tbuckley/cabot-search huggingface dataset:
Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell 'stemness' via the bone morphogenetic protein pathway
Authors: L. L. Kodach, R. J. Jacobs, P. W. Voorneveld, M. E. Wildenberg, H. W. Verspaget, T. van Wezel, H. Morreau, D. W. Hommes, M. P. Peppelenbosch, G. R. van den Brink, J. C. H. Hardwick
Journal: Gut (2011)

<h3>Background</h3> Promoter hypermethylation is an important and potentially reversible mechanism of tumour suppressor gene silencing in cancer. Compounds that demethylate tumour suppressor genes and induce differentiation of cancer cells, but do not have toxic side effects, would represent an exciting option in cancer therapy. Statins are cholesterol-lowering drugs with an excellent safety profile and associated with a reduced incidence of various cancers including colorectal cancer (CRC). The authors have previously shown that statins act by activating tumour suppressive bone morphogenetic protein (BMP) signalling in CRC, increasing expression of BMP2. <i>BMP2</i> is silenced by hypermethylation in gastric cancer. <h3>Aim</h3> To investigate whether <i>BMP2</i> is methylated in CRC, whether statins can reverse this, and what implications this has for the use of statins in CRC. <h3>Methods</h3> Methylation-specific PCR, bisulphite sequencing, immunoblotting, reverse transcription PCR, quantitative PCR, fluorescence-activated cell sorting analysis, an in vitro DNA methyltransferase (DNMT) assay, and cell viability studies were performed on CRC cells. The effect of statins was confirmed in a xenograft mouse model. <h3>Results</h3> <i>BMP2</i> is silenced by promoter hypermethylation in cell lines with the hypermethylator phenotype and in primary tumours. Treatment with lovastatin downregulates DNMT activity, leading to <i>BMP2</i> promoter demethylation and to upregulation of expression of <i>BMP2</i> as well as other genes methylated in CRC. Statins alter gene expression, indicating a shift from a stem-like state to a more differentiated state, thereby sensitising cells to the effects of 5-fluorouracil. In a xenograft mouse model, simvastatin treatment induces <i>BMP2</i> expression, leading to differentiation and reduced proliferation of CRC cells. <h3>Conclusions</h3> Statins act as DNMT inhibitors, demethylating the <i>BMP2</i> promoter, activating BMP signalling, inducing differentiation of CRC cells, and reducing 'stemness'. This study indicates that statins may be able to be used as differentiating agents in combined or adjuvant therapy in CRC with the CpG island methylator phenotype.
The evolution of evidence hierarchies: what can Bradford Hill's ‘guidelines for causation’ contribute?
Authors: Jeremy Howick, Paul Glasziou, Jeffrey K Aronson
Journal: Journal of the Royal Society of Medicine (2009)

High quality randomized controlled trials (RCTs) (concealed allocation, relevant groups blinded and sufficiently powered, etc.) will usually provide sufficient evidence to establish that a particular treatment caused an outcome. Yet sufficiently well‐conducted RCTs are rare.1 Trials can be under‐powered,2 or unsuccessfully blinded,3,4 and often suffer from many undetected biases. The results of most RCTs are therefore often insufficient to establish causation. At the same time, RCTs are often not required to establish causation.5 Treatments including the Heimlich manoeuvre, cardiac defibrillation and parachutes to prevent death6 have never been tested in RCTs, yet their effectiveness is surely strongly supported by evidence.

Evidence‐grading systems that place randomized trials at the top of a hierarchy7–13 will deliver misleading conclusions in cases where RCTs are insufficient or unnecessary. According to these hierarchies, trails of homeopathy – often generating positive results and generally of higher quality than RCTs of conventional treatments14 – will be considered to provide strong evidence, whereas the evidence base for the Heimlich manoeuvre to unblock airways and parachutes to prevent death will be judged as less strongly supported by evidence.

Sir Austin Bradford Hill, in a widely‐cited ‘pre‐EBM’ system for appraising evidence, suggested that several relevant factors must be considered before concluding causation. We investigated and revised the Bradford Hill ‘guidelines for causation’, in order to refine our intuitions about whether to believe that intervention is effective. Our intention is not to debunk previous attempts to grade evidence, but rather to contribute to their natural evolution and development.
Dietary Copper: Cholesterol and Lipoprotein Metabolism
Authors: K Y Lei
Journal: Annual Review of Nutrition (1991)

TISSUE CHOLESTEROL LEVELS AND PLASMA LIPOPROTEIN COMPOSITION. ...... . . . . .... . . . . . ... . . . . . .   .. . . . . .. ...... . . . ...... 266 Plasma and Tissue Cholesterol Concentrations  266 Plasma Lipoprotein Composition   267 CHOLESTEROL SyNTHESIS . . . . . . ...... . .   . . . . . ... . . . . . . . .....   . . . . ...... 270 Hepatic Cholesterogenesis and Lipogenesis from (4C]acetate   270 Hepatic 3-Hydroxy-3-Mel;llglutaryl Coenzyme A Reductase .. . . . . . . . . . . . . . . . . .. . . . . . . . . 27 1 Cholesterogenesis from [I Cjmevalonate  272 Cholesterogenesis from [3Hjwater.. . . . . .. .... . . . ..... . . . . . . .... . . . . ...... . . . . . . . . . . . . . . . . . . .. . 273 CHOLESTEROL ABSORPTION AND DEGRADATION . . . . . .... . . . . . ...... . .. .. ... . . .. .. .. 273 Lymphatic Absorption of Cholesterol   273 Biliary Steroid Excretion   274 Oxidation, Excretion. and Tissue Distribution of [26J4Cjcholesterol . . . . ..... . . . . . ... 275 LIPOPROTEIN METABOLISM . ....... . . . . ...... . . .... . . . . . ... . . . .. . ... . . . ....... . . . . ...... . . . . .. 276 High Density Lipoprotein Apolipoprotein and Cholesteryl Ester Catabolism......... 276 High Density Lipoprotein Binding to Liver Plasma Membranes  277 Specific Binding and Uptake of High Density Lipoprotein by Liver Cells   278 Lipoprotein and Hepatic Lipases ... . . ........     . ........ . ... 279 Plasma Lecithin: Cholesterol Acyltransferase  279 Apolipoprotein Synthesis and mRNA  279 CONCLUSIONS....... . .... . . .....   280
Central and Reflex Regulation of Sympathetic Vasoconstrictor Activity to Limb Muscles during Desynchronized Sleep in the Cat
Authors: GIORGIO BACCELLI, RENATO ALBERTINI, GIUSEPPE MANCIA, ALBERTO ZANCHETTI
Journal: Circulation Research (1974)

Desynchronized sleep (DS) in the cat is accompanied by a long-lasting (tonic) constriction of muscle blood vessels (conductance decrease 5-30%), on which are superimposed short-lasting (phasic) vasoconstrictor waves that occur simultaneously with bursts of rapid eye movements and body twitches. Both the tonic and the phasic vasoconstrictions are abolished after regional sympathectomy (conductance increase 5-10%). Tonic vasoconstriction can also be prevented by hind-limb deafferentation (bilateral section of the dorsal roots from L5 down) or by transection of the spinal cord at L4 in such a way as to separate sympathetic innervation from afferent input from the hind limbs. These procedures do not affect the phasic vasoconstrictions. After lumbar sympathectomy or hind-limb deafferentation, iliac blood flow decreases during the tonic fall in blood pressure associated with DS by exactly the amount (1-2 ml/min) predicted by pressure flow relationships observed during artificial lowering of iliac blood pressure. We conclude that tonic and phasic vasoconstrictions are both due to sympathetic discharges. However, phasic sympathetic discharges are driven by central descending influences, and tonic sympathetic vasoconstriction depends on reflex influences originating from the limbs themselves. When tonic sympathetic vasoconstriction is prevented, muscle blood vessels exhibit autoregulatory behavior during DS.
MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia
Authors: Yana Pikman, Benjamin H Lee, Thomas Mercher, Elizabeth McDowell, Benjamin L Ebert, Maricel Gozo, Adam Cuker, Gerlinde Wernig, Sandra Moore, Ilene Galinsky, Daniel J DeAngelo, Jennifer J Clark, Stephanie J Lee, Todd R Golub, Martha Wadleigh, D. Gary Gilliland, Ross L Levine
Journal: PLoS Medicine (2006)

The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR).DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis.Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD.
Induction of intracellular heat-shock protein 72 prevents the development of vascular smooth muscle cell calcification
Authors: Tzong-Shi Lu, Kenneth Lim, Guerman Molostvov, Yun-Chun Yang, Szu-Yu Yiao, Daniel Zehnder, Li-Li Hsiao
Journal: Cardiovascular Research (2012)

AimsVascular calcification (VC) is a significant contributor to cardiovascular mortality in patients with chronic kidney disease (CKD) and coronary artery disease (CAD). Osteo/chondrocytic transformation and simultaneous dedifferentiation of smooth muscle cells (SMCs) are important in the pathogenesis of VC. Heat-shock protein 72 (HSP72) is a cardioprotective inducible heat-shock protein that functions as a molecular chaperone. However, its role in the development of accelerated vascular dysfunction and calcification is largely unexplored.
Signaling by the Phosphoinositide 3-Kinase Family in Immune Cells
Authors: Klaus Okkenhaug
Journal: Annual Review of Immunology (2013)

Phosphoinositide 3-kinases (PI3Ks) control many important aspects of immune cell development, differentiation, and function. Mammals have eight PI3K catalytic subunits that are divided into three classes based on similarities in structure and function. Specific roles for the class I PI3Ks have been broadly investigated and are relatively well understood, as is the function of their corresponding phosphatases. More recently, specific roles for the class II and class III PI3Ks have emerged. Through vertebrate evolution and in parallel with the evolution of adaptive immunity, there has been a dramatic increase not only in the genes for PI3K subunits but also in genes for phosphatases that act on 3-phosphoinositides and in 3-phosphoinositide-binding proteins. Our understanding of the PI3Ks in immunity is guided by fundamental discoveries made in simpler model organisms as well as by appreciating new adaptations of this signaling module in mammals in general and in immune cells in particular.
Preoperative Staging of Large Primary Breast Cancer With [<sup>18</sup>F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Compared With Conventional Imaging Procedures
Authors: David Fuster, Joan Duch, Pilar Paredes, Martín Velasco, Montserrat Muñoz, Gorane Santamaría, Montserrat Fontanillas, Francesca Pons
Journal: Journal of Clinical Oncology (2008)

To evaluate the utility of positron emission tomography (PET) and [(18)F]fluorodeoxyglucose in the initial staging of large primary breast tumors.This prospective study was approved by the ethics committee, and all patients gave their informed consent before enrollment. Sixty consecutive patients with large (> 3 cm) primary breast cancer diagnosed by clinical examination and breast magnetic resonance imaging (MRI) were entered onto the study. The mean age was 57 +/- 13 years. Chest computed tomography (CT), liver ultrasonography, bone scan, and PET/CT were performed in all patients. All findings were histologically confirmed, and/or at least 1 year of follow-up was required. Correlation between parameters was calculated using Pearson's correlation coefficient. P < .05 was considered statistically significant.Primary tumor was identified by both PET/CT and MRI in all patients. Multifocal and/or multicentric tumors were found in 19 patients by MRI. Axillary lymph node metastases were found in 20 of 52 patients. Extra-axillary metastatic lymph nodes were also found in three patients. One patient showed an infiltrated lymph node in the contralateral axilla. The sensitivity and specificity for PET/CT to detect axillary lymph nodes metastases were 70% and 100%, respectively. PET/CT diagnosed all extra-axillary lymph nodes. The overall sensitivity and specificity of PET/CT in detecting distant metastases were 100% and 98%, respectively; whereas the sensitivity and specificity of conventional imaging were 60% and 83%, respectively. PET led to a change in the initial staging in 42% of patients.PET/CT underestimates locoregional lymph node staging in large primary breast cancer patients. PET/CT is a valuable tool to discard unsuspected extra-axillary lymph nodes and distant metastases.
Early molecular events induced by T cell receptor (TCR) signaling in immature CD4+ CD8+ thymocytes: increased synthesis of TCR-alpha protein is an early response to TCR signaling that compensates for TCR-alpha instability, improves TCR assembly, and parallels other indicators of positive selection.
Authors: K P Kearse, Y Takahama, J A Punt, S O Sharrow, A Singer
Journal: The Journal of Experimental Medicine (1995)

Differentiation of immature CD4+ CD8+ thymocytes into mature CD4+ or CD8+ T cells occurs within the thymus and is dependent upon expression of antigen receptor complexes (T cell receptor [TCR]) containing clonotypic alpha/beta proteins. We have recently found that CD4+ CD8+ thymocytes express low levels of surface TCR because of limitations placed on TCR assembly by the instability of nascent TCR-alpha proteins within the endoplasmic reticulum (ER) of immature thymocytes. Because TCR-alpha/beta expression increases during development, a molecular mechanism must exist for increasing the number of assembled TCR complexes present in immature CD4+ CD8+ thymocytes that have been signaled to differentiate into mature T cells, although no such mechanism has yet been described. In the current report we have examined the molecular consequences of intracellular signals generated by engagement of surface TCR complexes on immature CD4+ CD8+ thymocytes. Isolated TCR engagement generated signals that increased TCR-alpha RNA levels and increased synthesis of TCR-alpha proteins, which, in turn, significantly increased assembly of complete TCR-alpha/beta complexes in CD4+ CD8+ thymocytes. Increased TCR-alpha protein levels in TCR-signaled CD4+ CD8+ thymocytes was the result of increased synthesis and not increased stability of TCR-alpha proteins, indicating that TCR engagement compensates for, but does not correct, the inherent instability of TCR-alpha proteins in the ER of immature thymocytes. Consistent with the delivery by TCR engagement of a positive selection signal, TCR engagement also increased CD5 expression, decreased RAG-1 expression, and decreased CD4/CD8 coreceptor expression in immature CD4+ CD8+ thymocytes. These data identify amplified TCR-alpha expression as an initial response of immature CD4+ CD8+ thymocytes to TCR-mediated positive selection signals and provide a molecular basis for increased surface TCR density on developing thymocytes undergoing selection events within the thymus.
THE EFFECT OF SALT DEPRIVATION ON THE URINARY CONCENTRATING MECHANISM IN THE DOG*
Authors: Carl Goldsmith, H. Kent Beasley, Peggy J. Whalley, Floyd C. Rector, Donald W. Seldin
Journal: Journal of Clinical Investigation (1961)

According to the countercurrent theory (1-3), concentration of the urine results from the movement of water from the collecting tubule into the hypertonic medullary interstitium. Medullary hypertonicity is generated and maintained by the sodium transported out of the ascending limb of the loop of Henle and trapped in the medulla by the vasa recta which form a countercurrent exchanger. Consequently, the availability of sodium for reabsorption in the loop of Henle may assume a critical role in the regulation of urinary concentration. Various derangements in water excretion have been detected when the intake or renal excretion of sodium is altered. Patients with congestive heart failure, cirrhosis of the liver, and other conditions characterized by diminished sodium excretion frequently have been reported to have impaired urinary concentration in the absence of intrinsic renal disease. Levinsky, Davidson and Berliner (4) noted that dogs maintained on a sodium-free diet showed decreased maximal urinary concentration. Levitt, Levy and Polimeros (5), however, found that salt restriction in normal human subjects for 5 days had no effect on maximal urinary concentration. The present studies were undertaken to examine the relationship of sodium metabolism to urinary concentrating ability by evaluating the effects of varying sodium intake, glomerular filtration rate (GFR), aldosterone activity, and serum
Effect of Glycemic Treatment and Microvascular Complications on Menopause in Women With Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort
Authors: Catherine Kim, Patricia A. Cleary, Catherine C. Cowie, Barbara H. Braffett, Rodney L. Dunn, Mary E. Larkin, Patricia M. Gatcomb, Hunter B. Wessells, David M. Nathan, Aruna V. Sarma
Journal: Diabetes Care (2013)

OBJECTIVE We examined the impact of intensive versus conventional diabetes treatment upon menopause among women with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT), a randomized controlled trial of intensive diabetes treatment, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS In a secondary analysis of women in the DCCT/EDIC (n = 657), outcomes were the cumulative incidences of natural menopause and surgical menopause. Cox regression analyses were used to examine associations with treatment group, time-varying estimates of hemoglobin A1c (HbA1c), insulin dosage, BMI, and microvascular complications (retinopathy, nephropathy, and neuropathy). RESULTS By EDIC year 18, after an average of 28 years of follow-up, 240 (38%) women had experienced natural menopause and 115 (18%) women had experienced surgical menopause. Age at natural menopause was similar in the intensive versus conventional groups (49.9 vs. 49.0 years; P = 0.28), and age at surgical menopause was similar in the intensive versus conventional groups (40.8 vs. 42.0 years; P = 0.31). In multivariable models, treatment group, HbA1c, and microvascular complications were not associated with risk of natural or surgical menopause. Each 10 unit/day increase in insulin dosage decreased risk of natural menopause (hazard ratio [HR] 0.91, 95% CI 0.75-0.98) and each kg/m(2) increase in BMI increased risk of surgical menopause (HR 1.08, 95% CI 1.00-1.16). CONCLUSIONS In the DCCT/EDIC, intensive versus conventional treatment group and HbA1c level were not associated with menopause risk. Greater insulin dose was associated with lower menopause risk.
Sphingosine-1-phosphate modulation of basal permeability and acute inflammatory responses in rat venular microvessels
Authors: Roger H. Adamson, Rupinder K. Sarai, Ariungerel Altangerel, Twanda L. Thirkill, Joyce F. Clark, Fitz-Roy E. Curry
Journal: Cardiovascular Research (2010)

Although several cultured endothelial cell studies indicate that sphingosine-1-phosphate (S1P), via GTPase Rac1 activation, enhances endothelial barriers, very few in situ studies have been published. We aimed to further investigate the mechanisms whereby S1P modulates both baseline and increased permeability in intact microvessels. We measured attenuation by S1P of platelet-activating factor (PAF)- or bradykinin (Bk)-induced hydraulic conductivity (Lp) increase in mesenteric microvessels of anaesthetized rats. S1P alone (1–5 µM) attenuated by 70% the acute Lp increase due to PAF or Bk. Immunofluorescence methods in the same vessels under identical experimental conditions showed that Bk or PAF stimulated the loss of peripheral endothelial cortactin and rearrangement of VE-cadherin and occludin. Our results are the first to show in intact vessels that S1P pre-treatment inhibited rearrangement of VE-cadherin and occludin induced by PAF or Bk and preserved peripheral cortactin. S1P (1–5 µM, 30 min) did not increase baseline Lp. However, 10 µM S1P (60 min) increased Lp two-fold. Our results conform to the hypothesis that S1P inhibits acute permeability increase in association with enhanced stabilization of peripheral endothelial adhesion proteins. These results support the idea that S1P can be useful to attenuate inflammation by enhancing endothelial adhesion through activation of Rac-dependent pathways.