Soft tissue sarcomas of adults: state of the translational science.

Sarcomas--like leukemias, which are also mesodermal malignancies--carry biological significance disproportionate to their clinical frequency. Identification of mutations and translocations associated with these tumors has illuminated aberrant signaling pathways that cause these diseases, determine their behavior, and are therapeutic targets. Activated receptor-associated tyrosine kinase c-kit, mutated in most gastrointestinal stromal tumors, has proven a clinically effective target for enzyme inhibition. A translocation involving a single gene family, consisting of EWS and related genes, has been identified in five different sarcomas, and its chimeric protein products could prove similarly amenable to inhibitors. Resolution of the histopathological complexity is being aided by data from molecular and chromosomal characterization. Improvements in imaging, definition of prognostic factors, and surgical and radiotherapeutic treatment have resulted in improved local control. Continued progress will depend on further adapting the rapidly evolving technologies of genomics and proteomics. It will also depend upon accurate histopathological diagnosis based on validated reagents and consistent methodologies applied to adequate tissue samples derived from patients with complete clinical data. Finally, multicenter, coordinated trials, such as those that occurred with assessment of imatinib mesylate in metastatic gastrointestinal stromal tumors, will assure the most rapid reductions in morbidity and mortality.     

TREATMENT OF PALMOPLANTER HYPERHIDROSIS BY IONTOPHORESIS

Twenty-seven patients with idiopathic palmoplanter hyperhidrosis were treated with Iontotherapy over a one year period. In twenty-four cases there was a good response but maintenance therapy was required every 3-4 weeks.KEY WORDS: Iontophoresis, Palmoplanter hyperhidrosis     

A Hybrid Markov Chain–von Mises Density Model for the Drug-Dosing Interval and Drug Holiday Distributions

Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9713-5) contains supplementary material, which is available to authorized users.KEY WORDS: adherence, circular distribution, compliance, dosing patterns, runs     

Impact Strength of Preplaced Aggregate Concrete Comprising Glass Fibre Mesh and Steel Fibres: Experiments and Modeling

Concrete is the most widely used and most affordable construction material. The structural damage that concrete cracks and fractures may cause can be severe. These concerns have lately been alleviated by new developments in fibre concretes. Recent advancements in fibrous concrete and its evolution have been rapidly drawing researchers’ attentions worldwide, which motivates the development of a new type of composite with superior impact resistance. Preplaced aggregate fibrous concrete (PAFC) is a revolutionary composite comprising a higher dosage of fibres. It has outstanding impact resistance that surpasses those of traditional fibrous concrete. The impact behaviour of PAFC in addition to glass fibre mesh (GFM) has not been investigated thoroughly. To fill this research gap, this study investigates the impact performance of three-layered PAFC comprising steel fibres and GFM insertion. Eight different mixtures were prepared and can be divided into two groups. In the first group, specimens were made with 4% fibres and two single, double and triple layers of GFM insertion between the three-layered concrete. The second group of specimens was reinforced with 5, 2 and 5% steel fibres at the top, middle and bottom layers, respectively. However, the GFM insertion scheme for the second group was the same as the first. Rectangular specimens of size 500 × 100 × 100 mm were cast and tested against drop weight impact. The parameters studied were cracking impact numbers, failure impact number, ductility index and failure patterns. In addition, an analytical model was used to evaluate the impact failure energies. Results indicate that the combined action of steel fibre and GFM exhibited an excellent impact resistance. Increasing the number of GFM insertions between the specimen layer led to increased impact strength. The dose of the fibres utilized in the outer layer of the PAFC was increased, resulting in the material having a higher impact resistance. The cracking impact numbers improved from 28 to 40%, and failure impact numbers ranged from 58.8 to 92.2% when the GFM insertion numbers increased from one to three.     

Intravenous injection of oncolytic picornavirus SVV-001 prolongs animal survival in a panel of primary tumor–based orthotopic xenograft mouse models of pediatric glioma

Background

Seneca Valley virus (SVV-001) is a nonpathogenic oncolytic virus that can be systemically administered and can pass through the blood–brain barrier. We examined its therapeutic efficacy and the mechanism of tumor cell infection in pediatric malignant gliomas.

Methods

In vitro antitumor activities were examined in primary cultures, preformed neurospheres, and self-renewing glioma cells derived from 6 patient tumor orthotopic xenograft mouse models (1 anaplastic astrocytoma and 5 GBM). In vivo therapeutic efficacy was examined by systemic treatment of preformed xenografts in 3 permissive and 2 resistant models. The functional role of sialic acid in mediating SVV-001 infection was investigated using neuraminidase and lectins that cleave or competitively bind to linkage-specific sialic acids.

Results

SVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, preformed neurospheres, and self-renewing stemlike single glioma cells derived from 4 of the 6 glioma models in vitro. A single i.v. injection of SVV-001 (5 × 10¹² viral particles/kg) led to the infection of orthotopic xenografts without harming normal mouse brain cells, resulting in significantly prolonged survival in all 3 permissive and 1 resistant mouse models (P < .05). Treatment with neuraminidase and competitive binding using lectins specific for α2,3-linked and/or α2,6-linked sialic acid significantly suppressed SVV-001 infectivity (P < .01).

Conclusion

SVV-001 possesses strong antitumor activity against pediatric malignant gliomas and utilizes α2,3-linked and α2,6-linked sialic acids as mediators of tumor cell infection. Our findings support the consideration of SVV-001 for clinical trials in children with malignant glioma.     

Acute systemic immune activation following vaginal exposure to staphylococcal enterotoxin B--implications for menstrual shock

Menstrual toxic shock syndrome (mTSS) is an acute systemic inflammatory disease associated with the superantigenic exotoxin, toxic shock syndrome toxin (TSST)-1, produced by Staphylococcus aureus and the use of high absorbency tampons. Even though S. aureus is capable of elaborating several other superantigenic exotoxins, only TSST-1 has been implicated in the pathogenesis of mTSS possibly because most other superantigenic exotoxins are known enterotoxins. Nonetheless, we have shown recently that one of the enterotoxigenic staphylococcal superantigens, staphylococcal enterotoxin B (SEB), can cause robust systemic immune activation following exposure through non-enteric mucosa, including nasal or conjunctival routes. In a similar manner, we show here that vaginal administration of SEB in HLA class II transgenic mice can cause robust systemic immune activation characterized by profound elevation of proinflammatory cytokines in the serum, activation and expansion of SEB-reactive CD4(+) and CD8(+) T cells in peripheral lymphoid organs and SEB-induced deletion of immature thymocytes. Vaginal administration of SEB also caused leukocytic infiltration in major organs, such as liver and lung, reminiscent of human toxic shock syndrome. Systemic immune activation following vaginal superantigen delivery was independent of the stage of the estrus cycle in the mouse. Using HLA class II transgenic mice, we have shown that exposure to SEB through the vaginal canal can cause robust systemic immune activation. SEB could thus play a role in the pathogenesis of mTSS.     

Drop Weight Impact Test on Prepacked Aggregate Fibrous Concrete—An Experimental Study

In recent years, prepacked aggregate fibrous concrete (PAFC) is a new composite that has earned immense popularity and attracted researchers globally. The preparation procedure consists of two steps: the coarse aggregate is initially piled into a mold to create a natural skeleton and then filled with flowable grout. In this instance, the skeleton was completely filled with grout and bonded into an integrated body due to cement hydration, yielding a solid concrete material. In this research, experimental tests were performed to introduce five simple alterations to the ACI 544 drop weight impact test setup, intending to decrease result dispersion. The first alteration was replacing the steel ball with a steel bar to apply a line impact instead of a single point impact. The second and third introduced line and cross notched specimens at the specimen’s top surface and the load applied through a steel plate of cross knife-like or line load types. These modifications distributed impact load over a broader area and decrease dispersion of results. The fourth and fifth were bedding with sand and coarse aggregate as an alternate to the solid base plate. One-hundred-and-eight cylindrical specimens were prepared and tested in 12 groups to evaluate the suggested alteration methods. Steel and polypropylene fibers were utilized with a dosage of 2.4% to produce PAFC. The findings indicated that the line notched specimens and sand bedding significantly decreased the coefficient of variation (COV) of the test results suggesting some alterations. Using a cross-line notched specimen and line of impact with coarse bedding also effectively reduced COV for all mixtures.