tbuckley/cabot-search huggingface dataset:
Cervical Cancers Require the Continuous Expression of the Human Papillomavirus Type 16 E7 Oncoprotein Even in the Presence of the Viral E6 Oncoprotein
Authors: Sean F. Jabbar, Soyeong Park, Johannes Schweizer, Marthe Berard-Bergery, Henry C. Pitot, Denis Lee, Paul F. Lambert
Journal: Cancer Research (2012)

High-risk human papillomaviruses (HPV), such as HPV-16, are etiologic agents of a variety of anogenital and oral malignancies, including nearly all cases of cervical cancer. Cervical cancers arising in transgenic mice that express HPV-16 E7 in an inducible manner require the continuous expression of E7 for their maintenance. However, in HPV-associated cancers in vivo, E6 and E7 invariably are coexpressed. In this study, we investigated whether cervical cancers rely on the continuous expression of E7 in the context of constitutively expressed E6. We placed the inducible HPV-16 E7 transgene onto a background in which HPV-16 E6 was constitutively expressed. In transgenic mice with high-grade cervical dysplastic lesions and cervical cancer, repressing the expression of E7 led to the regression of all cancers and the vast majority of high-grade dysplastic lesions. In addition, cervical cancers were occasionally observed in transgenic mice in which E7 was repressed and then reexpressed. Our findings indicate that even in the presence of constitutively expressed E6, the continuous expression of E7 is required for the maintenance of cervical cancers and most precancerous lesions. These data have important implications for the potential clinical use of drugs designed to inhibit the expression and/or function of E7 to treat HPV-associated cancers.
Infertility in the third millennium: implications for the individual, family and society: Condensed Meeting Report from the Bertarelli Foundation's Second Global Conference
Authors: B. Lunenfeld
Journal: Human Reproduction Update (2004)

Primary infertility is a key issue in the developed world, while the developing world has high rates of secondary infertility. The impact of HIV/AIDS on fertility is insufficiently explored. One of the most important barriers to access to infertility treatment is cost; at the same time the role of social and cultural factors in restricting access should not be underestimated. IVF has become the standard therapy for female infertility, and ICSI for infertility of the male partner. However, the use of these therapies should not be initiated without a thorough investigation and, whenever possible, individual diagnosis of the underlying causes of infertility. Multiple gestation remains one of the most challenging and controversial issues in the treatment of infertility. Current IVF practices are often blamed for this; in this respect, attention should also be focused on the role of ovarian stimulation in ovulation induction. National guidelines and national registries for assisted reproductive technology (ART) are becoming more widespread and are expected to play an important role in promoting best practice in ART in the future.
A comparison of randomized concurrent control groups with matched historical control groups: are historical controls valid?
Authors: L F Diehl, D J Perry
Journal: Journal of Clinical Oncology (1986)

The use of a historical control group is predicated on the assumption that survival and relapse-free survival in the historical control group closely approximate the survival and relapse-free survival in a randomized concurrent control group. This assumption has never been tested. This study compares survival and relapse-free survival in randomized control groups with historical control groups matched for disease, stage, and follow-up. Of the 43 matched control groups, 42% varied by more than 10 percentage points, 21% varied by more than 20 percentage points, and 5% varied by more than 30 percentage points. Of the 18 that varied by greater than 10 percentage points, 17 had superior survival or relapse-free survival in the randomized concurrent control group. This study indicates that the assumption that historical control groups may replace randomized concurrent control groups is not valid.
CD34 cell dose in granulocyte colony-stimulating factor–mobilized peripheral blood mononuclear cell grafts affects engraftment kinetics and development of extensive chronic graft-versus-host disease after human leukocyte antigen–identical sibling transplantation
Authors: J. Maciej Zaucha, Theodore Gooley, William I. Bensinger, Shelly Heimfeld, Thomas R. Chauncey, Renata Zaucha, Paul J. Martin, Mary E. D. Flowers, Jan Storek, George Georges, Rainer Storb, Beverly Torok-Storb
Journal: Blood (2001)
Insulin Sensitivity and Associated Risk Factors in Mexican Children and Adolescents
Authors: Rodolfo Cisneros-Tapia, Francisco A. Navarrete, Ana C. Gallegos, Alma E. Robles-Sardin, Rosa O. Méndez, Mauro E. Valencia
Journal: Diabetes Care (2005)

There is an increasing amount of data showing that being overweight during childhood and adolescence is significantly associated with insulin resistance in young adulthood. Weight loss in obese youngsters results in a decrease in insulin concentration and improvement in insulin sensitivity (1). The objective of this study was to identify the principal risk factors associated with insulin sensitivity in a group of Mexican children and adolescents with a wide range of body weight.

One hundred male and female children and youth subjects aged between 10 and 20 years, from different socioeconomic levels, provided general information about their health status as well as blood samples for a 75-g oral glucose tolerance test (2) and basal and 2-h insulin and lipid determinations (triglycerides and HDL, LDL, and total cholesterol) (3,4). Insulin sensitivity was estimated by the insulin sensitivity index (ISI)0,120 method (5,6). Acanthosis nigricans (7) and blood pressure measurements were performed by a trained physician. Anthropometrical measurements included body weight, height, BMI, and waist circumference. Body composition and fat distribution were made by body density from air-displacement plethysmography measurements (8,9) and by dual-energy X-ray absorptiometry for abdominal fat …
Targeting Polo-Like Kinase: Learning Too Little Too Late?
Authors: David Olmos, Charles Swanton, Johann de Bono
Journal: Journal of Clinical Oncology (2008)

David Olmos, The Drug Development Unit, Royal Marsden National Health Services Foundation Trust and The Institute of Cancer Research, Surrey, United Kingdom Charles Swanton, Cancer Research UK Translational Cancer Therapeutics Laboratory, London Research Institute, London, United Kingdom Johann de Bono, The Drug Development Unit, Royal Marsden National Health Services Foundation Trust and The Institute of Cancer Research, Surrey, United Kingdom
Calmodulin and CaMKII as molecular switches for cardiac ion channels: Fig. 1
Authors: Geoffrey S. Pitt
Journal: Cardiovascular Research (2006)

Because changes in intracellular Ca(2+) concentration are the final signals of electrical activity in excitable cells, many mechanisms have evolved to regulate Ca(2+) influx. Among the most important are those pathways that directly regulate the ion channels responsible for regulating and generating the Ca(2+) influx signal. Recent work has demonstrated that the Ca(2+) binding protein calmodulin (CaM) and the Ca(2+)/CaM-sensitive kinase CaMKII are important modulators of cardiac ion channels. Thus, Ca(2+) participates in feedback modulation to control electrical activity. This review highlights various mechanisms by which CaM and CaMKII regulate cardiovascular ion channel activity and presents a novel model for CaMKII regulation of Ca(V)1.2 Ca(2+) channel function.
BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid
Authors: Chuanwu Wang, Shankar Thangamani, Myunghoo Kim, Bon-Hee Gu, Jee H. Lee, Elizabeth J. Taparowsky, Chang H. Kim
Journal: The Journal of Experimental Medicine (2013)

CCR9 and α4β7 are the major trafficking receptors for lymphocyte migration to the gut, and their expression is induced during lymphocyte activation under the influence of retinoic acid (RA). We report here that BATF (basic leucine zipper transcription factor, ATF-like), an AP-1 protein family factor, is required for optimal expression of CCR9 and α4β7 by T helper cells. BATF-deficient (knockout [KO]) mice had reduced numbers of effector T and regulatory T cells in the intestine. The intestinal T cells in BATF KO mice expressed CCR9 and α4β7 at abnormally low levels compared with their wild-type (WT) counterparts, and BATF KO CD4+ T cells failed to up-regulate the expression of CCR9 and α4β7 to WT levels in response to RA. Defective binding of RARα and histone acetylation at the regulatory regions of the CCR9 and Itg-α4 genes were observed in BATF KO T cells. As a result, BATF KO effector and FoxP3+ T cells failed to populate the intestine, and neither population functioned normally in the induction and regulation of colitis. Our results establish BATF as a cellular factor required for normal expression of CCR9 and α4β7 and for the homeostasis and effector functions of T cell populations in the intestine.
Renal Transplantation
Authors: Eliana Gotti, Norberto Perico, Annalisa Perna, Flavio Gaspari, Dario Cattaneo, Raffaele Caruso, Silvia Ferrari, Nadia Stucchi, Gianfranco Marchetti, Mauro Abbate, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. How to combine antirejection drugs and which is the optimal dose of steroids and calcineurin inhibitors beyond the first year after kidney transplantation to maintain adequate immunosuppression without major side effects are far from clear. Kidney transplant patients on steroid, cyclosporine (CsA), and azathioprine were randomized to per-protocol biopsy (n = 30) or no-biopsy (n = 29) 1 to 2 yr posttransplant. Steroid or CsA were discontinued or reduced on the basis of biopsy to establish effects on drug-related complications, acute rejection, and graft function over 3 yr of follow-up. Serum creatinine, GFR (plasma clearance of iohexol), RPF (renal clearance of p-aminohippurate), CsA pharmacokinetics, and adverse events were monitored yearly. At the end, patients underwent a second biopsy. Per-protocol biopsy histology revealed no lesions (n = 5, steroid withdrawal), CsA nephropathy (n = 13, CsA discontinuation/reduction), or chronic rejection (n = 12, standard therapy). Reducing the drug regimen led to overall fewer side effects related to immunosuppression as compared with standard therapy or no-biopsy. Steroids were safely stopped with no acute rejection or graft loss. Complete CsA discontinuation was associated with acute rejection in the first four patients. Lowering CsA to low target CsA trough (30 to 70 ng/ml) never led to acute rejection or major renal function deterioration. Biopsy patients on conventional regimen had no acute rejection, one graft loss, no significant change in GFR, and significant RPF decline. No-biopsy controls: no acute rejection, one graft loss, significant decline of GFR and RPF. By serial biopsy analysis, severe lesions did not develop in patients with steroid discontinuation in contrast to patients on standard therapy over follow-up. CsA reduction did not adversely affect histology. Per-protocol biopsy more than 1 yr after kidney transplantation is a safe procedure to guide change of drug regimen and to lower the risk of major side effects. E-mail: [email protected]
Long term high intensity exercise and damage of small joints in rheumatoid arthritis
Authors: Z de Jong
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To investigate the effect of long term high intensity weightbearing exercises on radiological damage of the joints of the hands and feet in patients with rheumatoid arthritis (RA). <b>Methods:</b> Data of the 281 completers of a 2 year randomised controlled trial comparing the effects of usual care physical therapy (UC) with high intensity weightbearing exercises were analysed for the rate of radiological joint damage (Larsen score) of the hands and feet. Potential determinants of outcome were defined: disease activity, use of drugs, change in physical capacity and in bone mineral density, and attendance rate at exercise sessions. <b>Results:</b> After 2 years, the 136 participants in high intensity weightbearing exercises developed significantly less radiological damage than the 145 participants in UC. The mean (SD) increase in damage was 3.5 (7.9) in the exercise group and 5.7 (10.2) in the UC group, p = 0.045. Separate analysis of the damage to the hands and feet suggests that this difference in rate of increase of damage is more pronounced in the joints of the feet than in the hands. The rate of damage was independently associated with less disease activity, less frequent use of glucocorticoids, and with an improvement in aerobic fitness. <b>Conclusion:</b> The progression of radiological joint damage of the hands and feet in patients with RA is not increased by long term high intensity weightbearing exercises. These exercises may have a protective effect on the joints of the feet.
Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing
Authors: Dan Xu, Toshi Nishimura, Sachiko Nishimura, Haili Zhang, Ming Zheng, Ying-Ying Guo, Marylin Masek, Sara A. Michie, Jeffrey Glenn, Gary Peltz
Journal: PLoS Medicine (2014)

Background Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. Methods and Findings Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. Conclusions FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors' Summary
Regulation of the antibody response to type III pneumococcal polysaccharide by contrasuppressor T cells.
Authors: H Braley-Mullen
Journal: The Journal of Experimental Medicine (1984)

A soluble membrane component of type III pneumococcal polysaccharide-coupled spleen cells (S3-SCSM) induces S3-specific suppressor T cells (Ts) in mice. These Ts can be detected only if mice are pretreated with cyclophosphamide (Cy) or if cells adherent to the lectin Vicia villosa are removed from the spleen cell population prior to transfer. The V. villosa-adherent spleen cells from mice injected with S3-SCSM could abrogate suppression mediated by Ts induced by S3-SCSM in Cy-treated mice. The V. villosa-adherent contrasuppressor cells were shown to be T cells that were I-J+ and of the Lyt-1 phenotype. Contrasuppressor T cells (Tcs) were not present in V. villosa-adherent spleen cell fractions obtained from normal mice, from mice injected with polyvinylpyrrolidone-coupled spleen cells, or from Cy-treated mice injected with S3-SCSM, i.e., mice in which Ts activity is dominant. The V. villosa-adherent cells that abrogated the activity of Ts induced by S3-SCSM in Cy-treated mice did not abrogate suppression mediated by a different subset of S3-specific Ts, suggesting that the Tcs described here do not have activity against all Ts subsets. The ability of S3-SCSM to activate Tcs in normal mice provides an explanation for the inability to detect S3-specific Ts in several previous studies.
A report of the medical team activity at the 2009 Special Olympics GB
Authors: Patrick C Wheeler, Tim Williamson, Catherine Stephens, Mike Ferguson
Journal: British Journal of Sports Medicine (2011)

To quantify and categorise medical workload from the 2009 Special Olympics GB (SOL GB) which involved 2500 athletes with learning disabilities across 21 different sports supported by nearly 9000 family members, volunteers and staff over a 7-day period.Prospective survey of all medical contacts that took place at the 2009 SOL GB with subsequent analysis of consultation rates, medical problems and medical activity.581 medical consultations occurred during the 2009 SOL GB, with 95% of these for athletes. The majority of the athlete consultations were for musculoskeletal disorders, followed by skin wound care. Most athletes were judged fit to participate following their consultation.A large multisport event for athletes with learning disabilities carries a significant medical workload that has not been studied previously, with different sports having different individual risks and demands. The vast majority of consultations are for systemically well athletes that can be managed locally without necessity for hospital admission. This study identifies the quantity and nature of medical consultations undertaken during this event in an attempt to inform planning for future events.
EMAP-II downregulation contributes to the beneficial effects of rapamycin after vascular injury
Authors: T. G. Nuhrenberg, N. Langwieser, J. B.K. Schwarz, Y. Hou, P. Frank, F. Sorge, S. Matschurat, S. Seidl, A. Kastrati, A. Schomig, M. A. Clauss, D. Zohlnhofer
Journal: Cardiovascular Research (2007)

Neointima formation after vascular injury is strongly associated with inflammation. Rapamycin inhibits human neointima formation and reduces expression of the proinflammatory cytokine endothelial-monocyte activating peptide II (EMAP-II) in vitro. Here we investigated the interplay between EMAP-II and rapamycin after vascular injury in vivo. In a mouse model of vascular injury, mice were either not treated, given everolimus, a rapamycin derivate, or subjected to simultaneous challenge with everolimus and EMAP-II. EMAP-II expression was measured in coronary artery smooth muscle cells (CASMC) and monocytic cells in vitro and in patients after percutaneous coronary intervention (PCI). After vascular injury, rapamycin reduced neointima formation and adventitial thickening. Immunohistochemistry revealed reduced EMAP-II protein expression and suppressed recruitment of inflammatory cells. Simultaneous challenge with EMAP-II counteracted these effects of rapamycin. Expression of EMAP-II and its inhibition by rapamycin was confirmed in CASMC and monocytic cells. In patients, EMAP-II upregulation was confined to PCI of distal coronary artery segments and profoundly suppressed by oral rapamycin treatment. These data suggest important yet unrecognized roles of EMAP-II and adventitial inflammation in neointima formation: Through inhibition of EMAP-II, rapamycin reduces the recruitment of inflammatory cells to the adventitia and supports an early and bland healing.
Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease
Authors: Stephanie Arndt, Eva Wacker, Christoph Dorn, Andreas Koch, Michael Saugspier, Wolfgang E Thasler, Arndt Hartmann, Anja Katrin Bosserhoff, Claus Hellerbrand
Journal: Gut (2014)

<h3>Objective</h3> Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease. <h3>Design</h3> BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6<sup>−/−</sup>) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets. <h3>Results</h3> BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6<sup>−/−</sup> compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6<sup>−/−</sup> mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs. <h3>Conclusions</h3> Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy.
Applying implementation science to sports injury prevention
Authors: Alex Donaldson, Caroline F Finch
Journal: British Journal of Sports Medicine (2013)

Recent commentary in the BJSM has argued that a key challenge for future sports injury prevention is to reduce the ‘research to practice’ gap.1 Unfortunately, very few examples of this type of research actually exist. In this issue, Myklebust et al 2 describe their approach to anterior cruciate ligament  (ACL) injury prevention in Norwegian Handball over the past 13 years. This is one of the first published papers on the long-term outcomes of a sports injury prevention intiative that has shown promising efficacy in controlled trials.3 While this paper describes an impressive intial research effort and outstanding example of long-term follow-up through an ACL Injury Surveillance Programme, it also highlights challenges associated with conducting sports injury prevention implementation research.

Like other reports of the implementation of sports injury prevention interventions,4–8 Myklebust et al have listed the implementation activities undertaken without providing details of theoretical frameworks, specifc evidence or guiding principles used to inform selection or operationalisation of these activities. While considerable effort is often invested in describing the details of, and the evidence-based underpinning, interventions, implementation research also requires detailed information about what specific implementation strategies were put in place, why and how they were selected and delivered, and how effective they were in reaching and influencing the behaviour of the targeted audience.9 It is insufficient to describe implementation activities in general …