Engaging Underrepresented Youth: Remote Transition of the Health Career Collaborative Program.

INTRODUCTION: Pipeline programs can help increase diversity in health care by engaging underrepresented minority groups to pursue higher education and training in medical fields. Here we describe the implementation of Health Career Collaborative, a pipeline program designed to connect high school students with health care professionals, and the transition to remote delivery of the curriculum. METHODS: This study is a retrospective, descriptive observational study where the baseline characteristics of participating students were evaluated via preparticipation surveys. This study took place in a community with an area deprivation index of 6 at a high school in southern California in conjunction with an academic medical center and level I trauma center. Due to the coronavirus disease 2019 pandemic, the program transitioned to a virtual setting in the second half of the academic year. RESULTS: A total of 37 high school student participants enrolled in the 2019-2020 Health Career Collaborative program, with over 97% identifying as Hispanic, 89% female, and 92% between the ages of 15 and 17. Ninety-five percent of students indicated plans to graduate from high school and attend college, and 89% agreed with having a mentor to help plan for their future. While high school students had exposure to several health topics prior to the program, students reported a preference to learn about health topics from doctors compared to other sources. CONCLUSIONS: An online platform helped facilitate more interaction with health care professionals and could improve feasibility of implementing pipeline programs because physical space and transportation are not required.

RNA binding protein IGF2BP1 synergizes with ETV6-RUNX1 to drive oncogenic signaling in B-cell Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common pediatric hematological malignancy, with ETV6::RUNX1 being the most prevalent translocation whose exact pathogenesis remains unclear. IGF2BP1 (Insulin-like Growth Factor 2 Binding Protein 1) is an oncofetal RNA binding protein seen to be specifically overexpressed in ETV6::RUNX1 positive B-ALL. In this study, we have studied the mechanistic role of IGF2BP1 in leukemogenesis and its synergism with the ETV6::RUNX1 fusion protein. METHODS: Gene expression was analyzed from patient bone marrow RNA using Real Time RT-qPCR. Knockout cell lines were created using CRISPR-Cas9 based lentiviral vectors. RNA-Seq and RNA Immunoprecipitation sequencing (RIP-Seq) after IGF2BP1 pulldown were performed using the Illumina platform. Mouse experiments were done by retroviral overexpression of donor HSCs followed by lethal irradiation of recipients using a bone marrow transplant model. RESULTS: We observed specific overexpression of IGF2BP1 in ETV6::RUNX1 positive patients in an Indian cohort of pediatric ALL (n=167) with a positive correlation with prednisolone resistance. IGF2BP1 expression was essential for tumor cell survival in multiple ETV6::RUNX1 positive B-ALL cell lines. Integrated analysis of transcriptome sequencing after IGF2BP1 knockout and RIP-Seq after IGF2BP1 pulldown in Reh cell line revealed that IGF2BP1 targets encompass multiple pro-oncogenic signalling pathways including TNFα/NFκB and PI3K-Akt pathways. These pathways were also dysregulated in primary ETV6::RUNX1 positive B-ALL patient samples from our center as well as in public B-ALL patient datasets. IGF2BP1 showed binding and stabilization of the ETV6::RUNX1 fusion transcript itself. This positive feedback loop led to constitutive dysregulation of several oncogenic pathways. Enforced co-expression of ETV6::RUNX1 and IGF2BP1 in mouse bone marrow resulted in marrow hypercellularity which was characterized by multi-lineage progenitor expansion and strong Ki67 positivity. This pre-leukemic phenotype confirmed their synergism in-vivo. Clonal expansion of cells overexpressing both ETV6::RUNX1 and IGF2BP1 was clearly observed. These mice also developed splenomegaly indicating extramedullary hematopoiesis. CONCLUSION: Our data suggest a combined impact of the ETV6::RUNX1 fusion protein and RNA binding protein, IGF2BP1 in activating multiple oncogenic pathways in B-ALL which makes IGF2BP1 and these pathways as attractive therapeutic targets and biomarkers.

Acute airway obstruction requiring nasotracheal intubation following hypoglossal neuromonitoring: a case report.

BACKGROUND: Intraoperative neurophysiological monitoring (IONM) is utilized for both the localization of critical structures and for real time detection and prevention of intraoperative neurological injury. Use of IONM to monitor the hypoglossal nerve is performed during neurosurgical, otolaryngological, and vascular procedures to improve surgical outcomes. There is a paucity of literature describing potential complications of IONM of the hypoglossal nerve, especially with respect to airway compromise. Here we present our findings regarding a case of acute airway obstruction following hypoglossal nerve monitoring. CASE PRESENTATION: A 54-year-old male was admitted for left far-lateral craniotomy and microsurgical clipping of a left posterior inferior cerebellar artery (PICA) aneurysm. Following induction and intubation but prior to the procedure start, the patient was placed in the ¾ prone position with the left side up and his neck was flexed approximately 10 degrees. He then underwent placement of subdermal needle electrodes into the facial muscles, trapezius muscles, soft palate, and tongue for IONM. The procedure lasted 523 minutes and was completed without complication. However, approximately one hour after emergence from general anesthesia, the patient experienced progressive difficulty breathing secondary to severe lingual swelling. He required emergent placement of a nasotracheal tube guided by a fiberoptic bronchoscope. He remained intubated for 3 days and was treated with dexamethasone, after which the swelling resolved, and the patient was successfully extubated. CONCLUSIONS: Acute lingual edema is a potentially life-threatening phenomenon that can lead to rapid airway compromise. Generally, causes of acute lingual swelling include hemorrhage, edema, infarction, and infection. In the case described above, we suspect traumatic injury to the tongue's vascular supply caused a deep tissue hematoma leading to postoperative acute lingual swelling and airway obstruction. With the widespread use of IONM, it becomes essential for providers to be aware that perioperative airway compromise is a potentially life-threatening complication, especially with respect to monitoring of the hypoglossal nerve. Awake fiberoptic nasotracheal intubation can successfully be employed to establish an emergency airway in such situations.

The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis.

Despite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes. Here, we find that the RNA-binding protein IGF2BP3, which is overexpressed in MLL-translocated leukemia, strongly amplifies MLL-Af4-mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4-driven leukemia and greatly attenuates disease, with a minimal impact on baseline hematopoiesis. At the cellular level, MLL-Af4 leukemia-initiating cells require Igf2bp3 for their function in leukemogenesis. At the molecular level, IGF2BP3 regulates a complex posttranscriptional operon governing leukemia cell survival and proliferation. IGF2BP3-targeted mRNA transcripts include important MLL-Af4-induced genes, such as those in the Hoxa locus, and the Ras signaling pathway. Targeting of transcripts by IGF2BP3 regulates both steady-state mRNA levels and, unexpectedly, pre-mRNA splicing. Together, our findings show that IGF2BP3 represents an attractive therapeutic target in this disease, providing important insights into mechanisms of posttranscriptional regulation in leukemia.

Return to Work and Sport After Distal Femoral Osteotomy: A Systematic Review.

CONTEXT: Distal femoral osteotomy (DFO) is a joint preservation procedure that corrects genu valgum deformities and patellofemoral maltracking, thereby restoring kinematics and unloading contact pressures in the lateral tibiofemoral and patellofemoral compartments. OBJECTIVE: To evaluate the rates of return to work (RTW) and return to sport (RTS) after DFO for valgus malalignment and lateral compartment osteoarthritis through a systematic review of the literature. DATA SOURCES: A systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted on the PubMed, Cochrane, and Embase databases. STUDY SELECTION: The search terms femoral osteotomy AND (sports OR work) were used. Studies in which patients underwent concomitant total knee arthroplasty were excluded. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 4 (systematic review of level 4 studies). DATA EXTRACTION: Data included the number of patients, age, gender, laterality of operation, time to follow-up, rate of RTW and RTS, time to RTS, activity level on return, and activity level scores (Tegner, Marx, Lysholm, and the International Knee Documentation Committee). Risk of bias was assessed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. RESULTS: Seven articles with 194 patients were included. The average age ranged from 19 to 49 years with a mean postoperative follow-up range of 36 to 90 months. RTW data were available for 125 patients, of whom 42.1% to 91.3% returned by final follow-up. Data on RTS were available for 149 patients, of whom 70% to 100% returned at a range of 8.3 to 16.9 months postoperatively, and 41.6% to 100% returned to the same or greater level of sports activity. The Tegner and Marx activity level scores ranged from 3 to 4 and from 5 to 11, respectively, at final follow-up. CONCLUSION: Patients treated with DFO reported high rates of RTW and RTS, with most patients being able to return to recreational sport after surgery.