The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor

Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson''s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson''s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson''s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson''s disease identified so far. It is especially frequent among cases with familial Parkinson''s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson''s disease.     

Genetic analysis of Paraoxonase (PON1) locus reveals an increased frequency of Arg192 allele in centenarians

Human Paraoxonase (PON1) is a High-Density Lipoprotein (HDL)-associated esterase that hydrolyses lipo-peroxides. PON1 has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two polymorphisms have been extensively studied: a Leucine (L allele) to Methionine (M allele) substitution at codon 55, and a Glutamine (A allele) to Arginine (B allele) substitution at codon 192. We have examined these two aminoacidic changes in 579 people aged 20 to 65 years old, and 308 centenarians. We found that the percentage of carriers of the B allele at codon 192 (B+ individuals) is higher in centenarians than in controls (0.539 vs 0.447), moreover we found that among the B+ individuals, the phenomenon was due to an increase of people carrying M alleles at codon 55 locus. In conclusion, we propose that genetic variability at PON1 locus affects survival at extreme advanced age.     

Anti-tumor activity of fenretinide complexed with human serum albumin in lung cancer xenograft mouse model

Sufficient knowledge regarding cellular and molecular basis of lung cancer progression and metastasis would help in the development of novel and effective strategies for the treatment of lung cancer. 4HPR is a synthetic retinoid with potential anti-tumor activity but is still limited because of its poor bioavailability. The use of albumin as a complexing agent for a hydrophobic drug is expected to improve the water solubility and consequently their bioavailability.This study investigated the antitumor activity of a novel complex between albumin and 4-HPR in a mouse model of human lung cancer and focuses on role and mechanism of Cav-1 mainly involved in regulating cancer and Acsvl3 mainly connected with tumor growth.Their expressions were assayed by immunohistochemistry and qRT-PCR, to demonstrate the reduction of the tumor growth following the drug treatment. Our results showed a high antitumor activity of 4HPR-HSA by reduction of the volume of tumor mass and the presence of a high level of apoptotic cell by TUNEL assay. The downregulation of Cav-1 and Acsvl3 suggested a reduction of tumor growth.In conclusion, we demonstrated the great potential of 4HPR-HSA in the treatment of lung cancer. More data about the mechanism of drug delivery the 4HPR-HSA are necessary.     

Nonsteroidal Androgen Receptor Ligands: Versatile Syntheses and Biological Data

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Efficacy of a nitric oxide-releasing nonsteroidal anti-inflammatory drug and cytotoxic drugs in human colon cancer cell lines in vitro and xenografts

We previously showed that NCX 4040 inhibits in vitro and in vivo tumor growth and induces apoptosis in human colon cancer cell lines. On the basis of these results, NCX 4040 antitumor activity in combination with 5-fluorouracil (5-FU) or oxaliplatin was evaluated in vitro and in vivo in human colon cancer models. The cytotoxicity of different NCX 4040 and 5-FU or oxaliplatin combination schemes was evaluated on a panel of colon cancer lines (LoVo, LoVo Dx, WiDr, and LRWZ) by the sulforhodamine B assay, and apoptosis was assessed by flow cytometry. NCX 4040 and 5-FU combination was always additive in vitro regardless of the scheme used. Sequential NCX 4040-->oxaliplatin treatment produced a strong synergism in three cell lines, with a ratio index ranging from 3.7 to 4. The synergistic effect was accompanied by apoptosis induction (up to 40%). In the in vivo experiments, xenografted mice were treated with the sequential combination of NCX 4040 and oxaliplatin, and apoptosis was evaluated immunohistochemically in excised tumors. Furthermore, in WiDr xenografts, this sequence caused a significantly higher reduction ( approximately 60%) in tumor growth compared with single-drug treatments and produced extensive apoptotic cell death (15.3%), significantly higher (P < 0.01) than that observed in untreated tumors (2.7%) or in tumors treated with NCX 4040 (5.1%) or oxaliplatin (5.7%) alone. These data show that NCX 4040 sensitizes colon cancer cell lines to the effect of antitumor drugs and suggests that their combination could be useful for the clinical management of colon cancer.     

Zinc deficiency and IL-6 -174G/C polymorphism in old people from different European countries: effect of zinc supplementation. ZINCAGE study

IL-6 SNP at position −174 is associated with age-related diseases characterized by an impaired Zn status. This polymorphism seems also relevant in regulating the expression of proteins, such as Metallothioneins (MT), involved in the modulation of Zn homeostasis. Since high IL-6 levels in elderly induce hypozinchemia, the IL-6−174 SNP may be useful to identify old subjects who are at risk for Zn deficiency. The objectives of this study are: (1) to choose old subjects who effectively need Zn supplementation and (2) to study the effect of Zn supplementation on Zn, immune and psychological status in genetically selected subjects. For this purpose, a baseline study comprising 895 healthy old subjects recruited in Central-Northern and Southern European Countries was carried out by evaluating their dietary intake, psychological and immune parameters as well as their Zn status. A Zn supplementation trial was performed in 110 old subjects selected on the basis of their plasma Zn levels and IL-6 SNP. After correcting for age and Zn intake, C− carriers displayed higher MT and lower levels of several parameters related to zinc status (plasma Zn, erythrocyte Zn and NO-induced release of Zn in PBMC) than C+ carriers. Better NK cell cytotoxicity and psychological functions (PSS, MMSE) were also found in C+ than C− carriers strictly related to the zinc status. However, independently by the polymorphism, all subjects with plasma zinc 10.5 μM showed the worst immune response and psychological functions. Supplementation was carried out in C+ and C− carriers with stable low plasma zinc levels (10.5 μM at baseline and at 1 year follow-up) and in C− carriers with unstable plasma zinc (10.5 μM at baseline and >10.5 μM at 1 year follow-up). C+ carriers with plasma zinc >10.5 μM were not supplemented because showing the best immune and psychological conditions. After 48 ± 2 days of supplementation with 10 mg/day of Zn-aspartate, the NO-induced release of Zn, erythrocyte Zn and NK cell cytotoxicity increased in all groups selected for supplementation, including C− with unstable plasma zinc. In conclusion, the sole assessment of plasma Zn level is not reliable to exclude C− carriers from Zn supplementation. A possible explanation for the conflicting data on the identification of IL-6−174G as a “risk allele” based on different dietary intake in the studied population is also suggested.     

Do Tardive Dyskinesia and l-Dopa Induced Dyskinesia Share Common Genetic Risk Factors? An Exploratory Study

Tardive dyskinesia (TD) in schizophrenia patients treated with antipsychotic medications and l-dopa induced dyskinesia (LID) among Parkinson's disease (PD) affected individuals share similar clinical features. Both conditions are induced by chronic exposure to drugs that target dopaminergic receptors (antagonists in TD and agonists in LID) and cause pulsatile and nonphysiological stimulation of these receptors. We hypothesized that the two motor adverse effects partially share genetic risk factors such that certain genetic variants exert a pleiotropic effect, influencing susceptibility to TD as well as to LID. In this pilot study, we focused on 21 TD-associated SNPs, previously reported in TD genome-wide association studies or in candidate gene studies. By applying logistic regression and controlling for relevant clinical risk factors, we studied the association of the SNPs with LID vulnerability in two independent pharmacogenetic samples. We included a Jewish Israeli sample of 203 PD patients treated with l-dopa for a minimum of 3 years and evaluated the existence or absence of LID (LID+?=?128; LID??=?75). An Italian sample was composed of early LID developers (within the first 3 years of treatment, N?=?187) contrasted with non-early LID developers (after 7 years or more of treatment, N?=?203). None of the studied SNPs were significantly associated with LID susceptibility in the two samples. Therefore, we were unable to obtain proof of concept for our initial hypothesis of an overlapping contribution of genetic risk factors to TD and LID. Further studies in larger samples are required to reach definitive conclusions.