Polymeric prodrugs of mitomycin C designed for tumour tropism and sustained activation

Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.     

The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene

The acid sphingomyelinase (ASM) gene, which has been implicated in ceramide-mediated cell signaling and atherogenesis, gives rise to both lysosomal SMase (L-SMase), which is reportedly cation-independent, and secretory SMase (S-SMase), which is fully or partially dependent on Zn2+ for enzymatic activity. Herein we present evidence for a model to explain how a single mRNA gives rise to two forms of SMase with different cellular trafficking and apparent differences in Zn2+ dependence. First, we show that both S-SMase and L-SMase, which contain several highly conserved zinc-binding motifs, are directly activated by zinc. In addition, SMase assayed from a lysosome-rich fraction of Chinese hamster ovary cells was found to be partially zinc-dependent, suggesting that intact lysosomes from these cells contain subsaturating levels of Zn2+. Analysis of Asn-linked oligosaccharides and of N-terminal amino acid sequence indicated that S-SMase arises by trafficking through the Golgi secretory pathway, not by cellular release of L-SMase during trafficking to lysosomes or after delivery to lysosomes. Most importantly, when Zn2+-dependent S-SMase was incubated with SMase-negative cells, the enzyme was internalized, trafficked to lysosomes, and became zinc-independent. We conclude that L-SMase is exposed to cellular Zn2+ during trafficking to lysosomes, in lysosomes, and/or during cell homogenization. In contrast, the pathway targeting S-SMase to secretion appears to be relatively sequestered from cellular pools of Zn2+; thus S-SMase requires exogeneous Zn2+ for full activity. This model provides important information for understanding the enzymology and regulation of L- and S-SMase and for exploring possible roles of ASM gene products in cell signaling and atherogenesis.     

Using a cost-construction model to assess the cost of educating undergraduate medical students at the University of Texas--Houston Medical School

Spontaneous resolution of deformities after excision of facial skin lesions has been known and used for a long time by plastic surgeons. The resorption mechanism of deformity is based on natural skin expansion, and seems to be directly related to the action of the muscles of facial expression and their skin relations. Natural expansion has been shown to be effective in children. Between 1990 and 1994 excision of skin lesions, including congenital nevi, leading to postoperative deformity of the cheek, labial commissure, nose, eyelid and forehead, was performed on 35 patients, aged from 3 month to 12 years. The average follow-up is 24 months. For 26 patients (74%), natural resorption was observed 4 or 6 weeks later with good aesthetic results. For 6 patients (17%), the deformity persisted 3 or 6 months later, but did not require any further surgery. For 3 patients (9%), a second operation was necessary. Using the skins natural capacity for expansion in the treatment of facial skin defects in children is a method of reconstruction which has already been used for excision in enforced position. The platysma and muscles of facial expression by their action on skin mobilisation, allow natural expansion. A better knowledge of cutaneous biomechanical properties enables plastic surgeons to find an alternative to other classical methods.     

Evaluating generalized predictive control for a brushless DC drive

This paper proposes a new control approach for a brushless DC motor drive using the generalized predictive control (GPC) algorithm. Based on the same least-squares framework as in the controller design, we further develop the method to design an observer. The GPC algorithm uses the receding horizon approach whereby the control signals are determined by minimizing a quadratic cost function. Our study shows that the rise time and settling time of the servo system have an approximate linear relationship with the prediction horizon. Thus, it is used to tune the controller of the drive. Moreover, the control weighting factor can be used to smooth the controller output. The proposed algorithm has been implemented using a digital signal processor (DSP) and tested in real time with a prototype system. The performance and robustness of the algorithms have been evaluated both in simulation and experiment. The results show that the drive performs reasonably well despite load changes and step changes in the position setpoint. Furthermore, it is fairly robust against motor parameters change     

Off-Site Exposure to Respirable Aerosols Produced during the Disk-Incorporation of Class B Biosolids

Field experiments were conducted at a Class B biosolids land application site in central Arizona to measure, model, and source-track the off-site transport of aerosols emitted when biosolids were disk-incorporated into soils. Real-time PM10 monitoring provided time-resolved aerosol information sufficient for verifying both off-site concentration and off-site exposure time model results. Under the conditions considered and at a distance of 165?m from the aerosol source, biosolids disk-incorporation resulted in an intermittent exposure to biosolids-derived aerosol concentration between 15 and 40?μg/m3 and an inhalable biosolids dose between 2 and 8?μg. Transport modeling predicted that these doses will decrease with increasing wind speed. In addition, three DNA sequence-based biosolids source tracking methods were applied to aerosol samples and confirmed the presence of biosolids in aerosols at 5, 65, and 165?m from the aerosol source. Field measurements and modeling indicate that the nature of biosolids-derived aerosol exposure is a series of intermittent high concentration puffs, rather than a continuous low concentration.     

Efficient Spreadsheet Algorithm for First-Order Reliability Method

A new spreadsheet-cell-object-oriented algorithm for the first-order reliability method is proposed and illustrated for cases with correlated nonnormals and explicit and implicit performance functions. The new approach differs from the writers earlier algorithm by obviating the need for computations of equivalent normal means and equivalent normal standard deviations. It obtains the solution faster and is more efficient, robust, and succinct. Other advantages include ease of initialization prior to constrained optimization, ease of randomization of initial values for checking robustness, and fewer required optimization constraints during spreadsheet-automated search for the design point. Two cases with implicit performance functions, namely an asymmetrically loaded beam on Winkler medium and a strut with complex supports are analyzed using the new approach and discussed. Comparisons are also made between the proposed approach and that based on Rosenblatt transformation.     

An efficient algorithm for the minimum cost min-max load terminal assignment problem

One of the main issues to be addressed in topological design of centralized networks is that of assigning terminals to concentrators in such a way that each terminal is assigned to one (and only one) concentrator and the total number of terminals assigned to any concentrator (which is referred to as load in this paper) does not overload that concentrator, i.e. is within the concentrator's capacity. Under these constraints, an assignment with the lowest possible cost is sought. An assignment of terminals to concentrators which minimizes the maximum load among the concentrators (which qualitatively represents congestion at some hot spots in a network service area) is referred to as a min-max load assignment. In this paper, we consider the problem of finding a min-max load assignment with the-lowest cost. We call this problem the Minimum Cost Min-Max Load Terminal Assignment Problem (MCMLTAP). We present an algorithm for MCMLTAP and prove that the problem is optimally solvable in polynomial time using our proposed algorithm.     

Effect of duodenum-preserving resection of the head of the pancreas on endocrine and exocrine pancreatic function in patients with chronic pancreatitis

Two mobilizable cloning vectors, designated pABW1 and pAWB2, were constructed basing on the E. coli vector pBGS18 and oriT originating from RK2. In pABW2 the kanamycin resistance gene was replaced by a novel tetracycline resistance cassette derived from Tn1721. Both vectors, specific for E. coli, allow to perform the cloning steps in E. coli and then to efficiently transfer the constructs by conjugation to the host of choice. A vector which cannot propagate in the given host can be applied for identification of the host specific plasmid replicator regions. With the use of pABW2 we defined the minimal replicator region of pTAV202-a mini-derivative of the large pTAV1 plasmid of P. versutus. We also proved that RepC' encoded on this fragment is the principal initiator replication protein and that oriV is located along its coding sequence.