tbuckley/cabot-search huggingface dataset:
Abstract OT2-6-02: Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): A global, placebo-controlled, randomized, double-blind, phase 3 clinical trial
Authors: PE Goss, CH Barrios, A Chan, DM Finkelstein, H Iwata, M Martin, A Braun, Y Zhou, T Maniar, RE Coleman
Journal: Cancer Research (2013)

Abstract Background: In women with early-stage breast cancer, the skeleton represents one of the most common sites for metastases and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab, a human IgG2 monoclonal antibody, binds RANKL with high specificity and affinity thus inhibiting RANKL activity. Denosumab has been approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. Purpose: The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS; primary endpoint) in the adjuvant breast cancer setting. Secondary endpoints include disease-free survival (DFS) and overall survival. Additional endpoints include safety, patient reported outcomes (pain, health utilities), as well as exploratory including breast density, time to first on-study SRE following the development of bone metastasis and biomarkers. Methods: In this global, randomized, double-blind, and placebo-controlled phase 3 trial, approximately 4500 women with stage II or III breast cancer at high risk for recurrence were randomized. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size &amp;gt; 5 cm (T3), or locally advanced disease (T4). Patients must be receiving or planned to receive standard-of-care adjuvant/neoadjuvant therapy (chemo-, endocrine, or HER-2 targeted), alone or in combination. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) are required. The primary efficacy and two interim efficacy analyses are planned and will be event-driven. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and completed enrollment in late 2012. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-02.
Cost-effectiveness of community-based strategies to strengthen the continuum of HIV care in rural South Africa: a health economic modelling analysis
Authors: Jennifer A Smith, Monisha Sharma, Carol Levin, Jared M Baeten, Heidi van Rooyen, Connie Celum, Timothy B Hallett, Ruanne V Barnabas
Journal: The Lancet HIV (2015)

Home HIV counselling and testing (HTC) achieves high coverage of testing and linkage to care compared with existing facility-based approaches, particularly among asymptomatic individuals. In a modelling analysis we aimed to assess the effect on population-level health and cost-effectiveness of a community-based package of home HTC in KwaZulu-Natal, South Africa.We parameterised an individual-based model with data from home HTC and linkage field studies that achieved high coverage (91%) and linkage to antiretroviral therapy (80%) in rural KwaZulu-Natal, South Africa. Costs were derived from a linked microcosting study. The model simulated 10,000 individuals over 10 years and incremental cost-effectiveness ratios were calculated for the intervention relative to the existing status quo of facility-based testing, with costs discounted at 3% annually.The model predicted implementation of home HTC in addition to current practice to decrease HIV-associated morbidity by 10–22% and HIV infections by 9–48% with increasing CD4 cell count thresholds for antiretroviral therapy initiation. Incremental programme costs were US$2·7 million to $4·4 million higher in the intervention scenarios than at baseline, and costs increased with higher CD4 cell count thresholds for antiretroviral therapy initiation; antiretroviral therapy accounted for 48–87% of total costs. Incremental cost-effectiveness ratios per disability-adjusted life-year averted were $1340 at an antiretroviral therapy threshold of CD4 count lower than 200 cells per μL, $1090 at lower than 350 cells per μL, $1150 at lower than 500 cells per μL, and $1360 at universal access to antiretroviral therapy.Community-based HTC with enhanced linkage to care can result in increased HIV testing coverage and treatment uptake, decreasing the population burden of HIV-associated morbidity and mortality. The incremental cost-effectiveness ratios are less than 20% of South Africa's gross domestic product per person, and are therefore classed as very cost effective. Home HTC can be a viable means to achieve UNAIDS' ambitious new targets for HIV treatment coverage.National Institutes of Health, Bill & Melinda Gates Foundation, Wellcome Trust.
GLOMERULAR LESIONS AND THE NEPHROTIC SYNDROME IN RABBITS GIVEN SACCHARATED IRON OXIDE INTRAVENOUSLY
Authors: John T. Ellis
Journal: The Journal of Experimental Medicine (1956)

Intravascular precipitates, comprised at least in part of iron, formed regularly in rabbits given one or more injections of a saccharated iron oxide preparation intravenously, and these lodged in numerous capillaries throughout the body, particularly those of the lungs and kidneys. Large numbers of the brownish precipitates remained in the capillaries of the renal glomeruli during the first few days following injection of the iron, but most of them disappeared after 5 to 7 days, with only moderate amounts of brown pigment remaining in the endothelial cells of the renal glomeruli. Signs of acute injury of the glomerular tufts-namely) pyknosis of some of the endothelial cells, margination of leukocytes within the glomerular capillaries, and slight proliferation of the epithelial cells-also developed some 5 to 7 days following injection of the iron, along with marked proteinuria, which proved transitory if no further injections were given. When the iron preparation was given repeatedly over prolonged intervals, however, the proteinuria persisted and became extreme, and hypoproteinemia developed, often with hypercholesterolemia and transitory edema as well. Histological studies of the kidneys of rabbits manifesting the nephrotic syndrome, as just described, disclosed that virtually all the renal glomeruli were greatly altered, mainly owing to proliferation of the epithelial cells, together with some fibrosis and atrophy. Some of the rabbits having marked proteinuria and other functional changes eventually developed azotemia following repeated injections of the iron, and several of them lost weight and died; the renal glomeruli of these animals showed changes like those just described, but the alterations were more extensive. Considered together, the findings provide evidence that the intravascular precipitates first occluded the glomerular capillaries for a period of several days following injection of the iron and then largely disappeared from them just prior to the development of morphologic signs of glomerular injury and proteinuria. Hence the possibility was considered that the intracapillary precipitates might have produced acute injury to the walls of the glomerular capllaries through the agency of anoxia. But it is plain that the findings of the present study do not disclose the essential nature of the anatomical change responsible for the proteinuria, or the means whereby this was produced. The findings as a whole were briefly considered in relation to the pathogenesis of the nephrotic syndrome as it occurs naturally in human beings.
Depletion of Serum Response Factor by RNA Interference Mimics the Mitogenic Effects of Platelet Derived Growth Factor-BB in Vascular Smooth Muscle Cells
Authors: Nihal Kaplan-Albuquerque, Vicki Van Putten, Mary C. Weiser-Evans, Raphael A. Nemenoff
Journal: Circulation Research (2005)

Promoters of many smooth muscle-specific genes (SM-genes) contain multiple CArG boxes, which represent a binding site for serum response factor (SRF). Transcriptional control through these regions involves interactions with SRF and specific coactivators such as myocardin. We have previously reported that suppression of SM-gene expression by platelet derived growth factor (PDGF) is associated with redistribution of SRF, leading to lower intra-nuclear levels, and a reduction in SRF transactivation. To further assess the role of SRF depletion on VSMC phenotype, the current study used RNA interference (RNAi). Two SRF-specific sequences constructed as hairpins were stably expressed in rat VSMC. Clones expressing SRF RNAi had no detectable SRF expression by immunoblotting, and showed diminished levels of SM alpha-actin protein and promoter activity. Unexpectedly, depletion of VSMC resulted in increased rates of proliferation and migration. Several genes whose expression is increased by PDGF stimulation, including c-Jun, were similarly induced in cells lacking SRF. Effects of SRF depletion were not attributable to altered PDGF receptor activity or alterations in activation of Akt. These data indicate that loss of SRF transactivation in VSMC, in this case through suppression via RNAi, induces biological responses similar to that seen with PDGF.
Inheritance of Nevus Number and Size in Melanoma and Dysplastic Nevus Syndrome Kindreds
Authors: D. E. Goldgar, L. A. Cannon-Albright, L. J. Meyer, M. W. Pipekorn, J. J. Zone, M. H. Skolnick
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article Inheritance of Nevus Number and Size in Melanoma and Dysplastic Nevus Syndrome Kindreds Get access D. E. Goldgar, D. E. Goldgar * 1(Genetic Epidemiology Group, Department of Medical Informatics), L. A. Cannon-Albright (Division of Hematology Oncology, Department of Internal Medicine). (Division of Dermatology, Department of Internal Medicine), University of Utah School of MedicineSalt Lake City, Utah *Correspondence to: David E. Goldgar, Ph.D., Genetic Epidemiology, 420 Chipeta Way, #180, Salt Lake City, UT 84108 Search for other works by this author on: Oxford Academic PubMed Google Scholar L. A. Cannon-Albright, L. A. Cannon-Albright Search for other works by this author on: Oxford Academic PubMed Google Scholar L. J. Meyer, L. J. Meyer 1(Genetic Epidemiology Group, Department of Medical Informatics), L. A. Cannon-Albright (Division of Hematology Oncology, Department of Internal Medicine). (Division of Dermatology, Department of Internal Medicine), University of Utah School of MedicineSalt Lake City, Utah Search for other works by this author on: Oxford Academic PubMed Google Scholar M. W. Pipekorn, M. W. Pipekorn 1(Genetic Epidemiology Group, Department of Medical Informatics), L. A. Cannon-Albright (Division of Hematology Oncology, Department of Internal Medicine). (Division of Dermatology, Department of Internal Medicine), University of Utah School of MedicineSalt Lake City, Utah Search for other works by this author on: Oxford Academic PubMed Google Scholar J. J. Zone, J. J. Zone 1(Genetic Epidemiology Group, Department of Medical Informatics), L. A. Cannon-Albright (Division of Hematology Oncology, Department of Internal Medicine). (Division of Dermatology, Department of Internal Medicine), University of Utah School of MedicineSalt Lake City, Utah Search for other works by this author on: Oxford Academic PubMed Google Scholar M. H. Skolnick M. H. Skolnick 1(Genetic Epidemiology Group, Department of Medical Informatics), L. A. Cannon-Albright (Division of Hematology Oncology, Department of Internal Medicine). (Division of Dermatology, Department of Internal Medicine), University of Utah School of MedicineSalt Lake City, Utah Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 23, 4 December 1991, Pages 1726–1733, https://doi.org/10.1093/jnci/83.23.1726 Published: 04 December 1991 Article history Revision received: 08 July 1991 Accepted: 16 August 1991 Received: 24 September 1991 Published: 04 December 1991
The helminth product ES-62 protects against septic shock via Toll-like receptor 4–dependent autophagosomal degradation of the adaptor MyD88
Authors: Padmam Puneet, Mairi A McGrath, Hwee Kee Tay, Lamyaa Al-Riyami, Justyna Rzepecka, Shabbir M Moochhala, Shazib Pervaiz, Margaret M Harnett, William Harnett, Alirio J Melendez
Journal: Nature Immunology (2011)
Inhibition of Caspases Increases the Sensitivity of L929 Cells to Necrosis Mediated by Tumor Necrosis Factor
Authors: Dominique Vercammen, Rudi Beyaert, Geertrui Denecker, Vera Goossens, Geert Van Loo, Wim Declercq, Johan Grooten, Walter Fiers, Peter Vandenabeele
Journal: The Journal of Experimental Medicine (1998)

Murine L929 fibrosarcoma cells treated with tumor necrosis factor (TNF) rapidly die in a necrotic way, due to excessive formation of reactive oxygen intermediates. We investigated the role of caspases in the necrotic cell death pathway. When the cytokine response modifier A (CrmA), a serpin-like caspase inhibitor of viral origin, was stably overexpressed in L929 cells, the latter became 1,000-fold more sensitive to TNF-mediated cell death. In addition, TNF sensitization was also observed when the cells were pretreated with Ac-YVAD-cmk or zDEVD-fmk, which inhibits caspase-1– and caspase-3–like proteases, respectively. zVAD-fmk and zD-fmk, two broad-spectrum inhibitors of caspases, also rendered the cells more sensitive, since the half-maximal dose for TNF-mediated necrosis decreased by a factor of 1,000. The presence of zVAD-fmk also resulted in a more rapid increase of TNF-mediated production of oxygen radicals. zVAD-fmk–dependent sensitization of TNF cytotoxicity could be completely inhibited by the oxygen radical scavenger butylated hydroxyanisole. These results indicate an involvement of caspases in protection against TNF-induced formation of oxygen radicals and necrosis.
Proinflammatory Mediators Upregulate Snail in Head and Neck Squamous Cell Carcinoma
Authors: Maie A. St. John, Mariam Dohadwala, Jie Luo, Guanyu Wang, Gina Lee, Hubert Shih, Eileen Heinrich, Kostantyn Krysan, Tonya Walser, Saswati Hazra, Li Zhu, Chi Lai, Elliot Abemayor, Michael Fishbein, David A. Elashoff, Sherven Sharma, Steven M. Dubinett
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1β (IL-1β) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC. Experimental Design: We evaluated the effect of IL-1β on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model was used to assess the effects of Snail overexpression. Results: Cyclooxygenase-2 (COX-2)-dependent pathways contribute to the modulation of E-cadherin expression in HNSCC. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL-1β caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 small hairpin RNA. IL-1β–treated HNSCC cell lines showed a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1β exposure led to enhanced Snail binding at the chromatin level. Small hairpin RNA–mediated knockdown of Snail interrupted the capacity of IL-1β to downregulate E-cadherin. In a SCID xenograft model, HNSCC Snail-overexpressing cells showed significantly increased primary and metastatic tumor burdens. Conclusions: IL-1β modulates Snail and thereby regulates COX-2–dependent E-cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy. (Clin Cancer Res 2009;15(19):6018–27)
Rheb/mTORC1 Signaling Promotes Kidney Fibroblast Activation and Fibrosis
Authors: Lei Jiang, Lingling Xu, Junhua Mao, Jianzhong Li, Li Fang, Yang Zhou, Wei Liu, Weichun He, Allan Zijian Zhao, Junwei Yang, Chunsun Dai
Journal: Journal of the American Society of Nephrology (2013)

Ras homolog enriched in brain (Rheb) is a small GTPase that regulates cell growth, differentiation, and survival by upregulating mammalian target of rapamycin complex 1 (mTORC1) signaling. The role of Rheb/mTORC1 signaling in the activation of kidney fibroblasts and the development of kidney fibrosis remains largely unknown. In this study, we found that Rheb/mTORC1 signaling was activated in interstitial myofibroblasts from fibrotic kidneys. Treatment of rat kidney interstitial fibroblasts (NRK-49F cell line) with TGFβ1 also activated Rheb/mTORC1 signaling. Blocking Rheb/mTORC1 signaling with rapamycin or Rheb small interfering RNA abolished TGFβ1-induced fibroblast activation. In a transgenic mouse, ectopic expression of Rheb activated kidney fibroblasts. These Rheb transgenic mice exhibited increased activation of mTORC1 signaling in both kidney tubular and interstitial cells as well as progressive interstitial renal fibrosis; rapamycin inhibited these effects. Similarly, mice with fibroblast-specific deletion of Tsc1, a negative regulator of Rheb, exhibited activated mTORC1 signaling in kidney interstitial fibroblasts and increased renal fibrosis, both of which rapamycin abolished. Taken together, these results suggest that Rheb/mTORC1 signaling promotes the activation of kidney fibroblasts and contributes to the development of interstitial fibrosis, possibly providing a therapeutic target for progressive renal disease.
T Cell Homeostasis
Authors: Afonso R.M. Almeida, José A.M. Borghans, António A. Freitas
Journal: The Journal of Experimental Medicine (2001)

We developed a novel experimental strategy to study T cell regeneration after bone marrow transplantation. We assessed the fraction of competent precursors required to repopulate the thymus and quantified the relationship between the size of the different T cell compartments during T cell maturation in the thymus. The contribution of the thymus to the establishment and maintenance of the peripheral T cell pools was also quantified. We found that the degree of thymus restoration is determined by the availability of competent precursors and that the number of double-positive thymus cells is not under homeostatic control. In contrast, the sizes of the peripheral CD4 and CD8 T cell pools are largely independent of the number of precursors and of the number of thymus cells. Peripheral “homeostatic” proliferation and increased export and/or survival of recent thymus emigrants compensate for reduced T cell production in the thymus. In spite of these reparatory processes, mice with a reduced number of mature T cells in the thymus have an increased probability of peripheral T cell deficiency, mainly in the naive compartment.
Regional Variation in Patients and Outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial
Authors: Marc A. Pfeffer, Brian Claggett, Susan F. Assmann, Robin Boineau, Inder S. Anand, Nadine Clausell, Akshay S. Desai, Rafael Diaz, Jerome L. Fleg, Ivan Gordeev, John F. Heitner, Eldrin F. Lewis, Eileen O’Meara, Jean-Lucien Rouleau, Jeffrey L. Probstfield, Tamaz Shaburishvili, Sanjiv J. Shah, Scott D. Solomon, Nancy K. Sweitzer, Sonja M. McKinlay, Bertram Pitt
Journal: Circulation (2014)

Background— Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas). Methods and Results— To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P &lt;0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone. Conclusions— This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00094302.
Clarithromycin (Biaxin)‐lenalidomide‐low‐dose dexamethasone (BiRd) versus lenalidomide‐low‐dose dexamethasone (Rd) for newly diagnosed myeloma
Authors: Francesca Gay, S. Vincent Rajkumar, Morton Coleman, Shaji Kumar, Tomer Mark, Angela Dispenzieri, Roger Pearse, Morie A. Gertz, John Leonard, Martha Q. Lacy, Selina Chen‐Kiang, Vivek Roy, David S. Jayabalan, John A. Lust, Thomas E. Witzig, Rafael Fonseca, Robert A. Kyle, Philip R. Greipp, A. Keith Stewart, Ruben Niesvizky
Journal: American Journal of Hematology (2010)

The objective of this case-matched study was to compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs. lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital-Cornell Medical Center were retrospectively compared with an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention-to-treat analysis, complete response (45.8% vs. 13.9%, P < 0.001) and very-good-partial-response or better (73.6% vs. 33.3%, P < 0.001) were significantly higher with BiRd. Time-to-progression (median 48.3 vs. 27.5 months, P = 0.071), and progression-free survival (median 48.3 vs. 27.5 months, P = 0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3-year OS: 89.7% vs. 73.0%, P = 0.170). Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs. 8.3%, P = 0.012). Infections (16.7% vs. 9.7%, P = 0.218) and dermatological toxicity (12.5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case-matched analysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results.