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1.  Modulation of Mitochondrial Outer Membrane Permeabilization and Apoptosis by Ceramide Metabolism 
PLoS ONE  2012;7(11):e48571.
The yeast Saccharomyces cerevisiae undergoes a mitochondrial-dependent programmed cell death in response to different stimuli, such as acetic acid, with features similar to those of mammalian apoptosis. However, the upstream signaling events in this process, including those leading to mitochondrial membrane permeabilization, are still poorly characterized. Changes in sphingolipid metabolism have been linked to modulation of apoptosis in both yeast and mammalian cells, and ceramides have been detected in mitochondria upon apoptotic stimuli. In this study, we aimed to characterize the contribution of enzymes involved in ceramide metabolism to apoptotic cell death induced by acetic acid. We show that isc1Δ and lag1Δ mutants, lacking inositol phosphosphingolipid phospholipase C and ceramide synthase, respectively, exhibited a higher resistance to acetic acid that was associated with lower levels of some phytoceramide species. Consistently, these mutant cells displayed lower levels of ROS production and reduced mitochondrial alterations, such as mitochondrial fragmentation and degradation, and decreased translocation of cytochrome c into the cytosol in response to acetic acid. These results suggest that ceramide production contributes to cell death induced by acetic acid, especially through hydrolysis of complex sphingolipids catalyzed by Isc1p and de novo synthesis catalyzed by Lag1p, and provide the first in vivo indication of its involvement in mitochondrial outer membrane permeabilization in yeast.
doi:10.1371/journal.pone.0048571
PMCID: PMC3511487  PMID: 23226203
2.  Treatment of lung cancer in the elderly: Influence of comorbidity on toxicity and survival 
Summary
Background
More than 50% of new cases of lung cancer (LC) are diagnosed in elderly patients. It is necessary to know correct treatment of these patients but there is a lack of evidence-based data regarding this age group, leading to an undertreatment based on a supposed lack of tolerance to radical treatments.
Aim
To evaluate the results of radiotherapy (RT) treatment in elderly patients with LC in our institution and the relation between survival, toxicity and comorbidities.
Materials and methods
We retrospectively analyzed all patients over 70 years old with LC, treated with RT with or without chemotherapy (CT), in the radiotherapy department of the Instituto Português de Oncologia do Porto Francisco Gentil (IPOPFG), between January 2000 and December 2007.
Results
Three-year overall survival (OS) rate was 33.8%. Median progression free survival was 18.1 months. For patients treated with exclusive radical radiotherapy the 3-year OS rate was 51.5% and for patients treated with sequential and concurrent CTRT, 3-year survival rates were 44% and 25.4%, respectively. We did not find a statistical relationship between the presence of comorbidities and survival. Toxicity presented by the patients was not influenced by comorbidities and did not influence survival.
Conclusion
Our results allow us to conclude that elderly patients are likely to benefit from radical treatments. Chemo-radiotherapy seems to increase survival but should be used carefully in old patients outside clinical trials. Comorbidities did not seem to influence survival and toxicity of treatments, although larger studies are necessary to prove this.
doi:10.1016/j.rpor.2011.01.001
PMCID: PMC3863214  PMID: 24376955
Lung cancer; Elderly; Radiotherapy; Toxicity; Comorbidity
3.  Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer 
BMC Cancer  2011;11:312.
Background
Monocarboxylate transporters (MCTs) are transmembrane proteins involved in the transport of monocarboxylates across the plasma membrane, which appear to play an important role in solid tumours, however the role of MCTs in prostate cancer is largely unknown. The aim of the present work was to evaluate the clinico-pathological value of monocarboxylate transporters (MCTs) expression, namely MCT1, MCT2 and MCT4, together with CD147 and gp70 as MCT1/4 and MCT2 chaperones, respectively, in prostate carcinoma.
Methods
Prostate tissues were obtained from 171 patients, who performed radical prostatectomy and 14 patients who performed cystoprostatectomy. Samples and clinico-pathological data were retrieved and organized into tissue microarray (TMAs) blocks. Protein expression was evaluated by immunohistochemistry in neoplastic (n = 171), adjacent non-neoplastic tissues (n = 135), PIN lesions (n = 40) and normal prostatic tissue (n = 14). Protein expression was correlated with patients' clinicopathologic characteristics.
Results
In the present study, a significant increase of MCT2 and MCT4 expression in the cytoplasm of tumour cells and a significant decrease in both MCT1 and CD147 expression in prostate tumour cells was observed when compared to normal tissue. All MCT isoforms and CD147 were expressed in PIN lesions. Importantly, for MCT2 and MCT4 the expression levels in PIN lesions were between normal and tumour tissue, which might indicate a role for these MCTs in the malignant transformation. Associations were found between MCT1, MCT4 and CD147 expressions and poor prognosis markers; importantly MCT4 and CD147 overexpression correlated with higher PSA levels, Gleason score and pT stage, as well as with perineural invasion and biochemical recurrence.
Conclusions
Our data provides novel evidence for the involvement of MCTs in prostate cancer. According to our results, we consider that MCT2 should be further explored as tumour marker and both MCT4 and CD147 as markers of poor prognosis in prostate cancer.
doi:10.1186/1471-2407-11-312
PMCID: PMC3157459  PMID: 21787388
4.  Development of a New Methodology for Screening of Human Immunodeficiency Virus Type 1 Microbicides Based on Real-Time PCR Quantification▿  
Potential topical retrovirucides or vaginal microbicides against human immunodeficiency virus type 1 (HIV-1) include nonnucleoside reverse transcriptase inhibitors (NNRTIs). To be successful, such agents have to be highly active against cell-free virions. In the present study, we developed a new real-time PCR-based assay to measure the natural endogenous reverse transcription (NERT) activity directly on intact HIV-1 particles in the presence of reverse transcriptase (RT) inhibitors. We further evaluated the permeability to nevirapine (NVP) and efavirenz (EFV) and their retention within nascent viral particles. We also demonstrated the NVP and EFV inhibitory effects on NERT activity and the impact of resistance mutations measured directly by this new strategy. Furthermore, the results showed a clear correlation between NERT activity and classical infectivity assays. The 50% inhibitory concentrations (IC50s) of NVP and EFV were demonstrated to be up to 100-fold higher for cell-free than for cell-associated virions, suggesting that cell-free virions are less permeable to these drugs. Our results suggest that NVP and EFV penetrate both the envelope and the capsid of HIV-1 particles and readily inactivate cell-free virions. However, the characteristics of these NNRTIs, such as lower permeability and lower retention during washing procedures, in cell-free virions reduce their efficacies as microbicides. Here, we demonstrate the usefulness of the NERT real-time PCR as an assay for screening novel antiretroviral compounds with unique mechanisms of action.
doi:10.1128/AAC.00749-06
PMCID: PMC1797782  PMID: 17116672
5.  Impact of Nelfinavir Resistance Mutations on In Vitro Phenotype, Fitness, and Replication Capacity of Human Immunodeficiency Virus Type 1 with Subtype B and C Proteases 
Human immunodeficiency virus type 1 subtype B and C proteases were manipulated to contain 90M, 88D, or 89L, and their in vitro biological properties were studied. We showed that D30N has significantly more impact in subtype C than in subtype B counterparts, accounting for the reported low prevalence of this mutation in patients failing nelfinavir-based regimens.
doi:10.1128/AAC.48.9.3552-3555.2004
PMCID: PMC514783  PMID: 15328124

Results 1-5 (5)