Spores of Clostridium engineered for clinical efficacy and safety cause regression and cure of tumors in vivo.

Spores of some species of the strictly anaerobic bacteria Clostridium naturally target and partially lyse the hypoxic cores of tumors, which tend to be refractory to conventional therapies. The anti-tumor effect can be augmented by engineering strains to convert a non-toxic prodrug into a cytotoxic drug specifically at the tumor site by expressing a prodrug-converting enzyme (PCE). Safe doses of the favored prodrug CB1954 lead to peak concentrations of 6.3 μM in patient sera, but at these concentration(s) known nitroreductase (NTR) PCEs for this prodrug show low activity. Furthermore, efficacious and safe Clostridium strains that stably express a PCE have not been reported. Here we identify a novel nitroreductase from Neisseria meningitidis, NmeNTR, which is able to activate CB1954 at clinically-achievable serum concentrations. An NmeNTR expression cassette, which does not contain an antibiotic resistance marker, was stably localized to the chromosome of Clostridium sporogenes using a new integration method, and the strain was disabled for safety and containment by making it a uracil auxotroph. The efficacy of Clostridium-Directed Enzyme Prodrug Therapy (CDEPT) using this system was demonstrated in a mouse xenograft model of human colon carcinoma. Substantial tumor suppression was achieved, and several animals were cured. These encouraging data suggest that the novel enzyme and strain engineering approach represent a promising platform for the clinical development of CDEPT

Heat Transfer Enhancement by Perforated and Louvred Fin Heat Exchangers

Multi-tube multi-fin heat exchangers are extensively used in various industries. In the current work, detailed experimental investigations were carried out to establish the flow/heat transfer characteristics in three distinct heat exchanger geometries. A novel perforated plain fin design was developed, and its performance was evaluated against standard plain and louvred fins designs. Experimental setups were designed, and the tests were carefully carried out which enabled quantification of the heat transfer and pressure drop characteristics. In the experiments the average velocity of air was varied in the range of 0.7 m/s to 4 m/s corresponding to Reynolds numbers of 600 to 2650. The water side flow rates in the tubes were kept at 0.12, 0.18, 0.24, 0.3, and 0.36 m3/h corresponding to Reynolds numbers between 6000 and 30,000. It was found that the louvred fins produced the highest heat transfer rate due to the availability of higher surface area, but it also produced the highest pressure drops. Conversely, while the new perforated design produced a slightly higher pressure drop than the plain fin design, it gave a higher value of heat transfer rate than the plain fin especially at the lower liquid flow rates. Specifically, the louvred fin gave consistently high pressure drops, up to 3 to 4 times more than the plain and perforated models at 4 m/s air flow, however, the heat transfer enhancement was only about 11% and 13% over the perforated and plain fin models, respectively. The mean heat transfer rate and pressure drops were used to calculate the Colburn and Fanning friction factors. Two novel semiempirical relationships were derived for the heat exchanger’s Fanning and Colburn factors as functions of the non-dimensional fin surface area and the Reynolds number. It was demonstrated that the Colburn and Fanning factors were predicted by the new correlations to within ±15% of the experiments

Rationalising drug delivery using nanoparticles: a combined simulation and immunology study of GnRH adsorbed to silica nanoparticles

Silica nanoparticles (SiNPs) have been shown to have significant potential for drug delivery and as adjuvants for vaccines. We have simulated the adsorption of GnRH-I (gonadotrophin releasing hormone I) and a cysteine-tagged modification (cys-GnRH-I) to model silica surfaces, as well as its conjugation to the widely-used carrier protein bovine serum albumin (BSA). Our subsequent immunological studies revealed no significant antibody production was caused by the peptide-SiNP systems, indicating that the treatment was not effective. However, the testosterone response with the native peptide-SiNPs indicated a drug effect not found with cys-GnRH-I-SiNPs; this behaviour is explained by the specific orientation of the peptides at the silica surface found in the simulations. With the BSA systems, we found significant testosterone reduction, particularly for the BSA-native conjugates, and an antibody response that was notably higher with the SiNPs acting as an adjuvant; this behaviour again correlates well with the epitope presentation predicted by the simulations. The range of immunological and hormone response can therefore be interpreted and understood by the simulation results and the presentation of the peptides to solution, paving the way for the future rational design of drug delivery and vaccine systems guided by biomolecular simulation

Interaction of β-Sheet Folds with a Gold Surface

The adsorption of proteins on inorganic surfaces is of fundamental biological importance. Further, biomedical and nanotechnological applications increasingly use interfaces between inorganic material and polypeptides. Yet, the underlying adsorption mechanism of polypeptides on surfaces is not well understood and experimentally difficult to analyze. Therefore, we investigate here the interactions of polypeptides with a gold(111) surface using computational molecular dynamics (MD) simulations with a polarizable gold model in explicit water. Our focus in this paper is the investigation of the interaction of polypeptides with β-sheet folds. First, we concentrate on a β-sheet forming model peptide. Second, we investigate the interactions of two domains with high β-sheet content of the biologically important extracellular matrix protein fibronectin (FN). We find that adsorption occurs in a stepwise mechanism both for the model peptide and the protein. The positively charged amino acid Arg facilitates the initial contact formation between protein and gold surface. Our results suggest that an effective gold-binding surface patch is overall uncharged, but contains Arg for contact initiation. The polypeptides do not unfold on the gold surface within the simulation time. However, for the two FN domains, the relative domain-domain orientation changes. The observation of a very fast and strong adsorption indicates that in a biological matrix, no bare gold surfaces will be present. Hence, the bioactivity of gold surfaces (like bare gold nanoparticles) will critically depend on the history of particle administration and the proteins present during initial contact between gold and biological material. Further, gold particles may act as seeds for protein aggregation. Structural re-organization and protein aggregation are potentially of immunological importance

The effects of spatial population dataset choice on estimates of population at risk of disease

Background: The spatial modeling of infectious disease distributions and dynamics is increasingly being undertaken for health services planning and disease control monitoring, implementation, and evaluation. Where risks are heterogeneous in space or dependent on person-to-person transmission, spatial data on human population distributions are required to estimate infectious disease risks, burdens, and dynamics. Several different modeled human population distribution datasets are available and widely used, but the disparities among them and the implications for enumerating disease burdens and populations at risk have not been considered systematically. Here, we quantify some of these effects using global estimates of populations at risk (PAR) of P. falciparum malaria as an example.Methods: The recent construction of a global map of P. falciparum malaria endemicity enabled the testing of different gridded population datasets for providing estimates of PAR by endemicity class. The estimated population numbers within each class were calculated for each country using four different global gridded human population datasets: GRUMP (~1 km spatial resolution), LandScan (~1 km), UNEP Global Population Databases (~5 km), and GPW3 (~5 km). More detailed assessments of PAR variation and accuracy were conducted for three African countries where census data were available at a higher administrative-unit level than used by any of the four gridded population datasets.Results: The estimates of PAR based on the datasets varied by more than 10 million people for some countries, even accounting for the fact that estimates of population totals made by different agencies are used to correct national totals in these datasets and can vary by more than 5% for many low-income countries. In many cases, these variations in PAR estimates comprised more than 10% of the total national population. The detailed country-level assessments suggested that none of the datasets was consistently more accurate than the others in estimating PAR. The sizes of such differences among modeled human populations were related to variations in the methods, input resolution, and date of the census data underlying each dataset. Data quality varied from country to country within the spatial population datasets.Conclusions: Detailed, highly spatially resolved human population data are an essential resource for planning health service delivery for disease control, for the spatial modeling of epidemics, and for decision-making processes related to public health. However, our results highlight that for the low-income regions of the world where disease burden is greatest, existing datasets display substantial variations in estimated population distributions, resulting in uncertainty in disease assessments that utilize them. Increased efforts are required to gather contemporary and spatially detailed demographic data to reduce this uncertainty, particularly in Africa, and to develop population distribution modeling methods that match the rigor, sophistication, and ability to handle uncertainty of contemporary disease mapping and spread modeling. In the meantime, studies that utilize a particular spatial population dataset need to acknowledge the uncertainties inherent within them and consider how the methods and data that comprise each will affect conclusions. © 2011 Tatem et al; licensee BioMed Central Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

2017 update of the WSES guidelines for emergency repair of complicated abdominal wall hernias

Emergency repair of complicated abdominal wall hernias may be associated with worsen outcome and a significant rate of postoperative complications. There is no consensus on management of complicated abdominal hernias. The main matter of debate is about the use of mesh in case of intestinal resection and the type of mesh to be used. Wound infection is the most common complication encountered and represents an immense burden especially in the presence of a mesh. The recurrence rate is an important topic that influences the final outcome. A World Society of Emergency Surgery (WSES) Consensus Conference was held in Bergamo in July 2013 with the aim to define recommendations for emergency repair of abdominal wall hernias in adults. This document represents the executive summary of the consensus conference approved by a WSES expert panel. In 2016, the guidelines have been revised and updated according to the most recent available literature.Peer reviewe

The role of open abdomen in non-trauma patient : WSES Consensus Paper

The open abdomen (OA) is defined as intentional decision to leave the fascial edges of the abdomen un-approximated after laparotomy (laparostomy). The abdominal contents are potentially exposed and therefore must be protected with a temporary coverage, which is referred to as temporal abdominal closure (TAC). OA use remains widely debated with many specific details deserving detailed assessment and clarification. To date, in patients with intra-abdominal emergencies, the OA has not been formally endorsed for routine utilization; although, utilization is seemingly increasing. Therefore, the World Society of Emergency Surgery (WSES), Abdominal Compartment Society (WSACS) and the Donegal Research Academy united a worldwide group of experts in an international consensus conference to review and thereafter propose the basis for evidence-directed utilization of OA management in non-trauma emergency surgery and critically ill patients. In addition to utilization recommendations, questions with insufficient evidence urgently requiring future study were identified.Peer reviewe