tbuckley/cabot-search huggingface dataset:
Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis
Authors: Shuji Matsumura, Judy Van de Water, Patrick Leung, Joseph A. Odin, Kazuhide Yamamoto, Gregory J. Gores, Keith Mostov, Aftab A. Ansari, Ross L. Coppel, Yasushi Shiratori, Eric M. Gershwin
Journal: Hepatology (2004)

Anti-mitochondrial antibodies (AMAs) have long been recognized as a serological hallmark of primary biliary cirrhosis (PBC). Although high titers of immunoglobulin (Ig)A AMAs are found in bile, saliva, and urine of patients, a pathogenic role for this antibody has remained elusive. Functional studies of this IgA in general have been impeded by low quantities of antibody and the inability to recover antigen-specific IgA in dimeric form. Using a newly defined synthetic group A. Streptococcus derived peptide, we purified large quantities of dimeric and monomeric IgA from patient sera. The purified IgA was incubated with Madine-Darby canine kidney (MDCK) cells transfected with the human polymeric Ig receptor (pIgR) and the cells studied by flow cytometric analysis for binding of carboxyfluorescein conjugated VAD-fmk peptide to activated caspase enzymes. A total of 87% of PBC patients that were anti-PDC-E2 positive had serum IgA that increased caspase activation in MDCK-pIgR+ cells compared to serum-derived IgA from controls with a maximum reaction 48 hours after addition of IgA. The titer of anti-PDC-E2 IgA among the PBC patients strongly correlated with caspase activation (cc = 0.88). Pre-absorption of the IgA using recombinant 2-oxo-acid dehydrogenase complex significantly diminished this activation. IgG from the same PBC patients did not induce caspase activation. These data suggest that during transcytosis through pIgR-positive cells, exposure to PDC-E2-specific dimeric IgA results in the initiation of caspase activation. In conclusion, we propose that due to an even greater concentration of dimeric IgA in biliary and mucosal secretions, constant transcytosis would render the exposed cells more susceptible to apoptosis resulting in subsequent bile duct damage. (Hepatology 2004;39:1415-1422.)
Circulating Tumor Cells: A Multifunctional Biomarker
Authors: Timothy A. Yap, David Lorente, Aurelius Omlin, David Olmos, Johann S. de Bono
Journal: Clinical Cancer Research (2014)

One of the most promising developments in translational cancer medicine has been the emergence of circulating tumor cells (CTC) as a minimally invasive multifunctional biomarker. CTCs in peripheral blood originate from solid tumors and are involved in the process of hematogenous metastatic spread to distant sites for the establishment of secondary foci of disease. The emergence of modern CTC technologies has enabled serial assessments to be undertaken at multiple time points along a patient's cancer journey for pharmacodynamic (PD), prognostic, predictive, and intermediate endpoint biomarker studies. Despite the promise of CTCs as multifunctional biomarkers, there are still numerous challenges that hinder their incorporation into standard clinical practice. This review discusses the key technical aspects of CTC technologies, including the importance of assay validation and clinical qualification, and compares existing and novel CTC enrichment platforms. This article discusses the utility of CTCs as a multifunctional biomarker and focuses on the potential of CTCs as PD endpoints either directly via the molecular characterization of specific markers or indirectly through CTC enumeration. We propose strategies for incorporating CTCs as PD biomarkers in translational clinical trials, such as the Pharmacological Audit Trail. We also discuss issues relating to intrapatient heterogeneity and the challenges associated with isolating CTCs undergoing epithelial-mesenchymal transition, as well as apoptotic and small CTCs. Finally, we envision the future promise of CTCs for the selection and monitoring of antitumor precision therapies, including applications in single CTC phenotypic and genomic profiling and CTC-derived xenografts, and discuss the promises and limitations of such approaches. See ALL articles in this CCR focus section, "Progress in pharmacodynamic endpoints."
Short course of zidovudine cuts transmission of HIV
Authors: T. Rutter
Journal: BMJ (1998)

The rates at which HIV is transmitted from infected mothers to their infants can be halved by a treatment regimen that is shorter and less expensive than the accepted standard of care, the Centers for Disease Control and Prevention in the United States announced last week.

The finding is particularly relevant to developing countries, where 90% of new HIV infections are estimated to occur. The World Health Organisation estimates that over the next five years 5-10 million children will contract HIV perinatally: most of them will be in the developing world.

For four years the antiretroviral drug zidovudine has been known to reduce perinatal transmission of HIV. In 1994 the AIDS Clinical Trials Group 076 showed that a treatment regimen of zidovudine reduced perinatal HIV transmission by up to 70%. Under the 076 regimen, a pregnant woman with HIV infection begins taking zidovudine at 24 weeks of pregnancy and continues to take it throughout the rest of her pregnancy. She receives an intravenous dose of zidovudine during labour, and the newborn baby is also given zidovudine. This has now become standard care …
Top-ups for cancer drugs: can we kill the zombie for good?
Authors: C. Donaldson
Journal: BMJ (2008)

Fiscal pressures are prevalent throughout the world’s healthcare systems. Under such strain, it is natural to opt for “solutions” that seem to make intuitive sense. The latest innovation in this regard is top-ups for expensive cancer treatments here in the UK. Funny how politicians always look for alternative words for what are essentially “user charges.” A popular one, emanating from insurance circles, is “copayments,” and another warm and fuzzy phrase is “diversifying the revenue stream.” But they are all different forms of user charge. The question then is whether such charges are a solution to the problem at hand. This is one area of policy on which there is evidence and virtually unanimous agreement among the experts. User charges are an idea that is intellectually dead, but it keeps coming back to threaten our publicly funded healthcare systems. It has thus been classed as a policy zombie.1

It seems powerful to say “Why not let people spend their hard-earned money in whatever way they like? Surely this relieves the public system of a burden, rather than placing one …
Activation of Cardiac Aldosterone Production in Rat Myocardial Infarction
Authors: Jean-Sébastien Silvestre, Christophe Heymes, Abdeslam Oubénaïssa, Valérie Robert, Brigitte Aupetit-Faisant, Alain Carayon, Bernard Swynghedauw, Claude Delcayre
Journal: Circulation (1999)

Background —This study analyzed the regulation and the role of the cardiac steroidogenic system in myocardial infarction (MI). Methods and Results —Seven days after MI, rats were randomized to untreated infarcted group or spironolactone- (20 and 80 mg · kg −1 · d −1 ), losartan- (8 mg · kg −1 · d −1 ), spironolactone plus losartan–, and L-NAME– (5 mg · kg −1 · d −1 ) treated infarcted groups for 25 days. Sham-operated rats served as controls. In the noninfarcted myocardium of the left ventricle (LV), MI raised aldosterone synthase mRNA (the terminal enzyme of aldosterone synthesis) by 2.0-fold and the aldosterone level by 3.7-fold. Conversely, MI decreased 11β-hydroxylase mRNA (the terminal enzyme of corticosterone synthesis) by 2.4-fold and the corticosterone level by 1.9-fold. MI also induced a 1.9-fold increase in cardiac angiotensin II level. Such cardiac regulations were completely prevented by treatment of the infarcted heart with losartan. The MI-induced collagen deposition in noninfarcted LV myocardium was prevented by 1.6-fold by both low and high doses of spironolactone and by 2.5-fold by losartan. In addition, norepinephrine level was unchanged in infarcted heart but was attenuated by both losartan and spironolactone treatments. Conclusions —MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This increase is mediated primarily by cardiac angiotensin II via AT 1 -subtype receptor and may be involved in post-MI ventricular fibrosis and in control of tissue norepinephrine concentration.
Different responsiveness in body weight and hepatic 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 mrna to 11β-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats
Authors: Ren-Shan Li, Yuichi Nakagawa, Toshiki Nakanishi, Yasuko Fujisawa, Takehiko Ohzeki
Journal: Metabolism (2004)
Directed Phenotype Switching as an Effective Antimelanoma Strategy
Authors: Magalí Sáez-Ayala, María F. Montenegro, Luis Sánchez-del-Campo, María Piedad Fernández-Pérez, Soledad Chazarra, Rasmus Freter, Mark Middleton, Antonio Piñero-Madrona, Juan Cabezas-Herrera, Colin R. Goding, José Neptuno Rodríguez-López
Journal: Cancer Cell (2013)
Amnesic patients give clues on structure of memory
Authors: Elaine Blume
Journal: JAMA (1983)

Human memory is not a single phenomenon but, rather, is made up of several distinct components, according to scientists who have been studying this function of the brain.  At a recent National Institute of Mental Health (NIMH) science writers' seminar, speakers explained that particular memory components can make possible different kinds of learning. Such components may or may not be impaired in a given amnestic syndrome and may respond in their own ways to psychoactive drugs.  Probably the most dramatic evidence for the existence of distinct memory components comes from patients who have sustained severe bilateral damage to the hippocampus and the amygdala—parts of the brain's limbic system. Such patients suffer from a syndrome known as global anterograde amnesia; they are essentially incapable of learning new information.  A patient with global amnesia is unable to remember what he had for breakfast, and, if he has moved since the brain damage
Congenital Duodenal Atresia in Four Sibs
Authors: John S. Hyde
Journal: JAMA (1965)

TO DATE it has not been possible to find a report of the familial occurrence of duodenal atresia in the pediatric or genetic literature. It is the purpose of this communication to present four premature infant sibs with this defect. This striking finding of identical duodenal atresias in a sibship suggests a genetic basis. Some of the problems encountered in understanding the etiological mechanisms of this anomaly are briefly commented on. <h3>Report of a Case</h3> A premature infant girl was born of Greek parents on March 22, 1963. Since family history indicated bowel obstruction at birth among sibs, the patient was seen immediately after birth by a pediatrician. A No. 8 French catheter was passed into the stomach with ease and bilecontaining fluid was obtained. An x-ray study of the abdomen taken three hours after birth revealed a large gastric air bubble and dilatation of the first portion of the
Effects of Right Ventriculotomy upon Activation of the Epicardial Surface of the Canine Right Ventricle
Authors: LAWRENCE J. GENENDER, JACKSON H. STUCKEY, SERGE L. JOMAIN, BRIAN F. HOFFMAN
Journal: Circulation (1963)

The sequence of activation of the epicardial surface of the right ventricle has been studied before and after right ventriculotomy. Normally, the area of the right ventricle adjacent to the anterior interventricular groove is activated first, the midportion of the wall second, and the area adjacent to the posterior interventricular groove and the anterior basal area are activated last. Activation of the entire epicardial surface of the right ventricle requires 25 to 40 msec. Right ventriculotomy does not alter the sequence of activation or the time of activation of the right ventricular epicardium if the incision passes medial to the free-running Purkinje fibers or through their arborization on the right, ventricular wall. When the ventriculotomy is made lateral to the arborization of these fibers, activation of that portion of the wall lateral to the incision is delayed, and activation of the entire ventricular surface requires 42 to 52 msec. There is no electrocardiographic evidence of bundle-branch block, complete or partial, following right ventriculotomy, regardless of the location of the incision.
Hydrogen Peroxide Inhibits Cytochrome P450 Epoxygenases
Authors: Brandon T. Larsen, David D. Gutterman, Atsushi Sato, Kazuyoshi Toyama, William B. Campbell, Darryl C. Zeldin, Vijay L. Manthati, John R. Falck, Hiroto Miura
Journal: Circulation Research (2007)

The cytochrome P450 epoxygenase (CYP)-derived metabolites of arachidonic acid the epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H2O2) both function as endothelium-derived hyperpolarizing factors (EDHFs) in the human coronary microcirculation. However, the relative importance of and potential interactions between these 2 vasodilators remain unexplored. We identified a novel inhibitory interaction between CYPs and H2O2 in human coronary arterioles, where EDHF-mediated vasodilatory mechanisms are prominent. Bradykinin induced vascular superoxide and H2O2 production in an endothelium-dependent manner and elicited a concentration-dependent dilation that was reduced by catalase but not by 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE), 6-(2-propargyloxyphenyl)hexanoic acid, sulfaphenazole, or iberiotoxin. However, in the presence of catalase, an inhibitory effect of these compounds was unmasked. In a tandem-bioassay preparation, application of bradykinin to endothelium-intact donor vessels elicited dilation of downstream endothelium-denuded detectors that was partially inhibited by donor-applied catalase but not by detector-applied EEZE; however, EEZE significantly inhibited dilation in the presence of catalase. EET production by human recombinant CYP 2C9 and 2J2, 2 major epoxygenase isozymes expressed in human coronary arterioles, was directly inhibited in a concentration-dependent fashion by H2O2 in vitro, as observed by high-performance liquid chromatography (HPLC); however, EETs were not directly sensitive to oxidative modification. H2O2 inhibited dilation to arachidonic acid but not to 11,12-EET. These findings suggest that an inhibitory interaction exists between 2 EDHFs in the human coronary microcirculation. CYP epoxygenases are directly inhibited by H2O2, and this interaction may modulate vascular EET bioavailability.
BDNF mRNA expression in the developing rat brain following kainic acid-induced seizure activity
Authors: Millicent M. Dugich-Djordjevic, Georges Tocco, David A. Willoughby, Imad Najm, Giulio Pasinetti, Richard F. Thompson, Michel Baudry, Paul A. Lapchak, Franz Hefti
Journal: Neuron (1992)
Congo polio immunisation campaign gets go ahead
Authors: A. Mach
Journal: BMJ (1999)

Since the World Health Organization (WHO) set a goal in 1988 of eradicating polio worldwide by 2000, the incidence of the disease has declined by 90% around the world, with national immunization days conducted in more than 120 countries. More than 450 million children were immunized in 1998 alone. Now, with only about 5000 annual cases of polio occurring, complete eradication can be achieved. To that end, and in a first-ever initiative, the heads of the World Health Organization (WHO) and UNICEF, jointly appealed to UN Secretary General Kofi Annan for help in bringing immunization against polio to children in war-torn Democratic Republic of Congo. Mr. Annan subsequently announced an initiative to negotiate several special ceasefire agreements in Congo so that approximately 10 million children under age 5 years can be immunized against poliomyelitis during July-September 1999. Both the president of Congo, Laurent Kabila, and rebel leaders have given their preliminary assurances that weapons will be laid down while Congolese children are sought out and vaccinated. A joint WHO-UNICEF planning mission will travel to Kinshasa in April to advise the Congolese Ministry of Health, which has main responsibility for the areas under governmental control. The $15 million project is expected to cover 3 rounds of immunization to bring population immunity to the highest possible level.
Chymopapain: tropical tree to surgical suite Chymopapain
Authors: Phil Gunby
Journal: JAMA (1983)

A bit of medical history is being made in connection with the Food and Drug Administration's recent approval of chymopapain to treat so-called slipped disks. First, take the Nov 10, 1982, decision itself— considered historic because it marks the successful conclusion of a long and sometimes highly controversial struggle to gain official approval for chymopapain. It's been more than 40 years since the papain enzyme was first isolated (1941). In 1956, author and medical commentator Lewis Thomas, MD, then a pathologist at New York University-Bellevue Medical Center, showed it could break down cartilaginous protein polysaccharide when injected into the tall, rigid ears of rabbits, causing the ears to collapse. About seven years later, Illinois orthopedic surgeon Lyman Smith, MD, developed chemonucleolysis, a technique in which chymopapain is injected into herniated lumbar intervertebral disks that have not responded to conservative therapy to hasten chondromucoprotein degradation (<i>JAMA</i>1964;187:137-140). Clinical trials began soon
Let's get the words right too
Authors: A. Breathnach
Journal: BMJ (2011)

How we use words is important, particularly in the debate about what is variously referred to as assisted dying, assisted suicide, euthanasia, or plain killing.1 Words can be used, perhaps unconsciously, for emotional as well as intellectual effect. Thus Delamothe describes Care not Killing as an outfit, an offensive term suggesting a ramshackle (possibly violent) organisation. Similarly, disabled people were …
Pernicious Anemia Due to Dietary Deficiency of Vitamin B<sub>12</sub>
Authors: Myron Pollycove, Leonard Apt, Marvin J. Colbert, Mary Pratt, Joan Donovan, Jack Sullivan, Thomas Giaveniello
Journal: New England Journal of Medicine (1956)

PERNICIOUS anemia is a deficiency state resulting from a lack of vitamin Bi2. This lack usually occurs as a result of an inability to absorb the vitamin from the intestinal tract because of the absence of a specific factor, present in normal gastric juice, known as the intrinsic factor of Castle.1 , 2 An optimal, well balanced diet contains 8 to 15 microgm. of vitamin B12 per day.3 , 4 A daily parenteral dose of 1 microgm. induces and maintains a complete remission in patients with pernicious anemia.5 , 6 It thus appears probable that only a small fraction of the normal dietary . . .
Researchers Focus on Recovery in Schizophrenia
Authors: M. J. Friedrich
Journal: JAMA (2014)

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Abstract A74: TGF-β in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma
Authors: Mitsuteru Natsuizaka, Shingo Kagawa, Kelly Whelan, Shinya Ohashi, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto, Anil K. Rustgi, Hiroshi Nakagawa
Journal: Cancer Research (2015)

Abstract There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44 (CD44H). CD44H cells have cancer stem-like characteristics and as few as ten CD44H cells can form tumors in an athymic nude mouse. Epithelial-mesenchymal transition (EMT) has a critical role to maintain CD44H cells in ESCC. Notch1-mediated signaling may facilitate either EMT or squamous-cell differentiation in a context-dependent manner. However, detailed mechanism how Notch signaling promotes either EMT or differentiation remains unclear. We investigated how TGF-β in tumor microenvironment might influence Notch signaling to maintain CD44H cells via EMT in ESCC. TGF-β promoted EMT and enriched CD44H cells by activating Notch1 and ZEB1 and suppressing Notch3, while in absence of TGF-β, Notch1 rather activated Notch3, one of pivotal transcription factors in keratinocyte differentiation, led to keratinocyte differentiation. Highly conserved binding sites of ZEB1 exist in the 2nd intron of Notch3. ZEB1 induced by TGF-β bound to the 2nd intron of Notch3 and sharply suppressed the Notch3 transcription, confirmed by CHIP and luciferase assay. Thus TGF-β and Notch1 cooperatively promote EMT and maintain tumor initiating cells. TGF-β signaling influences the tumor initiating capacity of ESCC by modulating novel opposing activities of Notch1 and Notch3 in EMT, and may have translational implications. Citation Format: Mitsuteru Natsuizaka, Shingo Kagawa, Kelly Whelan, Shinya Ohashi, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto, Anil K. Rustgi, Hiroshi Nakagawa. TGF-β in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A74. doi:10.1158/1538-7445.CHTME14-A74