tbuckley/cabot-search huggingface dataset:
Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era
Authors: Christian Gisselbrecht, Bertram Glass, Nicolas Mounier, Devinder Singh Gill, David C. Linch, Marek Trneny, Andre Bosly, Nicolas Ketterer, Ofer Shpilberg, Hans Hagberg, David Ma, Josette Brière, Craig H. Moskowitz, Norbert Schmitz
Journal: Journal of Clinical Oncology (2010)

Purpose Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown. Patients and Methods Patients with CD20 + DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT. Results The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P &lt; .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P &lt; .001). Conclusion In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP.
Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis
Authors: Osamu Yamaguchi, Tetsuya Watanabe, Kazuhiko Nishida, Kazunori Kashiwase, Yoshiharu Higuchi, Toshihiro Takeda, Shungo Hikoso, Shinichi Hirotani, Michio Asahi, Masayuki Taniike, Atsuko Nakai, Ikuko Tsujimoto, Yasushi Matsumura, Jun-ichi Miyazaki, Kenneth R. Chien, Atsushi Matsuzawa, Chiharu Sadamitsu, Hidenori Ichijo, Manuela Baccarini, Masatsugu Hori, Kinya Otsu
Journal: Journal of Clinical Investigation (2004)

The Raf/MEK/extracellular signal–regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle–specific Raf-1–knockout (Raf CKO) mice with Cre-loxP–mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal–regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK–independent mechanism.
Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes
Authors: J Macias
Journal: Gut (2005)

Liver biopsy is an invasive technique with associated major complications. There is no information on the validity of five non-invasive indexes based on routinely available parameters, estimated and validated in hepatitis C virus (HCV) monoinfected patients, in human immunodeficiency virus (HIV)/HCV coinfected patients.To validate these predictive models of liver fibrosis in HIV/HCV coinfected patients.A total of 357 (90%) of 398 patients from five hospitals were investigated, who underwent liver biopsy and who had complete data to validate all of the models considered.The predictive accuracy of the indexes was tested by measuring areas under the receiver operating characteristic curves. Diagnostic accuracy was calculated by estimating sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values.The models performed better when liver biopsies>or=15 mm were used as reference. In this setting, the Forns and Wai indexes, models aimed at discriminating significant fibrosis, showed PPV of 94% and 87%, respectively. Using these models, 27-34% of patients could benefit from exclusion of liver biopsy. If both models were applied sequentially, 41% of liver biopsies could be spared. The indexes aimed at predicting cirrhosis achieved NPV of up to 100%. However, they showed very low PPV.The diagnostic accuracy of these models was lower in HIV/HCV coinfected patients than in the validation studies performed in HCV monoinfected patients. However, simple fibrosis tests may render liver biopsy unnecessary in deciding anti-HCV treatment in over one third of patients with HIV infection and chronic hepatitis C.
Gene expression and hypoxia in breast cancer
Authors: Elena Favaro, Simon Lord, Adrian L Harris, Francesca M Buffa
Journal: Genome Medicine (2011)

Hypoxia is a feature of most solid tumors and is associated with poor prognosis in several cancer types, including breast cancer. The master regulator of the hypoxic response is the Hypoxia-inducible factor 1α (HIF-1α). It is becoming clear that HIF-1α expression alone is not a reliable marker of tumor response to hypoxia, and recent studies have focused on determining gene and microRNA (miRNA) signatures for this complex process. The results of these studies are likely to pave the way towards the development of a robust hypoxia signature for breast and other cancers that will be useful for diagnosis and therapy. In this review, we outline the existing markers of hypoxia and recently identified gene and miRNA expression signatures, and discuss their potential as prognostic and predictive biomarkers. We also highlight how the hypoxia response is being targeted in the development of cancer therapies.
Systematic Approaches to Toxicology in the Zebrafish
Authors: Randall T. Peterson, Calum A. MacRae
Journal: The Annual Review of Pharmacology and Toxicology (2011)

As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in vitro technologies and established preclinical in vivo models that can be scaled for high-throughput. In this review, we highlight the current status of zebrafish toxicology studies, identify potential future niches for the model in the drug development pipeline, and define the hurdles that must be overcome as zebrafish technologies are refined for systematic toxicology.
A phase I study of ridaforolimus in adult Chinese patients with advanced solid tumors
Authors: Lian Liu, Wen Zhang, Wenhua Li, Fangfang Lv, Zuguang Xia, Sheng Zhang, Wen Liu, Anthe S Zandvliet, Sylvia Waajen, Li Xin Zhang, Li Yan, Jin Li
Journal: Journal of Hematology & Oncology (2013)

Ridaforolimus (AP23573, MK-8669 or deforolimus) is an inhibitor of mammalian target of rapamycin (mTOR), an important regulator in the cell survival pathway. This open-label, single center phase I study aimed to investigate the pharmacokinetic (PK) and safety profiles of ridaforolimus in Chinese patients with treatment-refractory advanced or relapsed solid tumors. The PK data generated from these Chinese patients were further compared with those previously reported in Caucasian and Japanese patient populations. The patients were given an oral dose of 40 mg of ridaforolimus on Day 1 of the study. On Day 8, patients were initiated on a treatment regimen that comprised a once daily dose of 40 mg of ridaforolimus for five consecutive days, followed by a 2-day off-drug interval. Patients repeated this regimen until disease progression or intolerance. Blood samples were collected at specific times pre- and post-treatment to establish the PK profile of ridaforolimus in all patients. Fifteen patients were given at least one dose of 40 mg of ridaforolimus. The median absorption lag-time was 2 hours, the median Tmax was 4 hours and the mean elimination half-life was 53 hours. The accumulation ratio for AUC0-24hr was 1.3 on day 19 (steady state)/day 1 (after a single dose). The most common drug-related adverse events (AEs) that occurred in ≥40% of patients were stomatitis, proteinuria, leukopenia, hyperglycemia, and pyrexia. Grade 3/4 drug-related AEs were anemia, stomatitis, fatigue, thrombocytopenia, constipation, gamma glutamyltransferase increase, and proteinuria. All 11 evaluable patients achieved stable disease. Oral ridaforolimus at a daily dose of 40 mg were generally well tolerated in Chinese patients with advanced or refractory solid tumors. Adverse events and PK profiles of ridaforolimus in this study were similar to those from Caucasian and Japanese patients reported previously.
Dramatic Diversity of Ciliate Histone H4 Genes Revealed by Comparisons of Patterns of Substitutions and Paralog Divergences Among Eukaryotes
Authors: Laura A Katz, Jacob G Bornstein, Erica Lasek-Nesselquist, Spencer V Muse
Journal: Molecular Biology and Evolution (2004)

The accumulation of divergent histone H4 amino acid sequences within and between ciliate lineages challenges traditional views of the evolution of this essential eukaryotic protein. We analyzed histone H4 sequences from 13 species of ciliates and compared these data with sequences from well-sampled eukaryotic clades. Ciliate histone H4s differ from one another at as many as 46% of their amino acids, in contrast with the highly conserved character of this protein in most other eukaryotes. Equally striking, we find paralogs of histone H4 within ciliate genomes that differ by up to 25% of their amino acids, whereas paralogs in other eukaryotes share identical or nearly identical amino acid sequences. Moreover, the most divergent H4 proteins within ciliates are found in the lineages with highly processed macronuclear genomes. Our analyses demonstrate that the dual nature of ciliate genomes—the presence of a "germline" micronucleus and a "somatic" macronucleus within each cell—allowed the dramatic variation in ciliate histone genes by altering functional constraints or enabling adaptive evolution of the histone H4 protein, or both.
Psychophysiological and neuromotor indicators of brain concussion
Authors: Éric Le Bouthillier, Michel Caouette, Fanny Guérin
Journal: British Journal of Sports Medicine (2013)

Objective Post-concussion symptoms disappear from days up to 3 months in adults after a 1st concussion. 15% of adults have persistent sequelae. The athletes have a higher probability of experiencing a second concussion and to suffer from both prolonged due to the cumulative effect of these neurological injuries. Lower cognitive and physical skills of the athlete are more documented after concussion. Specifically, the impacts of concussion on neuromotor and neurophysiological functions are investigated. Design Case studies. Settings Rehabilitation in public and private practices. Patients Three athletes who sustained a concussion with persistent symptoms after several months to one year. Interventions Measures of frequency and heart rate variability at night; percentage of cardiac reserve on daily tasks of different intensities and a neuromotor assessment were performed. Main Outcome All three athletes show a cardiac reactivity to a task in mismatch with the actual engineering costs of the various tasks performed and, several months to one year post-concussion. They show motor strategies disorders and slower processing of visual information. Conclusions Cardiac monitoring and neuromotor assessment provides additional indicators in the detection of concussion, as a complement to the neurocognitive assessment, and should be included routinely in the management concussion protocols of athletes. These data are also valuable clinically to help reduce post-concussion symptoms. However research is needed to understand their impact on the recovery of the athlete so as to promote a safe return to play. Competing interests Neurosport is a private pratice who offers services to athlete for post-concussion assessment and neurorehabilitation.
Establishment of human double-positive thymocyte clones.
Authors: G De Libero, A Lanzavecchia
Journal: The Journal of Experimental Medicine (1989)

Human thymocytes were sorted according to the expression of CD4 and CD8 molecules and clones representing the four subpopulations (DP, DN, and single CD4 or CD8 positive) were established. DP clones can be maintained for long periods in tissue culture and give rise to a variable percentage of SP variants. These variants, when isolated and further expanded, do not revert to a DP phenotype. DP clones express a functional TCR-CD3 complex, suggesting that this molecule can interact with the thymic microenvironment during T cell differentiation.
Photothermal laser ablation of Barrett’s oesophagus: endoscopic and histological evidence of squamous re-epithelialisation
Authors: C P Barham, R L Jones, L R Biddlestone, R H Hardwick, N A Shepherd, H Barr
Journal: Gut (1997)

Background —Barrett’s oesophagus is acquired by severe gastro-oesophageal reflux and is a premalignant condition. Acid suppression or anti-reflux surgery alone do not cause significant regression of the metaplastic mucosa nor reduce the malignant potential. Recent reports have suggested that the combination of mucosal ablation with acid suppression may result in squamous regeneration. Aims —To destroy Barrett’s mucosa by thermal ablation (in the setting of acid suppression) and so induce squamous regeneration. Patients —Sixteen patients with non-dysplastic Barrett’s oesophagus were recruited from a surveillance programme. All had been on a proton pump inhibitor. Methods —At intervals, non-circumferential areas of columnar mucosa were ablated using the KTP laser. Acid suppression was obtained with 40 mg omeprazole daily. Multiple biopsy specimens were obtained for histological examination from ablated areas. Results —Ablation of all areas of glandular mucosa resulted in squamous regeneration. The number of treatments required depended on the length of the Barrett’s segment. In 11 patients there was evidence of squamous regeneration over remaining Barrett’s glands (in some of the post-treatment biopsy specimens) whilst in nine patients squamous metaplasia was seen within Barrett’s glands. Conclusion —Mucosal ablation of Barrett’s oesophagus by laser, in the setting of acid suppression, results in squamous regeneration (though some burying of Barrett’s glands did occur).
Specific oral tolerance induction in food allergy
Authors: B. Niggemann, U. Staden, C. Rolinck‐Werninghaus, K. Beyer
Journal: Allergy (2006)

Specific oral tolerance in food allergy can be induced by oral administration of the offending food, starting with very low dosages, gradually increasing the daily dosage up to an amount equivalent to a usually relevant dose for daily intake, followed up by a daily maintenance dose. Unfortunately, the body of scientific evidence concerning specific oral tolerance induction (SOTI) is still rather poor. Following a couple of case reports, only a few studies on a limited number of patients including different allergens are available. So far, no placebo‐controlled, long‐term study has been published. Concerning the underlying immunological mechanism, a limited number of studies have reported on changes in antibody production, and more recently on the role of different T‐cell populations. The individual pattern of clinical reaction during SOTI seems to vary considerably between patients and from allergen to allergen. Arguments in favour of SOTI are the safety for an inadvertent intake of the offending food and the increased quality of life. Arguments against SOTI are the necessity for a regular intake and possible long‐term compliance problems. Indications to consider SOTI in the future might be (i) importance of the incriminated food for the individual nutritional regimen, (ii) avoidance of the corresponding food cannot be assured and (iii) persistent severe food allergy. However, before SOTI can be recommended for the daily praxis, more studies are warranted to clarify whether certain patients may profit from SOTI and to understand the underlying mechanism.
colour is a culturalist category
Authors: j. van brakel
Journal: Behavioral and Brain Sciences (2005)

extrapolation of steels &amp; belpaeme's (s&amp;b) results show that colour is a culturalist category. populations will only share the category of colour if it is built into the system. if “left to themselves” different populations may or may not stumble on the colour category. populations that do not share a colour category may still be able to communicate in a wide variety of environments.
Persistent expression of autoantibodies in SLE patients in remission
Authors: Sergey Yurasov, Thomas Tiller, Makoto Tsuiji, Klara Velinzon, Virginia Pascual, Hedda Wardemann, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2006)

A majority of the antibodies expressed by nascent B cells in healthy humans are self-reactive, but most of these antibodies are removed from the repertoire during B cell development. In contrast, untreated systemic lupus erythematosus (SLE) patients fail to remove many of the self-reactive and polyreactive antibodies from the naive repertoire. Here, we report that SLE patients in clinical remission continue to produce elevated numbers of self-reactive and polyreactive antibodies in the mature naive B cell compartment, but the number of B cells expressing these antibodies is lower than in patients with active disease. Our finding that abnormal levels of self-reactive mature naive B cells persist in the majority of patients in clinical remission suggests that early checkpoint abnormalities are an integral feature of SLE.
Obesity. The report of the British Nutrition Foundation Task Force.: (Pp 258; pound29.99.) Oxford: Blackwell Science, 1999. ISBN 0-632-05298-8.
Authors: David C Wilson
Journal: British Journal of Sports Medicine (2000)

Use of imaging data for predicting clinical outcomeEDITOR,-We would like to air three points that arise from the paper Sonographic incidence of tendon microtears in athletes with chronic Achilles tendinosis. 1 Firstly, unfortunately the word "partial" has been omitted from the conclusion (abstract).The conclusion currently reads "There appears to be an association between microtear formation and Achilles tendon rupture".The distinction needs to be made, as the paper's Take home message concludes with the words "There may be a role for ultrasound in identifying athletes at high risk of tendon rupture", and in this case it appears that the authors mean complete tendon rupture.It is important that this ambiguity is clarified.Secondly, although it is well accepted that in many cases tendinosis precedes "spontaneous" tendon rupture, 2 it does not necessarily follow that sonographic abnormality will lead to (complete) tendon rupture.The tissue based pathologies found by Kannus and Jozsa may be more subtle than can be detected by sonography.We feel that, without longitudinal data in a large cohort with an appropriate control group, Gibbon and colleagues are not in a position to draw a conclusion on sonographic screenings of athletes.Thirdly, given the cross sectional study design, the authors should provide caveats emphasising that their theory of tendon remodelling paralleling that of bone is purely speculative.Cross sectional athlete-control comparisons (such as those provided to sustain the argument on tendon remodelling) do not provide evidence of causality-such diVerences can result merely from selection bias.If athlete-control diVerence were causally related, then one could take up basketball in order to grow tall.We emphasise the need for prospectively collected data to predict future outcome.Researchers and clinicians should desist from speculating as to the longitudinal clinical significance of imaging data collected at one point in time only.To our knowledge, there is only one published prospective ultrasonography and clinical correlation study in the tendon literature at present, 3 and it shows rather poor predictive value of ultrasonography in terms of development of symptoms and clinical findings of patellar tendinopathy in female basketball players.Until researchers and reviewers acknowledge the importance of longitudinally collected data for predicting clinical outcome, our imaging field will continue to be mired in a debate based on speculation rather than science.
Arterial–Venous Specification During Development
Authors: Matthew R. Swift, Brant M. Weinstein
Journal: Circulation Research (2009)

The major arteries and veins of the vertebrate circulatory system are formed early in embryonic development, before the onset of circulation, following de novo aggregation of “angioblast” progenitors in a process called vasculogenesis. Initial embryonic determination of artery or vein identity is regulated by variety of genetic factors that work in concert to specify endothelial cell fate, giving rise to 2 distinct components of the circulatory loop possessing unique structural characteristics. Work in multiple in vivo animal model systems has led to a detailed examination of the interacting partners that determine arterial and venous specification. We discuss the hierarchical arrangement of many signaling molecules, including Hedgehog (Hh), vascular endothelial growth factor (VEGF), Notch, and chicken ovalbumin upstream-transcription factor II (COUP-TFII) that promote or inhibit divergent pathways of endothelial cell fate. Elucidation of the functional role of these genetic determinants of blood vessel specification together with the epigenetic factors involved in subsequent modification of arterial–venous identity will allow for potential new therapeutic targets for vascular disorders.