tbuckley/cabot-search huggingface dataset:
Medicine in Free China
Authors: W. Penfield
Journal: BMJ (1944)

<h3>Abstract</h3> <h3>BACKGROUND</h3> While several key resources exist that interpret therapeutic significance of genomic alterations in cancer, many regional real-world issues limit access to drugs. There is a need for a pragmatic, evidence-based, context-adapted tool to guide clinical management based on molecular biomarkers. <h3>METHODS</h3> A compendium of approved and experimental therapies with associated biomarkers was built following a survey of drug regulatory databases, existing knowledge bases, and published literature. Each biomarker-disease-therapy triplet was then categorized using a tiering system reflective of key therapeutic considerations: approved and reimbursed standard-of-care therapies with respect to a jurisdiction (Tier 1), evidence of clinical activity (Tier 2), evidence of antitumour activity (Tier 3), and plausible biological rationale (Tier 4). Two resistance categories were defined: lack of clinical efficacy (Tier R1), and lack of antitumor activity (Tier R2). <h3>RESULTS</h3> Following comprehensive literature review and appraisal, we developed a curated knowledge base focused on drugs relevant and accessible in the Australian healthcare system (TOPOGRAPH: Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals). As of November 2020, TOPOGRAPH comprised 2810 biomarker-disease-therapy triplets in 989 expert-appraised entries, including 373 therapies, 199 predictive biomarkers, and 106 cancer types. In the 345 biomarker-linked therapies catalogued, 84 (24%) and 65 (19%) therapies in contexts of different cancer types have Tier 1 and 2 designations respectively, while 271 (79%) therapies were supported by preclinical studies, early clinical trials, retrospective studies, or case series (Tiers 3 and 4). A total of 119 of 373 (33%) therapies associated with biomarkers of resistance were also catalogued. A clinical algorithm was also developed to support therapeutic decision-making using predictive biomarkers. This resource is accessible online at https://topograph.info/. <h3>CONCLUSION – TOPOGRAPH</h3> is intended to support oncologists with context-appropriate clinical decision-making– optimising selection and accessibility of the most appropriate targeted therapy for any given genomic biomarker. Our approach can be readily adapted to build jurisdiction-specific resources to standardise decision-making in precision oncology.
Renal side-effects of cyclosporin A
Authors: JUNE MASON
Journal: British Journal of Dermatology (1990)

Cyclosporin A (CyA) has multiple effects on the kidney. The drug can cause changes in either the tubular or vascular system which may be either functional or structural, reversible or irreversible and frequent or seldom. Functional changes to the tubules and vessels are common, occur at low doses and are reversible, while structural changes to the tubules and vessels are rare, occur at high doses and are not always reversible. The changes of importance are vascular. By harnessing two strategies to restrain the development of side-effects-limiting the dose and restricting the functional changes-it is possible to avoid irreversible damage to the kidney in patients treated with CyA.
Did the Mitochondrial Processing Peptidase Evolve from a Eubacterial Regulator of Gene Expression?
Authors: Albert Bolhuis, Emmo Koetje, Jean-Yves Dubois, Jari Vehmaanper, Gerard Venema, Sierd Bron, Jan Maarten van Dijl*
Journal: Molecular Biology and Evolution (2000)

The recent sequencing of the genome of Rickettsia prowazekii, a eubacterium that is more closely related to mitochondria than to any other known prokaryote, has provided exciting new insights into the evolution of mitochondria and their genomes (Andersson et al. 1998). Consistent with the endosymbiont hypothesis (Gray et al. 1989; Gray 1993; Yang et al. 1985), many mitochondrial proteins appear to be functionally conserved in R. prowazekii and other eubacteria. An important exception concerns the proteins which make up the machinery for the import of mitochondrial proteins from the cytosol. In this study, we addressed the function of a eubacterial homolog of mitochondrial processing peptidases (MPPs), which remove targeting signals from proteins imported into the mitochondrial matrix compartment. Most mitochondrial proteins are encoded by nuclear DNA and synthesized in the cytosol. Hence, they have to be imported into mitochondria, for which purpose they are synthesized with an amino-terminal targeting (pre-)sequence. After translocation into the mitochondrial matrix, the presequence is removed by MPP (Brunner, Klaus, and Neupert 1994). MPP consists of two nonidentical but homologous subunits, designated a-MPP and b-MPP, which were identified in the mitochondria of several organisms (Braun and Schmitz 1995). Only the b subunit has catalytic activity (Arretz et al. 1994). All known MPP proteins belong to the socalled pitrilysin, or insulinase, family of endoproteases (Barret, Rawlings, and Woesner 1998). This family includes (1) Escherichia coli pitrilysin, a periplasmic protease involved in the degradation of small peptides; (2) insulinases from mammals and insects; (3) the PqqF protein from Klebsiella, involved in biosynthesis of the coenzyme PQQ; and (4) the N-arginine dibasic convertase from the rat. All catalytically active members of the pitrilysin family contain the motif His-x-x-Glu-His-x76Glu, in which the two histidine residues and the C-terminal glutamate are required for the binding of zinc
Role of vasoactive intestinal polypeptide in the internal anal sphincter relaxation of the opossum.
Authors: S Nurko, S Rattan
Journal: Journal of Clinical Investigation (1988)

The nature of the inhibitory neurotransmitter responsible for internal anal sphincter (IAS) relaxation in response to rectoanal reflex is not known. The objective of the present investigation was to examine the role of VIP in IAS relaxation in response to the rectoanal reflex in intact opossums with the use of VIP antagonists, [4CI-D-Phe6,Leu17] VIP and (N-AC-Tyr1,D-Phe2)-GRF (1-29)-NH2. Intraluminal pressures from the sphincter were monitored using low-compliance, continuously perfused catheters. VIP and the antagonists were administered close-intraarterially. The responses to VIP, rectoanal reflex, sacral nerve stimulation, and local intramural stimulation were examined before and after the VIP antagonists. The present studies in intact animals show: (a) VIP causes a dose-dependent fall in the IAS pressures by a direct action at the IAS smooth muscle; (b) VIP antagonists selectively and significantly antagonized the inhibitory action of VIP; and (c) VIP antagonists caused significant antagonism of the IAS relaxation caused by rectoanal reflex and the other neural stimuli. The antagonism of the IAS relaxation by the VIP antagonists, depending upon the volume of rectal distension used, ranged from 40% to 62% (P less than 0.05). From these results, we conclude that VIP acts as an inhibitory neurotransmitter for IAS relaxation during the rectoanal reflex.
Central role of the P2Y12 receptor in platelet activation
Authors: Robert T. Dorsam, Satya P. Kunapuli
Journal: Journal of Clinical Investigation (2004)

Platelet activation occurs in response to vessel injury and is important for the arrest of bleeding. Platelet activation during disease states leads to vascular occlusion and ischemic damage. The P2Y12 receptor, activated by ADP, plays a central role in platelet activation and is the target of P2Y12 receptor antagonists that have proven therapeutic value.
Eventration as a Cause of Thoracic Uptake on In-111 Octreotide Scintigraphy
Authors: TAMARA NOWLAND, ALLISON MALCOLM, PAUL ROACH
Journal: Clinical Nuclear Medicine (2003)

NOWLAND, TAMARA M.B.B.S.*; MALCOLM, ALLISON M.B.B.S.†; ROACH, PAUL F.R.A.C.P.* Author Information
Effect of Once- or Twice-Daily MMX Mesalamine (SPD476) for the Induction of Remission of Mild to Moderately Active Ulcerative Colitis
Authors: Gary R. Lichtenstein, Michael A. Kamm, Prabhakar Boddu, Natalya Gubergrits, Andrew Lyne, Todd Butler, Kirstin Lees, Raymond E. Joseph, William J. Sandborn
Journal: Clinical Gastroenterology and Hepatology (2007)
Total effective vascular compliance in patients with cirrhosis: A study of the response to acute blood volume expansion
Authors: Antoine Hadengue, Richard Moreau, Christophe Gaudin, Yannick Bacq, Bruno Champigneulle, Didier Lebrec
Journal: Hepatology (1992)

Although arterial vasodilation is a well-known feature in patients with cirrhosis, the venous system remains unexplored. To measure total effective vascular compliance, a reflection of the properties of the venous system, rapid volume expansion (300 ml of a gelatin solution in 3 min) was performed in 23 patients. Eleven patients had compensated cirrhosis (Child-Pugh grade A or B), and eight had decompensated cirrhosis (Child-Pugh grade C). Four control patients had mild chronic hepatitis, normal hepatic venous pressure and normal liver architecture. Cardiac index, hepatic venous pressures, hepatic and azygos blood flow and renal plasma flow were measured before and immediately after volume expansion. Right atrial pressure was recorded during volume expansion. This allowed the calculation of total effective vascular compliance, which was higher in patients with decompensated cirrhosis than in those with compensated cirrhosis (4.65 +/- 4.21 vs. 1.34 +/- 0.63 ml.mm Hg-1.kg-1; p less than 0.05). In response to volume expansion, renal vascular resistance decreased significantly in patients with compensated cirrhosis, but not in those with decompensated cirrhosis (-30% +/- 33% vs. +2% +/- 23%; p less than 0.05). No change was seen in glomerular filtration rate. Systemic oxygen consumption increased in patients with compensated cirrhosis, but not in those patients with decompensated cirrhosis (25% +/- 33% vs. -4% +/- 9%; p less than 0.05). Although in all patients with cirrhosis volume expansion increased central venous pressures, azygos blood flow and the hepatic venous pressure gradient did not change.(ABSTRACT TRUNCATED AT 250 WORDS)
Suffer the Children: The Story of Thalidomide
Authors: John Archer
Journal: JAMA (1979)

Written by a committee,<i>Suffer the Children</i>represents an effort to chronicle the worldwide disaster of about two decades ago produced by the new sedative and hypnotic, thalidomide. When taken by women in early pregnancy, the drug produced an array of fatal or severely crippling birth defects in the offspring. Phocomelia was a common deformity and the one most widely publicized. Mental retardation was not typical but sometimes occurred. Thalidomide was developed by the German pharmaceutical firm, Chemie Grünenthal, and was first marketed in 1957. Soon, it was being sold under license by many companies throughout the world, including one heavily featured in<i>Suffer the Children</i>, Distillers Company (Biochemicals) Ltd in Great Britain. The Food and Drug Administration never permitted its marketing in the United States, although it underwent extensive use there under investigational status. Various uses of the drug included treatment of nausea caused by pregnancy. Licensed companies evidently
Combined treatment with pegylated interferon (α-2b) and ribavirin in the acute phase of hepatitis C virus recurrence after liver transplantation
Authors: Lluís Castells, Víctor Vargas, Helena Allende, Itxarone Bilbao, José Luis Lázaro, Carlos Margarit, Rafael Esteban, Jaime Guardia
Journal: Journal of Hepatology (2005)
Tumor Angiogenic and Hypoxic Profiles Predict Radiographic Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and Irinotecan
Authors: Sith Sathornsumetee, Yiting Cao, Jennifer E. Marcello, James E. Herndon, Roger E. McLendon, Annick Desjardins, Henry S. Friedman, Mark W. Dewhirst, James J. Vredenburgh, Jeremy N. Rich
Journal: Journal of Clinical Oncology (2008)

The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy.In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2alpha were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers.Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016).In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.
356 ENHANCED EXPRESSION OF LIVER X RECEPTOR AND ITS LIPOGENIC AND INFLAMMATORY TARGETS IN NONALCOHOLIC FATTY LIVER DISEASE AND CHRONIC HEPATITIS C
Authors: E. Lima, M.V. García-Mediavilla, M.E. Miquilena-Colina, J. Vargas-Castrillón, T. Lozano-Rodríguez, M. Fernández-Bermejo, J.L. Olcoz, J. González-Gallego, C. García-Monzón, S. Sánchez-Campos
Journal: Journal of Hepatology (2010)
Human serum leads to differentiation of human hepatoma cells, restoration of very-low-density lipoprotein secretion, and a 1000-fold increase in HCV Japanese fulminant hepatitis type 1 titers
Authors: Rineke H.G. Steenbergen, Michael A. Joyce, Bradley S. Thomas, Daniel Jones, John Law, Rodney Russell, Michael Houghton, D. Lorne Tyrrell
Journal: Hepatology (2013)

In this study, we differentiated the human hepatoma cell line Huh7.5 by supplementing tissue culture media with human serum (HS) and examined the production of hepatitis C virus (HCV) by these cells. We compared the standard tissue culture protocol, using media supplemented with 10% fetal bovine serum (FBS), to media supplemented with 2% HS. Cells cultured in HS undergo rapid growth arrest, have a hepatocyte-like morphology, and increase the expression of hepatocyte differentiation markers. In addition, expression of cell adhesion proteins claudin-1, occludin, and e-cadherin are also increased. The lipid droplet content of these cells is highly increased, as are key lipid metabolism regulators liver X receptor alpha, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-γ. Very-low-density lipoprotein secretion, which is absent in FBS-grown cells, is restored in Huh7.5 cells that are cultured in HS. All these factors have been implicated in the life cycle of HCV. We show that viral production of Japanese fulminant hepatitis type 1 increases 1,000-fold when cells are grown in HS, compared to standard FBS culture conditions. The virus produced under these conditions is associated with apolipoprotein B, has a lower density, higher specific infectivity, and has a longer half-life than virus produced in media supplemented with FBS.We describe a convenient, cost-effective method to produce hepatocyte-like cells, which produce large amounts of virus that more closely resemble HCV present in serum of infected patients.
Association of Angiotensin-Converting Enzyme Gene <i>I/D</i> Polymorphism With Change in Left Ventricular Mass in Response to Physical Training
Authors: Hugh E. Montgomery, Peter Clarkson, Clare M. Dollery, Krishna Prasad, Maria-Angela Losi, Harry Hemingway, Deborah Statters, Mick Jubb, Martin Girvain, Amanda Varnava, Michael World, John Deanfield, Phillipa Talmud, Jean R. McEwan, William J. McKenna, Stephen Humphries
Journal: Circulation (1997)

Background The absence (deletion allele [ D ]) of a 287–base pair marker in the ACE gene is associated with higher ACE levels than its presence (insertion allele [ I ]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of DD genotype might show a greater hypertrophic response than those of II genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy. Methods and Results Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all P &lt;.0001). Response magnitude was strongly associated with ACE genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in II , ID and DD , respectively ( P &lt;.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of DD genotype (from 6 of 24 before training to 11 of 24 after training, P &lt;.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for DD and II , respectively ( P &lt;.001). Conclusions Exercise-induced LV growth in young males is strongly associated with the ACE I/D polymorphism.
Effect of posture on spontaneous and thermally stimulated cardiovascular oscillations
Authors: A. Lindqvist, J. Jalonen, P. Parviainen, K. Antila, L. A Laitinen
Journal: Cardiovascular Research (1990)

Journal Article Effect of posture on spontaneous and thermally stimulated cardiovascular oscillations Get access Ari Lindqvist, Ari Lindqvist Search for other works by this author on: Oxford Academic PubMed Google Scholar Jarmo Jalonen, Jarmo Jalonen Search for other works by this author on: Oxford Academic PubMed Google Scholar Pekka Parviainen, Pekka Parviainen Search for other works by this author on: Oxford Academic PubMed Google Scholar Kari Antila, Kari Antila Search for other works by this author on: Oxford Academic PubMed Google Scholar Lauri A Laitinen Lauri A Laitinen Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 24, Issue 5, May 1990, Pages 373–380, https://doi.org/10.1093/cvr/24.5.373 Published: 01 May 1990 Article history Received: 10 April 1989 Accepted: 15 December 1989 Published: 01 May 1990
Behavioral and Structural Differences in Migrating Peripheral Neutrophils from Patients with Chronic Obstructive Pulmonary Disease
Authors: Elizabeth Sapey, James A. Stockley, Hannah Greenwood, Ali Ahmad, Darren Bayley, Janet M. Lord, Robert H. Insall, Robert A. Stockley
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

There are increased neutrophils in the lungs of patients with chronic obstructive pulmonary disease (COPD), but it is unclear if this is due to increased inflammatory signal or related to the inherent behavior of the neutrophils. This is critical, because inaccurate or excessive neutrophil chemotaxis could drive pathological accumulation and tissue damage.To assess migratory dynamics of neutrophils isolated from patients with COPD compared with healthy smoking and nonsmoking control subjects and patients with α(1)-antitryspin deficiency.Migratory dynamics and structure were assessed in circulating neutrophils, using phase and differential interference contrast microscopy and time-lapse photography. The effect of COPD severity was studied. Surface expression of receptors was measured using flow cytometry. The in vitro effects of a phosphoinositide 3-kinase inhibitor (LY294002) were studied.COPD neutrophils moved with greater speed than cells from either control group but with reduced migratory accuracy, in the presence of IL-8, growth-related oncogene α, formyl-methionyl-leucyl-phenylalanine, and sputum. This was present across all stages of COPD. Structurally, COPD neutrophils formed fewer pseudopods during migration. There were no differences in surface expression of the receptors CXCR1, CXCR2, or FPR1. LY294002 reduced COPD neutrophil migratory speed while increasing chemotactic accuracy, returning values to normal. The inhibitor did not have these effects in healthy control subjects or patients with a similar degree of lung disease.COPD neutrophils are intrinsically different than cells from other studied populations in their chemotactic behavior and migratory structure. Differences are not due to surface expression of chemoattractant receptors but instead appear to be due to differences in cell signaling.
Australian doctors threaten industrial action over proposed indemnity levy
Authors: C. Zinn
Journal: BMJ (2003)

Doctors have warned of a “tidal wave” of resignations from Australia's public hospitals in the latest fallout from the federal government's attempts to fix the medical indemnity crisis.

The Australian Medical Association has rejected an 18 month moratorium on a controversial indemnity levy that doctors would have had to pay to raise sufficient funds to cover future non-funded negligence claims.

The Australian Salaried Medical Officers Federation, which represents 2400 specialists in public hospitals in New South Wales and Queensland, was meeting to discuss possible industrial action over the issue.

The Australian Medical Association's president, Bill Glasson, described the deal to suspend the levy as an “olive branch with spikes on …
Tc-99m Tetrofosmin Myocardial SPECT Combined With a Modified Exercise Protocol in an Unusual Case of Steal Phenomenon
Authors: Panagiotis Georgoulias, Nikolaos Demakopoulos, Petros Xaplanteris, Georgios Mortzos
Journal: Clinical Nuclear Medicine (2003)

A 61-year-old diabetic woman was referred for myocardial perfusion single photon emission computed tomographic (SPECT) imaging 4 years after coronary artery bypass grafting to the left anterior descending (LAD) artery using a left internal mammary artery (LIMA) graft. She had 3 months' angina associated with fatigue of her left upper extremity (the patient is left-handed). Stress myocardial imaging using a Bruce protocol did not exhibit significant myocardial ischemia, but because of her typical angina symptoms, she underwent repeat stress myocardial imaging in combination with exercise of her left arm. During the aforementioned modified stress protocol, the patient reported angina, and radionuclide perfusion imaging showed extensive myocardial ischemia. The patient underwent coronary angiography and arteriography of the left subclavian artery, which revealed severe stenosis before the origin of the LIMA, resulting in reversed blood flow from the LAD artery through the LIMA graft to the left subclavian artery.
GONORRHEA IN WOMEN.
Authors: JOSEPH RILUS EASTMAN
Journal: JAMA (1899)

There is no malady to which womankind is liable that should engage more consideration than gonorrhea. Strewn in the train of its ubiquitous and wily germ are pathologic ravages of surpassing import in their clinical and moral consequences, yet hardly recognized or understood. Sinclair, a decade ago, observed a strange indifference toward differential diagnosis of gonorrhea in the female, and even now, when, in the light of recent bacteriology, it is easily possible to demonstrate the gonococcus in the act of pathologic mischief, there exists a notable, if not notorious, tendency on the part of the most general practitioners, and some specialists, to disregard discriminating diagnosis in doubtful cases. The diagnosis of acute gonorrhea in women is comparatively easy, even without the microscope. What with a history of impure coitus, free purulent secretion from vulva, vagina and urethra, intertrigo, burning on micturition, and vesical tenesmus, the diagnosis is not far