Relative stability of human centrins and its relationship to calcium binding.

Centrins are calcium binding proteins that belong to the EF-hand superfamily with diverse biological functions. Herein we present the first systematic study that establishes the relative stability of related centrins via complementary biophysical techniques. Our results define the stepwise molecular behavior of human centrins by two-dimensional infrared (2D IR) correlation spectroscopy, the change in heat capacity and enthalpy of denaturation by differential scanning calorimetry, and the relative stability of the helical regions of centrins by circular dichroism. More importantly, 2D IR correlation spectroscopy provides unique information about the similarities and differences in dynamics between these related proteins. The thermally induced molecular behavior of human centrins can be used to predict biological target interactions that have a relative dependence on calcium affinity. This information is essential for understanding why certain isoforms may be used to rescue a phenotype and therefore also for explaining the different functions these proteins may have in vivo. Furthermore, this comparative approach can be applied to the study of recombinant therapeutic protein candidates for the treatment of disease states.

Radiotherapy for prolactin-secreting pituitary tumors.

Review the medical and surgical management of patients with prolactinomas and provide an in-depth appraisal of the role of radiotherapy in the treatment of prolactinomas. A thorough review of the pertinent literature was carried out and relevant topics were identified. Topics covered in this comprehensive review include: indications for the use of radiotherapy, choice between conventional radiotherapy and stereotactic radiosurgery, as well as the benefits and potential complications associated with each modality. Due to the excellent response rates with medical management, and rapid symptom relief afforded by resection or debulking surgery in patients who do not respond or tolerate medical therapy, radiotherapy is reserved for patients who do not respond to dopamine agonists and surgery. Both external beam radiotherapy and stereotactic radiosurgery retain important roles in the treatment of refractory or recurrent prolactinomas. Choosing the optimal approach is crucial in maximizing tumor control outcomes and minimizing the risks associated with treatment. The primary determinants of optimal radiation approach are proximity of the tumor to the optic apparatus and tumor size, with radiosurgery being our recommended treatment of choice unless the tumor is larger than 3-4 cm or within 3 mm of the optic nerves, chiasm or tracts. Optimal multidisciplinary management requires the identification of appropriate candidates for radiotherapy in order to take full advantage of treatment options available for each patient.

Therapeutic targeting of VEGF in the treatment of glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is the most common and aggressive type of primary malignant brain tumor in adults. Despite therapy with maximal safe surgical resection, radiation and temozolomide, prognosis remains poor at 14.6 months. Hence, there is an urgent need for developing novel therapeutic agents. In GBMs, the balance of angiogenic growth factors is skewed toward pro-angiogenesis and VEGF is identified as the key growth factor responsible for neovasculature. Targeting angiogenesis is hypothesized to arrest tumor growth and hence VEGF is an attractive therapeutic target. AREAS COVERED: The purpose of this review is to discuss VEGF pathway inhibitors, their efficacy as monotherapy or in combination with other drugs, the effects on the radiographic response/assessment for GBMs, mechanisms of resistance and associated biomarkers. A short summary of angiogenesis and of the biological characteristics of angiogenesis will also be provided to enhance the understanding of VEGF pathway inhibitors. EXPERT OPINION: Therapeutic targeting of VEGF has lead to improvements in progression-free survival in GBM patients without any change in the overall survival. VEGF-targeted therapy remains a promising therapeutic opportunity if improvements in biomarkers, imaging techniques and rational combination therapy are used to help advance the clinical efficacy of this approach.