplastic nevus status (P =.04), which were independently associated with CMM risk.DRC may modify the risk for melanoma in the presence of other strong risk factors, such as a low tanning ability and the presence of dysplastic nevi. The occurrence of melanoma in subjects without these risk factors appears to be independent of DRC.
A Randomized Trial of Fetal Endoscopic Tracheal Occlusion for Severe Fetal Congenital Diaphragmatic Hernia
Authors: Michael R. Harrison, Roberta L. Keller, Samuel B. Hawgood, Joseph A. Kitterman, Per L. Sandberg, Diana L. Farmer, Hanmin Lee, Roy A. Filly, Jody A. Farrell, Craig T. Albanese
Journal: New England Journal of Medicine (2003)

Experimental and clinical data suggest that fetal endoscopic tracheal occlusion to induce lung growth may improve the outcome of severe congenital diaphragmatic hernia. We performed a randomized, controlled trial comparing fetal tracheal occlusion with standard postnatal care.
Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors
Authors: Andrew R Reynolds, Ian R Hart, Alan R Watson, Jonathan C Welti, Rita G Silva, Stephen D Robinson, Georges Da Violante, Morgane Gourlaouen, Mishal Salih, Matt C Jones, Dylan T Jones, Garry Saunders, Vassiliki Kostourou, Françoise Perron-Sierra, Jim C Norman, Gordon C Tucker, Kairbaan M Hodivala-Dilke
Journal: Nature Medicine (2009)
Getting It Right: Being Smarter about Clinical Trials
Authors: Barnett S Kramer, Joan Wilentz, Duane Alexander, John Burklow, Lawrence M Friedman, Richard Hodes, Ruth Kirschstein, Amy Patterson, Griffin Rodgers, Stephen E Straus
Journal: PLoS Medicine (2006)

discuss "Moving from Observational Studies to Clinical Trials: Why Do We Sometimes Get It Wrong?" (a detailed summary
Adrenal function is related to prognosis in moderate community-acquired pneumonia
Authors: M. Kolditz, M. Halank, B. Schulte-Hubbert, G. Höffken
Journal: European Respiratory Journal (2010)

The aim of our study was to prospectively examine adrenal function, including cosyntropin stimulation, and its prognostic value in patients with moderate community-acquired pneumonia (CAP). 59 consecutive adult patients hospitalised on normal wards because of CAP were enrolled. A cosyntropin stimulation test was performed and serum concentrations of C-reactive protein, procalcitonin, interleukin-6, tumour necrosis factor-α, ACTH, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) were measured. Predefined outcome parameters were clinical instability after 72 h, mortality and combined intensive care unit (ICU) admission or mortality. Critical illness-related corticosteroid insufficiency (CIRCI) occurred in six patients (10.3%). Cortisol, age-corrected DHEA, ACTH and the DHEA/DHEAS ratio were elevated in patients remaining unstable after 72 h. In multivariate analysis, cortisol (p = 0.03), ACTH (p = 0.04) and the pneumonia severity index (PSI) score (p = 0.005) independently predicted clinical instability after 72 h, and only cortisol predicted mortality (p = 0.04) and combined ICU-admission or mortality (p = 0.006). The predictive value of serum cortisol after receiver operating characteristic curve analysis equalled that of the PSI score. Patients with serum cortisol &gt;734 nmol·L −1 had a high probability for mortality (OR 38.3; p = 0.002). CIRCI is rare in patients with moderate CAP. Adrenal function is related to the prognosis of CAP. The diagnostic accuracy of serum cortisol equals that of the PSI score. Serum cortisol should be evaluated within clinical prediction scores on larger studies.
Pulmonary artery banding in congenital heart disease associated with pulmonary hypertension
Authors: J. M. Reid, R. S. Barclay, E. N. Coleman, J. G. Stevenson, T. M. Welsh, N. McSwan
Journal: Thorax (1968)

A report is presented of pulmonary artery banding in 45 children with congenital heart disease associated with severe pulmonary hypertension. The majority were in uncontrollable heart failure and were in the age group 3 to 18 months. Nine older children not in heart failure were operated on because of serious pulmonary hypertension associated with malformations considered unsuitable for complete repair (truncus arteriosus, single ventricle). The mortality in those with uncomplicated ventricular septal defect was low (5.5%), but was much higher in those with accompanying lesions or more complex abnormalities (63%). All have been under supervision since operation and most have improved with diminution in cardiac size and recession of pulmonary congestion. Two have been recatheterized and both have undergone successful closure of their ventricular septal defect. It is our intention to reinvestigate many of the others three to four years after banding to assess the size of the defect prior to further surgery.
Mechanisms by which parasites influence cultures, and why they matter
Authors: Mark Schaller, Damian R. Murray
Journal: Behavioral and Brain Sciences (2012)

Abstract At least four conceptually distinct mechanisms may mediate relations between parasite-stress and cultural outcomes: genetic evolution, developmental plasticity, neurocognitive flexibility, and cultural transmission. These mechanisms may operate independently or in conjunction with one another. Rigorous research on specific mediating mechanisms is required to more completely articulate implications of parasite stress on human psychology and human culture.
ALLERGIC IRRITABILITY
Authors: Paul A. Lewis, Dorothy Loomis
Journal: The Journal of Experimental Medicine (1924)

The guinea pig infected with virulent tubercle bacilli develops much more anti-sheep amboceptor than do controls when given like amounts of sheep red blood corpuscles. The curve of antibody production in the guinea pig when treated with sheep red blood corpuscles shows a departure from curves previously determined in other animals. These facts were ascertained as part of an effort to learn mbre of the functional nature of the inheritable factors controlling natural resistance to disease. The nature of some of the problems involved is outlined, and the limited bearing of the experiments on these is discussed.
Nutrition in the Acute Phase of Critical Illness
Authors: Michael P. Casaer, Greet Van den Berghe
Journal: New England Journal of Medicine (2014)

The quality of randomized, controlled trials was considered to be high when the study had blinded study-group assignments, a sample size sufficiently large to detect the hypothesized treatment effect, a diagram showing how patients were selected, prespecified end points, and an intention-to-treat analysis.NA denotes not available because evidence is lacking from high-quality randomized, controlled trials.† No diagram showing how patients were selected was included in the study by Montejo et al. 10 ‡ No information on the way in which investigators concealed study-group assignments was included in the study by Acosta-Escribano et al. 13 § No sample-size calculation and only partial outcome data in the intention-to-treat population were included in the study by Pontes-Arruda et al., 22 and no diagram showing how patients were selected was included in the study by Umpierrez et al. 23 ¶ The study by Rice et al. 24was stopped prematurely for futility at the first interim analysis.
A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment
Authors: Robert S. Stearman, Lori Dwyer-Nield, Michael C. Grady, Alvin M. Malkinson, Mark W. Geraci
Journal: Cancer Research (2008)

Abstract One area of intensive investigation is to understand complex cellular and signaling interactions in the tumor microenvironment. Using a novel, although straightforward, microarray approach, we defined a gene expression signature from the lung tumor microenvironment in the murine A/J-urethane model of human lung adenocarcinoma. The tumor microenvironment is reflected by the composition of the cell types present and alterations in mRNA levels, resulting in a “Field Effect” around the tumor. The genes composing the Field Effect expression signature include proteases and their inhibitors, inflammation markers, and immune signaling molecules. By several criteria, the Field Effect expression signature can be attributed to the macrophage lineage, suggesting a qualitative change in the expression pattern of tumor-associated macrophages (TAM) observed in lung tumors. The protein expression levels for a number of Field Effect genes were verified by Western blot analysis of lung homogenates, and for their expression in macrophages and parenchymal cells outside of the tumors by immunohistochemistry. In addition, the Field Effect expression signature was used to classify bronchoalveolar lavage (BAL) cells from tumor-bearing or age-matched control mice. Using a variety of statistical measures, the Field Effect expression signature correctly classified the BAL cells &amp;gt;94% of the time. Finally, the protein levels for several Field Effect genes were higher in cell-free BAL fluid, indicating they may be secreted by the TAMs. This work suggests that TAMs generate a unique gene expression signature within the tumor microenvironment, and this signature could potentially be used for identifying lung cancer from BAL cells and/or fluid. [Cancer Res 2008;68(1):34–43]
c-Jun NH2-Terminal Kinase–Related Na+/H+ Exchanger Isoform 1 Activation Controls Hexokinase II Expression in Benzo(<i>a</i>)Pyrene-Induced Apoptosis
Authors: Laurence Huc, Xavier Tekpli, Jørn A. Holme, Mary Rissel, Anita Solhaug, Claire Gardyn, Gwénaelle Le Moigne, Morgane Gorria, Marie-Thérèse Dimanche-Boitrel, Dominique Lagadic-Gossmann
Journal: Cancer Research (2007)

Abstract Regulation of the balance between survival, proliferation, and apoptosis on carcinogenic polycyclic aromatic hydrocarbon (PAH) exposure is still poorly understood and more particularly the role of physiologic variables, including intracellular pH (pHi). Although the involvement of the ubiquitous pHi regulator Na+/H+ exchanger isoform 1 (NHE1) in tumorigenesis is well documented, less is known about its role and regulation during apoptosis. Our previous works have shown the primordial role of NHE1 in carcinogenic PAH-induced apoptosis. This alkalinizing transporter was activated by an early CYP1-dependent H2O2 production, subsequently promoting mitochondrial dysfunction leading to apoptosis. The aim of this study was to further elucidate how NHE1 was activated by benzo(a)pyrene (BaP) and what the downstream events were in the context of apoptosis. Our results indicate that the mitogen-activated protein kinase kinase 4/c-Jun NH2-terminal kinase (MKK4/JNK) pathway was a link between BaP-induced H2O2 production and NHE1 activation. This activation, in combination with BaP-induced phosphorylated p53, promoted mitochondrial superoxide anion production, supporting the existence of a common target for NHE1 and p53. Furthermore, we showed that the mitochondrial expression of glycolytic enzyme hexokinase II (HKII) was decreased following a combined action of NHE1 and p53 pathways, thereby enhancing the BaP-induced apoptosis. Taken together, our findings suggest that, on BaP exposure, MKK4/JNK targets NHE1 with consequences on HKII protein, which might thus be a key protein during carcinogenic PAH apoptosis. [Cancer Res 2007;67(4):1696–705]
Glutathione<i>S</i>-Transferase T1 and M1: Gene Sequence Variation and Functional Genomics
Authors: Ann M. Moyer, Oreste E. Salavaggione, Scott J. Hebbring, Irene Moon, Michelle A.T. Hildebrandt, Bruce W. Eckloff, Daniel J. Schaid, Eric D. Wieben, Richard M. Weinshilboum
Journal: Clinical Cancer Research (2007)

The glutathione S-transferases (GSTs) catalyze the glutathione conjugation of reactive electrophiles, including carcinogens and many antineoplastic drugs. GSTT1 and GSTM1 are polymorphically deleted, but the full range of genetic variation in these two genes has not yet been explored. We set out to systematically identify common polymorphisms in GSTT1 and GSTM1, followed by functional genomic studies.First, multiplex PCR was used to determine GSTT1 and GSTM1 copy number in 400 DNA samples (100 each from 4 ethnic groups). Exons, splice junctions, and 5'-flanking regions (5'-FR) were then resequenced using DNA samples that contained at least one copy of GSTT1 or GSTM1.Gene deletion frequencies among ethnic groups were from 33.5% to 73.5% for GSTT1 and from 50.5% to 78.0% for GSTM1. GSTT1 deletion data correlated with the results of mRNA microarray expression studies. The 18 single nucleotide polymorphisms (SNP) observed in GSTT1 included three nonsynonymous coding SNPs (cSNPs) and one single-nucleotide deletion, whereas the 51 GSTM1 SNPs included two nonsynonymous cSNPs. Two of the GSTT1 nonsynonymous cSNPs resulted in decreases in levels of immunoreactive protein to 56% and 12% of wild type (WT), whereas those in GSTM1 resulted in modest increases in protein levels. Reporter gene assays showed that one GSTT1 5'-FR haplotype, with a frequency of 32% in African-American subjects, resulted in an increase in transcription in JEG-3 cells to 351% of that for the WT sequence, and one GSTM1 5'-FR haplotype resulted in an increase in transcription in JEG-3 cells to 129% of WT.These observations suggest that functionally significant pharmacogenomic variation beyond GSTT1 and GSTM1 gene deletion may contribute to carcinogenesis or individual variation in antineoplastic drug therapy response.
Phase resetting and entrainment of pacemaker activity in single sinus nodal cells.
Authors: J M Anumonwo, M Delmar, A Vinet, D C Michaels, J Jalife
Journal: Circulation Research (1991)

The phase-resetting and entrainment properties of single pacemaker cells were studied using computer simulations in a model of the rabbit sinus nodal cell, as well as using the whole-cell patch-clamp (current-clamp) technique in isolated rabbit sinus nodal cells. Spontaneous electrical activity in the cell model was reconstructed using Hodgkin-Huxley-type equations describing time- and voltage-dependent membrane currents. In both simulations and experiments, single subthreshold current pulses (depolarizing or hyperpolarizing) were used to scan the spontaneous cycle of the cells. Such pulses perturbed the subsequent discharge, producing temporary phasic changes in pacemaker period, and enabled the construction of phase response curves. On the basis of these results, we studied entrainment characteristics of the cells. For example, application of repetitive pulses allowed for phasic changes in the spontaneous cycle and resulted in stable 1:1 entrainment at a range of basic cycle length around the spontaneous cycle, or a 2:1 pattern at basic cycle length values about half the spontaneous cycle length. Between the two entrainment zones, complex Wenckebach-like patterns (e.g., 5:4, 4:3, and 3:2) were observed. The experimental data from the isolated cell were further analyzed from a theoretical perspective, and the results showed that the topological characteristics of the phase-resetting behavior accounts for the experimentally observed patterns during repetitive stimulation of the cell. This first demonstration of phase resetting in single cells provides the basis for phenomena such as mutual entrainment between electrically coupled pacemaker cells, apparent intranodal conduction, and reflex vagal control of heart rate.
Biology of the Adenomatous Polyposis Coli Tumor Suppressor
Authors: Kathleen Heppner Goss, Joanna Groden
Journal: Journal of Clinical Oncology (2000)

ABSTRACT: The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.
Adenovirus antibodies assist HIV
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2008)

Adenovirus antibodies assist HIVAntibodies against a vaccine vector render T cells more susceptible to HIV-1 infection, say Perreau et al. on page 2717.Their results may help explain the failure of a recent HIV vaccine trial.The HIV-1 vaccine used in Merck's STEP trial relied on a weakened form of a common cold virus, Adenovirus 5 (Ad5), to carry bits of HIV into the body.One worry about the Ad5 vector was that widespread immunity to adenoviruses might cause the vaccine to be ousted before an anti-HIV response could develop.Instead, there was a chance that vaccine recipients who had circulating antibodies against Ad5 were contracting the virus more often, one factor that forced termination of the trial.Perreau et al. now show that HIV spread through T cell-dendritic cell (DC) co-cultures three times as fast when Ad5 and neutralizing antiserum-present in people with prior immunity-was added to the cultures.Ad5-antibody complexes triggered DC maturation in the presence of Fc␥ receptors (Fc␥R) and Toll-like receptor (TLR)-9.The authors suspect that Fc␥R facilitated the uptake of Ad5-antibody complexes into the cell, where viral components could then activate TLR9 to trigger DC maturation and activation.The mature DCs activated both CD4 + and CD8 + T cells, which may have assisted HIV infection in two ways.Activated CD4 + cells could provide HIV with more cells to infect.And activated Ad5-specifi c CD8 + T cells could attack infected DCs, thereby reducing the pool of DCs presenting HIV antigens.Indeed, weaker HIV-specifi c CD8 responses were seen in Ad5seropositive individuals in response to vaccination.Merck's vaccine may have made it to phase 2 trials because nonhuman primates don't naturally come in contact with human adenoviruses, and therefore the potential problem went unrecognized.AM