Current and future therapeutic strategies for high-grade gliomas leveraging the interplay between epigenetic regulators and kinase signaling networks.

Targeted therapies, including small molecule inhibitors directed against aberrant kinase signaling and chromatin regulators, are emerging treatment options for high-grade gliomas (HGG). However, when translating these inhibitors into the clinic, their efficacy is generally limited to partial and transient responses. Recent studies in models of high-grade gliomas reveal a convergence of epigenetic regulators and kinase signaling networks that often cooperate to promote malignant properties and drug resistance. This review examines the interplay between five well-characterized groups of chromatin regulators, including the histone deacetylase (HDAC) family, bromodomain and extraterminal (BET)-containing proteins, protein arginine methyltransferase (PRMT) family, Enhancer of zeste homolog 2 (EZH2), and lysine-specific demethylase 1 (LSD1), and various signaling pathways essential for cancer cell growth and progression. These specific epigenetic regulators were chosen for review due to their targetability via pharmacological intervention and clinical relevance. Several studies have demonstrated improved efficacy from the dual inhibition of the epigenetic regulators and signaling kinases. Overall, the interactions between epigenetic regulators and kinase signaling pathways are likely influenced by several factors, including individual glioma subtypes, preexisting mutations, and overlapping/interdependent functions of the chromatin regulators. The insights gained by understanding how the genome and epigenome cooperate in high-grade gliomas will guide the design of future therapeutic strategies that utilize dual inhibition with improved efficacy and overall survival.

Pharmacogenomics elective focused on advanced lab techniques, game-based learning, and business plan development.

BACKGROUND AND PURPOSE: Many medications contain labeling information related to pharmacogenomics. Effective education in this area is critical to ensure that future healthcare professionals are equipped with the skills needed to optimize patient therapy based on genetic testing results. This study focused on a novel elective course designed to educate students in pharmacogenomics. EDUCATIONAL ACTIVITY AND SETTING: We developed a one credit hour pharmacogenomics elective course divided into three main content areas. The first section incorporated traditional lecture to review and cover new content not otherwise covered in the curriculum. The second section applied foundational content from the first session through an educational review game and simulated business plan. The third section of the course provided students an overview of laboratory techniques and sample collection procedures. To evaluate the effectiveness of these activities, students provided feedback through course evaluations and completed pre- and posttests on basic pharmacogenomics content. FINDINGS: Overall, the course improved knowledge among students, and students provided positive feedback. Students averaged 9% higher on the posttest compared to the pretest (P = .03). Course evaluations trended positive with ratings close to "strongly agree." The most frequent comments stated an appreciation for the interactive components of the course and recommended increasing the elective to two credit hours. SUMMARY: Through incorporation of novel lab techniques, game-based learning, and an innovative business plan process, the course increased student knowledge and received positive feedback. These new techniques could serve as a model for other pharmacogenomics training programs.

Evaluating the Antiparasitic Activity of Novel BPZ Derivatives Against Toxoplasma gondii.

Prevalence studies revealed that one-third of the human population is chronically infected with Toxoplasma gondii. Presently, such infections are without medical treatment that effectively eradicates the parasite once it is in its latent form. Moreover, the therapeutics used to treat acute infections are poorly tolerated by patients and also cause the parasite to convert into long-lasting tissue cysts. Hence, there is a dire need for compounds with antiparasitic activity against all forms of T. gondii. This study examines the antiparasitic capacity of nine novel bisphenol Z (BPZ) derivatives to determine whether they possessed any activity that prevented T. gondii replication. To begin assessing the efficacy of the novel derivatives, parasites were treated with increasing concentrations of the compounds, then doubling assays and MitoTracker staining were performed. Three of the nine compounds demonstrated strong inhibitory activity, i.e., parasite replication significantly decreased with higher concentrations. Additionally, many of the treated parasites exhibited decreases in fluorescent signaling and disruption of mitochondrial morphology. These findings suggest that bisphenol Z compounds disrupt mitochondrial function to inhibit parasite replication and may provide a foundation for the development of new and effective treatment modalities against T. gondii.

Percutaneous Absorption of Lorazepam, Diphenhydramine Hydrochloride, and Haloperidol from ABH Gel.

The objective of this project was to study the percutaneous absorption of lorazepam, diphenhydramine hydrochloride, and haloperidol from a topical Pluronic lecithin organogel, also known as ABH gel, across the porcine ear skin and verify its suitability for topical application. ABH gel was prepared using lecithin in isopropyl palmitate solution (1:1) as an oil phase and 20% w/v Poloxamer 407 solution as an aqueous phase. The gel was characterized for pH, viscosity, drug content, and thermal behavior. A robust high-performance liquid chromatography method was developed and validated for simultaneous analysis of lorazepam, diphenhydramine hydrochloride, and haloperidol. The percutaneous absorption of lorazepam, diphenhydramine hydrochloride, and haloperidol from ABH gel was carried out using Franz cells across the Strat-M membrane and pig ear skin. The pH of ABH gel was found to be 5.66 ± 0.13. The retention time of diphenhydramine hydrochloride, haloperidol, and lorazepam was found to be 5.2 minutes, 7.8 minutes, and 18.9 minutes, respectively. The ABH gel was found to be stable for up to 30 days. Theoretical steady state plasma concentrations (CSS) of diphenhydramine hydrochloride, haloperidol, and lorazepam calculated from flux values were found to be 1.6 ng/mL, 0.13 ng/mL, and 2.30 ng/mL, respectively. The theoretical CSS of diphenhydramine hydrochloride, haloperidol, and lorazepam were much lower than required therapeutic concentrations for antiemetic activity to relieve chemotherapy-induced nausea and vomiting. From the percutaneous absorption data, it was evident that ABH gel failed to achieve required systemic levels of lorazepam, diphenhydramine hydrochloride, and haloperidol following topical application.

Design, synthesis, and biological evaluation of lipophilically modified bisphenol Z derivatives.

In the present study, a small library of bisphenol Z (BPZ) derivatives was synthesized and investigated for anti-proliferative effects in cultured breast and glioblastoma cell lines. Synthesized BPZ derivatives varied in molecular size, polarity, and lipophilicity. Of the 8 derivatives tested, compounds 4 and 6, both of which displayed the highest degree of lipophilicity, were most active at inducing cell death as determined by the XTT assay. Cell membranes were interrogated using trypan blue staining and were shown to remain intact during treatments with 4 and 6. Activation of caspase enzymes (3 and/or 7) was noted to occur following treatment with compound 4. Polar BPZ derivatives, those with a substituted amine or alcohol, were devoid of any inhibitory or proliferative effects. The remaining derivatives seem to lack sufficient lipophilicity to execute an overt toxic effect. Our results suggest that increasing the lipophilic character of BPZ enhances the cytotoxic effects.

Emerging oral VEGF inhibitors for the treatment of renal cell carcinoma.

INTRODUCTION: The incidence of renal cell carcinoma (RCC) has increased in recent years and, unfortunately, many patients initially present with metastatic disease. When surgery is not an option, treatment involves administration of targeted therapies. The vascular endothelial growth factor (VEGF) pathway has been identified as an important mediator for the development of RCC. Numerous agents target VEGF-mediated signaling, yet resistance and progressive disease still persists. Novel small molecule VEGF inhibitors with high affinity for the VEGF receptor (VEGFR) have been discovered and are currently under investigation for the management of RCC. AREAS COVERED: The VEGFR pathway, its aberrant signaling, and the agents under development that inhibit VEGFR signaling are discussed. The mechanism(s), pharmacokinetics, pharmacodynamics, efficacy, and toxicity of these investigational agents are also reviewed. EXPERT OPINION: Management of metastatic RCC involves combination immunotherapy or administration of oral VEGFR inhibitors and largely depends on risk stratification. Emerging and investigational oral VEGFR inhibitors, given as monotherapy or in combination with immunotherapy, could augment current treatment approaches and may mitigate toxicities associated with VEGFR inhibition.

Influence of temperature on the thirty-day chemical stability of extemporaneously prepared dexamethasone paste.

Dexamethasone, a high-potency synthetic glucocorticoid, is often used to treat various immunological and inflammatory conditions. Commercial preparations of dexamethasone facilitate administration to human patients. Veterinary use of dexamethasone may be complicated by the unavailability of commercial dosage forms. As such, compounded preparations containing dexamethasone, such as a topical paste, are used in veterinary medicine. The purpose of this study was to determine the 30-day stability of compounded dexamethasone 2 mg/mL paste when incubated in temperatures which may mimic storage conditions during any given season. Samples were incubated at room temperature, -20 degrees C, 4 degrees C, 40 degrees C, and 80 degrees C for 30 days. Samples were subsequently analyzed using a stability-indicating high-performance liquid chromatography method on a reverse phase column. Our data suggests that the chemical stability of dexamethasone, the active pharmaceutical ingredient, is well within the guidelines set forth in United States Pharmacopeia Chapter <795> (90% to 110% stated potency) for all tested temperatures, with the exception of 80 degrees C (approximately 176 degrees F).

Terahertz reflectivities of metal-coated mirrors.

Terahertz (THz) reflectivities of a variety of metal-coated mirrors were measured. Gold, silver, and aluminum coatings were tested and compared. It was found that all types of optical metal-coated mirrors perform equally well as THz reflectors.

Fatty acylation enhances cellular localization of dansylated phenylalanines.

Two series of fluorescent molecules were synthesized by acylation of dansyl ethylenediamine and phenylalanine dansyl ethylenediamine with one of either acetyl (C(2)), hexanyl (C(6)), cyclohexanecarbonyl (C(7)), myristyl (C(14)), or palmityl (C(16)) groups and examined for entry and localization in Chinese Hamster Ovary (CHO) cells in tissue culture. Gross total fluorescence retention and cellular microscopic fluorescence patterns were analyzed. In both series, molecules with myristyl or palmityl groups entered cells. Only in the phenylalanine series did hexyl and cyclohexanecarbonyl modification enable entry. Consistent with a mechanism of passive diffusion, entry of compounds into cells was neither energy dependent nor endocytosis linked. Acylated molecules were observed to localize in cytoplasm and not enter nuclei or associate with lipophilic plasma membranes.

Tunable negative group index in metamaterial structures with large form birefringence.

We experimentally verify the anomalous phase behavior in metamaterial structures with birefringent materials predicted by Mandatori, et. al. using form birefringent structures. Large birefringence as much as Deltan/n = 0.7 has been achieved by surface-treated form birefringent discs, making compact single layer Mandatori structures viable. With a reduced model of a single layer birefringent structure, the relationship between design parameters (thickness and orientation angle) and device operation and performance parameters (such as the center operation frequency, bandwidth, effective negative index, negative group index of refraction, and the transmission throughput) are derived and verified experimentally. Tunable group index of refraction from strong slow light of ng = 29.6 to fast light of ng = -1.1 are measured experimentally.

Methodologies for determining the dynamic ranges and signal-to-noise ratios of terahertz time-domain spectrometers.

We discuss procedures for calculating the signal-to-noise ratios and the dynamic ranges of terahertz time-domain spectrometers. We also offer recommendations for standardized calculations for time-domain and frequency-domain data.

Linearity calibration of amplitude and power measurements in terahertz systems and detectors.

We describe a device consisting of a set of silicon plates to be employed for calibrating the linearity of amplitude/power measurements of terahertz systems and detectors. The device is used to test a time-domain spectrometer, a pyroelectric sensor, and a Golay cell. The results demonstrate that the linearity of amplitude/power measurement cannot be assumed but must be experimentally verified.

Optimization of apodization functions in terahertz transient spectrometry.

A quadratic programming optimization procedure for designing asymmetric apodization windows tailored to the shape of time-domain sample waveforms recorded using a terahertz transient spectrometer is proposed. By artificially degrading the waveforms, the performance of the designed window in both the time and the frequency domains is compared with that of conventional rectangular, triangular (Mertz), and Hamming windows. Examples of window optimization assuming Gaussian functions as the building elements of the apodization window are provided. The formulation is sufficiently general to accommodate other basis functions.