tbuckley/cabot-search huggingface dataset:
Dynorphin B Is an Agonist of Nuclear Opioid Receptors Coupling Nuclear Protein Kinase C Activation to the Transcription of Cardiogenic Genes in GTR1 Embryonic Stem Cells
Authors: Carlo Ventura, Elisabetta Zinellu, Emiliana Maninchedda, Margherita Maioli
Journal: Circulation Research (2003)

The cardiac differentiation of embryonic stem (ES) cells was found to involve prodynorphin gene and dynorphin B expression and was associated with the interaction of secreted dynorphin B with cell surface opioid receptors coupled with protein kinase C (PKC) signaling and complex subcellular redistribution patterning of selected PKC isozymes. Here, confocal microscopy revealed the presence of immunoreactive dynorphin B-like material in GTR1 ES cells, suggesting that dynorphin peptides may also act intracellularly. Opioid binding sites were identified in ES cell nuclei, with a single dissociation constant in the low nanomolar range. A significant increase in Bmax for a kappa opioid receptor ligand was observed in nuclei isolated from ES-derived cardiomyocytes compared with nuclei from undifferentiated cells. Direct exposure of nuclei isolated from undifferentiated ES cells to dynorphin B or U-50,488H, a synthetic kappa opioid receptor agonist, time- and dose-dependently activated the transcription of GATA-4 and Nkx-2.5, 2 cardiac lineage-promoting genes. Nuclear exposure to dynorphin B also enhanced the rate of prodynorphin gene transcription. These responses were abolished in a stereospecific fashion by the incubation of isolated nuclei with selective opioid receptor antagonists. Nuclei isolated from undifferentiated cells were able to phosphorylate the acrylodan-labeled MARCKS peptide, a high-affinity fluorescent PKC substrate. Exposure of isolated nuclei to dynorphin B induced a remarkable increase in nuclear PKC activity, which was suppressed by opioid receptor antagonists. Nuclear treatment with PKC inhibitors abolished the capability of dynorphin B to prime the transcription of cardiogenic genes.
Psychological constructionism and cultural neuroscience
Authors: Lisa A. Hechtman, Narun Pornpattananangkul, Joan Y. Chiao
Journal: Behavioral and Brain Sciences (2012)

Lindquist et al. argue that emotional categories do not map onto distinct regions within the brain, but rather, arise from basic psychological processes, including conceptualization, executive attention, and core affect. Here, we use examples from cultural neuroscience to argue that psychological constructionism, not locationism, captures the essential role of emotion in the social and cultural brain.
Sequence-specific inhibition of duck hepatitis B virus reverse transcription by peptide nucleic acids (PNA)
Authors: Magdalena Robaczewska, Ramamurthy Narayan, Beatrice Seigneres, Olivier Schorr, Alexandre Thermet, Anna J. Podhajska, Christian Trepo, Fabien Zoulim, Peter E. Nielsen, Lucyna Cova
Journal: Journal of Hepatology (2004)
Better Late than Early: FDG-PET Imaging in Metastatic Renal Cell Carcinoma
Authors: Michael R. Harrison, Daniel J. George
Journal: Clinical Cancer Research (2011)

Abstract Sunitinib treatment benefits patients with metastatic renal cell carcinoma (mRCC), but response duration can vary widely and resistance is not predicted by standard measures. [18F]fluoro-2-deoxy-2-d-glucose positron emission tomography (FDG-PET) uptake is variable in mRCC, but changes in FDG-PET uptake may be useful in monitoring disease progression. Further work is needed to personalize treatment for patients with mRCC. Clin Cancer Res; 17(18); 5841–3. ©2011 AACR.
Lymphatic Mapping and Sentinel Lymph Node Biopsy in Patients With Melanoma: A Meta-Analysis
Authors: Matias E. Valsecchi, Damian Silbermins, Nicole de Rosa, Sandra L. Wong, Gary H. Lyman
Journal: Journal of Clinical Oncology (2011)

To perform a meta-analysis of all published studies of sentinel lymph node (SLN) biopsy for staging patients with melanoma.Published literature in all languages between 1990 and 2009 was critically appraised. Primary outcomes evaluated included the proportion successfully mapped (PSM) and test performance including false-negative rate (FNR), post-test probability negative (PTPN), and positive predictive value in the same nodal basin recurrence.A total of 71 studies including 25,240 patients met full eligibility criteria. The average PSM was 98.1% (95% CI, 97.3% to 98.6%) and increased with the year of publication, female sex, ulceration, age, and the quality score of the studies. The FNR ranged from 0.0% to 34.0%, averaging 12.5% overall (95% CI, 11% to 14.2%). FNR increased with the length of follow-up (P = .002) but decreased with greater PSM (P = .001). PTPN averaged 3.4% (95% CI, 3.0% to 3.8%), which also increased in studies with longer follow-up, younger age, female sex, deeper Breslow thickness, and with tumor ulceration while decreasing with greater PSM (P < .001). Approximately 20% of the patients with a positive SLN had additional lymph nodes in the complete lymph node dissection and 7.5% of the patients with positive SLN developed recurrence in the same nodal basin which was greater in studies that also reported higher FNR (P = .01).The estimated risk of nodal recurrence after a negative SLN biopsy was ≤ 5% supporting the use of this technology for staging patients with melanoma.
Cynthia Ruth Woodhall
Authors: J. S. S. Hill
Journal: BMJ (2013)

Cynthia Ruth Woodhall was brought up in the Black Country. After qualifying she undertook basic junior posts, but then specialised in paediatrics, spending an important and formative year in neonatology in Halifax, Nova Scotia.

After senior registrar training around Manchester, she was appointed to Whiston Hospital in 1986 to augment a team of two consultants. She had, by then, gained a great deal of experience in general paediatrics as well as neonates, with additional important experience in child and adolescent psychiatry, respiratory disease, and gastroenterology; with children with special needs; and, sadly, in child protection too. In total she had spent 10 years in paediatric …
Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial
Authors: Gerd R Burmester, Ricardo Blanco, Christina Charles-Schoeman, Jürgen Wollenhaupt, Cristiano Zerbini, Birgitta Benda, David Gruben, Gene Wallenstein, Sriram Krishnaswami, Samuel H Zwillich, Tamas Koncz, Koshika Soma, John Bradley, Charles Mebus
Journal: The Lancet (2013)
Emodin Down-Regulates Androgen Receptor and Inhibits Prostate Cancer Cell Growth
Authors: Tai-Lung Cha, Lin Qiu, Chun-Te Chen, Yong Wen, Mien-Chie Hung
Journal: Cancer Research (2005)

Abstract Hormone-refractory relapse is an inevitable and lethal event for advanced prostate cancer patients after hormone deprivation. A growing body of evidence indicates that hormone deprivation may promote this aggressive prostate cancer phenotype. Notably, androgen receptor (AR) not only mediates the effect of androgen on the tumor initiation but also plays the major role in the relapse transition. This provides a strong rationale for searching new effective agents targeting the down-regulation of AR to treat or prevent advanced prostate cancer progression. Here, we show that emodin, a natural compound, can directly target AR to suppress prostate cancer cell growth in vitro and prolong the survival of C3(1)/SV40 transgenic mice in vivo. Emodin treatment resulted in repressing androgen-dependent transactivation of AR by inhibiting AR nuclear translocation. Emodin decreased the association of AR and heat shock protein 90 and increased the association of AR and MDM2, which in turn induces AR degradation through proteasome-mediated pathway in a ligand-independent manner. Our work indicates a new mechanism for the emodin-mediated anticancer effect and justifies further investigation of emodin as a therapeutic and preventive agent for prostate cancer.
Systemic administration of the chemokine macrophage inflammatory protein 1 exacerbates inflammatory bowel disease in a mouse model
Authors: S L-F Pender
Journal: Gut (2005)

Exacerbations of inflammatory bowel disease are thought to be related to concurrent infections. As infections are associated with elevated local and serum concentrations of chemokines, we have determined whether systemic administration of the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha) exacerbates colitis in a mouse model.Colitis was induced in Balb/c mice using trinitrobenzene sulfonic acid (TNBS). Starting four days later, animals received daily intraperitoneal injections of recombinant MIP-1alpha. On day 7, mice were killed and pieces of colon taken for immunohistology and polymerase chain reaction analysis. The direct effects of MIP-1alpha on mucosal T cells and fibroblasts in vitro were also investigated.Systemic administration of MIP-1alpha markedly enhanced colitis with mice developing large transmural ulcers filled with granulation tissue. Treatment resulted in increased numbers of CD4 cells infiltrating the colonic lamina propria, increased interferon gamma (IFN-gamma) levels, and increased transcripts for tumour necrosis factor alpha (TNF-alpha) and matrix metalloproteinase 3 (MMP3). Isolated lamina propria lymphocytes from mice with TNBS colitis contained increased numbers of IFN-gamma and TNF-alpha transcripts when stimulated with MIP-1alpha in vitro. Colonic lamina propria fibroblasts also responded to MIP-1alpha with increased proliferation and decreased collagen 1 synthesis but fibroblast proliferation was not seen in vivo.These experiments show that increasing serum concentrations of a chemokine, MIP-1alpha, exacerbates immune mediated colitis. The effect seems to be due to the ability of MIP-1alpha to boost Th1 responses in the gut wall. Our findings also suggest a potential pathway by which peripheral infections can exacerbate inflammatory bowel disease.
Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer
Authors: Andrew H. Miller, Sonia Ancoli-Israel, Julienne E. Bower, Lucile Capuron, Michael R. Irwin
Journal: Journal of Clinical Oncology (2008)

Patients with cancer experience a host of behavioral alterations that include depression, fatigue, sleep disturbances, and cognitive dysfunction. These behavioral comorbidities are apparent throughout the process of diagnosis and treatment for cancer and can persist well into the survivorship period. There is a rich literature describing potential consequences of behavioral comorbidities in patients with cancer including impaired quality of life, reduced treatment adherence, and increased disease-related morbidity and mortality. Medical complications of cancer and its treatment such as anemia, thyroid dysfunction, and the neurotoxicity of cancer chemotherapeutic agents account in part for these behavioral changes. Nevertheless, recent advances in the neurosciences and immunology/oncology have revealed novel insights into additional pathophysiologic mechanisms that may significantly contribute to the development of cancer-related behavioral changes. Special attention has been focused on immunologic processes, specifically activation of innate immune inflammatory responses and their regulation by neuroendocrine pathways, which, in turn, influence CNS functions including neurotransmitter metabolism, neuropeptide function, sleep-wake cycles, regional brain activity, and, ultimately, behavior. Further understanding of these immunologic influences on the brain provides a novel conceptual framework for integrating the wide spectrum of behavioral alterations that occur in cancer patients and may reveal a more focused array of translational targets for therapeutic interventions and future research. Such developments warrant complementary advances in identification of cancer patients at risk as well as those currently suffering, including an increased emphasis on the status of behavior as a "sixth vital sign" to be assessed in all cancer patients throughout their disease encounter.
CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway.
Authors: E J Schattner, K B Elkon, D H Yoo, J Tumang, P H Krammer, M K Crow, S M Friedman
Journal: The Journal of Experimental Medicine (1995)

The Apo-1/Fas antigen (CD95) mediates programmed cell death of lymphocytes when bound by Fas ligand or anti-Apo-1/Fas antibody. In contrast, the CD40 antigen provides a potent activation and survival signal to B lymphocytes when it is engaged by its T cell ligand (CD40L, gp39) or cross-linked by anti-CD40 antibody. In this study, we use human tonsillar B cells and the Ramos Burkitt's lymphoma B cell line, which serves as a model for human germinal center B lymphocytes, to study the effectors of Apo-1/Fas expression and apoptosis of human B cells. We found that Apo-1/Fas expression was upregulated on both malignant and normal human B lymphocytes after CD40 ligation induced by (a) cognate T helper-B cell interaction mediated by microbial superantigen (SAg); (b) contact-dependent interaction with CD40L+, but not CD40L- Jurkat mutant T cell clones; and (c) monoclonal anti-CD40, but not any of a panel of control antibodies. Enhanced B cell Fas/Apo-1 expression is functionally significant. Coculture of Ramos Burkitt's lymphoma line cells with irradiated SAg-reactive CD4+ T cells with SAg or CD40L+ Jurkat T cells results in B cell apoptosis, evidenced by reduced cell viability and DNA laddering. This process is augmented by the addition of anti-Apo-1/Fas monoclonal antibody, consistent with an acquired susceptibility to Apo-1/Fas-mediated apoptosis. These data support an immunoregulatory pathway in which seemingly contradictory signals involving the B cell proliferation/survival antigen CD40, as well as the Apo-1/Fas molecule, which mediates programmed cell death of lymphocytes, are linked in the process of human B cell activation.
Acquired Mutations That Affect Pre-mRNA Splicing in Hematologic Malignancies and Solid Tumors
Authors: L. M. Scott, V. I. Rebel
Journal: JNCI Journal of the National Cancer Institute (2013)

The application of next-generation sequencing technologies to interrogate the genome of human hematologic malignancies is providing promising insights into their molecular etiology and into the pathogenesis of seemingly unrelated malignancies. Among the somatic mutations identified by this approach are ones that target components of the spliceosome, a ribonucleoprotein complex responsible for the posttranscriptional processing of primary transcripts to form mature messenger RNA species. These mutations were initially detected in patients with chronic lymphocytic leukemia or a myelodysplastic syndrome, but can also occur at relatively high frequency in some solid tumors, including uveal malignant melanoma, adenocarcinoma of the lung, and estrogen receptor–positive breast cancers. Their presence in a variety of malignancies suggests that the spliceosomal mutations may play a fundamental role in defining the malignant phenotype. The development and testing of drugs that eliminate cells bearing a spliceosomal mutation, or normalize their altered transcript splicing patterns, are therefore a priority. Here, we summarize the effects of spliceosome-associated mutations on transcript processing in vitro and in vivo, and their impact on disease initiation and/or progression and patient outcome. Moreover, we discuss the therapeutic potential of compounds already known to target splicing factor 3B subunit 1 (SF3B1), an essential component of the spliceosome that is frequently mutated.
Therapeutic Effects of an Anti-Myc Drug on Mouse Pancreatic Cancer
Authors: Dimitris Stellas, Matthias Szabolcs, Sanjay Koul, Zhe Li, Alexander Polyzos, Constantinos Anagnostopoulos, Zoe Cournia, Constantin Tamvakopoulos, Apostolos Klinakis, Argiris Efstratiadis
Journal: JNCI Journal of the National Cancer Institute (2014)

Pancreatic ductal adenocarcinoma (PDA) is frequently driven by oncogenic KRAS(KRAS*) mutations. We developed a mouse model of KRAS*-induced PDA and, based on genetic results demonstrating that KRAS* tumorigenicity depends on Myc activity, we evaluated the therapeutic potential of an orally administered anti-Myc drug.We tested the efficacy of Mycro3, a small-molecule inhibitor of Myc-Max dimerization, in the treatment of mouse PDA (n = 9) and also of xenografts of human pancreatic cancer cell lines (NOD/SCID mice, n = 3-12). Tumor responses to the drug were evaluated by PET/CT imaging, and histological, immunohistochemical, molecular and microarray analyses. The Student's t test was used for differences between groups. All statistical tests were two-sided.Transgenic overexpression of KRAS* in the pancreas resulted in pancreatic intraepithelial neoplasia in two-week old mice, which developed invasive PDA a week later and became moribund at one month. However, this aggressive form of pancreatic tumorigenesis was effectively prevented by genetic ablation of Myc specifically in the pancreas. We then treated moribund, PDA-bearing mice daily with the Mycro3 Myc-inhibitor. The mice survived until killed at two months. PET/CT image analysis (n = 5) demonstrated marked shrinkage of PDA, while immunohistochemical analyses showed an increase in cancer cell apoptosis and reduction in cell proliferation (treated/untreated proliferation index ratio: 0.29, P < .001, n = 3, each group). Tumor growth was also drastically attenuated in Mycro3-treated NOD/SCID mice (n = 12) carrying orthotopic or heterotopic xenografts of human pancreatic cancer cells (eg, mean tumor weight ± SD of treated heterotopic xenografts vs vehicle-treated controls: 15.2±5.8 mg vs 230.2±43.9 mg, P < .001).These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA.
THE INTRACELLULAR DISTRIBUTION OF GAMMA GLOBULIN IN A MOUSE PLASMA CELL TUMOR (X5563) AS REVEALED BY FLUORESCENCE AND ELECTRON MICROSCOPY
Authors: Richard A. Rifkind, Elliott F. Osserman, Konrad C. Hsu, Councilman Morgan
Journal: The Journal of Experimental Medicine (1962)

Ferritin- and fluorescein-conjugated antibody staining has been applied to a study of a mouse plasma cell tumor. The presence of myeloma globulin within cisternae of the endoplasmic reticulum was observed at a stage of the secretory process when the remainder of the cytoplasm was essentially free of labeled globulin. The distribution of ferritin suggested a functional heterogeneity among units of the endoplasmic reticulum. Apparently, progressive accumulation of globulin results in distension of the endoplasmic reticulum and, occasionally, in the appearance of considerable quantities of this secretory protein in the extracisternal cytoplasmic matrix. Participation of the Golgi apparatus in the packaging and release of small quantitites of globulin seems likely. In addition, however, fragmentation of the peripheral cytoplasm with rupture of distended ergastoplasmic vesicles appeared to be another pathway whereby globulin is secreted.
Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K+ channels in mouse B cells.
Authors: M Gembal, P Detimary, P Gilon, Z Y Gao, J C Henquin
Journal: Journal of Clinical Investigation (1993)

Glucose stimulation of insulin release involves closure of ATP-sensitive K+ channels (K(+)-ATP channels), depolarization, and Ca2+ influx in B cells. However, by using diazoxide to open K(+)-ATP channels, and 30 mM K to depolarize the membrane, we could demonstrate that another mechanism exists, by which glucose can control insulin release independently from changes in K(+)-ATP channel activity and in membrane potential (Gembal et al. 1992. J. Clin. Invest. 89:1288-1295). A similar approach was followed here to investigate, with mouse islets, the nature of this newly identified mechanism. The membrane potential-independent increase in insulin release produced by glucose required metabolism of the sugar and was mimicked by other metabolized secretagogues. It also required elevated levels of cytoplasmic Cai2+, but was not due to further changes in Cai2+. It could not be ascribed to acceleration of phosphoinositide metabolism, or to activation of protein kinases A or C. Thus, glucose did not increase inositol phosphate levels and hardly affected cAMP levels. Moreover, increasing inositol phosphates by vasopressin or cAMP by forskolin, and activating protein kinase C by phorbol esters did not mimic the action of glucose on release, and down-regulation of protein kinase C did not prevent these effects. On the other hand, it correlated with an increase in the ATP/ADP ratio in islet cells. We suggest that the membrane potential-independent control of insulin release exerted by glucose involves changes in the energy state of B cells.
Incidence of bacteremia following bronchoscopy with argon plasma coagulation
Authors: Alexander Guber, Alona Matveychuk, Olga Talker, David Shitrit
Journal: European Respiratory Journal (2013)

Background:  Little information exists concerning infectious complications associated with bronchoscopy with argon plasma coagulation (APC) (Bolliger CT et al.  Eur Respir J.  2002;19:356-73, Yigla M. et al.  Eur Respir J.  1999;14:789–791.). This evaluation was undertaken to determine the incidence of bacteremia and infectious complications associated with APC procedures.   Methods : Consecutive patients undergoing bronchoscopy with APC for treatment of endobronchial lesions were studied prospectively. Venous blood was drawn immediately after APC procedure for aerobic and anaerobic cultures. Saline washings of APC catheter were cultured. Patients with positive blood cultures underwent clinical review upon results arrival and all patients reviewed at 1 week and 3 months after APC procedure.   Results : 42 patients underwent 44 APC procedures. Mean age was 66±12 years; 30 (71%) were male. 36 (86%) patients were with malignant disease and 6 (14%) with non-malignant disease. One case (2.3%) had clinically not significant bacteremia with  Acinetobacter Iwolfii . APC catheter washing culture was positive in 14 (31.8%) procedures. Neither patient with the positive washing cultures had clinical infection. Phone review 1 week after the procedures revealed no complications. After 3 months eight patients (18%) died. All deaths related to the advanced lung malignancy.   Conclusions : The incidence of bacteremia following APC is comparable to that of routine flexible bronchoscopy. APC does not appear to increase the risk of bacteremia compared to airway insertion of the bronchoscope. Contamination of the APC catheter with oropharyngeal commensal bacteria is common; clinically significant infection following APC procedure is rare.