tbuckley/cabot-search huggingface dataset:
STUDIES WITH RADIOACTIVE DI-AZO DYES. 1. THE LOCALIZATION OF RADIOACTIVE DI-BROM TRYPAN BLUE IN INFLAMMATORY LESIONS
Authors: Francis D. Moore, Lester H. Tobin
Journal: Journal of Clinical Investigation (1942)

The localization of circulating colloidal dyes in areas of increased capillary permeability, and their ingestion there by phagocytic cells, has been under investigation for the past 30 years.First observed by Goldmann (1) during his early studies with the vital stains, it later became the subject of study by investigators working with the inflammatory process, who found that many types of inflammation caused sufficient increase in per- meability of the capillaries to produce local accu- mulations of dye (2, 3, 4).Evans (5) described the macrophage system as a separate entity as a result of its delineation by such dyes, following an extensive study of the intra-vitam reactions of many dyes of the benzidine series, such as trypan blue (6).More re- cently, many workers (7 to 10) have used dyeaccumulation as an index of the extent of permea- bility changes following injections of various ir- ritants, fractions of inflammatory exudates, or organ-extracts, in an effort to elucidate the details of the inflammatory sequence.Burrows (11) provides an excellent review of the work in this field prior to 1932.Keith, Rowntree and Geraghty ( 12) explored the use of colloidal dyes in blood-volume deter- minations, this application arising from the fact that many of the acid azo dyes remain intravascu- lar for fairly prolonged periods of time, and ap- pear to form a bond with plasma protein (13).They, and others who followed in the same field (Dawson, Evans and Whipple (14), and Gregerson, Gibson and Stead (15)) have added much to our knowledge of the intravascular reactions of the dyes through their quantitative observations on serum concentrations, rates of elimination from the blood stream, and toxicity.Through this
In Vivo Luminescence Imaging of NF‐κB Activity and Serum Cytokine Levels Predict Pain Sensitivities in a Rodent Model of Osteoarthritis
Authors: Robby D. Bowles, Brian A. Mata, Richard D. Bell, Timothy K. Mwangi, Janet L. Huebner, Virginia B. Kraus, Lori A. Setton
Journal: Arthritis & Rheumatology (2013)

Objective To investigate the relationship between NF‐κB activity, cytokine levels, and pain sensitivities in a rodent model of osteoarthritis (OA). Methods OA was induced in transgenic NF‐κB–luciferase reporter mice via intraarticular injection of monosodium iodoacetate (MIA). Using luminescence imaging we evaluated the temporal kinetics of NF‐κB activity and its relationship to the development of pain sensitivities and serum cytokine levels in this model. Results MIA induced a transient increase in joint‐related NF‐κB activity at early time points (day 3 after injection) and an associated biphasic pain response (mechanical allodynia). NF‐κB activity, serum interleukin‐6 (IL‐6), IL‐1β, and IL‐10 levels accounted for ∼75% of the variability in pain‐related mechanical sensitivities in this model. Specifically, NF‐κB activity was strongly correlated with mechanical allodynia and serum IL‐6 levels in the inflammatory pain phase of this model (day 3), while serum IL‐1β was strongly correlated with pain sensitivities in the chronic pain phase of the model (day 28). Conclusion Our findings suggest that NF‐κB activity, IL‐6, and IL‐1β may play distinct roles in pain sensitivity development in this model of arthritis and may distinguish the acute pain phase from the chronic pain phase. This study establishes luminescence imaging of NF‐κB activity as a novel imaging biomarker of pain sensitivities in this model of OA.
Impact of upward social mobility on population mortality: analysis with routine data
Authors: R. F Heller
Journal: BMJ (2002)

To examine the contribution of changes in the distribution of social class to the mortality of the whole population between 1970-2 and 1991-3.Examination of routine data at two time points: 1970-2 and 1991-3.Data provided by the Office for National Statistics.Difference for the total population in the number of deaths between 1971 and 1991. Proportion of difference accounted for by change in population size, change in risk of death within each social class, or change in distribution of population across social classes.Reductions in mortality between 1970-2 and 1991-3 among men in England and Wales were partially (16% of all deaths) attributable to increases in the proportion of men in higher social classes, representing 3943 fewer deaths per year or one less death for every 3056 men in 1991-3 compared with 1970-2.Some of the observed reduction in mortality seen between 1970-2 and 1991-3 can be accounted for by improved overall socioeconomic status of the population.
Associations Between Diabetes and Clinical Markers of Benign Prostatic Hyperplasia Among Community-Dwelling Black and White Men
Authors: Aruna V. Sarma, James P. Burke, Debra J. Jacobson, Michaela E. McGree, Jennifer St. Sauver, Cynthia J. Girman, Michael M. Lieber, William Herman, Jill Macoska, James E. Montie, Steven J. Jacobsen
Journal: Diabetes Care (2008)

The aim of this study was to examine associations between diabetes and clinical markers of benign prostatic hyperplasia (BPH) in community-dwelling white and black men aged 40-79 years.Data from the Olmsted County Study of Urinary Symptoms and Health Status and the Flint Men's Health Study were combined for a total study sample of 2,484 men. Severity of lower urinary tract symptoms (LUTS), peak urinary flow rates, prostate volume, and serum prostate-specific antigen (PSA) levels were examined by self-reported physician-diagnosed diabetes.Overall, 170 men (6.8%) reported a history of diabetes. Increased irritative LUTS and specifically nocturia were positively associated with diabetes. These patterns were consistent across race and persisted after adjustment for age, BMI, and various indicators of socioeconomic status. Furthermore, the relationship between irritative LUTS and diabetes was greater in black men. No significant associations were observed between diabetes and prostate volume, PSA level, and peak urinary flow rate.Our multiethnic community-based study demonstrates positive associations between diabetes and irritative LUTS and nocturia. Moreover, the association between irritative LUTS and diabetes is increased in black men. There was no strong evidence for an association between diabetes and BPH across measures more specific to BPH (i.e., prostate volume, PSA, and peak urinary flow rate). Taken together, our findings suggest that the presence of diabetes may be less related to prostate growth and more related to the dynamic components of lower urinary tract function. Further evaluations of the association between diabetes and BPH and related racial variations are warranted.
Respiratory disability: what is it, how can we measure it, what causes it and is it important?
Authors: P. Harber
Journal: Thorax (2009)

It is clear that mast cells expressing different mediators, enzymes and receptors will have different functions, but what those exact roles are is not known and can only be guessed at from the current study.Nevertheless, cells which do not express FceRI are unlikely to respond to allergen, while those expressing renin are likely to influence cardiovascular function.While it may be possible to isolate individual populations based on their receptor expression, at present it is not possible to do this with respect to intracellular contents, so determining their precise function will be a challenge.Others, however, have shown variability in lung mast cell density and size and examined their response to IgEdependent activation, but these studies did not examine the anatomical location of these cells. 24Interestingly, enzymatically dispersed parenchymal human lung mast cells fractionated using countercurrent elutriation were shown to range in size from 8 to 20 mm, with smaller diameter mast cells consistently releasing less histamine and PGD 2 than large mast cells following IgE-dependent activation. 24his differential mediator release could not be explained by cell surface IgE content which was similar in mast cells of all sizes.Furthermore, the concentration of anti-IgE for maximum histamine release was the same for mast cells of all sizes, suggesting similar receptor function and density.This and other studies 26 do not tally with the observation of Andersson that parenchymal lung mast cells do not express FceRI, suggesting that their immunohistochemical staining procedure might lack sensitivity.In summary, the study by Andersson and colleagues demonstrates clearly the extensive heterogeneity of human mast cells within a single organ-in this case, the lung.This is likely to extend well beyond the current findings, and there is a huge challenge ahead to unravel the precise function of these different mast cell phenotypes in both health and disease.
Proteolytic Processing of cGMP-Dependent Protein Kinase I Mediates Nuclear cGMP Signaling in Vascular Smooth Muscle Cells
Authors: Takahiro Sugiura, Hidehiko Nakanishi, Jesse D. Roberts
Journal: Circulation Research (2008)

Cyclic GMP modulates gene expression in vascular smooth muscle cells (SMCs) in part by stimulating cGMP-dependent protein kinase I (PKGI) and the phosphorylation of transcription factors. In some cells, cGMP increases nuclear translocation of PKGI and PKGI-dependent phosphorylation of transcription regulators; however, these observations have been variable, and the mechanisms mediating nuclear PKGI translocation are incompletely understood. We tested the hypothesis that proteolytic cleavage of PKGI is required for cGMP-stimulated nuclear compartmentation of PKGI and phosphorylation of transcription factors. We detected an NH 2 -terminal PKGI fragment with leucine zipper domain immunoreactivity in the cytosol and endoplasmic reticulum of SMCs, but only a COOH-terminal PKGI fragment containing the catalytic region (now termed PKGIγ ) was observed in the Golgi apparatus (GA) and nucleoplasm. Posttranslational PKGI processing in the GA was critical for nuclear compartmentation of PKGIγ because GA disruption with nocodazol or brefeldin A inhibited PKGIγ nuclear localization. PKGIγ immunoreactivity was particularly abundant in the nucleolus of interphase SMCs where its colocalization with the nucleolar dense fibrillar component protein fibrillarin closely matched the level of nucleolar assembly. Purified nucleolar PKGIγ enzyme activity was insensitive to cGMP stimulation, which is consistent with its lack of the NH 2 -terminal autoinhibitory domain. Mutation of a putative proteolytic cleavage region in PKGI inhibited cGMP-mediated phosphorylation of cAMP response element-binding protein, cAMP response element-dependent transcription, and nuclear localization of PKGIγ. These observations suggest that posttranslational modification of PKGI critically influences the nuclear translocation of PKGI and activities of cGMP in SMCs.
UTERINE ADENOMATA IN THE RABBIT
Authors: Harry S. N. Greene, John A. Saxton
Journal: The Journal of Experimental Medicine (1938)

83 cases of an adenomatous tumor of the uterine mucosa have been observed in a colony of rabbits during the past 4 years The results of a clinical and pathological study of the tumor, together with a description of transplantation experiments are included in the present report. The clinical histories of tumor bearing animals are similar in all cases. Discovery of the tumor is preceded by a long period of reproductive disturbance, and its subsequent course is one of slow, continuous growth which has terminated in death with metastasis in all animals held under observation for longer than 1 year. Microscopically, the tumor shows an atypical alveolar structure, and its characteristics closely resemble those of an adenocarcinoma of the uterine fundus in women. Pathological changes similar to those observed in mice after treatment with estrogenic substances occur in the thyroid, suprarenal, pituitary and mammary glands. Intraocular transplantation of the tumor has been successful, and at the present time the growth has been carried through 6 generations by serial transfer.
Leucine-rich repeat protein PRAME: expression, potential functions and clinical implications for leukaemia
Authors: Frances Wadelin, Joel Fulton, Paul A McEwan, Keith A Spriggs, Jonas Emsley, David M Heery
Journal: Molecular Cancer (2010)

Abstract PRAME/MAPE/OIP4 is a germinal tissue-specific gene that is also expressed at high levels in haematological malignancies and solid tumours. The physiological functions of PRAME in normal and tumour cells are unknown, although a role in the regulation of retinoic acid signalling has been proposed. Sequence homology and structural predictions suggest that PRAME is related to the leucine-rich repeat (LRR) family of proteins, which have diverse functions. Here we review the current knowledge of the structure/function of PRAME and its relevance in leukaemia.
<i>FGFR-4</i> Arg388 Enhances Prostate Cancer Progression via Extracellular Signal–Related Kinase and Serum Response Factor Signaling
Authors: Wendong Yu, Shu Feng, Olga Dakhova, Chad J. Creighton, Yi Cai, Jianghua Wang, Rile Li, Anna Frolov, Gustavo Ayala, Michael Ittmann
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Increased expression of FGFR-4 and its ligands have been linked to lethal prostate cancer (PCa). Furthermore, a germ line polymorphism in the FGFR-4 gene, resulting in arginine at codon 388 (Arg388) instead of glycine (Gly388), is associated with aggressive disease. The FGFR-4 Arg388 variant results in increased receptor stability, sustained receptor activation, and increased motility and invasion compared with Gly388. However, the impact of sustained signaling on cellular signal transduction pathways is unknown. Experimental Design: Expression microarray analysis of immortalized prostatic epithelial cells lines expressing FGFR-4 Arg388 or Gly388 was used to establish a gene signature associated with FGFR-4 Arg388 expression. Transient transfection of reporters and inhibitors was used to establish the pathways activated by FGFR-4 Arg388 expression. The impact of pathway knockdown in vitro and in an orthotopic model was assessed using inhibitors and/or short hairpin RNA (shRNA). Results: Expression of the FGFR-4 Arg388 protein leads to increased activity of the extracellular signal–related kinase (ERK) pathway, increased activity of serum response factor (SRF) and AP1, and transcription of multiple genes that are correlated with aggressive clinical behavior in PCa. Increased expression of SRF is associated with biochemical recurrence in men undergoing radical prostatectomy. Consistent with these observations, knockdown of FGFR-4 Arg388 in PCa cells decreases proliferation and invasion in vitro and primary tumor growth and metastasis in vivo. Conclusions: These studies define a signal transduction pathway downstream of FGFR-4 Arg388 that acts via ERK and SRF to promote PCa progression. Clin Cancer Res; 17(13); 4355–66. ©2011 AACR.
CIP2A Is Overexpressed in Gastric Cancer and Its Depletion Leads to Impaired Clonogenicity, Senescence, or Differentiation of Tumor Cells
Authors: Wenjuan Li, Zheng Ge, Cheng Liu, Zhifang Liu, Magnus Björkholm, Jihui Jia, Dawei Xu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic factor stabilizing c-MYC protein and driving cellular transformation. We determine whether CIP2A expression can serve as marker for gastric cancer and investigate the mechanism underlying CIP2A-mediated transformation and cell proliferation. Experimental Design: Normal and malignant gastric tissues derived from 37 patients with gastric cancer were analyzed for CIP2A expression using reverse transcription-PCR and immunohistochemical staining. Gastric and other cell lines with different p53 and pRB backgrounds were used to inhibit CIP2A expression using small interfering RNA and then examined for clonogenic potentials, senescence, or differentiation. Results: CIP2A mRNA was present in 34 of 37 (90%) of tumor specimens but absent in 27 of 37 (73%) of matched normal gastric mucosa. In 10 adjacent normal tissues with detectable CIP2A mRNA, 6 of them exhibited much weaker levels of CIP2A compared with their corresponding tumors. Thus, a total of 32 (87%) gastric cancer samples overexpressed CIP2A. CIP2A protein expression was readily detectable in the tumor tissues but absent in normal gastric mucosa. Depleting CIP2A expression substantially inhibited growth and clonogenic capabilities of tumor cell lines independently of p53 and pRB pathways. Gastric cancer–derived AGS cells underwent senescence following the inhibition of CIP2A expression. Moreover, CIP2A depletion triggered partial differentiation of leukemic HL60 cells. Conclusion: CIP2A in tumor cells is required for sustained proliferation by preventing cell growth arrest, senescence, or differentiation and its expression is significantly (P &amp;lt; 0.001) discriminatory between normal and cancerous gastric tissue.
Novel Aspects of Mevalonate Pathway Inhibitors as Antitumor Agents
Authors: Martin Thurnher, Oliver Nussbaumer, Georg Gruenbacher
Journal: Clinical Cancer Research (2012)

Abstract The mevalonate pathway for cholesterol biosynthesis and protein prenylation has been implicated in various aspects of tumor development and progression. Certain classes of drugs, such as statins and bisphosphonates, inhibit mevalonate metabolism and therefore have also been tested as antitumor agents. This concept is strongly supported by the recent finding that mutant p53, which is present in more than half of all human cancers, can significantly upregulate mevalonate metabolism and protein prenylation in carcinoma cells. The first evidence that mevalonate pathway inhibitors may have the potential to reverse the malignant phenotype has already been obtained. Moreover, recently discovered immunomodulatory properties of statins and bisphosphonates may also contribute to their known anticancer effects. Drug-induced inhibition of protein prenylation may induce sequential cellular stress responses, including the unfolded protein response and autophagy, that eventually translate into inflammasome-dependent and caspase-1-mediated activation of innate immunity. This review focuses on these novel capabilities of mevalonate pathway inhibitors to beneficially affect tumor biology and contribute to tumor immune surveillance. Clin Cancer Res; 18(13); 3524–31. ©2012 AACR.
<i>Helicobacter pylori</i>CagL dependent induction of gastrin expression via a novel αvβ<sub>5</sub>-integrin–integrin linked kinase signalling complex
Authors: Tobias Wiedemann, Stefan Hofbaur, Nicole Tegtmeyer, Sylwia Huber, Norbert Sewald, Silja Wessler, Steffen Backert, Gabriele Rieder
Journal: Gut (2012)

<h3>Objective</h3> One of the most important hormones in the human stomach is the peptide gastrin. It is mainly required for the regulation of gastric pH but is also involved in growth and differentiation of gastric epithelial cells. In <i>Helicobacter pylori</i> infected patients, gastrin secretion can be upregulated by the pathogen, resulting in hypergastrinaemia. <i>H pylori</i> induced hypergastrinaemia is described as being a major risk factor for the development of gastric adenocarcinoma. <h3>Design</h3> In this study, the upstream receptor complex and bacterial factors involved in <i>H pylori</i> induced gastrin gene expression were investigated, utilising gastric epithelial cells which were stably transfected with a human gastrin promoter luciferase reporter construct. <h3>Results</h3> Integrin linked kinase (ILK) and integrin β5, but not integrin β1, played an important role in gastrin promoter activation. Interestingly, a novel CagL/integrin β5/ILK signalling complex was characterised as being important for <i>H pylori</i> induced gastrin expression. On interaction of <i>H pylori</i> with αvβ<sub>5</sub>-integrin and ILK, the epidermal growth factor receptor (EGFR) →Raf→mitogen activated protein kinase kinase (MEK)→extracellular signal regulated kinase (Erk) downstream signalling cascade was identified which plays a central role in <i>H pylori</i> gastrin induction. <h3>Conclusion</h3> The newly discovered recognition receptor complex could be a useful target in treating precancerous conditions triggered by <i>H pylori</i> induced hypergastrinaemia.
Two Components of the Delayed Rectifier K <sup>+</sup> Current in Ventricular Myocytes of the Guinea Pig Type
Authors: Jinglin Zeng, Kenneth R. Laurita, David S. Rosenbaum, Yoram Rudy
Journal: Circulation Research (1995)

Abstract Two distinct delayed rectifier K + currents, I Kr and I Ks , were found recently in ventricular cells. We formulated these currents theoretically and investigated their roles in action potential repolarization and the restitution of action potential duration (APD). The Luo-Rudy (L-R) model of the ventricular action potential was used in the simulations. The single delayed rectifier K + current in the model was replaced by I Kr and I Ks . Our results show that I Ks is the major outward current during the plateau repolarization. A specific block of either I Kr or I Ks can effectively prolong APD to the same degree. Therefore, either channel provides a target for class III antiarrhythmic drugs. In the simulated guinea pig ventricular cell, complete block of I Kr does not result in early afterdepolarizations (EADs). In contrast, &gt;80% block of I Ks results in abnormal repolarization and EADs. This behavior reflects the high I Ks -to-I Kr density ratio (≈8:1) in this cell and can be reversed (ie, I Kr block can cause EADs) by reducing the ratio of I ks to I Kr . The computed APD restitution curve is consistent with the experimental behavior, displaying fast APD variation at short diastolic intervals (DIs) and downward shift at longer DIs with the decrease of basic drive cycle length (BCL). Examining the ionic currents and their underlying kinetic processes, we found that activation of both I Kr and I Ks is the primary determinant of the APD restitution at shorter DIs, with Ca 2+ current through L-type channels (I Ca ) playing a minor role. The rate of APD change depends on the relative densities of I Kr and I Ks ; it increases when the I Kr -to-I Ks density ratio is large. The BCL-dependent shift of restitution at longer DIs is primarily attributed to long-lasting changes in [Ca 2+ ] i . This in turn causes different degrees of Ca 2+ -dependent inactivation of I Ca and different degrees of Ca 2+ -dependent conductance of I Ks at very long DIs (&gt;5 s) for different BCLs. This BCL dependence of I Ca and I Ks that is secondary to long-lasting changes in [Ca 2+ ] i is responsible for APD changes at long DIs and can be viewed as a “memory property” of cardiac cells.