The natural history of EGFR and EGFRvIII in glioblastoma patients

Background  

The epidermal growth factor receptor (EGFR) is over expressed in approximately 50–60% of glioblastoma (GBM) tumors, and the most common EGFR mutant, EGFRvIII, is expressed in 24–67% of cases. This study was designed to address whether over expressed EGFR or EGFRvIII is an actual independent prognostic indicator of overall survival in a uniform body of patients in whom gross total surgical resection (GTR; ≥ 95% resection) was not attempted or achieved.     

Analysis of the dynamic characteristics of pressure transducers for studying respiratory mechanics at high frequencies

Differential pressure transducers are commonly used to study respiratory mechanics at physiological frequencies as well as during external forcing at high frequencies. In the latter condition, measuring errors could occur if the input impedance of the pressure transducers is not sufficiently large with respect to that of the respiratory system. In this work we analysed the input impedance Z and the transfer function H of two common pressure transducers (Validyne MP-45 and Celesco LCVR) equipped with membranes of different sensitivities and with connecting tubes of different lengths. Z was measured by the tube method and H was measured by comparison with a flat-response pressure transducer. In agreement with the predictions based on a simple lumped-parameters model, we found that Z reached very low values, especially at the frequencies where H had a resonance peak. For instance, for the widespread Validyne MP-45 transducer (200 Pa) with connecting tubes of 16 cm length and 3·8 mm internal diameter a minimum of Z of 8300 Pa s litre⁻¹ at 96 Hz was measured; at that frequency the amplitude of H attained a value of 3·1. Using the above transducer model we simulated the measurement of a rat input impedance up to 128 Hz using Validyne and Celesco transducers. With the Validyne MP-45 (200 Pa), equipped with the same connecting tubes as above, the computed error reached up to 50 per cent for the real part and 140 per cent for the imaginary part.     

Parametric and Nonparametric Nonlinear System Identification of Lung Tissue Strip Mechanics

Lung parenchyma is a soft biological material composed of many interacting elements such as the interstitial cells, extracellular collagen–elastin fiber network, and proteoglycan ground substance. The mechanical behavior of this delicate structure is complex showing several mild but distinct types of nonlinearities and a fractal-like long memory stress relaxation characterized by a power-law function. To characterize tissue nonlinearity in the presence of such long memory, we investigated the robustness and predictive ability of several nonlinear system identification techniques on stress–strain data obtained from lung tissue strips with various input wave forms. We found that in general, for a mildly nonlinear system with long memory, a nonparametric nonlinear system identification in the frequency domain is preferred over time-domain techniques. More importantly, if a suitable parametric nonlinear model is available that captures the long memory of the system with only a few parameters, high predictive ability with substantially increased robustness can be achieved. The results provide evidence that the first-order kernel of the stress–strain relationship is consistent with a fractal-type long memory stress relaxation and the nonlinearity can be described as a Wiener-type nonlinear structure for displacements mimicking tidal breathing. © 1999 Biomedical Engineering Society. PAC99: 8719Rr, 8710+e     

Nuclear localization of Nm23-H1 in head and neck squamous cell carcinoma is associated with radiation resistance

BACKGROUND:

Although radiation resistance is a primary issue in radiation therapy, attempts to find predictors of radiation resistance have met with little success. The authors therefore aimed to determine predictors for radiation resistance to improve the prognosis of head and neck squamous cell carcinoma (HNSCC).

METHODS:

HNSCC cell lines, SCC15, SCC25, and QLL1, irradiated with an acute dose of 4 grays (Gy) (RR‐4), a cumulative dose of 60 Gy (RR‐60), and a booster dose of 4 Gy over 60 Gy (RR‐60 + 4), were used with nonirradiated cell lines. Those were used in cDNA microarray, proteomics, Western blotting, and immunofluorescence, respectively. One hundred five HNSCC tissue samples with radiation resistance were analyzed by immunohistochemistry.

RESULTS:

Western blot analysis of RR‐60 cell lines was identical to the data of Nm23‐H1 overexpression by cDNA array and proteomic screening. Immunofluorescence demonstrated significant nuclear translocation of Nm23‐H1 in RR‐4 and RR‐60 cell lines, and less but still intense nuclear shuttling in RR‐60 + 4. Similarly, Nm23‐H1 nuclear localization was observed in 20% (21 of 105) of tissue samples. Univariate analysis demonstrated that Nm23‐H1 nuclear localization was strongly associated with overall and recurrence‐free survival. Multivariate stepwise Cox regression analysis showed that Nm23‐H1 nuclear localization (odds ratio [OR], 7.48) and N stage (OR, 2.13) were associated with overall survival, and Nm23‐H1 nuclear localization (OR, 3.02), T stage (OR, 1.43), and insufficient tumor margin (OR, 3.27) were associated with recurrence‐free survival.

CONCLUSIONS:

Overexpression of Nm23‐H1, specifically its nuclear translocation, may be a powerful predictor of radiation resistance in HNSCC. Cancer 2011. © 2010 American Cancer Society.     

Bcl-2 promotes malignant progression in a PDGF-B-dependent murine model of oligodendroglioma

A significant subset of gliomas arises after activation of the proproliferative platelet-derived growth factor (PDGF) pathway. The progression of low-grade gliomas to more malignant tumors may be due to oncogenic cellular programs combining with those suppressing apoptosis. Antiapoptotic genes are overexpressed in a variety of cancers, and the antiapoptotic gene, BCL2, is associated with treatment resistance and tumor recurrence in gliomas. However, the impact of antiapoptotic gene expression to tumor formation and progression is unclear. We overexpressed Bcl-2 in a PDGFB-dependent mouse model of oligodendroglioma, a common glioma subtype, to assess its effect in vivo. We hypothesized that the antiapoptotic effect would complement the proproliferative effect of PDGFB to promote tumor formation and progression to anaplastic oligodendroglioma (AO). Here, we show that coexpression of PDGFB and Bcl-2 results in a higher overall tumor formation rate compared to PDGFB alone. Coexpression of PDGFB and Bcl-2 promotes progression to AO with prominent foci of necrosis, a feature of high-grade gliomas. Median tumor latency was shorter in mice injected with PDGFB and Bcl-2 compared to those injected with PDGFB alone. Although independent expression of Bcl-2 was insufficient to induce tumors, suppression of apoptosis (detected by cleaved caspase-3 expression) was more pronounced in AOs induced by PDGFB and Bcl-2 compared to those induced by PDGFB alone. Tumor cell proliferation (detected by phosphohistone H3 activity) was also more robust in high-grade tumors induced by PDGFB and Bcl-2. Our results indicate that suppressed apoptosis enhances oligodendroglioma formation and engenders a more malignant phenotype.     

Structure-function relations in an elastase-induced mouse model of emphysema

Emphysema is a progressive disease characterized by the destruction of peripheral airspaces and subsequent decline in lung function. However, the relation between structure and function during disease progression is not well understood. The objective of this study was to assess the time course of the structural, mechanical, and remodeling properties of the lung in mice after elastolytic injury. At 2, 7, and 21 days after treatment with porcine pancreatic elastase, respiratory impedance, the constituents of lung extracellular matrix, and histological sections of the lung were evaluated. In the control group, no changes were observed in the structural or functional properties, whereas, in the treatment group, the respiratory compliance and its variability significantly increased by Day 21 (P < 0.001), and the difference in parameters decreased with increasing positive end-expiratory pressure. The heterogeneity of airspace structure gradually increased over time. Conversely, the relative amounts of elastin and type I collagen exhibited a peak (P < 0.01) at Day 2, but returned to baseline levels by Day 21. Structure-function relations manifested themselves in strong correlations between compliance parameters and both mean size and heterogeneity of airspace structure (r(2) > 0.9). Similar relations were also obtained in a network model of the parenchyma in which destruction was based on the notion that mechanical forces contribute to alveolar wall rupture. We conclude that, in a mouse model of emphysema, progressive decline in lung function is sensitive to the development of airspace heterogeneity governed by local, mechanical, force-induced failure of remodeled collagen.     

The utility of e-Learning to support training for a multicentre bladder online adaptive radiotherapy trial (TROG 10.01-BOLART)

Background and purpose

An e-Learning programme appeared useful for providing training and information regarding a multi-centre image guided radiotherapy trial. The aim of this study is to demonstrate the utility of this e-Learning programme.

Materials and methods

Modules were created on relevant pelvic anatomy, Cone Beam CT soft tissue recognition and trial details. Radiation therapist participants’ knowledge and confidence were evaluated before, at the end of, and after at least 6 weeks of e-Learning (long term).

Results

One hundred and eighty-five participants were recruited from 12 centres, with 118 in the first, and 67 in the second cohort. One hundred and forty-six participants had two tests (pre and post e-Learning) and 39 of these had three tests (pre, post, and long term). There was an increase confidence after completion of modules (p < 0.001). The first cohort pre scores increased from 67 ± 11 to 79 ± 8 (p < 0.001) post. The long term same question score was 73 ± 14 (p = 0.025, comparing to pre-test), and different questions’ score was 77 ± 13 (p = 0.014). In the second cohort, pre-test scores were 64 ± 10, post-test same question score 78 ± 9 (p < 0.001) and different questions’ score 81 ± 11 (p < 0.001).

Conclusions

e-Learning for a multi-centre clinical trial was feasible and improved confidence and knowledge.