ABSTRACT
Background: COVID-19 pandemic has influenced health care delivery. We conducted an observational study to understand how obstetric medicine (ObM) physicians utilized home blood pressure monitoring (HBPM) to manage hypertension in pregnancy. Methods: Pregnant participants with risk factors or diagnosis of hypertensive disorders of pregnancy (HDP) were enrolled, May 2020-December 2021, and provided with validated home blood pressure (BP) monitor. ObM physicians completed questionnaires to elicit how home BP readings were interpreted to manage HDP. Results: We enrolled 103 people: 44 antepartum patients (33.5 ± 5 years, gestational age of 24 ± 5 weeks); 59 postpartum patients (35 ± 6 years, enrolled 6 ± 4 days post-partum). ObM physicians used range of home BP readings (70%) for management of HDP. Conclusions: HBPM to manage HDP is acceptable and can be used to manage hypertension during pregnancy. Further studies are needed to assess the generalizability of our findings and the safety of HBPM reliance alone in management of HDP.
ABSTRACT
Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients; validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition.
Subject(s)
Brain Neoplasms/drug therapy , Cell Cycle Proteins/antagonists & inhibitors , Medulloblastoma/drug therapy , Molecular Targeted Therapy , Precision Medicine/methods , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pteridines/therapeutic use , Adolescent , Animals , Antineoplastic Agents/therapeutic use , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Cycle Proteins/genetics , Child , Child, Preschool , Cohort Studies , Humans , Infant , Medulloblastoma/genetics , Medulloblastoma/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics , Risk Factors , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Polo-Like Kinase 1ABSTRACT
Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant tumor. Recent studies have demonstrated the presence of several MB molecular subgroups, each distinct in terms of prognosis and predicted therapeutic response. Groups 1 and 2 are characterized by relatively good clinical outcomes and activation of the Wnt and Shh pathways, respectively. In contrast, groups 3 and 4 ("non-Shh/Wnt MBs") are distinguished by metastatic disease, poor patient outcome, and lack a molecular pathway phenotype. Current gene expression platforms have not detected brain tumor-initiating cell (BTIC) self-renewal genes in groups 3 and 4 MBs as BTICs typically comprise a minority of tumor cells and may therefore go undetected on bulk tumor analyses. Since increasing BTIC frequency has been associated with increasing tumor aggressiveness and poor patient outcome, we investigated the subgroup-specific gene expression profile of candidate stem cell genes within 251 primary human MBs from four nonoverlapping MB transcriptional databases (Amsterdam, Memphis, Toronto, Boston) and 74 NanoString-subgrouped MBs (Vancouver). We assessed the functional relevance of two genes, FoxG1 and Bmi1, which were significantly enriched in non-Shh/Wnt MBs and showed these genes to mediate MB stem cell self-renewal and tumor initiation in mice. We also identified their transcriptional regulation through reciprocal promoter occupancy in CD15+ MB stem cells. Our work demonstrates the application of stem cell data gathered from genomic platforms to guide functional BTIC assays, which may then be used to develop novel BTIC self-renewal mechanisms amenable to therapeutic targeting.
