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Simple Summary: We explored the potential of using proteins found in extracellular vesicles (EVs), which are tiny particles released by cancer cells, to predict treatment response and identify new drug targets. Unlike traditional tissue biopsies, analyzing EVs from blood samples offers a non-invasive way to obtain valuable information about the cancer. Our findings showed that certain proteins in EVs, such as B7-H3 and LAT1, are correlated with clinical markers such as PSA levels, PET scans, and serum alkaline phosphatase levels that are used to monitor disease burden and cancer progression. This approach could lead to more precise and personalized treatment options for patients with advanced prostate cancer, helping doctors choose the most effective therapies and improve outcomes. Introduction: Prostate cancer treatment has been revolutionized by targeted therapies, including PARP inhibitors, checkpoint immunotherapies, and PSMA-targeted radiotherapies. Despite such advancements, accurate patient stratification remains a challenge, with current methods relying on genomic markers, tissue staining, and imaging. Extracellular vesicle (EV)-derived proteins offer a novel non-invasive alternative for biomarker discovery, holding promise for improving treatment precision. However, the characterization of plasma-derived EVs in prostate cancer patients remains largely unexplored. Methods: We conducted proteomic analyses on EVs isolated from plasma in 27 metastatic castration-resistant prostate cancer (mCRPC) patients. EVs were purified using ultracentrifugation and analyzed via mass spectrometry. Proteomic data were correlated with clinical markers such as serum prostate-specific antigen (PSA) and bone lesion counts. Statistical significance was assessed using Mann–Whitney t-tests and Spearman correlation. Results: The median age of patients was 74 (range: 44–94) years. At the time of blood collection, the median PSA level was 70 (range: 0.5–1000) ng/mL. All patients had bone metastasis. A total of 5213 proteins were detected, including EV-related proteins (CD9, CD81, CD63, FLOT1, TSG101) and cancer-related proteins (PSMA, B7-H3, PD-L1). Proteomic profiling of plasma EVs revealed a significant correlation between specific EV-derived proteins and clinical prognostic markers. B7-H3, LAT1, and SLC29A1 showed a strong association with serum PSA levels and number of bone lesions, indicating potential for these proteins to serve as biomarkers of disease burden and therapy response. Conclusions: Our findings demonstrate the potential of EV-based proteomics for identifying biomarkers in mCRPC patients. Proteins such as B7-H3 and LAT1 could guide precision oncology approaches, improving patient stratification. Future research incorporating outcomes data and EV subpopulation analysis is needed to establish clinical relevance. [ABSTRACT FROM AUTHOR]

Background Graduate medical educators interested in designing and conducting education research may seek foundational general overview articles on education research methods. Objective We aimed to identify the most useful foundational education research methods articles for medical educators. Methods We identified candidate articles through a 2020 Ovid MEDLINE literature search augmented by the authors' personal files and by cross-checking references of included articles. Articles that were primarily about general education research principles were included; articles were excluded if they were not focused on medical education research methods, were published prior to the year 2000, were written in a non-English language, or had no available abstracts. We conducted a modified Delphi study with 10 participants representing a range of specialties and education research experience to find consensus about the most useful articles. We planned 3 rounds of the Delphi process, the first to eliminate any articles not deemed useful for this audience, and the second and third rounds to include articles that at least 80% of the panel deemed "most useful" to education researchers. Results Of 25 relevant articles identified in the literature search: one was excluded in round 1, 7 met the a priori threshold of 80% agreement for inclusion in round 2, and an additional 2 met inclusion in round 3. These 9 foundational education research methods articles relevant to graduate medical educators are described, along with a capsule summary and specific use for education researchers. Conclusions Our modified Delphi study of foundational education research methods articles identified 9 articles deemed useful for graduate medical educators who are seeking methods resources. [ABSTRACT FROM AUTHOR]

Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme's ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an in vitro biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases. [ABSTRACT FROM AUTHOR]

Purpose: 10-15% of prostate cancers (PCa) harbor recurrent FOXA1 aberrations whereby the alteration type and the effect on the forkhead( FKH) domain impacts protein-function. We developed a FOXA1 classification system to inform clinical management., Experimental Design: 5,014 PCa were examined using whole exome and transcriptome sequencing from the Caris database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain: these were in the first part of the FKH domain (class 1A: amino acids [AA] 168-246), within the Wing2 region of FKH (class 1B: AA 247-269), or outside FKH (class 1C: AA 1-167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted-truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1-269, class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims., Results: FOXA1 alterations did not influence survival when considered in aggregate, but had distinct prognostic effects when stratified by class. Class 1A alterations were associated with overall improved survival (HR=0.57, p=0.03); a similar trend was seen with Class 1B (HR=0.88, p=0.07). Conversely, class 1C exhibited worse survival upon 2nd-generation androgen receptor signaling inhibitor (ARSI) treatment (HR=1.93, p<0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR=2.05, p<0.001) and worse outcomes to first-line androgen-deprivation therapies (HR=2.5, p<0.001). Class 3A alterations indicated improved survival (HR=0.70; p=0.01) whereas class 3B alterations portended poor outcomes (HR=1.50; p<0.001). Amplifications (class 4) indicated poor outcomes (HR=1.48; p=0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European-Americans, African-Americans had increased class 1C alterations whereas Asian-Pacific patients had increased class 1B alterations., Conclusions: FOXA1alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision making for PCa patients and uncovers important racial differences.