tbuckley/cabot-search huggingface dataset:
Concurrent deletion of cyclin E1 and cyclin-dependent kinase 2 in hepatocytes inhibits DNA replication and liver regeneration in mice
Authors: Wei Hu, Yulia A. Nevzorova, Ute Haas, Nives Moro, Piotr Sicinski, Yan Geng, Mariano Barbacid, Christian Trautwein, Christian Liedtke
Journal: Hepatology (2013)

The liver has a strong regenerative capacity. After injury, quiescent hepatocytes can reenter the mitotic cell cycle to restore tissue homeostasis. This G(0) /G(1) -S cell-cycle transition of primed hepatocytes is regulated by complexes of cyclin-dependent kinase 2 (Cdk2) with E-type cyclins (CcnE1 or CcnE2). However, single genetic ablation of either E-cyclin or Cdk2 does not affect overall liver regeneration. Here, we systematically investigated the contribution of CcnE1, CcnE2, and Cdk2 for liver regeneration after partial hepatectomy (PH) by generating corresponding double- and triple-knockout (KO) mouse mutants. We demonstrate that conditional deletion of Cdk2 alone in hepatocytes resulted in accelerated induction of CcnE1, but otherwise normal initiation of S phase in vivo and in vitro. Excessive CcnE1 did not contribute to a noncanonical kinase activity, but was located at chromatin together with components of the pre-replication complex (pre-RC), such as the minichromosome maintenance (MCM) helicase. Concomitant ablation of Cdk2 and CcnE1 in hepatocytes caused a defect in pre-RC formation and further led to dramatically impaired S-phase progression by down-regulation of cyclin A2 and cell death in vitro and substantially reduced hepatocyte proliferation and liver regeneration after PH in vivo. Similarly, combined loss of CcnE1 and CcnE2, but also the Cdk2/CcnE1/CcnE2 triple KO in liver, significantly inhibited S-phase initiation and liver mass reconstitution after PH, whereas concomitant ablation of CcnE2 and Cdk2 had no effect. In the absence of Cdk2, CcnE1 performs crucial kinase-independent functions in hepatocytes, which are capable of driving MCM loading on chromatin, cyclin A2 expression, and S-phase progression. Thus, combined inactivation of Cdk2 and CcnE1 is the minimal requirement for blocking S-phase machinery in vivo.
ERK3 in lung cancer cell invasion
Authors: Arthee Yogendran
Journal: Thorax (2012)

ERK3 in lung cancer cell invasionERK3, an atypical mitogen-activated protein kinase, was first identified 20 years ago, and its role in cancer development is yet to be fully elucidated.Steroid receptor coactivator 3 (SRC-3) has been well described in a number of different cancers, including lung cancer, as a nuclear receptor coactivator of PEA3-regulated MMP expression to promote cancer cell invasion.The authors use immunoprecipitation analysis in H1299 lung cancer cells to identify the oncogene SRC-3 as a substrate of the ERK3-signalling cascade for phosphorylation at serine 857(S857).Additionally, overexpression of ERK3 and SRC-3 was shown to enhance MMP2 activity, while mutation of S857, as well as knockdown of ERK3 and SRC-3, inhibited MMP2 expression.Phosphorylation of S857 was an essential step in encouraging interaction of SRC-3 and PEA3 and occupancy at the MMP2 promoter.A 7.4-fold increased expression of ERK3 mRNA was noted in squamous cell lung carcinoma compared with normal lung tissue, which was confirmed with immunohistochemistry.Further experiments using mice models with ERK3/SRC-3 knockdown indicated eliminated invasion potential of H1299 cells, with no lung cancer cell colonisation seen after 5 weeks.This study works towards increasing understanding of the ERK3 signalling pathway: phosphorylation of SRC-3 at S857 and MMP expression via PEA coactivation.The clinical implications of upregulation of ERK3 in squamous cell lung cancer, and its role in promoting cell invasion, may provide a new potential therapeutic target for this cancer sub-group.
Aberrant A-V Impulse Propagation in the Dog Heart: A Study of Functional Bundle Branch Block
Authors: GORDON K. MOE, CARLOS MENDEZ, JAOK HAN
Journal: Circulation Research (1965)

Excessive delay and configurational change of ventricular responses to atrial premature beats, previously attributed to dissociation within the A-V node, were shown to be due to functional block of the right bundle branch. It was found that the refractory period (RP) of the right bundle branch often exceeded the functional refractory period (FRP) of the A-V node at slow heart rates, permitting an early premature atrial response to reach the ventricles before recovery of the right bundle. Vagal stimulation and rapid driving frequencies, by delaying the intranodal transit of the premature response, prevented the exposure of bundle branch block. Epinephrine in low doses sometimes facilitated its occurrence. Premature responses initiated in the His bundle in open heart preparations were commonly blocked in the right bundle under conditions in which atrial premature responses were normally propagated to the ventricles. Evidence was obtained in such preparations that the portion of the right bundle system beyond the site of the block was activated retrogradely from the left side. Under certain conditions the retrograde activation process returned to the His bundle and the atrium as an echo.
Aminoglycoside Prescribing and Surveillance in Cystic Fibrosis
Authors: Kelvin H-V Tan, Michael Mulheran, Alan J Knox, Alan R Smyth
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

lean mass, of which 70% is body water and the remainder muscle. After intravenous administration, aminoglycosides distribute rapThe potential of aminoglycoside antibiotics to cause ototoxic idly throughout the extracellular fluid compartment, with peak seand nephrotoxic damage was first discovered in 1945, during rum levels achieved within 30 minutes of the end of a 30-minute early clinical trials of streptomycin (1). Despite the introduction infusion. of newer classes of antibiotics, aminoglycosides continue to be Patients with CF are typically prescribed high dose prolonged widely prescribed in cystic fibrosis (CF) clinics and are likely to courses of intravenous antibiotics based upon reports of altered retain an important role in the management of CF lung disease pharmacokinetics (7) and due to the nature and severity of CF for the foreseeable future. They are highly active against Pseu- disease. The volume of distribution and the rate of clearance of domonas aeruginosa, display synergism with -lactam antibiotics aminoglycosides are increased, with the half-life of tobramycin (2), and effectively penetrate the sputum of patients with CF (3). between 2 and 3 hours. Aminoglycosides undergo minimal proPatients with CF can now expect to live into the fourth decade tein binding and are eliminated almost entirely by glomerular and beyond, with full-time education followed by employment filtration. and an active lifestyle being attainable goals. Therefore, the role of the CF clinician when prescribing repeated courses of Starting Dose potentially toxic drugs is to ensure optimal efficacy with minimal The starting dose of aminoglycosides is traditionally calculated cumulative toxicity. Guidance on how to prescribe aminoglyco- from body surface area (60–75 mg/m 2 /dose) (8), body weight sides effectively and minimize the risks of developing toxicity is (3.3–5 mg/kg/dose) (9), or from past records of doses that needed. achieved therapeutic levels. In our practice, the maximum total There remains controversy surrounding the prevalence, im- daily dose prescribed is 660 mg in three divided doses. Although portance, and the role of surveillance of aminoglycoside-induced these clinician-led techniques require only simple calculations,
Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure.
Authors: D J Beuckelmann, M Näbauer, E Erdmann
Journal: Circulation Research (1993)

Prolongation of the action potential has been postulated to be a major reason for the altered diastolic relaxation of the heart in patients with severe heart failure. To investigate the electrophysiological basis for this action potential prolongation in terminal heart failure, K+ currents were recorded in single ventricular myocytes isolated from 16 explanted hearts of patients undergoing transplantation. Results from diseased hearts were compared with ventricular cells isolated from six undiseased donor hearts. Action potential duration was significantly prolonged in cells from patients with heart failure. A delayed rectifier K+ current was hardly detectable in most cells, and if it could be recorded, it was very small in both diseased and undiseased cells. When currents were normalized for cell surface area, the average current density of the inward rectifier K+ current was significantly reduced in diseased cells when compared with normal control cells (hyperpolarization at -100 mV, -15.9 +/- 2.2 vs -9.0 +/- 1.2 microA/cm2; P &lt; .01). In addition, a large transient outward K+ current could be recorded in human myocytes. The average current density of the time-dependent component of this transient outward K+ current was significantly reduced in heart failure (depolarization at +40 mV, 9.1 +/- 1.0 vs 5.8 +/- 0.64 microA/cm2; P &lt; .01). Action potential prolongation in severe heart failure may partially be explained by a reduction in current densities of the inward rectifier K+ current and of the transient outward K+ current. These alterations may thereby have a significant effect on cardiac relaxation.
Pharmacogenomics — Drug Disposition, Drug Targets, and Side Effects
Authors: William E. Evans, Howard L. McLeod
Journal: New England Journal of Medicine (2003)

It is well recognized that different patients respond in different ways to the same medication. These differences are often greater among members of a population than they are within the same person at different times (or between monozygotic twins).1 The existence of large population differences with small intrapatient variability is consistent with inheritance as a determinant of drug response; it is estimated that genetics can account for 20 to 95 percent of variability in drug disposition and effects.2 Although many nongenetic factors influence the effects of medications, including age, organ function, concomitant therapy, drug interactions, and the nature of the . . .
Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib
Authors: Melissa G. Ooi, Patrick J. Hayden, Vassiliki Kotoula, Douglas W. McMillin, Elpida Charalambous, Emily Daskalaki, Noopur S. Raje, Nikhil C. Munshi, Dharminder Chauhan, Teru Hideshima, Leutz Buon, Martin Clynes, Peter O'Gorman, Paul G. Richardson, Constantine S. Mitsiades, Kenneth C. Anderson, Nicholas Mitsiades
Journal: Clinical Cancer Research (2009)

p53 is inactivated in many human malignancies through missense mutations or overexpression of the human homologue of Mdm2 (Hdm2), an E3 ubiquitin ligase that ubiquitinates p53, thereby promoting its proteasomal degradation. The cis-imidazoline nutlin-3 can disrupt the p53-Hdm2 interaction and activate p53, inducing apoptosis in vitro in many malignancies, including multiple myeloma (MM).We hypothesized that suppression of Hdm2-mediated p53 ubiquitination may augment sequelae of p53 accumulation caused by proteasomal inhibition. We compared the response of MM cells versus several epithelial cancer models to the proteasome inhibitor bortezomib in combination with nutlin-3.The combination of sublethal concentrations of bortezomib plus nutlin-3 induced additive cytotoxicity against bortezomib-sensitive MM cell lines. Importantly, however, in breast, prostate, colon, and thyroid (papillary, follicular, anaplastic, and medullary) carcinoma cell lines, this combination triggered synergistic cytotoxicity, and increased expression of p53, p21, Hdm2, Bax, Noxa, PUMA, and cleavage of caspase-3 and poly ADP ribose polymerase. Coculture with bone marrow stromal cells attenuated MM cell sensitivity to nutlin-3 monotherapy and was associated with evidence of suppression of p53 activity in MM cells, whereas combined bortezomib-nutlin-3 treatment maintained cytotoxicity even in the presence of bone marrow stromal cells.This differential response of MM versus epithelial carcinomas to combination of nutlin-3 with bortezomib sheds new light on the role of p53 in bortezomib-induced apoptosis. Concurrent Hdm2 inhibition with bortezomib may extend the spectrum of bortezomib applications to malignancies with currently limited sensitivity to single-agent bortezomib or, in the future, to MM patients with decreased clinical responsiveness to bortezomib-based therapy.
Ischemic Preconditioning in Humans
Authors: Fabrizio Tomai, Filippo Crea, Luigi Chiariello, Pier A. Gioffrè
Journal: Circulation (1999)

Abstract —Ischemic preconditioning, a powerful form of endogenous protection against myocardial infarction, has been demonstrated in several animal species and, recently, in isolated human cardiomyocytes. For both logistic and ethical reasons, no clinical study can meet the strict conditions of experimental studies on preconditioning with infarct size as the end-point. Nevertheless, the demonstration of adaptation to ischemia observed during in vitro studies on human atrial trabeculae, in patients in the setting of coronary bypass surgery, and in the setting of coronary angioplasty in the absence of collateral vessel recruitment strongly suggests that ischemic preconditioning occurs in humans. This notion is further supported by the observation that in these human models, the adaptation to ischemia is influenced by drugs acting on K ATP channels and on purinergic and α-adrenergic receptors, similar to what is observed in accepted experimental models of ischemic preconditioning. This important form of myocardial endogenous protection may also play a role in the warm-up phenomenon and in mediating the beneficial effects of preinfarction angina. The demonstration of ischemic preconditioning in humans and the identification of some of its mediators suggests that in patients at high risk for myocardial infarction, drugs known to block this endogenous form of protection should be used with caution, whereas drugs known to elicit preconditioning might have a relevant therapeutic role.
Bioluminescence Imaging of Stem Cell-Based Therapeutics for Vascular Regeneration
Authors: Ngan F. Huang, Janet Okogbaa, Anna Babakhanyan, John P. Cooke
Journal: Theranostics (2012)

Stem cell-based therapeutics show promise for treatment of vascular diseases.However, the survival of the cells after in vivo injection into diseased tissues remains a concern.In the advent of non-invasive optical imaging techniques such as bioluminescence imaging (BLI), cell localization and survival can be easily monitored over time.This approach has recently been applied towards monitoring stem cell treatments for vascular regeneration of the coronary or peripheral arteries.In this review, we will describe the application of BLI for tracking transplanted stem cells and associating their viability with therapeutic efficacy, in preclinical disease models of vascular disease.
Mary Maude Tudor
Authors: E. C. G. T. J. G. T. R. G. Tudor
Journal: BMJ (2015)

Mary Maude Tudor (“Mollie”) was encouraged to become a doctor by one of her teachers. She never regretted her decision and was immensely proud that two of her brothers, two sons, and one grandchild followed in her footsteps. Immediately after graduating she came to Birmingham, working initially at …
Detection and quantification of mammaglobin in the blood of breast cancer patients: can it be useful as a potential clinical marker? Preliminary results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study
Authors: G Gargano, V Agnese, V Calò, S Corsale, C Augello, L Bruno, L La Paglia, A Gullo, L Ottini, A Russo, F Fulfaro, G Rinaldi, A Crosta, G Cicero, O Majorana, L Palmeri, C Cipolla, A Agrusa, G Gulotta, V Morello, G Di Fede, V Adamo, G Colucci, R M Tomasino, M R Valerio, V Bazan, Antonio Russo
Journal: Annals of Oncology (2006)
Development of a National Guideline for the Diagnosis of Cow's Milk Allergy (CMA) in The Netherlands
Authors: B.J. Vlieg-Boerstra, C. Wensing, Y. Meijer, T. Kuijpers, H. Silvius, M. Luning, E. de Vries, T. Hendriks, C.M.F. Kneepkens, A.B. Sprikkelman
Journal: Journal of Allergy and Clinical Immunology (2012)
Distinct regulatory mechanism of immunoglobulin gene transcription in epithelial cancer cells
Authors: Xiaohui Zhu, Lina Wu, Li Zhang, Peng Hao, Shuai Zhang, Jing Huang, Jie Zheng, Yinan Liu, Wenjun Li, Yingmei Zhang, Chunyan Zhou, Youhui Zhang, C Cameron Yin, Xiaoyan Qiu
Journal: Cellular and Molecular Immunology (2010)
Is the “3 by 5” Initiative the Best Approach to Tackling the HIV Pandemic?
Authors: Jim Yong Kim, Arthur Ammann
Journal: PLoS Medicine (2004)

The World Health Organization (WHO) and its partners aim to treat 3 million people infected with HIV in poor and middle income countries with antiretroviral treatment by the end of 2005. The ambitious "3 by 5" initiative has had its supporters and its critics since its announcement in 2002.
Subchondral bone attrition may be a reflection of compartment-specific mechanical load: the MOST Study
Authors: T. Neogi, M. Nevitt, J. Niu, L. Sharma, F. Roemer, A. Guermazi, C. E. Lewis, J. Torner, K. Javaid, D. Felson
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Introduction</h3> Subchondral bone attrition (SBA), a feature of osteoarthritis, may be caused by excess focal load to bone, and/or inadequate bone quality to withstand loads through the joint. This study evaluated the effects of malalignment, which can cause focal excessive load, and systemic bone density on the presence and incidence of SBA. <h3>Methods</h3> The Multicenter Osteoarthritis Study is a cohort of individuals who have or are at high risk of knee osteoarthritis. Baseline alignment and bone mineral density (BMD) measures were assessed. Baseline and 30-month knee magnetic resonance images were graded for SBA (grade 0–3) using the whole-organ magnetic resonance imaging score. The study evaluated the association of alignment in medial and lateral compartments, respectively, and systemic BMD with baseline presence of SBA and incident SBA using logistic regression and adjusting for age, sex and body mass index. <h3>Results</h3> Of 1253 participants (mean age 62 years, mean BMI 30, 61% women), 33% had baseline SBA and 44% had knee osteoarthritis. Associations between the presence and incidence of SBA with malalignment in both compartments were noted (odds ratios (95% CI) 2.9 (2.1 to 4.0) and 1.9 (1.2 to 2.9), respectively, for varus knees in the medial compartment; 4.5 (2.8 to 7.1) and 2.1 (1.1 to 4.1), respectively, for valgus knees in the lateral compartment). Low BMD was not associated with SBA. <h3>Conclusions</h3> The presence and incidence of SBA are associated with malalignment in a compartment-specific manner, but not with low BMD. SBA may be a marker of increased load experienced by overlying cartilage, which may contribute to increased forces transmitted to the cartilage due to alteration in subchondral bone.
Evidence for direct linkage between antigen recognition and lytic expression in effector T cells.
Authors: R C Kuppers, C S Henney
Journal: The Journal of Experimental Medicine (1976)

The relationship between antigen recognition and lytic expression by effector T cells was examined by coculturing two cytolytically active lymphoid cell populations. When antigen recognition between the populations could occur only in one direction, then cytotoxicity was expressed only in that direction and the population whose antigens were recognized lost its lytic activity. In contrast, the cocultured effector cell population fully maintained its lytic potential. This lack of reciprocal inactivation was taken as evidence that T-cell receptor accomodation by surface antigen is linked to the expression of cytolytic activity by effector T lymphocytes.
K<sub>ATP</sub> channel openers: Structure‐activity relationships and therapeutic potential
Authors: Raimund Mannhold
Journal: Medicinal Research Reviews (2003)

Abstract ATP‐sensitive potassium channels (K ATP channels) are heteromeric complexes of pore‐forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. K ATP channels were identified in a variety of tissues including muscle cells, pancreatic β‐cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, K ATP channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via K ATP channels. Given their many physiological functions, K ATP channels represent promising drug targets. Sulfonylureas like glibenclamide block K ATP channels; they are used in the therapy of type 2 diabetes. Openers of K ATP channels (KCOs), for example, relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines, and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols. © 2003 Wiley Periodicals, Inc. Med Res Rev, 24, No. 2, 213–266, 2004
Peer Deviance, Parental Divorce, and Genetic Risk in the Prediction of Drug Abuse in a Nationwide Swedish Sample
Authors: Kenneth S. Kendler, Henrik Ohlsson, Kristina Sundquist, Jan Sundquist
Journal: JAMA Psychiatry (2014)

<h3>Importance</h3> Peer deviance (PD) strongly predicts externalizing psychopathologic conditions but has not been previously assessable in population cohorts. We sought to develop such an index of PD and to clarify its effects on risk of drug abuse (DA). <h3>Objectives</h3> To examine how strongly PD increases the risk of DA and whether this community-level liability indicator interacts with key DA risk factors at the individual and family levels. <h3>Design, Setting, and Participants</h3> Studies of future DA registration in 1 401 698 Swedish probands born from January 1, 1970, through December 31, 1985, and their adolescent peers in approximately 9200 small community areas.<i>Peer deviance </i>was defined as the proportion of individuals born within 5 years of the proband living in the same small community when the proband was 15 years old who eventually were registered for DA. <h3>Main Outcomes and Measures</h3> Drug abuse recorded in medical, legal, or pharmacy registry records. <h3>Results</h3> Peer deviance was associated with future DA in the proband, with rates of DA in older and male peers more strongly predictive than in younger or female peers. The predictive power of PD was only slightly attenuated by adding measures of community deprivation, collective efficacy, or family socioeconomic status. Probands whose parents were divorced were more sensitive to the pathogenic effects of high PD environments. A robust positive interaction was also seen between genetic risk of DA (indexed by rates of DA in first-, second-, and third-degree relatives) and PD exposure. <h3>Conclusions and Relevance</h3> With sufficient data, PD can be measured in populations and strongly predicts DA. In a nationwide sample, risk factors at the level of the individual (genetic vulnerability), family (parental loss), and community (PD) contribute substantially to risk of DA. Individuals at elevated DA risk because of parental divorce or high genetic liability are more sensitive to the pathogenic effects of PD. Although the effect of our PD measure on DA liability cannot be explained by standard measures of community or family risk, we cannot, with available data, discriminate definitively between the effect of true peer effects and other unmeasured risk factors.