Screen for Genetic Modifiers of stbm Reveals that Photoreceptor Fate and Rotation Can Be Genetically Uncoupled in the Drosophila Eye

BACKGROUND: Polarity of the Drosophila compound eye arises primarily as a consequence of two events that are tightly linked in time and space: fate specification of two photoreceptor cells, R3 and R4, and the subsequent directional movement of the unit eyes of the compound eye, or ommatidia. While it is thought that these fates dictate the direction of ommatidial rotation, the phenotype of mutants in the genes that set up this polarity led to the hypothesis that these two events could be uncoupled. METHODOLOGY/PRINCIPAL FINDINGS: To definitively demonstrate these events are genetically separable, we conducted a dominant modifier screen to determine if genes, when misexpressed, could selectively enhance subclasses of mutant ommatidia in which the direction of rotation does not follow the R3/R4 cell fates, yet not affect the number of ommatidia in which rotation follows the R3/R4 cell fates. We identified a subset of P element lines that exhibit this selective enhancement. We also identified lines that behave in the opposite manner: They enhance the number of ommatidia that rotate in the right direction, but do not alter the number of ommatidia that rotate incorrectly with respect to the R3/R4 fates. CONCLUSIONS/SIGNIFICANCE: These results indicate that fate and direction of rotation can be genetically separated, and that there are genes that act between R3/R4 fate specification and direction of ommatidial rotation. These data affirm what has been a long-standing assumption about the genetic control of ommatidial polarity

Minimum Technical Data Elements for Liquid Biopsy Data Submitted to Public Databases

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154656/1/cpt1747.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154656/2/cpt1747-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154656/3/cpt1747_am.pd

Clinical Research Networks: Strategies in Community-Academic Partnerships

Considerations for Collaborative Clinical Research Network Mission-Who and why Players-Don\u27t under/over estimate the landscape Process-Getting things done Governance/Structure-Transparent, diverse leadership Presentation: 37:2

Modeling the existing condition of a historic property to assist the Portal Heritage Society in its preservation efforts

Historical remains are a reminder of what our society used to be and it is our responsibility to preserve them so their significance will not be forgotten. Our service-learning Senior Project consisted in scanning the old and deteriorated Stewart House in Portal, Georgia, using a laser-based scanner to produce a virtual, three-dimensional, point-cloud model of it. The home, established in 1908, was the residence of the principal medical professional of Portal, James Stewart, until the 1950’s. The final model was presented to graduate student LynDee Winterton, who completed her Master’s Project around it to assist the Portal Heritage Society in its preservation efforts. This organization would now be equipped to restore the home and reopen it to the public as a museum. This project gave our Civil Engineering and Construction team an opportunity to assist our community in a service learning format and great understanding of the laser scanning techniques

BMX inhibition and HSD3B1 -driven resistance in prostate cancer in the Maverick trial

144 Background: Kinase inhibitors have been ineffective in prostate cancer and have no known role in androgen biosynthesis. Inheritance of the adrenal-permissive HSD3B1(1245C) allele encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from non-gonadal precursor steroids and confers poor clinical outcomes in castration-resistant prostate cancer (CRPC). About half of all men with prostate cancer inherit the adrenal-permissive HSD3B1 allele. Multiple clinical studies demonstrate that adrenal-permissive HSD3B1 allele inheritance confers more rapid progression on ADT and others also suggest worse CRPC outcomes even after treatment with abiraterone or enzalutamide. However, there is no known method to clinically block 3βHSD1. Furthermore, 3βHSD1 is not known to be phosphorylated. Methods: Mass spectrometry was used to identify protein phosphorylation sites and steroid metabolites, genetic and pharmacologic methods were used to identify the kinase required for 3βHSD1 phosphorylation and mouse xenograft studies were performed with BMX inhibition. The identified mechanism was used to design and launch a multicenter phase 2 study of the BMX inhibitor abivertinib in combination with abiraterone in men with metastatic CRPC. Results: 3βHSD1 enzyme activity requires tyrosine phosphorylation at Y344 by the BMX kinase. Androgen biosynthesis is blocked by a phosphorylation-defective 3βHSD1 344F, or BMX genetic knockdown, or BMX pharmacologic inhibition. BMX inhibition using zanubrutinib suppresses CRPC growth in the C4-2 and VCaP xenograft models by blocking intratumoral androgen synthesis and tumor androgen receptor (AR) signaling. Discovery of this mechanism provides the rationale for the phase 2 Maverick trial of abivertinib, a BMX inhibitor, combined with abiraterone, in men with CRPC with adrenal-permissive HSD3B1 allele inheritance (NCT05361915). Eligibility includes 1) presence of metastatic CRPC, 2) measurable and/or non-measurable disease, and 3) confirmed positivity of adrenal-permissive HSD3B1(1245C) allele inheritance via central testing (cap heterozygosity at 50%). Patients will be enrolled in 2 arms: 1) abiraterone naïve (n=45) and 2) abiraterone progressing (n=55). All patients will receive treatment with abivertinib 200mg twice daily with abiraterone 1000mg daily and prednisone 5mg by mouth twice daily. The primary outcome is 6-month radiographic progression-free survival. On-treatment biopsies will be used to inform mechanisms of response and resistance in patients. Conclusions: BMX is required for 3βHSD1 phosphorylation, androgen biosynthesis and CRPC progression with the adrenal-permissive HSD3B1(1245C) allele. The Maverick trial will test clinical proof-of-concept of BMX inhibition in men with adrenal-permissive HSD3B1(1245C) inheritance. Clinical trial information: NCT05361915

Tackling Diversity in Prostate Cancer Clinical Trials: A Report From the Diversity Working Group of the IRONMAN Registry

Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629 ), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care

Accelerating precision medicine in metastatic prostate cancer

Despite advances in prostate cancer screening and treatment, available therapy options, particularly in later stages of the disease, remain limited and the treatment-resistant setting represents a serious unmet medical need. Moreover, disease heterogeneity and disparities in patient access to medical advances result in significant variability in outcomes across patients. Disease classification based on genomic sequencing is a promising approach to identify patients whose tumors exhibit actionable targets and make more informed treatment decisions. Here we discuss how we can accelerate precision oncology to inform broader genomically-driven clinical decisions for men with advanced prostate cancer, drug development and ultimately contribute to new treatment paradigms

Practical Considerations and Challenges for Germline Genetic Testing in Patients With Prostate Cancer: Recommendations From the Germline Genetics Working Group of the PCCTC.

Germline genetic testing is now routinely recommended for patients with prostate cancer (PCa) because of expanded guidelines and options for targeted treatments. However, integrating genetic testing into oncology and urology clinical workflows remains a challenge because of the increased number of patients with PCa requiring testing and the limited access to genetics providers. This suggests a critical unmet need for genetic services outside of historical models. This review addresses current guidelines, considerations, and challenges for PCa genetic testing and offers a practical guide for genetic counseling and testing delivery, with solutions to help address potential barriers and challenges for both providers and patients. As genetic and genomic testing become integral to PCa care, developing standardized systems for implementation in the clinic is essential for delivering precision oncology to patients with PCa and realizing the full scope and impact of genetic testing