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Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study.
Curigliano, G, Gómez Pardo, P, Meric-Bernstam, F, Conte, P, Lolkema, MP, Beck, JT, Bardia, A, Martínez García, M, Penault-Llorca, F, Dhuria, S, et al
Breast (Edinburgh, Scotland). 2016;:191-8
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Abstract
OBJECTIVES Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling. RESULTS Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment. CONCLUSION The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).
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Low-fat, low-glycemic load diet and gene expression in human prostate epithelium: a feasibility study of using cDNA microarrays to assess the response to dietary intervention in target tissues.
Lin, DW, Neuhouser, ML, Schenk, JM, Coleman, IM, Hawley, S, Gifford, D, Hung, H, Knudsen, BS, Nelson, PS, Kristal, AR
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2007;(10):2150-4
Abstract
PURPOSE We examined the feasibility of using gene expression changes in human prostate epithelium as a measure of response to a dietary intervention. MATERIALS AND METHODS Eight men with newly diagnosed prostate cancer were randomized to a low-fat/low-glycemic load intervention arm (<20% energy from fat and total daily glycemic load <100) or a "standard American" control arm (approximately 35% energy from fat and total daily glycemic load >200). Prostate tissue was collected before randomization and approximately 6 weeks later, at the time of radical prostatectomy. Epithelium was acquired by laser capture microdissection, and transcript abundance levels were measured by cDNA microarray hybridization and confirmed by quantitative reverse transcription-PCR. RESULTS Men in the intervention arm consumed 39% less total energy (P = 0.004) and the difference in weight change between intervention and control arms was -6.1 kg (P = 0.02). In the intervention arm, 23 (0.46%) of 5,711 cDNAs with measurable expression were significantly altered (P < 0.05; false discovery rate, CONCLUSIONS A 6-week, low-fat/low-glycemic load diet was associated with significant gene expression changes in human prostate epithelium. These results show the feasibility of using prostate tissues collected at diagnosis and at surgery to study the effects of dietary manipulation on prostate tissue, which may give insight into the molecular mechanisms underlying the associations of diet and obesity with the development or progression of prostate cancer.
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Single and combination drug therapy for fetal hemoglobin augmentation in hemoglobin E-beta 0-thalassemia: Considerations for treatment.
Singer, ST, Kuypers, FA, Olivieri, NF, Weatherall, DJ, Mignacca, R, Coates, TD, Davies, S, Sweeters, N, Vichinsky, EP
Annals of the New York Academy of Sciences. 2005;:250-6
Abstract
Patients with hemoglobin E (Hb E)-beta 0-thalassemia, one of the most common hemoglobinopathies worldwide, could benefit from drugs that increase fetal and total hemoglobin levels and thereby decrease the need for transfusions. The long-term clinical outcome of such therapy, its hematologic effects, and which patients are likely to benefit from treatment are unknown. Consequently, the use of such drugs for Hb E-beta 0-thalassemia is limited, and countries where resources for safe and regular transfusion are scarce cannot benefit from them. In a multicenter trial of 42 patients treated with hydroxyurea for two years, almost half the patients demonstrated a significant increase in steady-state hemoglobin level. Drug toxicity was minimal. Combined treatment of hydroxyurea with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate was ineffective. After 5 years of follow-up, a subset of patients remained off transfusions. Hydroxyurea should be considered for a subset of Hb E-beta 0-thalassemia patients.
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Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.
Lowes, BD, Gilbert, EM, Abraham, WT, Minobe, WA, Larrabee, P, Ferguson, D, Wolfel, EE, Lindenfeld, J, Tsvetkova, T, Robertson, AD, et al
The New England journal of medicine. 2002;(18):1357-65
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Abstract
BACKGROUND Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy. METHODS We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a beta-adrenergic-receptor blocking agent (metoprolol or carvedilol) or placebo. The amount of messenger RNA (mRNA) for contractility-regulating genes (those encoding beta1- and beta2-adrenergic receptors, calcium ATPase in the sarcoplasmic reticulum, and alpha- and beta-myosin heavy-chain isoforms) and of genes associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide) was measured with a quantitative reverse-transcription polymerase chain reaction in total RNA extracted from biopsy specimens of the right ventricular septal endomyocardium. Myocardial levels of beta-adrenergic receptors were also measured. Measurements were conducted at base line and after six months of treatment, and changes in gene expression were compared with changes in the left ventricular ejection fraction as measured by radionuclide ventriculography. RESULTS Twenty-six of 32 beta-blocker-treated patients (those with complete mRNA measurements) had an improvement in left ventricular ejection fraction of at least 5 ejection-fraction (EF) units (mean [+/-SE] increase, 18.8+/-1.8). As compared with the six beta-blocker-treated patients who did not have a response (mean change, a decrease of 2.5+/-1.8 EF units), those who did have a response had an increase in sarcoplasmic-reticulum calcium ATPase mRNA and alpha-myosin heavy chain mRNA and a decrease in beta-myosin heavy chain mRNA. The change in sarcoplasmic-reticulum calcium ATPase was not present in the patients in the placebo group who had a spontaneous response. There were no differences between those who had a response and those who did not in terms of the change in mRNA or protein expression of beta-adrenergic receptors. CONCLUSIONS In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.