Biomedical subjects

Elai Davicioni

Publications and source records attributed to Elai Davicioni.

8 recordsLinked to original sources

PubMed2026

Characterizing the Activity of Inflammasome-Related Genes and Their Association With Oncological Outcomes in Prostate Cancer.

BACKGROUND: Inflammation plays a critical role in cancer cell proliferation; however, the specific role of inflammasomes, multiprotein complexes that regulate inflammation-associated signaling pathways, in prostate cancer (PCa) remains insufficiently explored. This study aims to characterize the expression of inflammasome-related genes in PCa and evaluate their association with clinical outcomes. METHODS: De-identified transcriptome data from the Decipher GRID RP, a cohort of 52,266 radical prostatectomy (RP) samples tested (2016-2024) with the Decipher prostate genomic classifier (Veracyte, San Diego, CA), were retrieved from the GRID registry (NCT02609269). Expression analysis of 34 genes involved in inflammatory pathways was conducted to associate their expression with clinical and genomic variables. Outcomes analyses were conducted on a retrospective cohort of 855 patients treated with RP (META855). RESULTS: Analysis of inflammasome gene expression in the GRID RP cohort revealed that most genes exhibit low baseline expression, whereas HSP90AB1, APP, TXN, and TXNIP demonstrate strong expression signals. Additionally, higher expression of most genes was associated with Gleason Grade Group 4-5 and very high Decipher scores. On survival analysis of the META855 cohort, higher expressions of AIM2 and HSP90AB1 were significantly associated with worse metastasis-free survival. Conversely, both high and low expression levels of NLRP3 were associated with better metastasis-free survival outcomes following RP compared to average expression. On multivariable Cox regression analysis, higher expressions of AIM2 (HR 1.75) and HSP90AB1 (HR 1.60) were significantly associated with shorter time to metastasis following RP. CONCLUSIONS: There is molecular heterogeneity within pro-inflammatory genes among patients with PCa. Our findings showed there is a potential association between the expression levels of certain inflammasomes, such as AIM2, HSP90AB1, and NLRP3, and oncological outcomes following RP.

Aged↗

PubMed2026

Understanding randomized controlled trial generalizability through an embedded molecular diagnostics trial.

BACKGROUND: Issues with randomized controlled trial generalizability are well described, but whether these issues result from differences in patient treatment across contexts remains unknown. We studied treatment of patients with high-risk prostate cancer after radical prostatectomy inside and outside a randomized controlled trial evaluating the impact of a genomic classifier on post-radical prostatectomy treatment decision making (Genomics in Michigan Impacting Observation of Radiation [G-MINOR]; ClinicalTrials.gov identifier NCT02783950). METHODS: G-MINOR enrolled 338 patients; propensity score-matched eligible but unenrolled patient cohorts (pretrial and trial contemporary) from the Michigan Urological Surgery Improvement Collaborative (MUSIC), in which the trial was embedded, were compared for rates and time to secondary treatment (adjuvant or salvage therapy) after prostatectomy. RESULTS: Among 338 patients in the G-MINOR cohort, 69 (31 adjuvant, 38 salvage) received secondary treatment compared with 266 (183 adjuvant, 83 salvage) and 104 (60 adjuvant, 44 salvage) in the 1014 contemporary and 338 pretrial-matched MUSIC cohorts. Time to secondary treatment was much shorter in the MUSIC cohort across all comparisons. For example, matching G-MINOR to synchronous MUSIC patients demonstrated 84% vs 74% estimated 2-year treatment-free survival for trial and real-world patients, respectively (P < .001). CONCLUSIONS: Controlling for key clinicopathologic factors, patients in the G-MINOR randomized controlled trial and MUSIC cohorts were treated differently, even after stratifying by genomic risk. These findings suggest that challenges in randomized controlled trial generalizability extend beyond the representativeness of trial participants. Differences in management may also explain why divergent patient outcomes are observed in randomized controlled trials vs real-world settings.

Aged↗

PubMed2025

A Prospective Validation of the Decipher Genomic Classifier in Men With Early Localized Prostate Cancer: The VANDAAM Study.

BACKGROUND: The emergence of genomic precision oncology has advanced personalized care for some patients with prostate cancer (PCa), while threatening to widen existing disparities due to the historically low recruitment of African American men (AAM), who have the highest disease burden. Here, we report the first prospective validation of a genomic classifier (GC) to predict rapid-onset biochemical recurrence (BCR) in AAM. METHODS: Between 2016 and 2021, this multicenter prospective validation study recruited 243 patients with low- or intermediate-risk PCa who received treatment for their disease. Patients were recruited on a 1:1 basis (AAM:White) and matched by CAPRA score. Patients who elected active surveillance were ineligible for participation. Decipher GC testing was ordered for all patients using their biopsy and/or radical prostatectomy (RP) tumor tissue. The primary outcome was to determine whether the GC could predict 2-year BCR rates-used as a surrogate for disease aggressiveness-following standard treatment. The secondary outcome evaluated the concordance between biopsy- and RP-derived GC risk scores for treatment recommendations. RESULTS: The final analytical cohort included 226 matched patients with genomic information, and 207 evaluable cases (104 AAM, 103 White) with both genomic and complete clinical outcome data. Overall, a high genomic-risk GC score was associated with a 5.25-fold increase in the odds of rapid-onset 2-year BCR compared with the low-risk group (odds ratio, 5.25 [95% CI, 1.27-21.66]; P=.021). In a subset of the surgical cohort (n=74), biopsy- and RP-derived GC scores exhibited a 77% concordance rate, defined as no reclassification in GC risk-based categories. CONCLUSIONS: This study represents the first prospective validation of GC performance in predicting early 2-year BCR in both AAM and White men. The findings provide strong evidence supporting the integration of the GC into clinical practice guidelines to improve risk stratification and management of AAM with early-stage PCa. CLINICALTRIALS: gov identifier: NCT02723734.

Aged↗

PubMed2025

Genomic and Transcriptomic Profiling of Radiation-Resistant, Locally Recurrent Prostate Cancer.

PURPOSE: The biology of locally radiorecurrent prostate cancer (LRR-PCa) is poorly understood. METHODS AND MATERIALS: We sought to explore the genomic and transcriptomic landscape of LRR-PCa with targeted DNA sequencing and RNA expression analysis from 41 biopsy-proven LRR-PCa tumors from 36 unique patients who had a recurrence at a median interval of 84 months (IQR, 70-124 months). Genomic alteration frequencies and transcriptomic data were compared between the LRR-PCa cohort and treatment-naïve patients from the Cancer Genome Atlas (genomic; n = 496) and Gleason grade-at-recurrence-matched patients from the Decipher Genomics Resource for Intelligent Discovery (transcriptomic; n = 22,320). RESULTS: Twenty-five patients (69%) had pathologic upgrading at recurrence (17% vs 64% with Gleason grade 4-5 disease; P < .001). The LRR-PCa cohort demonstrated significantly greater single-nucleotide variations in 29 genes known to be associated with prostate cancer, including several associated with increased aggressiveness and DNA repair: FAT1 (58.5% vs 1.0%), RAD51B (36.6% vs 0.4%), POLQ (34.1% vs 1.4%), KMT2C (34.1% vs 4.9%), BRCA2 (29.3% vs 1.8%), ATRX (26.8% vs 0.8%), and BRCA1 (24.4% vs 0.4%) (Pvalues < .001 for all). The LRR-PCa cohort had a significantly higher Decipher score (median, 0.80 vs 0.66; P = .05) and demonstrated significantly greater basal subtype based on PAM50 (56% vs 20%; P < .001) and lower androgen receptor activity (61% for LRR vs 9%; P < .001). CONCLUSIONS: Overall, these results suggest that LRR-PCa has a distinct genomic and transcriptomic landscape from de novo prostate cancer. Specifically, LRR-PCa has an enrichment in SNVs in genes associated with tumor aggressiveness and/or DNA repair, has higher Decipher scores, a more basal subtype, and has transcriptomic evidence of lower androgen receptor activity and loss of tumor suppressor genes.

Humans↗

PubMed2006

Transgenic mice expressing PAX3-FKHR have multiple defects in muscle development, including ectopic skeletal myogenesis in the developing neural tube.

The t(2;13) chromosomal translocation is found in the majority of human alveolar rhabdomyosarcomas (RMS). The resulting PAX3-FKHR fusion protein contains PAX3 DNA-binding domains fused to the potent transactivation domain of FKHR, suggesting that PAX3-FKHR functions to deregulate PAX3-specific target genes and signaling pathways. We previously developed transgenic mice expressing PAX3-FKHR under the control of mouse Pax3 regulatory sequences to test this hypothesis. We reported that PAX3-FKHR interferes with normal Pax3 developmental functions, with mice exhibiting neural tube and neural crest abnormalities that mimic those found in Pax3-deficient Splotch mice. Here we expanded those studies to show that developmental expression of PAX3-FKHR results in aberrant myogenesis in the developing somites and neural tube, leading to ectopic skeletal muscle formation in the mature spinal cord. Gene expression profiling indicated that PAX3-FKHR expression in the developing neural tube induces a myogenic pattern of gene expression at the expense of the normal neurogenic program. Somite defects in PAX3-FKHR transgenic animals resulted in skeletal malformations that included rib fusions and mis-attachments. As opposed to the neural tube defects, the severity of the rib phenotype was rescued by reducing Pax3 levels through mating with Splotch mice. Embryos from the transgenic line expressing the highest levels of PAX3-FKHR had severe neural tube defects, including exencephaly, and almost half of the embryos died between gestational ages E13.5-E15.5. Nearly all of the embryos that survived to term died after birth due to severe spina bifida, rather than the absence of a muscular diaphragm. These studies reveal a prominent role for PAX3-FKHR in disrupting Pax3 functions and in deregulating skeletal muscle development, suggesting that this fusion protein plays a critical role in the pathogenesis of alveolar RMS by influencing the commitment and differentiation of the myogenic cell lineage.

Animals↗

PubMed2006

Retinoic acid induces leukemia cell G1 arrest and transition into differentiation by inhibiting cyclin-dependent kinase-activating kinase binding and phosphorylation of PML/RARalpha.

Acute promyelocytic leukemia (APL) cells express promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) fusion protein, which leads to the blocking of APL cell differentiation. Treatment of APL with all-trans-retinoic acid (ATRA) induces disease remission by in vivo differentiation of APL cells. Differentiation requires cell cycle exit; yet how ATRA couples cell cycle exit to differentiation of APL remains largely unknown. We previously found that ATRA-induced cell differentiation accompanies ubiquitination-proteolysis of ménage à trois 1 (MAT1), an assembly factor and targeting subunit of cyclin-dependent kinase (CDK)-activating kinase (CAK) that regulates G1 exit. We report here that CAK binds to and phosphorylates PML/RARalpha in actively proliferating APL cells. In response to ATRA, PML/RARalpha is dissociated from CAK, leading to MAT1 degradation, G1 arrest, and decreased CAK phosphorylation of PML/RARalpha. CAK phosphorylation of PML/RARalpha is inhibited when MAT1 levels are reduced. Both MAT1 degradation and PML/RARalpha hypophosphorylation occur in ATRA-induced G1-arresting cells undergoing differentiation but not in the synchronized G1 cells that do not differentiate. These findings reveal a novel ATRA signaling on APL cell differentiation, in which ATRA coordinates G1 arrest and transition into differentiation by inducing MAT1 degradation and PML/RARalpha hypophosphorylation through disrupting PML/RARalpha binding and phosphorylation by CAK.

Carrier Proteins↗

PubMed2006

Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas.

Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.

Biomarkers, Tumor↗

PubMed2006

The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis.

The vast majority of deaths associated with cancer are a consequence of a complex phenotypic behavior, metastasis, by which tumor cells spread from their primary site of origin to regional and distant sites. This process requires the tumor cell to make numerous adjustments, both subtle and dramatic, to successfully reach, survive, and flourish at favorable secondary sites. It has been suggested that molecular mechanisms accounting for metastatic behavior can recapitulate those employed during embryogenesis. We have shown that the homeodomain transcription factor Six1, known to be required for normal development of migratory myogenic progenitor cells, is sufficient to promote metastatic spread in a mouse model of the pediatric skeletal muscle cancer rhabdomyosarcoma. Here, we report that Six1 is able to activate the expression of a set of protumorigenic genes (encoding cyclin D1, c-Myc, and Ezrin) that can control cell proliferation, survival, and motility. Although the role of Ezrin in cytoskeletal organization and adhesion has been well studied, the means by which its expression is regulated are poorly understood. We now show that the gene encoding Ezrin is a direct transcriptional target of Six1. Moreover, Ezrin is indispensable for Six1-induced metastasis and highly expressed in a panel of representative pediatric cancers. Our data indicate that Ezrin represents a promising therapeutic target for patients with advanced-stage rhabdomyosarcoma and perhaps other malignancies.

Animals↗