Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress.

Loss of parkin function is responsible for the majority of autosomal recessive parkinsonism. Here, we show that parkin is not only a stress-protective, but also a stress-inducible protein. Both mitochondrial and endoplasmic reticulum (ER) stress induce an increase in parkin-specific mRNA and protein levels. The stress-induced upregulation of parkin is mediated by ATF4, a transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin promoter. Interestingly, c-Jun can bind to the same site, but acts as a transcriptional repressor of parkin gene expression. We also present evidence that mitochondrial damage can induce ER stress, leading to the activation of the UPR, and thereby to an upregulation of parkin expression. Vice versa, ER stress results in mitochondrial damage, which can be prevented by parkin. Notably, the activity of parkin to protect cells from stress-induced cell death is independent of the proteasome, indicating that proteasomal degradation of parkin substrates cannot explain the cytoprotective activity of parkin. Our study supports the notion that parkin has a role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson's disease.

Destabilization of the Mg-H system through elastic constraints.

We tune the thermodynamics of hydrogen absorption in Mg by means of elastic clamping. The loading isotherms measured by hydrogenography show that Mg films covered with Mg-alloy-forming elements, such as Pd and Ni, have hydrogen plateau pressures more than 2 orders of magnitude higher than bulk Mg at the same temperature. An elastic model allows us to interpret the Mg thickness dependence of the hydrogen plateau pressure. Our results suggest an alternative route for the development of new hydrogen storage materials with optimized thermodynamic properties.

High-dose chemotherapy with bone marrow rescue for high-grade gliomas in adults.

High-grade malignant gliomas are inevitably fatal, despite every effort to improve this prognosis, including various radiotherapeutic modalities, radio- and chemotherapeutic associations, and combinations of several drugs. High-dose chemotherapy and autologous bone-marrow transplantation (ABMT) have been increasingly used in the last 10 years for solid tumors, and several phase II studies in high-grade glioma patients have been conducted in the setting of both adjuvant treatment and recurrent disease. The most frequently used drug in the conditioning regimens in BCNU at doses higher than that employed by other regimens in other pathologies (800-1000 mg/m2). These dosages involve a high toxicity that is not balanced by a significant improvement in survival. New drugs and/or regimens must be tested in randomized trials.

Medulloblastoma in adults: clinical characteristics and treatment.

Long-term survival is possible in adults with medulloblastoma with rates of approximately 50-60% at 5 years, and 40-50% at 10 years. As the literature data are based on retrospective studies, treatments are neither randomized nor uniform, however, some treatment cornerstones have been identified. The first step is surgery, which should be as radical as possible; adjuvant radiotherapy must be 55 Gy on the posterior fossa, and 36 Gy on the remaining cranial-spinal axis; adjuvant chemotherapy may be useful in patients at high risk of recurrence provided it is administered before radiotherapy in moderate-high dosages and includes cisplatin, etoposide and cyclophosphamide. This chemotherapy program should not overly delay the start of radiotherapy, be recycled as soon as blood count permits and not exceed two or three cycles. Adjuvant chemotherapy after radiotherapy, even if indicated in cases with persistent tumour, may have an adverse effect due to the poor marrow reserves of these patients. At recurrence the prospects of cure are very poor due to the deficient hematopoietic reserve, but in very young patients high dose chemotherapy with marrow rescue might be usefully employed.