A Realistic Model under which the Genetic Code is Optimal

The genetic code has a high level of error robustness. Using values of hydrophobicity scales as a proxy for amino acid character, and the Mean Square measure as a function quantifying error robustness, a value can be obtained for a genetic code which reflects the error robustness of that code. By comparing this value with a distribution of values belonging to codes generated by random permutations of amino acid assignments, the level of error robustness of a genetic code can be quantified. We present a calculation in which the standard genetic code is shown to be optimal. We obtain this result by (1) using recently updated values of polar requirement as input; (2) fixing seven assignments (Ile, Trp, His, Phe, Tyr, Arg, and Leu) based on aptamer considerations; and (3) using known biosynthetic relations of the 20 amino acids. This last point is reflected in an approach of subdivision (restricting the random reallocation of assignments to amino acid subgroups, the set of 20 being divided in four such subgroups). The three approaches to explain robustness of the code (specific selection for robustness, amino acid-RNA interactions leading to assignments, or a slow growth process of assignment patterns) are reexamined in light of our findings. We offer a comprehensive hypothesis, stressing the importance of biosynthetic relations, with the code evolving from an early stage with just glycine and alanine, via intermediate stages, towards 64 codons carrying todays meaning.Comment: 22 pages, 3 figures, 4 tables Journal of Molecular Evolution, July 201

Can adenine nucleotides predict primary nonfunction of the human liver homograft?

Sixty-eight primary liver grafts were analyzed to see whether adenine nucleotides (AN: ATP, ADP, and AMP) or purine catabolites (PC: adenosine, inosine, hypoxanthine, and xanthine) of tissue or effluent can predict primary graft nonfunction. AN, PC, and nicotinamide adenine dinucleotide, oxidized form (NAD+) of the tissue before (pretransplant) and after graft reperfusion (post-transplant) and of the effluent were analyzed. The graft outcome was classified into two groups (group A: successful, n = 64; group B: primary nonfunctioning, n = 4). No significant differences were observed in pretransplant measurements between groups A and B, whereas ATP, ADP, total AN, total AN + total PC (T) and NAD+, in post-transplant tissues, were significantly higher in group A. Xanthine in the effluent was significantly higher in group B than in group A. ATP, ADP, total AN, T, and NAD+ in post-transplant tissue were significantly associated with primary graft nonfunction by logistic regression analysis

Induction of Tumor Growth After Preoperative Portal Vein Embolization: Is It a Real Problem?

Although preoperative portal vein embolization (PVE) is an effective means to increase future remnant liver (FRL) volume, little has been published on possible adverse effects. This review discusses the clinical and experimental evidence regarding the effect of PVE on tumor growth in both embolized and nonembolized liver lobes, as well as potential strategies to control tumor progression after PVE. A literature review was performed using MEDLINE with keywords related to experimental and clinical studies concerning PVE, portal vein ligation (PVL), and tumor growth. Cross-references and references from reviews were also checked. Clinical and experimental data suggest that tumor progression can occur after preoperative PVE in embolized and nonembolized liver segments. Clinical evidence indicating possible tumor progression in patients with colorectal metastases or with primary liver tumors is based on studies with small sample size. Although multiple studies demonstrated tumor progression, evidence concerning a direct increase in tumor growth rate as a result of PVE is circumstantial. Three possible mechanisms influencing tumor growth after PVE can be recognized, namely changes in cytokines or growth factors, alteration in hepatic blood supply and an enhanced cellular host response promoting local tumor growth after PVE. Post-PVE chemotherapy and sequential transcatheter arterial chemoembolization (TACE) before PVE have been proposed to reduce tumor mass after PVE. We conclude that tumor progression can occur after PVE in patients with colorectal metastases as well as in patients with primary liver tumors. However, further research is needed in order to rate this risk of tumor progression after PV

Intraoperative fluid restriction in pancreatic surgery : a double blinded randomised controlled trial

Background : Perioperative fluid restriction in a variety of operations has shown improvement of: complications, recovery of gastrointestinal function and length of stay (LOS). We investigated effects of crystalloid fluid restriction in pancreatic surgery. Our hypothesis: enhanced recovery of gastrointestinal function. Methods : In this double-blinded randomized trial, patients scheduled to undergo pancreatoduodenectomy (PD) were randomized: standard (S: 10ml/kg/hr) or restricted (R:5ml/kg/hr) fluid protocols. Primary endpoint: gastric emptying scintigraphically assessed on postoperative day 7. Results : In 66 randomized patients, complications and 6-year survival were analyzed. 54 patients were analyzed in intention to treat: 24 S-group and 30 R-group. 32 patients actually underwent a PD and 16 patients had a palliative gastrojejunostomy bypass operation in the full protocol analysis. The median gastric emptying time (T1/2) was 104 minutes (S-group, 95% confidence interval: 74-369) versus 159 minutes (R-group, 95% confidence interval: 61-204) (P = 0.893, NS). Delayed gastric emptying occurred in 10 patients in the S-group and in 13 patients in the R-group (45% and 50%, P = 0.779, NS). The primary outcome parameter, gastric emptying time, did not show a statistically significant difference between groups. Conclusion : A fluid regimen of 10ml/kg/hr or 5ml/kg/hr during pancreatic surgery did not lead to statistically significant differences in gastric emptying. A larger study would be needed to draw definite conclusions about fluid restriction in pancreatic surgery

“SPLIT” Pancreaticojejunostomy in the Surgical Treatment of Chronic Pancreatitis

“Split” pancreaticojejunostomy is a procedure consisting of vertical transection of the pancreas and anastomosis of both sides of the cut pancreatic duct with an interposed, Roux-en-Y jejunal loop. In this paper we report the long term results of this procedure in the treatment of eight patients with chronic pancreatitis (CP)

Role of transcriptional regulation in controlling fluxes in central carbon metabolism of Saccharomyces cerevisiae - A chemostat culture study

FWN – Publicaties zonder aanstelling Universiteit Leide

An Engineered Yeast Efficiently Secreting Penicillin

This study aimed at developing an alternative host for the production of penicillin (PEN). As yet, the industrial production of this β-lactam antibiotic is confined to the filamentous fungus Penicillium chrysogenum. As such, the yeast Hansenula polymorpha, a recognized producer of pharmaceuticals, represents an attractive alternative. Introduction of the P. chrysogenum gene encoding the non-ribosomal peptide synthetase (NRPS) δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine synthetase (ACVS) in H. polymorpha, resulted in the production of active ACVS enzyme, when co-expressed with the Bacillus subtilis sfp gene encoding a phosphopantetheinyl transferase that activated ACVS. This represents the first example of the functional expression of a non-ribosomal peptide synthetase in yeast. Co-expression with the P. chrysogenum genes encoding the cytosolic enzyme isopenicillin N synthase as well as the two peroxisomal enzymes isopenicillin N acyl transferase (IAT) and phenylacetyl CoA ligase (PCL) resulted in production of biologically active PEN, which was efficiently secreted. The amount of secreted PEN was similar to that produced by the original P. chrysogenum NRRL1951 strain (approx. 1 mg/L). PEN production was decreased over two-fold in a yeast strain lacking peroxisomes, indicating that the peroxisomal localization of IAT and PCL is important for efficient PEN production. The breakthroughs of this work enable exploration of new yeast-based cell factories for the production of (novel) β-lactam antibiotics as well as other natural and semi-synthetic peptides (e.g. immunosuppressive and cytostatic agents), whose production involves NRPS's

Differentiation of hepatocellular adenoma and focal nodular hyperplasia using 18F-fluorocholine PET/CT

The aim of this pilot study was to evaluate the use of PET/CT with 18F-fluorocholine in the differentiation of hepatocellular adenoma (HCA) from focal nodular hyperplasia (FNH). Patients with liver lesions larger than 2 cm suspicious for HCA or FNH were prospectively included. All patients underwent PET/CT with 18F-fluorocholine and histopathological diagnosis was obtained by either liver biopsy or surgery. The ratios between the maximum standardized uptake value (SUV) of the lesion and the mean SUV of normal liver parenchyma were calculated and a receiver operating characteristic (ROC) curve analysis was performed. Ten patients with FNH and 11 with HCA were included. The mean SUV ratio was 1.68±0.29 (±SD) for FNH and 0.88±0.18 for HCA (p<0.001). An SUV ratio cut-off value between 1.12 and 1.22 differentiated patients with FNH from those with HCA with 100% sensitivity and 100% specificity. This pilot study showed that PET/CT with 18F-fluorocholine can differentiate HCA from FNH

From registration to publication: A study on Dutch academic randomized controlled trials

Introduction: Registration of clinical trials has been initiated in order to assess adherence of the reported results to the original trial protocol. This study aimed to investigate the publication rates, timely dissemination of results, and the prevalence of consistency in hypothesis, sample size, and primary endpoint of Dutch investigator-initiated randomized controlled clinical trials (RCTs). Methods: All Dutch investigator-initiated RCTs with a completion date between December 31, 2010, and January 1, 2012, and registered in the Trial Register of The Netherlands database were included. PubMed was searched for the publication of these RCT results until September 2016, and the time to the publication date was calculated. Consistency in hypothesis, sample size, and primary endpoint compared with the registry data were assessed. Results: The search resulted in a total of 168 Dutch investigator-initiated RCTs. In September 2016, the results of 129 (77%) trials had been published, of which 50 (39%) within 2 years after completion of accrual. Consistency in hypothesis with the original protocol was observed in 108 (84%) RCTs; in 71 trials (55%), the planned sample size was reached; and 103 trials (80%) presented the original primary endpoint. Consistency in all three parameters was observe