An Ordinal Latent Variable Model of Conflict Intensity

For the quantitative monitoring of international relations, political events are extracted from the news and parsed into "who-did-what-to-whom" patterns. This has resulted in large data collections which require aggregate statistics for analysis. The Goldstein Scale is an expert-based measure that ranks individual events on a one-dimensional scale from conflictual to cooperative. However, the scale disregards fatality counts as well as perpetrator and victim types involved in an event. This information is typically considered in qualitative conflict assessment. To address this limitation, we propose a probabilistic generative model over the full subject-predicate-quantifier-object tuples associated with an event. We treat conflict intensity as an interpretable, ordinal latent variable that correlates conflictual event types with high fatality counts. Taking a Bayesian approach, we learn a conflict intensity scale from data and find the optimal number of intensity classes. We evaluate the model by imputing missing data. Our scale proves to be more informative than the original Goldstein Scale in autoregressive forecasting and when compared with global online attention towards armed conflicts

Component-wise approximate Bayesian computation via Gibbs-like step

Approximate Bayesian computation methods are useful for generative models with intractable likelihoods. These methods are however sensitive to the dimension of the parameter space, requiring exponentially increasing resources as this dimension grows. To tackle this difficulty, we explore a Gibbs version of the Approximate Bayesian computation approach that runs component-wise approximate Bayesian computation steps aimed at the corresponding conditional posterior distributions, and based on summary statistics of reduced dimensions. While lacking the standard justifications for the Gibbs sampler, the resulting Markov chain is shown to converge in distribution under some partial independence conditions.The associated stationary distribution can further be shown to be close to the true posterior distribution and some hierarchical versions of the proposed mechanism enjoy a closed form limiting distribution. Experiments also demonstrate the gain in efficiency brought by the Gibbs version over the standard solution

Ameloblastic Fibrosarcoma: Clinicopathological and Molecular Analysis of 7 Cases Highlighting Frequent BRAF and Occasional NRAS Mutations

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Mismatch Repair Proteins hMLH1 and hMSH2 Are Differently Expressed in the Three Main Subtypes of Sporadic Renal Cell Carcinoma

Objectives: We studied the role of minor mismatch repair proteins (MMR) human MutL homologue 1 (hMLH1) and human MutS homologue 2 (hMSH2) in the main subtypes of renal cell carcinoma (RCC). Methods: Expression of MMR proteins hMLH1 and hMSH2 were investigated in 166 RCC tumors, containing the main subtypes by immunohistochemistry. Furthermore, each tumor was screened for microsatellite instability (MSI) using the National Cancer Institute consensus panel for hereditary non-polyposis colon carcinoma as well as for elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) by 10 additional markers. Results: MSI was found only in 2.0% of analyzable cases and EMAST was detected only in 1 patient. hMLH1 and hMSH2 expression was reduced in 83.7 (118/141) and 51.2% (65/127) of cases, respectively, in a subtype-specific manner. None of the clear cell RCC tumors retained a high hMLH1 expression and 92.0% lost hMLH1 completely, while papillary and chromophobe RCC preserved the expression in 25.0 and 33.3% of cases (p < 0.001). Subtype specificity was also present in hMSH2 staining, where chromophobe RCC retained a high expression in 41.7% of cases, while clear cell and papillary tumors did not (29.9 and 23.1%; p = 0.01). Conclusion: MSI and EMAST are rare events in sporadic RCC, whereas diminished MMR protein expression is linked to tumor entity and might contribute to the different biological behavior of the RCC subtypes

S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer

Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multi-targeting approach against PI3K, mTORC1/2 and MAPK

A Detailed Far-Ultraviolet Spectral Atlas of Main Sequence B Stars

We have constructed a detailed spectral atlas covering the wavelength region 930A to 1225A for 10 sharp-lined B0-B9 stars near the main sequence. Most of the spectra we assembled are from the archives of the FUSE satellite, but for nine stars wavelength coverage above 1188A was taken from high-resolution IUE or echelle HST/STIS spectra. To represent the tenth star at type B0.2 V we used the Copernicus atlas of tau Sco. We made extensive line identifications in the region 949A to 1225A of all atomic features having published oscillator strengths at types B0, B2, and B8. These are provided as a supplementary data product - hence the term detailed atlas. Our list of found features totals 2288, 1612, and 2469 lines, respectively. We were able to identify 92%, 98%, and 98% of these features with known atomic transitions with varying degrees of certainty in these spectra. The remaining lines do not have published oscillator strengths. Photospheric lines account for 94%, 87%, and 91%, respectively, of all our iden- tifications, with the remainder being due to interstellar (usually molecular H2) lines. We also discuss the numbers of lines with respect to the distributions of various ions for these three most studied spectral subtypes. A table is also given of 167 least blended lines that can be used as possible diagnostics of physical conditions in B star atmospheres.Comment: Accepted by ApJ Supplements, 186,175, 2010. Paper contains 42 pages, 4 figures, 5 tables. Auxiliary files contain ascii table of line IDs, 32 plots for Figs 1 and 2. FITS spectral data available upon reques

Two Multiplex Assays That Simultaneously Identify 22 Possible Mutation Sites in the KRAS, BRAF, NRAS and PIK3CA Genes

Recently a number of randomized trials have shown that patients with advanced colorectal cancer do not benefit from therapies targeting the epidermal growth factor receptor when their tumors harbor mutations in the KRAS, BRAF and PIK3CA genes. We developed two multiplex assays that simultaneously screen 22 nucleotides in the KRAS, NRAS, BRAF and PIK3CA genes for mutations. The assays were validated on 294 tumor DNA samples from patients with advanced colorectal cancer. In these samples 119 KRAS codon 12 and 13 mutations had been identified by sequence analysis, 126 tumors were wild-type for KRAS and the analysis failed in 49 of the 294 samples due to poor DNA quality. The two mutation assays detected 130 KRAS mutations, among which were 3 codon 61 mutations, and in addition 32 PIK3CA, 13 BRAF and 6 NRAS mutations. In 19 tumors a KRAS mutation was found together with a mutation in the PIK3CA gene. One tumor was mutant for both PIK3CA and BRAF. In summary, the mutations assays identified 161 tumors with a mutation, 120 were wild-type and the analysis failed in 13. The material cost of the 2 mutation assays was calculated to be 8-fold lower than the cost of sequencing required to obtain the same data. In addition, the mutation assays are less labor intensive. We conclude that the performance of the two multiplex mutation assays was superior to direct sequencing. In addition, these assays are cheaper and easier to interpret. The assays may also be of use for selection of patients with other tumor types

Identification and Diagnostic Performance of a Small RNA within the PCA3 and BMCC1 Gene Locus That Potentially Targets mRNA

Background: PCA3 is a long noncoding RNA (lncRNA) with unknown function, upregulated in prostate cancer. LncRNAs may be processed into smaller active species. We hypothesized this for PCA3. Methods: We computed feasible RNA hairpins within the BMCC1 gene (encompassing PCA3) and searched a prostate transcriptome for these. We measured expression using qRT-PCR in three cohorts of prostate cancer tissues (n = 60), exfoliated urinary cells (n = 484 with cancer and n = 166 controls), and in cell lines (n = 22). We used in silico predictions and RNA knockup to identify potential mRNA targets of short transcribed RNAs. Results: We predicted 13 hairpins, of which PCA3-shRNA2 was most abundant within the prostate transcriptome. PCA3-shRNA2 is located within intron 1 of PCA3 and appears regulated by androgens. Expression of PCA3-shRNA2 was upregulated in malignant prostatic tissues, exfoliated urinary cells from men with prostate cancer (13–273 fold change; t test P < 0.003), and closely correlated to PCA3 expression (r = 0.84–0.93; P < 0.001). Urinary PCA3-shRNA2 (C-index, 0.75–0.81) and PCA3 (C-index, 0.78) could predict the presence of cancer in most men. PCA3-shRNA2 knockup altered the expression of predicted target mRNAs, including COPS2, SOX11, WDR48, TEAD1, and Noggin. PCA3-shRNA2 expression was negatively correlated with COPS2 in patient samples (r = −0.32; P < 0.001). Conclusion: We identified a short RNA within PCA3, whose expression is correlated to PCA3, which may target mRNAs implicated in prostate biology

Diagnostic and Prognostic Implications of FGFR3(high)/Ki67(high) Papillary Bladder Cancers

Prognostic/therapeutic stratification of papillary urothelial cancers is solely based upon histology, despite activated FGFR3-signaling was found to be associated with low grade tumors and favorable outcome. However, there are FGFR3-overexpressing tumors showing high proliferation-a paradox of coexisting favorable and adverse features. Therefore, our study aimed to decipher the relevance of FGFR3-overexpression/proliferation for histopathological grading and risk stratification. N = 142 (n = 82 pTa, n = 42 pT1, n = 18 pT2-4) morphologically G1-G3 tumors were analyzed for immunohistochemical expression of FGFR3 and Ki67. Mutation analysis of FGFR3 and TP53 and FISH for FGFR3 amplification and rearrangement was performed. SPSS 23.0 was used for statistical analysis. Overall FGFR3(high)/Ki67(high) status (n = 58) resulted in a reduced Delta mean progression-free survival (PFS) (p < 0.01) of 63.92 months, and shorter progression-free survival (p < 0.01;mean PFS: 55.89 months) in pTa tumors (n = 50). FGFR3(mut)/TP53(mut) double mutations led to a reduced Delta mean PFS (p < 0.01) of 80.30 months in all tumors, and FGFR3(mut)/TP53(mut) pTa tumors presented a dramatically reduced PFS (p < 0.001;mean PFS: 5.00 months). Our results identified FGFR3(high)/Ki67(high) papillary pTa tumors as a subgroup with poor prognosis and encourage histological grading as high grade tumors. Tumor grading should possibly be augmented by immunohistochemical stainings and suitable clinical surveillance by endoscopy should be performed