tbuckley/cabot-search huggingface dataset:
Sarcoplasmic Reticulum Ca <sup>2+</sup> Release Is Not a Dominating Factor in Sinoatrial Node Pacemaker Activity
Authors: H. Honjo, S. Inada, M.K. Lancaster, M. Yamamoto, R. Niwa, S.A. Jones, N. Shibata, K. Mitsui, T. Horiuchi, K. Kamiya, I. Kodama, M.R. Boyett
Journal: Circulation Research (2003)

Recent work on isolated sinoatrial node cells from rabbit has suggested that sarcoplasmic reticulum Ca 2+ release plays a dominant role in the pacemaker potential, and ryanodine at a high concentration (30 μmol/L blocks sarcoplasmic reticulum Ca 2+ release) abolishes pacemaking and at a lower concentration abolishes the chronotropic effect of β-adrenergic stimulation. The aim of the present study was to test this hypothesis in the intact sinoatrial node of the rabbit. Spontaneous activity and the pattern of activation were recorded using a grid of 120 pairs of extracellular electrodes. Ryanodine 30 μmol/L did not abolish spontaneous activity or shift the position of the leading pacemaker site, although it slowed the spontaneous rate by 18.9±2.5% (n=6). After ryanodine treatment, β-adrenergic stimulation still resulted in a substantial chronotropic effect (0.3 μmol/L isoproterenol increased spontaneous rate by 52.6±10.5%, n=5). In isolated sinoatrial node cells from rabbit, 30 μmol/L ryanodine slowed spontaneous rate by 21.5±2.6% (n=13). It is concluded that sarcoplasmic reticulum Ca 2+ release does not play a dominating role in pacemaking in the sinoatrial node. The full text of this article is available at http://www.circresaha.org.
Complex Spliceosomal Organization Ancestral to Extant Eukaryotes
Authors: Lesley Collins, David Penny
Journal: Molecular Biology and Evolution (2005)

In higher eukaryotes, introns are spliced out of protein-coding mRNAs by the spliceosome, a massive complex comprising five non-coding RNAs (ncRNAs) and about 200 proteins. By comparing the differences between spliceosomal proteins from many basal eukaryotic lineages, it is possible to infer properties of the splicing system in the last common ancestor of extant eukaryotes, the eukaryotic ancestor. We begin with the hypothesis that, similar to intron length (that appears to have increased in multicellular eukaryotes), the spliceosome has increased in complexity throughout eukaryotic evolution. However, examination of the distribution of spliceosomal components indicates that not only was a spliceosome present in the eukaryotic ancestor but it also contained most of the key components found in today's eukaryotes. All the small nuclear ribonucleoproteins (snRNPs) protein components are likely to have been present, as well as many splicing-related proteins. Both major and trans-splicing are likely to have been present, and the spliceosome had already formed links with other cellular processes such as transcription and capping. However, there is no evidence as yet to suggest that minor (U12-dependent) splicing was present in the eukaryotic ancestor. Although the last common ancestor of extant eukaryotes appears to show much of the molecular complexity seen today, we do not, from this work, infer anything of the properties of the earlier "first eukaryote."
Autogenous Vaccine Therapy in Staphylococcic Infections
Authors: Kenneth L. McCoy
Journal: JAMA (1960)

Sixty cases of staphylococcic infection occurring during a 12-month period were treated with vaccine therapy and evaluated as follows: 5 cases of failure, 11 cases of improvement, and 44 cases of excellent response. The antigenicity of the vaccine depended on the use of a mild killing agent, avoiding subculture of the vaccine strain, standardizing the vaccine density before killing the organisms, and shaking the vaccine cell suspension during the incubation period. Autogenous vaccine prepared in the manner described offers a valuable therapeutic agent for recurring, persistent severe infections due to staphylococcic organisms.
Technical practices are important to consider when assessing noninvasive ventilation failure
Authors: A. Cuvelier, J-F. Muir
Journal: European Respiratory Journal (2005)

important aspects, such as the response of chemokines or adhesion molecules, as well as angiogenesis-related factors to resistive breathing.More research is needed to study not only the factors driving the expression of an angiogenetic programme within the respiratory muscles, but also the actual process of angiogenesis, as well as its clinical relevance.
Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets
Authors: D W Hommes
Journal: Gut (2002)

Over the last decade important advances have been made in our understanding of the molecular events underlying cellular responses to extracellular signals. Increased understanding of signal transduction mechanisms and gene regulation involved in immune responses has created opportunities for the discovery of novel therapeutic compounds useful in treating inflammatory disorders. One of the best studied signalling routes is the mitogen activated protein (MAP) kinase signal transduction pathway which plays a crucial role in many aspects of immune mediated inflammatory responses. Here, our current understanding of the MAP kinase pathway is reviewed, as well as recent advances in the design of novel agents that are able to modulate the activity of these signalling cascades.
Novel Intraoperative Molecular Test for Sentinel Lymph Node Metastases in Patients With Early-Stage Breast Cancer
Authors: Thomas B. Julian, Peter Blumencranz, Kenneth Deck, Pat Whitworth, Donald A. Berry, Scott M. Berry, Anne Rosenberg, Anees B. Chagpar, Douglas Reintgen, Peter Beitsch, Rache Simmons, Sukamal Saha, Eleftherios P. Mamounas, Armando Giuliano
Journal: Journal of Clinical Oncology (2008)

Purpose An accurate, intraoperative sentinel lymph node (SLN) test could decrease delayed axillary dissections. Molecular tests may be more sensitive than current intraoperative tests but historically have not been rapid enough and have not been properly validated. We present the results from a large, prospective evaluation of the first rapid molecular SLN test, the Breast Lymph Node (BLN) Assay. Methods A beta trial (n = 304) to determine the threshold levels of mammaglobin and cytokeratin 19 correlating with metastasis greater than 0.2 mm and a validation trial (n = 416) to validate the threshold cutoffs were conducted. Alternating portions from each SLN were processed for histology and the BLN Assay. Results BLN Assay performance against extensive permanent-section histology verified by central pathology review was similar to that expected of standard permanent-section histology: sensitivity, 87.6%; specificity, 94.2%; positive predictive value, 86.2%; and negative predictive value (NPV), 94.9%. In 319 patients with both frozen-section hematoxylin and eosin results and BLN Assay results, the BLN Assay had higher sensitivity (95.6%) and NPV (98.2%) than frozen section (sensitivity, 85.6%; NPV, 94.5%). The assay can be performed in approximately 36 to 46 minutes for one to three nodes. Conclusion The BLN Assay allows a rapid evaluation of 50% of each SLN. Comparison with permanent-section histology on adjacent node pieces evaluated by expert pathologists indicated that the BLN Assay was more sensitive than current intraoperative techniques while maintaining high specificity. These data indicate that the assay may be clinically useful for intraoperative or postoperative axillary lymph node dissection decisions.
B-Cell Non-Hodgkin's Lymphoma: Evidence for the t(14;18) Translocation in All Hematopoietic Cell Lineages
Authors: S. Yarkoni, M. Lishner, I. Tangi, A. Nagler, H. Lorberboum-Galski
Journal: JNCI Journal of the National Cancer Institute (1996)

B cells of patients with non-Hodgkin's lymphoma (B-NHL) harbor specific chromosomal translocations, including t(14; 18), the most common aberration found in this disease. The translocation involves the immunoglobulin (lg) heavy-chain joining (JH) region gene on chromosome 14 and the BCL2 gene on chromosome 18, resulting in dysregulated expression of the BCL2 gene. The t(14; 18) translocation has been thought to occur in the pre-B-cell stage, during the first event of Ig gene rearrangement. This study was conducted to investigate the potential involvement of nonlymphoid lineages in B-NHL. We studied the t(14; 18) translocation and other frequently occurring translocations in total bone marrow aspirates of 10 patients with B-NHL, with the use of the fluorescence in situ hybridization (FISH) technique. We also performed cytogenetic analyses on representative bone marrow aspirates from the patients. Moreover, to define which of the major cell lineages present in the bone marrow carry the t(14;18) translocation, we used a series of monoclonal antibodies together with fluorescence-activated cell sorter (FACS) analyses to purify cells positive for CD3 (T cells), CD19 (B cells), CD10 (CALLA-positive cells), CD41a (megakaryocytic cells), CD13 (myeloid cells), and glyco-phorin A (erythroid cells). The cells of each subgroup underwent FISH analysis with the use of JH and BCL2 probes to detect the t(14; 18) translocation. Bone marrow samples obtained from five healthy donors served as controls. Bone marrow cells from eight of the 10 patients studied carried the t(14;18) translocation. When present, the translocation was observed in many or even all of the cell lineages (lymphoid, myeloid, megakaryocytic, and erythroid) present in the bone marrow, including peripheral blood progenitor stem cells; for seven of the eight patients carrying the translocation, it was found in 96%–100% of the unfractionated bone marrow cells as well as in all of the FACS-purified cell fractions in which it could be detected or studied. Conventional cytogenetic analyses performed on representative bone marrow aspirates confirmed the results obtained by FISH analysis. Cells in control bone marrow samples obtained from the five healthy donors were negative for the t(14;18) translocation by FISH analysis. Our findings indicate that the t(14;18) translocation most probably occurs in a very early multilineage progenitor stem cell. Given that the t(14;18) chromosomal translocation was found in all types of bone marrow cells when only the B cells were malignant, our results suggest that this translocation is not sufficient to induce neoplastic transformation. This finding underscores the need for the development of new approaches for the detection and surveillance of B-NHL. [J Natl Cancer Inst 1996;88:973–9]
Role of rat α adducin in angiogenesis: Null effect of the F316Y polymorphism
Authors: C CAPPUZZELLO, R MELCHIONNA, A MANGONI, G TRIPODI, P FERRARI, L TORIELLI, D ARCELLI, M HELMERCITTERICH, G BIANCHI, M CAPOGROSSI
Journal: Cardiovascular Research (2007)

Rat alpha adducin point mutation (F316Y) has been associated with primary systemic arterial hypertension. As microcirculatory abnormalities are present in most forms of hypertension, the aim of the present study was to investigate whether rat alpha adducin may regulate endothelial cell (EC) functions in vitro and in vivo.The overexpression of rat wild type alpha adducin (WT-Add1) in ECs induced capillary-like structure development in Matrigel in vitro and enhanced capillary formation in Matrigel implants in vivo in CD1 mice. In contrast, the overexpression of the mutated form (MUT-Add1) of rat alpha adducin had a Null effect in vitro and lacked any significant activity in vivo. Further, adenovirus-mediated rat WT-Add1 but not MUT-Add1 gene transfer to murine ischemic hindlimb enhanced capillary formation in skeletal muscles. Gene profiling of human umbilical vein endothelial cells overexpressing alpha adducin was performed in order to identify putative effector molecules of alpha adducin-mediated activities on ECs. Interestingly, among a number of genes involved in angiogenesis regulation, retinoic acid-induced protein (RAI17) was found to be upregulated in WT-Add1 vs MUT-Add1 overexpressing cells, possibly representing a key molecule/axis for the functional Add1-induced effect.Rat WT alpha adducin enhanced EC functions both in vitro and in vivo. The expression of the F316Y variant, associated with the hypertensive phenotype, had a Null effect and might contribute to endothelial rarefaction/dysfunction in hypertension. RAI17 was found to be a putative effector molecule differentially regulated by the overexpression of the two forms of Add1 in endothelial cells.
European health systems and cancer care
Authors: A. Micheli, J.W. Coebergh, E. Mugno, E. Massimiliani, M. Sant, W. Oberaigner, J. Holub, H.H. Storm, D. Forman, M. Quinn, T. Aareleid, R. Sankila, T. Hakulinen, J. Faivre, H. Ziegler, L. Tryggvadòttir, R. Zanetti, M. Dalmas, O. Visser, F. Langmark, M. Bielska-Lasota, Z. Wronkowski, P.S. Pinheiro, D.H. Brewster, I. Pleško, V. Pompe-Kirn, C. Martinez-Garcia, L. Barlow, T. Möller, J.M. Lutz, M. André, J.A. Steward
Journal: Annals of Oncology (2003)
Physician and Stakeholder Perceptions of Conflict of Interest Policies in Oncology
Authors: A. Craig Lockhart, Marcia S. Brose, Edward S. Kim, David H. Johnson, Jeffrey M. Peppercorn, Dina L. Michels, Courtney D. Storm, Lynn M. Schuchter, W. Kimryn Rathmell
Journal: Journal of Clinical Oncology (2013)

The landscape of managing potential conflicts of interest (COIs) has evolved substantially across many disciplines in recent years, but rarely are the issues more intertwined with financial and ethical implications than in the health care setting. Cancer care is a highly technologic arena, with numerous physician-industry interactions. The American Society of Clinical Oncology (ASCO) recognizes the role of a professional organization to facilitate management of these interactions and the need for periodic review of its COI policy (Policy).To gauge the sentiments of ASCO members and nonphysician stakeholders, two surveys were performed. The first asked ASCO members to estimate opinions of the Policy as it relates to presentation of industry-sponsored research. Respondents were classified as consumers or producers of research material based on demographic responses. A similar survey solicited opinions of nonphysician stakeholders, including patients with cancer, survivors, family members, and advocates.The ASCO survey was responded to by 1,967 members (1% of those solicited); 80% were producers, and 20% were consumers. Most respondents (93% of producers; 66% of consumers) reported familiarity with the Policy. Only a small proportion regularly evaluated COIs for presented research. Members favored increased transparency about relationships over restrictions on presentations of research. Stakeholders (n = 264) indicated that disclosure was "very important" to "extremely important" and preferred written disclosure (77%) over other methods.COI policies are an important and relevant topic among physicians and patient advocates. Methods to simplify the disclosure process, improve transparency, and facilitate responsiveness are critical for COI management.
Epigenetic Inactivation of Galanin Receptor 1 in Head and Neck Cancer
Authors: Kiyoshi Misawa, Yo Ueda, Takeharu Kanazawa, Yuki Misawa, Ilwhan Jang, John Chadwick Brenner, Tetsuya Ogawa, Satoru Takebayashi, Reidar A. Grenman, James G. Herman, Hiroyuki Mineta, Thomas E. Carey
Journal: Clinical Cancer Research (2008)

Abstract Purpose: One copy of the galanin receptor 1 (GALR1) locus on 18q is often deleted and expression is absent in some head and neck squamous cell carcinoma (HNSCC) cell lines. To determine if loss of heterozygosity and hypermethylation might silence the GALR1 gene, promoter methylation status and gene expression were assessed in a large panel of HNSCC cell lines and tumors. Experimental Design: Promoter methylation of GALR1 in 72 cell lines and 100 primary tumor samples was analyzed using methylation-specific PCR. GALR1 expression and methylation status were analyzed further by real-time PCR and bisulfite sequencing analysis. Results: The GALR1 promoter was fully or partially methylated in 38 of 72 (52.7%) HNSCC cell lines but not in the majority 18 of 20 (90.0%) of nonmalignant lines. GALR1 methylation was also found in 38 of 100 (38%) primary tumor specimens. Methylation correlated with decreased GALR1 expression. In tumors, methylation was significantly correlated with increased tumor size (P = 0.0036), lymph node status (P = 0.0414), tumor stage (P = 0.0037), cyclin D1 expression (P = 0.0420), and p16 methylation (P = 0.0494) and survival (P = 0.045). Bisulfite sequencing of 36 CpG sites upstream of the transcription start site revealed that CpG methylation within transcription factor binding sites correlated with complete suppression of GALR1 mRNA. Treatment with trichostatin A and 5-azacytidine restored GALR1 expression. In UM-SCC-23 cells that have total silencing of GALR1, exogenous GALR1 expression and stimulation with galanin suppressed cell proliferation. Conclusions: Frequent promoter hypermethylation, gene silencing, association with prognosis, and growth suppression after reexpression support the hypothesis that GALR1 is a tumor suppressor gene in HNSCC.
Probing to Bone in Infected Pedal Ulcers
Authors: M. Lindsay Grayson
Journal: JAMA (1995)

To assess a bedside technique for diagnosing osteomyelitis.We prospectively assessed infected pedal ulcers for detectable bone by probing with a sterile, blunt, stainless steel probe. We then examined the relationship between detection of bone and the presence or absence of osteomyelitis that was defined histopathologically and/or clinically.A tertiary care center.Seventy-five hospitalized diabetic patients with a total of 76 infected foot ulcers were studied.Osteomyelitis was diagnosed in 50 instances (66%) and was excluded in 26 instances. Bone was detected by probing in 33 of 50 ulcers with contiguous osteomyelitis; in contrast, bone was probed in only four of 26 ulcers without contiguous osteomyelitis (P < .001). Bone detected on probing was visible in only three instances. Palpating bone on probing the pedal ulcer had a sensitivity of 66% for osteomyelitis, a specificity of 85%, a positive predictive value of 89%, and a negative predictive value of 56%.Palpation of bone in the depths of infected pedal ulcers in patients with diabetes is strongly correlated with the presence of underlying osteomyelitis. If bone is palpated on probing, specialized roentgenographic and radionuclide tests to diagnose osteomyelitis are unnecessary. Probing for bone should be included in the initial assessment of all diabetic patients with infected pedal ulcers.
Spontaneous cholecysto- and hepatolithiasis inMdr2?/? mice: A model for low phospholipid-associated cholelithiasis
Authors: Frank Lammert, David Q.-H. Wang, Sonja Hillebrandt, Andreas Geier, Peter Fickert, Michael Trauner, Siegfried Matern, Beverly Paigen, Martin C. Carey
Journal: Hepatology (2004)

Previously, we identified needle-like and filamentous, putatively “anhydrous” cholesterol crystallization in vitro at very low phospholipid concentrations in model and native biles. Our aim now was to address whether spontaneous gallstone formation occurs in Mdr2 ( Abcb4 ) knockout mice that are characterized by phospholipid-deficient bile. Biliary phenotypes and cholesterol crystallization sequences in fresh gallbladder biles and non-fixed liver sections were determined by direct and polarizing light microscopy. The physical chemical nature and composition of crystals and stones were determined by sucrose density centrifugation and before mass and infrared spectroscopy. Gallbladder biles of Mdr2 −/− mice precipitate needle-like cholesterol crystals at 12 weeks of age on chow. After 15 weeks, more than 50% of Mdr2 −/− mice develop gallbladder stones, with female mice displaying a markedly higher gallstone-susceptibility. Although gallbladder biles of Mdr2 −/− mice contain only traces (≤ 1.1 mM) of phospholipid and cholesterol, they become supersaturated with cholesterol and plot in the left 2-phase zone of the ternary phase diagram, consistent with “anhydrous” cholesterol crystallization. Furthermore, more than 40% of adult female Mdr2 −/− mice show intra- and extrahepatic bile duct stones. In conclusion, spontaneous gallstone formation is a new consistent feature of the Mdr2 −/− phenotype. The Mdr2 −/− mouse is therefore a model for low phospholipid-associated cholelithiasis recently described in humans with a dysfunctional mutation in the orthologous ABCB4 gene. The mouse model supports the concept that this gene is a monogenic risk factor for cholesterol gallstones and a target for novel therapeutic strategies. (Hepatology 2004;39:117-128.)
Long-term Follow-up Study of Ingenol Mebutate Gel for the Treatment of Actinic Keratoses
Authors: Mark Lebwohl, Stephen Shumack, Linda Stein Gold, Anita Melgaard, Thomas Larsson, Stephen K. Tyring
Journal: JAMA Dermatology (2013)

Ingenol mebutate is the active agent (a macrocyclic diterpene ester) in the sap of the plant Euphorbia peplus. This herb has been used as a traditional remedy for several different skin lesions, including skin cancers.To assess 12-month recurrence rates and safety associated with ingenol mebutate gel treatment in patients who previously had achieved complete clearance of actinic keratoses.The treatment area was observed for recurrence for 12 months after the original study. Patients were treated in an outpatient setting.Patients received ingenol mebutate gel, 0.015%, daily for 3 consecutive days for actinic keratoses on the face or scalp or ingenol mebutate gel, 0.05%, daily for 2 consecutive days for actinic keratoses on the trunk or extremities. Study participants had achieved complete clearance in a prespecified 25-cm2 area at day 57 of their original trial.Recurrence rates and safety were assessed. RESULTS In total, 108 patients with complete clearance of face or scalp lesions in the original trial and 76 patients with complete clearance of trunk or extremity lesions in the original trial were enrolled in the 12-month observational follow-up study. Of these, 100 patients (face or scalp) and 71 patients (trunk or extremities) completed all 12 months. The sustained lesion reduction rates compared with baseline were 87.2% for the face or scalp and 86.8% for the trunk or extremities. The estimated median times to recurrence were 365 days (face or scalp) and 274 days (trunk or extremities). There were no safety concerns during the follow-up period.Ingenol mebutate gel applied as field therapy for 2 or 3 consecutive days to treat actinic keratoses produced clinically relevant sustained clearance and long-term lesion reduction. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT00953732, NCT00952783, and NCT00989313.
DiscoverySpace: an interactive data analysis application.
Authors: Neil Robertson, Mehrdad Oveisi-Fordorei, Scott D Zuyderduyn, Richard J Varhol, Christopher Fjell, Marco Marra, Steven Jones, Asim Siddiqui
Journal: Genome biology (2007)

DiscoverySpace is a graphical application for bioinformatics data analysis. Users can seamlessly traverse references between biological databases and draw together annotations in an intuitive tabular interface. Datasets can be compared using a suite of novel tools to aid in the identification of significant patterns. DiscoverySpace is of broad utility and its particular strength is in the analysis of serial analysis of gene expression (SAGE) data. The application is freely available online.