Assessing the Cytotoxicity of TiO2-x Nanoparticles with a Different Ti3+(Ti2+)/Ti4+ Ratio.

Titanium dioxide (TiO2) nanoparticles are promising biomedical agents characterized by good biocompatibility. In this study, we explored the cytotoxicity of TiO2-x nanoparticles with a different Ti3+(Ti2+)/Ti4+ ratio and analyzed the efficiency of eryptosis indices as a tool in nanotoxicology. Two types of TiO2-x nanoparticles (NPs) were synthesized by the hydrolysis of titanium alkoxide varying the nitric acid content in the hydrolysis mixture. Transmission electron microscopy (TEM) images show that 1-TiO2-x and 2-TiO2-x NPs are 5 nm in size, whereas X-ray photoelectron spectroscopy (XPS) reveals different Ti3+ (Ti2+)/Ti4+ ratios in the crystal lattices of synthesized NPs. 1-TiO2-x nanoparticles contained 54% Ti4+, 38% Ti3+, and 8% Ti2+, while the relative amount of Ti4+ and Ti3+ in the crystal lattice of 2-TiO2-x nanoparticles was 63% and 37%, respectively. Cell viability and cell motility induced by TiO2-x nanoparticles were investigated on primary fibroblast cultures. Eryptosis modulation by the nanoparticles along with cell death mechanisms was studied on rat erythrocytes. We report that both TiO2-x nanoparticles do not decrease the viability of fibroblasts simultaneously stimulating cell migration. Data from in vitro studies on erythrocytes indicate that TiO2-x nanoparticles trigger eryptosis via ROS- (1-TiO2-x) and Ca2+-mediated mechanisms (both TiO2-x nanoparticles) suggesting that evaluation of eryptosis parameters is a more sensitive nanotoxicological approach for TiO2-x nanoparticles than cultured fibroblast assays. TiO2-x nanoparticles are characterized by low toxicity against fibroblasts, but they induce eryptosis, which is shown to be a promising tool for nanotoxicity screening. The Ti3+ (Ti2+)/Ti4+ ratio at least partly determines the cytotoxicity mechanisms for TiO2-x nanoparticles.

Correction to: Abstracts for MASCC/ISOO Annual Meeting 2019.

Missing abstracts in the original paper.

Correction to: Abstracts of the MASCC/ISOO 2016 Annual Meeting.

In the published Abstracts, the authorgroup of one abstract is incorrect. Matthew Kang was inadvertently deleted in abstract eP250, page 168. The correct authorgroup for eP250 is the the below.

C-reactive protein and familial risk for dementia: a phenotype for successful cognitive aging.

OBJECTIVES: Identifying phenotypes for successful cognitive aging, intact cognition into late-old age (>age 75), can help identify genes and neurobiological systems that may lead to interventions against and prevention of late-life cognitive impairment. The association of C-reactive protein (CRP) with cognitive impairment and dementia, observed primarily in young-elderly samples, appears diminished or reversed in late-old age (75+ years). A family history study determined if high CRP levels in late-old aged cognitively intact probands are associated with a reduced risk of dementia in their first-degree family members, suggesting a familial successful cognitive aging phenotype. METHODS: The primary sample was 1,329 parents and siblings of 277 cognitively intact male veteran probands at least 75 years old. The replication sample was 202 relatives of 51 cognitively intact community-ascertained probands at least 85 years old. Relatives were assessed for dementia by proband informant interview. Their hazard ratio (HR) for dementia as a function of the proband's log-transformed CRP was calculated using the proportional hazards model. RESULTS: Covarying for key demographics, higher CRP in probands was strongly associated with lower risk of dementia in relatives (HR = 0.55 [95% confidence interval (CI) 0.41, 0.74], p < 0.02). The replication sample relationship was in the same direction, stronger in magnitude, and also significant (HR = 0.15 [95% CI 0.06, 0.37], p < 0.0001). CONCLUSIONS: Relatives of successful cognitive aging individuals with high levels of CRP are relatively likely to remain free of dementia. High CRP in successful cognitive aging individuals may constitute a phenotype for familial-and thus possibly genetic-successful cognitive aging.

Genetic variations in the ADAMTS12 gene are associated with schizophrenia in Puerto Rican patients of Spanish descent.

ADAMTS12 belongs to the family of metalloproteinases that mediate a communication between specific cell types and play a key role in the regulation of normal tissue development, remodeling, and degradation. Members of this family have been implicated in neurodegenerative and neuroinflammatory, as well as in muscular-skeletal, cardiovascular, respiratory and renal diseases, and cancer. Several metalloproteinases have been associated with schizophrenia. In our previous study of the pedigree from a genetic isolate of Spanish origin in Puerto Rico, we identified a schizophrenia susceptibility locus on chromosome 5p13 containing ADAMTS12. This gene, therefore, is not only a functional but also a positional candidate gene for susceptibility to the disorder. In order to examine possible involvement of ADAMTS12 in schizophrenia, we performed mutation analysis of the coding, 5'- and 3'-untranslated, and putative promoter regions of the gene in affected members of the pedigree and identified 18 sequence variants segregated with schizophrenia. We then tested these variants in 135 unrelated Puerto Rican schizophrenia patients of Spanish origin and 203 controls and identified the intronic variant rs256792 (P = 0.0035; OR = 1.59; 95% CI = 1.16-2.17) and the two-SNP haplotype rs256603-rs256792 (P = 0.0023; OR = 1.62; 95% CI = 1.19-2.21) associated with the disorder. The association remained significant after correction for multiple testing. Our data support the hypothesis that genetic variations in ADAMTS12 influence the risk of schizophrenia.

Non-synonymous variants in the AMACR gene are associated with schizophrenia.

BACKGROUND: The AMACR gene is located in the schizophrenia susceptibility locus on chromosome 5p13, previously identified in a large Puerto Rican pedigree of Spanish origin. The AMACR-encoded protein is an enzyme involved in the metabolism of branched-chain fatty and bile acids. The enzyme deficiency causes structural and functional brain changes, and disturbances in fatty acid and oxidative phosphorylation pathways observed in individuals with schizophrenia. Therefore, AMACR is both a positional and functional candidate gene for susceptibility to schizophrenia. METHODS: The study had a two-step design: we performed mutation analysis of the coding and flanking regions of AMACR in affected members of the pedigree, and tested the detected sequence variants for association with schizophrenia in a Puerto Rican case-control sample (n=383) of Spanish descent. RESULTS AND CONCLUSION: We identified three missense variants segregating with the disorder in the family, rs2278008, rs2287939 and rs10941112. Two of them, rs2278008 and rs2287939, demonstrated significant differences in genotype (P = 4 × 10-4, P = 4 × 10-4) and allele (P = 1 × 10-4, P = 9.5 × 10-5) frequencies in unrelated male patients compare to controls, with the odds ratios (OR) 2.24 (95% CI: 1.48-3.40) and 2.25 (95% CI: 1.49-3.38), respectively. The G-C-G haplotype of rs2278008-rs2287939-rs10941112 revealed the most significant association with schizophrenia (P = 4.25 × 10-6, OR = 2.96; 95% CI: 1.85-4.76) in male subjects. There were no statistically significant differences in genotype, allele, and haplotype frequencies between female schizophrenia subjects and controls. Our results suggest that AMACR may play a significant role in susceptibility to schizophrenia in male patients.

Mutation analysis of the C1QTNF3 gene in patients with schizophrenia.

We previously identified a small region on chromosome 5p13 related to schizophrenia in a Puerto Rican pedigree. We screened one of the positional candidate genes, C1QTNF3, for mutations in affected family members. The direct sequencing identified 10 sequence variants, including five shared by all affected family members. Genotyping of the shared variants in a Puerto Rican sample of 118 cases and 136 controls did not reveal either allelic or genotype association with schizophrenia.

Fine mapping of the 5p13 locus linked to schizophrenia and schizotypal personality disorder in a Puerto Rican family.

A locus involved in schizophrenia and related disorders in a Puerto Rican family has previously been mapped to chromosome 5p. The maximum two-point log of the odds (LOD) score of 3.72 was obtained for marker D5S111, and increased to 4.37 by multipoint analysis, assuming autosomal dominant inheritance with 90% penetrance. Additional genotyping and haplotype analysis placed the novel locus on 5p13.2-p13.3 within the interval between markers D5S1993 and D5S631. In the current study, we saturated the interval between markers D5S1993 and D5S631 with densely spaced polymorphic markers, genotyped these markers in the most informative branch of the family, and narrowed the critical region to 2.8 Mb. G-protein-coupled receptor gene [somatostatin and angiotensin-like peptide receptor (SALPR)] is one of the candidate genes within the critical interval. Sequence analysis of the coding region and the putative promoter of somatostatin and angiotensin-like peptide receptor did not reveal functionally significant variants in affected family members, although several polymorphisms were detected.

Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism.

OBJECTIVE: Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region. METHOD: Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families. RESULTS: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci. CONCLUSIONS: A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.

Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.

We describe a family of Slovenian descent with progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy, and disruption of visual fixation by saccadic intrusions. Chromosome mapping indicated a mutation on 1p36, and this recessive disorder has been designated spinocerebellar ataxia with saccadic intrusions. Affected patients showed overshooting horizontal saccades, macrosaccadic oscillations, and increased velocity of larger saccades; other eye movements were normal. Slowed conduction in axons that are selectively vulnerable to the molecular defect could explain both the sensorimotor neuropathy and the saccadic disorder, which would be caused by delayed feedback control because of slow conduction in cerebellar parallel fibers.

Disease susceptibility genes for autism.

Autism is a complex neurodevelopmental disorder characterized by impairment in social interaction accompanied by a delay or lack of language, restricted interests, stereotyped behavior, and repetitive movement. Genetic predisposition to autism is evident from family and twin studies, and heritability in idiopathic autism is estimated at over 90%. Frequency of the disorder is approximately 1:2000 with a male to female ratio of 4:1. Affected individuals look normal at birth, and the symptoms manifest at the first 2-3 years of life. The spectrum of clinical symptoms and the severity of the disorder are variable even among siblings. Family studies and several genome-wide linkage analyses support the hypothesis of complex inheritance with involvement of as many as 10-100 genes of moderate effect. Identification of genes responsible for the phenotype would help to understand the molecular mechanisms of the disorder. Several genes have been proposed to play a role in susceptibility to autism, and this paper will overview those genes and their potential role in the disorder.