tbuckley/cabot-search huggingface dataset:
Targeted Epigenetic Therapies: The Next Frontier?
Authors: R. S. Tuma
Journal: JNCI Journal of the National Cancer Institute (2010)

W hen researchers look for mutations associated with cancer, they often expect to come up with alterations in signaling molecules or transcription factors. But an increasing number of the mutations found are in genes that regulate the epigenome — a system that alters DNA structure and regulates gene activity without changing the nucleotide sequence itself. On Sept. 8, investigators published two independent reports online — one in Science and one in the New England Journal of Medicine — showing that mutations in an epigenetic regulatory gene, ARID1a, were associated with approximately half of the ovarian clear-cell cancers tested. The two studies bolster the argument that epigenetics is important in tumor progression and possibly tumor formation, as well as that therapies targeted at specifi c epigenetic regulators or their effectors may improve patient outcomes. Although the approach’s viability remains unproven, many groups and companies are already working on molecularly targeted compounds designed to restore the epigenetic system.
CD24 Offers a Therapeutic Target for Control of Bladder Cancer Metastasis Based on a Requirement for Lung Colonization
Authors: Jonathan B. Overdevest, Shibu Thomas, Glen Kristiansen, Donna E. Hansel, Steven C. Smith, Dan Theodorescu
Journal: Cancer Research (2011)

Abstract Metastasis is lethal in most bladder cancer patients. Expression of CD24, a glycosyl phosphatidylinositol (GPI)-linked sialoglycoprotein and cancer stem cell marker, is associated with metastatic progression in multiple cancer types, yet the role of CD24 in this process remains unclear. While developing a murine model of human metastatic bladder cancer, we observed that tumor cell CD24 expression correlated with a propensity to metastasize to the lung. Our immunohistochemical evaluation of 60 paired primary and metastatic human bladder cancer samples revealed increased intensity (P &amp;lt; 0.001) and frequency (P &amp;lt; 0.001) of CD24 expression in metastases. To directly evaluate the role of CD24 in metastatic colonization, we manipulated CD24 expression in human bladder cancer cell lines using short hairpin RNA depletion, cDNA overexpression, and fluorescence-activated cell sorting selection. Although suppression of CD24 reduced acute tumor cell retention in the lungs of mice inoculated intravenously with cancer cells, this differential retention was no longer apparent after 24 hours, prompting us to evaluate the role of CD24 in lung colonization. Here, CD24 was found necessary for subsequent development of lung metastases. We next treated clinically detectable lung metastases in mice with anti-CD24 antibody and observed reduced tumor growth and prolonged survival. These findings suggest that CD24 is a lynchpin of metastatic progression and a promising therapeutic target for antimetastatic therapy. Cancer Res; 71(11); 3802–11. ©2011 AACR.
DNA Repair Defects in Stem Cell Function and Aging
Authors: Youngji Park, Stanton L. Gerson
Journal: Annual Review of Medicine (2004)

Cellular DNA is under constant challenge by exogenous and endogenous genotoxic stress, which results in both transient and accumulated DNA damage and genomic instability. All cells are equipped with DNA damage response pathways that trigger DNA repair, cell cycle arrest, and, if need be, apoptosis, to eliminate DNA damage or damaged cells. The consequences of these processes for stem cells can be profound: diminution in stem cell pools, or, because of altered gene expression, an increased chance for stem cell differentiation or malignant transformation. Furthermore, a number of DNA repair abnormalities are linked to premature aging syndromes, and these are associated with defects in the stem cell population. The specific DNA repair systems for which there are data regarding the impact of repair defects on stem cell function include O(6)-alkylguanine DNA alkyltransferase, nucleotide excision repair, base excision repair, mismatch repair, non-homologous DNA end-joining Fanconi's anemia protein complex, and homologous recombination. It has recently become clear that deficiencies of these processes are associated not only with cancer and/or aging but also with stem cell defects. This discovery raises the possibility of a link between aging and stem cell dysfunction. In this review, we provide evidence for a link between DNA repair systems and the maintenance and longevity of stem cells.
Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice
Authors: Yulia A. Nevzorova, Jörg-Martin Bangen, Wei Hu, Ute Haas, Ralf Weiskirchen, Nikolaus Gassler, Sebastian Huss, Frank Tacke, Piotr Sicinski, Christian Trautwein, Christian Liedtke
Journal: Hepatology (2012)

Liver fibrogenesis is associated with the transition of quiescent hepatocytes and hepatic stellate cells (HSCs) into the cell cycle. Exit from quiescence is controlled by E-type cyclins (cyclin E1 [CcnE1] and cyclin E2 [CcnE2]). Thus, the aim of the current study was to investigate the contribution of E-type cyclins for liver fibrosis in man and mice. Expression of CcnE1, but not of its homolog, CcnE2, was induced in fibrotic and cirrhotic livers from human patients with different etiologies and in murine wild-type (WT) livers after periodical administration of the profibrotic toxin, CCl4. To further evaluate the potential function of E-type cyclins for liver fibrogenesis, we repetitively treated constitutive CcnE1−/− and CcnE2−/− knock-out mice with CCl4 to induce liver fibrosis. Interestingly, CcnE1−/− mice were protected against CCl4-mediated liver fibrogenesis, as evidenced by reduced collagen type I α1 expression and the lack of septum formation. In contrast, CcnE2−/− mice showed accelerated fibrogenesis after CCl4 treatment. We isolated primary HSCs from WT, CcnE1−/−, and CcnE2−/− mice and analyzed their activation, proliferation, and survival in vitro . CcnE1 expression in WT HSCs was maximal when they started to proliferate, but decreased after the cells transdifferentiated into myofibroblasts. CcnE1−/− HSCs showed dramatically impaired survival, cell-cycle arrest, and strongly reduced expression of alpha smooth muscle actin, indicating deficient HSC activation. In contrast, CcnE2-deficient HSCs expressed an elevated level of CcnE1 and showed enhanced cell-cycle activity and proliferation, compared to WT cells. Conclusions : CcnE1 and CcnE2 have antagonistic roles in liver fibrosis. CcnE1 is indispensable for the activation, proliferation, and survival of HSCs and thus promotes the synthesis of extracellular matrix and liver fibrogenesis.
Type 2 Diabetes in Asian-Indian Urban Children
Authors: Ambady Ramachandran, Chamukuttan Snehalatha, Kumpatla Satyavani, Selvaraj Sivasankari, Viswanathan Vijay
Journal: Diabetes Care (2003)

Due to a background of high prevalence of type 2 diabetes and the increasing rate of obesity occurring in relatively young urban children, we felt the need to look for type 2 diabetes in children.A study of cases of type 2 diabetes with age at diagnosis of </=15 years seen at a diabetes speciality center in Chennai, India, is reported. A total of 18 children (5 boys and 13 girls) aged 9-15 years with insidious onset of diabetes responding to oral antidiabetic agents (ODAs) for periods from 2 months to 12 years were studied. Clinical details, anthropometry, and details of family history of diabetes were elicited. All of them were tested for the presence of anti-GAD(65) antibodies and for pancreatic beta-cell reserve by measuring serum C-peptide response (radioimmunoassay procedures).All children showed a response to ODAs, had good beta-cell reserve (>/=0.6 pmol/ml on stimulation), and negligible GAD(65) antibodies indicating the presence of type 2 diabetes. The children were nonketotic; nine were obese, four had acanthosis nigricans, and one had polycystic ovary syndrome. Positive family history of diabetes was present in all cases.The clinical, immunological, and biochemical profile showed that the children had type 2 diabetes. The profile of type 2 diabetes was similar to that described in children in many other countries. Although less common than type 1 diabetes, type 2 diabetes in children is a condition that needs to be recognized and looked for in Asian-Indians.
Prodromal trigeminal sensory neuropathy in progressive systemic sclerosis.
Authors: P Beighton, J M Gumpel, N G Cornes
Journal: Annals of the Rheumatic Diseases (1968)

Neurological disturbance occurring inprogressive systemic sclerosis (PSS)israreandwhenseen usually takes theformofconvulsions associated withhypertension andrenalfailure. Peripheral nerve lesions, suchasareseeninother connective tissue disorders, especially inrheumatoid disease and polyarteritis nodosa, areextremely uncommon. Isolated cranial nerve lesions donotappear tohave beenrecorded inPSSandwereport this casewhich presented withbilateral sensory trigeminal neuropathy. CaseReport A66-year-old white female wasreferred totheNeurological Clinic atSt.Thomas' Hospital inOctober, 1966, forinvestigation ofsensory changes onbothsides ofthe face, notedsometimeafter anuneventful cholecystectomyforgallstones earlier intheyear.Shewasfound tohaveblunting ofsensation topin-prick overanarea corresponding tothesecond divisions ofbothtrigeminal nerves. Thecorneal reflexes wereintact, andnoother abnormality wasnoted. Overtheensuing months, there wasaprogressive loss ofappreciation ofallmodalities ofsensation intheareas ofallthree divisions ofthetrigeminal nerve onbothsides oftheface.Atthesametimeshebecame conscious of agritty sensation inthemucousmembranes ofthecheeks andgums.Therewasno lackofsalivation. Concurrently, shedescribed theonsetofRaynaud's phenomenoninthehandsandfeet, apolyarthritis involving elbows, wrists, andproximal interphalangeal joints of thehands, weight lossof5stone, andgeneral muscle weakness mostmarkedintheneckandshoulder girdle. During this period, theskinofthechest, forearms, and handsbecame thickened andstiff, andshealsodeveloped severe dysphagia andsomedegree ofconstipation. InApril, 1967, shewasadmitted totheLambeth Hospital.
The deoxyribonucleoside phosphotransferase of Trichomonas vaginalis. A potential target for anti-trichomonial chemotherapy.
Authors: C C Wang, H W Cheng
Journal: The Journal of Experimental Medicine (1984)

Trichomonas vaginalis, a human protozoan parasite known to lack the capability of synthesizing purine and pyrimidine nucleotides de novo, was found also incapable of converting its ribonucleotides to deoxyribonucleotides. The only apparent means of providing deoxyribonucleotides for DNA synthesis relies on salvaging exogenous deoxyribonucleosides by a deoxyribonucleoside phosphotransferase activity in the T. vaginalis 10(5) g pelletable fraction. The activity, constituted by at least two isozymes I and II, can be solubilized by Triton X-100, has a pH optimum of 5.0-6.0, and recognizes only thymidine, deoxyadenosine, deoxyguanosine, and deoxycytidine as the phosphate acceptor. TMP, dAMP, dGMP, dCMP, dUMP, FdUMP, and p-nitrophenylphosphate can serve as phosphate donors. Enzyme I has been purified 10-fold by DEAE-Sepharose chromatography and Sephacryl 200 filtration, and is totally freed of the acid phosphatase of T. vaginalis. It has an estimated molecular weight of 200,000 and Km values of 2-3 mM for the four deoxyribonucleosides, which act on each other as competitive inhibitors. It also possesses phosphatase activity capable of hydrolyzing p-nitrophenylphosphate with a Michaelis constant of 0.74 mM. The rates of hydrolysis are enhanced by thymidine, which suggests that the latter may be the preferred phosphate acceptor, and Enzyme I may be, thus, more a transferase than a phosphatase. This enzyme could be a potential target for antitrichomonial chemotherapy.
Verification of a canine model of transient exercise induced myocardial dysfunction: antianginal effects of flestolol, an ultra short acting adrenoceptor antagonist
Authors: G. Fischer, J. G Grohs, G. Raberger
Journal: Cardiovascular Research (1990)

STUDY OBJECTIVE - The aim of the study was to verify the reproducibility of a canine model of treadmill exercise induced regional myocardial dysfunction designed to mimic exertional angina pectoris in man. DESIGN - Dogs trained to run on a treadmill were chronically instrumented with a microtip manometer in the left ventricle, a hydraulic occluder around the circumflex branch of the left coronary artery, two pairs of crystals for sonomicrometry, and arterial and venous catheters. Experiments were started 10 d after surgery, when the animals were submitted to seven treadmill exercise cycles, each of 3 min, with a 7 min recovery period. Ischaemia was adjusted so as not to impair regional function at rest but to produce progressive dysfunction with increasing work load. Flestolol (1 microgram.kg-1.min-1) was infused intravenously during the third and fourth exercise cycle. SUBJECTS - Six mongrel dogs, 13.5-29.5 kg, were used. MEASUREMENTS and RESULTS - Flestolol caused a marked reduction in the exercise induced increase in left ventricular positive dP/dtmax, and minor reductions in heart rate and systolic blood pressure, resulting in a decrease in myocardial oxygen demand and an improvement in regional function in the circumflex area of the left coronary artery. The functional improvement was transient and disappeared entirely after termination of flestolol infusion. CONCLUSIONS - The results show that flestolol is beneficial in conditions of limited coronary reserve and exercise induced myocardial dysfunction. The fact that the extent of regional myocardial dysfunction was comparable before and after flestolol infusion confirms the stability and usefulness of this experimental model in the evaluation of antianginal drugs.
Phase II studies of nebulised Arikace in CF patients with<i>Pseudomonas aeruginosa</i>infection
Authors: J P Clancy, L Dupont, M W Konstan, J Billings, S Fustik, C H Goss, J Lymp, P Minic, A L Quittner, R C Rubenstein, K R Young, L Saiman, J L Burns, J R W Govan, B Ramsey, R Gupta
Journal: Thorax (2013)

<h3>Rationale</h3> Arikace is a liposomal amikacin preparation for aerosol delivery with potent <i>Pseudomonas aeruginosa</i> killing and prolonged lung deposition. <h3>Objectives</h3> To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with <i>P aeruginosa</i>. <h3>Methods</h3> 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV<sub>1</sub>)), <i>P aeruginosa</i> density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire—Revised (CFQ-R). <h3>Results</h3> The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV<sub>1</sub> was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs −0.032L±0.119; p=0.003) versus placebo. Sputum <i>P aeruginosa</i> density decreased &gt;1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV<sub>1</sub> improvements at days 14, 28 and 42 (p&lt;0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum <i>P aeruginosa</i> density (n=49). <h3>Conclusions</h3> Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with <i>P aeruginosa</i> infection.
A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation
Authors: R. Vos, B.M. Vanaudenaerde, S.E. Verleden, S.I. De Vleeschauwer, A. Willems-Widyastuti, D.E. Van Raemdonck, A. Schoonis, T.S. Nawrot, L.J. Dupont, G.M. Verleden
Journal: European Respiratory Journal (2010)

Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV 1 ) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS. A double-blind randomised controlled trial of azithromycin (n = 40) or placebo (n = 43), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005–2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV 1 , airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV 1 with open-label azithromycin. BOS occurred less in patients receiving azithromycin: 12.5 versus 44.2% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092–0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV 1 (p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) over time. Open-label azithromycin for BOS improved FEV 1 in 52.2% patients. No serious adverse events were noted. Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV 1 and reduces BOS 2 yrs after LTx.
Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma
Authors: Srikumar Sengupta, Johan A. den Boon, I-How Chen, Michael A. Newton, David B. Dahl, Meng Chen, Yu-Juen Cheng, William H. Westra, Chien-Jen Chen, Allan Hildesheim, Bill Sugden, Paul Ahlquist
Journal: Cancer Research (2006)

Abstract To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC. (Cancer Res 2006; 66(16): 7999-8006)
Flow Cytometric Assessment of Cellular Expression Levels of Granzyme A, Granzyme B, and Perforin Predicts Rejection in Kidney Allograft Recipients
Authors: M. Vasudev, B.S. Vasudev, S. Hariharan, S.A. Stanhope, D.W. Schauer Jr., J.M. Routes, W.J. Grossman
Journal: Journal of Allergy and Clinical Immunology (2009)
Utility of overnight pulse oximetry and heart rate variability analysis to screen for sleep-disordered breathing in chronic heart failure
Authors: Neil R Ward, Martin R Cowie, Stuart D Rosen, Vitor Roldao, Manuel De Villa, Theresa A McDonagh, Anita Simonds, Mary J Morrell
Journal: Thorax (2012)

<h3>Background</h3> Sleep-disordered breathing (SDB) is under diagnosed in chronic heart failure (CHF). Screening with simple monitors may increase detection of SDB in a cardiology setting. This study aimed to evaluate the accuracy of heart rate variability analysis and overnight pulse oximetry for diagnosis of SDB in patients with CHF. <h3>Methods</h3> 180 patients with CHF underwent simultaneous polysomnography, ambulatory electrocardiography and wrist-worn overnight pulse oximetry. SDB was defined as an apnoea-hypopnoea index ≥15/h. To identify SDB from the screening tests, the per cent very low frequency increment (%VLFI) component of heart rate variability was measured with a pre-specified cutoff ≥2.23%, and the 3% oxygen desaturation index was measured with a pre-specified cutoff &gt;7.5 desaturations/h. <h3>Results</h3> 173 patients with CHF had adequate sleep study data; SDB occurred in 77 (45%) patients. Heart rate variability was measurable in 78 (45%) patients with area under the %VLFI receiver operating characteristic curve of 0.50. At the ≥2.23% cutoff, %VLFI sensitivity was 58% and specificity was 48%. The 3% oxygen desaturation index was measurable in 171 (99%) patients with area under the curve of 0.92. At the pre-specified cutoff of &gt;7.5 desaturations/h, the 3% oxygen desaturation index had a sensitivity of 97%, specificity of 32%, negative likelihood ratio of 0.08 and positive likelihood ratio of 1.42. Diagnostic accuracy was increased using a cutoff of 12.5 desaturations/h, with sensitivity of 93% and specificity of 73%. <h3>Conclusions</h3> The high sensitivity and low negative likelihood ratio of the 3% oxygen desaturation index indicates that pulse oximetry would be of use as a simple screening test to rule out SDB in patients with CHF in a cardiology setting. The %VLFI component of heart rate variability is not suitable for detection of SDB in CHF.
World Epidemics and their Relationship as Cause and Effect to Social Conditions
Authors: G. M. Cullen
Journal: BMJ (1927)

MeDIcA JORPN 306 genic value is high, it is non-toxic, and has given very good results in many severe cases of local and metastatic comiiplicatiolls.l'olar Body lProdluction in Organisms other than the -(on ococcos.Althlouiglh perhliaps outside the quiestion unider review the followinig geiieral remarks may be of interest by way of conifirmation.Polar bodies, which we have been able to obtain in 33 per celnt. of all gonococcus strains-provided the necessary elemenits for their formation are present in the culture me(liliu and the physical conditions requiired for theit devel-opment are maintained-have also been found to develop in a certain percentage of strains of every oirganiisrmi investigated up to the present.For example, this (levelopment has been observed in strains of B. tubercutlosis (bovine), staphylococci, streptococci, pneumococci, Firiedlhinder's bacillus, B. coli, B. catarrhalis, B. crassus, B. inlfltenzae (Pfeiffer), B. septits, Hoffmanni's bacillus, B. xerosis, etc.In the case of the above, with the solitary exception of B. coli, a very large percentage of the strains show this development.In the case of the truie B. diphtheriae, this organism, as is well known, develops polar bodies on Loeffler's medium, and wvhen siubeultured upon nucleo- protein media show-s a remarkably increased prodluction of polar bodies.