ROHMM-A flexible hidden Markov model framework to detect runs of homozygosity from genotyping data.

Runs of long homozygous (ROH) stretches are considered to be the result of consanguinity and usually contain recessive deleterious disease-causing mutations. Several algorithms have been developed to detect ROHs. Here, we developed a simple alternative strategy by examining X chromosome non-pseudoautosomal region to detect the ROHs from next-generation sequencing data utilizing the genotype probabilities and the hidden Markov model algorithm as a tool, namely ROHMM. It is implemented purely in java and contains both a command line and a graphical user interface. We tested ROHMM on simulated data as well as real population data from the 1000G Project and a clinical sample. Our results have shown that ROHMM can perform robustly producing highly accurate homozygosity estimations under all conditions thereby meeting and even exceeding the performance of its natural competitors.

Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe.

Phosphomannomutase 2 deficiency (PMM2-CDG) is an autosomal recessive congenital disorder of glycosylation, characterized by multisystem phenotypes, mostly including neurological involvement. In Turkey, due to high rates of consanguinity, many patients with autosomal recessive disorders have homozygous variants and these diseases are more common, compared to Europe. However, published reports of PMM2-CDG from Turkey are scarce. Here, we describe clinical and molecular characteristics of PMM2-CDG patients diagnosed in three centers in Turkey, using data obtained retrospectively from hospital records. We also analyzed an in-house exome database of 1,313 individuals for PMM2 variants and estimated allele, carrier and disease frequencies, using the Hardy-Weinberg law. Eleven patients were identified from 10 families, displaying similar characteristics to previous publications, with the exception of the first report of epilepsia partialis continua and increased prevalence of sensorineural hearing loss. p.Val231Met was the most common variant, and was homozygous in four patients. This novel genotype results in a neurological phenotype with subclinical visceral involvement. Exome database analysis showed an estimated prevalence of 1:286,726 for PMM2-CDG, which is much lower than expected (1:20,000 in Europe) because of the lack of predominance of the common European p.Asp141His allele, associated with a severe phenotype (allele frequency of 1:2,622 compared to 1:252 in gnomAD). These data suggest that prevalence, phenotypes and genotypes of PMM2-CDG in Turkey differ significantly from those in Europe: Milder phenotypes may be more common, but the disease itself rarer, requiring a higher clinical suspicion for diagnosis. The association of sensorineural hearing loss with PMM2-CDG warrants further study.

A palladium(II)-saccharinate complex of terpyridine exerts higher anticancer potency and less toxicity than cisplatin in a mouse allograft model.

The main aim of this study is to assess the safety and antitumor efficacy of a palladium(II) (Pd)-saccharinate complex with terpyridine. To characterize the Pd(II) complex in vitro, its cytotoxicity was evaluated using a water-soluble tetrazolium salt cell viability assay and the mechanism of cell death was assessed by DNA fragmentation/condensation and live cell imaging analyses. The antitumor efficacy and safety of the Pd(II) complex in-vivo were examined by analyzing reduction in tumor size, changes in body and organ weight, histopathological analysis of liver, kidney, and tumor sections, and biochemical analysis of serum in C57BL/6 mice. Our results showed that the Pd(II) complex was more cytotoxic to cancer cells than noncancer cell lines and caused cell death through apoptotic pathways. The treatment of the Pd(II) complex in tumor-bearing mice effectively reduced the tumor size at half the dose used for cisplatin. The Pd(II) complex appeared to exert less liver damage than the cisplatin-based complex on changes in the hepatic enzymes levels in the serum. Hence, the complex appears to be a potential chemotherapeutic drug with high antitumor efficacy and fewer hepatotoxic complications, providing an avenue for further studies.

A platinum blue complex exerts its cytotoxic activity via DNA damage and induces apoptosis in cancer cells.

Here, we describe the characteristics of a Pt-blue complex [Pt4 (2-atp)8 (H2 O)(OH)] (2-atp: 2-aminothiophenol) as a prodrug for its DNA-binding properties and its use in cancer therapy. The nature of the interaction between the Pt-blue complex and DNA was evaluated based on spectroscopic measurements, the electronic absorption spectra, thermal behavior, viscosity, fluorometric titration, and agarose gel electrophoresis. Our results suggested that the compound was able to partially intercalate DNA and appeared to induce both single- and double-stranded breaks (DBS) on DNA in vitro, but no DSBs in cells. The ability of the compound to induce DNA damage was dependent on reactive oxygen species (ROS) in vitro. There was also elevated formation of ROS and SOD expression in response to drug treatment in cell culture. The complex was found to be more cytotoxic to cancer cells in comparison with noncancer controls using WST-1 assay. The mean of cell death was determined to be apoptosis as assessed via biochemical, morphological, and molecular observations, including DNA condensation/fragmentation analysis, live cell imaging microscopy, TUNEL analyses, and increase in the levels of pro-apoptotic genes such as Bag3, Bak, Bik, Bmf, and Hrk. Hence, the Pt-blue complex under study grants premise for further studies.