Computing microRNA-gene interaction networks in pan-cancer using miRDriver.

DNA copy number aberrated regions in cancer are known to harbor cancer driver genes and the short non-coding RNA molecules, i.e., microRNAs. In this study, we integrated the multi-omics datasets such as copy number aberration, DNA methylation, gene and microRNA expression to identify the signature microRNA-gene associations from frequently aberrated DNA regions across pan-cancer utilizing a LASSO-based regression approach. We studied 7294 patient samples associated with eighteen different cancer types from The Cancer Genome Atlas (TCGA) database and identified several cancer-specific and common microRNA-gene interactions enriched in experimentally validated microRNA-target interactions. We highlighted several oncogenic and tumor suppressor microRNAs that were cancer-specific and common in several cancer types. Our method substantially outperformed the five state-of-art methods in selecting significantly known microRNA-gene interactions in multiple cancer types. Several microRNAs and genes were found to be associated with tumor survival and progression. Selected target genes were found to be significantly enriched in cancer-related pathways, cancer hallmark and Gene Ontology (GO) terms. Furthermore, subtype-specific potential gene signatures were discovered in multiple cancer types.

Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain.

OBJECTIVE: Previously we reported that exposure of 6-day-old (P6) rhesus macaques to isoflurane for 5 hours triggers a robust neuroapoptosis response in developing brain. We have also observed (unpublished data) that isoflurane causes apoptosis of cellular profiles in the white matter that resemble glia. We analyzed the cellular identity of the apoptotic white matter profiles and determined the magnitude of this cell death response to isoflurane. METHODS: Neonatal (P6) rhesus macaques were exposed for 5 hours to isoflurane anesthesia according to current clinical standards in pediatric anesthesia. Brains were collected 3 hours later and examined immunohistochemically to analyze apoptotic neuronal and glial death. RESULTS: Brains exposed to isoflurane displayed significant apoptosis in both the white and gray matter throughout the central nervous system. Approximately 52% of the dying cells were glia, and 48% were neurons. Oligodendrocytes (OLs) engaged in myelinogenesis were selectively vulnerable, in contrast to OL progenitors, astrocytes, microglia, and interstitial neurons. When adjusted for control rates of OL apoptosis, the percentage of OLs that degenerated in the forebrain white matter of the isoflurane-treated group was 6.3% of the total population of myelinating OLs. INTERPRETATION: Exposure of the infant rhesus macaque brain to isoflurane for 5 hours is sufficient to cause widespread apoptosis of neurons and OLs throughout the developing brain. Deletion of OLs at a stage when they are just beginning to myelinate axons could potentially have adverse long-term neurobehavioral consequences that might be additive to the potential consequences of isoflurane-induced neuroapoptosis.

Strain-specific differences in perinatal rodent oligodendrocyte lineage progression and its correlation with human.

Progress in the development of rat models of human periventricular white matter injury (WMI) has been hampered by uncertainty about the developmental window in different rodent strains that coincides with cerebral white matter development in human premature infants. To define strain-specific differences in rat cerebral white matter maturation, we analyzed oligodendrocyte (OL) lineage maturation between postnatal days (P)2 and P14 in three widely studied strains of rat: Sprague-Dawley, Long-Evans and Wistar (W). We previously reported that late OL progenitors (preOL) are the major vulnerable cell type in human periventricular WMI. Strain-specific differences in preOL maturation were found at P2, such that the W rat had the highest percentage and density of preOL relative to the other strains. Overall, at P2, the state of OL maturation was similar to preterm human cerebral white matter. However, by P5, all three strains displayed a similar magnitude and extent of OL maturation that persisted with progressive myelination between P7 and P14. PreOL were the predominant OL lineage stage present in the cerebral cortex through P14, and thus OL lineage maturation occurred latter than in white matter. The hippocampus also displayed a later onset of preOL maturation in all three strains, such that OL lineage maturation and early myelination was not observed to occur until about P14. This timing of preOL maturation in rat cortical gray matter coincided with a similar timing in human cerebral cortex, where preOL also predominated until at least 8 months after full-term birth. These studies support that strain-specific differences in OL lineage immaturity were present in the early perinatal period at about P2, and they define a narrow window of preterm equivalence with human that diminishes by P5. Later developmental onset of preOL maturation in both cerebral cortex and hippocampus coincides with an extended window of potential vulnerability of the OL lineage to hypoxia-ischemia in these gray matter regions.

Diffusion characteristics associated with neuronal injury and glial activation following hypoxia-ischemia in the immature brain.

To identify quantitative MRI indices of injury in the brain following neonatal hypoxic-ischemic brain injury, we subjected mouse pups to hypoxia-ischemia on postnatal day 7 and obtained conventional and diffusion-weighted in vivo images of the brain 24 h later followed by histological assessment. T(2)-weighted images showed increased signal intensity in the CA1 and CA2 regions of the hippocampus ipsilateral to the injury and adjacent white matter. In contrast, diffusion imaging showed reduced apparent diffusion coefficient (ADC) values in CA1 and CA2, but increased values in the adjacent white matter. Histological analysis showed widespread gliosis with degenerating oligodendrocytes in the ipsilateral hippocampus. In addition, white matter areas that were abnormal by MRI showed an increase in the number of activated microglia (CD45 positive cells). Activated caspase-3 immunostaining showed a marked increase in neurons in the hippocampal regions corresponding to those with reduced ADC, and a quantitative measure of staining showed a statistically significant correlation with the ADC. In contrast, ADC was higher in adjacent white matter, where histology showed activation of microglia and reactive oligodendrocytes but not caspase-3 activation. These results suggest that the ADC response differs between areas of neuronal injury as compared with those showing glial changes without marked cell death.

Prevalence of colon polyps detected by colonoscopy screening in asymptomatic black and white patients.

CONTEXT: Compared with white individuals, black men and women have a higher incidence and mortality from colorectal cancer and may develop cancer at a younger age. Colorectal cancer screening might be less effective in black individuals, if there are racial differences in the age-adjusted prevalence and location of cancer precursor lesions. OBJECTIVES: To determine and compare the prevalence rates and location of polyps sized more than 9 mm in diameter in asymptomatic black and white individuals who received colonoscopy screening. DESIGN, SETTING, AND PATIENTS: Colonoscopy data were prospectively collected from 67 adult gastrointestinal practice sites in the United States using a computerized endoscopic report generator between January 1, 2004, and December 31, 2005. Data were transmitted to a central data repository, where all asymptomatic white (n = 80 061) and black (n = 5464) patients who had received screening colonoscopy were identified. MAIN OUTCOME MEASURES: Prevalence and location of polyps sized more than 9 mm, adjusted for age, sex, and family history of colorectal cancer in a multivariate analysis. RESULTS: Both black men and women had a higher prevalence of polyps sized more than 9 mm in diameter compared with white men and women (422 [7.7%] vs 4964 [6.2%]; P < .001). Compared with white patients, the adjusted odds ratio (OR) for black men was 1.16 (95% confidence interval [CI], 1.01-1.34) and the adjusted OR for black women was 1.62 (95% CI, 1.39-1.89). Black and white patients had a similar risk of proximal polyps sized more than 9 mm (OR, 1.13;95% CI, 0.93-1.38). However, in a subanalysis of patients older than 60 years, proximal polyps sized more than 9 mm were more likely prevalent in black men (P = .03) and women (P < .001) compared with white men and women. CONCLUSION: Compared with white individuals, black men and women undergoing screening colonoscopy have a higher risk of polyps sized more than 9 mm, and black individuals older than 60 years are more likely to have proximal polyps sized more than 9 mm.

Polyp size and advanced histology in patients undergoing colonoscopy screening: implications for CT colonography.

BACKGROUND & AIMS: Colorectal cancer screening with diagnostic imaging can detect polyps. The management of patients whose largest polyp is less than 10 mm is uncertain. The primary aim of this study was to determine rates of advanced histology in patients undergoing colorectal cancer screening whose largest polyp is 9 mm or less. METHODS: Subjects include all asymptomatic adults receiving colonoscopy for screening during 2005 from 17 practice sites, which provide both colonoscopy and pathology reports to the Clinical Outcomes Research Initiative repository. Patients were classified by size of largest polyp. Advanced histology was defined as an adenoma with villous or serrated histology, high-grade dysplasia, or an invasive cancer. Risk factors for advanced histology were determined using Pearson chi(2) and Fisher exact tests. RESULTS: Among 13,992 asymptomatic patients who had screening colonoscopy, 6360 patients (45%) had polyps, with complete histology available in 5977 (94%) patients. The proportion with advanced histology was 1.7% in the 1- to 5-mm group, 6.6% in the 6- to 9-mm group, 30.6% in the greater than 10-mm group, and 72.1% in the tumor group. Distal location was associated with advanced histology in the 6- to 9-mm group (P = .04) and in the greater than 10-mm group (P = .002). CONCLUSIONS: One in 15 asymptomatic patients whose largest polyp is 6 to 9 mm will have advanced histology and would undergo surveillance at 3 years based on current guidelines. Because histology is necessary for this decision, most of these patients should be offered colonoscopy. Further study should determine whether patients whose largest polyp is 1-5 mm can be safely followed without polypectomy.

Terahertz imaging with compressed sensing and phase retrieval.

We describe a novel, high-speed pulsed terahertz (THz) Fourier imaging system based on compressed sensing (CS), a new signal processing theory, which allows image reconstruction with fewer samples than traditionally required. Using CS, we successfully reconstruct a 64 x 64 image of an object with pixel size 1.4 mm using a randomly chosen subset of the 4096 pixels, which defines the image in the Fourier plane, and observe improved reconstruction quality when we apply phase correction. For our chosen image, only about 12% of the pixels are required for reassembling the image. In combination with phase retrieval, our system has the capability to reconstruct images with only a small subset of Fourier amplitude measurements and thus has potential application in THz imaging with cw sources.

Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury.

OBJECTIVE: Abnormal myelination is a major pathological sequela of chronic periventricular white matter injury in survivors of premature birth. We tested the hypothesis that myelination failure in chronic hypoxia-ischemia-induced periventricular white matter injury is related to persistent depletion of the oligodendrocyte (OL) precursor pool required to generate mature myelinating OLs. METHODS: A neonatal rat model of hypoxia-ischemia was used where acute degeneration of late OL progenitors (preOLs) occurs via a mostly caspase-independent mechanism. The fate of OL lineage cells in chronic cerebral lesions was defined with OL lineage-specific markers. RESULTS: Acute caspase-3-independent preOL degeneration from hypoxia-ischemia was significantly augmented by delayed preOL death that was caspase-3-dependent. Degeneration of preOLs was offset by a robust regenerative response that resulted in a several-fold expansion in the pool of surviving preOLs in chronic lesions. However, these preOLs displayed persistent maturation arrest with failure to differentiate and generate myelin. When preOL-rich chronic lesions sustained recurrent hypoxia-ischemia at a time in development when white matter is normally resistant to injury, an approximately 10-fold increase in caspase-dependent preOL degeneration occurred relative to lesions caused by a single episode of hypoxia-ischemia. INTERPRETATION: The mechanism of myelination failure in chronic white matter lesions is related to a combination of delayed preOL degeneration and preOL maturation arrest. The persistence of a susceptible population of preOLs renders chronic white matter lesions markedly more vulnerable to recurrent hypoxia-ischemia. These data suggest that preOL maturation arrest may predispose to more severe white matter injury in preterm survivors that sustain recurrent hypoxia-ischemia.

Synthesis of natural product-inspired inhibitors of Mycobacterium tuberculosis mycothiol-associated enzymes: the first inhibitors of GlcNAc-Ins deacetylase.

Synthesis and evaluation of a chemical library of inhibitors of the mycothiol biosynthesis enzyme GlcNAc-Ins deacetylase (MshB) and the mycothiol-dependent detoxification enzyme mycothiol- S-conjugate amidase (MCA) from Mycobacterium tuberculosis are reported. The library was biased to include structural features of a group of natural products previously shown to competitively inhibit MCA. Molecular docking studies that reproducibly placed the inhibitors in the active site of the enzyme MshB reveal the mode of binding and are consistent with observed biological activity.