tbuckley/cabot-search huggingface dataset:
<i>EGFR-T790M</i> Is a Rare Lung Cancer Susceptibility Allele with Enhanced Kinase Activity
Authors: Haris Vikis, Mitsuo Sato, Michael James, Daolong Wang, Yian Wang, Min Wang, Dongmei Jia, Yan Liu, Joan E. Bailey-Wilson, Christopher I. Amos, Susan M. Pinney, Gloria M. Petersen, Mariza de Andrade, Ping Yang, Jonathan S. Wiest, Pamela R. Fain, Ann G. Schwartz, Adi Gazdar, Colette Gaba, Henry Rothschild, Diptasri Mandal, Elena Kupert, Daniela Seminara, Avinash Viswanathan, Ramaswamy Govindan, John Minna, Marshall W. Anderson, Ming You
Journal: Cancer Research (2007)

Abstract The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer. [Cancer Res 2007;67(10):4665–70]
JNK3 Perpetuates Metabolic Stress Induced by Aβ Peptides
Authors: Sung Ok Yoon, Dong Ju Park, Jae Cheon Ryu, Hatice Gulcin Ozer, Chhavy Tep, Yong Jae Shin, Tae Hee Lim, Lucia Pastorino, Ajaya J. Kunwar, James C. Walton, Alan H. Nagahara, Kun Ping Lu, Randy J. Nelson, Mark H. Tuszynski, Kun Huang
Journal: Neuron (2012)

Although Aβ peptides are causative agents in Alzheimer's disease (AD), the underlying mechanisms are still elusive. We report that Aβ42 induces a translational block by activating AMPK, thereby inhibiting the mTOR pathway. This translational block leads to widespread ER stress, which activates JNK3. JNK3 in turn phosphorylates APP at T668, thereby facilitating its endocytosis and subsequent processing. In support, pharmacologically blocking translation results in a significant increase in Aβ42 in a JNK3-dependent manner. Thus, JNK3 activation, which is increased in human AD cases and a familial AD (FAD) mouse model, is integral to perpetuating Aβ42 production. Concomitantly, deletion of JNK3 from FAD mice results in a dramatic reduction in Aβ42 levels and overall plaque loads and increased neuronal number and improved cognition. This reveals AD as a metabolic disease that is under tight control by JNK3.
Inhibition of Bone Morphogenetic Proteins Protects Against Atherosclerosis and Vascular Calcification
Authors: Yucheng Yao, Brian J. Bennett, Xuping Wang, Michael E. Rosenfeld, Cecilia Giachelli, Aldons J. Lusis, Kristina I. Boström
Journal: Circulation Research (2010)

The bone morphogenetic proteins (BMPs), a family of morphogens, have been implicated as mediators of calcification and inflammation in the vascular wall.To investigate the effect of altered expression of matrix Gla protein (MGP), an inhibitor of BMP, on vascular disease.We used MGP transgenic or MGP-deficient mice bred to apolipoprotein E mice, a model of atherosclerosis. MGP overexpression reduced vascular BMP activity, atherosclerotic lesion size, intimal and medial calcification, and inflammation. It also reduced expression of the activin-like kinase receptor 1 and the vascular endothelial growth factor, part of a BMP-activated pathway that regulates angiogenesis and may enhance lesion formation and calcification. Conversely, MGP deficiency increased BMP activity, which may explain the diffuse calcification of vascular medial cells in MGP deficient aortas and the increase in expression of activin-like kinase receptor 1 and vascular endothelial growth factor. Unexpectedly, atherosclerotic lesion formation was decreased in MGP-deficient mice, which may be explained by a dramatic reduction in expression of endothelial adhesion molecules limiting monocyte infiltration of the artery wall.Our results indicate that BMP signaling is a key regulator of vascular disease, requiring careful control to maintain normal vascular homeostasis.
Inferring the number of evolutionary events from DNA coding sequence differences.
Authors: R C Lewontin
Journal: Molecular Biology and Evolution (1989)

The estimation of the amount of evolutionary divergence that has taken place between two DNA coding sequences depends strongly on the degree of constraint on amino acid replacements. If amino acid replacements are relatively unconstrained, the individual nucleotide is the appropriate unit of analysis and the method of Tajima and Nei can be used. If amino acid replacements are constrained, however, this method is shown to be inapplicable. For sequences with strong amino acid constraints, a method is outlined analogous to the Tajima and Nei method using codons as the unit of analysis. Only synonymous substitutions are used. Codon usage data can be employed to estimate the necessary parameters of the calculation, or a priori models of substitution may be employed. Sequences with significant but intermediate constraints on amino acid replacements are, in principle, unanalyzable.
Decreased Pigment Epithelium–Derived Factor Expression in Human Breast Cancer Progression
Authors: Jun Cai, Christian Parr, Gareth Watkins, Wen G. Jiang, Mike Boulton
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The aim of this study was to correlate the expression of pigment epithelium–derived factor (PEDF), a potent endogenous antiangiogenic molecule, with severity and prognosis in breast cancer. Experimental Design: To investigate the gene expression profile of PEDF in human breast cancer in relation to a patient's clinical variables, we examined human breast cancer tissue (n = 119), background breast tissue (n = 33), and a range of cell lines for mRNA and protein levels of PEDF by using reverse transcription PCR, real-time quantitative PCR, immunohistochemistry, and ELISA. Results: By using reverse transcription PCR, real-time quantitative PCR, immunohistochemistry, and ELISA, PEDF expression was found to be dramatically decreased in breast cancer. An overall outlook for the patients inversely correlated with PEDF mRNA levels. Exogenous PEDF inhibits endothelial tubule formation induced by breast cancer cell–conditioned medium, in vitro. Conclusion: These observations collectively support the hypothesis that a lack of PEDF expression is a potent factor for the enhancement of tumor growth and angiogenesis in breast cancer.
Role of Repetitive Antigen Patterns for Induction of Antibodies Against Antibodies
Authors: Thomas Fehr, Martin F. Bachmann, Etienne Bucher, Ulrich Kalinke, Franco E. Di Padova, Alois B. Lang, Hans Hengartner, Rolf M. Zinkernagel
Journal: The Journal of Experimental Medicine (1997)

Antibody responses against antibodies, such as rheumatoid factors, are found in several immunopathological diseases and may play a role in disease pathogenesis. Experience shows that they are usually difficult to induce experimentally. Antibodies specific for immunoglobulin constant regions (anti-allotypic) or for variable regions (anti-idiotypic) have been investigated in animal models; the latter have even been postulated to regulate antibody and T cell responses via network-like interactions. Why and how such anti-antibodies are induced during autoimmune diseases, has remained largely unclear. Because repetitively arranged epitopes in a paracrystalline structure of a viral envelope cross-link B cell receptors efficiently to induce a prompt T-independent IgM response, this study used immune complexes containing viruses or bacteria to evaluate the role of antigen pattern for induction of anti-antibody responses. We present evidence that antibodies bound to strictly ordered, but not to irregularly arranged, antigens dramatically enhance induction of anti-antibodies, already after a single immunization and without using adjuvants. The results indicate a novel link between anti-antibody responses and infectious agents, and suggest a similar role for repetitive self-antigens such as DNA or collagen involved in chronic immunopathological diseases.
Effects of Mobile Phone SMS to Improve Glycemic Control Among Patients With Type 2 Diabetes in Bangladesh: A Prospective, Parallel-Group, Randomized Controlled Trial
Authors: Sheikh Mohammed Shariful Islam, Louis W. Niessen, Uta Ferrari, Liaquat Ali, Jochen Seissler, Andreas Lechner
Journal: Diabetes Care (2015)

Mobile phone technologies have emerged as an essential tool for strengthening health systems and improving disease outcomes in many countries (1). In recent years, the government of Bangladesh and the World Health Organization have adopted information technologies for health in their strategic plans. However, data to support a successful model of mobile phone short message service (SMS) in diabetes management are scarce. In this trial, we assessed whether the addition of an automated SMS service to standard diabetes care would improve glycemic control in patients with type 2 diabetes.

A total of 236 adult patients with type 2 diabetes (diagnosed within the previous 5 years) on oral medication therapy with access to SMS and attending the outpatient department of the Bangladesh Institute of Health Sciences in Dhaka, Bangladesh, were recruited (September 2013–August 2014) and randomly assigned 1:1 to SMS intervention and standard care groups. Data were collected through face-to-face interviews with a structured questionnaire, anthropometric measurements, and blood tests for …
Remarks on the Rational Treatment of Phthisis, with Reference to Nordrach Sanatorium
Authors: R. M. Smyth
Journal: BMJ (1898)

KWIC" o= 983 I , 983~~~~p oint: the question as to whether the life should be loaded where an operation had been done with an apparently successful issue.He quite agreed with him that a certain extra premium should be put on, because he had seen cases where that idea had been borne out within the last two months.A child of 2 years had a mastoid operation done some time ago for mastoid disease, and after three weeks in hospital went out quite well.From the age of 3 to Q she had an interval of perfect health, but there must have been some mischief left behind, as there was a recurrence of the old trouble, which spread to the brain, and temporo-sphenoidal abscess re- sulted, and as the child was in a critical condition he operated.Next morning he went down to see her, as he thought, dead, but he found her well.The case did splendidly, and she went out apparently perfectly cured.But the question arose, if that life was to be insured, what were they to do, as there might be a recrudescence?One point they should insist upon was that, even though operation had been done, the patient might be sitting over a powder magazine, or one might get a recrudescence of the disease.In this operation complications might not have occurred if the original Stacke's operation had been done instead of trephining the mastoid antrum only, as the cavities were not thrown into onie, and therefore some disease was probably left behind.Every case must be treated on its own merits; that was very important and obvious to all of them.They got on the forms of insurance companies certain questions and were asked, and, so to speak, to draw a hard-and-fast line.It was absolutely iiipossible to draw a hard-and-fast line; it was,very important when it got into a law court.It was ridicu- lous and foolish to swear anything absolute in reference to the human body, for cases must be treated on their own merits, and it seemed to him that it would save insurance companies a lot of risk, and would be of some advantage if, if in doubt, the person referred to consulted an expert, and each case was treated absolutely on its own merits.
Toward an integration of P3 research with cognitive neuroscience
Authors: Rolf Verleger
Journal: Behavioral and Brain Sciences (1998)

In this response, I will first summarize my 1988 argument on the issue of expectancy. Second, I will re-evaluate that argument in the light of the findings made by Sommer et al. and by others. Third, I will describe some other problems with the 1988 views. Fourth, I will outline the direction in which I feel that a hypothesis on the P3 complex should be pursued further.
Transcutaneous detection of aortic arch atheromas by suprasternal harmonic imaging
Authors: Ehud Schwammenthal, Yvonne Schwammenthal, David Tanne, Alexander Tenenbaum, Alex Garniek, Michael Motro, Babeth Rabinowitz, Michael Eldar, Micha S. Feinberg
Journal: Journal of the American College of Cardiology (2002)
Vaginal Microbial Flora: Composition and Influences of Host Physiology
Authors: BRYAN LARSEN
Journal: Annals of Internal Medicine (1982)

The normal bacterial flora of the female genital tract is composed of various aerobic and anaerobic bacteria. Because the normal flora may be a source of disease-causing organisms or may interact antagonistically or synergistically with exogenous pathogens, it is important to characterize physiologic determinants of the genital microflora. Mechanisms of cervical-vaginal colonization are not well understood although it appears that differences in estrogen levels are able to influence primarily the anaerobic species. The genital tract after surgery, parturition, or during menstruation is a microenvironment conducive to proliferation of various bacteria.
Cardiac lysosomal derangements in mouse heart after long-term exposure to nonmetabolizable sugars.
Authors: K Wildenthal, J H Dees, L M Buja
Journal: Circulation Research (1977)

Hearts of late fetal mice were maintained in organ culture in the presence of 30-100 mM sucrose or mannitol. Activities of several lysosomal enzymes (cathepsin D, beta-acetylglucosaminidase, acid phosphatase) were increased by up to 30% after 18-24 hours and by up to 50% after 48-72 hours, as compared to enzyme activities in litter-matched hearts maintained in control medium or medium supplemented with equimolar urea. Simultaneously, the ratio of nonsedimentable to sedimentable enzyme activity was significantly increased, suggesting increased lysosomal fragility. Light and electron microsopic examination of the hearts revealed marked vacuolization in myocytic, interstitial, and endothelial cells. The vacuoles were limited by single membranes, often contained particulate or amorphous cellular debris resulting from autophagocytosis, and in cytochemical preparations frequently exhibited an electron-dense reaction product indicative of acid phosphatase activity. Hydrocortisone failed to prevent the marked lysosomal activation induced by the sugars. In conclusion, prolonged exposure to nonmetabolizable sugars induces severe lysosomal derangements with prominent autophagy, in fetal mouse heart maintained in organ culture.
MicroRNA-7a regulates pancreatic β cell function
Authors: Mathieu Latreille, Jean Hausser, Ina Stützer, Quan Zhang, Benoit Hastoy, Sofia Gargani, Julie Kerr-Conte, Francois Pattou, Mihaela Zavolan, Jonathan L.S. Esguerra, Lena Eliasson, Thomas Rülicke, Patrik Rorsman, Markus Stoffel
Journal: Journal of Clinical Investigation (2014)

Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic β cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of β cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in β cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates β cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in β cells developed diabetes due to impaired insulin secretion and β cell dedifferentiation. Interestingly, perturbation of miR-7a expression in β cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine β cell mass. Furthermore, we found that miR-7a levels are decreased in obese/diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated β cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic β cells and support a role for miR-7 in the adaptation of pancreatic β cell function in obesity and type 2 diabetes.
Randomized Trial of Single Compared With Tandem High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantation in Patients With Chemotherapy-Sensitive Metastatic Breast Cancer
Authors: Nicolaus Kröger, Markus Frick, Oleg Gluz, Svjetlana Mohrmann, Bernd Metzner, Christian Jackisch, Yon Ko, Hans-Walter Lindemann, Carl Richard Meier, Hans Peter Lohrmann, Ute Ruffert, Matthias Hänel, Heinrich Bodenstein, Andreas Neubauer, Gerhard Ehninger, Hans-Heinrich Wolf, Kathrin Kolbe, Karin Burock, Axel R. Zander, Ulrike Nitz
Journal: Journal of Clinical Oncology (2006)

To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients.Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation.One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival.Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.
Volumes and Compliances Measured Simultaneously in the Right and Left Ventricles of the Dog
Authors: MICHAEL M. LAKS, DANIEL GARNER, H. J. C. SWAN
Journal: Circulation Research (1967)

In 10 normal dogs, the right and left ventricular volumes and compliances were determined in the fresh post-mortem heart. With the use of a SigmaMotor pump, Ringer's solution at 23°C was simultaneously infused into both ventricles within an hour after death. When the ventricles were full but open to atmospheric pressure, the mean volumes were 35.8 ml/m 2 for the right and 23.1 ml/m 2 for the left ventricle; when the transmural pressure was increased by 10 mm Hg, the mean volumes were 56.9 ml/m 2 for the right and 41.9 ml/m 2 for the left ventricle; at 20 mm Hg, the values were 60.8 and 48.5 ml/m 2 , respectively. The initial volumes and the increases in volume produced by increase in transmural pressure were affected by the position of the ventricular septum and by the presence of rigor mortis. With infusions into only one ventricle, right and left ventricular volumes were 20 to 74% greater at 10 mm Hg than the values when both ventricles were filled simultaneously. Compliance began to decrease 40 to 60 min after death; at 130 min after death (23°C), the change in volume when the transmural pressure was increased to 10 mm Hg was only about 1/5 of that immediately after death.
Preclinical Evaluation of the Engineered Stem Cell Chemokine Stromal Cell–Derived Factor 1α Analog in a Translational Ovine Myocardial Infarction Model
Authors: John W. MacArthur, Jeffrey E. Cohen, Jeremy R. McGarvey, Yasuhiro Shudo, Jay B. Patel, Alen Trubelja, Alexander S. Fairman, Bryan B. Edwards, George Hung, William Hiesinger, Andrew B. Goldstone, Pavan Atluri, Robert L. Wilensky, James J. Pilla, Joseph H. Gorman, Robert C. Gorman, Y. Joseph Woo
Journal: Circulation Research (2013)

After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.
Tumours and Cysts of the Mediastinum
Authors: I. M. Morrison
Journal: Thorax (1958)

these authors' series with the present series.In some it has been necessary to exclude cases which do not fall within that definition of mediastinal tumour which has been used for this paper.Other authors have omitted types of tumour which are included here; thus Ringertz and Lidholm exclude thyroid tumours and several authors exclude lymphomas, although Heuer and Andrus (1940) found that lymphomas constituted 32% of all mediastinal tumours.