tbuckley/cabot-search huggingface dataset:
Gene Expansion and Retention Leads to a Diverse Tyrosine Kinase Superfamily in Amphioxus
Authors: S. D'Aniello, M. Irimia, I. Maeso, J. Pascual-Anaya, S. Jimenez-Delgado, S. Bertrand, J. Garcia-Fernandez
Journal: Molecular Biology and Evolution (2008)

Tyrosine kinase (TK) proteins play a central role in cellular behavior and development of animals. The expansion of this superfamily is regarded as a key event in the evolution of the complex signaling pathways and gene networks of metazoans and is a prominent example of how shuffling of protein modules may generate molecular novelties. Using the intron/exon structure within the TK domain (TK intron code) as a complementary tool for the assignment of orthology and paralogy, we identified and studied the 118 TK proteins of the amphioxus Branchiostoma floridae genome to elucidate TK gene family evolution in metazoans and chordates in particular. Unlike all characterized metazoans to date, amphioxus has members of all known widespread TK families, with not a single loss. Putting amphioxus TKs in an evolutionary context, including new data from the cnidarian Nematostella vectensis, the echinoderm Strongylocentrotus purpuratus, and the ascidian Ciona intestinalis, we suggest new evolutionary histories for different TK families and draw a new global picture of gene loss/gain in the different phyla. Surprisingly, our survey also detected an unprecedented expansion of a group of closely related TK families, including TIE, FGFR, PDGFR, and RET, due most probably to massive gene duplication and exon shuffling. Based on their highly similar intron/exon structure at the TK domain, we suggest that this group of TK families constitute a superfamily of TK proteins, which we termed EXpanding TK, after their seemingly unique propensity to gene duplication and exon shuffling, not only in amphioxus but also across all metazoan groups. Due to this extreme tendency to both retention and expansion of TK genes, amphioxus harbors the richest and most diverse TK repertoire among all metazoans studied so far, retaining most of the gene complement of its ancestors, but having evolved its own repertoire of genetic novelties.
GPs with links to private health firms may be excluded from commissioning role
Authors: A. O'Dowd
Journal: BMJ (2010)

Fears have been raised that GPs with a stake in private healthcare firms may be unable to hold a leadership role in the new GP led commissioning consortia being set up as part of NHS reforms.

A survey of 350 GPs carried out by Pulse magazine found that 27% of GPs had an investment in a private provider of NHS services in their local area.

The survey also found 8% had an investment in a company providing non-health services to the NHS and 12% had a stake in another private company. Many respondents (69%) said they were concerned that the government’s plan to hand responsibility for commissioning to GPs would create …
THE NOGO SIGNALING PATHWAY FOR REGENERATION BLOCK
Authors: Zhigang He, Vuk Koprivica
Journal: Annual Review of Neuroscience (2004)

A hostile environment and decreased regenerative capacity may contribute to the failure of axon regeneration in the adult central nervous system. Recent studies leading to the identification of several myelin-associated inhibitors and their signaling molecules provide opportunitities to assess the contribution of these inhibitory molecules in restricting axon regeneration. These findings may ultimately allow for the development of strategies to alleviate the inhibitory effects of such molecules in an effort to encourage axon regeneration after spinal cord and brain injury.
Serum microRNA Profiles Serve as Novel Biomarkers for HBV Infection and Diagnosis of HBV-Positive Hepatocarcinoma
Authors: Li-Min Li, Zhi-Bin Hu, Zhen-Xian Zhou, Xi Chen, Fen-Yong Liu, Jun-Feng Zhang, Hong-Bing Shen, Chen-Yu Zhang, Ke Zen
Journal: Cancer Research (2010)

Diagnosis of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), particularly HCC independent of cirrhosis etiology, presents a great challenge because of a lack of biomarkers. Here we test the hypothesis that expression profiles of microRNAs (miRNAs) in serum can serve as biomarkers for diagnosis of HBV infection and HBV-positive HCC. We recruited 513 subjects (210 controls and 135 HBV-, 48 hepatitis C virus (HCV)-, and 120 HCC-affected individuals) and employed a strategy of initial screening by Solexa sequencing followed by validation with TaqMan probe-based quantitative reverse transcription-PCR assay. First, because of a close link between chronic hepatitis B and HCC, we compared miRNA expression profiles in HBV serum with that in control serum and successfully obtained 13 miRNAs that were differentially expressed in HBV serum. This 13-miRNA-based biomarker accurately discriminated not only HBV cases from controls and HCV cases, but also HBV-positive HCC cases from control and HBV cases. Second, we directly compared miRNA expressions in HCC serum with those in controls and identified 6 miRNAs that were significantly upregulated in HCC samples. Interestingly, 2 of these miRNAs, miR-375 and miR-92a, were also identified by our first approach as HBV specific. When we employed 3 of these miRNAs (miR-25, miR-375, and let-7f) as biomarkers, we could clearly separate HCC cases from controls, and miR-375 alone had an ROC of 0.96 (specificity: 96%; sensitivity: 100%) in HCC prediction. In conclusion, our study demonstrates for the first time that serum miRNA profiles can serve as novel and noninvasive biomarkers for HBV infection and HBV-positive HCC diagnosis.
The Importance of Biodiversity to Medicine
Authors: Aaron S Bernstein, David S Ludwig
Journal: JAMA (2008)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
S15 FVC or TLCO? Impact on treatment following NICE (National Institute for Health and Care Excellence) approval of pirfenidone: Abstract S15 Table 1.
Authors: G Saini, T McKeever, R Braybrooke, R Hubbard, G Jenkins
Journal: Thorax (2013)

<h3>Introduction</h3> Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal lung disease with median survival of 3 years (1). NICE has recently approved Pirfenidone, which is the first licensed treatment for IPF. Pirfenidone is licensed for mild to moderate IPF, and the current NICE recommendation is that all patients with FVC (Forced Vital capacity) between 50–80% predicted should be considered for therapy. However, there is no agreed classification of disease severity in IPF. In clinical practice a combination of both FVC and DL<sub>CO</sub> (diffusion of lung carbon monoxide) is used to monitor disease progression. We explore the practical impact of using FVC on Pirfenidone prescribing. <h3>Methods</h3> 218 incident cases of IPF have been enrolled in a prospective cohort study PROFILE in Central England from September 2009 to June 2013. All patients had a diagnosis of definite or probable IPF based on the ATS consensus 2000. The patients were stratified according to both FVC and DLco. Lung function defects were considered mild (FVC&gt;80%, DL<sub>CO</sub>&gt;60%), moderate (FVC 50–80%, DL<sub>CO </sub>40–60%) and severe (FVC&lt;50%, DL<sub>CO</sub> &lt;40%). <h3>Results</h3> The median age was 72 years with majority cohort males (77% males’ vs 23%females). 181(84%) cases met diagnostic criteria for definite IPF. There was only a moderate correlation between FVC and T<sub>L</sub>CO with correlation coefficient = 0.54 and p &lt; 0.001. A total of 79 patients (44%) would be eligible for treatment based on FVC criteria. However, this includes 46 patients (25%) who might be considered to have severe disease based on DLco criteria. (Table 1) <h3>Conclusion</h3> Over half our patients eligible for Pirfenidone, based on current NICE criteria, will have severely reduced DL<sub>CO</sub>. This highlights the need for an agreed classification of IPF disease severity. Follow up of PROFILE study patients may help guide a classification system. <h3>References</h3> Navaratnam <i>et al, Thorax</i> 2011 Jun;66(6):462–7. doi: 10.1136/thoraxjnl-2013-204457.22
Interruptions of Chest Compressions During Emergency Medical Systems Resuscitation
Authors: Terence D. Valenzuela, Karl B. Kern, Lani L. Clark, Robert A. Berg, Marc D. Berg, David D. Berg, Ronald W. Hilwig, Charles W. Otto, Daniel Newburn, Gordon A. Ewy
Journal: Circulation (2005)

Survival after nontraumatic out-of-hospital (OOH) cardiac arrest in Tucson, Arizona, has been flat at 6% (121/2177) for the decade 1992 to 2001. We hypothesized that interruptions of chest compressions occur commonly and for substantial periods during treatment of OOH cardiac arrest and could be contributing to the lack of improvement in resuscitation outcome.Sixty-one adult OOH cardiac arrest patients treated by automated external defibrillator (AED)-equipped Tucson Fire Department first responders from November 2001 through November 2002 were retrospectively reviewed. Reviews were performed according to the code arrest record and verified with the AED printout. Validation of the methodology for determining the performance of chest compressions was done post hoc. The median time from "9-1-1" call receipt to arrival at the patient's side was 6 minutes, 27 seconds (interquartile range [IQR, 25% to 75%], 5 minutes, 24 seconds, to 7 minutes, 34 seconds). An additional 54 seconds (IQR, 38 to 74 seconds) was noted between arrival and the first defibrillation attempt. Initial defibrillation shocks never restored a perfusing rhythm (0/21). Chest compressions were performed only 43% of the time during the resuscitation effort. Although attempting to follow the 2000 guidelines for cardiopulmonary resuscitation, chest compressions were delayed or interrupted repeatedly throughout the resuscitation effort. Survival to hospital discharge was 7%, not different from that of our historical control (4/61 versus 121/2177; P=0.74).Frequent interruption of chest compressions results in no circulatory support during more than half of resuscitation efforts. Such interruptions could be a major contributing factor to the continued poor outcome seen with OOH cardiac arrest.
Remodeling by ventricular pacing in hypertrophying dog hearts
Authors: M van Oosterhout
Journal: Cardiovascular Research (2001)

Objective: Asynchronous electrical activation of the left ventricle (LV), induced by ventricular pacing (VP), reduces mechanical load in early- and enhances it in late-activated regions. Consequently, chronic VP leads to asymmetric hypertrophy. We investigated whether such locally induced myocardial hypertrophy also occurs in the presence of pressure overload hypertrophy (POH). Methods: POH was induced by aortic banding in puppies. At age 9 months, seven dogs were paced at the right ventricular (RV) apex at physiological heart rate for 6 months (POH-pace group), while four POH dogs served as POH-control group. Changes in volume of the LV cavity and the total LV wall and of five LV wall sectors were measured by means of 2D-echocardiography and X-ray marker detection. Results: During the last 6 months of the protocol the volume of the five LV wall sectors increased in the POH-control group, ranging from 27±9 to 30±5% (mean±S.D.). In POH-pace animals sector wall volume in the four sectors at intermediate to long distance from the pacing site increased to a similar extent (ranging from 31±16 to 35±17%), but wall volume in the early-activated apical septum increased significantly less (17±21%). In these hearts myocyte diameter was significantly smaller in the apical septum than in the lateral LV wall. The regional difference in wall volume changes (19±21%) was significantly smaller in the POH-pace group than in chronically paced, non-hypertrophic, canine hearts in a previous study from our laboratory (43±14%). Conclusions: In hypertrophying hearts chronic pacing at the RV apex suppresses the development of hypertrophy in the early-activated apical septum but does not cause additional hypertrophy in late-activated regions, as is the case in non-hypertrophic hearts. The latter suggests that the local growth response is reduced in hypertrophying hearts.
A Common Cancer-Associated DNA Polymerase ϵ Mutation Causes an Exceptionally Strong Mutator Phenotype, Indicating Fidelity Defects Distinct from Loss of Proofreading
Authors: Daniel P. Kane, Polina V. Shcherbakova
Journal: Cancer Research (2014)

Exonucleolytic proofreading and DNA mismatch repair (MMR) act in series to maintain high-fidelity DNA replication and to avoid mutagenesis. MMR defects elevate the overall mutation rate and are associated with increased cancer incidence. Hypermutable colorectal and endometrial tumors with functional MMR were recently reported to carry amino acid substitutions in the exonuclease domain of DNA polymerase ε (Polε). This created a notion that loss of the proofreading activity of Polε is an initiating cause of some sporadic human cancers. In this study, we identified a somatic P286R substitution in the conserved ExoI motif of Polε in a collection of 52 sporadic colorectal tumor specimens. This change has been repeatedly observed in colorectal and endometrial tumors in previous studies despite many possible ways to inactivate Polε proofreading. To understand the reasons for the recurrent appearance of the P286R variant, we characterized its functional consequences using the yeast model system. An analogous substitution in the yeast Polε produced an unusually strong mutator phenotype exceeding that of proofreading-deficient mutants by two orders of magnitude. This argues that the P286R mutation acts at some level other than loss of exonuclease to elevate cancer risk. Heterozygosity for the variant allele caused a strong mutator effect comparable with that of complete MMR deficiency, providing an explanation for why loss of heterozygosity is not required for the development of Polε-mutant human tumors.
Long-Term Graft Survival with Neoral and Tacrolimus
Authors: Bruce Kaplan, Jesse D Schold, Herwig-Ulf Meier-Kriesche
Journal: Journal of the American Society of Nephrology (2003)

Calcineurin inhibitors (CNI) are an important component of most immunosuppressive protocols utilized in renal transplantation. Both CNI available (cyclosporine and tacrolimus) have been used for many years. Studies comparing the efficacy of these two agents in terms of long-term graft or patient survival have thus far failed to show an advantage for either agent. This failure to show a difference could possibly be due to underpowering of clinical trials. The authors used the SRTR database to analyze 5-yr graft survival of the microemulsion formulation of cyclosporine (Neoral) as compared with tacrolimus. To minimize the donor variability and bias, a paired kidney analysis was used. Deceased donors from the years 1995-2002 were analyzed from the SRTR database. All paired kidneys during this period, where one kidney was allocated to a patient receiving initial Neoral therapy and its mate allocated to a patient receiving initial tacrolimus therapy were evaluated. Multivariate and univariate analysis were performed. Univariate analysis demonstrated equivalent graft survival for Neoral compared with tacrolimus (66.9% versus 65.9%, respectively). Multivariate analysis could not demonstrate a difference in risk for 5-yr patient survival or graft loss. Renal function was superior for tacrolimus at all time points, whereas the slope of 1/Cr over time did not differ for the two agents. In this paired kidney analysis, no difference in 5-yr renal allograft survival could be found between the two agents. Renal function was superior in the patients receiving initial tacrolimus therapy; however, slope of 1/Cr did not differ between the agents.
Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: P. Moreau, J. San Miguel, P. Sonneveld, M.V. Mateos, E. Zamagni, H. Avet-Loiseau, R. Hajek, M.A. Dimopoulos, H. Ludwig, H. Einsele, S. Zweegman, T. Facon, M. Cavo, E. Terpos, H. Goldschmidt, M. Attal, C. Buske
Journal: Annals of Oncology (2017)
Randomized Multicenter Trial of the Effects of Melanoma-Associated Helper Peptides and Cyclophosphamide on the Immunogenicity of a Multipeptide Melanoma Vaccine
Authors: Craig L. Slingluff, Gina R. Petroni, Kimberly A. Chianese-Bullock, Mark E. Smolkin, Merrick I. Ross, Naomi B. Haas, Margaret von Mehren, William W. Grosh
Journal: Journal of Clinical Oncology (2011)

Purpose This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8 + T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4 + or CD8 + T-cell responses to that vaccine. Patients and Methods In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex–restricted melanoma peptides (12MP) to stimulate CD8 + T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4 + T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded. Results Vaccination with 12MP plus tetanus induced CD8 + T-cell responses in 78% of patients and CD4 + T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8 + responses in 19% of patients and CD4 + responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm. Conclusion Melanoma-associated helper peptides paradoxically decreased CD8 + T-cell responses to a melanoma vaccine (P &lt; .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells.
Use of sodA sequencing for the identification of clinical isolates of coagulase-negative staphylococci
Authors: V. Sivadon, M. Rottman, J.-C. Quincampoix, V. Avettand, S. Chaverot, P. de Mazancourt, P. Trieu-Cuot, J.-L. Gaillard
Journal: Clinical Microbiology and Infection (2004)
Ethical Challenges to Cell-Based Interventions for the Central Nervous System: Some Recommendations for Clinical Trials and Practice
Authors: P. H. Schwartz, M. W. Kalichman
Journal: The American Journal of Bioethics (2009)

Duggan and colleagues (2009) make the case that cell-based interventions (CBIs) involving the central nervous system will plausibly alter cognition, mood, or behavior; therefore, we should incorpor...
"Splitting of the Mind" Revisited: Recent Neuroimaging Evidence for Functional Dysconnection in Schizophrenia and Its Relation to Symptoms
Authors: Sohee Park, Katharine N. Thakkar
Journal: American Journal of Psychiatry (2010)

Bleuler coined the term "schizophrenia" to capture the fragmentation and disintegration of the mind and behavior as the essence of the disorder (1).The splitting of thoughts, feelings, and actions was duly noted, but very few studies over the past century have addressed how and why these functions are dissociated in schizophrenia.Despite the robust evidence for the influence of emotion on cognition and vice versa (2, 3), the nature of these interactions and their role in psychotic symptoms are not clearly elucidated.Vast evidence indicates that emotion affects memory processes (4).Further, it has long been known that schizophrenia is associated with chronically elevated levels of anxiety and stress (5), and paranoid symptoms are hypothesized to be related to abnormal threat processing (6).As such, the influence of emotion on cognitive processes in schizophrenia deserves more attention than it has received.
The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans
Authors: C. Cristina Quarta, Joel N. Buxbaum, Amil M. Shah, Rodney H. Falk, Brian Claggett, Dalane W. Kitzman, Thomas H. Mosley, Kenneth R. Butler, Eric Boerwinkle, Scott D. Solomon
Journal: New England Journal of Medicine (2014)

Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure.
A Disaccharide-Based Inhibitor of Glycosylation Attenuates Metastatic Tumor Cell Dissemination
Authors: Jillian R. Brown, Mark M. Fuster, Ruixia Li, Nissi Varki, Charles A. Glass, Jeffrey D. Esko
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The binding of hematogenously borne malignant cells that express the carbohydrate sialyl Lewis X (sLeX) to selectin adhesion receptors on leukocytes, platelets, and endothelial cells facilitates metastasis. The glycosylation inhibitor, per-O-acetylated GlcNAcβ1,3Galβ-O-naphthalenemethanol (AcGnG-NM), inhibits the biosynthesis of sLeX in tumor cells. To evaluate the efficacy of AcGnG-NM as an antimetastatic agent, we examined its effect on experimental metastasis and on spontaneous hematogenous dissemination of murine Lewis lung carcinoma and B16BL6 melanoma cells. Experimental Design: Tumor cells were treated in vitro with AcGnG-NM, and the degree of selectin ligand inhibition and experimental metastasis was analyzed in wild-type and P-selectin-deficient mice. Conditions were developed for systemic administration of AcGnG-NM, and the presence of tumor cells in the lungs was assessed using bromodeoxyuridine labeling in vivo. The effect of AcGnG-NM on inflammation was examined using an acute peritonitis model. Results: In vitro treatment of Lewis lung carcinoma cells with AcGnG-NM reduced expression of sLeX- and P-selectin-dependent cell adhesion to plates coated with P-selectin. Treatment also reduced formation of lung foci when cells were injected into syngeneic mice. Systemic administration of the disaccharide significantly inhibited spontaneous dissemination of the cells to the lungs from a primary s.c. tumor, whereas an acetylated disaccharide not related to sLeX in structure had no effect. AcGnG-NM did not alter the level of circulating leukocytes or platelets, the expression of P-selectin ligands on neutrophils, or sLeX-dependent inflammation. Conclusion: Taken together, these data show that AcGnG-NM provides a targeted glycoside-based therapy for the treatment of hematogenous dissemination of tumor cells.
Gene therapy of RAG-2−/− mice: sustained correction of the immunodeficiency
Authors: Frank Yates, Michèle Malassis-Séris, Daniel Stockholm, Cécile Bouneaud, Frédérique Larousserie, Patricia Noguiez-Hellin, Olivier Danos, Donald B. Kohn, Alain Fischer, Jean-Pierre de Villartay, Marina Cavazzana-Calvo
Journal: Blood (2002)