Protein kinase CK2 is important for the function of glioblastoma brain tumor initiating cells.

Protein kinase CK2 is a ubiquitously expressed serine/threonine kinase composed of two catalytic subunits (α) and/or (α') and two regulatory (ß) subunits. The expression and kinase activity of CK2 is elevated in many different cancers, including glioblastoma (GBM). Brain tumor initiating cells (BTICs) are a subset of cells that are highly tumorigenic and promote the resistance of GBM to current therapies. We previously reported that CK2 activity promotes prosurvival signaling in GBM. In this study, the role of CK2 signaling in BTIC function was examined. We found that expression of CK2α was increased in CD133+ BTICs compared to CD133- cells within the same GBM xenolines. Treatment with CX-4945, an ATP-competitive inhibitor of CK2, led to reduced expression of Sox2 and Nestin, transcription factors important for the maintenance of stem cells. Similarly, inhibition of CK2 also reduced the frequency of CD133+ BTICs over the course of 7 days, indicating a role for CK2 in BTIC persistence and survival. Importantly, using an in vitro limiting dilution assay, we found that inhibition of CK2 kinase activity with CX-4945 or siRNA knockdown of the CK2 catalytic subunits reduced neurosphere formation in GBM xenolines of different molecular subtypes. Lastly, we found that inhibition of CK2 led to decreased EGFR levels in some xenolines, and combination treatment with CX-4945 and Gefitinib to inhibit CK2 and EGFR, respectively, provided optimal inhibition of viability of cells. Therefore, due to the integration of CK2 in multiple signaling pathways important for BTIC survival, CK2 is a promising target in GBM.

Diagnostic & interventional radiology residency program directors' perspectives on the USMLE step 1 exam shift to pass/fail scoring.

RATIONALE AND OBJECTIVES: As of January 2022, Step 1 of the United States Medical Licensing Examination (USMLE) has changed to pass/fail grading. The purpose of this study was to share survey results and communicate changes Diagnostic (DR) and integrated Interventional (IR) Radiology residency program directors (PDs) will make and aspire to make, given this change. MATERIALS AND METHODS: An online survey was sent to DR and IR PDs. Data was collected over four months. Custom R programming and MATLAB language scripts were used to evaluate the survey responses. Chi squared tests were used to determine statistical significance for multiple choice questions regarding PD views of Step 1 transitioning to pass-fail. Paired t-tests were used to differentiate pre- and post-values for questions in which PDs ranked criteria for resident selection. RESULTS: After USMLE Step 1 becomes pass/fail, most respondents will use Step 2 CK scores as a more important factor than previously, believe medical schools should share National Board of Medical Examiners (NBME) shelf exam scores, do not believe students will be better prepared clinically, and believe a student's medical school rank will be considered more. CONCLUSION: The added emphasis on Step 2 CK scores, NBME shelf exam scores, class rank, and a student's medical institution may negate the positive impacts of changing Step 1 to pass/fail. Alternatively, it may present an opportunity for programs to evaluate students more broadly.

Human gut microbial communities dictate efficacy of anti-PD-1 therapy in a humanized microbiome mouse model of glioma.

BACKGROUND: Although immunotherapy works well in glioblastoma (GBM) preclinical mouse models, the therapy has not demonstrated efficacy in humans. To address this anomaly, we developed a novel humanized microbiome (HuM) model to study the response to immunotherapy in a preclinical mouse model of GBM. METHODS: We used 5 healthy human donors for fecal transplantation of gnotobiotic mice. After the transplanted microbiomes stabilized, the mice were bred to generate 5 independent humanized mouse lines (HuM1-HuM5). RESULTS: Analysis of shotgun metagenomic sequencing data from fecal samples revealed a unique microbiome with significant differences in diversity and microbial composition among HuM1-HuM5 lines. All HuM mouse lines were susceptible to GBM transplantation, and exhibited similar median survival ranging from 19 to 26 days. Interestingly, we found that HuM lines responded differently to the immune checkpoint inhibitor anti-PD-1. Specifically, we demonstrate that HuM1, HuM4, and HuM5 mice are nonresponders to anti-PD-1, while HuM2 and HuM3 mice are responsive to anti-PD-1 and displayed significantly increased survival compared to isotype controls. Bray-Curtis cluster analysis of the 5 HuM gut microbial communities revealed that responders HuM2 and HuM3 were closely related, and detailed taxonomic comparison analysis revealed that Bacteroides cellulosilyticus was commonly found in HuM2 and HuM3 with high abundances. CONCLUSIONS: The results of our study establish the utility of humanized microbiome mice as avatars to delineate features of the host interaction with gut microbial communities needed for effective immunotherapy against GBM.