Continuous Regional Arterial Infusion with Fluorouracil and Octreotide Attenuates Severe Acute Pancreatitis in a Canine Model

Aim: To investigate the therapeutic effects of fluorouracil (5-Fu) and octreotide (Oct) continuous regional arterial infusion (CRAI,) alone or in combination, was administered in a canine model of severe acute pancreatitis (SAP). Materials and Methods: The animals were divided into five groups; group A (Sham), group B (SAP), group C (SAP and 5-Fu), group D (SAP and Oct), and group E (SAP and 5-Fu + Oct). Levels of amylase, alpha-tumor necrosis factor (TNF-alpha), blood urea nitrogen (BUN), creatinine, thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured both before and after the induction of SAP. Pathologic examination of the pancreas and kidneys was performed after termination of the study. Results: Pathologic changes noted in the pancreas in SAP significantly improved following CRAI with either single or combined administration of 5-Fu and Oct, where combination therapy demonstrated the lowest injury score. All treatment groups had significantly lower levels of serum TNF-alpha and amylase activity (P<0.05), though only groups D and E had a lower BUN level as compared to group B. The plasma thromboxane B-2 level increased in SAP, but the ratio of thromboxane B-2/6-keto-prostaglandin F-1 alpha decreased in the treatment groups, with the combination therapy (group E) demonstrating the lowest ratio as compared to the other 3 experimental groups (P<0.05). Conclusions: The findings in the present study demonstrate an attenuation of SAP in a canine model following CRAI administration with 5-Fu or Oct, alone or in combination

The Complete Mitochondrial Genomes of Six Heterodont Bivalves (Tellinoidea and Solenoidea): Variable Gene Arrangements and Phylogenetic Implications

BACKGROUND: Taxonomy and phylogeny of subclass Heterodonta including Tellinoidea are long-debated issues and a complete agreement has not been reached yet. Mitochondrial (mt) genomes have been proved to be a powerful tool in resolving phylogenetic relationship. However, to date, only ten complete mitochondrial genomes of Heterodonta, which is by far the most diverse major group of Bivalvia, have been determined. In this paper, we newly sequenced the complete mt genomes of six species belonging to Heterodonta in order to resolve some problematical relationships among this subclass. PRINCIPAL FINDINGS: The complete mt genomes of six species vary in size from 16,352 bp to 18,182. Hairpin-like secondary structures are found in the largest non-coding regions of six freshly sequenced mt genomes, five of which contain tandem repeats. It is noteworthy that two species belonging to the same genus show different gene arrangements with three translocations. The phylogenetic analysis of Heterodonta indicates that Sinonovacula constricta, distant from the Solecurtidae belonging to Tellinoidea, is as a sister group with Solen grandis of family Solenidae. Besides, all five species of Tellinoidea cluster together, while Sanguinolaria diphos has closer relationship with Solecurtus divaricatus, Moerella iridescens and Semele scaba rather than with Sanguinolaria olivacea. CONCLUSIONS/SIGNIFICANCE: By comparative study of gene order rearrangements and phylogenetic relationships of the five species belonging to Tellinoidea, our results support that comparisons of mt gene order rearrangements, to some extent, are a useful tool for phylogenetic studies. Based on phylogenetic analyses of multiple protein-coding genes, we prefer classifying the genus Sinonovacula within the superfamily Solenoidea and not the superfamily Tellinoidea. Besides, both gene order and sequence data agree that Sanguinolaria (Psammobiidae) is not monophyletic. Nevertheless, more studies based on more mt genomes via combination of gene order and phylogenetic analysis are needed to further understand the phylogenetic relationships in subclass Heterodonta

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

ENHANCEMENT OF ORAL BIOAVAILABILITY OF REPAGLINIDE BY SELF-NANOEMULSIFYING DRUG DELIVERY SYSTEM

Repaglinide is considered the drug of choice for diabetic patients with impaired kidney function as it is excreted mainly in the bile. Unfortunately, it possesses low oral bioavailability of approximately 56 %. Therefore, nano-sized globules containing the drug are expected to enhance its bioavailability and sustain its glucose lowering action. Self nano-emulsifying drug delivery systems (SNEDDS) of repaglinide have been prepared for improving the water solubility and oral bioavailability of the drug. Various compositions of SNEDDS were prepared using four types of oils (oleic acid, isopropyl myristate IPM. Labrafil 1944 and 2125), surfactants (chromophore El35, chromophore RH 40, Labrasol and Span 20) and a variety of co- surfacatnts. Low energy emulsification was adopted as the method of preparation for its feasibility and low cost. The prepared nano-emulsions showed small average droplet size (13.5-20 nm) and low polydispersity index (0.10 - 0.30). In-vitro dissolution studies indicated that the drug release from some of the prepared nanoemulsion droplets reached 75 % within the first 30 minutes. The in-vivo data demonstrated that repaglinide in the nano-emulsion formulations F8 (IPM, Cremophor EL35 and Propylene glycol) and F16 (Oleic acid, Cremophor RH40 and Lauroglycol FCC) lowered the plasma glucose level (< 110 mg/dL) of experimental rabbits in a similar trend to that of the commercial product (Novonorm®), moreover, it caused an excess reduction in blood glucose level at the end of the 24 hrs period by virtue of its long circulation time compared to the marketed formula