tbuckley/cabot-search huggingface dataset:
Exploration and confirmation of factors associated with uncomplicated pregnancy in nulliparous women: prospective cohort study
Authors: L. C. Chappell, P. T. Seed, J. Myers, R. S. Taylor, L. C. Kenny, G. A. Dekker, J. J. Walker, L. M. E. McCowan, R. A. North, L. Poston
Journal: BMJ (2013)

<b>Objective</b> To identify factors at 15 and 20 weeks' gestation associated with a subsequent uncomplicated pregnancy. <b>Design</b> Prospective international multicentre observational cohort study. <b>Setting</b> Auckland, New Zealand and Adelaide, Australia (exploration and local replication dataset) and Manchester, Leeds, and London, United Kingdom, and Cork, Republic of Ireland (external confirmation dataset). <b>Participants</b> 5628 healthy nulliparous women with a singleton pregnancy. <b>Main outcome measure</b> Uncomplicated pregnancy, defined as a normotensive pregnancy delivered at &gt;37 weeks' gestation, resulting in a liveborn baby not small for gestational age, and the absence of any other significant pregnancy complications. In a stepwise logistic regression the comparison group was women with a complicated pregnancy. <b>Results</b> Of the 5628 women, 3452 (61.3%) had an uncomplicated pregnancy. Factors that reduced the likelihood of an uncomplicated pregnancy included increased body mass index (relative risk 0.74, 95% confidence intervals 0.65 to 0.84), misuse of drugs in the first trimester (0.90, 0.84 to 0.97), mean diastolic blood pressure (for each 5 mm Hg increase 0.92, 0.91 to 0.94), and mean systolic blood pressure (for each 5 mm Hg increase 0.95, 0.94 to 0.96). Beneficial factors were prepregnancy fruit intake at least three times daily (1.09, 1.01 to 1.18) and being in paid employment (per eight hours' increase 1.02, 1.01 to 1.04). Detrimental factors not amenable to alteration were a history of hypertension while using oral contraception, socioeconomic index, family history of any hypertensive complications in pregnancy, vaginal bleeding during pregnancy, and increasing uterine artery resistance index. Smoking in pregnancy was noted to be a detrimental factor in the initial two datasets but did not remain in the final model. <b>Conclusions</b> This study identified factors associated with normal pregnancy through adoption of a novel hypothesis generating approach, which has shifted the emphasis away from adverse outcomes towards uncomplicated pregnancies. Although confirmation in other cohorts is necessary, this study implies that individually targeted lifestyle interventions (normalising maternal weight, increasing prepregnancy fruit intake, reducing blood pressure, stopping misuse of drugs) may increase the likelihood of normal pregnancy outcomes. <b>Trial registration</b> Australian New Zealand Clinical Trials Registry ACTRN12607000551493.
ACC/AHA/ESC Guidelines for the Management of Patients With Supraventricular Arrhythmias—Executive Summary
Authors: Carina Blomström-Lundqvist, Melvin M. Scheinman, Etienne M. Aliot, Joseph S. Alpert, Hugh Calkins, A. John Camm, W. Barton Campbell, David E. Haines, Karl H. Kuck, Bruce B. Lerman, D. Douglas Miller, Charlie Willard Shaeffer, William G. Stevenson, Gordon F. Tomaselli, Elliott M. Antman, Sidney C. Smith, Joseph S. Alpert, David P. Faxon, Valentin Fuster, Raymond J. Gibbons, Gabriel Gregoratos, Loren F. Hiratzka, Sharon Ann Hunt, Alice K. Jacobs, Richard O. Russell, Silvia G. Priori, Jean-Jacques Blanc, Andzrej Budaj, Enrique Fernandez Burgos, Martin Cowie, Jaap Willem Deckers, Maria Angeles Alonso Garcia, Werner W. Klein, John Lekakis, Bertil Lindahl, Gianfranco Mazzotta, João Carlos Araujo Morais, Ali Oto, Otto Smiseth, Hans-Joachim Trappe
Journal: Circulation (2003)
Modeling oncology surrogate markers
Authors: K. Johnson, B. Stokes, D. Anthony, R. Ward, N. Freemantle, S. Hill
Journal: Journal of Clinical Oncology (2005)

9639 Background The use of surrogates in clinical trials relies on evidence that treatment benefit on an unmeasured outcome can be reliably predicted from treatment effect on the surrogate. Surrogates for survival have the potential to improve the efficiency and economy of clinical trials. To explore this we model treatment effects on surrogates and outcomes across trials. Methods An exhaustive search was done for randomised trials of medical therapy in advanced colorectal cancer (CC) and non-small cell lung cancer (LC) using standard reporting of median survival and tumour response rate (RR) or median time-to-progression (TTP). Data were also extracted on treatments, quality, age, stage, performance status, rescue therapy, and intent-to-treat. Survival difference between arms was modelled as a function of RR or TTP difference between maximal 2-arms in first line trials weighted by size. Because biology suggests monotonicity without curvilinearity, a linear model was fitted. Adjusted R2 (aR2) and 95% confidence and prediction bands were estimated. Results 13938 search and 25 other citations, 1639 abstracts, and 544 articles yielded 144 (CC) and 190 (LC) qualifying trials of 34862 and 43534 patients. Quality was generally poor. Diagnostics were satisfactory. All models sloped upward to the right indicating more benefit with greater RR or TTP differences. For models RR-CC, RR-LC, TTP-CC, TTP-LC slopes were 7.6, 8.1, 0.87, and 0.85 (all p<0.001) and aR2 0.08, 0.12, 0.19, and 0.31. Modeling both RR and TTP increased aR2 for CC to 0.36 but not for LC. Prediction bands crossed y=0 at 35–50% for RR models and 3–4 months for TTP models. Modeling certain drug class subset increased aR2 and slope but no two slopes significantly differed; adding covariates or fitting fractional polynomials changed results little (data not shown). Conclusions By these data RR and TTP show validity only with large differences. Surrogate validity is graded, not binary, and it independently varies with slope steepness and data scatter. This approach deserves wider exploration. Limitations include incomplete reporting, unsuspected important covariates, and measurement, trial design, and statistical issues. Supported by the Department of Health and Ageing, Canberra Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, sanofi-aventis, Amgen Pfizer, sanofi-aventis, Amgen Pfizer, sanofi-aventis, Amgen Pfizer, sanofi-aventis, Amgen
The Thalidomide Analogue, CC-4047, Induces Apoptosis Signaling and Growth Arrest in Childhood Acute Lymphoblastic Leukemia Cells <i>In vitro</i> and <i>In vivo</i>
Authors: Shabnam Shalapour, Andrea Zelmer, Madlen Pfau, Eva Moderegger, Cristiane Costa-Blechschmidt, Frank K.H. van Landeghem, Tillmann Taube, Iduna Fichtner, Christoph Bührer, Günter Henze, Karl Seeger, Sven Wellmann
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Thalidomide and its analogues have shown promise in the treatment of multiple myeloma but their therapeutic potential has not been evaluated in models of acute lymphoblastic leukemia (ALL). Experimental Design: We assessed the effects of the thalidomide analogue, CC-4047, on the growth and apoptosis signaling of human B cell precursor (BCP) ALL cell lines and freshly obtained childhood BCP-ALL cells grown with or without stromal cells. In addition, we studied the effects of CC-4047 on the progression and dissemination of xenotransplanted human BCP-ALL cells in nonobese diabetic/severe combined immunodeficiency mice. Results: CC-4047 reduced the proliferation of human BCP-ALL cell lines in vitro. In contrast with the antileukemic effect of cytarabin, this was more pronounced when cell lines or freshly obtained childhood BCP-ALL cells were cocultured with stromal cells. CC-4047 induced the cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase in stroma-cocultured BCP-ALL cells. The inhibition of tumor growth, caspase-3 cleavage, and reduced microvessel density was observed in nonobese diabetic/severe combined immunodeficiency mice inoculated s.c. with childhood BCP-ALL cells upon CC-4047 treatment. After i.v. BCP-ALL xenotransplantation, CC-4047 reduced splenic dissemination. Conclusions: The thalidomide analogue, CC-4047, displays profound cytostatic effects on stroma-supported human ALL cells both in vitro and in vivo.
A Genetically Enhanced Anaerobic Bacterium for Oncopathic Therapy of Pancreatic Cancer
Authors: Z. Li, J. Fallon, J. Mandeli, J. Wetmur, S. L. C. Woo
Journal: JNCI Journal of the National Cancer Institute (2008)

A major obstacle in treatment of solid tumors is the inefficient delivery of therapeutic agents to the hypoxic cores. Hypoxia offers the potential for anaerobic bacteria colonization and tumor destruction by the bacteria, and dormant spores of wild-type Clostridium perfringens (Cp) germinate and proliferate within the hypoxic cores of pancreatic tumors in mice. However, the oncopathic effects of Cp were limited by host inflammatory responses and by Cp's residual tolerance to oxygen, which caused toxic effects in animals.Recombinant Cp strains in which superoxide dismutase, a major oxygen tolerance gene, was deleted (Cp/sod(-)) were constructed to enhance its selective growth in tumors. In addition, Panton-Valentine Leukocidin (PVL), an inflammation-suppressing gene from Staphylococcus aureus, was inserted into the Cp/sod(-) genome to enhance its oncopathic potency. The ability of the recombinant Cp strains to kill tumors was investigated in C57/BL6 mice bearing murine PANC02 tumors. Systemic and organ toxic effects were assessed by monitoring serum chemistries and histopathological examination. Statistical tests were two-sided.Cp/sod(-) showed reduced toxic effects compared with wild-type Cp when spores were administered intravenously into PANC02 tumor-bearing mice. Mice treated with Cp/sod(-)/PVL spores demonstrated a reduction in neutrophils and macrophages in tumors, logarithmically elevated growth of intratumoral bacteria, enhanced tumor necrosis, and substantially prolonged survival without apparent systemic and organ toxic effects, compared with mice treated with both wild-type Cp and Cp/sod(-) spores. Accordingly, 47% of Cp/sod(-)/PVL-treated mice (n = 15) achieved tumor-free survival for over 120 days, whereas all mice treated with Cp/sod(-) or phosphate-buffered saline (n = 10 per group) died within 50 days. The median survival for Cp/sod(-)/PVL-treated mice was 77 days (95% confidence interval [CI] = 45 to 120 days) and for Cp/sod(-)-treated mice was 30 days (95% CI = 23 to 36 days; P < .001).Cp/sod(-)/PVL provides a prototype for a novel class of oncopathic microbes that may have potential for the safe and effective treatment of pancreatic cancer and other poorly vascularized tumors.
Increased Neointima Formation in Cysteine-Rich Protein 2–Deficient Mice in Response to Vascular Injury
Authors: Jiao Wei, Terri E. Gorman, Xiaoli Liu, Bonna Ith, Alan Tseng, Zhiping Chen, Daniel I. Simon, Matthew D. Layne, Shaw-Fang Yet
Journal: Circulation Research (2005)

In response to arterial injury, medial vascular smooth muscle cells (VSMCs) proliferate and migrate into the intima, contributing to the development of occlusive vascular disease. The LIM protein cysteine-rich protein (CRP) 2 associates with the actin cytoskeleton and may maintain the cytoarchitecture. CRP2 also interacts with transcription factors in the nucleus to mediate SMC gene expression. To test the hypothesis that CRP2 may be an important regulator of vascular development or function we generated Csrp2 (gene symbol of the mouse CRP2 gene)-deficient (Csrp2(-/-)) mice by targeted mutation. Csrp2(-/-) mice did not have any gross vascular defects or altered expression levels of SM alpha-actin, SM22alpha, or calponin. Following femoral artery injury, CRP2 expression persisted in the vessel wall at 4 days and then decreased by 14 days. Intimal thickening was enhanced 3.4-fold in Csrp2(-/-) compared with wild-type (WT) mice 14 days following injury. Cellular proliferation was similar between WT and Csrp2(-/-) VSMC both in vivo and in vitro. Interestingly, Csrp2(-/-) VSMC migrated more rapidly in response to PDGF-BB and had increased Rac1 activation. Our data demonstrate that CRP2 is not required for vascular development. However, an absence of CRP2 enhanced VSMC migration and increased neointima formation following arterial injury.
GFP-like Proteins as Ubiquitous Metazoan Superfamily: Evolution of Functional Features and Structural Complexity
Authors: Dmitry A. Shagin, Ekaterina V. Barsova, Yurii G. Yanushevich, Arkady F. Fradkov, Konstantin A. Lukyanov, Yulii A. Labas, Tatiana N. Semenova, Juan A. Ugalde, Ann Meyers, Jose M. Nunez, Edith A. Widder, Sergey A. Lukyanov, Mikhail V. Matz
Journal: Molecular Biology and Evolution (2004)

Homologs of the green fluorescent protein (GFP), including the recently described GFP-like domains of certain extracellular matrix proteins in Bilaterian organisms, are remarkably similar at the protein structure level, yet they often perform totally unrelated functions, thereby warranting recognition as a superfamily. Here we describe diverse GFP-like proteins from previously undersampled and completely new sources, including hydromedusae and planktonic Copepoda. In hydromedusae, yellow and nonfluorescent purple proteins were found in addition to greens. Notably, the new yellow protein seems to follow exactly the same structural solution to achieving the yellow color of fluorescence as YFP, an engineered yellow-emitting mutant variant of GFP. The addition of these new sequences made it possible to resolve deep-level phylogenetic relationships within the superfamily. Fluorescence (most likely green) must have already existed in the common ancestor of Cnidaria and Bilateria, and therefore GFP-like proteins may be responsible for fluorescence and/or coloration in virtually any animal. At least 15 color diversification events can be inferred following the maximum parsimony principle in Cnidaria. Origination of red fluorescence and nonfluorescent purple-blue colors on several independent occasions provides a remarkable example of convergent evolution of complex features at the molecular level.
Ectopic Activation of Germline and Placental Genes Identifies Aggressive Metastasis-Prone Lung Cancers
Authors: Sophie Rousseaux, Alexandra Debernardi, Baptiste Jacquiau, Anne-Laure Vitte, Aurélien Vesin, Hélène Nagy-Mignotte, Denis Moro-Sibilot, Pierre-Yves Brichon, Sylvie Lantuejoul, Pierre Hainaut, Julien Laffaire, Aurélien de Reyniès, David G. Beer, Jean-François Timsit, Christian Brambilla, Elisabeth Brambilla, Saadi Khochbin
Journal: Science Translational Medicine (2013)

Large-scale detection of ectopic gene activations reveals a source of potential cancer biomarkers and correlates with aggressive metastasis-prone lung tumors.
Through Her Eyes
Authors: Julie B. Schnur, Rachel E. Goldsmith
Journal: Journal of Clinical Oncology (2011)

An optical illusion mesmerizes us with its ability to look entirely different depending on our perspective. Our patients can challenge our perceptions, too. Many people are familiar with the famous illusion of Rubin's vase; the picture can appear to be two faces in profile or simply a vase. With someone pointing the way, viewers can learn to see both images, but without a guide, viewers may falsely conclude that they are seeing the full picture when they miss another interpretation. Similarly, we believed that our training and experience over the last 10 years with hundreds of patients with cancer had provided us with a sufficiently broad perspective to understand and detect patients' concerns, fears, and traumas. Yet when we met Mary, heard her story, and witnessed her pain, we learned to see cancer care procedures through her eyes, and our own eyes were opened.
Phasic release of adenosine during steady state metabolic stimulation in the isolated guinea pig heart.
Authors: D F DeWitt, R D Wangler, C I Thompson, H V Sparks
Journal: Circulation Research (1983)

If adenosine is the major factor responsible for myocardial metabolic vasodilation, its release should be sustained as long as oxygen consumption and coronary flow are augmented. To see if adenosine meets this criterion, we examined the time course of its release during norepinephrine infusion in isolated, non-working guinea pig hearts (n = 8). During an 11-minute infusion period (steady state perfusate concentration = 6 X 10(-8) M), the coronary effluent was collected over 30-second intervals for measurements of coronary flow (ml/min per g), and adenosine and inosine release (pmol/min per g). Myocardial oxygen consumption (MVO2 = microliter O2/min per g) was measured at 1, 4, 6.5, and 11 minutes. Control values of coronary flow, myocardial oxygen consumption, and adenosine and inosine release were 7.5 +/- 0.4, 85 +/- 5, 22 +/- 5, and 431 +/- 39, respectively. During norepinephrine infusion, coronary flow, myocardial oxygen consumption, and adenosine release attained maximal levels within one minute (inosine within 2 minutes). These values were 10.6 +/- 0.4, 125 +/- 9, 849 +/- 110, and 2595 +/- 581, respectively. Thereafter, coronary flow and myocardial oxygen consumption values were sustained. In contrast, adenosine and inosine release significantly declined to nadirs by 9.5 minutes. Thereafter, steady state levels were maintained at 117 +/- 24 and 960 +/- 294, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Therapeutic Targeting of Autophagy in Disease: Biology and Pharmacology
Authors: Yan Cheng, Xingcong Ren, William N. Hait, Jin-Ming Yang
Journal: Pharmacological Reviews (2013)

Autophagy, a process of self-digestion of the cytoplasm and organelles through which cellular components are recycled for reuse or energy production, is an evolutionarily conserved response to metabolic stress found in eukaryotes from yeast to mammals. It is noteworthy that autophagy is also associated with various pathophysiologic conditions in which this cellular process plays either a cytoprotective or cytopathic role in response to a variety of stresses such as metabolic, inflammatory, neurodegenerative, and therapeutic stress. It is now generally believed that modulating the activity of autophagy through targeting specific regulatory molecules in the autophagy machinery may impact disease processes, thus autophagy may represent a new pharmacologic target for drug development and therapeutic intervention of various human disorders. Induction or inhibition of autophagy using small molecule compounds has shown promise in the treatment of diseases such as cancer. Depending on context, induction or suppression of autophagy may exert therapeutic effects via promoting either cell survival or death, two major events targeted by therapies for various disorders. A better understanding of the biology of autophagy and the pharmacology of autophagy modulators has the potential for facilitating the development of autophagy-based therapeutic interventions for several human diseases.
Chronic ethanol consumption causes alterations in the structural integrity of mitochondrial DNA in aged rats
Authors: Alan Cahill, Gabriel J. Stabley, Xiaolan Wang, Jan B. Hoek
Journal: Hepatology (1999)

Chronic ethanol consumption adversely affects the respiratory activity of rat liver mitochondria. It causes increased cellular production of oxygen radical species and selectively decreases mitochondrial glutathione (GSH) levels. Here we show, using Southern hybridization techniques on total rat genomic DNA, that long-term (11-13 months) ethanol feeding, using the Lieber-DeCarli diet, results in a 36% ( P &lt; .05; n = 4) decrease in hepatic mitochondrial DNA (mtDNA) levels when compared with paired controls. UV quantitation of mtDNA isolated from hepatic mitochondria showed that chronic ethanol intake (11-13 months) causes a 44% ( P &lt; .01; n = 6) decrease in the amount of mtDNA per milligram of mitochondrial protein. No significant decline in mtDNA levels was seen in ethanol-fed animals maintained on the diet for 1 to 5 months. Ethanol feeding caused a 42% ( P &lt; .01; n = 4) and a 132% ( P &lt; .05; n = 3) increase in 8-hydroxydeoxyguanosine (8-OHdG) formation in mtDNA in animals maintained on the diet for 3 to 6 months and 10 to 11 months, respectively. In addition, agarose gel electrophoresis revealed a 49% increase ( P &lt; .05; n = 3) in mtDNA single-strand breaks (SSB) in animals fed ethanol for more than 1 year. These findings suggest that chronic ethanol consumption causes enhanced oxidative damage to mtDNA in older animals along with increased strand breakage, and that this results in its selective removal/degradation by mtDNA repair enzymes.
Pleural abrasion via axillary thoracotomy in the era of video assisted thoracic surgery.
Authors: D A Simansky, A Yellin
Journal: Thorax (1994)

Recurrent episodes of spontaneous pneumothorax can be managed medically or surgically by various methods, video assisted thoracoscopy being the latest and most attractive.A retrospective analysis was made of 43 pleural abrasions performed in 39 patients through a 4-6 cm axillary thoracotomy incision.There were no deaths and complications were few. At a mean follow up of 33 months there were two recurrences, neither of which required drainage.Compared with results achieved with video assisted thoracoscopic surgery, open pleural abrasion via a small thoracotomy may be the treatment of choice in most hospitals.
Darzi’s five pledges fail to quell doctors’ anxieties about polyclinics
Authors: Adrian O’Dowd
Journal: BMJ (2008)

Legislation to regulate the use of human embryos for research in the United Kingdom had its second reading in the House of Commons this week, but ministers face a fight to push the most contentious measures through.The Human Fertilisation and Embryology Bill, which updates 1990 legislation to take account of advances in technology, passed the second reading by 340 votes to 78, with only nine Labour MPs rebelling.
Insulin Sensitizers May Attenuate Lean Mass Loss in Older Men With Diabetes
Authors: Christine G. Lee, Edward J. Boyko, Elizabeth Barrett-Connor, Iva Miljkovic, Andrew R. Hoffman, Susan A. Everson-Rose, Cora E. Lewis, Peggy Mannen Cawthon, Elsa S. Strotmeyer, Eric S. Orwoll
Journal: Diabetes Care (2011)

OBJECTIVE To examine longitudinal changes in total and appendicular lean body mass in older men with impaired fasting glucose (IFG) or diabetes and to determine whether these changes differ by diabetes treatment. RESEARCH DESIGN AND METHODS A total of 3,752 ambulatory men aged ≥65 years at baseline participated in a multicenter longitudinal cohort study. Baseline glycemic status was categorized as normoglycemia, IFG, undiagnosed/untreated diabetes, or treated diabetes. Insulin sensitizer medication use (metformin and/or thiazolidinediones) was assessed by prescription medication inventory. The change in total lean and appendicular lean mass was derived from dual X-ray absorptiometry scans taken at baseline and 3.5 ± 0.7 years later. RESULTS This male cohort included 1,853 individuals with normoglycemia, 1,403 with IFG, 234 with untreated diabetes, 151 with diabetes treated with insulin sensitizers, and 111 with diabetes treated without insulin sensitizers. Men with untreated diabetes, diabetes treated without insulin sensitizers, or IFG had greater percentage loss in total or appendicular lean mass (P ≤ 0.05 in comparison to normoglycemic men). There remained a significantly greater percentage loss in appendicular lean mass for these groups even after adjustment for medical comorbidities or lifestyle factors. In contrast, the percentage loss in total or appendicular lean mass in men with diabetes treated with insulin sensitizers was significantly less than that in normoglycemic men in minimally and fully adjusted models. CONCLUSIONS Skeletal muscle loss was accelerated in men with IFG and diabetes, except when the latter was treated with insulin sensitizers. These findings suggest that insulin sensitizers may attenuate muscle loss.