A Multicompartmental Diffusion Model for Improved Assessment of Whole-Body Diffusion-weighted Imaging Data and Evaluation of Prostate Cancer Bone Metastases.

Purpose To develop a multicompartmental signal model for whole-body diffusion-weighted imaging (DWI) and apply it to study the diffusion properties of normal tissue and metastatic prostate cancer bone lesions in vivo. Materials and Methods This prospective study (: NCT03440554) included 139 men with prostate cancer (mean age, 70 years ± 9 [SD]). Multicompartmental models with two to four tissue compartments were fit to DWI data from whole-body scans to determine optimal compartmental diffusion coefficients.

Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.

Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping.

An unsupervised learning approach to identify novel signatures of health and disease from multimodal data.

Background: Modern medicine is rapidly moving towards a data-driven paradigm based on comprehensive multimodal health assessments. Integrated analysis of data from different modalities has the potential of uncovering novel biomarkers and disease signatures.

Methods: We collected 1385 data features from diverse modalities, including metabolome, microbiome, genetics, and advanced imaging, from 1253 individuals and from a longitudinal validation cohort of 1083 individuals.

Relationship between kurtosis and bi-exponential characterization of high b-value diffusion-weighted imaging: application to prostate cancer.

Background: High b-value diffusion-weighted imaging has application in the detection of cancerous tissue across multiple body sites. Diffusional kurtosis and bi-exponential modeling are two popular model-based techniques, whose performance in relation to each other has yet to be fully explored.

Purpose: To determine the relationship between excess kurtosis and signal fractions derived from bi-exponential modeling in the detection of suspicious prostate lesions.

Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults.

Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality.

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

Objectives: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age.

Design: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis).

Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.

Background: Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction.

Methods And Findings: Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5).

Restriction spectrum imaging: An evolving imaging biomarker in prostate MRI.

Unlabelled: Restriction spectrum imaging (RSI) is a novel diffusion-weighted MRI technique that uses the mathematically distinct behavior of water diffusion in separable microscopic tissue compartments to highlight key aspects of the tissue microarchitecture with high conspicuity. RSI can be acquired in less than 5 min on modern scanners using a surface coil. Multiple field gradients and high b-values in combination with postprocessing techniques allow the simultaneous resolution of length-scale and geometric information, as well as compartmental and nuclear volume fraction filtering.

Voxel Level Radiologic-Pathologic Validation of Restriction Spectrum Imaging Cellularity Index with Gleason Grade in Prostate Cancer.

Purpose: Restriction spectrum imaging (RSI-MRI), an advanced diffusion imaging technique, can potentially circumvent current limitations in tumor conspicuity, in vivo characterization, and location demonstrated by multiparametric magnetic resonance imaging (MP-MRI) techniques in prostate cancer detection. Prior reports show that the quantitative signal derived from RSI-MRI, the cellularity index, is associated with aggressive prostate cancer as measured by Gleason grade (GG). We evaluated the reliability of RSI-MRI to predict variance with GG at the voxel-level within clinically demarcated prostate cancer regions.

Restriction spectrum imaging improves MRI-based prostate cancer detection.

Purpose: To compare the diagnostic performance of restriction spectrum imaging (RSI), with that of conventional multi-parametric (MP) magnetic resonance imaging (MRI) for prostate cancer (PCa) detection in a blinded reader-based format.

Methods: Three readers independently evaluated 100 patients (67 with proven PCa) who underwent MP-MRI and RSI within 6 months of systematic biopsy (N = 67; 23 with targeting performed) or prostatectomy (N = 33). Imaging was performed at 3 Tesla using a phased-array coil.

Prostate diffusion imaging with distortion correction.

Purpose: Diffusion imaging in the prostate is susceptible to distortion from B0 inhomogeneity. Distortion correction in prostate imaging is not routinely performed, resulting in diffusion images without accurate localization of tumors. We performed and evaluated distortion correction for diffusion imaging in the prostate.

Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.

Background: Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.

Methods And Results: Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels.

MRI-Derived Restriction Spectrum Imaging Cellularity Index is Associated with High Grade Prostate Cancer on Radical Prostatectomy Specimens.

Purpose: We evaluate a novel magnetic resonance imaging (MRI) technique to improve detection of aggressive prostate cancer (PCa).

Materials And Methods: We performed a retrospective analysis of pre-surgical prostate MRI scans using an advanced diffusion-weighted imaging technique called restriction spectrum imaging (RSI), which can be presented as a normalized z-score statistic. Scans were acquired prior to radical prostatectomy.

Relative capability of MR imaging and FDG PET to depict changes associated with prodromal and early Alzheimer disease.

Purpose: To quantify the effect sizes of regional metabolic and morphometric measures in patients with preclinical and mild Alzheimer disease (AD) to aid in the identification of noninvasive biomarkers for the early detection of AD.

Materials And Methods: The study was conducted with institutional review board approval and in compliance with HIPAA regulations. Written informed consent was obtained from each participant or participant's legal guardian.

Neurons detect increases and decreases in oxygen levels using distinct guanylate cyclases.

Homeostatic sensory systems detect small deviations in temperature, water balance, pH, and energy needs to regulate adaptive behavior and physiology. In C. elegans, a homeostatic preference for intermediate oxygen (O2) levels requires cGMP signaling through soluble guanylate cyclases (sGCs), proteins that bind gases through an associated heme group.

Structural MRI biomarkers for preclinical and mild Alzheimer's disease.

Noninvasive MRI biomarkers for Alzheimer's disease (AD) may enable earlier clinical diagnosis and the monitoring of therapeutic effectiveness. To assess potential neuroimaging biomarkers, the Alzheimer's Disease Neuroimaging Initiative is following normal controls (NC) and individuals with mild cognitive impairment (MCI) or AD. We applied high-throughput image analyses procedures to these data to demonstrate the feasibility of detecting subtle structural changes in prodromal AD.

Alzheimer disease: quantitative structural neuroimaging for detection and prediction of clinical and structural changes in mild cognitive impairment.

Purpose: To use structural magnetic resonance (MR) images to identify a pattern of regional atrophy characteristic of mild Alzheimer disease (AD) and to investigate whether presence of this pattern prospectively can aid prediction of 1-year clinical decline and increased structural loss in mild cognitive impairment (MCI).

Materials And Methods: The study was conducted with institutional review board approval and compliance with HIPAA regulations. Written informed consent was obtained from each participant.

A distributed chemosensory circuit for oxygen preference in C. elegans.

The nematode Caenorhabditis elegans has complex, naturally variable behavioral responses to environmental oxygen, food, and other animals. C. elegans detects oxygen through soluble guanylate cyclase homologs (sGCs) and responds to it differently depending on the activity of the neuropeptide receptor NPR-1: npr-1(lf) and naturally isolated npr-1(215F) animals avoid high oxygen and aggregate in the presence of food; npr-1(215V) animals do not.

Nitric oxide binding to prokaryotic homologs of the soluble guanylate cyclase beta1 H-NOX domain.

The heme cofactor in soluble guanylate cyclase (sGC) is a selective receptor for NO, an important signaling molecule in eukaryotes. The sGC heme domain has been localized to the N-terminal 194 amino acids of the beta1 subunit of sGC and is a member of a family of conserved hemoproteins, called the H-NOX family (Heme-Nitric Oxide and/or OXygen-binding domain). Three new members of this family have now been cloned and characterized, two proteins from Legionella pneumophila (L1 H-NOX and L2 H-NOX) and one from Nostoc punctiforme (Np H-NOX).

Characterization of functional heme domains from soluble guanylate cyclase.

Soluble guanylate cyclase (sGC) is a heterodimeric, nitric oxide (NO)-sensing hemoprotein composed of two subunits, alpha1 and beta1. NO binds to the heme cofactor in the beta1 subunit, forming a five-coordinate NO complex that activates the enzyme several hundred-fold. In this paper, the heme domain has been localized to the N-terminal 194 residues of the beta1 subunit.

Crystal structure of an oxygen-binding heme domain related to soluble guanylate cyclases.

Soluble guanylate cyclases are nitric oxide-responsive signaling proteins in which the nitric oxide sensor is a heme-binding domain of unknown structure that we have termed the heme-NO and oxygen binding (H-NOX) domain. H-NOX domains are also found in bacteria, either as isolated domains, or are fused through a membrane-spanning region to methyl-accepting chemotaxis proteins. We have determined the crystal structure of an oxygen-binding H-NOX domain of one such signaling protein from the obligate anaerobe Thermoanaerobacter tengcongensis at 1.

Spectroscopic characterization of the soluble guanylate cyclase-like heme domains from Vibrio cholerae and Thermoanaerobacter tengcongensis.

Soluble guanylate cyclase (sGC) is a nitric oxide- (NO-) sensing hemoprotein that has been found in eukaryotes from Drosophila to humans. Prokaryotic proteins with significant homology to the heme domain of sGC have recently been identified through genomic analysis. Characterization of two of these proteins is reported here.

Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue.

Specialized oxygen-sensing cells in the nervous system generate rapid behavioural responses to oxygen. We show here that the nematode Caenorhabditis elegans exhibits a strong behavioural preference for 5-12% oxygen, avoiding higher and lower oxygen levels. 3',5'-cyclic guanosine monophosphate (cGMP) is a common second messenger in sensory transduction and is implicated in oxygen sensation.