Core and borehole logging and stress measurements of a 817m long borehole drilled from 2.9km depth toward the Moab Khotsong 2014 M5.5 aftershock zone (ICDP DSeis project in South Africa)

ISSN:1029-7006ISSN:1607-796

Anti-Epidermal Growth Factor Receptor Gene Therapy for Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh.10 gene transfer vector. The data demonstrates that single, local delivery of an anti-EGFR antibody by an AAVrh.10 vector coding for cetuximab (AAVrh.10Cetmab) reduces GBM tumor growth and increases survival in xenograft mouse models of a human GBM EGFR-expressing cell line and patient-derived GBM. AAVrh10.CetMab-treated mice displayed a reduction in cachexia, a significant decrease in tumor volume and a prolonged survival following therapy. Adeno-associated-directed delivery of a gene encoding a therapeutic anti-EGFR monoclonal antibody may be an effective strategy to treat GBM

The RNA Binding Protein Mex-3B Is Required for IL-33 Induction in the Development of Allergic Airway Inflammation

Allergic airway inflammation is one of the primary features of allergic asthma. Interleukin-33 (IL-33) is recognized as a key pro-inflammatory cytokine that mediates allergic airway inflammation, and its expression is elevated in this condition, but little is known about the regulatory mechanisms underlying IL-33 induction. Here, we show that the RNA binding protein Mex-3B plays a critical role in the induction of IL-33 in the development of allergic airway inflammation. We generated Mex3b−/− mice and found that they develop significantly less airway inflammation than wild-type mice due to reduced induction of IL-33. Furthermore, we show that Mex-3B directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33. Moreover, we show that inhalation of an antisense oligonucleotide targeting Mex-3B suppresses allergic airway inflammation. Our data identify a signaling pathway that post-transcriptionally regulates IL-33 expression and suggest that Mex-3B could be a promising molecular target for the treatment of allergic asthma

Treatment of mice with U87MG:wtEGFR human glioblastoma xenografts treated 8 days after xenograft implementation.

<p><b>A.</b> Quantitative CNS MRI assessment of tumor volume. Male NOD/SCID mice received a CNS administration of 10⁵ U87MG:wtEGFR glioblastoma cells. Eight days after xenograft implant, mice received 10¹¹ gc AAVrh.10Cetmab or PBS (n = 3 each group). Arrow indicates time of vector administration. MRI imaging of the tumors was carried out at 3 and 4 wk after treatment administration. Shown is quantitative assessment of tumor volume of PBS-treated control (n = 3) <i>vs</i> AAVrh.10CetMab-treated mice (n = 3). <b>B.</b> Survival. NOD/SCID mice (n = 10, male) received CNS administration of 10⁵ U87MG:wtEGFR glioblastoma cells. Eight days after xenograft implant, mice received 10¹¹ gc AAVrh.10CetMab or PBS (n = 5 each group). Arrow indicates the time of treatment.</p

Cetuximab expression in the mouse brain after single administration of AAVrh.10CetMab.

<p><b>A.</b> diagram of the mouse brain illustrating the site of vector administration and expression analysis. R = right; L = left. The vector was administered in region R1. <b>B.</b> Cetuximab expression in the mouse CNS. NOD/SCID mice (n = 4, male) received a single administration of 10¹¹ genome copies (gc) of AAVrh.10CetMab. Cetuximab expression was quantified by ELISA in brain homogenates 3 wk after administration. Cetuximab levels were normalized per mg of tissue (mean ± standard error).</p

Survival of mice with patient-derived human glioblastoma xenograft treated with AAVrh.10CetMab.

<p>Male NOD/SCID mice received a CNS administration of 10⁵ primary glioblastoma cells isolated from a patient (isolate #0709). Three weeks after xenograft implant, mice received 10¹¹ gc AAVrh.10CetMab or PBS (n = 7 each group) and survival was assessed as a function of time. Arrow indicates the time of treatment.</p