Impact of electronic cigarettes on pediatric, adolescent and young adult leukemia patients.

Electronic cigarettes, which deliver an aerosolized, nicotine-containing product upon inhalation, are a public health issue that continue to gain popularity among adolescents and young adults in the United States. Use of electronic cigarettes is wide, and extends to pediatric patients with multiple comorbidities, including childhood cancer, leaving them vulnerable to further negative health outcomes. Acute leukemias are the most common type of cancer in pediatric populations, and treatment outcomes for these patients are improving; consequently, there is an increased emphasis on the effect of behavioral lifestyle factors on quality of life in survivorship. The rate of electronic cigarette use is higher among pediatric patients with a history of cancer than those without a history of cancer. Because electronic cigarettes are relatively new, much about their acute and long-term consequences remains unknown, as is their effect on therapy outcomes and long-term survivorship. This review article summarizes current knowledge about electronic cigarettes, including their composition and the trends in use among pediatric patients. Furthermore, this review provides a comprehensive description of the impact electronic cigarettes have on leukemia development, treatment and survivorship and highlights gaps in knowledge that will be necessary for developing recommendations, management strategies, and tailored treatments for pediatric leukemia patients and survivors who use these nicotine products.

Case series: Stenotrophomonas maltophilia in pediatric oncology patients.

BACKGROUND: Stenotrophomonas maltophilia is a bacterial pathogen that can be fatal in hospitalized and immunocompromised patients with mortality as high as 69%. Pediatric cancer patients often have risk factors that are common for this infection, making them particularly susceptible. Managing S. maltophilia is especially challenging as it has inherent resistance to several antibiotics. Furthermore, soft tissue infections in neutropenic patients may deviate from the typical clinical presentation of S. maltophilia. CASE DETAILS: This case series describes an in-depth examination of three cases involving immunocompromised pediatric patients with S. maltophilia infections. Each case exhibited a distinct clinical presentation, encompassing infection of the blood, lung, and skin, which highlights the variability in which S. maltophilia manifests in immunocompromised pediatric patients. These patients were treated at MD Anderson Cancer Center (MDACC) from 2020 to 2023, unfortunately resulting in fatality. CONCLUSIONS: The study aims to provide valuable insights and guidance for the management of patients with S. maltophilia infections. Emphasizing a heightened clinical suspicion will potentially lead to early initiation of directed therapy against S. maltophilia. Timely intervention may play a pivotal role in improving patient outcomes and reduce further burden to the healthcare system.

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.

Comparison of pharmacological inhibitors of lysine-specific demethylase 1 in glioblastoma stem cells reveals inhibitor-specific efficacy profiles.

Introduction: Improved therapies for glioblastoma (GBM) are desperately needed and require preclinical evaluation in models that capture tumor heterogeneity and intrinsic resistance seen in patients. Epigenetic alterations have been well documented in GBM and lysine-specific demethylase 1 (LSD1/KDM1A) is amongst the chromatin modifiers implicated in stem cell maintenance, growth and differentiation. Pharmacological inhibition of LSD1 is clinically relevant, with numerous compounds in various phases of preclinical and clinical development, but an evaluation and comparison of LSD1 inhibitors in patient-derived GBM models is lacking. Methods: To assess concordance between knockdown of LSD1 and inhibition of LSD1 using a prototype inhibitor in GBM, we performed RNA-seq to identify genes and biological processes associated with inhibition. Efficacy of various LSD1 inhibitors was assessed in nine patient-derived glioblastoma stem cell (GSC) lines and an orthotopic xenograft mouse model. Results: LSD1 inhibitors had cytotoxic and selective effects regardless of GSC radiosensitivity or molecular subtype. In vivo, LSD1 inhibition via GSK-LSD1 led to a delayed reduction in tumor burden; however, tumor regrowth occurred. Comparison of GBM lines by RNA-seq was used to identify genes that may predict resistance to LSD1 inhibitors. We identified five genes that correlate with resistance to LSD1 inhibition in treatment resistant GSCs, in GSK-LSD1 treated mice, and in GBM patients with low LSD1 expression. Conclusion: Collectively, the growth inhibitory effects of LSD1 inhibition across a panel of GSC models and identification of genes that may predict resistance has potential to guide future combination therapies.

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.

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.