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1. Longitudinal measurement of subcutaneous and intratibial human prostate cancer xenograft growth and response to ionizing radiation by plasma Alu and LINE‐1 ctDNA: A comparison to standard methods

   https://doi.org/10.1002/pros.24171  

   Mishra, Alok ; Zennami, Kenji ; Velarde, Esteban ; Thorek, Daniel L. J. ; Yegnasubramanian, Srinivasan ; DeWeese, Theodore L. ; Lupold, Shawn E. ( May 2021 , The Prostate)

   Current preclinical models of metastatic prostate cancer (PCa) require sophisticated technologies and/or genetically engineered cells for the noninvasive monitoring of tumors in remote sites, such as bone. Recent developments in circulating tumor DNA (ctDNA) analysis provide an alternative method for noninvasive tumor monitoring at a low cost. Here, we sought to evaluate human Alu and LINE‐1 ctDNA for the longitudinal measurement of subcutaneous and intratibial human PCa xenograft growth and response to ionizing radiation (IR) through comparison with standard slide caliper and bioluminescence measurements.

   Intratibial and subcutaneous xenografts were established in male athymic nude mice using LNCaP cells that stably express firefly luciferase. A subset of tumors was treated with a single dose of IR (CT‐guided focal IR, 6 Gy). Tumor measurements were simultaneously taken by slide caliper (subcutaneous only), in vivo bioluminescence imaging, and quantitative real‐time PCR (qPCR) of human‐specific Alu and LINE‐1 ctDNA for several weeks.

   Levels of ctDNA and bioluminescence increased concordantly with subcutaneous and intratibial tumor growth. A statistically significant correlation (Spearman) was observed between ctDNA and subcutaneous tumor volume (LINE‐1,r = .94 and Alu,r = .95,p < .0001), ctDNA and bioluminescence (LINE‐1,r = .66 and Alu,r = .60,p < .002), and bioluminescence and tumor volume (r = .66,p = .0003). Bioluminescence and ctDNA were also significantly correlated in intratibial tumors (LINE‐1,r = .82 and Alu,r = .81,p < .0001). Following external beam IR, the tumor responses varied briefly by method of measurement, but followed a similar trend. Statistically significant correlations were maintained between ctDNA and slide caliper measurement in irradiated subcutaneous tumors (LINE‐1,r = .64 and Alu,r = .44,p < .02), and ctDNA and bioluminescence in intratibial tumors (LINE‐1,r = .55,p = .018).

   Real‐time qPCR of circulating human Alu and LINE‐1 DNA provides an accurate measurement of subcutaneous and intratibial xenograft burden that is comparable with conventional bioluminescence imaging and slide caliper measurement. Transient differences in measurements were observed following tumor‐targeted IR, but overall all measurements mirrored tumor growth and response.

    

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2. The Association between Whole‐Brain MR Spectroscopy and IDH Mutation Status in Gliomas

   https://doi.org/10.1111/jon.12685  

   Goryawala, Mohammed ; Saraf‐Lavi, Efrat ; Nagornaya, Natalia ; Heros, Deborah ; Komotar, Ricardo ; Maudsley, Andrew A. ( December 2019 , Journal of Neuroimaging)

   Mutations in isocitrate dehydrogenase (IDH) have a direct effect on gliomagenesis. The purpose of this study is to quantify differences in brain metabolites due to IDH mutations.

   Magnetic Resonance Spectroscopic Imaging (MRSI) was performed in 35 patients with gliomas of different grade and varied IDH mutation status. Volumes of interest (VOIs) for active tumor (tVOI), peritumoral area (pVOI), and contralateral normal‐appearing white matter (cVOI) were created. Metabolite ratios of Choline (Cho) to bothN‐acetylaspartate (NAA) and Creatine (Cr) were estimated. Ratios of Glutamate/Glutamine complex (Glx) and myoinositol (mIno) to Cr were also quantified. General linear models (GLMs) were used to estimate the effects of IDH mutation on metabolite measures, with age, gender, and tumor grade used as covariates.

   GLM analysis showed that maximum Cho/NAA and Cho/Cr in the tVOI were significantly (P< .05) higher in IDH mutant lesions as compared to wild‐type. In the pVOI, mean Cho/Cr was found to be significantly different among IDH mutant and wild‐type gliomas. Mean Cho/NAA (P= .306) and Cho/Cr (P= .292) within the tVOI were not significantly different. Ratios of Glx/Cr and mIno/Cr in any region showed no significant differences between IDH mutant and wild‐type gliomas. No significant differences in metabolite ratios were seen in the cVOI between IDH mutants and wild‐types.

   IDH mutation's effect in gliomas show an increase in Cho in the tumor and perilesional regions as compared to wild‐type lesions but do not show widespread changes across the brain.

    

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3. A single-cell based precision medicine approach using glioblastoma patient-specific models

   https://doi.org/10.1038/s41698-022-00294-4  

   Park, James H. ; Feroze, Abdullah H. ; Emerson, Samuel N. ; Mihalas, Anca B. ; Keene, C. Dirk ; Cimino, Patrick J. ; de Lomana, Adrian Lopez Garcia ; Kannan, Kavya ; Wu, Wei-Ju ; Turkarslan, Serdar ; et al ( August 2022 , npj Precision Oncology)

   Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multi-omic single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multi-omic data with single-cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that modulate cell state transitions across subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches to an individual patient in a concurrent, adjuvant, or recurrent setting.

    

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4. Integration of a polygenic score into guideline-recommended prediction of cardiovascular disease

   https://doi.org/10.1093/eurheartj/ehae048  

   Li, Ling ; Pang, Shichao ; Starnecker, Fabian ; Mueller-Myhsok, Bertram ; Schunkert, Heribert ( March 2024 , European Heart Journal)

   It is not clear how a polygenic risk score (PRS) can be best combined with guideline-recommended tools for cardiovascular disease (CVD) risk prediction, e.g. SCORE2.

   A PRS for coronary artery disease (CAD) was calculated in participants of UK Biobank (n = 432 981). Within each tenth of the PRS distribution, the odds ratios (ORs)—referred to as PRS-factor—for CVD (i.e. CAD or stroke) were compared between the entire population and subgroups representing the spectrum of clinical risk. Replication was performed in the combined Framingham/Atherosclerosis Risk in Communities (ARIC) populations (n = 10 757). The clinical suitability of a multiplicative model ‘SCORE2 × PRS-factor’ was tested by risk reclassification.

   In subgroups with highly different clinical risks, CVD ORs were stable within each PRS tenth. SCORE2 and PRS showed no significant interactive effects on CVD risk, which qualified them as multiplicative factors: SCORE2 × PRS-factor = total risk. In UK Biobank, the multiplicative model moved 9.55% of the intermediate (n = 145 337) to high-risk group increasing the individuals in this category by 56.6%. Incident CVD occurred in 8.08% of individuals reclassified by the PRS-factor from intermediate to high risk, which was about two-fold of those remained at intermediate risk (4.08%). Likewise, the PRS-factor shifted 8.29% of individuals from moderate to high risk in Framingham/ARIC.

   This study demonstrates that absolute CVD risk, determined by a clinical risk score, and relative genetic risk, determined by a PRS, provide independent information. The two components may form a simple multiplicative model improving precision of guideline-recommended tools in predicting incident CVD.

    

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5. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

   https://doi.org/10.1002/mds.29337  

   Sugier, Pierre‐Emmanuel ; Lucotte, Elise_A ; Domenighetti, Cloé ; Law, Matthew_H ; Iles, Mark_M ; Brown, Kevin ; Amos, Christopher ; McKay, James_D ; Hung, Rayjean_J ; Karimi, Mojgan ; et al ( February 2023 , Movement Disorders)

   Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties.

   We used results from genome‐wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors.

   We used individual data for participants of European ancestry from the Courage‐PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta‐Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross‐phenotypes polygenic risk score (PRS) analyses.

   We confirmed a previously reported positive genetic correlation of PD with melanoma (G_corr= 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G_corr= 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of theNSFgene (17q21.31).

   We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors.Movement Disorderspublished by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

    

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