Histopathological correlations to ureteral lesions visualized during ureteroscopy

PURPOSE: To correlate ureteral lesions visualized during ureteroscopy with histopathological findings.MATERIALS AND METHODS: Ureteral access sheaths (UAS) sized 13/15 Fr. were inserted bilaterally in 22 laboratory pigs. During retraction of the UAS with a semirigid ureteroscope inside, ureteral lesions were evaluated and registered using the Post-ureteroscopic lesion scale (PULS). Ureters were excised in vivo between the uretero-pelvic junction and the uretero-vesical junction. Embedded in paraffin, 4-µm thick sections were step sectioned at 250-300 µm intervals and haematoxylin and eosin (HE) stained. Histopathological scoring of ureteral wall lesions was subsequently performed according to PULS.RESULTS: In 72.1% of ureters, the highest histopathological score was at least 1 grade higher than the highest endoscopic PULS score. For 12 (27.9%) lesions, the difference was 2 scores higher, and for 1 (2.3%), it was 3 scores higher. The histopathological PULS grade was higher than the endoscopical PULS grade at all minimum, quartile, and maximum scores. There was a significant difference in the distribution of highest lesional scores between the endoscopic and histopathological PULS (p = 0.002). The calculated mean of the highest scores was 1.49 for endoscopic PULS and 2.51 for histopathological PULS (p &lt; 0.0001).CONCLUSION: Histopathological evaluation of ureteral wall lesions after UAS placement revealed a significantly higher degree of severity than observed endoscopically. Thus, endoscopy underestimated the histopathological extent of the lesion in the majority of cases.</p

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer

Published first January 24, 2022.Purpose: DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. Experimental Design: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). Results: Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucosederived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. Conclusions: Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK–mediated aggressive disease phenotypes.Emanuela Dylgjeri, Vishal Kothari, Ayesha A. Shafi, Galina Semenova, Peter T. Gallagher, Yi F. Guan, Angel Pang, Jonathan F. Goodwin, Swati Irani, Jennifer J. McCann, Amy C. Mandigo, Saswati Chand, Christopher M. McNair, Irina Vasilevskaya, MatthewJ. Schiewer, Costas D. Lallas, Peter A. McCue, Leonard G. Gomella, Erin L. Seifert, Jason S. Carroll, Lisa M. Butler, Jeff Holst, William K. Kelly, and Karen E. Knudse