Renal Ischemia-Induced Cholesterol Loading : Transcription Factor Recruitment and Chromatin Remodeling along the HMG CoA Reductase Gene

Parkinson disease (PD) typically affects the cortical regions during the later stages of disease, with neuronal loss, gliosis, and formation of diffuse cortical Lewy bodies in a significant portion of patients with dementia. To identify novel proteins involved in PD progression, we prepared synaptosomal fractions from the frontal cortices of pathologically verified PD patients at different stages along with age-matched controls. Protein expression profiles were compared using a robust quantitative proteomic technique. Approximately 100 proteins displayed significant differences in their relative abundances between PD patients at various stages and controls; three of these proteins were validated using independent techniques. One of the confirmed proteins, glutathione S-transferase Pi, was further investigated in cellular models of PD, demonstrating that its level was intimately associated with several critical cellular processes that are directly related to neurodegeneration in PD. These results have, for the first time, suggested that the levels of glutathione S-transferase Pi may play an important role in modulating the progression of PD.Parkinson disease (PD), the second most common neurodegenerative disease after Alzheimer disease (AD), has been recognized recently as a disease that includes more than just nigrostriatal degeneration with motor dysfunction.^1,2 More specifically, a significant portion of PD patients suffer from non-motor symptoms, including anosmia, constipation, depression, autonomic failure, and cognitive dysfunction.^1,2,3 In fact, PD patients commonly develop reduced cognitive abilities, ranging from mild cognitive impairment to full-blown dementia, as the disease advances.^1,2The prevailing hypothesis for PD development is that the disease likely results from genetic or environmental causes, or their combinations with processes of aging, that culminate in mitochondrial and/or proteasomal dysfunction and increased oxidative stress.^1,3 Additionally, pathological observations derived from human PD cases and toxicant-based animal models suggest a dying-back mode of neurodegeneration in PD.^1,4 More specifically, loss of presynaptic terminals (for example, the axonal connections from the substantia nigra pars compacta to the striatum) precedes the loss of neuronal cell bodies. Nonetheless, the molecular pathways leading to PD progression are largely unknown. While progressive dopaminergic degeneration can be important, its link to cognitive impairment is not clear. On the other hand, most, if not all, PD patients with dementia demonstrate cortical Lewy bodies (LBs), a pathological hallmark of PD, and/or pathology related to AD.^1,2,5 Indeed, though still controversial, it appears that, at least in a subset of PD patients, progression of the disease is accompanied by spreading of LBs from the brainstem to the limbic system and, eventually, to the isocortex, including the frontal cortex.^5,6 In this study, we have elected to focus on this particular cohort of PD patients, given our ability to classify them unequivocally.Herein, using a robust shotgun proteomic approach in conjunction with an isotope labeling technique, isobaric tagging for relative and absolute quantification (iTRAQ), we quantitatively compared the protein profiles of synaptosomal fractions, the subcellular compartment likely involved in the early process of neurodegeneration, from the frontal cortex of patients with PD at different pathological stages of disease, with and without dementia, as well as with age-matched controls. The study revealed many novel proteins with quantitative expression differences as the disease progressed, and provided more detailed molecular mechanisms for one of these proteins, glutathione S-transferase Pi (GSTP1), that may modulate the progression of human PD.     

On the involvement of H2S in nitroso signaling and other mechanisms of H2S action

Both endogenously produced and exogenously administered H2S exert numerous biological effects. However, the molecular mechanisms underlying these effects are not fully understood. This review surveys the biological effects of H2S and summarizes the molecular mechanisms of H2S action. It focuses on the role of H2S/HS--induced NO release from nitroso compounds, modulation of ion channels and the antioxidant and radical properties of H2S in the molecular mechanism of its effects. The potential involvement of H2S in nitroso signaling underlying its diverse biological effects is also discussed.     

Delivering affordable cancer care in high-income countries

The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.     

Comparison of the diagnostic performance of human whole genome microarrays using mixed-tissue RNA reference samples

Universal approaches for assessing the diagnostic performance of microarray assays are essential for the application of microarray technology to clinical and regulatory settings. Reference systems for diagnostic assays in laboratory medicine typically involve the utilization of reference samples, metrics, and reference datasets to ensure that measurements are comparable and true. For microarray performance evaluation and process improvement, reference samples can be composed of mixes of different tissue or cell line RNAs that contain tissue-selective analytes at defined target ratios. The diagnostic accuracy of detected changes in expression, measured as the area under the curve from receiver-operating characteristic plots, can provide a single commutable value for comparing assay specificity and sensitivity. Examples of applying this method for assessing overall performance are provided using public datasets generated on five commercial human whole genome microarray platforms for the MicroArray Quality Control project, a community-wide effort to address issues surrounding microarray data reliability.     

Carcinoma broncogénico en pacientes con trasplante de órgano sólido. Papel de la cirugía

Background

The incidence of neoplastic diseases is higher in patients undergoing solid organ transplant. However, the incidence of bronchogenic carcinoma (BC) is controversial. The objective of our study was to determine the incidence of BC in a large cohort of transplant patients and the role of surgery.

Material and methods

Until December 2006, 3596 patients underwent solid organ transplant at our institution; 24 (0.7%) patients subsequently developed BC, of which 6 (24%) were classified as clinical stage I and submitted to surgical treatment. Survival was estimated by the Kaplan-Meier method.

Results

Three patients received a liver transplant, two a kidney transplant and one a heart transplant. All were male and all had a smoking history. Mean age was 58.6 years. Two patients had cough, one accompanied by bloody expectoration, and BC was an incidental finding in the remaining cases. The interval between transplant and diagnosis of BC was 38.1 months. Epidermoid carcinoma was the most frequent histological type. Mean tumour size was 3.6 cm (range, 1.3-6). One tumour was classified as pathological stage IA, four as stage IB and one as IIB due to parietal pleural invasion. No patient died during the perioperative period and only one had a haemothorax which resolved with chest tube drainage. Mean hospital stay was 8.5 days (range, 7-11). The immunosuppression regimen was maintained continuously. In subsequent follow-up, one patient died from BC metastasis, one from sepsis, one from chronic renal failure, and three remained alive. The probability of survival at 5 years was 40%, and median survival was established at 5 years.

Conclusions

The incidence of BC in patients undergoing solid organ transplant and the proportion of patients diagnosed in early stages does not differ from non-transplant patients diagnosed with BC, which questions the role of immunosuppression in the genesis and aggressiveness of BC in transplant patients. Surgery may offer acceptable results in early stages, with acceptable rates of perioperative morbidity and mortality.