tbuckley/cabot-search huggingface dataset:
Evaluation of Treatment Benefit: Randomized Controlled Trials and Population-Based Observational Research
Authors: Christopher M. Booth, Ian F. Tannock
Journal: Journal of Clinical Oncology (2013)

TO THE EDITOR: An editorial by Goodwin et al 1 prioritized randomized controlled trials (RCTs) over observational research for demonstrating benefits of treatment. We agree that RCTs remain the gold standard for establishing efficacy of new cancer therapies under controlled conditions. However, we suggest that the editorial undervaluedtheabilityofpopulation-basedobservationalresearchtoinvestigate effects of new therapies among patients treated in routine practice.Wedisagreewiththeeditorialstatement 1 thatRCTsestablish both efficacy and effectiveness and propose that population-based studies are necessary and complementary to ensure that results of RCTs translate into benefits for the general population, that is, to demonstrate effectiveness. The strength of RCTs derives from the power of randomization toensurethattheonlydifferencebetweentreatmentarmsisexposure to the treatment of interest. However, problems related to design, analysis,andreportinglimitmanyRCTsandhowtheycanbeapplied to manage patients in routine practice. Older patients, patients with comorbidities,andpatientsfromdisadvantagedsocioeconomicbackgrounds are underrepresented in RCTs, and there can be substantial differences in the provision of care for patients in RCTs compared with routine practice. Surrogate end points are used widely in RCTs despite lack of validation that they predict improvement in duration or quality of survival. RCTs underestimate and under-report harms from new cancer therapies, especially chronic toxicities in patients receiving targeted agents. 2 Selective reporting can sometimes give the impressionthatexperimentaltherapyisprovidingbenefitwhenthere is no difference in the primary outcome compared with the control arm and/or increased toxicities associated with the new treatment. 3,4 Large sample sizes of RCTs allow detection of differences between armsthatarestatisticallysignificantbutofmarginalclinicalrelevance. Given the greater toxicity expected when treatment is applied to a population with greater comorbidity, a small increase in overall (or progression-free) survival observed in a large RCT may disappear when some treatments are applied in routine practice. Advances in information technology have enabled large-scale population-based observational studies to combine databases such as cancer registries and hospital records. These studies can provide insights into benefits and treatment-related toxicities of patients underrepresented in RCTs, including the elderly and patients with comorbidities. Examples include the finding of increased cardiovascular disease and diabetes among men treated with androgen deprivation for localized prostate cancer 5 and risks of cardiac disease after radiotherapyforbreastcancer. 6 Population-basedstudiescanidentify
De novo mutations in neurological and psychiatric disorders: effects, diagnosis and prevention
Authors: Julie Gauthier, Guy A Rouleau
Journal: Genome Medicine (2012)

Neurological and psychiatric disorders account for a considerable proportion of the global disease burden. Although there is a high heritability and a significant genetic component in these disorders, the genetic cause of most cases has yet to be identified. Advances in DNA sequencing allowing the analysis of the whole human genome in a single experiment have led to an acceleration of the discovery of the genetic factors associated with human disease. Recent studies using these platforms have highlighted the important role of de novo mutations in neurological and psychiatric disorders. These findings have opened new avenues into the understanding of genetic disease mechanisms. These discoveries, combined with the increasing ease with which we can sequence the human genome, have important implications for diagnosis, prevention and treatment. Here, we present an overview of the recent discovery of de novo mutations using key examples of neurological and psychiatric disorders. We also discuss the impact of technological developments on diagnosis and prevention.
Effects of hyperglycemia on glucose transporters of the muscle
Authors: D Dimitrakoudis, M Vranic, A Klip
Journal: Journal of the American Society of Nephrology (1992)

Individuals with non-insulin dependent or insulin-dependent diabetes mellitus present insulin resistance in peripheral tissues. This is reflected in a subnormal whole body insulin-dependent glucose utilization, largely dependent on skeletal muscle. Glucose transport across the cell membrane of this tissue is rate limiting in the utilization of the hexose. Therefore, it is possible that a defect exists in insulin-dependent glucose transport in skeletal muscle in diabetic states. This review focuses on two questions: is there a defect at the level of glucose transporters in skeletal muscle of diabetic animal models, and is this a consequence of abnormal insulin or glucose levels? The latter question arises from the fact that these parameters usually vary inversely to each other. Glucose transport into skeletal muscle occurs by two membrane proteins, the GLUT1 and GLUT4 gene products. By subcellular fractionation and Western blotting with isoform-specific antibodies, it was determined that isolated plasma membranes (PM) contain GLUT4 and GLUT1 proteins at a molar ratio of 3.5:1 and that an intracellular fraction (internal membranes; IM) different from sarcoplasmic reticulum contains only GLUT4 transporters. The IM furnishes transporters to the PM in response to insulin. Both transporter isoforms bind cytochalasin B in a D-glucose-protectable fashion. In streptozocin-induced diabetes of the rat with normal fasting insulin levels and marked hyperglycemia, the number of cytochalasin B-binding sites and of GLUT4 proteins diminishes in the PM whereas the GLUT1 proteins increase to a new ratio of about 1.5:1 GLUT4:GLUT1. In the IM, the levels of GLUT4 protein drop, as does the cellular GLUT4 mRNA. To investigate if these changes are associated with hyperglycemia, glucose levels were corrected back to normal values for a 24-h period with sc injections of phlorizin to block proximal tubule glucose reabsorption. This treatment restored cytochalasin B binding, restored GLUT4 and GLUT1 values back to normal levels in the PM, and partly restored cytochalasin B binding but not GLUT4 levels in the IM, consistent with only a partial recovery of GLUT4 mRNA. It is concluded that GLUT4 protein in the PM correlates inversely whereas GLUT1 protein correlates directly with glycemia. It is proposed that the decrease in GLUT4 levels is a protective mechanism, sparing skeletal muscle from gaining glucose and experiencing diabetic complications, albeit at the expense of becoming insulin resistant.(ABSTRACT TRUNCATED AT 400 WORDS)
Expression of Cell Adhesion Molecules in Dilated Cardiomyopathy
Authors: Michel Noutsias, Bettina Seeberg, Heinz-Peter Schultheiss, Uwe Kühl
Journal: Circulation (1999)

Background —Dilated cardiomyopathy (DCM) is pathogenically linked to inflammatory cardiomyopathy (InfCM), which is characterized by intramyocardial infiltration. The transendothelial migration of immunocompetent cells is mediated by cell adhesion molecules (CAMs). Methods and Results —We investigated the expression pattern of CAMs (immunoglobulin superfamily, 32 selectins, and β 1 - and β 2 -integrins) in endomyocardial biopsies from DCM patients (n=152; left ventricular ejection fraction &lt;40%) using immunohistochemistry. Whereas few specimens obtained at autopsy (controls; n=14) presented enhanced expression regarding single endothelial CAMs (human leukocyte antigen [HLA] class I, 7%; HLA-DR, 14%; CD29, 14%), none demonstrated concurrent abundance of &gt;3 CAMs (inflammatory endothelial activation), nor did any control tissue prove positive for InfCM (&gt;7.0 CD3+ lymphocytes per 1 mm 2 ). In comparison, 64% (n=97) of the DCM biopsies were evaluated positive for InfCM and 67% (n=101) for inflammatory endothelial activation, respectively. Whereas expression of HLA class I, HLA-DR, intercellular cell adhesion molecule-1, and CD29 was distributed homogeneously within a patient’s serial sections, immunoreactivity of vascular cell adhesion molecule-1, lymphocyte function antigen-3, and the selectins was accentuated on single vascular endothelia. Sixty-six percent of the DCM biopsies presented CD29 abundance also within the extracellular matrix and the sarcolemma. CD62P and CD62E were present in 16% and 40% of the DCM patients, respectively. Endothelial CAM representatives correlated with one another ( P &lt;0.05), except for CD62P with HLA. Endothelial CAM expression correlated with intramyocardial infiltrates phenotyped by the corresponding counterreceptors. Conclusions —Inflammatory endothelial activation is present in 67% of DCM patients. Because CAM expression correlates with the immunohistological diagnosis of InfCM and counterreceptor-bearing intramyocardial infiltrates, evaluation of endothelial CAMs might be of diagnostic significance in InfCM.
A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma
Authors: Sumanta Pal, Arun Azad, Shailender Bhatia, Harry Drabkin, Brian Costello, John Sarantopoulos, Ravindran Kanesvaran, Richard Lauer, Alexander Starodub, Ralph Hauke, Christopher J. Sweeney, Noah M. Hahn, Guru Sonpavde, Stephen Richey, Timothy Breen, Gabriel Kremmidiotis, Annabell Leske, Elizabeth Doolin, David C. Bibby, Jeremy Simpson, Jose Iglesias, Thomas Hutson
Journal: Clinical Cancer Research (2015)

BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC).
Hypoparathyroidism and coeliac disease: a potentially dangerous combination
Authors: Sibylle Kohler, John AH Wass
Journal: Journal of the Royal Society of Medicine (2009)

Hypoparathyroidism and co-existing coeliac disease can lead to dramatic fluctuations in plasma calcium levels, a therapeutic challenge doctors should be aware of. Acquired hypoparathyroidism is usually the result of surgery and is estimated to occur in 0.5–6.6% of patients following total thyroidectomy, with an even higher rate in some case series, but a lower rate in endocrine surgical centres, where it ranges from 0.9% to 1.6%.1–4 The occurrence of hypoparathyroidism depends on the surgeon's experience, the extent of thyroid resection and the underlying thyroid disease, with the presence of substernal goitre, cancer or Graves' disease increasing the risk.5 Hypoparathyroidism may also occur secondary to autoimmune invasion and destruction of the parathyroid gland, as in polyglandular syndrome type 1.

In comparison, coeliac disease has a high prevalence of 1:300 in white Caucasians of northern European ancestry.6 Both these conditions lead to hypocalcaemia. When calcium levels in a previously stable treated patient with hypoparathyroidism decrease or begin to fluctuate significantly, the differential diagnosis includes prolonged use of laxatives or anticonvulsant therapy, chronic renal failure, decreased dietary intake of calcium and Vitamin D or malabsorption such as occurs with coeliac disease. On the other hand, the institution of and adherence to a gluten-free diet in a newly-diagnosed patient with coeliac disease on Vitamin D may lead to rapid improvement of intestinal absorption with prompt increases in plasma calcium levels. Here we present two patients diagnosed with hypoparathyroidism, both of whom went on to develop coeliac disease at a later stage. Profound alterations in calcium balance occurred before and after the diagnosis of coeliac disease, which serves to illustrate the changes in calcium levels that may result from the combination of hypoparathyroidism and coeliac disease, and to alert us to the potential complications of this combination of pathologies.
Chromosome 4q31 locus in COPD is also associated with lung cancer
Authors: R.P. Young, C.F. Whittington, R.J. Hopkins, B.A. Hay, M.J. Epton, P.N. Black, G.D. Gamble
Journal: European Respiratory Journal (2010)

Chronic obstructive pulmonary disease (COPD) is the single greatest risk factor for lung cancer in smokers and is found in 50–90% of lung cancer cases. The link between COPD and lung cancer may stem in part from the matrix remodelling and repair processes underlying COPD, and the development of epithelial–mesenchymal transition (EMT) that underlies lung carcinogenesis. The Hedgehog-interacting protein (HHIP), which mediates the epithelial response (EMT) to smoking, has been implicated in COPD and lung cancer. Recent genome-wide and candidate gene studies of COPD implicate genetic variants on the chromosomal 4q31 ( HHIP /glycophorin A ( GYPA )) locus. In a case–control study of smokers with normal lung function, COPD and lung cancer (subphenotyped for COPD), we show the GG genotype of the rs 1489759 HHIP single-nucleotide polymorphism (SNP) and the CC genotype of the rs 2202507 GYPA SNP confers a “protective” effect on COPD (OR 0.59, p = 0.006 for HHIP and OR = 0.65, p = 0.006 for GYPA ) and lung cancer (OR = 0.70 (p = 0.05) for HHIP and OR 0.70 (p = 0.02) for GYPA ). This study suggests that, in smokers, genetic variants of the 4q31 locus conferring a protective effect for COPD are also protective in lung cancer. We conclude that genetic susceptibility to lung cancer includes COPD-related gene variants.
Many Patients Continue Using Proton Pump Inhibitors After Negative Results From Tests for Reflux Disease
Authors: Andrew J. Gawron, Jami Rothe, Angela J. Fought, Anita Fareeduddin, Erin Toto, Lubomyr Boris, Peter J. Kahrilas, John E. Pandolfino
Journal: Clinical Gastroenterology and Hepatology (2012)
Are technicians showing bronchial hyperreactivity able to safely perform bronchial provocation tests
Authors: Maria Gabrovska, Marie Bruyneel, Vincent Ninane
Journal: European Respiratory Journal (2014)

Introduction: 

According to the ERS/ATS guidelines technicians with asthma are at increased risk of bronchospasm during bronchial provocation tests and should take precautions to minimize their exposure or shouldn't perform them. Performing methacholine/histamine challenge tests on technicians involved in these tests is thought to be useful.

Aims of the study: 

This study intended to assess if passive exposure to histamine during bronchial provocation tests can lead to significant response in subjects with a high level of bronchial hyperreactivity.

Methods: 

Thirteen adult patients with positive histamine challenge test at the first dose were retested within a few days during passive exposure. None of them had a previous diagnosis of asthma.

During the passive testing they remained close (about 1 meter from the body box) to the technician that performed the classical bronchial provocation test using histamine in volunteers with previously known negative results. After each increasing dose the study patients performed spirometry. The procedure was stopped at FEV1 fall exceeding 20% or at last classical dose. The results (provocative dose) of active and passive exposure were compared.

Results: 

No reaction to passive histamine exposure was observed in 12 of the 13 patients. One patient had a weak reaction at 10mg/ml concentration or at PD 20 of 614.6. Neither the severity of reaction at the first active challenge test nor the initial presenting symptoms were related to passive test results.

Conclusion: 

Patients with symptoms of asthma and a very positive histamine challenge test do not show important reactivity during passive exposure.
Early Embryonic Renal Tubules of Wild-Type and Polycystic Kidney Disease Kidneys Respond to cAMP Stimulation with Cystic Fibrosis Transmembrane Conductance Regulator/Na+,K+,2Cl− Co-Transporter–Dependent Cystic Dilation
Authors: Brenda S. Magenheimer, Patricia L. St. John, Kathryn S. Isom, Dale R. Abrahamson, Robert C. De Lisle, Darren P. Wallace, Robin L. Maser, Jared J. Grantham, James P. Calvet
Journal: Journal of the American Society of Nephrology (2006)

Metanephric organ culture has been used to determine whether embryonic kidney tubules can be stimulated by cAMP to form cysts. Under basal culture conditions, wild-type kidneys from embryonic day 13.5 to 15.5 mice grow in size and continue ureteric bud branching and tubule formation over a 4- to 5-d period. Treatment of these kidneys with 8-Br-cAMP or the cAMP agonist forskolin induced the formation of dilated tubules within 1 h, which enlarged over several days and resulted in dramatically expanded cyst-like structures of proximal tubule and collecting duct origin. Tubule dilation was reversible upon withdrawal of 8-Br-cAMP and was inhibited by the cAMP-dependent protein kinase inhibitor H89 and the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR(inh)172. For further testing of the role of CFTR, metanephric cultures were prepared from mice with a targeted mutation of the Cftr gene. In contrast to kidneys from wild-type mice, those from Cftr -/- mice showed no evidence of tubular dilation in response to 8-Br-cAMP, indicating that CFTR Cl(-) channels are functional in embryonic kidneys and are required for cAMP-driven tubule expansion. A requirement for transepithelial Cl(-) transport was demonstrated by inhibiting the basolateral Na(+),K(+),2Cl(-) co-transporter with bumetanide, which effectively blocked all cAMP-stimulated tubular dilation. For determination of whether cystic dilation occurs to a greater extent in PKD kidneys in response to cAMP, Pkd1(m1Bei) -/- embryonic kidneys were treated with 8-Br-cAMP and were found to form rapidly CFTR- and Na(+),K(+),2Cl(-) co-transporter-dependent cysts that were three- to six-fold larger than those of wild-type kidneys. These results suggest that cAMP can stimulate fluid secretion early in renal tubule development during the time when renal cysts first appear in PKD kidneys and that PKD-deficient renal tubules are predisposed to abnormally increased cyst expansion in response to elevated levels of cAMP.
Integrin-linked kinase regulates cell proliferation and tumour growth in murine colitis-associated carcinogenesis
Authors: K Assi, J Mills, D Owen, C Ong, R St Arnaud, S Dedhar, B Salh
Journal: Gut (2008)

<h3>Background:</h3> Integrins are transmembrane cell surface receptors that mediate cell–cell and cell–matrix contacts. Integrin-linked kinase (ILK) is the binding partner of β1 and β3 integrins, and has been ascribed essential roles in development, angiogenesis and tumourigenesis. However, in vivo evidence for the latter is currently lacking. <h3>Aim:</h3> The hypothesis that epithelial cell-specific deletion of ILK would impact on murine tumourigenesis was tested using a colitis-associated cancer model. <h3>Methods:</h3> To create intestinal epithelial cell ILK knockout animals, Fabp/Cre mice (Cre recombinase expressed under the control of a modified Fabp promoter) were used, and they were mated with mice carrying a loxP-flanked (floxed) ILK gene (ILK<sup>flox/flox</sup>). <h3>Results:</h3> ILK intestinal knockout mice exhibited a reduction in the size of the caecum, and reduced crypt height in the colon. Immunohistochemical analysis confirmed that there was diminished ILK expression, and bromodeoxyuridine (BrdU) staining was significantly reduced in the knockout animals as compared with the wild-type animals in both the caecum and colon (p&lt;0.001 for both). Following azoxymethane and dextran sodium sulfate (DSS) treatment, fewer total tumours were observed in the ILK knockout animals, which were mosaic with respect to ILK expression. Cyclin D1, Snail, fibronectin and matrix metalloproteinase 9 (MMP9) were all reduced, and active caspase 3 increased, in tumours from ILK knockout mice, as compared with wild-type mice, on immunohistochemical analysis. Using small interfering RNA (siRNA) to knock down ILK in colonic cancer cell lines, it was confirmed that it is capable of regulating cyclin D1, Snail, MMP9 and fibronectin transcription. <h3>Conclusions:</h3> From these findings, it is concluded that ILK plays an important role in intestinal epithelial cell proliferation, and that it influences the development of colitis-associated cancer, through modulation of cyclin D1, the extracellular matrix and MMP9.
Novel Method to Enhance Sternal Healing After Harvesting Bilateral Internal Thoracic Arteries With Use of Basic Fibroblast Growth Factor
Authors: A. Iwakura, Y. Tabata, M. Miyao, M. Ozeki, N. Tamura, A. Ikai, K. Nishimura, T. Nakamura, Y. Shimizu, M. Fujita, M. Komeda
Journal: Circulation (2000)

Poor healing of the sternum often limits the use of bilateral internal thoracic arteries (BITAs) in coronary bypass surgery, especially for diabetic patients. We have reported that basic fibroblast growth factor (bFGF) enhanced regeneration of the skull. This study was designed to evaluate the effects of topical use of bFGF on sternal healing after removing the BITAs.Forty-five Wistar rats were subjected to median sternotomy and were divided into 3 groups: 15 had the BITAs removed and had a bFGF sheet applied on the posterior table of the sternum (group A), 15 had just the BITAs removed (group B), and 15 had intact BITAs (group C). Five and 10 rats were euthanized 2 and 4 weeks after surgery, respectively, in all 3 groups. Peristernal blood flow, measured with use of a noncontact laser flowmeter, decreased after removal of the BITAs (P:<0.001). Four weeks after the surgery, PBF markedly increased only in group A (9.7+/-1.2, 6.5+/-0.6, and 8.2+/-0.5 mL x min(-1) x 100 g(-1) for groups A, B, and C, respectively; P:<0.01 by ANOVA). Four weeks after surgery, the following findings were obtained only in group A: (1) nearly completely healed sternum filled with regenerated bone tissue, (2) marked angiogenesis around the sternum, and (3) osteoblasts in an active form around the edge of the sternum.The results suggest that use of the bFGF sheet offset the sternal ischemia and accelerated sternal healing. This method may help to decrease sternal necrosis in high-risk patients or allow extended use of BITAs in coronary bypass surgery.
Rare intrathoracic complications in acute pancreatitis.
Authors: D J Shewring, H G Naerger, H W Steer
Journal: Thorax (1991)

Ascites and pleural effusions may complicate pancreatitis but pericarditis with pericardial effusion and tamponade is rare and necrosis of mediastinal fat has not been described before. All these complications occurred in the case reported here.