Safety and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase in Mitochondrial Neurogastrointestinal Encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP; dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients; these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile

The spatial distribution of radiodense breast tissue: a longitudinal study

Introduction Mammographic breast density is one of the strongest known markers of susceptibility to breast cancer. To date research into density has relied on a single measure ( for example, percent density (PD)) summarising the average level of density for the whole breast, with no consideration of how the radiodense tissue may be distributed. This study aims to investigate the spatial distribution of density within the breast using 493 mammographic images from a sample of 165 premenopausal women (similar to 3 medio-lateral oblique views per woman).Methods Each breast image was divided into 48 regions and the PD for the whole breast ( overall PD) and for each one of its regions ( regional PD) was estimated. The spatial autocorrelation ( Moran's I value) of regional PD for each image was calculated to investigate spatial clustering of density, whether the degree of clustering varied between a woman's two breasts and whether it was affected by age and other known density correlates.Results The median Moran's / value for 165 women was 0.31 (interquartile range: 0.26, 0.37), indicating a clustered pattern. High-density areas tended to cluster in the central regions of the breast, regardless of the level of overall PD, but with considerable between-woman variability in regional PD. The degree of clustering was similar between a woman's two breasts (mean within-woman difference in Moran's / values between left and right breasts = 0.00 (95% confidence interval (CI) = -0.01, 0.01); P = 0.76) and did not change with aging (mean within-woman difference in I values between screens taken on average 8 years apart = 0.01 (95% CI = -0.01, 0.02); P = 0.30). Neither parity nor age at first birth affected the level of spatial autocorrelation of density, but increasing body mass index (BMI) was associated with a decrease in the degree of spatial clustering.Conclusions This study is the first to demonstrate that the distribution of radiodense tissue within the breast is spatially autocorrelated, generally with the high-density areas clustering in the central regions of the breast. The degree of clustering was similar within a woman's two breasts and between women, and was little affected by age or reproductive factors although it declined with increasing BMI

Markov Chain Ontology Analysis (MCOA)

<p>Abstract</p> <p>Background</p> <p>Biomedical ontologies have become an increasingly critical lens through which researchers analyze the genomic, clinical and bibliographic data that fuels scientific research. Of particular relevance are methods, such as enrichment analysis, that quantify the importance of ontology classes relative to a collection of domain data. Current analytical techniques, however, remain limited in their ability to handle many important types of structural complexity encountered in real biological systems including class overlaps, continuously valued data, inter-instance relationships, non-hierarchical relationships between classes, semantic distance and sparse data.</p> <p>Results</p> <p>In this paper, we describe a methodology called Markov Chain Ontology Analysis (MCOA) and illustrate its use through a MCOA-based enrichment analysis application based on a generative model of gene activation. MCOA models the classes in an ontology, the instances from an associated dataset and all directional inter-class, class-to-instance and inter-instance relationships as a single finite ergodic Markov chain. The adjusted transition probability matrix for this Markov chain enables the calculation of eigenvector values that quantify the importance of each ontology class relative to other classes and the associated data set members. On both controlled Gene Ontology (GO) data sets created with Escherichia coli, Drosophila melanogaster and Homo sapiens annotations and real gene expression data extracted from the Gene Expression Omnibus (GEO), the MCOA enrichment analysis approach provides the best performance of comparable state-of-the-art methods.</p> <p>Conclusion</p> <p>A methodology based on Markov chain models and network analytic metrics can help detect the relevant signal within large, highly interdependent and noisy data sets and, for applications such as enrichment analysis, has been shown to generate superior performance on both real and simulated data relative to existing state-of-the-art approaches.</p

Morphometric Relationship, Phylogenetic Correlation, and Character Evolution in the Species-Rich Genus Aphis (Hemiptera: Aphididae)

The species-rich genus Aphis consists of more than 500 species, many of them host-specific on a wide range of plants, yet very similar in general appearance due to convergence toward particular morphological types. Most species have been historically clustered into four main phenotypic groups (gossypii, craccivora, fabae, and spiraecola groups). To confirm the morphological hypotheses between these groups and to examine the characteristics that determine them, multivariate morphometric analyses were performed using 28 characters measured/counted from 40 species. To infer whether the morphological relationships are correlated with the genetic relationships, we compared the morphometric dataset with a phylogeny reconstructed from the combined dataset of three mtDNA and one nuclear DNA regions.Based on a comparison of morphological and molecular datasets, we confirmed morphological reduction or regression in the gossypii group unlike in related groups. Most morphological characteristics of the gossypii group were less variable than for the other groups. Due to these, the gossypii group could be morphologically well separated from the craccivora, fabae, and spiraecola groups. In addition, the correlation of the rates of evolution between morphological and DNA datasets was highly significant in their diversification.The morphological separation between the gossypii group and the other species-groups are congruent with their phylogenetic relationships. Analysis of trait evolution revealed that the morphological traits found to be significant based on the morphometric analyses were confidently correlated with the phylogeny. The dominant patterns of trait evolution resulting in increased rates of short branches and temporally later evolution are likely suitable for the modality of Aphis speciation because they have adapted species-specifically, rapidly, and more recently on many different host plants

Transcriptional Upregulation of NLRC5 by Radiation Drives STING- and Interferon-Independent MHC-I Expression on Cancer Cells and T Cell Cytotoxicity.

Radiation therapy has been shown to enhance the efficacy of various T cell-targeted immunotherapies that improve antigen-specific T cell expansion, T regulatory cell depletion, or effector T cell function. Additionally, radiation therapy has been proposed as a means to recruit T cells to the treatment site and modulate cancer cells as effector T cell targets. The significance of these features remains unclear. We set out to determine, in checkpoint inhibitor resistant models, which components of radiation are primarily responsible for overcoming this resistance. In order to model the vaccination effect of radiation, we used a Listeria monocytogenes based vaccine to generate a large population of tumor antigen specific T cells but found that the presence of cells with cytotoxic capacity was unable to replicate the efficacy of radiation with combination checkpoint blockade. Instead, we demonstrated that a major role of radiation was to increase the susceptibility of surviving cancer cells to CD8+ T cell-mediated control through enhanced MHC-I expression. We observed a novel mechanism of genetic induction of MHC-I in cancer cells through upregulation of the MHC-I transactivator NLRC5. These data support the critical role of local modulation of tumors by radiation to improve tumor control with combination immunotherapy

Polycystic ovary syndrome

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.Robert J Norman, Ruijin Wu and Marcin T Stankiewic

Lateral Transfer of a Lectin-Like Antifreeze Protein Gene in Fishes

Fishes living in icy seawater are usually protected from freezing by endogenous antifreeze proteins (AFPs) that bind to ice crystals and stop them from growing. The scattered distribution of five highly diverse AFP types across phylogenetically disparate fish species is puzzling. The appearance of radically different AFPs in closely related species has been attributed to the rapid, independent evolution of these proteins in response to natural selection caused by sea level glaciations within the last 20 million years. In at least one instance the same type of simple repetitive AFP has independently originated in two distant species by convergent evolution. But, the isolated occurrence of three very similar type II AFPs in three distantly related species (herring, smelt and sea raven) cannot be explained by this mechanism. These globular, lectin-like AFPs have a unique disulfide-bonding pattern, and share up to 85% identity in their amino acid sequences, with regions of even higher identity in their genes. A thorough search of current databases failed to find a homolog in any other species with greater than 40% amino acid sequence identity. Consistent with this result, genomic Southern blots showed the lectin-like AFP gene was absent from all other fish species tested. The remarkable conservation of both intron and exon sequences, the lack of correlation between evolutionary distance and mutation rate, and the pattern of silent vs non-silent codon changes make it unlikely that the gene for this AFP pre-existed but was lost from most branches of the teleost radiation. We propose instead that lateral gene transfer has resulted in the occurrence of the type II AFPs in herring, smelt and sea raven and allowed these species to survive in an otherwise lethal niche