Les effets d'un traitement par l'hormone de croissance sur l'expression ventriculaire des peptides natriurétiques et des isoformes de myosine de chaînes lourdes chez le hamster cardiomyopathique

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thyroid hormone and gland status of Greenland sledge dogs (Canis lupus familiaris) exposed to contaminated blubber

As a model of high trophic level carnivores, sledge dogs were fed from 2 to 18 months of age with minke whale blubber containing organohalogen compounds (OHC) corresponding to 128 µg PCB/day. Controls were fed uncontaminated porcine fat. Thyroid hormone levels were assessed in 7 exposed and 7 control sister bitches (sampled at age 6-18 months) and 4 exposed and 4 control pups, fed the same diet as their mothers (sampled age 3-12 months). Lower free and total T3 and T4 were seen in exposed vs. control bitches beyond 10 months of age, and total T3 was lower through 3-12 months of age in exposed pups. A negative correlation with thyroid gland weight was significant for SumDDT, as was a positive association with total T3 for dieldrin. This study therefore supports observational data that OHCs may adversely affect thyroid functions, and it suggests that OHC exposure duration of 10 months or more may be required for current OHC contamination levels to result in detectable adverse effects on thyroid hormone dynamics.

Attenuation of monocyte chemotaxis--a novel anti-inflammatory mechanism of action for the cardio-protective hormone B-type natriuretic peptide

B-type natriuretic peptide (BNP) is a prognostic and diagnostic marker for heart failure (HF). An anti-inflammatory, cardio-protective role for BNP was proposed. In cardiovascular diseases including pressure overload-induced HF, perivascular inflammation and cardiac fibrosis are, in part, mediated by monocyte chemoattractant protein (MCP)1-driven monocyte migration. We aimed to determine the role of BNP in monocyte motility to MCP1. A functional BNP receptor, natriuretic peptide receptor-A (NPRA) was identified in human monocytes. BNP treatment inhibited MCP1-induced THP1 (monocytic leukemia cells) and primary monocyte chemotaxis (70 and 50 %, respectively). BNP did not interfere with MCP1 receptor expression or with calcium. BNP inhibited activation of the cytoskeletal protein RhoA in MCP1-stimulated THP1 (70 %). Finally, BNP failed to inhibit MCP1-directed motility of monocytes from patients with hypertension (n = 10) and HF (n = 6) suggesting attenuation of this anti-inflammatory mechanism in chronic heart disease. We provide novel evidence for a direct role of BNP/NPRA in opposing human monocyte migration and support a role for BNP as a cardio-protective hormone up-regulated as part of an adaptive compensatory response to combat excess inflammation.

Cabazitaxel for hormone-relapsed metastatic prostate cancer previously treated with a docetaxel-containing regimen (review of TA255)

Prostate cancer is the most common cancer amongst men in the England and currently affects ~40,000 people around 6,000 of whom suffer from metastatic disease. Overall patients with metastatic disease have a life expectancy of less than 24 months and a poor prognosis.

Docetaxel was the first agent to show survival benefit in metastatic Hormone Refractory Prostate Cancer (mHRPC) and since approval by NICE in 2006 (TA101) has for many years been the mainstay of treatment.

To appraise the clinical and cost effectiveness of cabazitaxel within its marketing authorisation for treating hormone-relapsed metastatic prostate cancer previously treated with a docetaxel-containing regimen.

Gut hormone GPCRs: structure, function, drug discovery

Crystallization and determination of the high resolution three-dimensional structure of the β2-adrenergic receptor in 2007 was followed by structure elucidation of a number of other receptors, including those for neurotensin and glucagon. These major advances foster the understanding of structure-activity relationship of these receptors and structure-based rational design of new ligands having more predictable activity. At present, structure determination of gut hormone receptors in complex with their ligands (natural, synthetic) and interacting signalling proteins, for example, G-proteins, arrestins, represents a challenge which promises to revolutionize gut hormone endocrinonology.

Cabazitaxel for Hormone-Relapsed Metastatic Prostate Cancer Previously Treated With a Docetaxel-Containing Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures cabazitaxel (Jevtana(®), Sanofi, UK) to submit evidence for the clinical and cost effectiveness of cabazitaxel for treatment of patients with metastatic hormone-relapsed prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the company's submission to NICE. Clinical evidence for cabazitaxel was derived from a multinational randomised open-label phase III trial (TROPIC) of cabazitaxel plus prednisone or prednisolone compared with mitoxantrone plus prednisone or prednisolone, which was assumed to represent best supportive care. The NICE final scope identified a further three comparators: abiraterone in combination with prednisone or prednisolone; enzalutamide; and radium-223 dichloride for the subgroup of people with bone metastasis only (no visceral metastasis). The company did not consider radium-223 dichloride to be a relevant comparator. Neither abiraterone nor enzalutamide has been directly compared in a trial with cabazitaxel. Instead, clinical evidence was synthesised within a network meta-analysis (NMA). Results from TROPIC showed that cabazitaxel was associated with a statistically significant improvement in both overall survival and progression-free survival compared with mitoxantrone. Results from a random-effects NMA, as conducted by the company and updated by the ERG, indicated that there was no statistically significant difference between the three active treatments for both overall survival and progression-free survival. Utility data were not collected as part of the TROPIC trial, and were instead taken from the company's UK early access programme. Evidence on resource use came from the TROPIC trial, supplemented by both expert clinical opinion and a UK clinical audit. List prices were used for mitoxantrone, abiraterone and enzalutamide as directed by NICE, although commercial in-confidence patient-access schemes (PASs) are in place for abiraterone and enzalutamide. The confidential PAS was used for cabazitaxel. Sequential use of the advanced hormonal therapies (abiraterone and enzalutamide) does not usually occur in clinical practice in the UK. Hence, cabazitaxel could be used within two pathways of care: either when an advanced hormonal therapy was used pre-docetaxel, or when one was used post-docetaxel. The company believed that the former pathway was more likely to represent standard National Health Service (NHS) practice, and so their main comparison was between cabazitaxel and mitoxantrone, with effectiveness data from the TROPIC trial. Results of the company's updated cost-effectiveness analysis estimated a probabilistic incremental cost-effectiveness ratio (ICER) of £45,982 per quality-adjusted life-year (QALY) gained, which the committee considered to be the most plausible value for this comparison. Cabazitaxel was estimated to be both cheaper and more effective than abiraterone. Cabazitaxel was estimated to be cheaper but less effective than enzalutamide, resulting in an ICER of £212,038 per QALY gained for enzalutamide compared with cabazitaxel. The ERG noted that radium-223 is a valid comparator (for the indicated sub-group), and that it may be used in either of the two care pathways. Hence, its exclusion leads to uncertainty in the cost-effectiveness results. In addition, the company assumed that there would be no drug wastage when cabazitaxel was used, with cost-effectiveness results being sensitive to this assumption: modelling drug wastage increased the ICER comparing cabazitaxel with mitoxantrone to over £55,000 per QALY gained. The ERG updated the company's NMA and used a random effects model to perform a fully incremental analysis between cabazitaxel, abiraterone, enzalutamide and best supportive care using PASs for abiraterone and enzalutamide. Results showed that both cabazitaxel and abiraterone were extendedly dominated by the combination of best supportive care and enzalutamide. Preliminary guidance from the committee, which included wastage of cabazitaxel, did not recommend its use. In response, the company provided both a further discount to the confidential PAS for cabazitaxel and confirmation from NHS England that it is appropriate to supply and purchase cabazitaxel in pre-prepared intravenous-infusion bags, which would remove the cost of drug wastage. As a result, the committee recommended use of cabazitaxel as a treatment option in people with an Eastern Cooperative Oncology Group performance status of 0 or 1 whose disease had progressed during or after treatment with at least 225 mg/m(2) of docetaxel, as long as it was provided at the discount agreed in the PAS and purchased in either pre-prepared intravenous-infusion bags or in vials at a reduced price to reflect the average per-patient drug wastage.

The Influence of Estrogens on the Biological and Therapeutic Actions of Growth Hormone in the Liver

[EN]GH is main regulator of body growth and composition, somatic development, intermediate metabolism and gender-dependent dimorphism in mammals. The liver is a direct target of estrogens because it expresses estrogen receptors which are connected with development, lipid metabolism and insulin sensitivity, hepatic carcinogenesis, protection from drug-induced toxicity and fertility. In addition, estrogens can modulate GH actions in liver by acting centrally, regulating pituitary GH secretion, and, peripherally, by modulating GHR-JAK2-STAT5 signalling pathway

Ovarian suppression using luteinizing hormonereleasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: A meta-analysis of randomized studies

Background: The role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS). Methods: A literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models. Results: A total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23-0.57; P < 0.001), yet with significant heterogeneity (I2 = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41-0.73, P < 0.001) without heterogeneity (I2 = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02-3.28, P = 0.041; I2 = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49-2.04, P = 0.939; I2 = 68.0%, Pheterogeneity = 0.044). Conclusion: Temporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis.

Ontogeny and nutritional programming of the hepatic growth hormone-insulin-like growth factor-prolactin axis in the sheep

The liver is an important metabolic and endocrine organ in the fetus but the extent to which its hormone receptor (R) sensitivity is developmentally regulated in early life is not fully established. We, therefore, examined developmental changes in mRNA abundance for the growth hormone (GH) and prolactin (PRL) receptors (R) plus insulin-like growth factor (IGF)-I and –II and their receptors. Fetal and postnatal sheep were sampled at either 80, or 140 days gestation, 1, 30 days or six months of age. The effect of maternal nutrient restriction between early to mid (i.e. 28 to 80 days gestation, the time of early liver growth) gestation on gene expression was also examined in the fetus and juvenile offspring. Gene expression for the GHR, PRLR and IGF-IR increased through gestation peaking at birth, whereas IGF-I was maximal near to term. In contrast, IGF-II mRNA decreased between mid and late gestation to increase after birth whereas IGF-IIR remained unchanged. A substantial decline in mRNA abundance for GHR, PRLR and IGF-IR then occurred up to six months. Maternal nutrient restriction reduced GHR and IGF-IIR mRNA abundance in the fetus, but caused a precocious increase in the PRLR. Gene expression for IGF-I and –II were increased in juvenile offspring born to nutrient restricted mothers. In conclusion, there are marked differences in the developmental ontogeny and nutritional programming of specific hormones and their receptors involved in hepatic growth and development in the fetus. These could contribute to changes in liver function during adult life.

Hormone-Mediated Gene-Specific Translation Regulation

The central role of translation regulation in the control of critical cellular processes has long been recognized. Yet the systematic exploration of quantitative changes in translation at a genome-wide scale in response to specific stimuli has only recently become technically feasible. Using a genetic approach, we have identified new Arabidopsis weak-ethylene insensitive mutants that also display defects in translation, which suggested the existence of a previously unknown molecular module involved in ethylene-mediated translation regulation of components of this signaling pathway. To explore this link in detail, we implemented for Arabidopsis the ribosome-footprinting technology, which enables the study of translation at a whole-genome level at single codon resolution[1]. Using ribosome-footprinting we examined the effects of short exposure to ethylene on the Arabidopsis translatome looking for ethylene-triggered changes in translation rates that could not be explained by changes in transcript levels. The results of this research, in combination with the characterization of a subset of the aforementioned weak-ethylene insensitive mutants that are defective in the UPF genes (core-components of the nonsense-mediated mRNA decay machinery), uncovered a translation-based branch of the ethylene signaling pathway[2]. In the presence of ethylene, translation of a negative regulator of ethylene signaling EBF2 is repressed, despite induced transcription of this gene. These translational effects of ethylene require the long 3´UTR of EBF2 (3´EBF2), which is recognized by the C-terminal end of the key ethylene-signaling protein EIN2 (EIN2C) in the cytoplasm once EIN2C is released from the ER-membrane by proteolytic cleavage. EIN2C binds the 3´EBF2, recruits the UPF proteins and moves to P-bodies, where the translation of EBF2 in inhibited despite its mRNA accumulation. Once the ethylene signal is withdrawn, the translation of the stored EBF2 mRNAs is resumed, thus rapidly dampening the ethylene response. These findings represent a mechanistic paradigm of gene-specific regulation of translation in response to a key growth regulator. Translation regulatory elements can be located in both 3′ and 5′ UTRs. We are now focusing on the ead1 and ead2 mutants, another set of ethylene-signaling mutants defective in translational regulation. Ribosome-footprinting on the ead1 mutant revealed an accumulation of translating ribosomes in the 5´UTRs of uORF-containing genes and reduction in the levels of ribosomes in the main ORF. The mutant is also impaired in the translation of GFP when this reporter is fused to WT 5´UTR of potential EAD1 targets but not when GFP is fused to the uORF-less versions of the same 5´UTRs. Our hypothesis is that EAD1/2 work as a complex that is required for the efficient translation of mRNAs that have common structural (complex 5´UTR with uORFs) and functional (regulation of key cellular processes) features. We are working towards the identification of the conditions where the EAD1 regulation of translation is required. [1] Ingolia, N. et al. (2009) Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling. Science, 324; 218-222 [2] Merchante, C. et al. (2015) Gene-Specific Translation Regulation Mediated by the Hormone-Signaling Molecule EIN2. Cell, 163(3): 684-697