Correlation between tamoxifen elimination and biomarker recovery in a primary prevention trial.

We have shown previously that a reduction from the conventional dose of tamoxifen is associated with a comparable modulation of circulating biomarkers, including insulin-like growth factor-I and cholesterol. In the present study, we have correlated serum tamoxifen elimination with biomarker recovery in healthy subjects completing a 5-year intervention period. Tamoxifen, N-desmethyltamoxifen, and biomarker levels were measured at 0 (baseline), 2, 4, and 6 weeks after completion of treatment in 23 healthy postmenopausal women allocated to tamoxifen 20 mg/day and in 6 women allocated to placebo.

Timing of breast cancer surgery in relation to the menstrual cycle: an update of developments.

It is well-established that hormones have multiple effects on breast cancer. Some, but not all studies indicate that the phase of the menstrual cycle (and hence hormonal status) at the time of breast surgery may influence survival. In this paper we review the literature in this area, explore how it is possible that such an association may occur, and note that randomised studies which unambiguously determined the phase of the cycle at the time of the operation are lacking.

Beneficial effects on skeletal muscle of the angiotensin II type 1 receptor blocker irbesartan in experimental heart failure.

Background: In congestive heart failure (CHF), skeletal muscle shows increased expression of fast myosin heavy chains (MHC) and fibers, muscle atrophy, increased fatigability, and decreased endurance. Atrophy is secondary to myocyte apoptosis, which is probably triggered by tumor necrosis factor-alpha (TNFalpha). Angiotensin II receptors are thought to play a role in controlling apoptosis.

Inhibition of fasL sustains phagocytic cells and delays myogenesis in regenerating muscle fibers.

Macrophage-muscle cell interactions are complex, and the majority is unknown. The persistence of inflammatory cells in skeletal muscle could be critical for myofiber viability. In the present paper, we show that FasL plays a role in the resolution of muscle inflammation.

Caspase 3 expression correlates with skeletal muscle apoptosis in Duchenne and facioscapulo human muscular dystrophy. A potential target for pharmacological treatment?

Apoptosis was detected in different muscular diseases, including severe dystrophin deficiency, but apoptotic mechanisms are not completely described in adult skeletal muscle. Studying patients affected by Duchenne muscular dystrophy (DMD) and by facio-scapulo-humeral dystrophy (FSHD) we showed an increase of apoptotic myonuclei, bax, and bcl-2-positive myofibers. Positive correlation was detected between apoptotic nuclei and bax expression (p < 0.

Loss of dystrophin and some dystrophin-associated proteins with concomitant signs of apoptosis in rat leg muscle overworked in extension.

This study investigated the basis for the high severity of damage to skeletal muscle due to eccentric exercise, i.e., to muscles generating force while lengthened.

Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes.

Objective: To investigate the contribution of apoptosis in the development of the skeletal myopathy in chronic heart failure.

Design: The electrophoretic pattern of myosin heavy chains (MHC), fibre cross sectional area, number of in situ nick end labelling (TUNEL) positive apoptotic myocyte nuclei, and the tissue levels of caspase-3, Bcl-2, and ubiquitin were determined in biopsies taken from the vastus lateralis muscle. The study involved nine patients with severe chronic heart failure caused by ischaemic heart disease and hibernating myocardium and five controls.

Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy.

Objectives: We investigated the role of cardiac troponin I (cTnI) in patients with aggressive malignancies treated with high-dose chemotherapy (HDC).

Background: High dose chemotherapy is potentially limited by cardiac toxicity. Considering the fact that cardiac dysfunction may become clinically evident weeks or months after HDC, the availability of an early marker of myocardial injury, able to predict late ventricular impairment, is a current need.

Apoptosis of skeletal muscles during development and disease.

Cells from multicellular organisms self-destroy when no longer needed or when damaged. They do this by activating genetically controlled machineries that lead to apoptosis. Skeletal muscles in adult animals are fully differentiated syncytial cells.

Apoptosis and atrophy in rat slow skeletal muscles in chronic heart failure.

Congestive heart failure is characterized by a skeletal muscle myopathy with muscle bulk loss. The mechanisms responsible for these changes are not clear at present. We have investigated the role of apoptosis in the rat "slow" soleus muscle during the development of heart failure, which was induced by injection of monocrotaline (30 mg/kg).

Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women.

Purpose: Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction.

Patients And Methods: We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 mg on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d).

Apoptosis of skeletal muscle myofibers and interstitial cells in experimental heart failure.

Unlabelled: Congestive heart failure (CHF) is characterized by a limb skeletal muscle myopathy with shift from the slow aerobic, fatigue resistant fibers, to the fast, anaerobic ones, and muscle bulk loss. Apoptosis (A) has been recently demonstrated to play a role in several cardiovascular diseases.

Aim Of The Study: we have investigated the role of A in the skeletal muscle of the hindlimbs in an experimental model of CHF.

Apoptosis of myofibres and satellite cells: exercise-induced damage in skeletal muscle of the mouse.

Apoptosis is well accepted as a type of cell death occurring in the development of mammalian muscles, but the death of adult myofibres in neuromuscular disorders and exercise-induced muscle damage is usually explained in terms of muscle necrosis. The current view that apoptosis precedes necrosis in death of dystrophin-deficient muscle fibres of mdx mouse has been well substantiated. Moreover, apoptotic myonuclei have been reported to increase in mdx mice 2 days after spontaneous exercise.

Biologic activity of tamoxifen at low doses in healthy women.

Background: Results of a clinical trial recently completed in the United States indicate that administration of tamoxifen (20 mg/day) to women at risk can reduce breast cancer incidence by approximately 50% but is associated with an increased risk of developing endometrial cancer and venous thromboembolic events. Since these adverse effects may be dose related, we investigated the effect of tamoxifen on several biomarkers when the drug was given at doses lower than those currently in use.

Methods: In two sequential experiments, 127 healthy hysterectomized women aged 35-70 years were randomly assigned to one of the following four treatment arms: placebo (n = 31) or tamoxifen at 20 mg/day (n = 30) (first experiment); or tamoxifen at 10 mg/day (n = 34) or tamoxifen at 10 mg/ alternate days (n = 32) (second experiment).

Dystrophin deficient myotubes undergo apoptosis in mouse primary muscle cell culture after DNA damage.

Apoptosis has been demonstrated to occur in differentiated myocardial muscle, neonatal skeletal muscle and skeletal myoblasts in response to injury. In this report, we studied differentiated normal and dystrophin deficient murine skeletal muscle cell cultures that have been injured by a pulse of cis-platinum (2 h). Forty-eight hours after DNA damage, dystrophin positive myotubes appeared almost normal though some myoblasts showed DNA fragmentation.

Physiological regulation of eukaryotic topoisomerase II.

Topoisomerase II is an essential enzyme in all organisms with several independent roles in DNA metabolism. In this article we review our knowledge on the regulation of the expression and catalytic activity of topoisomerase II in both lower and higher eukaryotes. Current data indicate that the regulation of topoisomerase II gene expression is complex, with positive and negative controls in evidence at the level of both promoter activity and mRNA stability.

Apoptotic myonuclei in human Duchenne muscular dystrophy.

The current view that apoptosis precedes necrosis in death of dystrophin-deficient muscle fibers of the mdx mouse has been well substantiated. Moreover, apoptotic myonuclei have been reported to increase in dystrophin-deficient mice 2 days after spontaneous exercise. To investigate the role of apoptosis in human muscular dystrophy, muscles from 11 patients of different ages with Duchenne muscular dystrophy were analyzed for apoptosis.

Exercise induces myonuclear ubiquitination and apoptosis in dystrophin-deficient muscle of mice.

Apoptosis plays a major role in several diseases, including viral infections, autoimmune diseases, cancer, cardiac infarct, and neurological disorders. To investigate the role of apoptosis in muscular dystrophy, dystrophin-deficient (mdx) mice were subjected to spontaneous exercise and skeletal muscles were analyzed for apoptosis and ubiquitin. The increase of apoptotic myonuclei after exercise was detected by TUNEL, by electron microscopy, and by DNA analyses for high molecular weight and for ladder fragments.

p53 regulates the minimal promoter of the human topoisomerase IIalpha gene.

DNA topoisomerase IIalpha is an essential enzyme for chromosome segregation during mitosis. Consistent with a cell division-specific role, the expression of the topoisomerase IIalpha gene is strongly influenced by the proliferation status of cells. The p53 protein is one of the most important regulators of cell cycle progression in mammals, with an apparent dual role in the induction of cell cycle arrest following cytotoxic insults and in the regulation of the apoptotic cell death pathway.

Differential expression of the topoisomerase II alpha and beta genes in human breast cancers.

Topoisomerase II is a key target for several anti-cancer drugs used for breast cancer therapy, including doxorubicin, epirubicin and mitoxantrone. Two isoforms of topoisomerase II (alpha and beta) have been described in human cells which differ in their subcellular localisation, biochemical properties and susceptibility to inhibition by anti-cancer drugs. The relative level of expression of the alpha and beta isoforms may contribute to the degree of tumour responsiveness to different chemotherapeutic agents.

Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exercise.

The current view indicates that after eccentric exercise myofibers are mechanically damaged and therefore an inflammatory and necrotic process occurs. In the present paper we examine the possibility that apoptosis plays a role in normal and dystrophin-deficient muscles after running. We analysed for apoptosis normal and dystrophin-deficient mouse muscles after a night of spontaneous wheel-running followed by two days of rest.

Effects of beta 1-integrin antisense phosphorothioate-modified oligonucleotide on myoblast behaviour in vitro.

Myoblasts gene-engineered in vitro and then injected in vivo are safe, efficient options for gene therapy. While isolation of satellite cells is routinely achieved, their proliferation potential in vitro remains a limiting factor for cell transplantation under clinical conditions. We have studied the role of reversible inhibition of gene expression by antisense oligonucleotides on the proliferation of the myogenic cells.

High-resolution sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunochemical identification of the 2X and embryonic myosin heavy chains in complex mixtures of isomyosins.

In mammals myosin heavy chains (MHC) are polypeptides with a molecular mass of about 200 kDa whose isoforms can be identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunochemistry. Electrophoretic analysis is the only method for quantitating MHC profiles in single myofibers and/or cryostat sections of biopsied muscle. We present a method for SDS-PAGE of adult rat skeletal muscle which resolves MHC into four bands: 1, 2B, 2X, and 2A from the faster to the slower migrating band.