A single H/ACA small nucleolar RNA mediates tumor suppression downstream of oncogenic RAS.

Small nucleolar RNAs (snoRNAs) are a diverse group of non-coding RNAs that direct chemical modifications at specific residues on other RNA molecules, primarily on ribosomal RNA (rRNA). SnoRNAs are altered in several cancers; however, their role in cell homeostasis as well as in cellular transformation remains poorly explored. Here, we show that specific subsets of snoRNAs are differentially regulated during the earliest cellular response to oncogenic RASG12V expression. We describe a novel function for one H/ACA snoRNA, SNORA24, which guides two pseudouridine modifications within the small ribosomal subunit, in RAS-induced senescence in vivo. We find that in mouse models, loss of Snora24 cooperates with RASG12V to promote the development of liver cancer that closely resembles human steatohepatitic hepatocellular carcinoma (HCC). From a clinical perspective, we further show that human HCCs with low SNORA24 expression display increased lipid content and are associated with poor patient survival. We next asked whether ribosomes lacking SNORA24-guided pseudouridine modifications on 18S rRNA have alterations in their biophysical properties. Single-molecule Fluorescence Resonance Energy Transfer (FRET) analyses revealed that these ribosomes exhibit perturbations in aminoacyl-transfer RNA (aa-tRNA) selection and altered pre-translocation ribosome complex dynamics. Furthermore, we find that HCC cells lacking SNORA24-guided pseudouridine modifications have increased translational miscoding and stop codon readthrough frequencies. These findings highlight a role for specific snoRNAs in safeguarding against oncogenic insult and demonstrate a functional link between H/ACA snoRNAs regulated by RAS and the biophysical properties of ribosomes in cancer

How good are Global Newton methods? Part 2

Newton's method applied to certain problems with a discontinuous derivative operator is shown to be effective. A global Newton method in this setting is exhibited and its computational complexity is estimated. As an application a method is proposed to solve problems of linear inequalities (linear programming, phase 1). Using an example of the Klee-Minty type due to Blair, it was found that the simplex method (used in super-lindo) required over 2,000 iterations, while the method above required an average of 8 iterations (Newton steps) over 15 random starting values.Naval Surface Weapons Center, Dahlgren, VAhttp://archive.org/details/howgoodareglobal00goldO&MN Direct FundingApproved for public release; distribution is unlimited

Transmission of α-synucleinopathy from olfactory structures deep into the temporal lobe

Supplemental files to the publication Transmission of α-synucleinopathy from olfactory structures deep into the temporal lobe : Supplemental information (PDF): Materials and methods, tables, and supplemental figures S1-S8 (all supplemental figures are mentioned in the main text). Two mp4 movie files showing perinuclear localization of pSer129 signal (red) around NeuN+ nuclei (green). One movie shows a rotating cell and in the other video, the red pSer129 signal is peeled away to reveal the underlying green NeuN+ nucleus. Four high resolution figures (TIFF files)

Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters

<p>Abstract</p> <p>Background</p> <p>Surgical resection is one important curative treatment for hepatocellular carcinoma (HCC), but the prognosis following surgery differs substantially and such large variation is mainly unexplained. A review of the literature yields a number of clinicopathologic parameters associated with HCC prognosis. However, the results are not consistent due to lack of systemic approach to establish a prediction model incorporating all these parameters.</p> <p>Methods</p> <p>We conducted a retrospective analysis on the common clinicopathologic parameters from a cohort of 572 ethnic Chinese HCC patients who received curative surgery. The cases were randomly divided into training (n = 272) and validation (n = 300) sets. Each parameter was individually tested and the significant parameters were entered into a linear classifier for model building, and the prediction accuracy was assessed in the validation set</p> <p>Results</p> <p>Our findings based on the training set data reveal 6 common clinicopathologic parameters (tumor size, number of tumor nodules, tumor stage, venous infiltration status, and serum α-fetoprotein and total albumin levels) that were significantly associated with the overall HCC survival and disease-free survival (time to recurrence). We next built a linear classifier model by multivariate Cox regression to predict prognostic outcomes of HCC patients after curative surgery This analysis detected a considerable fraction of variance in HCC prognosis and the area under the ROC curve was about 70%. We further evaluated the model using two other protocols; leave-one-out procedure (n = 264) and independent validation (n = 300). Both were found to have excellent prediction power. The predicted score could separate patients into distinct groups with respect to survival (p-value = 1.8e-12) and disease free survival (p-value = 3.2e-7).</p> <p>Conclusion</p> <p>This described model will provide valuable guidance on prognosis after curative surgery for HCC in clinical practice. The adaptive nature allows easy accommodation for future new biomarker inputs, and it may serve as the foundation for future modeling and prediction for HCC prognosis after surgical treatment.</p

Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study

Objective: Serum α-fetoprotein (AFP) is the most commonly used biomarker for screening hepatocellular carcinoma (HCC) but fails to detect about half of the patients. Thus, we investigated if circulating microRNAs (miRNAs) could outperform AFP for HCC detection. Design: A retrospective cohort study. Setting: Two clinical centres in China. Participants: The exploration phase included 96 patients with HCC who received primary curative hepatectomy, and the validation phase included 29 hepatitis B carriers, 57 patients with HCC and 30 healthy controls. Main outcome measures: Expression of miRNAs was measured by real-time quantitative reverse transcription-PCR. Areas under receiver operating characteristic curves were used to determine the feasibility of using serum miRNA concentration as a diagnostic marker for defining HCC. A multivariate logistic regression analysis was used to evaluate performances of combined serum miRNAs. Results: In the exploration phase, miRNA profiling on resected tumour/adjacent non-tumour tissues identified miR-15b, miR-21, miR-130b and miR-183 highly expressed in tumours. These miRNAs were also detectable in culture supernatants of HCC cell lines and in serum samples of patients. Remarkably, these serum miRNAs were markedly reduced after surgery, indicating the tumour-derived source of these circulating miRNAs. In a cross-centre validation study, combined miR-15b and miR-130b demonstrated as a classifier for HCC detection, yielding a receiver operating characteristic curve area of 0.98 (98.2% sensitivity and 91.5% specificity). The detection sensitivity of the classifier in a subgroup of HCCs with low AFP (<20 ng/ml) was 96.7%. The classifier also identified early-stage HCC cases that could not be detected by AFP. Conclusion: The combined miR-15b and miR-130b classifier is a serum biomarker with clinical value for HCC screening.published_or_final_versio

Cellular Milieu Imparts Distinct Pathological α-Synuclein Strains in α-Synucleinopathies

Introduction: In Lewy body diseases-including Parkinson\u27s disease, without or with dementia, dementia with Lewy bodies, and Alzheimer\u27s disease with Lewy body co-pathology -α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites. By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) Objective: Our objective was to determine the conformational and biological profiles of a-Syn strains. Methods: The following methods were used to collect and analyze data: Recombinant α-Syn purification and in vitro fibrillization. Preparation of sarkosyl-insoluble fractions from disease and control brains. Sandwich ELISA. Cell cultures. Stereotaxic injection of sarkosyl-insoluble fraction of pathological α-Syn and α-Syn PFFs. Immunohistochemistry. Purification and depletion of α-Syn from the sarkosyl-insoluble fraction by immunoprecipitation. Results: GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments. Discussion: Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB- α-Syn, respectively) is conformationally and biologically distinct. Furthermore, we showed that distinct α-Syn strains had no cell type preference in seeding a-Syn pathology and are generated by different intracellular milieu

Cytoplasmic Forkhead Box M1 (FoxM1) in Esophageal Squamous Cell Carcinoma Significantly Correlates with Pathological Disease Stage

Abstract: Esophageal cancer is a deadly cancer with esophageal squamous cell carcinoma (ESCC) as the major type. Until now there has been a lack of reliable prognostic markers for this malignancy. This study aims to investigate the clinical correlation between Forkhead box M1 (FoxM1) and patients' parameters in ESCC. Methods: Immunohistochemistry was performed to investigate the expression and localization of FoxM1 in 64 ESCC tissues and 10 nontumor esophageal tissues randomly selected from 64 patients before these data were used for clinical correlations. Results: Cytoplasmic and nuclear expressions of FoxM1 were found in 63 and 16 of the 64 ESCC tissues, respectively. Low cytoplasmic expression of FoxM1 was correlated with early pathological stage in ESCC (P = 0.018), while patients with nuclear FoxM1 were younger in age than those without nuclear expression (P < 0.001). Upregulation of FoxM1 mRNA was found in five ESCC cell lines (HKESC-1, HKESC-2, HKESC-3, HKESC-4, and SLMT-1) when compared to non-neoplastic esophageal squamous cell line NE-1 using quantitative polymerase chain reaction (qPCR). Except for HKESC-3, all studied ESCC cell lines demonstrated a high expression of FoxM1 protein using immunoblot. A high mRNA level of FoxM1 was observed in all of the ESCC tissues examined when compared to their adjacent nontumor tissues using qPCR. Conclusion: Cytoplasmic FoxM1 was correlated with pathological stage and might be a biomarker for advanced ESCC. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Gene Signatures Derived from a c-MET-Driven Liver Cancer Mouse Model Predict Survival of Patients with Hepatocellular Carcinoma

Biomarkers derived from gene expression profiling data may have a high false-positive rate and must be rigorously validated using independent clinical data sets, which are not always available. Although animal model systems could provide alternative data sets to formulate hypotheses and limit the number of signatures to be tested in clinical samples, the predictive power of such an approach is not yet proven. The present study aims to analyze the molecular signatures of liver cancer in a c-MET-transgenic mouse model and investigate its prognostic relevance to human hepatocellular carcinoma (HCC). Tissue samples were obtained from tumor (TU), adjacent non-tumor (AN) and distant normal (DN) liver in Tet-operator regulated (TRE) human c-MET transgenic mice (n = 21) as well as from a Chinese cohort of 272 HBV- and 9 HCV-associated HCC patients. Whole genome microarray expression profiling was conducted in Affymetrix gene expression chips, and prognostic significances of gene expression signatures were evaluated across the two species. Our data revealed parallels between mouse and human liver tumors, including down-regulation of metabolic pathways and up-regulation of cell cycle processes. The mouse tumors were most similar to a subset of patient samples characterized by activation of the Wnt pathway, but distinctive in the p53 pathway signals. Of potential clinical utility, we identified a set of genes that were down regulated in both mouse tumors and human HCC having significant predictive power on overall and disease-free survival, which were highly enriched for metabolic functions. In conclusions, this study provides evidence that a disease model can serve as a possible platform for generating hypotheses to be tested in human tissues and highlights an efficient method for generating biomarker signatures before extensive clinical trials have been initiated

Original Article SOD2 rs4880 CT/CC genotype predicts poor survival for Chinese gastric cancer patients received platinum and fluorouracil based adjuvant chemotherapy

Abstract: Adjuvant chemotherapy is a standard therapy for gastric cancer patients, however, treatment response is quite heterogeneous. Molecular biomarkers will be highly valuable to guide the therapy and predict the response and prognosis in these patients. The antioxidant enzymes superoxide dismutase 2 (SOD2) and glutathione S-transferase pi 1 (GSTP1) are involved in oxidative stress and drug detoxification, which modulate the efficacy of anticancer drugs. Here, we investigated the clinical associations of two functional single nucleotide polymorphisms of SOD2 and GSTP1 in stage II-III postoperative gastric cancer patients. SOD2 rs4880 and GSTP1 rs1695 were genotyped in 207 patients received postoperative platinum and fluorouracil based chemotherapy and 304 patients who did not. SOD2 rs4880 CT/CC significantly associated with decreased median overall survival time of 23 months when compared to the TT genotype (mean overall survival time of 65.2 months, P=0.002) only for patients received adjuvant chemotherapy. Stratification analysis showed SOD2 rs4880 C