tbuckley/cabot-search huggingface dataset:
A Positive Feedback Signaling Loop between ATM and the Vitamin D Receptor Is Critical for Cancer Chemoprevention by Vitamin D
Authors: Huei-Ju Ting, Sayeda Yasmin-Karim, Shian-Jang Yan, Jong-Wei Hsu, Tzu-Hua Lin, Weisi Zeng, James Messing, Tzong-Jeng Sheu, Bo-Ying Bao, Willis X. Li, Edward Messing, Yi-Fen Lee
Journal: Cancer Research (2011)

Abstract Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1α,25-dihydroxyvitamin D3 (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which 1,25-VD prevents tumorigenesis remains incomplete. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation. In this model, 1,25-VD promoted expression of the DNA repair genes RAD50 and ATM, both of which are critical for mediating the signaling responses to DNA damage. Correspondingly, 1,25-VD protected cells from genotoxic stress and growth inhibition by promoting double-strand break DNA repair. Depletion of the vitamin D receptor (VDR) reduced these genoprotective effects and drove malignant transformation that could not be prevented by 1,25-VD, defining an essential role for VDR in mediating the anticancer effects of 1,25-VD. Notably, genotoxic stress activated ATM and VDR through phosphorylation of VDR. Mutations in VDR at putative ATM phosphorylation sites impaired the ability of ATM to enhance VDR transactivation activity, diminishing 1,25-VD–mediated induction of ATM and RAD50 expression. Together, our findings identify a novel vitamin D–mediated chemopreventive mechanism involving a positive feedback loop between the DNA repair proteins ATM and VDR. Cancer Res; 72(4); 958–68. ©2011 AACR.
Ku70 Is Required for DNA Repair but Not for T Cell Antigen Receptor Gene Recombination In Vivo
Authors: Honghai Ouyang, Andre Nussenzweig, Akihiro Kurimasa, Vera da Costa Soares, Xiaoling Li, Carlos Cordon-Cardo, Wen-hui Li, Nge Cheong, Michel Nussenzweig, George Iliakis, David J. Chen, Gloria C. Li
Journal: The Journal of Experimental Medicine (1997)

Ku is a complex of two proteins, Ku70 and Ku80, and functions as a heterodimer to bind DNA double-strand breaks (DSB) and activate DNA-dependent protein kinase. The role of the Ku70 subunit in DNA DSB repair, hypersensitivity to ionizing radiation, and V(D)J recombination was examined in mice that lack Ku70 (Ku70−/−). Like Ku80−/− mice, Ku70−/− mice showed a profound deficiency in DNA DSB repair and were proportional dwarfs. Surprisingly, in contrast to Ku80−/− mice in which both T and B lymphocyte development were arrested at an early stage, lack of Ku70 was compatible with T cell receptor gene recombination and the development of mature CD4+CD8− and CD4−CD8+ T cells. Our data shows, for the first time, that Ku70 plays an essential role in DNA DSB repair, but is not required for TCR V(D)J recombination. These results suggest that distinct but overlapping repair pathways may mediate DNA DSB repair and V(D)J recombination.
The Value of Axial Diameters and Obstruction Scores for Determining the Echocardiographic Right Ventricular Dysfunction in Acute Pulmonary Embolism
Authors: Alpay Arıbaş, Suat Keskin, Hakan Akıllı, Mehmet Kayrak, Halil İbrahim Erdoğan, İbrahim Güler, Oğuzhan Yıldırım, Taha Tahir Bekçi
Journal: Journal of the American College of Cardiology (2013)
Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis
Authors: Aditi Gupta, Wei Cao, Meenakshi A Chellaiah
Journal: Molecular Cancer (2012)

Bone loss and pathological fractures are common skeletal complications associated with androgen deprivation therapy and bone metastases in prostate cancer patients. We have previously demonstrated that prostate cancer cells secrete receptor activator of NF-kB ligand (RANKL), a protein essential for osteoclast differentiation and activation. However, the mechanism(s) by which RANKL is produced remains to be determined. The objective of this study is to gain insight into the molecular mechanisms controlling RANKL expression in metastatic prostate cancer cells.We show here that phosphorylation of Smad 5 by integrin αvβ3 and RUNX2 by CD44 signaling, respectively, regulates RANKL expression in human-derived PC3 prostate cancer cells isolated from bone metastasis. We found that RUNX2 intranuclear targeting is mediated by phosphorylation of Smad 5. Indeed, Smad5 knock-down via RNA interference and inhibition of Smad 5 phosphorylation by an αv inhibitor reduced RUNX2 nuclear localization and RANKL expression. Similarly, knockdown of CD44 or RUNX2 attenuated the expression of RANKL. As a result, conditioned media from these cells failed to support osteoclast differentiation in vitro. Immunohistochemistry analysis of tissue microarray sections containing primary prostatic tumor (grade2-4) detected predominant localization of RUNX2 and phosphorylated Smad 5 in the nuclei. Immunoblotting analyses of nuclear lysates from prostate tumor tissue corroborate these observations.Collectively, we show that CD44 signaling regulates phosphorylation of RUNX2. Localization of RUNX2 in the nucleus requires phosphorylation of Smad-5 by integrin αvβ3 signaling. Our results suggest possible integration of two different pathways in the expression of RANKL. These observations imply a novel mechanistic insight into the role of these proteins in bone loss associated with bone metastases in patients with prostate cancer.
Trust missed breast cancer in eight women, review finds
Authors: A. O'Dowd
Journal: BMJ (2010)

A trust failed to identify breast cancer in eight women who had been screened, an independent review has found.

All the women are now being treated by the North Cumbria University Hospitals NHS Trust in Cumbria, where the screening failings emerged last month.

Screening experts have said the case is not typical and is one of a handful of instances over the past 20 years.

Last month the trust announced that breast cancer screening was being temporarily halted for a major review to be carried out after the regional screening programme’s quality assurance team raised concerns.

The trust …
HER-2 Gene Amplification Correlates with Higher Levels of Angiogenesis and Lower Levels of Hypoxia in Primary Breast Tumors
Authors: Kimberly L. Blackwell, Mark W. Dewhirst, Vlayka Liotcheva, Stacey Snyder, Gloria Broadwater, Rex Bentley, Anita Lal, Gregory Riggins, Steve Anderson, Jim Vredenburgh, Alan Proia, Lyndsay N. Harris
Journal: Clinical Cancer Research (2004)

Abstract Purpose: This study investigated the connection among HER-2 gene amplification, HER-2 protein expression, and markers of tumor angiogenesis and oxygenation in patients with operable, invasive breast tumors. Experimental Design: From 1988 to 1995, 425 patients with metastatic breast cancer were enrolled in a study of high-dose chemotherapy with autologous transplant. Primary tumor blocks were obtained and evaluated using immunohistochemistry (IHC) staining of vessels with von Willebrand factor antibody. Mean microvessel densities (MVD) were determined by counting von Willebrand factor stained cells in three separate “vascular hot spots” using image analysis. Tumor samples were also stained for HER-2 by IHC, HER-2 gene amplification by fluorescence in situ hybridization, carbonic anhydrase 9 by IHC, and vascular endothelial growth factor (VEGF) by IHC. Plasma from 36 patients with primary tumor samples had VEGF (R&amp;D Systems, MN) and d-dimer (American Diagnostica, Greenwich, CT) levels determined. Results: There was a significant positive correlation between HER-2 gene amplification and both maximum and average MVD (Spearman coefficient = 0.51 and 0.50; P = 0.03 and 0.05, respectively). There was an inverse correlation with HER-2 gene amplification and expression of the tumor hypoxia marker CA-9 (χ2 P = 0.02). The level of HER-2 gene amplification correlated with plasma d-dimer levels (Spearman coefficient = 0.43; P = 0.021). Interestingly, tumors with HER-2 by IHC had decreased amounts of VEGF staining (χ2 = 5.81; P = 0.01). There was no correlation between HER-2 by IHC and MVD or d-dimer. Of all of the variables examined, only average (P = 0.0016) and maximum MVD (P = 0.0128) predicted disease-free survival (Cox univariate model). Conclusions: HER-2-amplified breast cancers have increased amounts of angiogenesis, decreased amounts of hypoxia, and increased markers of fibrin degradation. These findings have prognostic, predictive, and therapeutic implications in breast cancer treatment.
The Public Health Impact of Obesity
Authors: Tommy LS Visscher, Jacob C Seidell
Journal: Annual Review of Public Health (2001)

The increase in obesity worldwide will have an important impact on the global incidence of cardiovascular disease, type 2 diabetes mellitus, cancer, osteoarthritis, work disability, and sleep apnea. Obesity has a more pronounced impact on morbidity than on mortality. Disability due to obesity-related cardiovascular diseases will increase particularly in industrialized countries, as patients survive cardiovascular diseases in these countries more often than in nonindustrialized countries. Disability due to obesity-related type 2 diabetes will increase particularly in industrializing countries, as insulin supply is usually insufficient in these countries. As a result, in these countries, an increase in disabling nephropathy, arteriosclerosis, neuropathy, and retinopathy is expected. Increases in the prevalence of obesity will potentially lead to an increase in the number of years that subjects suffer from obesity-related morbidity and disability. A 1% increase in the prevalence of obesity in such countries as India and China leads to 20 million additional cases of obesity. Prevention programs will stem the obesity epidemic more efficiently than weight-loss programs. However, only a few prevention programs have been developed or implemented, and the success rates reported to date have been low. Obesity prevention programs should be high on the scientific and political agenda in both industrialized and industrializing countries.
The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: A placebo-controlled randomized clinical trial
Authors: A.Enrique Caballero, Rola Saouaf, Su Chi Lim, Osama Hamdy, Karim Abou-Elenin, Colleen O'Connor, Frank W. LoGerfo, Edward S. Horton, Aristidis Veves
Journal: Metabolism (2003)
Poster session 4. Molecular diagnosis &amp; biomarkers
Authors: J. A. Lynch, C. M. Choi, Y. S. Park, J. C. Lee, M. J. Park, H. R. Kim, N. Y. Shih, G. C. Chang, S. W. Tseng, K. J. Liu, K. C. Hsiao, H. C. Lin, J. Y. Wang, H. L. Tsai, V. Barak, Y. J. Chen, Y. L. Hsieh, P. H. Chien, Y. F. Chien, W. C. Huang, S. R. Lin, F. Y. Chung, L. C. Yen, H. L. Tsai, O. Rixe, A. M. Salkeni, J. M. Furgason, C. McPherson, R. Warnick, M. Bahassi, T. A. Hembrough, D. V. T. Catenacci, W. L. Liao, S. Thyparambil, P. Xu, L. Henderson, J. Burrows, D. G. Bebb, A. A. Elegbede, E. Kubota, L. F. Petersen, S. M. Otsuka, S. P. Lees-Miller
Journal: Annals of Oncology (2013)
The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease
Authors: M Olivares, A Neef, G Castillejo, G De Palma, V Varea, A Capilla, F Palau, E Nova, A Marcos, I Polanco, C Ribes-Koninckx, L Ortigosa, L Izquierdo, Y Sanz
Journal: Gut (2014)

Intestinal dysbiosis has been associated with coeliac disease (CD), but whether the alterations are cause or consequence of the disease is unknown. This study investigated whether the human leukocyte antigen (HLA)-DQ2 genotype is an independent factor influencing the early gut microbiota composition of healthy infants at family risk of CD.As part of a larger prospective study, a subset (n=22) of exclusively breastfed and vaginally delivered infants with either high genetic risk (HLA-DQ2 carriers) or low genetic risk (non-HLA-DQ2/8 carriers) of developing CD were selected from a cohort of healthy infants with at least one first-degree relative with CD. Infant faecal microbiota was analysed by 16S rRNA gene pyrosequencing and real time quantitative PCR.Infants with a high genetic risk had significantly higher proportions of Firmicutes and Proteobacteria and lower proportions of Actinobacteria compared with low-risk infants. At genus level, high-risk infants had significantly less Bifidobacterium and unclassified Bifidobacteriaceae proportions and more Corynebacterium, Gemella, Clostridium sensu stricto, unclassified Clostridiaceae, unclassified Enterobacteriaceae and Raoultella proportions. Quantitative real time PCR also revealed lower numbers of Bifidobacterium species in infants with high genetic risk than in those with low genetic risk. In high-risk infants negative correlations were identified between Bifidobacterium species and several genera of Proteobacteria (Escherichia/Shigella) and Firmicutes (Clostridium).The genotype of infants at family risk of developing CD, carrying the HLA-DQ2 haplotypes, influences the early gut microbiota composition. This finding suggests that a specific disease-biased host genotype may also select for the first gut colonisers and could contribute to determining disease risk.
Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy
Authors: Masahisa Katsuno, Hiroaki Adachi, Manabu Doyu, Makoto Minamiyama, Chen Sang, Yasushi Kobayashi, Akira Inukai, Gen Sobue
Journal: Nature Medicine (2003)
Effect of the Accountable Care Act of 2010 on Clinical Trial Insurance Coverage
Authors: Sheetal M. Kircher, Al B. Benson, Matthew Farber, Halla S. Nimeiri
Journal: Journal of Clinical Oncology (2011)

The Affordable Care Act (ACA) of 2010 implemented dramatic changes in our health care system. The new law requires that insurers and health plans provide coverage for individuals participating in clinical trials. Currently, there are states that already have laws or agreements requiring clinical trial coverage, but there remain deficiencies that will need to be addressed to achieve compliance with the new law.State mandates were reviewed to determine current laws and agreements. The ACA was reviewed to outline its provisions, and these were compared with current mandates to identify deficiencies.Eighteen states meet the requirements set forth by the ACA either through a state law or agreement; 33 states do not meet the requirements. Of these 33 states, 15 do not have any existing laws or agreements in place regarding clinical trials. In states that have deficient policies in place, the most common deficiency is the lack of phase I coverage. The second most common deficiency in policy is coverage of only therapeutic studies.Most states currently do not meet the requirements of the ACA and will be required to make changes by 2014. The implications of the ACA with regard to insurance coverage of clinical trials remain unclear as implementation of the legislation unfolds. State governments can take steps to ensure insurance coverage by creating and expanding agreements with insurance companies.
Usefulness of transesophageal echocardiography in assessment of aortic dissection.
Authors: R S Ballal, N C Nanda, R Gatewood, B D'Arcy, T E Samdarshi, W L Holman, J K Kirklin, A D Pacifico
Journal: Circulation (1991)

BACKGROUND The value of transesophageal echocardiography in the assessment of patients with aortic dissection was studied. METHODS AND RESULTS Group 1 (34 patients) represented all patients studied at our institution with this technique in whom aortic dissection was proven by aortography, surgery, or autopsy. Group 2 (27 patients) represented all patients studied with this technique at our institution in whom aortic dissection was excluded by aortography. Transesophageal echocardiography made a correct diagnosis of aortic dissection in 33 of 34 patients (sensitivity, 97%; specificity, 100%). It also correctly demonstrated the type of dissection in all 29 patients with aortographic or surgical proof. On the other hand, computed tomography scanning, performed in 24 of 34 patients in group 1, made a correct diagnosis in only 67% of patients and misclassified the type of dissection in 33%. Transesophageal echocardiography correctly identified involvement of the coronary arteries by aortic dissection in six of seven patients as well as absence of both left and right coronary artery involvement in 10 patients with aortic dissection. This technique was also useful in detecting communications between the true and false lumens, presence of thrombi in the false lumen, and, in two patients, localized dissection rupture with formation of a false aneurysm. In both groups 1 and 2, transesophageal echocardiography correctly identified patients with moderate to severe aortic regurgitation. CONCLUSIONS Transesophageal echocardiography is very useful in the assessment of aortic dissection.
Reply to A. Goyal et al
Authors: Ahmed O. Kaseb, Jeffrey S. Morris, Manal M. Hassan, James L. Abbruzzese
Journal: Journal of Clinical Oncology (2012)

no better than a coin-flip (no discrimination), whereas a value of 1.0 indicates perfect discrimination. 3 Using c-index analysis, Kaseb et al state that "the IV-BCLC system was more accurate at predicting OS [overall survival] and provided better stratification than BCLC (P Ͻ .001),I-BCLC (P ϭ .002),or V-BCLC (P Ͻ .001)alone." 1(p3895) C-index for each staging system was as follows: BCLC, 0.65; V-BCLC, 0.66; I-BCLC, 0.68; and IV-BCLC, 0.68.Given that IV-BCLC and I-BCLC staging have the same c-index, it is not clear what prognostic value is added by the VEGF level.On the basis of these results, the assertion that VEGF levels improve prognostic stratification of patients with HCC seems overstated.We agree with the importance of identifying new, noninvasive, predictive and prognostic biomarkers in HCC.Low IGF-1 levels correlate with many known, poor prognostic features in this study, such as increased tumor size, worse liver function, and vascular invasion.It would be particularly compelling to show that IGF-1 is an independent prognostic biomarker when adjusted for other known prognostic variables that can be obtained without tissue, in addition to BCLC staging.In addition, we have preliminary data that show that a high body mass index (BMI) is associated with increased vascular invasion in tumors of patients with HCC. 4 Because BMI and IGF-1 levels are often correlated, it would be interesting to see if IGF-1 levels remain prog-nostic after controlling for increased BMI and other markers of the metabolic syndrome in a prospective study.We have begun such a study to further evaluate these associations.
Insulin-Like Growth Factor 1 and Prostate Cancer Risk: A Population-Based, Case-Control Study
Authors: A. Wolk, C. S. Mantzoros, S.-O. Andersson, R. Bergstrom, L. B. Signorello, P. Lagiou, H.-O. Adami, D. Trichopoulos
Journal: JNCI Journal of the National Cancer Institute (1998)

Background. Recent epidemiologic investigations have suggested an association between increased blood levels of insulin-like growth factor 1 (IGF-1) and increased risk of prostate cancer Our goal was to determine whether an association exists between serum levels of IGF-1 and one of its binding proteins, insulin-like growth factorbinding protein 3 (IGFBP-3), and prostate cancer risk. Methods: An immunoradiometric assay was used to quantify IGF-1 levels and IGFBP-3 levels in serum samples as part of a populationbased, case-control study in Sweden. The study population comprised 210 patients with newly diagnosed, untreated prostate cancer and 224 frequency-matched control subjects. Data were analyzed by use of unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Reported P values are twosided. Results: The mean serum IGF-1 level for case patients (158.4 ng/mL) was significantly higher than that for control subjects (147.4 ng/mL) (P =.02); corresponding mean serum IGFBP-3 levels were not significantly different between case patients (2668 ng/mL) and control subjects (2518 ng/ mL) (P =.09). We found a moderately strong and statistically significant (P = .04) positive association between serum levels of IGF-1 levels and risk of prostate cancer (OR = 1.51; 95% CI = 1.0-2.26 per 100 ng/mL increment); the association was particularly strong for men younger than 70 years of age (OR = 2.93; 95% CI = 1.43–5.97). No association was found between serum IGF-1 levels and disease stage. Serum IGFBP-3 levels were not significantly associated with increased risk of disease, and adjustment for IGFBP-3 had little effect on the association between IGF-1 levels and risk of prostate cancer. Conclusion Elevated serum IGF-1 levels may be an important predictor of risk for prostate cancer. However, our results do not support an important role for serum IGFBP-3 as a predictor of risk for this disease. [J Nall Cancer Inst 1998;90:911-5]
Effect of Resynchronization Therapy Stimulation Site on the Systolic Function of Heart Failure Patients
Authors: Christian Butter, Angelo Auricchio, Christoph Stellbrink, Eckart Fleck, Jiang Ding, Yinghong Yu, Etienne Huvelle, Julio Spinelli
Journal: Circulation (2001)

Background — Cardiac resynchronization therapy (CRT) improves systolic function in heart failure patients with ventricular conduction delay by stimulating the left ventricle (LV) or both ventricles (biventricular, BV). Optimal LV site selection is of major clinical interest for CRT device implantation; however, the dependence of hemodynamics on LV stimulation site has not been established. Thus, the objective of this study was to compare the hemodynamic response to CRT for 2 LV coronary vein sites: the free wall and anterior wall. Methods and Results — A total of 30 patients (mean NYHA class, 2.7; mean QRS interval, 152 ms; mean PR interval, 194 ms) enrolled in the PATH-CHF-II trial were studied. CRT was administered with LV and BV stimulation in VDD mode at 4 AV delays. LV stimulation was at the lateral free wall or anterior wall, whereas right ventricular stimulation was fixed near the apex. LV+dP/dt max and aortic pulse pressure changes from baseline during CRT were compared for LV sites. Free wall sites with LV and BV stimulation yielded significantly larger LV+dP/dt max (14% versus 6%, P &lt;0.001 for LV; 12% versus 5%, P &lt;0.001 for BV) and pulse pressure (8% versus 4%, P &lt;0.001 for LV; 9% versus 5%, P &lt;0.001 for BV) compared with anterior sites. In one third of patients, CRT at free wall sites increased LV+dP/dt max , whereas it decreased at anterior sites over most AV delays. Conclusion — CRT with LV free wall stimulation produced significantly better LV systolic performance compared with anterior stimulation. Further studies are warranted to prove the clinical superiority of the LV free wall as a site for long-term CRT.