A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis.

Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.

The Pharmacologic Treatment of Stuttering and Its Neuropharmacologic Basis.

Stuttering is a DSM V psychiatric condition for which there are no FDA-approved medications for treatment. A growing body of evidence suggests that dopamine antagonist medications are effective in reducing the severity of stuttering symptoms. Stuttering shares many similarities to Tourette's Syndrome in that both begin in childhood, follow a similar male to female ratio of 4:1, respond to dopamine antagonists, and symptomatically worsen with dopamine agonists. In recent years, advances in the neurophysiology of stuttering have helped further guide pharmacological treatment. A newer medication with a novel mechanism of action, selective D1 antagonism, is currently being investigated in FDA trials for the treatment of stuttering. D1 antagonists possess different side-effect profiles than D2 antagonist medications and may provide a unique option for those who stutter. In addition, VMAT-2 inhibitors alter dopamine transmission in a unique mechanism of action that offers a promising treatment avenue in stuttering. This review seeks to highlight the different treatment options to help guide the practicing clinician in the treatment of stuttering.

A human FSHB promoter SNP associated with low FSH levels in men impairs LHX3 binding and basal FSHB transcription.

FSH production is important for human gametogenesis. In addition to inactivating mutations in the FSHB gene, which result in infertility in both sexes, a G/T single-nucleotide polymorphism (SNP) at -211 relative to the transcription start site of the 5' untranslated region of FSHB has been reported to be associated with reduced serum FSH levels in men. In this study, we sought to identify the potential mechanism by which the -211 SNP reduces FSH levels. Although the SNP resides in a putative hormone response element, we showed that, unlike the murine gene, human FSHB was not induced by androgens or progestins in gonadotropes. On the other hand, we found that the LHX3 homeodomain transcription factor bound to an 11-bp element in the human FSHB promoter that includes the -211 nucleotide. Furthermore, we also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared with the -211 G/T mutation and that LHX3 binding was more effectively competed with excess wild-type oligonucleotide than with the SNP. Finally, we showed that FSHB transcription was decreased in gonadotrope cells with the -211 G/T mutation compared with the wild-type FSHB promoter. Altogether, our results suggest that decreased serum FSH levels in men with the SNP likely result from reduced LHX3 binding and induction of FSHB transcription.