Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease.

Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of a clonally expanded hematopoietic stem cell caused by a leukemogenic mutation in individuals without evidence of hematologic malignancy, dysplasia, or cytopenia. CHIP is associated with a 0.5-1.0% risk per year of leukemia. Remarkably, it confers a two-fold increase in cardiovascular risk independent of traditional risk factors. Roughly 80% of patients with CHIP have mutations in epigenetic regulators DNMT3A, TET2, ASXL1, DNA damage repair genes PPM1D, TP53, the regulatory tyrosine kinase JAK2, or mRNA spliceosome components SF3B1, and SRSF2. CHIP is associated with a pro-inflammatory state that has been linked to coronary artery disease, myocardial infarction, and venous thromboembolic disease, as well as prognosis among those with aortic stenosis and heart failure. Heritable and acquired risk factors are associated with increased CHIP prevalence, including germline variation, age, unhealthy lifestyle behaviors (i.e. smoking, obesity), inflammatory conditions, premature menopause, HIV and exposure to cancer therapies. This review aims to summarize emerging research on CHIP, the mechanisms underlying its important role in propagating inflammation and accelerating cardiovascular disease, and new studies detailing the role of associated risk factors and co-morbidities that increase CHIP prevalence.

B7-H3 as a Prognostic Biomarker and Therapeutic Target in Pediatric central nervous system Tumors.

B7-H3 (CD276), a member of the B7 superfamily, is an important factor in downregulating immune responses against tumors. It is also aberrantly expressed in many human malignancies. Beyond immune regulatory roles, its overexpression has been linked to invasive metastatic potential and poor prognosis in patients with cancer. Antibody-dependent cell-mediated cytotoxicity strategies targeting B7-H3 are currently in development, and early-phase clinical trials have shown encouraging preliminary results. To understand the role of B7-H3 in pediatric central nervous system (CNS) malignancies, a comprehensive panel of primary CNS tumors of childhood was examined by immunohistochemistry for levels and extent of B7-H3 expression. In addition, B7-H3 m-RNA expression status and association with overall survival in various pediatric CNS tumor types was accessed by curating publicly available patient gene expression data sets derived from bioinformatics analysis and visualization platforms (GlioVis). We demonstrate that B7-H3 is broadly expressed in pediatric glial and nonglial CNS tumors, and its aberrant expression, as determined by immunohistochemical staining intensity, correlates with tumor grade. Moreover, high B7-H3 m-RNA expression is significantly associated with worse survival and could potentially improve prognostication in various brain tumor types of childhood. B7-H3 can be used as a therapeutic target, given its tumor selectivity and the availability of targeted therapeutic agents to this antigen.

The PreOp Program: Intensive Preclinical Surgical Exposure is Associated With Increased Medical Student Surgical Interest and Competency.

OBJECTIVE: As medical students' interest in surgical fields wanes, we investigated the impact of a preclinical surgical exposure program on students' attitudes toward pursuing surgical careers. DESIGN: This is a prospective longitudinal study of PreOp, a preclinical rotation-based surgical exposure program for first-year medical students, from 2013 to 2017. Surveys assessed PreOp rotation quality, students' surgical interest, and students' self-reported preparedness for the surgical clerkship. Surgery clerkship grades were obtained as a measure of surgical competency and compared to class-wide peers. Match data was collected and compared to class-wide peers as well as historical norms. SETTING: NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY; tertiary care center. PARTICIPANTS: Fifty-four PreOp students from 2013 to 2017. RESULTS: Fifty-four PreOp participants were recruited. After completing the PreOp program, 66.7% of PreOp students reported being very likely to apply into a surgical field compared to 29.4% when they started medical school. Ultimately, 71.4% of PreOp students versus 21.7% of non-PreOp class-wide peers matched into surgical fields (p < 0.001). From the preceding 5 match years before PreOp implementation, 21.4% of all students matched into surgical fields compared to 25.6% of all students after PreOp was started (p = 0.26). In terms of preparedness, 75% of PreOp students reported feeling more prepared for the third-year surgery clerkship than their non-PreOp peers after the second year of medical school. PreOp students were significantly more likely than non-PreOp class-wide peers to receive honors in the surgery clerkship when controlling for cumulative clerkship GPA (p = 0.012, adjusted odds ratio = 5.5 [95% confidence interval 1.5-22.1]). CONCLUSIONS: Hands-on preclinical surgical exposure was associated with student-reported increased surgical interest that was maintained longitudinally and reflected in significantly increased surgical matches relative to non-PreOp class-wide peers. This study uniquely demonstrates that participation in PreOp was also associated with increased self-reported surgical preparedness and significantly higher surgery clerkship grades relative to overall academic performance.

Real-Time, in Vivo Correlation of Molecular Structure with Drug Distribution in the Brain Striatum Following Convection Enhanced Delivery.

The blood-brain barrier (BBB) represents a major obstacle in delivering therapeutics to brain lesions. Convection-enhanced delivery (CED), a method that bypasses the BBB through direct, cannula-mediated drug delivery, is one solution to maintaining increased, effective drug concentration at these lesions. CED was recently proven safe in a phase I clinical trial against diffuse intrinsic pontine glioma (DIPG), a childhood cancer. Unfortunately, the exact relationship between drug size, charge, and pharmacokinetic behavior in the brain parenchyma are difficult to observe in vivo. PET imaging of CED-delivered agents allows us to determine these relationships. In this study, we label different modifications of the PDGFRA inhibitor dasatinib with fluorine-18 or via a nanofiber-zirconium-89 system so that the effect of drug structure on post-CED behavior can accurately be tracked in vivo, via PET. Relatively unchanged bioactivity is confirmed in patient- and animal-model-derived cell lines of DIPG. In naïve mice, significant individual variability in CED drug clearance is observed, highlighting a need to accurately understand drug behavior during clinical translation. Generally, the half-life for a drug to clear from a CED site is short for low molecular weight dasatinib analogs that bare different charge; 1-3 (1, 32.2 min (95% CI: 27.7-37.8), 2, 44.8 min (27.3-80.8), and 3, 71.7 min (48.6-127.6) minutes) and is much longer for a dasatinib-nanofiber conjugate, 5, (42.8-57.0 days). Positron emission tomography allows us to accurately measure the effect of drug size and charge in monitoring real-time drug behavior in the brain parenchyma of live specimens.

18F-Radiolabeled Panobinostat Allows for Positron Emission Tomography Guided Delivery of a Histone Deacetylase Inhibitor.

Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood-brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored. We report chemistry for radiolabeling the HDAC inhibitor, panobinostat, with fluoride-18 (compound-1). Like panobinostat, compound 1 retains nanomolar efficacy in diffuse intrinsic pontine glioma (DIPG IV and XIII) cells (IC50 = 122 and 108 nM, respectively), with lesser activity against U87 glioma. With a favorable therapeutic ratio, 1 is highly selective to glioma and demonstrates considerably less toxicity toward healthy astrocyte controls (IC50 = 5265 nM). Compound 1 is stable in aqueous solution at physiological pH (>7 days, fetal bovine serum), and its delivery can be imaged by positron emission tomography (PET). Compound 1 is synthesized in two steps, and employs rapid, late-stage aqueous isotopic exchange 18F-radiochemistry. PET is used to image the in vivo delivery of [18F]-1 to the murine central nervous system via convection enhanced delivery.

Advances in Molecular Imaging of Locally Delivered Targeted Therapeutics for Central Nervous System Tumors.

Thanks to the recent advances in the development of chemotherapeutics, the morbidity and mortality of many cancers has decreased significantly. However, compared to oncology in general, the field of neuro-oncology has lagged behind. While new molecularly targeted chemotherapeutics have emerged, the impermeability of the blood-brain barrier (BBB) renders systemic delivery of these clinical agents suboptimal. To circumvent the BBB, novel routes of administration are being applied in the clinic, ranging from intra-arterial infusion and direct infusion into the target tissue (convection enhanced delivery (CED)) to the use of focused ultrasound to temporarily disrupt the BBB. However, the current system depends on a "wait-and-see" approach, whereby drug delivery is deemed successful only when a specific clinical outcome is observed. The shortcomings of this approach are evident, as a failed delivery that needs immediate refinement cannot be observed and corrected. In response to this problem, new theranostic agents, compounds with both imaging and therapeutic potential, are being developed, paving the way for improved and monitored delivery to central nervous system (CNS) malignancies. In this review, we focus on the advances and the challenges to improve early cancer detection, selection of targeted therapy, and evaluation of therapeutic efficacy, brought forth by the development of these new agents.