bluuebunny/crossref_metadata_2025_split huggingface dataset:
Formal Modeling and Verifying the TTCAN Protocol from a Probabilistic Perspective
Authors: Li Xin , Guo Jian , Zhao Yongxin , Zhu Xiaoran 
Published: October 2018

The time-triggered CAN (TTCAN) protocol has been widely used in the automotive industry to fulfil the safety and real-time requirements of the application. As an extension of the standard CAN protocol, the TTCAN protocol aims to guarantee a safe and deterministic communication by introducing time-triggered messages with respect to a global synchronized time, which are scheduled in independent transmission windows within the system matrix. However, the new features bring more difficulties in designing and verifying the reliable applications in the TTCAN network. In this paper, we first present a formal probabilistic model of the TTCAN protocol with a consideration of its novel features. A TTCAN system consisting of three parts, i.e., a system matrix, an arbitration and some nodes, is modeled as discrete Markov chains model. Furthermore, five probabilistic properties are described and verified in the probabilistic model checker tool PRISM. Our work gives a quantitative analysis method for the given requirements, which facilitates the designers to a formal understanding of TTCAN protocol.
Origin of the Ordovician Mansehra granite in the NW Himalaya, Pakistan: constraints from Sr–Nd isotopic data, zircon U–Pb age and Hf isotopes
Authors: Ogasawara Masatsugu , Fukuyama Mayuko , Siddiqui Rehanul Haq , Zhao Ye 
Published: October 2018

Abstract

The Mansehra granite in the NW Himalaya is a typical Lesser Himalayan granite. We present here new whole-rock geochemistry, Rb–Sr and Sm–Nd isotope data, together with zircon U–Pb ages and Hf isotope data, for the Mansehra granite. Geochemical data for the granite show typical S-type characteristics. Zircon U–Pb dating yields
206
Pb/
238
U crystallization ages of 483–476 Ma. The zircon grains contain abundant inherited cores and some of these show a clear detrital origin. The
206
Pb/
238
U ages of the inherited cores in the granite cluster in the ranges 889–664, 1862–1595 and 2029 Ma. An age of 664 Ma is considered to be the maximum age of the sedimentary protoliths. Thus the Late Neoproterozoic to Cambrian sedimentary rocks must be the protolith of the Mansehra granitic magma. The initial Sr isotope ratios are high, ranging from 0.7324 to 0.7444, whereas the
ε
Nd(t) values range from −9.2 to −8.6, which strongly suggests a large contribution of old crustal material to the protoliths. The two-stage Nd model ages and zircon Hf model ages are Paleoproterozoic, indicating that the protolith sediments were derived from Paleoproterozoic crustal components.
SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer
Authors: Tao Zhen , McCall Neal S. , Wiedemann Norbert , Vuagniaux Grégoire , Yuan Zhiyong , Lu Bo 
Published: October 2018

Abstract

Purpose:
Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrial-derived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity.

Experimental Design:
To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8+ T cells and TNFα, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFα, or anti-IFNγ antibodies. Tumor-infiltrating OVA-specific CD8+ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFα, IFNγ, and IL1β and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA.

Results:
ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8+ cells, TNFα, and IFNγ with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs.

Conclusions:
Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFα, IFNγ, and CD8+ T-cell–dependent manner. This provides a novel strategy to enhance the immunogenicity of ART.
Serum Nardilysin, a Surrogate Marker for Epithelial–Mesenchymal Transition, Predicts Prognosis of Intrahepatic Cholangiocarcinoma after Surgical Resection
Authors: Yoh Tomoaki , Hatano Etsuro , Kasai Yosuke , Fuji Hiroaki , Nishi Kiyoto , Toriguchi Kan , Sueoka Hideaki , Ohno Mikiko , Seo Satoru , Iwaisako Keiko , Taura Kojiro , Yamaguchi Rina , Kurokawa Masato , Fujimoto Jiro , Kimura Takeshi , Uemoto Shinji , Nishi Eiichiro 
Published: October 2018

Abstract

Purpose:
Few studies have investigated prognostic biomarkers in patients with intrahepatic cholangiocarcinoma (ICC). Nardilysin (NRDC), a metalloendopeptidase of the M16 family, has been suggested to play important roles in inflammation and several cancer types. We herein examined the clinical significance and biological function of NRDC in ICC.
Experimental Design: We measured serum NRDC levels in 98 patients with ICC who underwent surgical resection in two independent cohorts to assess its prognostic impact. We also analyzed NRDC mRNA levels in cancerous tissue specimens from 43 patients with ICC. We investigated the roles of NRDC in cell proliferation, migration, gemcitabine sensitivity, and gene expression in ICC cell lines using gene silencing.

Results:
High serum NRDC levels were associated with shorter overall survival and disease-free survival in the primary (n = 79) and validation (n = 19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels of NRDC (Spearman ρ = 0.413; P = 0.006). The gene knockdown of NRDC in ICC cell lines attenuated cell proliferation, migration, and tumor growth in xenografts, and increased sensitivity to gemcitabine. The gene knockdown of NRDC was also accompanied by significant changes in the expression of several epithelial–mesenchymal transition (EMT)-related genes. Strong correlations were observed between the mRNA levels of NRDC and EMT-inducing transcription factors, ZEB1 and SNAI1, in surgical specimens from patients with ICC.

Conclusions:
Serum NRDC, a possible surrogate marker reflecting the EMT state in primary tumors, predicts the outcome of ICC after surgical resection.
Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530
Authors: Locatelli Silvia L. , Careddu Giuseppa , Serio Simone , Consonni Francesca M. , Maeda Akihiro , Viswanadha Srikant , Vakkalanka Swaroop , Castagna Luca , Santoro Armando , Allavena Paola , Sica Antonio , Carlo-Stella Carmelo 
Published: October 2018

Abstract

Purpose:
Tumor-associated macrophages (TAMs) and the hyperactivation of the PI3K/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma and affect disease outcome. Because the δ and γ isoforms of PI3K are overexpressed in Hodgkin/Reed–Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kδ/γ inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response.

Experimental Design:
Hodgkin lymphoma cell lines (L-540, KM-H2, and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in Hodgkin lymphoma cell line xenografts.

Results:
In vitro, RP6530 besides killing and inhibiting the proliferation of Hodgkin lymphoma cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3Kδ/γ-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator pyruvate kinase M2 as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into proinflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, patients with Hodgkin lymphoma experiencing objective responses (complete response and partial response) in a phase I trial using RP6530 showed a significant inhibition of circulating myeloid-derived suppressor cells and an average mean reduction in serum thymus and activation-regulated chemokine levels of 40% (range, 4%–76%).

Conclusions:
Our results support PI3Kδ/γ inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.
Enhancing Abiraterone Acetate Efficacy in Androgen Receptor–positive Triple-negative Breast Cancer: Chk1 as a Potential Target
Authors: Grellety Thomas , Callens Celine , Richard Elodie , Briaux Adrien , Vélasco Valérie , Pulido Marina , Gonçalves Anthony , Gestraud Pierre , MacGrogan Gaetan , Bonnefoi Hervé , Cardinaud Bruno 
Published: October 2018

AbstractPurpose:Our aim was to identify predictive factors of abiraterone acetate efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial.Experimental Design: We defined abiraterone acetate response as either complete or partial response, or stable disease at 6 months. We sequenced 91 general and breast cancer–associated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a NanoString platform and performed IHC using tissue microarrays. We assessed abiraterone acetate and Chk1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo.Results:Classic IHC apocrine markers including AR, FOXA1, GGT1, and GCDFP15, from patients' tumors allowed identifying abiraterone acetate-responders and nonresponders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in nonresponders, of CHEK1, a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. On the basis of cell line experiments, abiraterone acetate and Chk1 inhibitor combination showed at least additive effect on cell viability, cell cycle, apoptosis, and accumulation of DNA damages. In vivo, orthotopic xenograft experiments confirmed the efficacy of this combination therapy.Conclusions:This study suggests that apocrine features can be helpful in the identification of abiraterone acetate-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.
Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14–mutant Non–small Cell Lung Cancer
Authors: Suzawa Ken , Offin Michael , Lu Daniel , Kurzatkowski Christopher , Vojnic Morana , Smith Roger S. , Sabari Joshua K. , Tai Huichun , Mattar Marissa , Khodos Inna , de Stanchina Elisa , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Lockwood William W. , Drilon Alexander , Ladanyi Marc , Somwar Romel 
Published: October 2018

Abstract

Purpose:
MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear.

Experimental Design:
We examined clinical and genomic data from 113 patients with lung cancer with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models.

Results:
Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models.

Conclusions:
KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.
Elastography Can Map the Local Inverse Relationship between Shear Modulus and Drug Delivery within the Pancreatic Ductal Adenocarcinoma Microenvironment
Authors: Wang Hexuan , Mislati Reem , Ahmed Rifat , Vincent Phuong , Nwabunwanne Solumtochukwu F. , Gunn Jason R. , Pogue Brian W. , Doyley Marvin M. 
Published: October 2018

AbstractPurpose:High tissue pressure prevents chemotherapeutics from reaching the core of pancreatic tumors. Therefore, targeted therapies have been developed to reduce this pressure. While point probes have shown the effectiveness of these pressure-reducing therapies via single-location estimates, ultrasound elastography is now widely available as an imaging technique to provide real-time spatial maps of shear modulus (tissue stiffness). However, the relationship between shear modulus and the underlying tumor microenvironmental causes of high tissue pressure has not been investigated. In this work, elastography was used to investigate how shear modulus influences drug delivery in situ, and how it correlates with collagen density, hyaluronic acid content, and patent vessel density—features of the tumor microenvironment known to influence tissue pressure.Experimental Design:Intravenous injection of verteporfin, an approved human fluorescent drug, was used in two pancreatic cancer xenograft models [AsPC-1 (n = 25) and BxPC-3 (n = 25)].Results:Fluorescence intensity was higher in AsPC-1 tumors than in BxPC-3 tumors (P &lt; 0.0001). Comparing drug uptake images and shear wave elastographic images with histologic images revealed that: (i) drug delivery and shear modulus were inversely related, (ii) shear modulus increased linearly with increasing collagen density, and (iii) shear modulus was marginally correlated with the local assessment of hyaluronic acid content.Conclusions:These results demonstrate that elastography could guide targeted therapy and/or identify patients with highly elevated tissue pressure.See related commentary by Nia et al., p. 2024
Targeting Resistance to Targeted Therapies: Combating a Resilient Foe
Authors: Devarakonda Siddhartha , Govindan Ramaswamy 
Published: October 2018

Abstract
While the advent of third-generation therapies has dramatically changed the treatment paradigm for EGFR-mutated lung cancer, resistance to these agents inevitably emerges. Understanding resistance mechanisms and their genomic underpinnings is crucial for developing innovative strategies that are capable of meaningfully prolonging patient survival.
See related article by Le et al., p. 6195
Quality of Life in a Randomized Breast Cancer Prevention Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women
Authors: Serrano Davide , Gandini Sara , Guerrieri-Gonzaga Aliana , Feroce Irene , Johansson Harriet , Macis Debora , Aristarco Valentina , Bonanni Bernardo , DeCensi Andrea 
Published: October 2018

Abstract
Menopausal symptoms are the main reason for withdrawal in tamoxifen prevention trials. Here, we present Menopause Quality of Life (MenQoL) assessment within a randomized 2 × 2 phase II clinical trial of low-dose tamoxifen and the synthetic retinoid fenretinide. A total of 235 premenopausal women at higher risk for breast cancer were randomized to either tamoxifen 5 mg daily, fenretinide 200 mg daily, their combination, or placebo. Climacteric symptoms were investigated using the MenQoL questionnaire which was self-administered at each visit for 2 years of treatment and for 1 year of follow-up. CYP2D6 was genotyped in subjects taking tamoxifen to study the association with menopausal symptoms. The MenQoL effect size analysis showed no statistically significant difference among the four treatment arms for all four domains (vasomotor, physical, psychosocial, and sexual). Vasomotor symptoms only slightly increased under tamoxifen, with a score at year two of 1.45, 1.21, 0.58, and 1.17 in the combined, tamoxifen, fenretinide, and placebo arms, respectively. Compared with the slow metabolizers, a higher percentage of subjects with CYP2D6 extensive metabolizer genotype complained of a ≥3 score in the vasomotor, psychosocial, and sexual domain in the tamoxifen arms (P value = 0.01, 0.007, and 0.007, respectively). QoL in premenopausal or perimenopausal women was not significantly worsened by low-dose tamoxifen or fenretinide. Our findings suggest that a low dose of tamoxifen may increase its acceptability for breast cancer prevention.
Circulating Receptor Activator of Nuclear Factor-κB (RANK), RANK ligand (RANKL), and Mammographic Density in Premenopausal Women
Authors: Toriola Adetunji T. , Appleton Catherine M. , Zong Xiaoyu , Luo Jingqin , Weilbaecher Katherine , Tamimi Rulla M. , Colditz Graham A. 
Published: October 2018

Abstract
The receptor activator of nuclear factor-κB (RANK) pathway plays essential roles in breast development. Mammographic density is a strong risk factor for breast cancer, especially in premenopausal women. We, therefore, investigated the associations of circulating RANK and soluble RANK ligand (sRANKL) with mammographic density in premenopausal women. Mammographic density was measured as volumetric percent density in 365 cancer-free premenopausal women (mean age, 47.5 years) attending screening mammogram at the Washington University School of Medicine (St. Louis, MO). We used linear regression models adjusted for confounders, to compare the least-square means of volumetric percent density across tertiles of circulating RANK and sRANKL. Furthermore, because RANKL levels in mammary tissue are modulated by progesterone, we stratified analyses by progesterone levels. The mean volumetric percent density increased across tertiles of circulating RANK from 8.6% in tertile 1, to 8.8% in tertile 2, and 9.5% in tertile 3 (Ptrend = 0.02). For sRANKL, the mean volumetric percent density was 8.5% in tertile 1, 9.4% in tertile 2, and 9.0% in tertile 3 (Ptrend = 0.30). However, when restricted to women with higher progesterone levels, the mean volumetric percent density increased from 9.1% in sRANKL tertile 1 to 9.5% in tertile 2, and 10.1% in tertile 3 (Ptrend = 0.01). Circulating RANK was positively associated with volumetric percent density, while circulating sRANKL was positively associated with volumetric percent density among women with higher progesterone levels. These findings support the inhibition of RANKL signaling as a pathway to reduce mammographic density and possibly breast cancer incidence in high-risk women with dense breasts.
Interventions to Reduce Future Cancer Incidence from Diesel Engine Exhaust: What Might Work?
Authors: Carey Renee N. , Fritschi Lin , Driscoll Timothy R. , Peters Susan , Glass Deborah C. , Benke Geza , Reid Alison 
Published: October 2018

Abstract
Exposure to diesel engine exhaust (DEE) contributes appreciably to the burden of occupational cancer. This study aims to estimate the potential impact of a range of interventions on the future burden of cancer from occupational exposure to DEE in Australia. The future excess fraction method, a novel method based on the lifetime risk approach, was used to model changes in the future burden of cancer among the Australian working age population exposed to DEE at work in 2012 under various intervention strategies. The interventions modeled were based on the widely accepted hierarchy of control model. At baseline, 600 (0.4%) future bladder and 4,450 (0.6%) future lung cancer cases over the lifetime of the cohort were estimated to be attributable to occupational exposure to DEE in those exposed in 2012. Up to 2,000 of these cases were estimated to be avoidable through the use of various interventions. Exhaust hoses (engineering controls) were estimated to be particularly effective. This study provides an indication of which intervention strategies may be most useful in reducing the future burden of cancer associated with occupational DEE exposure. These results show the potential effect of changing current exposure, rather than focusing on past exposures, and thus provide relevant information for policy planning.
Sirt1 Antisense Long Noncoding RNA Promotes Cardiomyocyte Proliferation by Enhancing the Stability of Sirt1
Authors: Li Bing , Hu Yinlan , Li Xinzhong , Jin Guoqing , Chen Xiaoqiang , Chen Guojun , Chen Yanmei , Huang Senlin , Liao Wangjun , Liao Yulin , Teng Zhonghua , Bin Jianping 
Published: October 2018

Background

Antisense long noncoding RNAs (lnc
RNA
s) are single‐stranded
RNA
s that overlapped gene‐coding regions on the opposite
DNA
strand and play as critical regulators in cardiovascular diseases. The high conservation and stability may be good advantages for antisense lnc
RNA
s. However, the roles of antisense lnc
RNA
s in cardiomyocyte proliferation and cardiac regeneration are still unknown.

Methods and Results

In this study, we found that Silent information regulator factor 2 related enzyme 1 (Sirt1) antisense lnc
RNA
expression was significantly increased during heart development. By gain and loss function of Sirt1 antisense lnc
RNA
using adenovirus and locked nucleic acid, respectively, we demonstrated that Sirt1 antisense lnc
RNA
promoted cardiomyocyte proliferation in vitro and in vivo, and the suppression of Sirt1 antisense lnc
RNA
inhibited cardiomyocyte proliferation. Moreover, overexpression of Sirt1 antisense lnc
RNA
enhanced cardiomyocyte proliferation, attenuated cardiomyocyte apoptosis, improved cardiac function, and decreased mortality rate after myocardial infarction. Furthermore, Sirt1 antisense lnc
RNA
can bind the Sirt1 3′‐untranslated region, enhancing the stability of Sirt1 and increasing Sirt1 abundance at both the
mRNA
and protein levels. Finally, we found that Sirt1 was involved in Sirt1 antisense lnc
RNA
‐induced cardiomyocyte proliferation.

Conclusions

The present study identified Sirt1 antisense lnc
RNA
as a novel regulator of cardiomyocyte proliferation and cardiac regeneration by interacting and stabilizing Sirt1
mRNA
, which may serve as an effective gene target for preventing myocardial infarction.