tbuckley/cabot-search huggingface dataset:
Prognostic Significance of Nuclear ING3 Expression in Human Cutaneous Melanoma
Authors: Yemin Wang, Derek L. Dai, Magdalena Martinka, Gang Li
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The novel tumor-suppressor ING3 has been shown to modulate transcription, cell cycle control, and apoptosis. Our previous study showed that ING3 promotes UV-induced apoptosis via the Fas/caspase-8–dependent pathway in melanoma cells. To investigate the putative role of ING3 in the development of melanoma, we examined the expression of ING3 in melanocytic lesions at different stages and analyzed the correlation between ING3 expression and clinicopathologic variables and patient survival. Experimental Design: Using tissue microarray and immunohistochemistry, we evaluated nuclear and cytoplasmic ING3 staining in 58 dysplastic nevi, 114 primary melanomas, and 50 metastatic melanomas. Results: Nuclear ING3 expression was remarkably reduced in malignant melanomas compared with dysplastic nevi (P &amp;lt; 0.001), which was significantly correlated with the increased ING3 level in cytoplasm (P &amp;lt; 0.05). Furthermore, the reduced nuclear ING3 expression was significantly correlated with a poorer disease-specific 5-year survival of patients with primary melanoma, especially for the high-risk melanomas (thickness ≥2.0 mm) with the survival rate reducing from 93% for patients with strong nuclear ING3 staining in their tumor biopsies to 44% for those with negative-to-moderate nuclear ING3 staining (P = 0.004). Strikingly, our multivariate Cox regression analysis revealed that reduced nuclear ING3 expression is an independent prognostic factor to predict patient outcome in primary melanomas (P = 0.038). Conclusions: Our data indicate that ING3 may be an important marker for human melanoma progression and prognosis as well as a potential therapeutic target.
Revalidation in Sport and Exercise Medicine: a UK perspective
Authors: Mark E Batt, Rod D Jaques
Journal: British Journal of Sports Medicine (2010)

The era of professional self regulation in medicine is over. In 2006, it was recognised in the UK Chief Medical Officer's report, ‘Good doctors, Safer patients,’ that an enhanced system of quality assurance and performance management of doctors was required, not only for the profession but to protect the safety of patients.1 From this developed a proposal for five-yearly revalidation of doctors, which is to have two elements, relicensing and recertification. The former, relicensing, began in November 2009. Doctors in the UK are required to hold a licence to practise, which sits alongside their General Medical Council (GMC) registration. Licensure is required by all doctors currently undertaking those professional activities that were previously restricted by law to doctors registered with the GMC.2 Relicensing is the process set up to demonstrate that doctors are practising in accordance with generic standards of practice broadly based upon the guidance provided by the GMC in Good Medical Practice.3

The purpose of this editorial is to bring into focus the requirements for recertification of those doctors practising Sport and Exercise Medicine in the UK. Before considering the specific requirements, it is important to understand that the purpose of revalidation is to ensure that doctors who are registered and have a licence to practise are up to …
The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells
Authors: Hidetoshi Sumimoto, Fumie Imabayashi, Tomoko Iwata, Yutaka Kawakami
Journal: The Journal of Experimental Medicine (2006)

The mitogen-activated protein kinase (MAPK) pathway is frequently activated in human cancers, leading to malignant phenotypes such as autonomous cellular proliferation. Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation. The suppressive activity of the culture supernatants from the melanoma cells on the production of inflammatory cytokines IL-12 and tumor necrosis factor alpha by dendritic cells upon lipopolysaccharide stimulation was markedly reduced after transduction with BRAF(V600E) RNAi, comparable to the effects observed with STAT3 RNAi transduction. No additive or synergistic effects were observed by the simultaneous transduction of RNAi for both BRAF(V600E) and STAT3. Furthermore, specific DNA binding and transcriptional activity of STAT3 were not affected by down-regulation of the MAPK signaling with the BRAF RNAi. These results indicate that the MAPK signal, along with the STAT3 signal, is essential for immune evasion by human melanomas that have constitutively active MAPK signaling and is a potential molecular target for overcoming melanoma cell evasion of the immune system.
The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease
Authors: Alexander H. Stephan, Ben A. Barres, Beth Stevens
Journal: Annual Review of Neuroscience (2012)

An unexpected role for the classical complement cascade in the elimination of central nervous system (CNS) synapses has recently been discovered. Complement proteins are localized to developing CNS synapses during periods of active synapse elimination and are required for normal brain wiring. The function of complement proteins in the brain appears analogous to their function in the immune system: clearance of cellular material that has been tagged for elimination. Similarly, synapses tagged with complement proteins may be eliminated by microglial cells expressing complement receptors. In addition, developing astrocytes release signals that induce the expression of complement components in the CNS. In the mature brain, early synapse loss is a hallmark of several neurodegenerative diseases. Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complement-mediated synapse elimination potentially driving disease progression.
Genotype-Phenotype Relationships in U.S. Melanoma-Prone Families With CDKN2A and CDK4 Mutations
Authors: A. M. Goldstein
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Two genes have been implicated in the development of cutaneous malignant melanoma (CMM). CDK4 (the gene encoding cyclin-dependent kinase 4, an oncogene) has exhibited germline mutations found in only three melanoma-prone families to date. CDKN2A is a tumor suppressor gene that encodes p16 (which inhibits activity of the cyclin D1–CDK4 complex) with germline mutations detected in 10%–25% of melanoma-prone families, some of whom are also prone to pancreatic cancer. Methods: We compared 104 CMM patients from 17 CDKN2A families and 12 CMM case subjects from two CDK4 families. We used nonparametric statistics to test for differences in median age at first CMM diagnosis, numbers of CMMs, and numbers of nevi. The three recurrent mutations were haplotyped. All P values were two-sided. Results: The median age at CMM diagnosis (P = .70) and the median numbers of CMMs (P = .73) did not differ between CMM case subjects from CDKN2A versus CDK4 families. Assessment of CMM case subjects from CDKN2A families with and without pancreatic cancer revealed no statistically significant differences in median age at diagnosis (P = .80) or in tumor number (P = .24). There was, however, a statistically significant difference in age-adjusted median numbers of nevi (P = .004), and CMM case subjects from CDKN2A families without pancreatic cancer had greater numbers of nevi. Recurrent CDKN2A mutations were a change from valine to aspartic acid at codon 126 (n = 3) and from glycine to tryptophan at codon 101 (n = 3). Six CDKN2A families had pancreatic cancer. Both CDK4 families carried a mutation resulting in an arginine-to-cysteine substitution at codon 24. Analyses of recurrent CDKN2A and CDK4 mutations suggested common haplotypes. Conclusions: The recurrent CDKN2A mutations were observed in families with and without pancreatic cancer, which suggests that other factors may be involved in the development of pancreatic cancer. Despite hypothetical differences in the mechanisms of action between CDKN2A and CDK4, clinical factors were indistinguishable between CMM case subjects from CDKN2A versus CDK4 families.
Identification of a novel fusion gene, TTL, fused to ETV6 in acute lymphoblastic leukemia with t(12;13)(p13;q14), and its implication in leukemogenesis
Authors: Y Qiao, S Ogawa, A Hangaishi, K Yuji, K Izutsu, A Kunisato, Y Imai, L Wang, N Hosoya, Y Nannya, Y Sato, K Maki, K Mitani, H Hirai
Journal: Leukemia (2003)
Correlation Between Dopamine D2 Receptors in the Ventral Striatum and Central Processing of Alcohol Cues and Craving
Authors: A. Heinz
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Alcohol and other drugs of abuse stimulate dopamine release in the ventral striatum, which includes the nucleus accumbens, a core region of the brain reward system, and reinforce substance intake. Chronic alcohol intake is associated with down-regulation of central dopamine D2 receptors, and delayed recovery of D2 receptor sensitivity after detoxification is positively correlated with high risk for relapse. Prolonged D2 receptor dysfunction in the ventral striatum may interfere with a dopamine-dependent error detection signal and bias the brain reward system toward excessive attribution of incentive salience to alcohol-associated stimuli. METHOD: Multimodal imaging, with the radioligand [18F]desmethoxyfallypride and positron emission tomography as well as functional magnetic resonance imaging (fMRI), was used to compare 11 detoxified male alcoholics with 13 healthy men. The authors measured the association of D2-like dopamine receptors in the ventral striatum with alcohol craving and central processing of alcohol cues. RESULTS: Activation of the medial prefrontal cortex and striatum by alcohol-associated stimuli, relative to activation by neutral visual stimuli, was greater in the detoxified alcoholics than in the healthy men. The alcoholics displayed less availability of D2-like receptors in the ventral striatum, which was associated with alcohol craving severity and with greater cue-induced activation of the medial prefrontal cortex and anterior cingulate as assessed with fMRI. DISCUSSION: In alcoholics, dopaminergic dysfunction in the ventral striatum may attribute incentive salience to alcohol-associated stimuli, so that alcohol cues elicit craving and excessive activation of neural networks associated with attention and behavior control.
Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21
Authors: Albert Tenesa, Susan M Farrington, James G D Prendergast, Mary E Porteous, Marion Walker, Naila Haq, Rebecca A Barnetson, Evropi Theodoratou, Roseanne Cetnarskyj, Nicola Cartwright, Colin Semple, Andrew J Clark, Fiona J L Reid, Lorna A Smith, Kostas Kavoussanakis, Thibaud Koessler, Paul D P Pharoah, Stephan Buch, Clemens Schafmayer, Jürgen Tepel, Stefan Schreiber, Henry Völzke, Carsten O Schmidt, Jochen Hampe, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Stefan Wilkening, Federico Canzian, Gabriel Capella, Victor Moreno, Ian J Deary, John M Starr, Ian P M Tomlinson, Zoe Kemp, Kimberley Howarth, Luis Carvajal-Carmona, Emily Webb, Peter Broderick, Jayaram Vijayakrishnan, Richard S Houlston, Gad Rennert, Dennis Ballinger, Laura Rozek, Stephen B Gruber, Koichi Matsuda, Tomohide Kidokoro, Yusuke Nakamura, Brent W Zanke, Celia M T Greenwood, Jagadish Rangrej, Rafal Kustra, Alexandre Montpetit, Thomas J Hudson, Steven Gallinger, Harry Campbell, Malcolm G Dunlop
Journal: Nature Genetics (2008)
Association of hypoadiponectinemia in men with early onset of coronary heart disease and multiple coronary artery stenoses
Authors: Naotake Hashimoto, Junji Kanda, Tomonori Nakamura, Atsuya Horie, Hiroko Kurosawa, Toru Hashimoto, Kazutoshi Sato, Syunichi Kushida, Masaru Suzuki, Shingo Yano, Rie Iwai, Hidenori Takahashi, Shouji Yoshida
Journal: Metabolism (2006)
Inefficacy of infliximab in ankylosing spondylitis is correlated with antibody formation
Authors: M K de Vries, G J Wolbink, S O Stapel, E R de Groot, B A C Dijkmans, L A Aarden, I E van der Horst-Bruinsma
Journal: Annals of the Rheumatic Diseases (2006)

Tumour necrosis factor blocking agents such as infliximab have proved to be effective in patients with ankylosing spondylitis as up to 60–70% of the patients meet the 20% response criteria of assessment in ankylosing spondylitis (ASAS).1,2 However, it cannot be explained why 30% of patients fail to respond and develop adverse reactions.

In rheumatoid arthritis, inefficacy to infliximab was associated with low serum trough infliximab levels and the presence of antibodies to infliximab (ATI).3

This study was designed to identify whether infliximab levels and ATI predict clinical inefficacy and adverse events in ankylosing spondylitis.

Eight patients with active ankylosing spondylitis (fulfilling the 1984 modified New York Criteria …
Targeted Interleukin-2 Therapy for Spontaneous Neuroblastoma Metastases to Bone Marrow
Authors: H. N. Lode, R. Xiang, C. S. Dolman, R. A. Reisfeld, N. M. Varki, S. D. Gillies
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Advanced (stage 4) cases of neuroblastoma, a childhood cancer of the nervous system, are associated with high relapse rates, even after intensive chemotherapy, radiotherapy, and autologous bone marrow transplantation. Therefore, the use of monoclonal antibodies directed against the neuroblastoma tumor marker disialoganglioside GD 2 (GD 2 ), in combination with recombinant human interleukin 2 (rhIL-2), is under clinical investigation. We hypothesize that targeted cytokine immunotherapy with a recombinant anti-GD 2 antibody—interleukin 2 fusion protein (ch14.18-IL-2) is superior to a combination of ch14.18 and rhIL-2. Our purpose was as follows: 1) to develop a syngeneic model for murine neuroblastoma that expresses GD 2 and features both experimental and spontaneous metastases to bone marrow and liver, and 2) to assess anti-GD 2 -targeted IL-2 therapy in this model. Methods: A hybrid neuroblastoma cell line was used to generate the GD 2 -positive NXS2 cell line. Bone marrow and liver metastases were quantified by reverse transcription—polymerase chain reaction for tyrosine hydroxylase and by organ weight or counts of macroscopic tumor foci, respectively. All P values reported are two-sided. Results: Injection of NXS2 cells resulted in disseminated bone marrow and liver metastases exhibiting stable, but heterogeneous expression of GD 2 . Treatment with fusion protein (10 μg/day for 6 days) effectively suppressed growth of both experimental and spontaneous metastases to bone marrow and liver ( P <.001). In contrast, a mixture of rhIL-2 and ch14.18 at equivalent dose levels was inefficient. Only mice treated with ch14.18-IL-2 showed a twofold prolongation in life span ( P <.001). Conclusion: Targeted IL-2 therapy with a ch14.18-IL-2 fusion protein elicits an effective antitumor response. Our data suggest that a study of ch14.18-IL-2 as an adjuvant treatment in patients with minimal residual disease may be of value.
THE NECESSITY FOR FULLER CONSIDERATION OF THE LOCAL PROCESSES OF DISEASE AND REPAIR IN THE TREATMENT OF PULMONARY TUBERCULOSIS
Authors: H. M. Davies
Journal: BMJ (1918)

TREATMENT OF PULMONARY TUBERCULOSIS. [APRIL 6, Igz8.pathologists who have had the opportunity of examining the nervous centres after death tell us that distinct marks of feebly inflammatory decay -are not inconspicuous in the brain; the spinal cord being normal.Especially in the Rolandic area signs of a slow pia-arachnitis are found, with degeneration of the cortical cells and some ehronic cell proliferation.There are no affinities of this disease to rheumatic fever, but it would seem to be a result of some infection.In this case, as in others of the kind, the lheart is unaffected.The causes of the mala,dy are in complete obscurity; the discussions of its antecedents in thie textbooks are trivial.
p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells.
Authors: L Tuosto, F Michel, O Acuto
Journal: The Journal of Experimental Medicine (1996)

p95vav, the product of the vav protooncogene, has been implicated in the T cell receptor (TCR)-mediated signaling cascade p95vav is phosphorylated on tyrosine residues after TCR stimulation by anti-TCR/CD3 antibodies and possesses a number of landmark features of signaling molecules such as a putative guanine nucleotide exchange factor domain, a pleckstrin homology domain, and an Sre homology (SH) 2 and two SH3 domains, which provide the capacity to form multimeric signaling complexes. However, the precise role of p95vav in TCR signaling remains unclear. In this work we show that physiological stimulation of T cell hybridomas with antigen presented by major histocompatibility complex class II molecules leads to a strong tyrosine phosphorylation of p95vav and its association with tyrosine-phosphorylated SLP-76. SLP-76 is a newly described SH2-containing protein that has been previously found to bind to the adapter molecule Grb2. Moreover, we provide evidence that p95vav-SI P-76 association is SH2-mediated by demonstrating that this interaction can be inhibited by a phosphopeptide containing a putative p95vav-SH2-binding motif (pYESP) present in SLP-76. Furthermore, in vitro experiments show that after antigen stimulation, phosphorylated p95vav-SLP-76 can bind to Grb2 in a complex that contains pp36/38 and pp116 proteins. Our data provide a clue to explain recent independent observations that overexpression of p95vav or SLP-76 enhances TCR-mediated gene activation.
Regulation and Function of NF-κB Transcription Factors in the Immune System
Authors: Sivakumar Vallabhapurapu, Michael Karin
Journal: Annual Review of Immunology (2009)

The mammalian Rel/NF-κB family of transcription factors, including RelA, c-Rel, RelB, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation. The five members of the NF-κB family are normally kept inactive in the cytoplasm by interaction with inhibitors called IκBs or the unprocessed forms of NF-κB1 and NF-κB2. A wide variety of signals emanating from antigen receptors, pattern-recognition receptors, receptors for the members of TNF and IL-1 cytokine families, and others induce differential activation of NF-κB heterodimers. Although work over the past two decades has shed significant light on the regulation of NF-κB transcription factors and their functions, much progress has been made in the past two years revealing new insights into the regulation and functions of NF-κB. This recent progress is covered in this review.
Reversal of lidocaine effects on sodium currents by isoproterenol in rabbit hearts and heart cells.
Authors: H C Lee, J J Matsuda, S I Reynertson, J B Martins, E F Shibata
Journal: Journal of Clinical Investigation (1993)

We demonstrated recently that isoproterenol enhanced the cardiac voltage-dependent sodium currents (INa) in rabbit ventricular myocytes through dual G-protein regulatory pathways. In this study, we tested the hypothesis that isoproterenol reverses the sodium channel blocking effects of class I antiarrhythmic drugs through modulation of INa. The experiments were performed in rabbit ventricular myocytes using whole-cell patch-clamp techniques. Reversal of lidocaine suppression of INa by isoproterenol (1 microM) was significant at various concentrations of lidocaine (20, 65, and 100 microM, P < 0.05). The effects of isoproterenol were voltage dependent, showing reversal of INa suppression by lidocaine at normal and hyperpolarized potentials (negative to -80 mV) but not at depolarized potentials. Isoproterenol enhanced sodium channel availability but did not alter the steady state activation or inactivation of INa nor did it improve sodium channel recovery in the presence of lidocaine. The physiological significance of the single cell INa findings were corroborated by measurements of conduction velocities using an epicardial mapping system in isolated rabbit hearts. Lidocaine (10 microM) significantly suppressed epicardial impulse conduction in both longitudinal (theta L, 0.430 +/- 0.024 vs. 0.585 +/- 0.001 m/s at baseline, n = 7, P < 0.001) and transverse (theta T, 0.206 +/- 0.012 vs. 0.257 +/- 0.014 m/s at baseline, n = 8, P < 0.001) directions. Isoproterenol (0.05 microM) significantly reversed the lidocaine effects with theta L of 0.503 +/- 0.027 m/s and theta T of 0.234 +/- 0.015 m/s (P = 0.014 and 0.004 compared with the respective lidocaine measurements). These results suggest that enhancement of INa is an important mechanism by which isoproterenol reverses the effects of class I antiarrhythmic drugs.
<i>In vitro</i>Canine Distemper Virus Infection of Canine Lymphoid Cells: A Prelude to Oncolytic Therapy for Lymphoma
Authors: Steven E. Suter, May B. Chein, Veronika von Messling, Becky Yip, Roberto Cattaneo, William Vernau, Bruce R. Madewell, Cheryl A. London
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Measles virus (MV) causes the regression of human lymphoma xenografts. The purpose of this study was to determine if canine lymphoid cells could be infected in vitro with MV or canine distemper virus (CDV, the canine Morbillivirus equivalent of MV) and determine if in vitro viral infection leads to apoptotic cell death. Experimental Design: Reverse transcriptase-PCR was used to examine the expression of both signal lymphocyte activation molecule (CD150) and membrane cofactor molecule (CD46) mRNA. An attenuated CDV expressing enhanced green fluorescent protein was used to infect canine cells in vitro. Both flow cytometry and reverse transcriptase-PCR was used to document CDV infection. Cell death was examined using a propidium iodide staining assay and Annexin V binding. Results: Canine lymphoid cell lines and neoplastic B and T lymphocytes collected from dogs with spontaneous lymphoma expressed the Morbillivirus receptor CD150 mRNA. In contrast, only neoplastic lymphocytes expressed detectable levels of CD46 mRNA. Although MV did not infect canine cells, CDV efficiently infected between 40% and 70% of all three canine lymphoid lines tested. More importantly, CDV infected 50% to 90% of neoplastic lymphocytes isolated from dogs with both B and T cell lymphoma. Apoptosis of CDV-infected cell lines was documented. Conclusions: Attenuated CDV may be a useful treatment for canine lymphoma. As such, dogs with lymphoma may represent a biologically relevant large animal model to investigate the feasibility, safety, and efficacy of Morbillivirus therapy in a clinical setting with findings that may have direct applicability in the treatment of human non-Hodgkin's lymphoma.