Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.

Importance: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater).

Objective: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers.

Design, Setting, And Participants: RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers.

MyProstateScore in men considering repeat biopsy: validation of a simple testing approach.

Background: Men with persistent risk of Grade Group (GG) ≥ 2 cancer after a negative biopsy present a unique clinical challenge. The validated MyProstateScore test is clinically-available for pre-biopsy risk stratification. In biopsy-naïve patients, we recently validated a straightforward testing approach to rule-out GG ≥ 2 cancer with 98% negative predictive value (NPV) and 97% sensitivity.

CRISPRs in the human genome are differentially expressed between malignant and normal adjacent to tumor tissue.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) have been identified in bacteria, archaea and mitochondria of plants, but not in eukaryotes. Here, we report the discovery of 12,572 putative CRISPRs randomly distributed across the human chromosomes, which we termed hCRISPRs. By using available transcriptome datasets, we demonstrate that hCRISPRs are distinctively expressed as small non-coding RNAs (sncRNAs) in cell lines and human tissues.

Urinary MyProstateScore (MPS) to Rule out Clinically-Significant Cancer in Men with Equivocal (PI-RADS 3) Multiparametric MRI: Addressing an Unmet Clinical Need.

Objective: To evaluate the complementary value of urinary MyProstateScore (MPS) testing and multiparametric MRI (mpMRI) and assess outcomes in patients with equivocal mpMRI.

Materials And Methods: Included patients underwent mpMRI followed by urine collection and prostate biopsy at the University of Michigan between 2015 -2019. MPS values were calculated from urine specimens using the validated model based on serum PSA, urinary PCA3, and urinary TMPRSS2:ERG.

Association of MyProstateScore (MPS) with prostate cancer grade in the radical prostatectomy specimen.

Background: To evaluate the association between urinary MyProstateScore (MPS) and pathologic grade group (GG) at surgery in men diagnosed with GG1 prostate cancer (PCa) on biopsy.

Methods: Using an institutional biospecimen protocol, we identified men with GG1 PCa on biopsy and PSA ≤10 ng/ml who underwent radical prostatectomy (RP) at the University of Michigan. MPS was retrospectively calculated using prospectively collected, post-DRE urine samples.

Association of Urinary MyProstateScore, Age, and Prostate Volume in a Longitudinal Cohort of Healthy Men: Long-term Findings from the Olmsted County Study.

Background: Serum prostate-specific antigen (PSA), used in prostate cancer screening, is nonspecific for cancer and is affected by age and prostate volume. More specific biomarkers could be more accurate for early detection of prostate cancer and reduce unnecessary prostate biopsies.

Objective: To evaluate the association of age and prostate volume with urinary MyProstateScore (MPS) in a screened, longitudinal cohort without evidence of prostate cancer.

Use of the MyProstateScore Test to Rule Out Clinically Significant Cancer: Validation of a Straightforward Clinical Testing Approach.

Purpose: The MyProstateScore test was validated for improved detection of clinically significant (grade group ≥2) prostate cancer relative to prostate specific antigen based risk calculators. We sought to validate an optimal MyProstateScore threshold for clinical use in ruling out grade group ≥2 cancer in men referred for biopsy.

Materials And Methods: Biopsy naïve men provided post-digital rectal examination urine prior to biopsy.

Impact of the MyProstateScore (MPS) Test on the Clinical Decision to Undergo Prostate Biopsy: Results From a Contemporary Academic Practice.

Objective: To evaluate the association of the MyProstateScore (MPS) urine test on the decision to undergo biopsy in men referred for prostate biopsy in urology practice.

Methods: MPS testing was offered as an alternative to immediate biopsy in men referred to the University of Michigan for prostate biopsy from October 2013 through October 2016. The primary endpoint was the decision to perform biopsy.

The role of the histone H3 variant CENPA in prostate cancer.

Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. The centromeric histone H3 variant centromere protein A (CENPA) is an epigenetic mark that determines centromere identity. Here, using an array of approaches, including RNA-sequencing and ChIP-sequencing analyses, immunohistochemistry-based tissue microarrays, and various cell biology assays, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines and that the level of CENPA expression correlates with the disease stage in a large cohort of patients.

Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing.

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response.

TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination.

Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets.

Early Notch Signals Induce a Pathogenic Molecular Signature during Priming of Alloantigen-Specific Conventional CD4 T Cells in Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 h after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit the expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection.

Coordinating Tissue Regeneration Through Transforming Growth Factor-β Activated Kinase 1 Inactivation and Reactivation.

Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-β activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production.

The DEK Oncoprotein Functions in Ovarian Cancer Growth and Survival.

DNA damage repair alterations play a critical role in ovarian cancer tumorigenesis. Mechanistic drivers of the DNA damage response consequently present opportunities for therapeutic targeting. The chromatin-binding DEK oncoprotein functions in DNA double-strand break repair.

MiPanda: A Resource for Analyzing and Visualizing Next-Generation Sequencing Transcriptomics Data.

The Michigan Portal for the Analysis of NGS data portal (http://mipanda.org) is an open-access online resource that provides the scientific community with access to the results of a large-scale computational analysis of thousands of high-throughput RNA sequencing (RNA-seq) samples. The portal provides access to gene expression profiles, enabling users to interrogate expression of genes across myriad normal and cancer tissues and cell lines.

Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression.

The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction.

Multigene Profiling of CTCs in mCRPC Identifies a Clinically Relevant Prognostic Signature.

The trend toward precision-based therapeutic approaches dictated by molecular alterations offers substantial promise for men with metastatic castration-resistant prostate cancer (mCRPC). However, current approaches for molecular characterization are primarily tissue based, necessitating serial biopsies to understand changes over time and are limited by the challenges inherent to extracting genomic material from predominantly bone metastases. Therefore, a circulating tumor cell (CTC)-based assay was developed to determine gene expression across a panel of clinically relevant and potentially actionable prostate cancer-related genes.

Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA.

Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role.

Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology.

Accurate histopathologic diagnosis is essential for providing optimal surgical management of pediatric brain tumors. Current methods for intraoperative histology are time- and labor-intensive and often introduce artifact that limit interpretation. Stimulated Raman histology (SRH) is a novel label-free imaging technique that provides intraoperative histologic images of fresh, unprocessed surgical specimens.

Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated Raman scattering microscopy.

Conventional methods for intraoperative histopathologic diagnosis are labour- and time-intensive, and may delay decision-making during brain-tumour surgery. Stimulated Raman scattering (SRS) microscopy, a label-free optical process, has been shown to rapidly detect brain-tumour infiltration in fresh, unprocessed human tissues. Here, we demonstrate the first application of SRS microscopy in the operating room by using a portable fibre-laser-based microscope and unprocessed specimens from 101 neurosurgical patients.

Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification.

Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations.

A Critical Analysis of the Role of SNARE Protein SEC22B in Antigen Cross-Presentation.

Cross-presentation initiates immune responses against tumors and viral infections by presenting extracellular antigen on MHC I to activate CD8 T cell-mediated cytotoxicity. In vitro studies in dendritic cells (DCs) established SNARE protein SEC22B as a specific regulator of cross-presentation. However, the in vivo contribution of SEC22B to cross-presentation has not been tested.

TACO produces robust multisample transcriptome assemblies from RNA-seq.

Accurate transcript structure and abundance inference from RNA sequencing (RNA-seq) data is foundational for molecular discovery. Here we present TACO, a computational method to reconstruct a consensus transcriptome from multiple RNA-seq data sets. TACO employs novel change-point detection to demarcate transcript start and end sites, leading to improved reconstruction accuracy compared with other tools in its class.