tbuckley/cabot-search huggingface dataset:
Modulation of Ca <sup>2+</sup> Release in Cardiac Myocytes by Changes in Repolarization Rate
Authors: Rajan Sah, Rafael J. Ramirez, Peter H. Backx
Journal: Circulation Research (2002)

The early rate of action potential (AP) repolarization varies in the mammalian heart regionally, during development, and in disease. We used confocal microscopy to assess the effects of changes in repolarization rate on spatially resolved sarcoplasmic reticulum (SR) Ca 2+ release. The kinetics and peak amplitude of Ca 2+ transients were reduced, and the amplitude, frequency, and temporal synchronization of Ca 2+ spikes decreased as the rate of repolarization was slowed. The first latencies and temporal dispersion of Ca 2+ spikes tracked closely with the time to peak and the width of the L-type Ca 2+ current ( I Ca,L ), suggesting that the effects of repolarization on excitation-contraction coupling occur primarily via changes in I Ca,L . Next, we examined the effect of changes in the rapid early repolarization rate (phase 1) of a model human AP on SR Ca 2+ release by varying the amount of transient outward K + current. Slowing of phase-1 repolarization also caused a loss of temporal synchrony and recruitment of Ca 2+ -release events, associated with a reduced amplitude and lengthened time to peak of I Ca,L . Isoproterenol application enhanced and largely resynchronized SR Ca 2+ release, while it increased the magnitude and shortened the time to peak of I Ca,L . Our data demonstrate that membrane repolarization modulates the recruitment and synchronization of SR Ca 2+ release via I Ca,L and illustrate a physiological role for the phase-1 notch of the AP in optimizing temporal summation and recruitment of Ca 2+ -release events. The effects of slowing phase-1 repolarization can be overcome by β-adrenergic stimulation.
Studies on Specific Transplantation Resistance to Polyoma-Virus-Induced Tumors. IV. Stability of the Polyoma Cell Antigen&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Hans Olof Sjögren
Journal: JNCI Journal of the National Cancer Institute (1964)

The stability of the polyoma-specific cell antigen was studied. Thirteen single-cell clones of a polyoma tumor induced in vivo were equally susceptible to the polyoma-induced transplantation resistance, but were previously shown to vary with regard to other properties, such as spontaneous virus release, karyotype, or sensitivity to infection with polyoma or vaccinia virus. Two polyoma tumors were passaged serially 42 and 19 times, respectively, in virus-infected mice with a minimum super-threshold cell dose without any significant change in antigenicity, which indicated a remarkable stability of the polyoma cell antigen. In contrast to the polyoma tumors a methylcholanthrene-induced MCB sarcoma, exceptional because it was susceptible to polyoma-induced resistance, lost most of its susceptibility on 21 passages in virus-immune mice.
Recurrent cerebral infarction and the antiphospholipid syndrome: effect of intravenous gammaglobulin in a patient with systemic lupus erythematosus.
Authors: G Sturfelt, F Mousa, H Jonsson, O Nived, H Thysell, F Wollheim
Journal: Annals of the Rheumatic Diseases (1990)

A 23 year old woman with systemic lupus erythematosus and antiphospholipid syndrome developed severe thrombocytopenia (5-10 X 10(9)/l) and cerebral infarction. Treatment with high doses of corticosteroids and cytostatic drugs was not effective. The condition was successfully treated only when three courses of intravenous gammaglobulin at 400 mg/kg daily was added. A clear relation was found between the immunoglobulin infusions and rising platelet counts, whereas an effect on the levels of anticardiolipin antibodies could not be recorded. The findings suggested that the mechanisms responsible may be modification and solubilisation of immune complexes or interference with anticardiolipin binding to platelet membranes, or both.
Cholesterol and bile salt studies on the bile of patients with cholesterol gallstones
Authors: F. Heller, I. A. D. Bouchier
Journal: Gut (1973)

Gallbladder bile from patients with cholesterol stones and control patients without cholesterol stones was analysed for the relative concentrations of bile salts, phospholipids, and cholesterol. It was not possible to distinguish stone-forming from control biles when these were plotted on triangular coordinates. There was a significant increase in the dihydroxy: trihydroxy bile salt ratio in the patients with cholesterol gallstones. The maximum cholesterol holding capacity for the bile salts was determined and no difference could be detected in the ability of the bile salts from either cholesterol stone-containing and control bile samples to dissolve cholesterol.
Clinical Uses of Microsatellite Instability Testing in Colorectal Cancer: An Ongoing Challenge
Authors: C. Richard Boland
Journal: Journal of Clinical Oncology (2007)

Microsatellite instability (MSI) is the mutational signature found in colorectal cancers (CRCs) that evolve as a result of inactivation of the DNA mismatch repair (MMR) system.MSI can be found in approximately 15% of all CRCs.Approximately 3% of all CRCs are a consequence of Lynch Syndrome, and nearly all Lynch Syndrome CRCs have MSI. 1 Another 12% of CRCs represent the noninherited form of DNA MMR inactivation that is induced by methylation of the promoter of the MLH1 gene, which silences gene expression. 2MSI is one of the premier molecular markers in CRC because it indicates the pathophysiologic genesis of the tumor, and it provides some clinical information that is of use in caring for this subset of CRC patients.Testing for MSI is within the grasp of a molecular diagnostic laboratory, and many investigators have proposed various clinical applications of this information.This issue of the Journal of Clinical Oncology includes two articles on testing the clinical utility of MSI 3,4 ; one of which confirms its utility in identifying Lynch Syndrome families, 3 the other casts doubt on its utility as a prognostic and predictive marker in sporadic CRC. 4 These articles illustrate the utility of molecular diagnostics, but also note the challenges of using new technologies.Valle and colleagues 3 gathered 64 familial clusters of CRC from a Spanish national registry, all of whom met the Amsterdam-I criteria. 5Each family had a pedigree that included at least three members with CRC, and at least one affected member was younger than 50 years old.This was the classic algorithm to identify Lynch Syndrome families, and it was initially assumed to be very specific for this diagnosis.However, a registry of familial clusters of CRC (the Colon Cancer Family Registry, or Colon CFR) reported that only Ϸ60% of these classic clusters can be linked to a germline mutation in a DNA MMR gene.The other 40% of families had microsatellite stable (MSS) tumors, and these families have been given the temporary designation "Syndrome X"; the genetic basis of this syndrome is being explored. 6Valle et al 3 found that virtually the same proportion of the Spanish families had MSI CRCs (59.4%), a highly reassuring confirmation of the data from the Colon CFR.Her group was able to find the responsible germline mutation in 65.7% of these families, which is critical for clinical care, because this permits accurate case finding and genetic counseling.Moreover, they confirmed that true Lynch Syndrome families developed their cancers earlier in life (mean age 45.5 years v 53 years for families with MSS tumors), that 70.6% of the CRCs were proximally located in the MSI families, and that the tumor spec-
Effect of aerosol fenoterol on the severity of bronchial hyperreactivity in patients with asthma.
Authors: C M Salome, R E Schoeffel, K Yan, A J Woolcock
Journal: Thorax (1983)

Beta adrenergic agents given by aerosol decrease the responsiveness of the airways to histamine and methacholine in subjects with asthma, causing a shift of the dose response curve to the right. To find out whether the shift is related to the dose of beta adrenergic agent given and to determine the duration of the reduced responsiveness, eight subjects with asthma were given histamine inhalation tests after inhaled saline and after increasing doses of inhaled fenoterol on different days. The histamine inhalation tests were repeated at hourly intervals for five hours after a selected dose of fenoterol. Fenoterol caused a dose related shift to the right of the histamine dose response curve in each subject and in some the dose response relationship reached the "non-symptomatic range." The shift in the dose response curve was short lived and had returned towards the control position within three hours in all subjects. There was no change in shape of the curves at the time of maximal shift. The results show that inhaled fenoterol greatly reduces the airway responsiveness to histamine, but up to 400 micrograms of fenoterol every four to five hours may be needed to keep the responsiveness of the airways in the non-symptomatic range.
SYK Is a Candidate Kinase Target for the Treatment of Advanced Prostate Cancer
Authors: Veerander P.S. Ghotra, Shuning He, Geertje van der Horst, Steffen Nijhoff, Hans de Bont, Annemarie Lekkerkerker, Richard Janssen, Guido Jenster, Geert J.L.H. van Leenders, A. Marije M. Hoogland, Esther I. Verhoef, Zuzanna Baranski, Jiangling Xiong, Bob van de Water, Gabri van der Pluijm, B. Ewa Snaar-Jagalska, Erik H.J. Danen
Journal: Cancer Research (2014)

Improved targeted therapies are needed to combat metastatic prostate cancer. Here, we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. Although SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin α2β1 and CD44 were diminished. RNAi-mediated silencing of α2β1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for α2β1 in this setting. Notably, pharmacologic inhibitors of SYK kinase currently in phase I-II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer.
RasGRP1 Overexpression in the Epidermis of Transgenic Mice Contributes to Tumor Progression during Multistage Skin Carcinogenesis
Authors: Courtney T. Luke, Carolyn E. Oki-Idouchi, J. Mark Cline, Patricia S. Lorenzo
Journal: Cancer Research (2007)

Abstract RasGRP1 is a guanine nucleotide exchange factor for Ras, activated in response to the second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters. We have previously shown that RasGRP1 is expressed in mouse epidermal keratinocytes and that transgenic mice overexpressing RasGRP1 in the epidermis under the keratin 5 promoter (K5.RasGRP1) are prone to developing spontaneous papillomas and squamous cell carcinomas, suggesting a role for RasGRP1 in skin tumorigenesis. Here, we examined the response of the K5.RasGRP1 mice to multistage skin carcinogenesis, using 7,12-dimethylbenz(a)anthracene as carcinogen and 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor promoter. We found that whereas tumor multiplicity did not differ between transgenic and wild-type groups, the transgenic tumors were significantly larger than those observed in the wild-type mice (wild-type, 4.58 ± 0.25 mm; transgenic, 9.83 ± 1.05 mm). Histologic analysis further revealed that squamous cell carcinomas generated in the transgenic mice were less differentiated and more invasive than the wild-type tumors. Additionally, 30% of the transgenic mice developed tumors in the absence of initiation, suggesting that RasGRP1 overexpression could partially substitute for the initiation step induced by dimethylbenz(a)anthracene. In primary keratinocytes isolated from K5.RasGRP1 mice, TPA stimulation induced higher levels of Ras activation compared with the levels measured in the wild-type cells, indicating that constitutive overexpression of RasGRP1 in epidermal cells leads to elevated biochemical activation of endogenous Ras in response to TPA. The present data suggests that RasGRP1 participates in skin carcinogenesis via biochemical activation of endogenous wild-type Ras and predisposes to malignant progression in cooperation with Ras oncogenic signals. [Cancer Res 2007;67(21):10190–7]
HLA association with dermatitis herpetiformis is accounted for by a cis or transassociated DQ heterodimer.
Authors: M A Hall, J S Lanchbury, W J Bolsover, K I Welsh, P J Ciclitira
Journal: Gut (1991)

HLA-DR, DQ, and DP restriction fragment genotyping was undertaken in 23 dermatitis herpetiformis patients and 53 healthy control subjects. HLA-DQw2 was present in 100% of patients with dermatitis herpetiformis (23 of 23) versus 40% of control subjects (21 of 53). Significant secondary associations occurred with HLA-DR3 (91% of patients versus 28% of control subjects) and DPw1 (39% of patients versus 11% of control subjects). Dermatitis herpetiformis and coeliac disease thus share an identical HLA class II association. It is likely that HLA class II genes directly influence the immune responses leading to mucosal damage in both diseases. The strongest candidate for disease susceptibility to dermatitis herpetiformis is DQw2. The HLA molecule most likely to be involved in coeliac disease is a specific DQ alpha/DQ beta heterodimer, encoded in cis arrangement in DR3 haplotypes or in trans arrangement in a DR5, 7 genotype. Our data on dermatitis herpetiformis patients fits this model perfectly. All these patients are capable of expressing this molecule, which may be responsible for the gluten sensitive enteropathy seen in a subgroup of patients with dermatitis herpetiformis and coeliac disease.
Axial Stretch of Rat Single Ventricular Cardiomyocytes Causes an Acute and Transient Increase in Ca <sup>2+</sup> Spark Rate
Authors: Gentaro Iribe, Christopher W. Ward, Patrizia Camelliti, Christian Bollensdorff, Fleur Mason, Rebecca A.B. Burton, Alan Garny, Mary K. Morphew, Andreas Hoenger, W. Jonathan Lederer, Peter Kohl
Journal: Circulation Research (2009)

We investigate acute effects of axial stretch, applied by carbon fibers (CFs), on diastolic Ca2+ spark rate in rat isolated cardiomyocytes. CFs were attached either to both cell ends (to maximize the stretched region), or to the center and one end of the cell (to compare responses in stretched and nonstretched half-cells). Sarcomere length was increased by 8.01+/-0.94% in the stretched cell fraction, and time series of XY confocal images were recorded to monitor diastolic Ca2+ spark frequency and dynamics. Whole-cell stretch causes an acute increase of Ca2+ spark rate (to 130.7+/-6.4%) within 5 seconds, followed by a return to near background levels (to 104.4+/-5.1%) within 1 minute of sustained distension. Spark rate increased only in the stretched cell region, without significant differences in spark amplitude, time to peak, and decay time constants of sparks in stretched and nonstretched areas. Block of stretch-activated ion channels (2 micromol/L GsMTx-4), perfusion with Na+/Ca2+-free solution, and block of nitric oxide synthesis (1 mmol/L L-NAME) all had no effect on the stretch-induced acute increase in Ca2+ spark rate. Conversely, interference with cytoskeletal integrity (2 hours of 10 micromol/L colchicine) abolished the response. Subsequent electron microscopic tomography confirmed the close approximation of microtubules with the T-tubular-sarcoplasmic reticulum complex (to within approximately 10(-8)m). In conclusion, axial stretch of rat cardiomyocytes acutely and transiently increases sarcoplasmic reticulum Ca2+ spark rate via a mechanism that is independent of sarcolemmal stretch-activated ion channels, nitric oxide synthesis, or availability of extracellular calcium but that requires cytoskeletal integrity. The potential of microtubule-mediated modulation of ryanodine receptor function warrants further investigation.
Association of Low-Level Ozone and Fine Particles With Respiratory Symptoms in Children With Asthma
Authors: Janneane F Gent, Elizabeth W Triche, Theodore R Holford, Kathleen Belanger, Michael B Bracken, William S Beckett, Brian P Leaderer
Journal: JAMA (2003)

Exposure to ozone and particulate matter of 2.5 microm or less (PM2.5) in air at levels above current US Environmental Protection Agency (EPA) standards is a risk factor for respiratory symptoms in children with asthma.To examine simultaneous effects of ozone and PM2.5 at levels below EPA standards on daily respiratory symptoms and rescue medication use among children with asthma.Daily respiratory symptoms and medication use were examined prospectively for 271 children younger than 12 years with physician-diagnosed, active asthma residing in southern New England. Exposure to ambient concentrations of ozone and PM2.5 from April 1 through September 30, 2001, was assessed using ozone (peak 1-hour and 8-hour) and 24-hour PM2.5. Logistic regression analyses using generalized estimating equations were performed separately for maintenance medication users (n = 130) and nonusers (n = 141). Associations between pollutants (adjusted for temperature, controlling for same- and previous-day levels) and respiratory symptoms and use of rescue medication were evaluated.Respiratory symptoms and rescue medication use recorded on calendars by subjects' mothers.Mean (SD) levels were 59 (19) ppb (1-hour average) and 51 (16) ppb (8-hour average) for ozone and 13 (8) microg/m3 for PM2.5. In copollutant models, ozone level but not PM2.5 was significantly associated with respiratory symptoms and rescue medication use among children using maintenance medication; a 50-ppb increase in 1-hour ozone was associated with increased likelihood of wheeze (by 35%) and chest tightness (by 47%). The highest levels of ozone (1-hour or 8-hour averages) were associated with increased shortness of breath and rescue medication use. No significant, exposure-dependent associations were observed for any outcome by any pollutant among children who did not use maintenance medication.Asthmatic children using maintenance medication are particularly vulnerable to ozone, controlling for exposure to fine particles, at levels below EPA standards.
Plasma Epidermal Growth Factor Receptor Mutation Analyses in Japanese Advanced Non-Small-Cell Lung Cancer Patients Horboring Egfr Mutation By Rnase H-Dependent Pcr and Blocking Oligo Dependent Pcr Methods
Authors: Y. Hisamatsu, H. Kenmotsu, H. Akamatsu, M. Serizawa, K. Wakuda, H. Imai, A. Ono, T. Taira, T. Naito, H. Murakami, M. Endo, Y. Fukuda, K. Yamasaki, R. Umehara, N. Yamamoto, T. Takahashi, Y. Koh
Journal: Annals of Oncology (2014)
Abstract 3035: Functional roles of HS6ST3 in human breast cancer in vitro
Authors: Omid Iravani, George W. Yip, Boon-Huat Bay
Journal: Cancer Research (2011)

Abstract Introduction: Heparan sulfate is a sulfated polysaccharide that is found on the cell surface and extracellular matrix of all human cells. It interacts with a variety of proteins and is thus involved in numerous biological processes such as growth and development. Heparan sulfate's function critically depends on the number and the position of sulfate groups, which modulate the binding sites for proteins such as growth factors, cytokines, receptors, enzymes, and inhibitors. However, little is known about their roles both in vitro and in vivo. Alterations in heparan sulfation may be associated with pathologic conditions such as cancer. Heparan sulfate 6-O-sulfotransferases (HS6STs) catalyze the transfer of sulfate groups to the carbon 6 position in heparan sulfate. Three isoforms of these enzymes have been discovered in humans. Recently, several studies have proposed that dysregulation of 6-O-sulfation patterns may be involved in carcinogenesis. This study aimed to analyze the functional role of HS6ST3 in T47D breast cancer cell line. Procedures: HS6ST3 was silenced using siRNA by more than 85%. Functional studies such as proliferation, cell cycle, apoptosis, adhesion and migration assays were then performed. Results: The study demonstrated that silencing HS6ST3 in T47D breast cancer cell line enhanced apoptosis and cellular adhesion; and diminished proliferation with cell cycle arrest at G0/G1. Taken together the results demonstrated that silencing HS6ST3 decreased the tumoral progression in breast cancer. Conclusions: This could be happen through alteration of heparan sulfate interactions with ligands such as growth factors. HS6ST3 could be used not only as a valuable biomarker for diagnostic and prognostic purposes but in cancer gene therapy in near future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3035. doi:10.1158/1538-7445.AM2011-3035
Court confirms right to palliative treatment for mental distress
Authors: C. Dyer
Journal: BMJ (1997)

The right of doctors to give terminally ill patients palliative treatment to relieve mental distress as well as physical pain and suffering was confirmed in a test case settled in the High Court in London last week.

Annie Lindsell, who has motor neurone disease, sought a court declaration that her GP, Dr Simon Holmes, could administer large enough doses of diamorphine to render her unconscious when her ability to swallow food became affected. Having seen friends die of the disease, she did not want to go through the final stages choking on her food and unable to speak. She has …
Phase III Trial of Fluorouracil-Based Chemotherapy Regimens Plus Radiotherapy in Postoperative Adjuvant Rectal Cancer: GI INT 0144
Authors: Stephen R. Smalley, Jacqueline K. Benedetti, Stephen K. Williamson, John M. Robertson, Norman C. Estes, Tracy Maher, Barbara Fisher, Tyvin A. Rich, James A. Martenson, John W. Kugler, Al B. Benson, Daniel G. Haller, Robert J. Mayer, James N. Atkins, Christine Cripps, John Pedersen, Phillip O. Periman, Michael S. Tanaka, Cynthia G. Leichman, John S. Macdonald
Journal: Journal of Clinical Oncology (2006)

Adjuvant chemoradiotherapy after or before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. We studied three postoperative fluorouracil (FU) radiochemotherapy regimens.After resection of T3-4, N0, M0 or T1-4, N1, 2M0 rectal adenocarcinoma, 1,917 patients were randomly assigned to arm 1, with bolus FU in two 5-day cycles every 28 days before and after radiotherapy (XRT) plus FU via protracted venous infusion (PVI) 225 mg/m2/d during XRT; arm 2 (PVI-only arm), with PVI 42 days before and 56 days after XRT + PVI; or arm 3 (bolus-only arm), with bolus FU + leucovorin (LV) in two 5-day cycles before and after XRT, plus bolus FU + LV (levamisole was administered each cycle before and after XRT). Patients were stratified by operation type, T and N stage, and time from surgery.Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 49% to 55% of the bolus arms versus 4% in the PVI arm. No disease-free survival (DFS) or OS difference was detected (3-year DFS, 67% to 69% and 3-year OS, 81% to 83% in all arms). Locoregional failure (LRF) at first relapse was 8% in arm 1, 4.6% in arm 2, and 7% in arm 3. LRF in T1-2, N1-2, and T3, N0-2 primaries who received low anterior resection (those most suitable for primary resection) was 5% in arm 1, 3% in arm 2, and 5% in arm 3.All arms provide similar relapse-free survival and OS, with different toxicity profiles and central catheter requirements. LRF with postoperative therapy is low, justifying initial resection for T1-2, N0-2 and T3, and N0-2 anterior resection candidates.