tbuckley/cabot-search huggingface dataset:
Errors in genome annotation
Authors: Steven E. Brenner
Journal: Trends in Genetics (1999)

At the time that Watson and Crick proposed a structure for DNA, a visionary might have suggested that the complete genetic sequence of an organism would eventually be known. However, nobody could have realistically proposed that machines could automatically indicate gene functions. Yet precisely this has been achieved: with no laboratory experiments at all, the roles of most genes in several organisms have been reported.
Oral rehydration therapy: efficacy of sodium citrate equals to sodium bicarbonate for correction of acidosis in diarrhoea.
Authors: M R Islam, A R Samadi, S M Ahmed, P K Bardhan, A Ali
Journal: Gut (1984)

Forty patients with moderate degrees of dehydration and acidosis because of acute watery diarrhoea were successfully treated randomly with either WHO recommended oral rehydration solution containing 2.5 g sodium bicarbonate or an oral solution containing 2.94 g sodium citrate in place of sodium bicarbonate per litre of oral rehydration rehydration solution. Efficacies were compared by measuring oral fluid intake, stool and vomitus output, change in body weight, hydration status, and rate of correction of acidosis during a period of 48 hours. Seventy five per cent (21 cases) in the citrate group and 83% (19 cases) in the bicarbonate group were successfully rehydrated (p greater than 0.05). There were no significant differences in intake, output, gain in body weight, fall in haematocrit and plasma specific gravity, and correction of acidosis between the two groups of patients within 48 hours after initiation of therapy. The solution with sodium citrate base was as effective as WHO-oral rehydration solution for management of diarrhoea. This study shows the efficacy, safety, and acceptability of citrate containing oral rehydration solution for rehydration and correction of acidosis in diarrhoea.
Randomized Multicenter Phase II Trial of Two Different Schedules of Capecitabine Plus Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer
Authors: Werner Scheithauer, Gabriela V. Kornek, Markus Raderer, Birgit Schüll, Katharina Schmid, Erwin Kovats, Bruno Schneeweiss, Fritz Lang, Alfred Lenauer, Dieter Depisch
Journal: Journal of Clinical Oncology (2003)

Capecitabine and oxaliplatin, two new agents with potential synergistic activity, have demonstrated promising antitumor efficacy in advanced colorectal cancer (ACC). Preclinical and clinical evidence indicating that dose intensification of the oral fluorouracil prodrug might result in improved therapeutic results led us to the present randomized multicenter phase II study.Eighty-nine patients with bidimensionally measurable ACC previously untreated for metastatic disease were randomly allocated to receive oxaliplatin 130 mg/m(2) day 1 plus capecitabine 2,000 mg/m(2)/d days 1 to 14 every 3 weeks (arm A) or to receive oxaliplatin 85 mg/m(2) days 1 and 14 combined with capecitabine 3,500 mg/m(2) days 1 to 7 and 14 to 21 every 4 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months unless there was prior evidence of progression of disease.Patients allocated to the high-dose capecitabine combination arm B had a higher radiologically confirmed response rate (54.5% v 42.2%) and a significantly longer median progression-free survival time than those allocated to control arm A (10.5 v 6.0 months; P =.0013). Median overall survival times cannot be calculated for either treatment arm at this point. Despite a 34% higher dose intensity of capecitabine in arm B, there was no difference in hematologic toxicity between treatment arms (neutropenia/thrombocytopenia: 60%/43% in arm B v 56%/33% in arm A). Similarly, the incidence rate and degree of nonhematologic adverse events were comparable: The most commonly encountered symptoms (all grades, arm A and arm B) included nausea/emesis (A: 58%; B: 62%), diarrhea (A: 44%; B: 31%), peripheral sensory neuropathy (A: 80%; B: 83%), and fatigue (A: 40%; B: 50%).Results of this study indicate that both combination regimens are feasible, tolerable, and clinically active. The dose-intensified bimonthly capecitabine arm, however, seems to be more effective in increasing both response rate and progression-free survival time.
Cellular and molecular aspects of ovarian follicle ageing
Authors: Carla Tatone, Fernanda Amicarelli, Maria Cristina Carbone, Patrizia Monteleone, Donatella Caserta, Roberto Marci, Paolo Giovanni Artini, Paola Piomboni, Riccardo Focarelli
Journal: Human Reproduction Update (2008)

It is well established that age-related decline of the biological capacity of a woman to reproduce is primarily related to the poor developmental potential of her gametes. This renders female ageing the most significant determinant of success in IVF. Starting with a reference picture of the main molecular and cellular failures of aged oocytes, granulosa cells and follicular microenvironment, this review focuses on age-related biochemical mechanisms underlying these changes. According to the most relevant concept of ageing, age-associated malfuction results from physiological accumulation of irreparable damage to biomolecules as an unavoidable side effect of normal metabolism. More than a decade after the free radical theory of ovarian ageing, biological and clinical research supporting the involvement of oxidative injuries in follicle ageing is discussed. Looking for the aetiology of oxidative stress, we consider the effect of ageing on ovarian and follicular vascularization. Then, we propose a potential role of advanced glycation end-products known to be involved in the physiological ageing of most tissues and organs. We conclude that future investigation of age-related molecular damage in the different ovarian components will be imperative in order to evaluate the possibility to save or rescue the developmental potential of aged oocytes.
Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data
Authors: Denis Xavier, Prem Pais, PJ Devereaux, Changchun Xie, D Prabhakaran, K Srinath Reddy, Rajeev Gupta, Prashant Joshi, Prafulla Kerkar, S Thanikachalam, KK Haridas, TM Jaison, Sudhir Naik, AK Maity, Salim Yusuf
Journal: The Lancet (2008)
Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of “Rebound” Revascularization as Mode of Escape
Authors: Emmanuelle di Tomaso, Matija Snuderl, Walid S. Kamoun, Dan G. Duda, Pavan K. Auluck, Ladan Fazlollahi, Ovidiu C. Andronesi, Matthew P. Frosch, Patrick Y. Wen, Scott R. Plotkin, E. Tessa Hedley-Whyte, A. Gregory Sorensen, Tracy T. Batchelor, Rakesh K. Jain
Journal: Cancer Research (2011)

Abstract Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are 2 prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular, and vascular parameters in autopsy tissues from 5 rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus 7 patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood–brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM, cellular density in the central area of the tumor was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemoradiation. Finally, cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy—characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology—without a second wave of angiogenesis. Cancer Res; 71(1); 19–28. ©2011 AACR.
Managing allegations of research misconduct
Authors: Edmund Hey
Journal: Journal of the Royal Society of Medicine (2009)

If science is about the search for truth then dishonesty has to be the gravest sin, and a sin to which biomedical science is going to be particularly vulnerable because observations – if right – are not always replicable in the way they are in the physical sciences. Many of these issues were addressed in a brief report published by the Royal College of Physicians in 1991,1 but it was the publication of the subsequent book on ‘fraud and misconduct in biomedical research’ in 1993 that first brought the issue to the attention of a much wider audience. A new, fourth, and much revised, edition of this book appeared last year and a study of the way the book has evolved over time reveals much about the piecemeal and often rather unsatisfactory way the challenge has been addressed in the UK during the last 15 years.2
Acquisition of Endonuclease Specificity during Evolution of L1 Retrotransposon
Authors: K. Ichiyanagi, H. Nishihara, D. D. Duvernell, N. Okada
Journal: Molecular Biology and Evolution (2007)

L1 is the most proliferative autonomous retroelement that comprises about 20% of mammalian genomes. Why L1s have proliferated so extensively in mammalian genomes is an important yet unsolved question. L1 copies are amplified via retrotransposition, in which the DNA cleavage specificity by the L1-encoded endonuclease (EN) primarily dictates sites of insertion. Whereas mammalian L1s show target preference for 5′-TTAAAA-3′, other L1-like elements exhibit various degrees of target specificity. To gain insights on diversification of the EN specificity during L1 evolution, ENs of zebrafish L1 elements were analyzed here. We revealed that they form 3 discrete clades, M, F, and Tx1, which is in stark contrast to a single L1 clade in mammalian species. Interestingly, zebrafish clade M elements cluster as a sister group of mammalian L1s and show target-site preference for 5′-TTAAAA-3′. In contrast, elements of the clade F, the immediate outgroup of the clade M, show little specificity. We identified certain clade-specific amino acid residues in EN, many of which are located in the cleft that recognizes the substrate, suggesting that these amino acid alterations have generated 2 types of ENs with different substrate specificities. The distribution pattern of the 3 clades suggests a possibility that the acquisition of target specificity by the L1 ENs improved the L1 fitness under the circumstances in mammalian hosts.
Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study
Authors: Brenda Banwell, Lauren Krupp, Julia Kennedy, Raymond Tellier, Silvia Tenembaum, Jayne Ness, Anita Belman, Alexei Boiko, Olga Bykova, Emmanuelle Waubant, Jean K Mah, Cristina Stoian, Marcelo Kremenchutzky, Maria Rita Bardini, Martino Ruggieri, Mary Rensel, Jin Hahn, Bianca Weinstock-Guttman, E Ann Yeh, Kevin Farrell, Mark Freedman, Matti Iivanainen, Meri Sevon, Virender Bhan, Marie-Emmanuelle Dilenge, Derek Stephens, Amit Bar-Or
Journal: The Lancet Neurology (2007)
Regulation of macrophage and granulocyte proliferation. Specificities of prostaglandin E and lactoferrin
Authors: LM Pelus, HE Broxmeyer, JI Kurland, MAS Moore
Journal: The Journal of Experimental Medicine (1979)

Hemopoietic colony-forming cells committed to macrophage differentiation (M-CFC) are selectively and differentially inhibited by prostaglandin E (PGE). A hierarchy of sensitivity was observed among murine CFC stimulated by colony-stimulating factors (CSF) which differ in their ability to initiate proliferation of morphologically distinct colony types, or stimulated by CSF provided by macrophage feeder layers. Inhibition of macrophage colony formation to 50 percent levels occurred with PGE concentrations between 10(-8) and 10(-9) M, and was still evident at 10(-10) -10(-11) M PGE concentrations. The growth of mixed colonies containing both macrophages and neutrophils was less sensitive to the inhibitory effects of PGE, however, the monocytoid component of these colonies was reduced in the presence of PGE. Neutrophil progenitor cell proliferation was not influenced by PGE concentrations below 10(-6) M, regardless of time of addition of PGE, whereas clonal macrophage expansion, as well as clone size, was sensitive to inhibition by PGE when added as late as 3 d after culture initiation. Prostaglandin F(2α), was not inhibitory to colony formation. Experimental evidence for a selective role of macrophage PGE in the regulation of macrophage colony formation was directly provided by utilizing resident peritoneal macrophages as a source of CSF for bone marrow target cell overlays. Simultaneous morphological analysis of colonies proliferating in bilayer culture in response to increasing concentrations of macrophages, and direct measurements of PGE synthesized by an identical number of macrophages maintained in liquid culture demonstrate that a specific decline in macrophage colony formation occurs coincident with a linear increase in macrophage PGE synthesis. Inhibition of macrophage PGE synthesis by indomethacin results in the specific enhancement of macrophage colony formation. Furthermore, macrophage PGE synthesis is induced by CSF preparations with the selective capacity to differentially stimulate macrophage proliferation, but not by those which preferentially stimulate granulocyte colony formation. In comparison to the effects of PGE on M-CFC, polymorphonuclear granulocyte-derived lactoferrin (LF) reduces macrophage production of colony-stimulating activities for macrophage, mixed macrophage- neutrophil and neutrophil colony formation. The ability of LF to reduce macrophage PGE synthesis, presumably by decreasing CSF production, suggests that LF and PGE can interact in the control of macrophage and granulocyte proliferation.
The significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions
Authors: Yevgeniy Balagula, Ralph P. Braun, Harold S. Rabinovitz, Stephen W. Dusza, Alon Scope, Tracey N. Liebman, Ines Mordente, Katherine Siamas, Ashfaq A. Marghoob
Journal: Journal of the American Academy of Dermatology (2011)
Ranibizumab for Neovascular Age-Related Macular Degeneration
Authors: Philip J. Rosenfeld, David M. Brown, Jeffrey S. Heier, David S. Boyer, Peter K. Kaiser, Carol Y. Chung, Robert Y. Kim
Journal: New England Journal of Medicine (2006)

Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration.In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months.We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab.Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. (ClinicalTrials.gov number, NCT00056836 [ClinicalTrials.gov].).
Career destinations seven years on among doctors who qualified in the United Kingdom in 1988: postal questionnaire survey
Authors: T. W Lambert, M. J Goldacre
Journal: BMJ (1998)

<b>Objective:</b> To report the career choices and career destinations in 1995 of doctors who qualified in the United Kingdom in 1988. <b>Design:</b> Postal questionnaire. <b>Setting:</b> United Kingdom. <b>Subjects:</b> All doctors who qualified in the United Kingdom in 1988. <b>Main outcome measures:</b> Current employment. <b>Results:</b> Of the 3724 doctors who were sent questionnaires, eight had died and three declined to participate. Of the remaining 3713 doctors, 2885 (77.7%) replied. 16.9% (608/3593; 95% confidence interval 16.1% to 17.8%) of all 1988 qualifiers from medical schools in Great Britain were not working in the NHS in Great Britain in 1995 compared with 17.0% (624/3674; 16.1% to 17.9%) of the 1983 cohort in 1990. The proportion of doctors working in general practice was lower than in previous cohorts. The percentage of women in general practice (44.3% (528/1192)) substantially exceeded that of men (33.1% (443/1340)). 53% (276/522) of the women in general practice and 20% (98/490) of the women in hospital specialties worked part time. <b>Conclusions:</b>Concerns about recruitment difficulties in general practice are justified. Women are now entering general practice in greater numbers than men. There is no evidence of a greater exodus from the NHS from the 1988 qualifiers than from earlier cohorts.
Muscle-derived cell injection to treat anal incontinence due to obstetric trauma: pilot study with 1 year follow-up
Authors: A Frudinger, D Kolle, W Schwaiger, J Pfeifer, J Paede, S Halligan
Journal: Gut (2009)

<h3>Objective:</h3> To treat anal incontinence due to obstetric external anal sphincter disruption via injection of autologous myoblast cells. <h3>Design:</h3> Observational pilot study. <h3>Setting:</h3> University hospital and district hospital <h3>Patients:</h3> 10 women suffering from anal incontinence due to obstetric anal sphincter injury, refractory to conventional non-surgical therapy. <h3>Interventions:</h3> Autologous myoblasts were cultured from a pectoralis muscle biopsy, harvested, and injected into the external anal sphincter defect using direct ultrasound guidance. <h3>Main outcome measures:</h3> Wexner incontinence score, anal squeeze pressures, and quality of life 12 months after injection. Safety and technical feasibility. <h3>Results:</h3> The procedure was well tolerated and no adverse events were observed. At 12 months the Wexner incontince score had decreased by a mean of 13.7 units (95% CI, −16.3 to −11.2), anal squeeze pressures were unchanged, and overall quality of life scores improved by a median of 30 points (95% CI, 25 to 42). Anal squeeze pressures did rise significantly at 1 month and 6 months post-injection (p = 0.03). <h3>Conclusions:</h3> Injection of autologous myoblasts is safe, well tolerated, and significantly improves symptoms of anal incontinence due to obstetric anal sphincter trauma.
Treatment Of Severe And Persistent Food Allergy With Omalizumab
Authors: M. Peña Peloche, M. Hinojosa Macías, B. De La Hoz Caballer, S. Terrados Cepeda, M. Berges Gimeno, B. Huertas Barbudo, E. Álvarez-Cuesta
Journal: Journal of Allergy and Clinical Immunology (2011)
Leflunomide and methotrexate reduce levels of activated matrix metalloproteinases in complexes with 2 macroglobulin in serum of rheumatoid arthritis patients
Authors: I Tchetverikov, M C Kraan, B van El, R Hanemaaijer, J DeGroot, T W J Huizinga
Journal: Annals of the Rheumatic Diseases (2007)

To analyse the effects of leflunomide and methotrexate treatment on matrix metalloproteinase (MMP) activity levels in alpha2 macroglobulin/MMP (alpha2M/MMP) complexes in the systemic circulation of rheumatoid arthritis (RA) patients.A total of 102 RA patients from a prospective, double-blind, randomised clinical trial comparing leflunomide and methotrexate were selected; clinical data and blood samples were collected at baseline, at 4 months and at 1 year. Serum MMP activity levels in alpha2M were quantified using low molecular weight fluorogenic substrates, indicating the proportion of activated MMPs that were not inhibited by specific tissue inhibitors of MMP (TIMP).Patients had active disease as shown by high disease activity score (DAS, mean of 6.9 and 7.0 for methotrexate and leflunomide patients respectively), which was reduced over the study period (4.2 and 5.2 respectively, p<0.001). In leflunomide-treated patients a significant reduction of MMP activity levels was observed as early as at the 4 months timepoint persisting thereafter, whereas in methotrexate-treated patients the reduction was seen at 1 year.The results show that systemic levels of activated MMPs are reduced in RA patients upon exposure to leflunomide or methotrexate.
Recent strategies in the development of new human cytomegalovirus inhibitors
Authors: Ana Martinez, Ana Castro, Carmen Gil, Concepcion Perez
Journal: Medicinal Research Reviews (2001)

Abstract Human cytomegalovirus (HCMV) is one of the most common opportunistic infections in immunucompromised individuals, such as AIDS patients and organ transplant recipients, and is the most frequent congenital viral infection in humans. Despite a reduction of the incidence of AIDS‐related opportunistic infections in patients under highly active antiretroviral treatment, attention should be paid to the HCMV risk factor in these individuals. Furthermore, HCMV may have an important role in atherosclerosis. Existing antiviral treatments for the HCMV infection suffer from poor bioavailability, toxicity, and limited effectiveness, mainly due to the development of drug resistance. Fortunately there are novel and potentially very effective new compounds undergoing pre‐clinical and clinical evaluation. This review provides an overview in the last five years of new HCMV inhibitors (chemical structures, SAR, and new mechanisms of action) with the aim to provide new clues for the development of future drugs against this opportunistic virus. © 2001 John Wiley &amp; Sons, Inc. Med Res Rev, 21, No. 3, 227–244, 2001