tbuckley/cabot-search huggingface dataset:
Predictive Biomarkers of Sensitivity to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Breast Cancer Models
Authors: Jennifer R. Diamond, S. Gail Eckhardt, Aik Choon Tan, Timothy P. Newton, Heather M. Selby, Kelsey L. Brunkow, Maria I. Kachaeva, Marileila Varella-Garcia, Todd M. Pitts, Mark R. Bray, Graham C. Fletcher, John J. Tentler
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The Aurora kinases are a family of conserved serine-threonine kinases with key roles in mitotic cell division. As with other promising anticancer targets, patient selection strategies to identify a responsive subtype will likely be required for successful clinical development of Aurora kinase inhibitors. The purpose of this study was to evaluate the antitumor activity of the Aurora and angiogenic kinase inhibitor ENMD-2076 against preclinical models of breast cancer with identification of candidate predictive biomarkers. Experimental Design: Twenty-nine breast cancer cell lines were exposed to ENMD-2076 and the effects on proliferation, apoptosis, and cell-cycle distribution were evaluated. In vitro activity was confirmed in MDA-MB-468 and MDA-MB-231 triple-negative breast cancer xenografts. Systematic gene expression analysis was used to identify up- and downregulated pathways in the sensitive and resistant cell lines, including within the triple-negative breast cancer subset. Results: ENMD-2076 showed antiproliferative activity against breast cancer cell lines, with more robust activity against cell lines lacking estrogen receptor expression and those without increased HER2 expression. Within the triple-negative breast cancer subset, cell lines with a p53 mutation and increased p53 expression were more sensitive to the cytotoxic and proapoptotic effects of ENMD-2076 exposure than cell lines with decreased p53 expression. Conclusions: ENMD-2076 exhibited robust anticancer activity against models of triple-negative breast cancer and the candidate predictive biomarkers identified in this study may be useful in selecting patients for Aurora kinase inhibitors in the future. Clin Cancer Res; 19(1); 291–303. ©2012 AACR.
Case of Twins: In Which Both Placentae Were Expelled Previous to the Delivery of the Last F tus, without Consequent Haemorrhage
Authors: S. Tyler
Journal: BMJ (1843)

CASE OF TWINS-BOTH PLACENTA!EXPELLED WITHOUT R&MORRHAGE. 245 delivering it footling through the natural passages; but my colleagues, without doubting in the least the practicability of this method, were disposed to regard the woman as moribund, and to prefer that mode of delivery which would least endanger the life of the child, if, perchance, it still survived; tlley, therefore, insisted on resorting to the abdominal section.Ob- serving that a division of the abdominal integuments through the old cicatrix would be unattended with pain or hnmorrhage, owing to its imperfect union
Recruitment of Patients Into an Internet-Based Clinical Trials Database: The Experience of OncoLink and the National Colorectal Cancer Research Alliance
Authors: S.J. Wei, J.M. Metz, C. Coyle, M. Hampshire, H.A. Jones, S. Markowitz, A.K. Rustgi
Journal: Journal of Clinical Oncology (2004)

In March 2001, the National Colorectal Cancer Research Alliance (NCCRA) and OncoLink (http://www.oncolink.org) established a database to facilitate patient enrollment onto clinical trials. This study describes the population registering with the database and identifies discrepancies between individuals registering through the Internet and those registering through a telephone call center.Participants registered with the NCCRA/OncoLink database through the Internet or a telephone call center. All participants entering the database completed a questionnaire regarding basic demographics, colon cancer risk factors, and indicated how they became aware of the database. Comparisons were made between individuals registering through the Internet and those registering through the telephone call center.A total of 2,162 participants registered during the first 16 months of the database. Most patients registered through the Internet rather than the telephone call center (88% v 12%; P < .001). More females than males registered (73% v 27%; P < .001). The majority (89%) were white. Participants registering through the Internet were younger than those registering through the call center (mean, 48.8 v 55.0 years; P < .001). There was no difference between the two groups with regard to sex or ethnicity.The Internet has the potential to increase the likelihood that interested individuals find appropriate clinical trials. Some of the discrepancies that are known to exist for access to the Internet were also seen for those registering with the database through the Internet. Despite these differences, the potential to increase clinical trial enrollment with this type of Internet-based database is high.
A Prospective Multicenter Randomized Comparative Study Between the U- and H-type Methods of the TVT SECUR Procedure for the Treatment of Female Stress Urinary Incontinence: 1-Year Follow-Up
Authors: Kyu-Sung Lee, Young-Suk Lee, Ju Tae Seo, Yong Gil Na, Myung-Soo Choo, Joon Chul Kim, Jun Hyoung Seo, Jong Min Yoon, Jeong Gu Lee, Duk Yoon Kim, Eun Sang Yoo, Kweon Sik Min, Jae Yup Hong, Jeong Zoo Lee
Journal: European Urology (2010)
Subjective (CAT, MMRC) versus objective (PFT, 6MWD, SPO2) assessment in stable COPD patients
Authors: Hassan Ghobadi Marallu, Shahrzad M. Lari, Nasrin Fouladi, Katrin Beukaghazade
Journal: European Respiratory Journal (2012)

Background : Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease that leads to morbidity and mortality in the word. The excess of investigation has shown that this illness is not confined only to the respiratory system, but it is a systemic inflammatory disease which affects different system of patients.

The aim of this study was to investigate the relationship between subjective tests such as COPD assessment test (CAT) and Modified Medical Research Council (MMRC) scale with objective tests in stable COPD patients.

Methods : We evaluated 60 stable COPD patients in a cross-sectional study, quantifying the following: dyspnea with MMRC scale, lung function parameters, exercise capacity with six-minute walk distance (6MWD), oxygen saturation (Spo2), BODE index and the number of exacerbation during the last year. Then, the CAT questionnaire was completed by all patents.

Results : There was a significant difference between the CAT score with BODE index (p<0.001). Significant correlation was observed between CAT score and MMRC scale (p<0.001, r=0.55). The negative association was found between CAT with FEV1%, and Spo2 (p<0.005, r=-0.39 and p<0.001, r=-0.47 respectively). There was negative significant correlation between the CAT score and 6MWD (p<0.001, r=-0.49). Frequent exacerbation was found in patients with higher CAT scores.

Conclusion : The CAT score is a reliable indicator of airflow obstro.39uction, dyspnea scale, exercise capacity and saturation of arterial oxygen in COPD patients and can be used as a predictor of exacerbation risk in stable COPD.Key word: COPD exacerbation, CAT, MMRC, 6MWD.
Differential Gene Expression Analysis Reveals Generation of an Autocrine Loop by a Mutant Epidermal Growth Factor Receptor in Glioma Cells
Authors: Deepti B. Ramnarain, Seongmi Park, Diana Y. Lee, Kimmo J. Hatanpaa, Shane O. Scoggin, Hasan Otu, Towia A. Libermann, Jack M. Raisanen, Raheela Ashfaq, Eric T. Wong, Julian Wu, Robert Elliott, Amyn A. Habib
Journal: Cancer Research (2006)

Abstract The epidermal growth factor receptor (EGFR) gene is commonly amplified and rearranged in glioblastoma multiforme leading to overexpression of wild-type and mutant EGFRs. Expression of wild-type EGFR ligands, such as transforming growth factor-α (TGF-α) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells. Glioblastoma multiformes express a characteristic EGFR mutant (EGFRvIII, de 2-7) that does not bind ligand, signals constitutively, and is more tumorigenic than the wild-type receptor. However, the downstream signals that mediate this increased tumorigenicity are not well understood. We hypothesized that signals induced specifically by EGFRvIII and not the wild-type receptor are more likely to mediate its increased tumorigenic activity and examined the gene expression profiles resulting from inducible expression of comparable levels of either wild-type EGFR or EGFRvIII in a U251-MG glioma cell line. Expression of EGFRvIII resulted in specific up-regulation of a small group of genes. Remarkably, all these genes, which include TGFA, HB-EGF, EPHA2, IL8, MAP4K4, FOSL1, EMP1, and DUSP6, influence signaling pathways known to play a key role in oncogenesis and function in interconnected networks. Increased expression of EGFRvIII-induced genes was validated by real-time PCR. The mutant receptor does not bind ligand, and EGFRvIII-induced expression of TGF-α and HB-EGF suggests that EGFRvIII plays a role in generating an autocrine loop using the wild-type EGFR in glioma. It also raises the possibility that EGFRvIII may signal, at least in part, through the wild-type receptor. Indeed, we show that inhibiting the activity of HB-EGF, a potent mitogen, with neutralizing antibodies reduces cell proliferation induced by expression of EGFRvIII. This suggests that the EGFRvIII-HB-EGF-wild-type EGFR autocrine loop plays an important role in signal transduction by EGFRvIII in glioma cells. We also show by immunohistochemistry that HB-EGF expression correlates with the presence of EGFRvIII in glioblastoma multiforme. Thus, our study provides a new insight into oncogenic signaling by EGFRvIII and improves our understanding of how autocrine loops are generated in glioma. (Cancer Res 2006; 66(2): 867-74)
Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring
Authors: I.B. Van den Veyver, T.K. Al-Hussaini
Journal: Human Reproduction Update (2006)

Highly recurrent hydatidiform moles (HMs) studied to date are not androgenetic but have biparental genomic contribution (BiHM). Affected women have an autosomal recessive mutation that causes their pregnancies to develop into HM. Although there is genetic heterogeneity, a major locus maps to chromosome 19q13.42, but a mutated gene has not yet been identified. Molecular studies have shown that maternal imprinting marks are deregulated in the BiHM trophoblast. The mutations that cause this condition are, therefore, hypothesized to occur in genes that encode transacting factors required for the establishment of imprinting marks in the maternal germline or for their maintenance in the embryo. Although only DNA methylation marks at imprinted loci have been studied in the BiHM, the mutation may affect genes that are essential for other forms of chromatin remodelling at imprinted loci and necessary for correct maternal allele-specific DNA methylation and imprinted gene expression. Normal pregnancies interspersed with BiHM have been reported in some of the pedigrees, but affected women repeatedly attempting pregnancy should be counselled about the risk for invasive trophoblastic disease with each subsequent BiHM.
P250 Incidence, clinical profile and outcomes of ventilator-associated pneumonia in a tertiary hospital
Authors: R. M. Panaligan, J. P. Guiang
Journal: Thorax (2010)

<h3>Background</h3> Pneumonia is still the most important nosocomial infection among critically ill patients receiving mechanical ventilation despite advancement in the diagnostic technology available, introduction of new antimicrobials and employment of preventive strategies. Our aim was to prospectively identify the occurrence of ventilator-associated pneumonia (VAP) in a tertiary hospital as well as to determine its clinical profile and outcomes. <h3>Methods</h3> A prospective, observational study was performed including 52 patients with VAP in a tertiary hospital. All adult patients admitted who required mechanical ventilation regardless of site of care was included and followed up until successful weaning, discharge or death. <h3>Results</h3> During the 12-month study period (1 May 2009–30 April 2010), a total of 52 patients (7.6%) developed VAP among the 686 patients who received mechanical ventilation. Most common co-morbid conditions documented were diabetes mellitus and hypertension. Higher APACHE II scores (p≤0.001), inappropriate antimicrobial use (p=0.027) and the presence of underlying malignancy (p=0.03) are correlated with mortality. The most common pathogen isolated was <i>Pseudomonas aeruginosa</i> (23%) and carbapenems as the most commonly used antimicrobial. Mortality rate was 38.5%. Non-survivors had numerically longer ICU stay and length of mechanical ventilation (Abstract P250 Table 1). <h3>Conclusion</h3> In our setting, current VAP incidence rate is 7.6% with mortality of 38.5%. This highlights the current magnitude of VAP which should prompt hospital administrators and health care workers to complement rational antibiotic use with non-pharmacologic strategies to at least decrease VAP incidence and alleviate its burden especially in a developing country.
Glycemic Index, Dietary Fiber, and Risk of Type 2 Diabetes in a Cohort of Older Australians
Authors: Alan W. Barclay, Victoria M. Flood, Elena Rochtchina, Paul Mitchell, Jennie C. Brand-Miller
Journal: Diabetes Care (2007)

The role of glycemic index (GI) in the prevention of diabetes remains controversial. Some, but not all, prospective cohort studies have yielded positive relationships (1–8). A significant limitation of studies to date has been the fact that the food frequency questionnaires (FFQs) used were not validated for their ability to accurately assess GI. The purpose of this study was to assess the relationship of GI and fiber with incidence of type 2 diabetes in older Australians whose dietary intake was estimated by a fully validated FFQ.

In 1991, 4,433 residents aged 49+ years were identified, of which 3,654 (82%) participated in detailed examinations during 1992–1994 (9,10). Of these, 2,335 (75% of survivors) returned for 5-year and 1,952 (76%) for 10-year examinations (2002–2004). Individuals were largely of Caucasian origin and broadly representative of the older Australian population (11).

Diagnostic criteria were either self-reported diabetes and current use of diabetes medications or fasting glucose concentration ≥126 mg/dl (12). Diabetes incidence was defined in participants without diabetes at baseline who were diagnosed with diabetes before or at the 5- or 10-year follow-up. In total, 2,564 individuals were followed from baseline. After excluding 163 participants with existing diabetes and 52 with missing data, 2,349 were considered at risk of incident diabetes. An additional 226 participants did not have fasting blood tests at either the 5- or …
Nasobridles as a retaining device to provide nutrition support
Authors: A. Young, L. Leedham
Journal: Gut (2011)

<h3>Introduction</h3> Nasogastric feeding tubes are displaced with an increased risk of aspiration and problems impacting on patient recovery/prognosis. Prior to the introduction of nasal bridles, options for patients who repeatedly self-removed NG tubes were limited. Gastrostomy devices would be inserted with the associated risks impacting on 30 day mortality. A bridle allows time to assess the patients9 response to nutritional support without proceeding to PEG. Protocol dictates that a patient must have pulled out three feeding tubes before a bridle will be considered. Assessment includes risk of self-harm, contraindications, MDT involvement, rationale for use and appropriateness of device. <h3>Aim</h3> To investigate the effectiveness of nasobridles on patient management and outcomes. All patients referred to Nutrition Nurses for nasobridle assessment over a three year period reviewed. We analysed number of referrals, number of patients requiring an NG tube only, number that required a nasobridle and the effectiveness and complications of nasobridles. <h3>Results</h3> NG tube and bridle placement occurred in the audit period of October 2007–October 2010. 302 referrals were received. 56 % (170) were placed, of these 14% (24) died with bridle in-situ. Those that proceeded to PEG were 18% (31). Those that died following gastrostomy insertion were 2% (3). Bridle complications included; 4% (2) were displaced while the patient was being fed leading to aspiration pneumonia; 1.5%(1) pulled septum out. Minor complications included pulling NG through the bridle 11% (19), blocked NG 6% (10) and patients unpicking the bridle 2% (3).No reported incidents of ulceration or sinusitis since bridles being introduced. 44% (132) did not have bridles placed. The main reasons for not placing included 22% (30) were eating, 5% (7) died, 16%(22) 3 NG insertions had not been attempted and 4%(7) at risk of self-harm. <h3>Conclusion</h3> Appropriately managed bridles allow successful administration of medications/feed in patients that would previously have had delays. Allowing patients time to recover from illness or unfortunately die. A thorough assessment by dedicated specialists does prevent nasobridles from being inappropriately placed. Adverse complications of bridle placement are minimal and benefits outweigh potential complications. Issues with nursing staff cutting out bridles 6% (10) were highlighted. Education is important and the nutrition nurses provide training and support to staff also reviewing patients post placement. In conclusion nasobridles are an effective, efficient device that enhances patient care and prevents placement of PEG in patients that are at increased risk from a 30 day mortality perspective.
REAL WORLD APPLICATION OF STENTING OF UNPROTECTED LEFT MAIN CORONARY STENOSIS: A SINGLE-CENTER EXPERIENCE
Authors: Calvin Leung, Timothy C. Ball, Jeremiah R. Brown, Mandeep S. Sidhu, James T. Devries, John F. Robb, Aaron V. Kaplan, David J. Malenka, Craig A. Thompson
Journal: Journal of the American College of Cardiology (2010)
The opioid agonist codeine and antagonist naltrexone do not affect voluntary suppression of capsaicin induced cough in healthy subjects
Authors: HA Hutchings, R Eccles
Journal: European Respiratory Journal (1994)

Opioids exert an analgesic action by mimicking the effects of endogenous neurotransmitter substances in the central nervous system. Opioids are widely used as antitussives, and it is reasonable to assume that endogenous opioids are involved in the control of cough. In order to investigate this hypothesis, a parallel design study was carried out to examine the effects of 50 mg codeine (opioid agonist), 50 mg naltrexone (opioid antagonist) and placebo on capsaicin-induced cough in 80 healthy volunteers (mean age 25 yrs). Volunteers received two capsaicin challenge units (each consisting of five inhalations of different concentrations of capsaicin, 0.00-3.33 x 10(-4) M). On one challenge unit subjects were instructed to suppress cough, and on the other challenge unit subjects coughed freely. Coughs were recorded on a tape cassette player and later played back into a pen recorder to produce integrated sound traces. The number of coughs in the suppression challenge unit was significantly reduced in all three treatment groups compared to that recorded in the non-suppression challenge unit. Comparisons between the three treatment groups showed that there was no statistical difference between the three groups both before and 90 min after treatment for the total coughs in the suppression challenge unit and for the total coughs in the non-suppression challenge unit. These results demonstrate that capsaicin-induced cough can be voluntarily suppressed, but that both suppressed and non-suppressed cough were unaffected by treatment with codeine, naltrexone or placebo. These results do not provide any support for the hypothesis that capsaicin-induced cough is influenced by endogenous opioid substances.
Inhibition of tumor cell growth by interferon-gamma is mediated by two distinct mechanisms dependent upon oxygen tension: induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide.
Authors: T M Aune, S L Pogue
Journal: Journal of Clinical Investigation (1989)

Growth of a variety of human tumor cell lines is inhibited by interferon-gamma (IFN-gamma) in vitro. This mechanism is not well understood. The present experiments identify two separate mechanisms which account for the growth inhibitory activity of IFN-gamma. Cell lines most sensitive to IFN-gamma (inhibited by 10-30 U/ml IFN-gamma in 3 d) were stimulated by IFN-gamma to oxidize tryptophan in media to kynurenine and completely eliminated tryptophan from the culture media after 48-72 h. Addition of L-tryptophan, but not other aromatic amino acids, other essential amino acids, or D-tryptophan, prevented inhibition of cell growth by IFN-gamma. The amount of IFN-gamma required to yield 50% inhibition of cell growth was directly related to the concentration of L-tryptophan in culture media and increased from approximately 3 to 600 U/ml as the concentration of tryptophan in the media was increased from 25 to 1,000 microM. By contrast, inhibition of growth of the cell lines, BT20 and HT29, was not prevented by addition of tryptophan. Inhibition by IFN-gamma (100-300 U/ml after 5-6 d) was, however, completely prevented by addition of two inhibitors of adenosine diphosphate-ribosyl transferase (ADP-RT), 3-aminobenzamide or nicotinamide. Activity of ADP-RT was increased in these cell lines after addition of IFN-gamma. ADP-RT catalyzes the incorporation of the ADP moiety of nicotinamide adenine dinucleotide (NAD) into proteins and causes depletion of intracellular NAD. All tumor cell lines tested had reduced levels of intracellular NAD after treatment with IFN-gamma and loss of NAD preceded inhibition of cell growth by 12-24 h. Inhibitors of IFN-gamma-mediated inhibition of cell growth prevented loss of levels of intracellular NAD. Generation of reactive oxygen species lead to DNA strand breaks which result in activation of ADP-RT. Increased DNA strand breaks were induced in BT20 and HT29 cells but not ME180 and A549 cells after culture with IFN-gamma. The two enzymes known to catalyze the decyclization of tryptophan to kynurenine require superoxide anion for activity. Increased amounts of superoxide anion were released from ME180 and A549 cells after culture with IFN-gamma. Reduced oxygen concentration decreased the ability of IFN-gamma to inhibit tumor cell growth in vitro. Intracellular glutathione has been shown to protect cells against oxidative damage by various agents. Elevation or reduction of intracellular glutathione concentrations lowered or raised sensitivity of cell lines to IFN-gamma, respectively. These data indicate that at least two distinct mechanisms can account for IFN-gamma-madiated inhibition of tumor cell growth. Both mechanisms appear to be sensitive to oxygen tension and to changes in intracellular glutathione concentrations, and both mechanisms lead to loss of intracellular NAD.
Primary care in the United States: Primary care gatekeeping and referrals: effective filter or failed experiment?
Authors: C. B Forrest
Journal: BMJ (2003)

was similar to that found in the single previous randomised controlled trial comparing five statins. 5e are aware that there have been no direct comparisons of the clinical outcomes in patients taking different statins and, realistically, such studies are unlikely.Initial serum cholesterol concentrations were higher in our study than in the randomised controlled trials, therefore the absolute risk reductions in primary care patients (and hence the overall population benefits) may be greater than thought.Achieving target cholesterol values of <5mmol/l may, however, be unrealistic.We thank the participating general practices; Andy Meal, Vicky Hammersley and Lynne Wright for advice on MIQUEST queries; and Lindsay Groom and Janet Yates for their comments on a late draft.