An integrated model for predicting KRAS dependency

The clinical approvals of KRAS G12C inhibitors have been a revolutionary advance in precision oncology, but response rates are often modest. To improve patient selection, we developed an integrated model to predict KRAS dependency. By integrating molecular profiles of a large panel of cell lines from the DEMETER2 dataset, we built a binary classifier to predict a tumor's KRAS dependency. Monte Carlo cross validation via ElasticNet within the training set was used to compare model performance and to tune parameters α and λ. The final model was then applied to the validation set. We validated the model with genetic depletion assays and an external dataset of lung cancer cells treated with a G12C inhibitor. We then applied the model to several Cancer Genome Atlas (TCGA) datasets. The final "K20" model contains 20 features, including expression of 19 genes and KRAS mutation status. In the validation cohort, K20 had an AUC of 0.94 and accurately predicted KRAS dependency in both mutant and KRAS wild-type cell lines following genetic depletion. It was also highly predictive across an external dataset of lung cancer lines treated with KRAS G12C inhibition. When applied to TCGA datasets, specific subpopulations such as the invasive subtype in colorectal cancer and copy number high pancreatic adenocarcinoma were predicted to have higher KRAS dependency. The K20 model has simple yet robust predictive capabilities that may provide a useful tool to select patients with KRAS mutant tumors that are most likely to respond to direct KRAS inhibitors

Classifications of dense languages

Let X be a finite alphabet containing more than one letter. A dense language over X is a language containing a disjunctive language. A language L is an n-dense language if for any distinct n words w(1), w(2),..., w(n) is an element of X+, there exist two words u, v is an element of X* such that uw(1)v, uw(2)v,... uw(n)v is an element of L. In this paper we classify dense languages into strict n- dense languages and study some of their algebraic properties. We show that for each n >= 0, the n- dense language exists. For an n- dense language L, n not equal 1, the language L boolean AND Q is a dense language, where Q is the set of all primitive words over X. Moreover, for a given n >= 1, the language L is such that L boolean AND Q is an element of D-n(X), then L is an element of D-m( X) for some m, n = 0, can be split into disjoint union of infinitely many n- dense languages

New Fermions at e+^+e−^- Colliders: I. Production and Decay

We analyze the production in $e^+e^-$ collisions of new heavy fermions stemming from extensions of the Standard Model. We write down the most general expression for the production of two heavy fermions and their subsequent decays, allowing for the polarization of the e$^+$e$^-$ initial state and taking into account the final polarization of the fermions. We then discuss the various decay modes including cascade and three body decays, and the production mechanisms, both pair production and single production in association with ordinary fermions.Comment: 21 pages (no figures), Preprint UdeM-LPN-TH-93-15

Neural network parametrization of spectral functions from hadronic tau decays and determination of QCD vacuum condensates

The spectral function $\rho_{V-A}(s)$ is determined from ALEPH and OPAL data on hadronic tau decays using a neural network parametrization trained to retain the full experimental information on errors, their correlations and chiral sum rules: the DMO sum rule, the first and second Weinberg sum rules and the electromagnetic mass splitting of the pion sum rule. Nonperturbative QCD vacuum condensates can then be determined from finite energy sum rules. Our method minimizes all sources of theoretical uncertainty and bias producing an estimate of the condensates which is independent of the specific finite energy sum rule used. The results for the central values of the condensates $O_6$ and $O_8$ are both negative.Comment: 29 pages, 18 ps figure

Tau Polarimetry with Multi Meson States

It is demonstrated that the analyzing power of multi-meson final states in semileptonic $\tau$ decays with respect to the $\tau$ spin is equal and maximal for all decay modes.Comment: 4 pages, LaTex. The complete paper is also available via anonymous ftp at ftp://ttpux2.physik.uni-karlsruhe.de/ , or via www at http://ttpux2.physik.uni-karlsruhe.de/cgi-bin/preprints

Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β–induced Serpine1

In tumors, extravascular fibrin forms provisional scaffolds for endothelial cell (EC) growth and motility during angiogenesis. We report that fibrin-mediated angiogenesis was inhibited and tumor growth delayed following postnatal deletion of Tgfbr2 in the endothelium of Cdh5-CreERT2 Tgfbr2fl/fl mice (Tgfbr2iECKOmice). ECs from Tgfbr2iECKO mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpine1, also known as PAI-1), due in part to uncoupled TGF-β–mediated suppression of miR-30c. Bypassing TGF-β signaling with vascular tropic nanoparticles that deliver miR-30c antagomiRs promoted PAI-1–dependent tumor growth and increased fibrin abundance, whereas miR-30c mimics inhibited tumor growth and promoted vascular-directed fibrinolysis in vivo. Using single-cell RNA-Seq and a NanoString miRNA array, we also found that subtypes of ECs in tumors showed spectrums of Serpine1 and miR-30c expression levels, suggesting functional diversity in ECs at the level of individual cells; indeed, fresh EC isolates from lung and mammary tumor models had differential abilities to degrade fibrin and launch new vessel sprouts, a finding that was linked to their inverse expression patterns of miR-30c and Serpine1 (i.e., miR-30chi Serpine1lo ECs were poorly angiogenic and miR-30clo Serpine1hi ECs were highly angiogenic). Thus, by balancing Serpine1 expression in ECs downstream of TGF-β, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation

Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis

Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma

Regioselective deacetylation based on teicoplanin-complexed Orf2*crystal structures

Lipoglycopeptide antibiotics are more effective than vancomycin against MRSA as they carry an extra aliphatic acyl side chain on glucosamine (Glm) at residue 4 (r4). The biosynthesis of the r4 N-acyl Glc moiety at teicoplanin (Tei) or A40926 has been elucidated, in which the primary amine nucleophile of Glm is freed from the r4 GlcNac pseudo-Tei precursor by Orf2* for the subsequent acylation reaction to occur. In this report, two Orf2* structures in complex with beta-D-octyl glucoside or Tei were solved. Of the complexed structures, the substrate binding site and a previously unknown hydrophobic cavity were revealed, wherein r4 GlcNac acts as the key signature for molecular recognition and the cavity allows substrates carrying longer acyl side chains in addition to the acetyl group. On the basis of the complexed structures, a triple-mutation mutant S98A/V121A/F193Y is able to regioselectively deacetylate r6 GlcNac pseudo-Tei instead of that at r4. Thereby, novel analogs can be made at the r6 sugar moiety

Institutional pedagogical waypoints : reflections on doctoral journeys between Taiwan and Australia

Spatial, social and academic journeys undertaken between Taiwan and Australia for doctoral education are the focus of reflection here. The discussion centres on the authors’ experiences of, on the one hand, the development of a Faculty of Education’s doctoral pedagogies in the early 2000s to reflect its international PhD candidature profile – especially from Taiwan – and, on the other, of Taiwanese doctoral candidates’ journeys through their PhDs in the Faculty. The authors write from their particular perspectives: Evans as an Australian academic and a manager of doctoral studies, and Liou as a Taiwanese academic pursuing her doctorate in an Australian university. The article considers the Australian and Taiwanese doctoral contexts between which the students transited. The institutional pedagogical strategies, from pre-enrolment to completion, are examined as waypoints on the doctoral journey for both staff and candidates

Neutralino Decays at the CERN LHC

We study the distribution of lepton pairs from the second lightest neutralino decay \tchi^0_2\to\tchi^0_1 l^+l^-. This decay mode is important to measure the mass difference between \tchi^0_2 and the lightest neutralino \tchi^0_1, which helps to determine the parameters of the minimal supersymmetric standard model at the CERN LHC. We found that the decay distribution strongly depends on the values of underlying MSSM parameters. For some extreme cases, the amplitude near the end point of the lepton invariant mass distribution can be suppressed so strongly that one needs the information of the whole m_{ll} distribution to extract m_{\tchi^0_2}-m_{\tchi^0_1}. On the other hand, if systematic errors on the acceptance can be controlled, this distribution can be used to constrain slepton masses and the Z\tchi^0_2\tchi^0_1 coupling. Measurements of the velocity distribution of \tchi^0_2 from samples near the end point of the m_{ll} distribution, and of the asymmetry of the p_T of leptons, would be useful to reduce the systematic errors.Comment: 23 pages, latex2e, 9 figures, minor change, accepted to PR