tbuckley/cabot-search huggingface dataset:
Mitochondrial MKP1 Is a Target for Therapy-Resistant HER2-Positive Breast Cancer Cells
Authors: Demet Candas, Chung-Ling Lu, Ming Fan, Frank Y.S. Chuang, Colleen Sweeney, Alexander D. Borowsky, Jian Jian Li
Journal: Cancer Research (2014)

Abstract The MAPK phosphatase MKP1 (DUSP1) is overexpressed in many human cancers, including chemoresistant and radioresistant breast cancer cells, but its functional contributions in these settings are unclear. Here, we report that after cell irradiation, MKP1 translocates into mitochondria, where it prevents apoptotic induction by limiting accumulation of phosphorylated active forms of the stress kinase JNK. Increased levels of mitochondrial MKP1 after irradiation occurred in the mitochondrial inner membrane space. Notably, cell survival regulated by mitochondrial MKP1 was responsible for conferring radioresistance in HER2-overexpressing breast cancer cells, due to the fact that MKP1 serves as a major downstream effector in the HER2-activated RAF–MEK–ERK pathway. Clinically, we documented MKP1 expression exclusively in HER2-positive breast tumors, relative to normal adjacent tissue from the same patients. MKP1 overexpression was also detected in irradiated HER2-positive breast cancer stem-like cells (HER2+/CD44+/CD24−/low) isolated from a radioresistant breast cancer cell population after long-term radiation treatment. MKP1 silencing reduced clonogenic survival and enhanced radiosensitivity in these stem-like cells. Combined inhibition of MKP1 and HER2 enhanced cell killing in breast cancer. Together, our findings identify a new mechanism of resistance in breast tumors and reveal MKP1 as a novel therapeutic target for radiosensitization. Cancer Res; 74(24); 7498–509. ©2014 AACR.
Blood pressure changes during daytime sleep and comparison of daytime and nighttime sleep-related blood pressure changes in patients with chronic renal failure.
Authors: S J Rosansky, K L Johnson, C Hutchinson, S Erdel
Journal: Journal of the American Society of Nephrology (1993)

Blood pressure has a diurnal pattern primarily related to activity and sleep. Chronic renal failure patients may lack the normal nocturnal decline in blood pressure during sleep. In 33 subjects (14 with normal renal function and 19 with renal dysfunction), the relationship between depth of daytime sleep, as determined by electroencephalographic sleep phase, and change in mean arterial blood pressure (MAP) and heart rate measured oscillometrically, was correlated. In 15 chronic renal failure patients, the effect of daytime and nighttime sleep on MAP and heart rate was compared. The percent change in night asleep versus day awake MAP and heart rate was measured (with Space Labs ambulatory blood pressure monitors) and compared with the percent change in daytime sleep-related MAP and heart rate measured during a daytime sleep electroencephalographic study. During daytime sleep, MAP changes are not significantly different in the normal versus renal dysfunction groups. In the 33 study subjects, MAP declines progressively from the upright position to Phase 3/4 sleep (118 +/- 3.6 to 106 +/- 3.6 mm Hg). The largest decline occurs between the upright to recumbent position, before sleep. Heart rate declines moving from the upright to recumbent position, 76 +/- 2.3 to 70 +/- 2.1 beats/min, but does not decline further with sleep. In 15 chronic renal failure patients, heart rate (10.8 +/- 2.8%; P < 0.05), but not MAP, declines during nighttime sleep. Both MAP (7.7 +/- 3.3%) and heart rate (5.4 +/- 1.9%) decline significantly during daytime sleep. The responses of MAP and heart rate to daytime and nighttime sleep were in opposite directions in 3 of 15 subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Association of Plasma Leptin Levels With Incident Alzheimer Disease and MRI Measures of Brain Aging
Authors: Wolfgang Lieb, Alexa S. Beiser, Ramachandran S. Vasan, Zaldy S. Tan, Rhoda Au, Tamara B. Harris, Ronenn Roubenoff, Sanford Auerbach, Charles DeCarli, Philip A. Wolf, Sudha Seshadri
Journal: JAMA (2009)

<h3>Context</h3>The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes β-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD).<h3>Objective</h3>To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors.<h3>Design, Setting, and Participants</h3>Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed.<h3>Main Outcome Measure</h3>Incidence of dementia and AD during follow-up until December 31, 2007.<h3>Results</h3>During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance.<h3>Conclusion</h3>Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.
<i>In vivo</i> Efficacy of STX213, A Second-Generation Steroid Sulfatase Inhibitor, for Hormone-Dependent Breast Cancer Therapy
Authors: Paul A. Foster, Simon P. Newman, Surinder K. Chander, Chloe Stengel, Roma Jhalli, Lawrence L.W. Woo, Barry V.L. Potter, Michael J. Reed, Atul Purohit
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model. Experimental Design: MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly. Results: STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P &amp;lt; 0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity. Conclusions: This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.
The endometrial effects of SERMs
Authors: A. Cano
Journal: Human Reproduction Update (2000)

The ideal selective oestrogen receptor modulator (SERM) would retain an oestrogen-like effect on the bones, the heart and cardiovascular apparatus, and the central nervous system, while acting as an anti-oestrogen on the breast and the genital tract. It seems, however, that such a compound is not available for clinical use yet. The uterine tissue, and particularly the endometrium, defines an area of special interest in the SERM action, since endometrial hyperplasia and cancer has been linked to agonistic oestrogen effects. Additionally, tamoxifen, the SERM which accumulates most of the clinical experience, has been associated with stimulatory effects on endometrium, including the development of cancer. In contrast, the more recent benzothiophenes, led by raloxifene, seem to operate as endometrial antagonists, thus providing an interesting alternative for clinical use. This review analyses the endometrial action of tamoxifen, including the information gathered from laboratory models, the observed endometrial effects in women using tamoxifen, and the epidemiological and molecular data which link the use of tamoxifen with endometrial cancer. A parallel examination of the raloxifene data presents the available experimental and clinical information, suggesting the endometrial neutrality of this compound.
Effect of Recall Rate on Earlier Screen Detection of Breast Cancers Based on the Dutch Performance Indicators
Authors: Johannes D. M. Otten, Nico Karssemeijer, Jan H. C. L. Hendriks, Johanna H. Groenewoud, Jacques Fracheboud, André L. M. Verbeek, Harry J. de Koning, Roland Holland
Journal: JNCI Journal of the National Cancer Institute (2005)

The recall rate (i.e., the rate at which mammographically screened women are recalled for additional assessment) in the Dutch breast screening program (0.89% in 2000 for subsequent examinations) is the lowest worldwide, with possible consequences including higher rates of late-detected (i.e., "missed") interval and screen-detected cancers. To estimate the effect of changes in recall rate on earlier detection of cancers, we carried out a blinded review of interval and screen-detected cancers in the Dutch screening program.A total of 495 sets of screen-negative mammograms (prediagnostic mammogram and the immediate previous mammogram) were collected from women participating in the biennial Dutch screening program. Of these, 250 were from control subjects, and 245 were from women who were subsequently diagnosed with breast cancer (123 interval and 122 screen-detected cancers). These mammograms were read by 15 radiologists who specialize in screening mammography and were blinded to outcome. Mean detection sensitivities for different false-positive rates were calculated using a linear mixed model. These results were used to calculate the effect of recall rate adjustment on earlier detection of cancers and numbers of false-positives.Increasing the recall rate to 2.0% would increase the detection rate from 4.20 per thousand to 4.52 per thousand due to the earlier detection of interval cancers. Moreover, 0.54 per thousand of the screen-detected cancers would be detected 2 years earlier (late screen-detected cancers). At recall rates of 3.0% and 4.0% the detection rate would increase to 4.58 per thousand and 4.63 per thousand, respectively, and 0.64 per thousand and 0.72 per thousand, respectively, of the screen-detected cancers would be detected 2 years earlier. For each 1.0% incremental increase in recall rate above 5.0%, the detection rate would increase by approximately 0.03 per thousand, with positive predictive values decreasing to below 10%.Breast cancer can be detected earlier by lowering the threshold for recall, especially for recall rates of 1%-4%. With further recall rate increases, cancer detection levels off with a disproportionate increase of false-positive rates.
Ena/VASP Is Required for Neuritogenesis in the Developing Cortex
Authors: Adam V. Kwiatkowski, Douglas A. Rubinson, Erik W. Dent, J. Edward van Veen, Jonathan D. Leslie, Jiangyang Zhang, Leslie M. Mebane, Ulrike Philippar, Elaine M. Pinheiro, Aurora A. Burds, Roderick T. Bronson, Susumu Mori, Reinhard Fässler, Frank B. Gertler
Journal: Neuron (2007)
Geometric Differences of the Mitral Apparatus Between Ischemic and Dilated Cardiomyopathy With Significant Mitral Regurgitation
Authors: Jun Kwan, Takahiro Shiota, Deborah A. Agler, Zoran B. Popović, Jian Xin Qin, Marc A. Gillinov, William J. Stewart, Delos M. Cosgrove, Patrick M. McCarthy, James D. Thomas
Journal: Circulation (2003)

This study was conducted to elucidate the geometric differences of the mitral apparatus in patients with significant mitral regurgitation caused by ischemic cardiomyopathy (ICM-MR) and by idiopathic dilated cardiomyopathy (DCM-MR) by use of real-time 3D echocardiography (RT3DE).Twenty-six patients with ICM-MR caused by posterior infarction, 18 patients with DCM-MR, and 8 control subjects were studied. With the 3D software, commissure-commissure plane and 3 perpendicular anteroposterior (AP) planes were generated for imaging the medial, central, and lateral sides of the mitral valve (MV) during mid systole. In 3 AP planes, the angles between the annular plane and each leaflet (anterior, Aalpha; posterior, Palpha) were measured. In ICM-MR, Aalpha measured in the medial and central planes was significantly larger than that in the lateral plane (39+/-5 degrees, 34+/-6 degrees, and 27+/-5 degrees, respectively; P<0.01), whereas Palpha showed no significant difference in any of the 3 AP planes (61+/-7 degrees, 57+/-7 degrees, and 56+/-7 degrees, P>0.05). In DCM-MR, both Aalpha (38+/-8 degrees, 37+/-9 degrees, and 36+/-7 degrees, P>0.05) and Palpha (59+/-6 degrees, 58+/-5 degrees, and 57+/-6 degrees, P>0.05) revealed no significant differences in the 3 planes.The pattern of MV deformation from the medial to the lateral side was asymmetrical in ICM-MR, whereas it was symmetrical in DCM-MR. RT3DE is a helpful tool for differentiating the geometry of the mitral apparatus between these 2 different types of functional mitral regurgitation.
Phosphatidylinositide-3-Kinase Inhibitors: Addressing Questions of Isoform Selectivity and Pharmacodynamic/Predictive Biomarkers in Early Clinical Trials
Authors: Paul A. Clarke, Paul Workman
Journal: Journal of Clinical Oncology (2011)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2011.38.7167 Journal of Clinical Oncology - published online before print December 12, 2011 PMID: 22162582 Phosphatidylinositide-3-Kinase Inhibitors: Addressing Questions of Isoform Selectivity and Pharmacodynamic/Predictive Biomarkers in Early Clinical Trials Paul A. ClarkexPaul A. ClarkeSearch for articles by this author , Paul WorkmanxPaul WorkmanSearch for articles by this author Show More The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom https://doi.org/10.1200/JCO.2011.38.7167 First Page Full Text PDF Figures and Tables © 2011 by American Society of Clinical Oncology
Experimental Autoimmune Anti–Glomerular Basement Membrane Glomerulonephritis
Authors: A. Richard Kitching, Amanda L. Turner, Timothy Semple, Ming Li, Kristy L. Edgtton, Gabrielle R. Wilson, Jennifer R. Timoshanko, Billy G. Hudson, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2004)

Previous studies have shown that strawberry extract increases the transepithelial transport of tenofovir disoproxil, an esterase-sensitive prodrug of the antiviral compound tenofovir (formerly PMPA), across Caco-2 monolayers. This increase in transport was at least partially due to inhibition of its intestinal metabolism. To further study the feasibility of this absorption enhancing strategy, the influence of various concentrations of strawberry extract (0–2%) on the intestinal absorption of tenofovir disoproxil (100 μM) was assessed using an in situ perfusion model with immediate blood sampling from the mesenteric vein, a model closer to the in vivo situation than the in vitro Caco-2 system. Inclusion of strawberry extract (1%) resulted in a 7-fold increase in the appearance of tenofovir equivalents. The metabolism of tenofovir disoproxil in the intestinal perfusate was significantly lower in the presence of strawberry extract (1%), showing that the metabolism of tenofovir disoproxil is reduced by the flavoring extract.
Genetic Variation in the Prostaglandin E<sub>2</sub> Pathway Is Associated with Primary Graft Dysfunction
Authors: Joshua M. Diamond, Tatiana Akimova, Altaf Kazi, Rupal J. Shah, Edward Cantu, Rui Feng, Matthew H. Levine, Steven M. Kawut, Nuala J. Meyer, James C. Lee, Wayne W. Hancock, Richard Aplenc, Lorraine B. Ware, Scott M. Palmer, Sangeeta Bhorade, Vibha N. Lama, Ann Weinacker, Jonathan Orens, Keith Wille, Maria Crespo, David J. Lederer, Selim Arcasoy, Ejigayehu Demissie, Jason D. Christie
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses.We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach.Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1.After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10(-5)). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells.Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.
Age and Sex Influence Cystatin C in Adolescents With and Without Type 1 Diabetes
Authors: David M. Maahs, Nicole Prentice, Kim McFann, Janet K. Snell-Bergeon, Diana Jalal, Franziska K. Bishop, Brittany Aragon, R. Paul Wadwa
Journal: Diabetes Care (2011)

OBJECTIVE To compare serum cystatin C levels, a novel biomarker of renal function, in adolescents with and without type 1 diabetes and to determine what factors affect cystatin C levels. RESEARCH DESIGN AND METHODS Cystatin C was measured in youth 12–19 years of age with (n = 259, diabetes duration 9 ± 3 years, HbA1c 8.9 ± 1.6%) and without diabetes (n = 78). Data were compared by diabetes status, and linear regression was used to determine factors affecting cystatin C. RESULTS Cystatin C (0.698 ± 0.083 vs. 0.688 ± 0.127 mg/L, P = 0.40) was similar by diabetes status. In multiple linear regression, cystatin C was associated with age and serum creatinine in nondiabetic subjects and sex, age, and serum creatinine in subjects with diabetes (P &amp;lt; 0.05). CONCLUSIONS These data suggest sex differences and age-related changes in cystatin C in adolescents with type 1 diabetes. An understanding of these changes is needed to determine the potential role of cystatin C as a marker of renal function in this population.
Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits
Authors: N VANROYEN, I HOEFER, I BUSCHMANN, S KOSTIN, M VOSKUIL, C BODE, W SCHAPER, J PIEK
Journal: Cardiovascular Research (2002)

The objective of our study was to quantify the arteriogenic potency of Monocyte Chemoattractant Protein-1 (MCP-1) under hyperlipidemic conditions. Additionally, we aimed to determine the effects of locally applied MCP-1 on systemic serum lipid levels as well as on atherosclerosis.A total of sixty-four Watanabe rabbits was treated with either low dose MCP-1 (1 microg/kg/week), high dose MCP-1 (3.3 microg/kg/week) or PBS as a control substance. Substances were applied directly into the collateral circulation via an osmotic minipump with the catheter placed in the proximal stump of the ligated femoral artery. Either 1 week or 6 months after initiation of the treatment X-ray angiography was performed as well as measurements of collateral conductance using fluorescent microspheres. The extent of atherosclerosis was quantified in whole aortas using Sudan IV staining.One week after ligation of the femoral artery a significant increase in collateral conductance was observed in animals treated with high dose MCP-1 (control: 2.2+/-0.8 ml/min/100 mmHg vs. MCP-1 high dose: 8.9+/-2.0 ml/min/100 mmHg, P<0.05). Six months after femoral artery ligation no differences were found between the treated and the control group (PBS; 44.9+/-11.6 ml/min/100 mmHg, MCP-1; 47.8+/-11.5 ml/min/100 mmHg, P=NS). No influence was found on serum lipids or on the development of atherosclerosis in the present model.MCP-1 accelerates arteriogenesis upon femoral artery ligation under hyperlipidemic conditions. Six months after treatment these pro-arteriogenic effects of MCP-1 can no longer be observed. The present data do not show an effect of local MCP-1 treatment on serum lipids or on atherosclerosis. It should be noted however that a high standard deviation was observed for the data on atherosclerotic surface area, necessitating additional experiments in a different model of atherosclerosis.