tbuckley/cabot-search huggingface dataset:
Introns and reading frames: correlation between splicing sites and their codon positions
Authors: M. Tomita, N. Shimizu, D. L. Brutlag
Journal: Molecular Biology and Evolution (1996)

Computer analyses of the entire GenBank database were conducted to examine correlation between splicing sites and codon positions in reading frames. Intron insertion patterns (i.e., splicing site locations with respect to codon positions) have been analyzed for all of the 74 codons of all the eukaryote taxonomic groups: primates, rodents mammals, vertebrates, invertebrates, and plants. We found that reading frames are interrupted by an intron at a codon boundary (as opposed to the middle of a codon) significantly more often than expected. This observation is consistent with the exon shuffling hypothesis, because exons that end at codon boundaries can be concatenated without causing a frame shift and thus are evolutionarily advantageous. On the other hand, when introns interrupt at the middles of codons, they exist in between the first and second bases much more frequently than between the second and third bases, despite the fact that boundaries between the first and second bases of codons are generally far more important than those between the second and third bases. The reason for this is not clear and yet to be explained. We also show that the length of an exon is a multiple of 3 more frequently than expected. Furthermore, the total length of two consecutive exons is also more frequently a multiple of 3. All the observations above are consistent with results recently published by Long, Rosenberg, and Gilbert (1995).
Lymphogranuloma venereum variant L2b-specific polymerase chain reaction: insertion used to close an epidemiological gap
Authors: S.P. Verweij, A. Catsburg, S. Ouburg, A. Lombardi, R. Heijmans, F. Dutly, R. Frei, S.A. Morré, D. Goldenberger
Journal: Clinical Microbiology and Infection (2011)
Five Versus More Than Five Years of Tamoxifen for Lymph Node-Negative Breast Cancer: Updated Findings From the National Surgical Adjuvant Breast and Bowel Project B-14 Randomized Trial
Authors: B Fisher, J Dignam, J Bryant, N Wolmark
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Previously reported information from B-14, a National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized, placebo-controlled clinical trial, demonstrated that patients with estrogen receptor (ER)-positive breast cancer and negative axillary lymph nodes experienced a prolonged benefit from 5 years of tamoxifen therapy. When these women were rerandomized to receive either placebo or more prolonged tamoxifen therapy, they obtained no additional advantage from tamoxifen through 4 years of follow-up. Because the optimal duration of tamoxifen administration continues to be controversial and because there have been 3 more years of follow-up and a substantial increase in the number of events since our last report, an update of the B-14 study is appropriate. Methods: Patients (n = 1172) who had completed 5 years of tamoxifen therapy and who were disease free were rerandomized to receive placebo (n = 579) or tamoxifen (n = 593). Survival, disease-free survival (DFS), and relapse-free survival (RFS) were estimated by the Kaplan–Meier method; the differences between the treatment groups were assessed by the log-rank test. Relative risks of failure (with 95% confidence intervals) were determined by the Cox proportional hazards model. P values were two-sided. Results: Through 7 years after reassignment of tamoxifen-treated patients to either placebo or continued tamoxifen therapy, a slight advantage was observed in patients who discontinued tamoxifen relative to those who continued to receive it: DFS = 82% versus 78% (P = .03), RFS = 94% versus 92% (P = .13), and survival = 94% versus 91% (P = .07), respectively. The lack of benefit from additional tamoxifen therapy was independent of age or other characteristics. Conclusion: Through 7 years of follow-up after rerandomization, there continues to be no additional benefit from tamoxifen administered beyond 5 years in women with ER-positive breast cancer and negative axillary lymph nodes.
Biological invasions: Theory and practice By Nanako Shigesada and Kohkichi Kawasaki Oxford University Press (Oxford series in ecology and evolution), 1997. £39.50 hbk, £17.95 pbk (xiii + 205 pages) ISBN 0 19 8548524 / 0 19 8548516
Authors: P Kareiva
Journal: Trends in Ecology & Evolution (1997)
Clinical and functional characteristics of Italian and Spanish patients with alpha 1-antitrypsin deficiency
Authors: Barbara Piras, Ilaria Ferrarotti, Beatriz Lara, Maria Teresa Martinez, Ana Bustamante, Pietro Pirina, Maurizio Luisetti, Marc Miravitlles
Journal: European Respiratory Journal (2012)

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition associated with pulmonary disease, for which national and international registries play a crucial role.  Methods: With the aim of providing a clinically better characterisation of AADT patients, we conducted an observational cross sectional study on adult patients affected by severe AATD enrolled in the Spanish and Italian national registries.  Results: We assessed 745 subjects, 416 enrolled in the Spanish and 329 in the Italian Registries with a mean age of 49.9 years (SD=13.8). The 57.2% of subjects were male and the 64.9% smokers or former smokers. The majority were index cases (81.2%), mostly with PI*ZZ genotype (73.4%), the mean diagnostic delay was 9 years (SD=12.1). Compared with PI*ZZ (n=547), PI*SZ (n=124) subjects had an older age at diagnosis and better preserved lung function despite a higher mean smoking consumption. Characteristics of PI*ZZ patients with chronic obstructive pulmonary disease (COPD)(n=412) were compared according to GOLD severity stages. Mean age was similar in GOLD I, III and IV, but subjects in GOLD II were older. In GOLD I women and non-index cases were prevailing. The rate of never smokers significantly decreased when severity of COPD increased. Augmentation therapy was administered to 19% of GOLD I, 48% of GOLD II, 59% of GOLD III and 51% of GOLD IV patients.  Conclusions: Early diagnosis of AATD is still an unmet need. PI*ZZ patients in both registries had more severe respiratory disease than PI*SZ, despite less smoking consumption. Augmentation therapy is provided to similar proportions of patients with all degrees of severity of airflow obstruction from GOLD II to IV.
Progress in Pediatric Cancer
Authors: Susan E. Bates
Journal: Clinical Cancer Research (2012)

The articles in this CCR Focus section create a sense that we are at the threshold of important therapeutic discoveries in the treatment of childhood cancer. Pediatric oncologists can be proud of their track record in treating children with cancer. As shown in Fig. 1, there has been steady, stepwise progress in the treatment of almost every tumor type over the last 35 years (1). Given the rarity of childhood cancer, this progress is in no small part due to the willingness of pediatric oncologists to work in cooperative groups. Investigators have worked out the treatment of acute lymphoblastic leukemia iteratively, adding and subtracting agents for induction therapy, and altering treatment durations and consolidation therapies. The result is a 90% 5-year survival rate. However, the field has had its challenges. New agents are classically developed in adults before children, with safety in mind, but this has had the effect of placing more emphasis on discoveries in adults than in children. The rarity of the diseases has made them more difficult to study and investigators more reliant on model systems. In addition, success has generated long-term survivors with chronic medical problems due to long-term toxicity.Our understanding of the basis of these cancers has dramatically increased with the sequencing of the cancer genome and allowed the identification of new potential therapeutic targets. Further, our increased understanding of the molecular basis of immune response and of pharmacology offers new directions going forward. Guest Editors Carol Thiele and Susan Cohn have assembled a team to examine pediatric cancer in the era of molecular oncology. Matthay and colleagues take us beyond MYCN to the identification of 3 new targets in neuroblastoma, Loh and Mullighan identify new targets for therapy in acute lymphoblastic leukemia, and Lawlor and Thiele show that epigenetic dysregulation may underlie most childhood cancers. Lee and colleagues discuss new approaches for targeting the immune system against tumor cells, and Pinto and colleagues address the potential use of pharmacogenomics to avert toxicity from therapy. Together, these articles represent highlights and hope in our effort to protect our smallest patients from these rare but mortal diseases.As with every edition of CCR Focus, it is our hope that the articles will inform and intrigue both the expert in the field and the interested but nonexpert observer.
Cystic Fibrosis–Related Diabetes
Authors: Henrik U. Andersen, Susanne Lanng, Tania Pressler, Caroline S. Laugesen, Elisabeth R. Mathiesen
Journal: Diabetes Care (2006)

Cystic fibrosis (CF)-related diabetes has been regarded as a mild form of diabetes with a low risk of severe diabetes complications. The prevalence of CF-related diabetes increases with age, resulting in a 50% prevalence of diabetes at age 30 years. We sought to investigate whether microvascular complications in CF-related diabetes appear with a relevant frequency.Thirty-eight patients aged 30 (range 18-55) years with CF-related diabetes for 20 (0-31) years were screened for diabetes complications. Because of chronic pulmonary infections, the majority of patients were regularly treated with aminoglycoside and cyclosporine given frequently.Since the pharmacological treatment of lung transplant patients could influence metabolical regulation and renal function, the results are given separately for nontransplanted (n = 29) and transplanted (n = 9) CF patients. Nine patients (27%) had retinopathy, two of which had proliferative retinopathy and needed laser treatment. Lung transplantation did not affect the prevalence of retinopathy. In nontransplanted patients, nine had hypertension, three microalbuminuria, and one elevated creatinine. None had macroalbuminuria. In transplanted patients, eight of nine had hypertension, two had microalbuminuria, and none had macroalbuminuria. Seven of nine lung transplant patients had elevated plasma creatinine, and severely reduced glomerular filtration rate was significantly more frequent.A high frequency of diabetic retinopathy was found in patients with insulin-treated CF-related diabetes, stressing the need for a regular screening program as in type 1 diabetes. Severely impaired kidney function was common in lung transplant patients, probably secondary to cyclosporine treatment.
Tumour necrosis factor α −308G→A polymorphism is not associated with response to TNFα blockers in Caucasian patients with rheumatoid arthritis: systematic review and meta-analysis
Authors: Stephan Pavy, Erik J M Toonen, Corinne Miceli-Richard, Pilar Barrera, Piet L C M van Riel, Lindsey A Criswell, Xavier Mariette, Marieke J H Coenen
Journal: Annals of the Rheumatic Diseases (2009)

Background There is a need for biomarkers that can predict anti-tumour necrosis factor (anti-TNF) treatment outcome in patients with rheumatoid arthritis (RA). Several studies have suggested that the rare A allele of the tumour necrosis factor α (TNFA) −308G→A polymorphism could be associated with a poorer response to anti-TNF therapy. Nevertheless, these results remain controversial. Objective To determine by a meta-analysis whether the TNFA −308G→A polymorphism is associated with response to anti-TNF treatment in patients with RA. Methods A bibliographic search identified studies in which the TNFA −308G→A gene polymorphism was investigated in Caucasian patients with RA treated with anti-TNF agents. Complementary data were requested when the 28-joint count Disease Activity Score (DAS28) was not used as the primary outcome measure. Odds ratios (ORs) for response based on DAS28 and standardised mean difference (SMD) for mean improvement of DAS28 were calculated to assess the potential association between TNFA −308 genotypes and response to anti-TNF agents. Results The bibliographic search yielded 12 studies that met the inclusion criteria, which were supplemented with the data from a large Dutch cohort (n=426). The OR based on the 12 studies including 1721 patients was 1.24 (95% CI 0.98 to 1.56) and the SMD based on 11 studies including 2579 patients was −0.18 (95% CI −0.36 to 0.1). Subgroup analysis based on the two classes of anti-TNF agents did not demonstrate any association between TNFA −308 genotypes and anti-TNF treatment outcome. Conclusion According to this meta-analysis, the TNFA −308 polymorphism is not a predictor of the clinical response to anti-TNF treatment in RA.
Hepatitis C virus infection and MALT-type ocular adnexal lymphoma
Authors: P. Arnaud, M.-C. Escande, M. Lecuit, P. Validire, C. Levy, C. Plancher, A. Vincent-Salomon, N. Brousse, P. de Cremoux, O. Hermine, D. Decaudin
Journal: Annals of Oncology (2006)
BONE MARROW TRANSPLANTATION STRATEGIES IN ACUTE LEUKAEMIA
Authors: B Löwenberg, A Hagenbeek, W Sizoo, G.C De Gast, L.F Verdonck, D Maraninchi, B Mascret, J.A Gastaut, G Sebahoun, G Novakovitch, N Tubiana, Y Carcassonne
Journal: The Lancet (1984)
Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study
Authors: F. Nuzzo, C. Gallo, S. Lastoria, M. Di Maio, M.C. Piccirillo, A. Gravina, G. Landi, E. Rossi, C. Pacilio, V. Labonia, F. Di Rella, A. Bartiromo, G. Buonfanti, G. De Feo, G. Esposito, R. D'Aniello, P. Maiolino, S. Signoriello, E. De Maio, V. Tinessa, G. Colantuoni, M. De Laurentiis, M. D'Aiuto, M. Di Bonito, G. Botti, P. Giordano, G. Daniele, A. Morabito, N. Normanno, A. de Matteis, F. Perrone
Journal: Annals of Oncology (2012)
Glycogen synthase kinase 3 (GSK‐3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation
Authors: Ana Martinez, Ana Castro, Isabel Dorronsoro, Mercedes Alonso
Journal: Medicinal Research Reviews (2002)

Abstract Glycogen synthase kinase 3 (GSK‐3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. Two forms of the enzyme, GSK‐3α and GSK‐3β, have been previously identified. Small molecules inhibitors of GSK‐3 may, therefore, have several therapeutic uses, including the treatment of neurodegenerative diseases, diabetes type II, bipolar disorders, stroke, cancer, and chronic inflammatory disease. As there is lot of recent literature dealing with the involvement of GSK‐3 in the molecular pathways of different diseases, this review is mainly focused on the new GSK‐3 inhibitors discovered or specifically developed for this enzyme, their chemical structure, synthesis, and structure–activity relationships, with the aim to provide some clues for the future optimization of these promising drugs. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 4, 373–384, 2002; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10011
DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns
Authors: Kaie Lokk, Vijayachitra Modhukur, Balaji Rajashekar, Kaspar Märtens, Reedik Mägi, Raivo Kolde, Marina Koltšina, Torbjörn K Nilsson, Jaak Vilo, Andres Salumets, Neeme Tõnisson
Journal: Genome biology (2014)

DNA epigenetic modifications, such as methylation, are important regulators of tissue differentiation, contributing to processes of both development and cancer. Profiling the tissue-specific DNA methylome patterns will provide novel insights into normal and pathogenic mechanisms, as well as help in future epigenetic therapies. In this study, 17 somatic tissues from four autopsied humans were subjected to functional genome analysis using the Illumina Infinium HumanMethylation450 BeadChip, covering 486 428 CpG sites.Only 2% of the CpGs analyzed are hypermethylated in all 17 tissue specimens; these permanently methylated CpG sites are located predominantly in gene-body regions. In contrast, 15% of the CpGs are hypomethylated in all specimens and are primarily located in regions proximal to transcription start sites. A vast number of tissue-specific differentially methylated regions are identified and considered likely mediators of tissue-specific gene regulatory mechanisms since the hypomethylated regions are closely related to known functions of the corresponding tissue. Finally, a clear inverse correlation is observed between promoter methylation within CpG islands and gene expression data obtained from publicly available databases.This genome-wide methylation profiling study identified tissue-specific differentially methylated regions in 17 human somatic tissues. Many of the genes corresponding to these differentially methylated regions contribute to tissue-specific functions. Future studies may use these data as a reference to identify markers of perturbed differentiation and disease-related pathogenic mechanisms.
Evaluation of Whether Accelerated Protein Evolution in Chordates Has Occurred before, after, or Simultaneously with Gene Duplication
Authors: C. R. Johnston, C. O'Dushlaine, D. A. Fitzpatrick, R. J. Edwards, D. C. Shields
Journal: Molecular Biology and Evolution (2006)

Gene duplication and loss are predicted to be at least of the order of the substitution rate and are key contributors to the development of novel gene function and overall genome evolution. Although it has been established that proteins evolve more rapidly after gene duplication, we were interested in testing to what extent this reflects causation or association. Therefore, we investigated the rate of evolution prior to gene duplication in chordates. Two patterns emerged; firstly, branches, which are both preceded by a duplication and followed by a duplication, display an elevated rate of amino acid replacement. This is reflected in the ratio of nonsynonymous to synonymous substitution (mean nonsynonymous to synonymous nucleotide substitution rate ratio [Ka:Ks]) of 0.44 compared with branches preceded by and followed by a speciation (mean Ka:Ks of 0.23). The observed patterns suggest that there can be simultaneous alteration in the selection pressures on both gene duplication and amino acid replacement, which may be consistent with co-occurring increases in positive selection, or alternatively with concurrent relaxation of purifying selection. The pattern is largely, but perhaps not completely, explained by the existence of certain families that have elevated rates of both gene duplication and amino acid replacement. Secondly, we observed accelerated amino acid replacement prior to duplication (mean Ka:Ks for postspeciation preduplication branches was 0.27). In some cases, this could reflect adaptive changes in protein function precipitating a gene duplication event. In conclusion, the circumstances surrounding the birth of new proteins may frequently involve a simultaneous change in selection pressures on both gene-copy number and amino acid replacement. More precise modeling of the relative importance of preduplication, postduplication, and simultaneous amino acid replacement will require larger and denser genomic data sets from multiple species, allowing simultaneous estimation of lineage-specific fluctuations in mutation rates and adaptive constraints.
IBD and arthropathies: a practical approach to its diagnosis and management
Authors: L. K. P. M. Brakenhoff, D. M. van der Heijde, D. W. Hommes
Journal: Gut (2011)

Arthropathies are a major clinical problem in patients with inflammatory bowel disease (IBD). Often it is difficult to control the articular symptoms with the anti-inflammatory strategies used for IBD. Studies evaluating specific treatments aimed at articular manifestations in patients with IBD are rare. Although there has been considerable interest in the gut–joint axis over the last decade, the pathophysiological mechanisms driving IBD-associated arthropathy are still unknown. Recently, interest in the multidisciplinary approach to patients with IBD and arthropathy has been increasing. New research and clinical projects aimed at understanding the mechanisms of disease may advance the development of effective therapies. In this review, the pathophysiology of IBD-associated arthropathy is discussed, as well as clinical manifestations, the classification and current therapeutic strategies.
Molecular analysis of the fructose transporter gene (GLUT5) in isolated fructose malabsorption.
Authors: D Wasserman, J H Hoekstra, V Tolia, C J Taylor, B S Kirschner, J Takeda, G I Bell, R Taub, E B Rand
Journal: Journal of Clinical Investigation (1996)

Fructose, a naturally occurring monosaccharide, is increasingly used as an added sweetener in processed foods in the form of high fructose corn syrup. Increased fructose intake combined with the identification of children with clinical evidence of isolated fructose malabsorption (IFM) has stimulated interest in possible disorders of fructose absorption. The intestinal absorption of fructose is carried out by the facilitative hexose transporter, which has been designated as GLUT5. Functional properties and tissue distribution of GLUT5 suggest that IFM might be due to mutations in the GLUT5 gene. To test this hypothesis, we screened the GLUT5 gene for mutations in a group of eight patients with IFM and in one subject with global malabsorption, as compared with 15 healthy parents of subjects and up to 6 unrelated controls. No mutations were found in the protein coding region of this gene in any of the subjects. A single G to A substitution in the 5' untranslated region of exon 1 was identified in the subject with global malabsorption. This subject and her healthy mother were heterozygous for the variant sequence, suggesting that it was unlikely to be clinically significant. In addition, sequence analysis of each of the 12 GLUT5 exons was performed in the index case and confirmed the negative single-strand conformation polymorphism findings. These studies demonstrate that IFM does not result from the expression of mutant GLUT5 protein.
Tissue-resident Macrophages Protect the Liver From Ischemia Reperfusion Injury via a Heme Oxygenase-1-Dependent Mechanism
Authors: Luke Devey, David Ferenbach, Elodie Mohr, Kathryn Sangster, Christopher O Bellamy, Jeremy Hughes, Stephen J Wigmore
Journal: Molecular Therapy (2008)

Kupffer cells are the resident macrophage population of the liver and have previously been implicated in the pathogenesis of hepatic ischemia-reperfusion injury (IRI). Kupffer cells are the major site of expression of hepatic heme oxygenase-1 (HO-1), which has been shown to have anti-inflammatory actions and to protect animals and cells from oxidative injury. Kupffer cells and circulating monocytes were selectively ablated using liposomal clodronate (LC) in the CD11b DTR mouse before induction of hepatic ischemia. Kupffer cell depletion resulted in loss of HO-1 expression and increased susceptibility to hepatic IRI, whereas ablation of circulating monocytes did not affect IRI phenotype. Targeted deletion of HO-1 rendered mice highly susceptible to hepatic IRI. In vivo, HO-1 deletion resulted in pro-inflammatory Kupffer cell differentiation characterized by enhanced Ly6c and MARCO (macrophage receptor with collagenous structure) expression as well as decreased F4/80 expression, mirrored by an expansion in immature circulating monocytes. In vitro, HO-1 inhibition throughout macrophage differentiation led to increased cell numbers, and pro-inflammatory Ly6c+ CD11c- F4/80- phenotype. These data support a critical role for tissue-resident macrophages in homeostasis following ischemic injury, and a co-dependence of HO-1 expression and tissue-resident macrophage differentiation.