Nanoparticle Strategies to Improve the Delivery of Anticancer Drugs across the Blood-Brain Barrier to Treat Brain Tumors.

Primary brain and central nervous system (CNS) tumors are a diverse group of neoplasms that occur within the brain and spinal cord. Although significant advances in our understanding of the intricate biological underpinnings of CNS neoplasm tumorigenesis and progression have been made, the translation of these discoveries into effective therapies has been stymied by the unique challenges presented by these tumors' exquisitely sensitive location and the body's own defense mechanisms (e.g., the brain-CSF barrier and blood-brain barrier), which normally protect the CNS from toxic insult. These barriers effectively prevent the delivery of therapeutics to the site of disease. To overcome these obstacles, new methods for therapeutic delivery are being developed, with one such approach being the utilization of nanoparticles. Here, we will cover the current state of the field with a particular focus on the challenges posed by the BBB, the different nanoparticle classes which are under development for targeted CNS tumor therapeutics delivery, and strategies which have been developed to bypass the BBB and enable effective therapeutics delivery to the site of disease.

Overcoming translational barriers in H3K27-altered diffuse midline glioma: Increasing the drug-tumor residence time.

Background: H3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach. Methods: We used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats. Results: Aurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs. Conclusions: These studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG.

STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma.

BACKGROUND: H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. METHODS: We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts. RESULTS: Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPR/Cas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG. CONCLUSIONS: STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials.

Perceptions of Barriers and Facilitators to Becoming a Medical Professional Among Underrepresented Undergraduate and Postbaccalaureate Learners.

OBJECTIVE: To assess underrepresented undergraduate and postbaccalaureate learners' perceptions of (1) the medical field, (2) barriers that might prevent individuals from pursuing professional medical careers, and (3) resources that assist in overcoming these barriers. PARTICIPANTS AND METHODS: A qualitative study with focus groups was designed to achieve the objective. Participants were recruited from a community initiative to provide early exploration of the medical field to disadvantaged and minority individuals. Thirty-five individuals voluntarily participated in semistructured interviews. Audio from the interviews was analyzed using a qualitative descriptive approach and thematic analysis. This study was conducted from October 20, 2018, to April 6, 2019. RESULTS: Participants identified multiple characteristics related to the health care work environment and desirable attributes of health care personnel. The following barriers were identified: financial burden, lacking knowledge of the path to becoming a medical professional, inadequate social support, and lacking the metrics of a competitive candidate. Resources identified by participants to overcome barriers included professional networks and programmatic considerations. CONCLUSION: The study participants discussed negative and positive aspects of the health care environment, such as implicit and explicit biases and attributes that promote or sustain success. Participants expounded on financial, academic, social, and personal factors as barriers to success. In regard to resources that were believed to be helpful to mitigate barriers and promote success, participants commented on activities that simulate a professional medical environment, include networking with medical personnel, support well-being, and provide exposure to structured information on the process of obtaining professional medical training.

Penile Fracture Caused by Straddle Injury to a Nonerect Penis.

We present the case of a 36-year-old male who sustained a straddle injury with classic signs of a urethral injury. He had blood at the meatus, a high-riding prostate, a butterfly hematoma, and he was unable to void. A retrograde urethrogram confirmed a bulbar urethral injury. After attempts at primary realignment with a Foley failed, he underwent suprapubic tube placement. However, when his physical examination worsened, an MRI revealed a concomitant injury to his left corpus cavernosum. This is the first reported case in the literature in which blunt trauma to a nonerect penis caused a penile fracture.

Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals.

Multiple human diseases ensue from a hereditary or acquired deficiency of iron-transporting protein function that diminishes transmembrane iron flux in distinct sites and directions. Because other iron-transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. Here we report that a small-molecule natural product, hinokitiol, can harness such gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. These findings illuminate a general mechanistic framework for small molecule-mediated site- and direction-selective restoration of iron transport. They also suggest that small molecules that partially mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases.

Sulfate and thiosulfate inhibit oxalate transport via a dPrestin (Slc26a6)-dependent mechanism in an insect model of calcium oxalate nephrolithiasis.

Nephrolithiasis is one of the most common urinary tract disorders, with the majority of kidney stones composed of calcium oxalate (CaOx). Given its prevalence (US occurrence 10%), it is still poorly understood, lacking progress in identifying new therapies because of its complex etiology. Drosophila melanogaster (fruitfly) is a recently developed model of CaOx nephrolithiasis. Effects of sulfate and thiosulfate on crystal formation were investigated using the Drosophila model, as well as electrophysiological effects on both Drosophila (Slc26a5/6; dPrestin) and mouse (mSlc26a6) oxalate transporters utilizing the Xenopus laevis oocyte heterologous expression system. Results indicate that both transport thiosulfate with a much higher affinity than sulfate Additionally, both compounds were effective at decreasing CaOx crystallization when added to the diet. However, these results were not observed when compounds were applied to Malpighian tubules ex vivo. Neither compound affected CaOx crystallization in dPrestin knockdown animals, indicating a role for principal cell-specific dPrestin in luminal oxalate transport. Furthermore, thiosulfate has a higher affinity for dPrestin and mSlc26a6 compared with oxalate These data indicate that thiosulfate's ability to act as a competitive inhibitor of oxalate via dPrestin, can explain the decrease in CaOx crystallization seen in the presence of thiosulfate, but not sulfate. Overall, our findings predict that thiosulfate or oxalate-mimics may be effective as therapeutic competitive inhibitors of CaOx crystallization.