tbuckley/cabot-search huggingface dataset:
Differential Cellular Responses to Prolonged LDR-IR in MLH1-Proficient and MLH1-Deficient Colorectal Cancer HCT116 Cells
Authors: Tao Yan, Yuji Seo, Timothy J. Kinsella
Journal: Clinical Cancer Research (2009)

MLH1 is a key DNA mismatch repair (MMR) protein involved in maintaining genomic stability by participating in the repair of endogenous and exogenous mispairs in the daughter strands during S phase. Exogenous mispairs can result following treatment with several classes of chemotherapeutic drugs, as well as with ionizing radiation. In this study, we investigated the role of the MLH1 protein in determining the cellular and molecular responses to prolonged low-dose rate ionizing radiation (LDR-IR), which is similar to the clinical use of cancer brachytherapy.An isogenic pair of MMR(+) (MLH1(+)) and MMR(-) (MLH1(-)) human colorectal cancer HCT116 cells was exposed to prolonged LDR-IR (1.3-17 cGy/h x 24-96 h). The clonogenic survival and gene mutation rates were examined. Cell cycle distribution was analyzed with flow cytometry. Changes in selected DNA damage repair proteins, DNA damage response proteins, and cell death marker proteins were examined with Western blotting.MLH1(+) HCT116 cells showed greater radiosensitivity with enhanced expression of apoptotic and autophagic markers, a reduced HPRT gene mutation rate, and more pronounced cell cycle alterations (increased late-S population and a G(2)/M arrest) following LDR-IR compared with MLH1(-) HCT116 cells. Importantly, a progressive increase in MLH1 protein levels was found in MLH1(+) cells during prolonged LDR-IR, which was temporally correlated with a progressive decrease in Rad51 protein (involved in homologous recombination) levels.MLH1 status significantly affects cellular responses to prolonged LDR-IR. MLH1 may enhance cell radiosensitivity to prolonged LDR-IR through inhibition of homologous recombination (through inhibition of Rad51).
BIVENTRICULAR VERSUS LEFT VENTRICULAR PACING FOR CARDIAC RESYNCHRNOIZATION THERAPY: COMPARISON OF THE ACUTE HEMODYNAMIC RESPONSE AND OPTIMAL AV DELAY
Authors: Michael Robert Gold, Imran Niazi, Michael Giudici, Robert Leman, J Lacy Sturdivant, Michael Kim, Yinghong Yu
Journal: Journal of the American College of Cardiology (2010)
Mapping the Journey to an HIV Vaccine
Authors: Margaret Ackerman, Galit Alter
Journal: New England Journal of Medicine (2013)

Universal" vaccines that elicit cross-reactive and broadly neutralizing antibodies (bNAbs) are the ultimate goal of efforts to provide protective immunity against both the influenza virus and the human immunodeficiency virus (HIV).Infection with either virus leads to the induction of abundant strain-specific antibodies that are easily evaded by subsequent viral variants.However, the circulating diversity of HIV is greater than that of influenza by orders of magnitude, posing a tremendous challenge to the achievement of vaccine-mediated protection.New hope for a universal sterilizing HIV vaccine arose several years ago with the evidence that bNAbs emerge in 10 to 30% of infected persons. 1 Because these bNAb responses typically appear after 2 to 3 years of infection, they fail to control established infection: the kinetics of the evolving B-cell response lag behind the rapidly diversifying virus, and they cannot "catch up" to control established infection.However, these bNAbs have provided protection from infection at remarkably low doses in animals, suggesting that vaccine-induced bNAbs could provide sterilizing immunity if they were present before infection.Translating our current knowledge of bNAbs into a vaccine remains a daunting challenge, since the mechanism by which such antibodies are induced remains enigmatic.As compared with other antibodies, bNAbs have unusual characteristics, including odd physical structures (e.g., elongated antigen-binding loops) and remarkably high levels of mutation that affect antibody-antigen binding and structural domains. 2 These changes accumulate over years of infection as exposure to diverse viral variants drives antibody evolution, resulting in the generation of a set of antibodies that bears little similarity to their original antigen-naive B-cell ancestors (i.e., germline sequences).Liao et al. 3 have recently described the path along which bNAbs develop.They tracked the
P470Disturbed flow promotes endothelial cell injury via the induction of developmental genes
Authors: M Mahmoud, R Kim, A De Luca, I Gauci, S Hsiao, PC Evans
Journal: Cardiovascular Research (2014)

Purpose: Atherosclerosis, a disease of arteries that can cause heart attack and stroke, is influenced by local blood flow patterns which exert wall shear stress (WSS) on endothelial cells (EC). Low, oscillatory WSS promotes atherosclerosis by inducing EC apoptosis and activation, while high, unidirectional WSS is athero-protective. We recently used microarray technology coupled to computational fluid dynamics to study the transcriptome of EC at regions of the porcine aorta exposed to low, oscillatory or high, unidirectional WSS. The study revealed differential expression of multiple genes (GATA4, HAND2, TWIST1, FZD5, BMP2, SLIT2, PDGFRA, FBN2 and GJA5) that co-ordinate embryonic development. We hypothesised that this gene set includes key regulators of EC survival in response to haemodynamic forces. Methods and Results: EC were isolated from distinct anatomical regions of the porcine aorta using collagenase (n=6), and quantitative RT-PCR revealed elevated expression of developmental genes (GATA4, HAND2, TWIST1, FZD5, BMP2, SLIT2, PDGFRA, and FBN2) at the inner (low WSS) compared to the outer curvature (high WSS) (all p<0.05). Similarly, en face staining demonstrated that expression of GATA4 protein in EC was higher at the inner compared to the outer curvature of the murine aortic arch (p<0.05). Studies using cultured porcine aortic EC (n=7) or human umbilical vein EC (n=7) revealed that GATA4, HAND2, TWIST1, FZD5, BMP2, SLIT2, PDGFRA, and FBN2 were induced in HUVEC or PAEC exposed to low, oscillatory WSS for 72h using either the orbital shaking (210 rpm; +/-WSS 4 dyn/cm2) or IBIDI™ (+/-5 dyn/cm2 at 2Hz) systems (all p<0.05). The rate of caspase-3 activation was significantly higher in EC exposed to low, oscillatory WSS compared to high, unidirectional WSS (3.1% vs 0.7%; p<0.0001; n=10). Silencing of GATA4, FZD5 and BMP2 using gene specific siRNA sequences significantly reduced apoptosis in EC exposed to low, oscillatory WSS (1.2%, 0.6% and 1.6%; p<0.05; n=3). Conclusions: We conclude that WSS influences EC viability through the induction of GATA4, FZD5 and BMP2; molecules that have a well-defined role in embryonic development. Further work is required to define the molecular mechanisms that underlie the induction of apoptosis by these molecules. Our observations illuminate the molecular mechanisms that regulate the focal nature of vascular injury and atherosclerosis.
Antiviral drug discovery: Ten more compounds, and ten more stories (part B)
Authors: Erik De Clercq
Journal: Medicinal Research Reviews (2009)

Abstract This review article that complements the previous review article on “The discovery of antiviral agents: ten different compounds, ten different stories” presents ten more compounds and ten more stories in which I have been closely involved at one or another point of my scientific career: (i) interferon (IFN) (in particular, IFN‐β); (ii) poly(I).poly(C); (iii) suramin; (iv) novel acyclic nucleoside phosphonates; (v) the double prodrug of [9‐(2‐phosphonomethoxyethyl)guanine]; (vi) cyclic nucleoside phosphonates; (vii) picornavirus inhibitors; (viii) human immunodeficiency virus (HIV) co‐receptor inhibitors; (ix) nonimmunosuppressive cyclosporin A analogues; and (x) bicyclic (furanopyrimidine) nucleoside analogues. With the exception of the HIV co‐receptor CCR5 inhibitor none of the compounds described here have already been marketed (for the indication they were initially developed). Successful antiviral drug development depends on the interplay of three disciplines, chemistry, biology/medicine, and industry, crucial factors being open mindedness for the unexpected, preparedness to explore serendipitous observations, and perseverance (in trying) to overcome the hurdles or setbacks inevitably compounding any drug development. © 2009 Wiley Periodicals, Inc. Med Res Rev
Government proposals conflict
Authors: Robert Kahn, John Godfrey
Journal: BMJ (2007)

Cerebral arteries are relatively unresponsive to sympathetic nerve stimulation, in spite of extensive adrenergic innervation. To determine whether these nerves are functional, release of endogenous norepinephrine (NE) was measured using a radioenzymatic assay. Fractional release of NE per stimulation pulse was more than 5 times greater from the rabbit basilar artery than from the ear artery. Thus, while the NE content of the two vessels is quite similar, transmitter release is considerably greater in the basilar artery. Since NE accumulation is also much greater in the basilar artery, it seems possible that an active parameter such as NE release or accumulation may be a better index of functional nerve capacity than NE content. Previous studies have shown that alpha adrenergic blocking agents do not block the contractile response to nerve stimulation of the basilar artery, but actually increase it. Thus, the possibility that blockade of presynaptic adrenergic receptors leads to increased transmitter release was tested. Indeed, both phenoxybenzamine and phentolamine significantly increased stimulation-evoked NE release. It appears that postsynaptic events in cerebral arteries are atypical, while release of transmitter, including modulation by presynaptic alpha adrenergic receptors is similar to other blood vessels.
Diminished Operative Morbidity and Mortality in Renal Revascularization
Authors: Andrew C. Novick
Journal: JAMA (1981)

From 1974 to 1980, one hundred consecutive patients with atherosclerotic renovascular disease underwent revascularization. There were two operative deaths and eight postoperative complications. This low operative morbidity is attributed to preoperative screening, correction of existing coronary or cerebrovascular disease, and reliance on methods of revascularization that obviate operation on a badly diseased aorta. The results in 78 patients with renovascular hypertension were 40% cured, 51% improved, and 9% failed. In 22 patients in whom revascularization was performed to preserve renal function, the postoperative serum creatinine levels were improved in 19 patients, remained stable in two patients, and increased in one patient. (<i>JAMA</i>1981:246:749-753)
Mismatched unrelated cord blood transplantation in a patient with T-cell prolymphocytic leukemia
Authors: T E Tanimoto, A Hirano, K Nagafuji, S Yamasaki, M Hashiguchi, T Okamura, K Kamezaki, K Takase, A Numata, T Miyamoto, T Fukuda, M Harada
Journal: Leukemia (2005)
Don’t add aspirin for associated stable vascular disease in a patient with atrial fibrillation receiving anticoagulation
Authors: Gregory Y H Lip
Journal: BMJ (2008)

#### Key points

Atrial fibrillation is the commonest cardiac arrhythmia, with increasing prevalence and incidence.1 Adjusted dose oral anticoagulation (such as with warfarin) is the most effective treatment for stroke prevention in high risk patients with atrial fibrillation.2

However, common practice is to add aspirin (or other antiplatelet treatment) to warfarin in atrial fibrillation if there is associated chronic stable coronary or peripheral artery disease.2 This is despite relatively little evidence that adding aspirin to warfarin reduces stroke or other vascular events in patients with atrial fibrillation.

I propose here that we should not add aspirin for associated stable vascular disease in a patient with atrial fibrillation receiving anticoagulation, given the lack of evidence for benefit and the potential for harm.

Randomised clinical trials in patients with atrial fibrillation using combinations of anticoagulation and aspirin either compared fixed dose (or low intensity, international normalised ratio (INR) <1.5) anticoagulation …
In Vitro Effects of the Platelet Glycoprotein IIb/IIIa Receptor Antagonist c7E3 Fab on the Activated Clotting Time
Authors: Tameshwar Ammar, Lesley E. Scudder, Barry S. Coller
Journal: Circulation (1997)

Background In the Evaluation of 7E3 for the Prevention of Ischemic Complications study (EPIC), the activated coagulation (clotting) times (ACTs) were longer in heparinized patients treated with c7E3 Fab than in those treated with placebo. The present study was designed to further investigate this observation by assessing whether the in vitro addition of c7E3 Fab to blood would affect the ACT. Methods and Results Native or heparinized blood obtained from normal volunteers was preincubated with antibodies c7E3 Fab (anti-GPIIb/IIIa and anti-α v β 3 ), 10E5 (anti-GPIIb/IIIa), or LM609 (anti-α v β 3 ). The ACTs of the heparinized, but not native samples were significantly prolonged by the addition of c7E3 Fab and 10E5 but not LM609, indicating that the prolongation was due to GPIIb/IIIa blockade. The addition of c7E3 Fab also significantly prolonged the ACTs of blood anticoagulated with the direct thrombin inhibitors hirudin and d -phenylalanyl- l -prolyl- l -arginyl chloromethyl ketone, indicating that the effect of c7E3 Fab was not exclusively related to decreased release of PF4, a heparin-neutralizing factor, from platelets. Conclusions These data support the conclusion that the prolongation of the ACT in patients in EPIC was due to c7E3 Fab blockade of GPIIb/IIIa receptors. This raises the possibility that in vivo c7E3 Fab functions not only as an antiplatelet agent but also as an anticoagulant; direct in vivo data will, however, be required for assessment of this possibility.
Emotional and cognitive processing in empathy and moral behavior
Authors: Paul J. Eslinger, Jorge Moll, Ricardo de Oliveira-Souza
Journal: Behavioral and Brain Sciences (2002)

Within the perception-action framework, the underlying mechanisms of empathy and its related processes of moral behavior need to be investigated. fMRI studies have shown different frontal cortex activation patterns during automatic processing and judgment tasks when stimuli have moral content. Clinical neuropsychological studies reveal different patterns of empathic alterations after dorsolateral versus orbital frontal cortex damage, related to deficient cognitive and emotional processing. These processing streams represent different neural levels and mechanisms underlying empathy.
FDG PET/CT Imaging to Rule Out Extrahepatic Metastases Before Liver Transplantation
Authors: Bharat Mocherla, Jongho Kim, Sasan Roayaie, Suzanne Kim, Josef Machac, Lale Kostakoglu
Journal: Clinical Nuclear Medicine (2007)

FDG PET/CT, an established imaging modality for staging and restaging workup of malignancies, also demonstrates increased uptake in infectious or inflammatory conditions, including both infectious and noninfectious granulomatous processes. A 65-year-old man with a history of hepatocellular carcinoma status post-wedge resection and chemoembolization of the primary tumor referred for evaluation of extrahepatic metastases for determining the surgical eligibility for a liver transplantation. The patient underwent FDG PET/CT imaging associated with a separately acquired contrast enhanced CT (CECT) of the chest, abdomen, and pelvis. FDG PET/CT imaging revealed multiple FDG-avid pulmonary nodules that were subsequently confirmed to represent Mycobacterium avium intracellular infection on histology.
Calcium-Blocker Therapy for Unstable Angina Pectoris
Authors: Robert Zelis
Journal: New England Journal of Medicine (1982)

Now that the calcium blockers are available, how does this change the modern management of angina pectoris? Although there are relatively unusual causes of angina, such as hypertrophic cardiomyopathy and aortic stenosis, the vast majority of these patients have fixed atherosclerotic coronary-artery disease, and pain occurs when myocardial oxygen requirements increase. This pathophysiologic process gives rise to the syndrome of chronic stable exertional angina. Current therapy consists of nitrates and beta-adrenergic-receptor blocking agents to decrease myocardial oxygen consumption, with coronary-bypass surgery for patients at high risk of myocardial infarction or those unresponsive to medical therapy.A few patients have a . . .
Decreased Levels of Helper T Cells
Authors: Vitaya Sridama, Furio Pacini, Sen-Lian Yang, Atef Moawad, Maureen Reilly, Leslie J. DeGroot
Journal: New England Journal of Medicine (1982)

DECREASED maternal immune responsiveness during pregnancy may partly explain the survival of the fetus as an allograft. It may also account for changes in disease activity and antibody production in several autoimmune diseases during pregnancy and in the post-partum period. Previous in vitro studies of cellular immunity in pregnant women have demonstrated decreased lymphocyte responses to phytohemagglutinin,1 to mixed lymphocyte culture,1 and to soluble antigens.2 An increased incidence and severity of certain viral infections has also been observed.1 , 3 An imbalance between helper and suppressor T cells has recently been demonstrated in several autoimmune diseases4 , 5 and in immunodeficiency states,4 in studies . . .
Pulmonary vascular and alveolar development in tetralogy of Fallot: a recommendation for early correction.
Authors: R J Johnson, S G Haworth
Journal: Thorax (1982)

Using quantitative morphometric techniques, we analysed pulmonary arterial and alveolar development in the lungs of seven children aged 1.2-12 years who died during or soon after repair of tetralogy of Fallot. One child had a residual ventricular septal defect and survived for five months. One other child had had a previous Waterston-Cooley anastomosis (Waterston shunt). Postmortem lung volume in relation to body surface area was generally below normal for age, the alveoli were small, and the total alveolar number was below normal in five of the seven cases. Microscopically, airway and alveolar structure appeared normal. The preacinar arteries were larger and the intra-acinar arteries were smaller than normal for age. The preacinar elastic pulmonary arteries appeared to contain less elastin and in both preacinar and intra-acinar muscular arteries the media was thinner than normal, although muscle was normally distributed along the arterial pathway. Eccentric areas of intimal fibrosis were small and uncommon. The bronchial arteries were generally more prominent than usual both macroscopically and microscopically, but no abnormal bronchopulmonary connections were present. After corrective surgery a residual ventricular septal defect and pulmonary hypertension were associated with arterial medial hypertrophy, and this change was also found in the right lung of a normotensive patient who had had a Waterston shunt. This group probably represents the most favourable clinical picture of tetralogy in patients who usually survive but, even so, pulmonary arterial and alveolar development was abnormal. The structural findings are discussed in relation to the functional outcome in patients with tetralogy who have survived. Repair of the abnormality during the first two to three years of life is recommended.
Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis
Authors: Pier Paolo Pandolfi, Matthew E. Roth, Alar Karis, Mark W. Leonard, E. Dzierzak, Frank G. Grosveld, James Douglas Engel, Michael H. Lindenbaum
Journal: Nature Genetics (1995)
On the Treatment of Spasmodic Cholera
Authors: G. Fife
Journal: BMJ (1843)

Di-acetate of lead, four grains; Syrup of poppies, two drachms; Fennel water, two otnces.'rwo teaspoonfuls to a child from two to ten years every five hours;half an ounce for an adult.It is said to cure generally in three days (?)There is other confirmative evidence in favor of lead in this disease, and a formula in combination with conium is giveil in our report of the IReadiug Patholo- gical Society for 1842.Mlr. C. H. Chavasse (" Lancet," May 30, 1840) speaks highly of the following formula:- Sulphate of copper, half a grain; Syrup of poppies, half an ounce; Anise water, an ounce and a half.Mix.A teaspoonful to be taken every second or fouirtlh hour, according to the age.Sir William Watson's celebrated prescription was- Tartar emetic, one grain; Tincture of opiujn, twenty minims; Distilled water, one ounce.Mix.A teaspoonful every, or every other night.Mr. Pearson, after premising anl emetic, relied much upon- Tincture of opium, one minim; Ipecacuanha wine, five drops; Carbonate of soda, twvo grains; Water, half an ounce.Majle a draught, to be taken every four hours.Dr. C. Wachtl, of Viemna (vide Provincial Journal, January 21, 1843) has found cochineal very useful in rapidly checking the paroxysms.Cochineal, ten grains; Bitartrate of potash, one scruple; Sugar, one ounce; Water, six ounces.A teaspoonful every four or six hours.
Surreptitious Habitual Vomiting Simulating Bartter's Syndrome
Authors: Emilio Ramos, Mary Hall-Craggs, Laurence M. Demers
Journal: JAMA (1980)

A patient with hypokalemic alkalosis, normotensive hyperreninism, hyperaldosteronism, increased levels of urinary and plasma prostaglandin E, and vascular hyporesponsivity to angiotensin II was thought to have Bartter's syndrome. Results of a kidney biopsy showed hyperplasia of the juxtaglomerular apparatus but no renomedullary cell hyperplasia. A 24-hour urine collection showed a low chloride level and no increase in the fractional chloride clearance, thus excluding Bartter's syndrome. Subsequent disclosure of surreptitious, habitual vomiting explained the hypokalemia. (<i>JAMA</i>243:1070-1072, 1980)
Astrocytes are the primary source of tissue factor in the murine central nervous system. A role for astrocytes in cerebral hemostasis.
Authors: M Eddleston, J C de la Torre, M B Oldstone, D J Loskutoff, T S Edgington, N Mackman
Journal: Journal of Clinical Investigation (1993)

Hemostasis in the brain is of paramount importance because bleeding into the neural parenchyma can result in paralysis, coma, and death. Consistent with this sensitivity to hemorrhage, the brain contains large amounts of tissue factor (TF), the major cellular initiator of the coagulation protease cascades. However, to date, the cellular source for TF in the central nervous system has not been identified. In this study, analysis of murine brain sections by in situ hybridization demonstrated high levels of TF mRNA in cells that expressed glial fibrillary acidic protein, a specific marker for astrocytes. Furthermore, primary mouse astrocyte cultures and astrocyte cell lines from mouse, rat, and human constitutively expressed TF mRNA and functional protein. These data indicated that astrocytes are the primary source of TF in the central nervous system. We propose that astrocytes forming the glia limitans around the neural vasculature and deep to the meninges are intimately involved in controlling hemorrhage in the brain. Finally, we observed an increase in TF mRNA expression in the brains of scrapie-infected mice. This modulation of TF expression in the absence of hemorrhage suggested that TF may function in processes other than hemostasis by altering protease generation in normal and diseased brain.