tbuckley/cabot-search huggingface dataset:
Toward Personalized Lymphoma Immunotherapy: Identification of Common Driver Mutations Recognized by Patient CD8+ T Cells
Authors: Julie S. Nielsen, Colin G. Sedgwick, Aniqa Shahid, Zusheng Zong, Zabrina L. Brumme, Stephen Yu, Lewis Liu, David R. Kroeger, Steven P. Treon, Joseph M. Connors, Randy D. Gascoyne, Brian R. Berry, Marco A. Marra, Ryan D. Morin, Nicol Macpherson, Brad H. Nelson
Journal: Clinical Cancer Research (2015)

A fundamental challenge in the era of next-generation sequencing (NGS) is to design effective treatments tailored to the mutational profiles of tumors. Many newly discovered cancer mutations are difficult to target pharmacologically; however, T-cell-based therapies may provide a valuable alternative owing to the exquisite sensitivity and specificity of antigen recognition. To explore this concept, we assessed the immunogenicity of a panel of genes that are common sites of driver mutations in follicular lymphoma, an immunologically sensitive yet currently incurable disease.Exon capture and NGS were used to interrogate tumor samples from 53 patients with follicular lymphoma for mutations in 10 frequently mutated genes. For 13 patients, predicted mutant peptides and proteins were evaluated for recognition by autologous peripheral blood T cells after in vitro priming.Mutations were identified in 1-5 genes in 81% (43/53) of tumor samples. Autologous, mutation-specific CD8(+) T cells were identified in 23% (3/13) of evaluated cases. T-cell responses were directed toward putative driver mutations in CREBBP and MEF2B. Responding T cells showed exquisite specificity for mutant versus wild-type proteins and recognized lymphoma cells expressing the appropriate mutations. Responding T cells appeared to be from the naïve repertoire, as they were found at low frequencies and only at single time points in each patient.Patients with follicular lymphoma harbor rare yet functionally competent CD8(+) T cells specific for recurrent mutations. Our results support the concept of using NGS to design individualized immunotherapies targeting common driver mutations in follicular lymphoma and other malignancies. Clin Cancer Res; 22(9); 2226-36. ©2015 AACR.
Exertional dyspnoea and cortical oxygenation in patients with COPD
Authors: Yuji Higashimoto, Noritsugu Honda, Toshiyuki Yamagata, Akiko Sano, Osamu Nishiyama, Hiroyuki Sano, Takashi Iwanaga, Hiroaki Kume, Yasutaka Chiba, Kanji Fukuda, Yuji Tohda
Journal: European Respiratory Journal (2015)

This study was designed to investigate the association of perceived dyspnoea intensity with cortical oxygenation and cortical activation during exercise in patients with chronic obstructive pulmonary disease (COPD) and exertional hypoxaemia. Low-intensity exercise was performed at a constant work rate by patients with COPD and exertional hypoxaemia (n=11) or no hypoxaemia (n=16), and in control participants (n=11). Cortical oxyhaemoglobin (oxy-Hb) and deoxyhaemoglobin (deoxy-Hb) concentrations were measured by multichannel near-infrared spectroscopy. Increased deoxy-Hb is assumed to reflect impaired oxygenation, whereas decreased deoxy-Hb signifies cortical activation. Exercise decreased cortical deoxy-Hb in control and nonhypoxaemic patients. Deoxy-Hb was increased in hypoxaemic patients and oxygen supplementation improved cortical oxygenation. Decreased deoxy-Hb in the pre-motor cortex (PMA) was significantly correlated with exertional dyspnoea in control participants and patients with COPD without hypoxaemia. In contrast, increased cortical deoxy-Hb concentration was correlated with dyspnoea in patients with COPD and hypoxaemia. With the administration of oxygen supplementation, exertional dyspnoea was correlated with decreased deoxy-Hb in the PMA of COPD patients with hypoxaemia. During exercise, cortical oxygenation was impaired in patients with COPD and hypoxaemia compared with control and nonhypoxaemic patients; this difference was ameliorated with oxygen supplementation. Exertional dyspnoea was related to activation of the pre-motor cortex in COPD patients.
TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis
Authors: Sajedah M. Hindi, Ashok Kumar
Journal: Journal of Clinical Investigation (2015)

Satellite cells are a stem cell population within adult muscle and are responsible for myofiber regeneration upon injury. Satellite cell dysfunction has been shown to underlie the loss of skeletal muscle mass in many acquired and genetic muscle disorders. The transcription factor paired box-protein-7 (PAX7) is indispensable for supplementing the reservoir of satellite cells and driving regeneration in normal and diseased muscle. TNF receptor-associated factor 6 (TRAF6) is an adaptor protein and an E3 ubiquitin ligase that mediates the activation of multiple cell signaling pathways in a context-dependent manner. Here, we demonstrated that TRAF6-mediated signaling is critical for homeostasis of satellite cells and their function during regenerative myogenesis. Selective deletion of Traf6 in satellite cells of adult mice led to profound muscle regeneration defects and dramatically reduced levels of PAX7 and late myogenesis markers. TRAF6 was required for the activation of MAPKs ERK1/2 and JNK1/2, which in turn activated the transcription factor c-JUN, which binds the Pax7 promoter and augments Pax7 expression. Moreover, TRAF6/c-JUN signaling repressed the levels of the microRNAs miR-1 and miR-206, which promote differentiation, to maintain PAX7 levels in satellite cells. We also determined that satellite cell-specific deletion of Traf6 exaggerates the dystrophic phenotype in the mdx (a mouse model of Duchenne muscular dystrophy) mouse by blunting the regeneration of injured myofibers. Collectively, our study reveals an essential role for TRAF6 in satellite stem cell function.
Assessment of competence to complete advance directives: validation of a patient centred approach
Journal: BMJ (1999)

Objective To examine the association between use of aspirin or other non-steroidal anti-inflammatory drugs and intracerebral haemorrhage.Design Case-control study.Setting 13 major city hospitals in the Melbourne and metropolitan area.Subjects 331 consecutive cases of stroke verified by computed tomography or postmortem examination, and 331 age (± 5 years) and sex matched controls who were community based neighbours.Interventions Questionnaire administered to all subjects either directly or by proxy with the next of kin.Drug use was validated by reviewing prescribing records held by the participants' doctors.Main outcome measures Previous use of aspirin or other non-steroidal anti-inflammatory drugs.Results Univariate analysis showed no increased risk of intracerebral haemorrhage with low dose aspirin use in the preceding 2 weeks.Using multiple logistic regression to control for possible confounding factors, the odds ratio associated with the use of aspirin was 1.00 (95% confidence interval 0.60 to 1.66, P = 0.998) and the odds ratio associated with the use of other non-steroidal anti-inflammatory drugs was 0.85 (0.45 to 1.61, P = 0.611) compared with respective non-users in the preceding fortnight.Moderate to high doses of aspirin ( > 1225 mg/week spread over at least three doses) yielded an odds ratio of 3.05 (1.02 to 9.14, P = 0.047).There was no evidence of an increased risk among subgroups defined by age, sex, blood pressure status, alcohol intake, smoking, and the presence or absence of previous cardiovascular disease.Conclusions No increase in risk of intracerebral haemorrhage was found among aspirin users overall or among those who took low doses of the drug or other non-steroidal anti-inflammatory drugs.These data provide evidence that doses of aspirin usually used for prophylaxis against vascular disease produce no substantial increase in risk of intracerebral haemorrhage.
The small-subunit ribosomal RNA gene sequences from the hypotrichous ciliates Oxytricha nova and Stylonychia pustulata.
Authors: H J Elwood, G J Olsen, M L Sogin
Journal: Molecular Biology and Evolution (1985)

We have determined the complete nucleotide sequence of the small-subunit ribosomal RNA genes for the ciliate protozoans Stylonychia pustulata and Oxytricha nova. The sequences are homologous and sufficiently similar that these organisms must be closely related. In a phylogeny inferred from comparisons of several eukaryotic small-subunit ribosomal RNAs, the divergence of the ciliates from the eukaryotic line of descent is seen to coincide with the radiation of the plants, the animals, and the fungi. This radiation is preceded by the divergence of the slime mold, Dictyostelium discoideum.
Spectrum of epidemiological and clinical findings in patients with heart failure with preserved ejection fraction stratified by study design: a systematic review
Authors: Muthiah Vaduganathan, Alexander Michel, Kathryn Hall, Claire Mulligan, Savina Nodari, Sanjiv J. Shah, Michele Senni, Marco Triggiani, Javed Butler, Mihai Gheorghiade
Journal: European Journal of Heart Failure (2015)
Ongoing Use of Pulmonary Artery Catheters Despite Negative Trial Findings
Authors: Derek C. Angus
Journal: JAMA Internal Medicine (2015)

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Determinants of Hypofiltration during Acute Renal Allograft Rejection
Authors: Alkesh Jani, Catherine Polhemus, Geraldine Corrigan, Osun Kwon, Bryan D. Myers, Martha Pavlakis
Journal: Journal of the American Society of Nephrology (2002)

This study sought to determine the extent to which GFR is decreased during acute renal allograft rejection in human subjects and to determine the mechanism of the decrease in GFR. Eight patients with biopsy-proven acute rejection were compared with 18 recipients of optimally functioning renal allografts. GFR and renal plasma flow (RPF) were measured as the clearance of inulin and para-aminohippuric acid, respectively. Arterial BP was determined, blood was sampled, and plasma oncotic pressure (pi(A)) was measured. Glomeruli obtained by biopsy during rejection were subjected to morphometric analysis, for determination of K(f). Control morphometric values for healthy glomeruli were provided by 10 living donors from whom biopsies were obtained at the time of organ donation. The subjects in the acute rejection group exhibited a significantly reduced GFR of 17 +/- 4 ml/min per 1.73 m(2), compared with 72 +/- 4 ml/min per 1.73 m(2) for control subjects (P < 0.001). With the use of a sensitivity analysis to take into account the unknown para-aminohippuric acid extraction ratio, the RPF rate was calculated to have likely been significantly decreased, by 45 to 70%, in the acute rejection group. Neither the plasma oncotic pressure nor the mean arterial pressure differed between the two groups. Morphometric analysis revealed no difference in the single-nephron K(f) values for the acute rejection group, compared with the control group. These results indicate that acute renal allograft rejection causes a profound decrease in GFR, which is attributable to a decrease in RPF alone or in combination with a decrease in the glomerular transcapillary hydraulic pressure gradient (DeltaP).
Extensive Horizontal Transfer and Homologous Recombination Generate Highly Chimeric Mitochondrial Genomes in Yeast
Authors: Baojun Wu, Adnan Buljic, Weilong Hao
Journal: Molecular Biology and Evolution (2015)

The frequency of horizontal gene transfer (HGT) in mitochondrial DNA varies substantially. In plants, HGT is relatively common, whereas in animals it appears to be quite rare. It is of considerable importance to understand mitochondrial HGT across the major groups of eukaryotes at a genome-wide level, but so far this has been well studied only in plants. In this study, we generated ten new mitochondrial genome sequences and analyzed 40 mitochondrial genomes from the Saccharomycetaceae to assess the magnitude and nature of mitochondrial HGT in yeasts. We provide evidence for extensive, homologous-recombination-mediated, mitochondrial-to-mitochondrial HGT occurring throughout yeast mitochondrial genomes, leading to genomes that are highly chimeric evolutionarily. This HGT has led to substantial intraspecific polymorphism in both sequence content and sequence divergence, which to our knowledge has not been previously documented in any mitochondrial genome. The unexpectedly high frequency of mitochondrial HGT in yeast may be driven by frequent mitochondrial fusion, relatively low mitochondrial substitution rates and pseudohyphal fusion to produce heterokaryons. These findings suggest that mitochondrial HGT may play an important role in genome evolution of a much broader spectrum of eukaryotes than previously appreciated and that there is a critical need to systematically study the frequency, extent, and importance of mitochondrial HGT across eukaryotes.
Detection of influenza A(H3N2) clade 3C.2a viruses in patients with suspected mumps in British Columbia, Canada, during the 2014/15 influenza season
Authors: Catharine Chambers, Danuta M. Skowronski, Suzana Sabaiduc, Michelle Murti, Reka Gustafson, Sue Pollock, Dee Hoyano, Sandra Allison, Mel Krajden
Journal: Eurosurveillance (2015)

Preview this article: Detection of influenza A(H3N2) clade 3C.2a viruses in patients with suspected mumps in British Columbia, Canada, during the 2014/15 influenza season, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/20/36/eurosurv-20-30015-4-1.gif
Should psychiatrists administer anesthesia for ECT?
Authors: T Pearlman, M Loper, L Tillery
Journal: American Journal of Psychiatry (1990)

Whether psychiatrists are qualified to give anesthesia for ECT is controversial. At the authors' hospital, over a 9-year period ECT resulted in no mortality and minimal morbidity; in 98.8% of the treatments, anesthesia was given by psychiatrists. The average nursing time required for cases in which anesthesiologists administered anesthetic was longer than that for psychiatrists' cases. This difference may be related to succinylcholine dose and efficacy of ECT. The authors' surveys indicated that psychiatrists and anesthesiologists have differing opinions on whether psychiatrists should administer anesthesia for ECT and that few psychiatry residency programs which teach ECT provide training in anesthesia.
Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma
Authors: Jia Ruan, Peter Martin, Bijal Shah, Stephen J. Schuster, Sonali M. Smith, Richard R. Furman, Paul Christos, Amelyn Rodriguez, Jakub Svoboda, Jessica Lewis, Orel Katz, Morton Coleman, John P. Leonard
Journal: New England Journal of Medicine (2015)

Mantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy.We conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life.A total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome ("tumor flare") (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval [CI], 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be 85% (95% CI, 67 to 94), and the 2-year overall survival 97% (95% CI, 79 to 99). A response to treatment was associated with improvement in quality of life.Combination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle-cell lymphoma. (Funded by Celgene and Weill Cornell Medical College; ClinicalTrials.gov number, NCT01472562.).
Tailored and biodegradable poly(2-oxazoline) microbeads as 3D matrices for stem cell culture in regenerative therapies
Authors: Steffen Lück, René Schubel, Jannick Rüb, Dominik Hahn, Evelien Mathieu, Heike Zimmermann, Dieter Scharnweber, Carsten Werner, Sophie Pautot, Rainer Jordan
Journal: Biomaterials (2015)
Colon Cancer: The New Chronic Disease
Authors: Al B. Benson
Journal: Journal of the National Comprehensive Cancer Network (2014)

However, progress in treating CRC has not been limited to advances in systemic therapy for metastatic disease. This progress is exemplified by critical refinements in surgery and radiation oncology, including liver and lung resections for increasing numbers of patients, particularly those who have received neoadjuvant or “conversion” combination chemotherapy; laparoscopic surgery in both colon and rectal cancers; adequate lymph node sampling for prognostication; total mesorectal excision surgery as the standard of care for rectal cancers; and the emergence of neoadjuvant chemoradiation as the preferred approach for locally advanced rectal cancer, and for its effect on local recurrence, including downstaging and sphincter preservation. Pathologic evaluation has played a role with the use of database-driven analyses that demarcate subsets of patients, most notably those with stages II and III CRC, highlighted in the AJCC staging manual who show marked variability in prognosis within a given stage. The past few years have introduced genomic profiles that are important for treatment selection and prognosis: KRAS mutation determination (now extended RAS assessment) before considering anti–epidermal growth factor receptor (EGFR) therapy; BRAF mutation status as a prognostic tool, and microsatellite instability analysis, particularly for patients with stage II colon cancer, as a prognostic indicator and negative predictive marker for use of adjuvant 5-FU. Experts anticipate that, in the future, genomic analyses will be integrated with anatomic staging as a more robust or precise prognostic measure. For the generation of oncologists who have witnessed this treatment evolution and its impact on survival, both a cause for celebration and a sense of urgency exist. Investigators must further unravel the mysteries of human tumor biology that challenge the ability to select patients most likely to benefit from a given therapeutic approach, and to develop agents that will most effectively “hit the target,” whether as a single drug, in combination, or in sequential regimens. The continuum of care for metastatic CRC is a strategy of sequential therapy over time using all available drugs cited in the NCCN Guidelines for Colon and Rectal Cancers. We now have multiple lines of therapies (more appropriately stated as “initial therapy and therapy after first, second, and third progression”), with numerous choices of combinations administered in sequence over time.
Concerted evolution of light satellite DNA in genus Mus implies amplification and homogenization of large blocks of repeats.
Authors: B Dod, E Mottez, E Desmarais, F Bonhomme, G Roizés
Journal: Molecular Biology and Evolution (1989)

Light satellite DNA components present in species belonging to the genus Mus and to related murids were studied using the Southern blot technique. The results show species variations in both the amount and periodic structure of the repeating units, which suggests that families of related higher-order repeats developed in a common ancestor and were then amplified and/or deleted to different extents during the subsequent evolutionary period. Although the patterns generated by a series of type B enzymes (restriction enzymes that possess sites in a limited number of segments making up the total satellite DNA) in the species closely related to the M. musculus complex were very similar, sequence analysis of cloned unit repeats in two of these species (M. musculus domesticus and M. spretoides) showed near fixation of species-diagnostic variant nucleotides. This suggests that the important amplification and homogenization events that occurred after the divergence of M. spretus must have involved large blocks of sequences.