Loss of oxidative defense and potential blockade of satellite cell maturation in the skeletal muscle of patients with cancer but not in the healthy elderly

Purpose: Muscle wasting in old age or cancer may result from failure of myofibre regeneration and /or accelerated apoptosis both of which may be up-regulated by oxidative stress or inflammation. The aim of this study was to determine from the transcriptome in human skeletal muscle whether there is evidence for oxidative stress and its relationship with satellite cell differentiation or apoptosis in the muscle of patients with cancer (weight-stable: CWS or weight-losing: CWL) or healthy elderly (HE) when compared with healthy middle aged controls (HMAC) . Design: 28 patients with resectable upper GI/pancreatic cancer (CWS: 14 and CWL14), 17 HE and 22 HMAC underwent biopsy of the quadriceps muscle. Markers of muscle regeneration, inflammation, oxidative stress and apoptosis were measured by qPCR. Results: The expression of transcription factors responsible for muscle regeneration (Pax3, Pax7 and MyoD) were increased in the skeletal muscle of CWS and HE when compared with HMAC (P<0.001). In contrast, the expression of myogenic differentiation markers (MyoG and Myh2) was reduced in CWS and CWL but increased in HE when compared with HMAC (P<0.0001). The expression of the pro-apoptotic gene Bax was significantly increased in CWS, CWL and HE compared with HMAC (P<0.0001). Pro-inflammatory cytokine expression was variable with increased expression of TNF in CWS and HE, increased Il-6 in CWS and increased Il-1 in CWL when compared with HMAC. Expression of the oxidative defense genes SOD2, GCLM, and NRF2 was decreased in CWS and CWL but increased in HE when compared with HMA (P<0.0001). Conclusion: There is evidence for blockade of satellite cell maturation, upregulation of apoptosis and reduced oxidative defense in the skeletal muscle of cancer patients. In contrast, in muscle from healthy elderly the potential for myotube differentiation and oxidative defense is maintained

NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

INTRODUCTION:Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.METHODS:The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation.RESULTS:We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion � hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.CONCLUSION:NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials

Plant community attributes affect dry grassland orchid establishment

Several factors have been taken into account to explain the distribution of orchid species. We explored the extent to which plant community attributes affect the abundance and reproductive fitness of three orchid species (Anacamptis morio, Himantoglossum adriaticum and Ophrys sphegodes), native to dry grasslands. Structural attributes of plant community (e.g. cover and height) were assessed in ninety 4 m(2) plots scattered on three hill massifs of the Veneto Region (NE Italy). For the three target orchid species, the height of the flowering stalk, the relative ramet height and the number of flowers and fruits were recorded in 203 tagged ramets. Generalized Linear Model revealed that plant community attributes such as cover and height of the herb layer exert a negative effect on the abundance of orchid populations. Furthermore, regression models indicated that O. sphegodes and H. adriaticum reproductive fitness, determined as fruit/flower ratio, was positively affected by relative ramet height. Our results revealed that local herbaceous vegetation structure influences the cover and fruit set of target orchid species. However, there can be substantial variation in the response of different species and variation in the structural attributes of surrounding vegetation may be associated with differences in the strength of selection. In order to achieve effective results in orchid species conservation, protocols for the in situ conservation must detail the range of vegetation covers and heights at which orchid species are favoured and can produce the most effective inflorescences

Étude comparée de l'émergence et des impacts macroéconomiques du véhicule électrique en Europe et en Chine

Pas de résum

Committed emissions from existing and planned power plants and asset stranding required to meet the Paris Agreement

Over the coming decade, the power sector is expected to invest ∼7.2 trillion USD in power plants and grids globally, much of it into CO2-emitting coal and gas plants. These assets typically have a long lifetime and commit large amounts of (future) CO2 emissions. Here, we analyze the historic development of emission commitments from power plants and compare the emissions committed by current and planned plants with remaining carbon budgets. Based on this comparison we derive the likely amount of stranded assets that would be required to meet the 1.5 ◦C–2 ◦C global warming goal. We find that even though the growth of emission commitments has slowed down in recent years, currently operating generators still commit us to emissions (∼300 GtCO2) above the levels compatible with the average 1.5 ◦C–2 ◦C scenario (∼240 GtCO2). Furthermore, the current pipeline of power plants would add almost the same amount of additional commitments (∼270 GtCO2). Even if the entire pipeline was cancelled, therefore, ∼20% of global capacity would need to be stranded to meet the climate goals set out in the Paris Agreement. Our results can help companies and investors re-assess their investments in fossil-fuel power plants, and policymakers strengthen their policies to avoid further carbon lock-in

Committed emissions from existing and planned power plants and asset stranding required to meet the Paris Agreement

Over the coming decade, the power sector is expected to invest ∼7.2 trillion USD in power plants and grids globally, much of it into CO2-emitting coal and gas plants. These assets typically have a long lifetime and commit large amounts of (future) CO2 emissions. Here, we analyze the historic development of emission commitments from power plants and compare the emissions committed by current and planned plants with remaining carbon budgets. Based on this comparison we derive the likely amount of stranded assets that would be required to meet the 1.5 ◦C–2 ◦C global warming goal. We find that even though the growth of emission commitments has slowed down in recent years, currently operating generators still commit us to emissions (∼300 GtCO2) above the levels compatible with the average 1.5 ◦C–2 ◦C scenario (∼240 GtCO2). Furthermore, the current pipeline of power plants would add almost the same amount of additional commitments (∼270 GtCO2). Even if the entire pipeline was cancelled, therefore, ∼20% of global capacity would need to be stranded to meet the climate goals set out in the Paris Agreement. Our results can help companies and investors re-assess their investments in fossil-fuel power plants, and policymakers strengthen their policies to avoid further carbon lock-in

Building climate resilience into power systems plans: reflections on potential ways forward for Bangladesh

The consideration of climate resilience in power system planning and operations by utilities around the world is very limited to date. This article assimilates some of the initial thoughts developed as part of a World Bank project on climate resilience for Bangladesh. It briefly reflects on the current literature, and focuses on the specific flooding risks faced in Bangladesh to illuminate the way forward to enhance planning practices