tbuckley/cabot-search huggingface dataset:
In Vitro Fertilization with Preimplantation Genetic Screening
Authors: Sebastiaan Mastenbroek, Moniek Twisk, Jannie van Echten-Arends, Birgit Sikkema-Raddatz, Johanna C. Korevaar, Harold R. Verhoeve, Niels E.A. Vogel, Eus G.J.M. Arts, Jan W.A. de Vries, Patrick M. Bossuyt, Charles H.C.M. Buys, Maas Jan Heineman, Sjoerd Repping, Fulco van der Veen
Journal: New England Journal of Medicine (2007)

Pregnancy rates in women of advanced maternal age undergoing in vitro fertilization (IVF) are disappointingly low. It has been suggested that the use of preimplantation genetic screening of cleavage-stage embryos for aneuploidies may improve the effectiveness of IVF in these women.We conducted a multicenter, randomized, double-blind, controlled trial comparing three cycles of IVF with and without preimplantation genetic screening in women 35 through 41 years of age. The primary outcome measure was ongoing pregnancy at 12 weeks of gestation. The secondary outcome measures were biochemical pregnancy, clinical pregnancy, miscarriage, and live birth.Four hundred eight women (206 assigned to preimplantation genetic screening and 202 assigned to the control group) underwent 836 cycles of IVF (434 cycles with and 402 cycles without preimplantation genetic screening). The ongoing-pregnancy rate was significantly lower in the women assigned to preimplantation genetic screening (52 of 206 women [25%]) than in those not assigned to preimplantation genetic screening (74 of 202 women [37%]; rate ratio, 0.69; 95% confidence interval [CI], 0.51 to 0.93). The women assigned to preimplantation genetic screening also had a significantly lower live-birth rate (49 of 206 women [24%] vs. 71 of 202 women [35%]; rate ratio, 0.68; 95% CI, 0.50 to 0.92).Preimplantation genetic screening did not increase but instead significantly reduced the rates of ongoing pregnancies and live births after IVF in women of advanced maternal age. (Current Controlled Trials number, ISRCTN76355836 [controlled-trials.com].).
EpCAM overexpression prolongs proliferative capacity of primary human breast epithelial cells and supports hyperplastic growth
Authors: Agnieszka Martowicz, Johannes Rainer, Julien Lelong, Gilbert Spizzo, Guenther Gastl, Gerold Untergasser
Journal: Molecular Cancer (2013)

The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. However, effects of EpCAM overexpression on normal breast epithelial cells have never been studied before. Therefore, we analyzed effects of transient adenoviral overexpression of EpCAM on proliferation, migration and differentiation of primary human mammary epithelial cells (HMECs).HMECs were transfected by an adenoviral system for transient overexpression of EpCAM. Thereafter, changes in cell proliferation and migration were studied using a real time measurement system. Target gene expression was evaluated by transcriptome analysis in proliferating and polarized HMEC cultures. A Chicken Chorioallantoic Membrane (CAM) xenograft model was used to study effects on in vivo growth of HMECs.EpCAM overexpression in HMECs did not significantly alter gene expression profile of proliferating or growth arrested cells. Proliferating HMECs displayed predominantly glycosylated EpCAM isoforms and were inhibited in cell proliferation and migration by upregulation of p27(KIP1) and p53. HMECs with overexpression of EpCAM showed a down regulation of E-cadherin. Moreover, cells were more resistant to TGF-β1 induced growth arrest and maintained longer capacities to proliferate in vitro. EpCAM overexpressing HMECs xenografts in chicken embryos showed hyperplastic growth, lack of lumen formation and increased infiltrates of the chicken leukocytes.EpCAM revealed oncogenic features in normal human breast cells by inducing resistance to TGF-β1-mediated growth arrest and supporting a cell phenotype with longer proliferative capacities in vitro. EpCAM overexpression resulted in hyperplastic growth in vivo. Thus, we suggest that EpCAM acts as a prosurvival factor counteracting terminal differentiation processes in normal mammary glands.
In vitro electrical activity in canine colon.
Authors: N L Shearin, K L Bowes, Y J Kingma
Journal: Gut (1979)

In vitro slow wave activity was studied in strips of right and left canine colon with silver/silver chloride electrodes. Using visual and computer analysis, slow wave frequency and coupling was assessed between different recording sites and the effect of a cholinergic agonist on coupling and frequency was determined. A regular slow wave was always found to be present. Frequency in the left colon was slightly higher than in the right with a slight decline noted with time. Spike activity was rarely seen in unstimulated specimens. Administration of a cholinergic agonist produced a decrease in frequency with no improvement in coupling. Coupling was usually better in a circular than in a longitudinal direction. It was concluded that if electrical activity is important in the control of colon contractions, it is more likely to be involved in the control of segmentation than in propagated contractions.
Evaluating cap-assisted colonoscopy: the relevance of study design
Authors: David A Westwood, Nicholas Alexakis, Saxon J Connor
Journal: Gut (2012)

Article abstract-The 50-kd dystrophin-associated glycoprotein (50DAG or adhalin) in the skeletal muscle has been shown to be deficient in patients with severe childhood autosomal recessive muscular dystrophy prevalent in North Africa. To elucidate the frequency of patients having the 50DAG deficiency in a muscular dystrophy population in Japan, we immunocytochemically examined 50DAG, 43DAG, dystrophin, and utrophin. A total of 243 patients with muscular dystrophy, among 1,035 diagnostic muscle biopsies during the past 2.5 years, were analyzed. We identified five unrelated patients (three females and two males who have no family history) with 50DAG deficiency in the sarcolemma. Thus, 2.1% (5/243) of our muscular dystrophy patient population had 50DAG deficiency. <b>NEUROLOGY 1995;45: </b> 551-554
Abnormalities of fatty acid metabolism in CF
Authors: S Bailey
Journal: Thorax (2004)

▴ Freedman SD, Blanco PG, Zaman MM, et al . Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med2004;350:560–9 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] This study found low tissue levels of the fatty acid docosahexaenoic acid (DA) and a raised ratio of arachidonic acid (AA) to DA in patients with cystic fibrosis (CF) compared with healthy controls in nasal and rectal biopsy specimens (p<0.001 and p = 0.009 for the ratios, respectively). In cells from … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DFreedman%26rft.auinit1%253DS.%2BD.%26rft.volume%253D350%26rft.issue%253D6%26rft.spage%253D560%26rft.epage%253D569%26rft.atitle%253DAssociation%2Bof%2BCystic%2BFibrosis%2Bwith%2BAbnormalities%2Bin%2BFatty%2BAcid%2BMetabolism%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa021218%26rft_id%253Dinfo%253Apmid%252F14762183%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa021218&link_type=DOI [3]: /lookup/external-ref?access_num=14762183&link_type=MED&atom=%2Fthoraxjnl%2F59%2F5%2F380.atom [4]: /lookup/external-ref?access_num=000188712800007&link_type=ISI
Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation
Authors: Shimobi C. Onuoha, Mathieu Ferrari, Daniele Sblattero, Costantino Pitzalis
Journal: Arthritis & Rheumatology (2015)

Biologic drugs, such as the anti-tumor necrosis factor (anti-TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies. Activatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM-1), which is up-regulated at sites of inflammation, and anti-TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM-1 and an internal arm that comprises the therapeutic domain of an anti-TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)-cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets. Intact aDVD constructs demonstrated significantly reduced binding and anti-TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti-TNF inhibitory capacities as the parent molecules. The design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off-target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of RA and other inflammatory diseases.
Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite
Authors: Gary D. Lopaschuk, John R. Ussher, Jagdip S. Jaswal
Journal: Pharmacological Reviews (2010)

The central nervous system mediates energy balance (energy intake and energy expenditure) in the body; the hypothalamus has a key role in this process. Recent evidence has demonstrated an important role for hypothalamic malonyl CoA in mediating energy balance. Malonyl CoA is generated by the carboxylation of acetyl CoA by acetyl CoA carboxylase and is then either incorporated into long-chain fatty acids by fatty acid synthase, or converted back to acetyl-CoA by malonyl CoA decarboxylase. Increased hypothalamic malonyl CoA is an indicator of energy surplus, resulting in a decrease in food intake and an increase in energy expenditure. In contrast, a decrease in hypothalamic malonyl CoA signals an energy deficit, resulting in an increased appetite and a decrease in body energy expenditure. A number of hormonal and neural orexigenic and anorexigenic signaling pathways have now been shown to be associated with changes in malonyl CoA levels in the arcuate nucleus (ARC) of the hypothalamus. Despite compelling evidence that malonyl CoA is an important mediator in the hypothalamic ARC control of food intake and regulation of energy balance, the mechanism(s) by which this occurs has not been established. Malonyl CoA inhibits carnitine palmitoyltransferase-1 (CPT-1), and it has been proposed that the substrate of CPT-1, long-chain acyl CoA(s), may act as a mediator(s) of appetite and energy balance. However, recent evidence has challenged the role of long-chain acyl CoA(s) in this process, as well as the involvement of CPT-1 in hypothalamic malonyl CoA signaling. A better understanding of how malonyl CoA regulates energy balance should provide novel approaches to targeting intermediary metabolism in the hypothalamus as a mechanism to control appetite and body weight. Here, we review the data supporting an important role for malonyl CoA in mediating hypothalamic control of energy balance, and recent evidence suggesting that targeting malonyl CoA synthesis or degradation may be a novel approach to favorably modify appetite and weight gain.
Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
Authors: C. J. Bossley, S. Saglani, C. Kavanagh, D. N. R. Payne, N. Wilson, L. Tsartsali, M. Rosenthal, I. M. Balfour-Lynn, A. G. Nicholson, A. Bush
Journal: European Respiratory Journal (2009)

This study describes the clinical characteristics and corticosteroid responsiveness of children with difficult asthma (DA). We hypothesised that complete corticosteroid responsiveness (defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction ( F eNO ) and no bronchodilator responsiveness (BDR &lt;12%)) is uncommon in paediatric DA. We report on 102 children, mean± sd age 11.6±2.8 yrs, with DA in a cross-sectional study. 89 children underwent spirometry, BDR and F eNO before and after 2 weeks of systemic corticosteroids (corticosteroid response study). Bronchoscopy was performed after the corticosteroid trial. Of the 102 patients in the cross-sectional study, 88 (86%) were atopic, 60 (59%) were male and 52 (51%) had additional or alternative diagnoses. Out of the 81 patients in the corticosteroid response study, nine (11%) were complete responders. Of the 75 patients with symptom data available, 37 (49%) responded symptomatically, which was less likely if there were smokers in the home (OR 0.31, 95% CI 0.02–0.82). Of the 75 patients with available spirometry data, 35 (46%) had normal spirometry, with associations being BAL eosinophilia (OR 5.43, 95% CI 1.13–26.07) and high baseline forced expiratory volume in 1 s (FEV 1 ) (OR 1.08, 95% CI 1.02–1.12). Of these 75 patients, BDR data were available in 64, of whom 36 (56%) had &lt;12% BDR. F eNO data was available in 70 patients, of whom 53 (75%) had normal F eNO . Airflow limitation data was available in 75 patients, of whom 17 (26%) had persistent airflow limitation, which was associated with low baseline FEV 1 (OR 0.93, 95% CI 0.90–0.97). Only 11% of DA children exhibited complete corticosteroid responsiveness. The rarity of complete corticosteroid responsiveness suggests alternative therapies are needed for children with DA.
Viral genes involved in leukemogenesis. I. Generation of recombinants between oncogenic and nononcogenic mouse type-C viruses in tissue culture.
Authors: S A Aaronson, M Barbacid
Journal: The Journal of Experimental Medicine (1980)

An approach toward elucidation of the mechanisms of action of mammalian leukemia viruses has been made by the generation in tissue culture of recombinant viruses between a potent murine leukemia virus (MuLV), Rauscher-MuLV, and an endogenous xenotropic mouse type-C virus, BALB:virus-2, without known malignant potential. Using a double selection system devised to select against the temperature-sensitive (ts) lesion associated with a mutant of Rauscher-MuLV and the xenotropic host range of BALB:virus-2, recombinant viruses were obtained at frequencies ranging from 0.01 to 0.1%. Recombinant viruses were identified on the basis of the type specific antigenic determinants in the translational products of gag (p15, p12, p30, and p10 proteins), pol (reverse transcriptase), and env (gp70 glycoprotein) genes. By this approach, the partial genetic maps of a large number of recombinants were obtained. The fact that p10 of Rauscher-MuLV ts 25, the mutant utilized, was the only protein uniformly lacking in recombinant viruses, localized the lesion inhibiting gag precursor cleavage in this mutant at the carboxy terminus of its gag gene. The recombinant viruses demonstrated two host range phenotypes as defined by Fv-1 host cell restriction. In each case, NB-tropic recombinants possessed the p30 of BALB:virus-2 p30. Thus, it was possible to assign the site of Fv-1 action at, or closely linked, to the viral p30. The target within the viral genome of a second host restriction was also mapped. A serum factor, previously shown to specifically inactivate xenotropic virus infectivity, was demonstrated to exert its action on the viral env gene product. The system described here allows the generation of specific recombinant genotypes that should be useful in defining those regions of the viral genome involved in leukemogenesis.
Skin lesions as the only manifestation of the hypereosinophilic syndrome
Authors: M. Barna, L. Kemény, A. Dobozy
Journal: British Journal of Dermatology (1997)

Journal Article Skin lesions as the only manifestation of the hypereosinophilic syndrome Get access M. Barna, M. Barna Department of Dermatology, Albert Szent‐Györgyi Medical University, H‐6701 Szeged, PO Box 480, Hungary Search for other works by this author on: Oxford Academic Google Scholar L. Kemény, L. Kemény Department of Dermatology, Albert Szent‐Györgyi Medical University, H‐6701 Szeged, PO Box 480, Hungary Search for other works by this author on: Oxford Academic Google Scholar A. Dobozy A. Dobozy Department of Dermatology, Albert Szent‐Györgyi Medical University, H‐6701 Szeged, PO Box 480, Hungary Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 136, Issue 4, 1 April 1997, Pages 646–647, https://doi.org/10.1111/j.1365-2133.1997.tb02176.x Published: 01 April 1997
Parkinsonism, L-Dopa and Intelligence
Authors: ARMAND W. LORANGER, HELEN GOODELL, FLETCHER H. MCDOWELL, JOHN E. LEE, RICHARD D. SWEET
Journal: American Journal of Psychiatry (1973)

Although many patients with parkinsonism undergo a significant amount of intellectual impairment, several investigators, including the authors, have observed an improvement in intellectual functioning during the first year of treatment with L-dopa. Upon reexamining subjects after 30 months of treatment, however, the authors found that most of their patients did not maintain this improvement. The reasons for the decline are not yet clear, but probably involve the waning influence of L-dopa, the onset or progression of the intellectual impairment common to parkinsonism and the normal aging process, and the impact of other physical illnesses.
Effect of home-based hand exercises in women with hand osteoarthritis: a randomised controlled trial
Authors: Toril Hennig, Liv Hæhre, Vivian Tryving Hornburg, Petter Mowinckel, Ellen Sauar Norli, Ingvild Kjeken
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Hand exercises are recommended for patients with hand osteoarthritis (HOA), though evidence for their effect is conflicting. <h3>Objective</h3> To evaluate, in a randomised controlled trial, the effect of HOA information plus home-based hand exercises (exercise group) compared with information only (control group) in women with HOA. <h3>Methods</h3> Interventions were delivered by two occupational therapists. Exercise group participants received eight follow-up calls over the 3-month study and recorded adherence, pain after exercises and adverse events in a diary. Primary outcome was activity performance measured after 3 months by the Patient-Specific Functional Scale (PSFS), with a range of 0–10. Secondary outcomes were measurements of hand function, disease activity, symptoms and number of responders to treatment according to the OMERACT-OARSI criteria. <h3>Results</h3> Of 80 women randomised (40 : 40) (mean age (SD) 60.8 years (7.0)), follow-up was 89% (n=71). An intention-to-treat analysis was performed. The adjusted mean difference for the exercise versus control group was 1.4 points (95% CI 0.6 to 2.2, effect size 1.0) for the PSFS score. Thirteen patients in the exercise group versus three participants in the control group reached a positive minimal clinical important difference of 2.2 points in the PSFS total score, while none versus two, respectively, had a negative change (p=0.007). For secondary outcomes, significant mean differences were found in grip strength and thumb web space, in fatigue, joint pain and the Functional Index for HOA activity performance scores. Sixteen exercise-group participants fulfilled the OMERACT-OARSI response criteria versus two control-group participants (p&lt;0.001). <h3>Conclusions</h3> Hand exercises were well tolerated and significantly improved activity performance, grip strength, pain and fatigue in women with HOA. <h3>Trial registration number:</h3> ISRTCN79019063.
Pharmacogenomic Identification of Targets for Adjuvant Therapy with the Topoisomerase Poison Camptothecin
Authors: Jonathan P. Carson, Nianyi Zhang, Garrett M. Frampton, Norman P. Gerry, Marc E. Lenburg, Michael F. Christman
Journal: Cancer Research (2004)

Abstract The response of tumor cells to the unusual form of DNA damage caused by topoisomerase poisons such as camptothecin (CPT) is poorly understood, and knowledge regarding which drugs can be effectively combined with CPT is lacking. To better understand the response of tumor cells to CPT and to identify potential targets for adjuvant therapy, we examined global changes in mRNA abundance in HeLa cells after CPT treatment using Affymetrix U133A GeneChips, which include all annotated human genes (22,283 probe sets). Statistical analysis of the data using a Bayesian/Cyber t test and a modified Benjamini and Hochberg correction for multiple hypotheses testing identified 188 probe sets that are induced and 495 that are repressed 8 h after CPT treatment at a False Discovery Rate of &amp;lt;0.05 and a minimum 3-fold change. This pharmacogenomic approach led us to identify two pathways that are CPT induced: (a) the epidermal growth factor receptor; and (b) nuclear factor-κB-regulated antiapoptotic factors. Experiments using HeLa cells in our lab and prior animal model studies performed elsewhere confirm that inhibitors of these respective pathways super-additively enhance CPT’s cytotoxicity, suggesting their potential as targets for adjuvant therapy with CPT.
Phase I Trial and Pharmacokinetic Study of the Farnesyltransferase Inhibitor Tipifarnib in Children With Refractory Solid Tumors or Neurofibromatosis Type I and Plexiform Neurofibromas
Authors: Brigitte C. Widemann, Wanda L. Salzer, Robert J. Arceci, Susan M. Blaney, Elizabeth Fox, David End, Andrea Gillespie, Patricia Whitcomb, Joseph S. Palumbo, Aaron Pitney, Nalini Jayaprakash, Peter Zannikos, Frank M. Balis
Journal: Journal of Clinical Oncology (2006)

Purpose This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1) –related plexiform neurofibromas. Patients and Methods Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m 2 /dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m 2 /dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation. Results Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m 2 /dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m 2 /dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m 2 /dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs. Conclusion Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m 2 /dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.