bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host-rock deformation during the emplacement of the Mourne Mountains granite pluton: Insights from the regional fracture pattern
Authors: Mattsson Tobias , Burchardt Steffi , Mair Karen , Place Joachim 
Published: December 2019

AbstractThe Mourne Mountains magmatic center in Northern Ireland consists of five successively intruded granites emplaced in the upper crust. The Mourne granite pluton has classically been viewed as a type locality of a magma body emplaced by cauldron subsidence. Cauldron subsidence makes space for magma through the emplacement of ring dikes and floor subsidence. However, the Mourne granites were more recently re-interpreted as laccoliths and bysmaliths. Laccolith intrusions form by inflation and dome their host rock. Here we perform a detailed study of the deformation in the host rock to the Mourne granite pluton in order to test its emplacement mechanism. We use the host-rock fracture pattern as a passive marker and microstructures in the contact-metamorphic aureole to constrain large-scale magma emplacement-related deformation. The dip and azimuth of the fractures are very consistent on the roof of the intrusion and can be separated into four steeply inclined sets dominantly striking SE, S, NE, and E, which rules out pluton-wide doming. In contrast, fracture orientations in the northeastern wall to the granites suggest shear parallel to the contact. Additionally, contact-metamorphic segregations along the northeastern contact are brecciated. Based on the host-rock fracture pattern, the contact aureole deformation, and the north-eastward–inclined granite-granite contacts, we propose that mechanisms involving either asymmetric “trap-door” floor subsidence or laccolith and bysmalith intrusion along an inclined or curved floor accommodated the emplacement of the granites and led to deflection of the northeastern wall of the intrusion.
IL6/STAT3 Signaling Orchestrates Premetastatic Niche Formation and Immunosuppressive Traits in Lung
Authors: Jing Bo , Wang Tong , Sun Beibei , Xu Jianhua , Xu Dongliang , Liao Yueling , Song Hongyong , Guo Wenzheng , Li Kaimi , Hu Min , Zhang Siwei , Ling Jing , Kuang Yanbin , Zhang Tuo , Zhou Binhua P. , Yao Feng , Deng Jiong 
Published: December 2019

Abstract
Cancer cells that succeed in forming metastasis need to be reprogrammed to evade immune surveillance and survive in a new microenvironment. This is facilitated by metastatic niches that are either postformed through reciprocal signaling between tumor cells and local stromal cells or preformed as premetastatic niches before tumor cell arrival. IL6/STAT3 signaling is aberrantly activated in lung tumorigenesis and metastasis, however, the roles and mechanisms of action of IL6 remain controversial. Here, we showed that blockade of intrinsic STAT3 signaling in lung tumor cells suppressed lung metastasis in immune-competent syngeneic mice, but not in immune-deficient nude mice. Consistently, repression of STAT3 signaling in tumor cells made them susceptible to T-cell–mediated cytotoxicity. Thus, STAT3-mediated immunosuppression is crucial for metastasis. Noticeably, lung metastasis was greatly increased in Gprc5a-knockout (ko; 5a−/−) mice compared with wild-type mice, which correlated with upregulated IL6 in the tumor microenvironment. Depletion of IL6 via combined deletion of Il6 and Gprc5a genes almost completely eliminated lung metastasis in Gprc5a-ko/Il6-ko (5a−/−;Il6−/−) mice. Mechanistically, dysregulated IL6 reprogrammed the STAT3 pathway in metastatic tumor cells, and induced recruitment of myeloid-derived suppressor cells and polarized macrophages to evade host immunity. Consistently, IHC staining showed that activated STAT3 correlated with repressed infiltration of CD8+ T cells in non–small cell lung cancer. Therefore, IL6/STAT3 signaling is crucial for orchestrating premetastatic niche formation and immunosuppression in lung.
Significance: IL6 plays important roles not only in cell autonomous propensity for metastasis, but also in establishing the metastatic niche.
Mitochondrial Haplotype of the Host Stromal Microenvironment Alters Metastasis in a Non-cell Autonomous Manner
Authors: Brinker Amanda E. , Vivian Carolyn J. , Beadnell Thomas C. , Koestler Devin C. , Teoh Shao Thing , Lunt Sophia Y. , Welch Danny R. 
Published: December 2019

AbstractMitochondria contribute to tumor growth through multiple metabolic pathways, regulation of extracellular pH, calcium signaling, and apoptosis. Using the Mitochondrial Nuclear Exchange (MNX) mouse models, which pair nuclear genomes with different mitochondrial genomes, we previously showed that mitochondrial SNPs regulate mammary carcinoma tumorigenicity and metastatic potential in genetic crosses. Here, we tested the hypothesis that polymorphisms in stroma significantly affect tumorigenicity and experimental lung metastasis. Using syngeneic cancer cells (EO771 mammary carcinoma and B16-F10 melanoma cells) injected into wild-type and MNX mice (i.e., same nuclear DNA but different mitochondrial DNA), we showed mt-SNP–dependent increases (C3H/HeN) or decreases (C57BL/6J) in experimental metastasis. Superoxide scavenging reduced experimental metastasis. In addition, expression of lung nuclear-encoded genes changed specifically with mt-SNP. Thus, mitochondrial–nuclear cross-talk alters nuclear-encoded signaling pathways that mediate metastasis via both intrinsic and extrinsic mechanisms.Significance:Stromal mitochondrial polymorphisms affect metastatic colonization through reactive oxygen species and mitochondrial–nuclear cross-talk.
Biomarkers of Exposure and Effect in the Lungs of Smokers, Nonsmokers, and Electronic Cigarette Users
Authors: Song Min-Ae , Freudenheim Jo L. , Brasky Theodore M. , Mathe Ewy A. , McElroy Joseph P. , Nickerson Quentin A. , Reisinger Sarah A. , Smiraglia Dominic J. , Weng Daniel Y. , Ying Kevin L. , Wewers Mark D. , Shields Peter G. 
Published: December 2019

AbstractBackground:Nicotine-containing electronic cigarette (e-cig) use has become widespread. However, understanding the biological impact of e-cigs compared with smoking on the lung is needed. There are major gaps in knowledge for chronic effects and for an etiology to recent acute lung toxicity leading to death among vapers.Methods:We conducted bronchoscopies in a cross-sectional study of 73 subjects (42 never-smokers, 15 e-cig users, and 16 smokers). Using bronchoalveolar lavage and brushings, we examined lung inflammation by cell counts, cytokines, genome-wide gene expression, and DNA methylation.Results:There were statistically significant differences among never-smokers, e-cig users, and smokers for inflammatory cell counts and cytokines (FDR q &lt; 0.1). The e-cig users had values intermediate between smokers and never-smokers, with levels for most of the biomarkers more similar to never-smokers. For differential gene expression and DNA methylation, e-cig users also more like never-smokers; many of these genes corresponded to smoking-related pathways, including those for xenobiotic metabolism, aryl hydrocarbon receptor signaling, and oxidative stress. Differentially methylated genes were correlated with changes in gene expression, providing evidence for biological effects of the methylation associations.Conclusions:These data indicate that e-cigs are associated with less toxicity than cigarettes for smoking-related pathways. What is unknown may be unique effects for e-cigs not measured herein, and a comparison of smokers completely switching to e-cigs compared with former smokers. Clinical trials for smokers switching to e-cigs who undergo serial bronchoscopy and larger cross-sectional studies of former smokers with and without e-cig use, and for e-cigs who relapse back to smoking, are needed.Impact:These data can be used for product regulation and for informing tobacco users considering or using e-cigs. What is unknown may be unique effects for e-cigs not measured herein, and clinical trials with serial bronchoscopy underway can demonstrate a direct relationship for changes in lung biomarkers.
The Proteomic Landscape of Pancreatic Ductal Adenocarcinoma Liver Metastases Identifies Molecular Subtypes and Associations with Clinical Response
Authors: Law Henry C.-H. , Lagundžin Dragana , Clement Emalie J. , Qiao Fangfang , Wagner Zachary S. , Krieger Kimiko L. , Costanzo-Garvey Diane , Caffrey Thomas C. , Grem Jean L. , DiMaio Dominick J. , Grandgenett Paul M. , Cook Leah M. , Fisher Kurt W. , Yu Fang , Hollingsworth Michael A. , Woods Nicholas T. 
Published: December 2019

Abstract

Purpose:
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease that can be separated into distinct subtypes based on molecular signatures. Identifying PDAC subtype-specific therapeutic vulnerabilities is necessary to develop precision medicine approaches to treat PDAC.

Experimental Design:
A total of 56 PDAC liver metastases were obtained from the UNMC Rapid Autopsy Program and analyzed with quantitative proteomics. PDAC subtypes were identified by principal component analysis based on protein expression profiling. Proteomic subtypes were further characterized by the associated clinical information, including but not limited to survival analysis, drug treatment response, and smoking and drinking status.

Results:
Over 3,960 proteins were identified and used to delineate four distinct PDAC microenvironment subtypes: (i) metabolic; (ii) progenitor-like; (iii) proliferative; and (iv) inflammatory. PDAC risk factors of alcohol and tobacco consumption correlate with subtype classifications. Enhanced survival is observed in FOLFIRINOX treated metabolic and progenitor-like subtypes compared with the proliferative and inflammatory subtypes. In addition, TYMP, PDCD6IP, ERAP1, and STMN showed significant association with patient survival in a subtype-specific manner. Gemcitabine-induced alterations in the proteome identify proteins, such as serine hydroxymethyltransferase 1, associated with drug resistance.

Conclusions:
These data demonstrate that proteomic analysis of clinical PDAC liver metastases can identify molecular signatures unique to disease subtypes and point to opportunities for therapeutic development to improve the treatment of PDAC.
Low-Dose Anti-Angiogenic Therapy Sensitizes Breast Cancer to PD-1 Blockade
Authors: Li Qian , Wang Yifan , Jia Weijuan , Deng Heran , Li Guangdi , Deng Weiye , Chen Jiewen , Kim Betty Y.S. , Jiang Wen , Liu Qiang , Liu Jieqiong 
Published: December 2019

Abstract

Purpose:
Despite its enormous successes, the overall response rate of cancer immunotherapy remains suboptimal, especially in breast cancer. There is an increased interest in combining immune checkpoint inhibitor with targeted agents to enhance antitumor effect. Anti-angiogenic drugs have been shown to synergize with immune checkpoint blockades, but the optimal setting for combining these two modalities and the underlying mechanisms of synergistic responses are not fully understood.

Experimental Design:
We tested the combination of anti–PD-1 and different doses of VEGFR2-targeting agents in syngeneic breast cancer mouse models. Tumor-infiltrated immune cell subsets were profiled by flow cytometry. A cytokine array was carried out to identify inflammatory changes in different treatment conditions. The efficacy of combined anti-angiogenic and anti–PD-1 therapy was further evaluated in patients with advanced triple-negative breast cancer (TNBC).

Results:
Blockade of VEGFR2 sensitizes breast tumors to PD-1 blockade in a dose-dependent manner. Although both conventional and low-dose anti-VEGFR2 antibody treatments normalize tumor vessels, low-dose VEGFR2 blockade results in more robust immune cell infiltration and activation and promotes the secretion of osteopontin (OPN) by CD8+ T cells. OPN subsequently induces tumor cell production of TGF-β, which in turn upregulates PD-1 expression on immune cells. In patients with advanced TNBC, combined treatment with low-dose anti-VEGFR2 inhibitor and anti–PD-1 demonstrated excellent tolerability and efficacy. Higher OPN and TGF-β expressions correlated with improved treatment responses.

Conclusions:
Together, these results demonstrate a dose-dependent synergism between anti-angiogenic therapy and immune checkpoint blockade, thus providing important insights into the optimal strategies for combining immunotherapy with molecular-targeted agents.
A Biparatopic Antibody That Modulates MET Trafficking Exhibits Enhanced Efficacy Compared with Parental Antibodies in MET-Driven Tumor Models
Authors: DaSilva John O. , Yang Katie , Perez Bay Andres E. , Andreev Julian , Ngoi Peter , Pyles Erica , Franklin Matthew C. , Dudgeon Drew , Rafique Ashique , Dore Anthony , Delfino Frank J. , Potocky Terra B. , Babb Robert , Chen Gang , MacDonald Douglas , Olson William C. , Thurston Gavin , Daly Christopher 
Published: December 2019

Abstract

Purpose:
Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating MET as a therapeutic target. Although antibody-mediated blockade of the MET pathway has not been successful in the clinic, the failures are likely the result of inadequate patient selection strategies as well as suboptimal antibody design. Thus, our goal was to generate a novel MET blocking antibody with enhanced efficacy.

Experimental Design:
Here, we describe the activity of a biparatopic MET×MET antibody that recognizes two distinct epitopes in the MET Sema domain. We use a combination of in vitro assays and tumor models to characterize the effect of our antibody on MET signaling, MET intracellular trafficking, and the growth of MET-dependent cells/tumors.

Results:
In MET-driven tumor models, our biparatopic antibody exhibits significantly better activity than either of the parental antibodies or the mixture of the two parental antibodies and outperforms several clinical-stage MET antibodies. Mechanistically, the biparatopic antibody inhibits MET recycling, thereby promoting lysosomal trafficking and degradation of MET. In contrast to the parental antibodies, the biparatopic antibody fails to activate MET-dependent biological responses, consistent with the observation that it recycles inefficiently and induces very transient downstream signaling.

Conclusions:
Our results provide strong support for the notion that biparatopic antibodies are a promising therapeutic modality, potentially having greater efficacy than that predicted from the properties of the parental antibodies.
Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models
Authors: Greene Sarah , Robbins Yvette , Mydlarz Wojciech K. , Huynh Angel P. , Schmitt Nicole C. , Friedman Jay , Horn Lucas A. , Palena Claudia , Schlom Jeffrey , Maeda Dean Y. , Zebala John A. , Clavijo Paul E. , Allen Clint 
Published: December 2019

Abstract

Purpose:
Natural killer (NK)-cell–based immunotherapy may overcome obstacles to effective T-cell–based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC.

Experimental Design:
The ability of peripheral and tumor-infiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell–inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a small-molecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells.

Results:
Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2+ neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFβ and production of H2O2. Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2+ CD15+ PMN-MDSC and CD14+ monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFβ and nitric oxide.

Conclusions:
The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.
Preclinical Evaluation of a Cabazitaxel Prodrug Using Nanoparticle Delivery for the Treatment of Taxane-Resistant Malignancies
Authors: Xie Binbin , Wan Jianqin , Chen Xiaona , Han Weidong , Wang Hangxiang 
Published: December 2019

Abstract
Taxane-based chemotherapeutics are clinically available as frontline treatment regimens for cervical cancer. However, drug resistance and life-threatening toxicity impair the clinical efficacy of taxanes, so more effective and less toxic therapeutic modalities are urgently needed. Cabazitaxel has attracted increasing interest due to its potential to circumvent the drug resistance by taxanes. We previously showed that tethering docosahexaenoic acid (DHA) to cabazitaxel enabled the prodrug to self-assemble into nanoparticles in water. Despite this encouraging finding, the DHA–cabazitaxel conjugate formulation requires further optimization to enhance nanoparticle retention and tumor delivery. We here integrated this conjugate into amphiphilic poly(ethylene glycol)-block-poly(D,L-lactic acid) copolymers to assemble dCTX NPs. The nanoparticle abrogated P-glycoprotein–mediated resistance in cancer cells. In a docetaxel-resistant cervical tumor xenograft-bearing mouse model, the efficacy was augmented by the nanotherapy when compared with solution-based free drugs (i.e., docetaxel and cabazitaxel). Dose intensification of dCTX NPs markedly suppressed the tumor growth in this model. Detailed studies revealed that systemic toxicity was alleviated, and MTD of dCTX NPs was at least 3 times higher than that of free cabazitaxel in animals, which may enable dose increases for clinical studies. In conclusion, the new formulation addresses essential requirements in terms of the stability, safety, and translational capacity for initiating early-phase clinical trials.
Aurora B Kinase Promotes CHIP-Dependent Degradation of HIF1α in Prostate Cancer Cells
Authors: Biswas Kuntal , Sarkar Sukumar , Said Neveen , Brautigan David L. , Larner James M. 
Published: December 2019

Abstract
Hypoxia is a major factor in tumor progression and resistance to therapies, which involves elevated levels of the transcription factor HIF1α. Here, we report that prostate tumor xenografts express high levels of HIF1α and show greatly enhanced growth in response to knockdown of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein). In multiple human prostate cancer cell lines under hypoxia, taxol treatment induces the degradation of HIF1α, and this response is abrogated by knockdown of CHIP, but not by E3 ligase VHL or RACK1. HIF1α degradation is accompanied by loss of function, evidenced by reduced expression of HIF1α-dependent genes. CHIP-dependent HIF1α degradation also occurs in cells arrested in mitosis by nocodazole instead of taxol. Mitotic kinase Aurora B activity is required for taxol-induced HIF1α degradation. Purified Aurora B directly phosphorylates HIF1α at multiple sites, and these modifications enhance its polyubiquitination by CHIP in a purified reconstituted system. Our results show how activation of Aurora B promotes CHIP-dependent degradation of HIF1α in prostate cancer cells. This new knowledge may affect the use of mitotic kinase inhibitors and open new approaches for treatment of hypoxic prostate tumors.
“When a Lion is Chided by an Ant”: Everyday Saints and the Making of Sufi Kings in ʿAttār’s Elāhi-nāma
Authors: Dabiri Ghazzal 
Published: December 2019

Abstract
This paper addresses Farid al-Din ʿAttār’s views on social and kingly ethics as espoused in the Elāhi-nāma. It offers a holistic reading of its stories, which are suffused with the tenets of Sufism, to illustrate the myriad ways that the Elāhi-nāma adopts and adapts the characteristics and tropes of practical ethics and Sufi hagiographies to advance its views. Indeed, the Elāhi-nāma promotes the ideal Sufi king and society by encouraging its members—saints, kings, and common folk—to be responsible, as individuals, for nurturing their souls, each other, and a love for the divine. It accomplishes this through a number of tale types, such as the saint or ruler who stumbles his or her way into self-awareness, the Sufi master or ruler who falters and is in need of guidance, or the hagiographical portraits of kings-as-Sufi lovers. In order to provide the appropriate context for the arguments herein, the paper explores several prominent themes and tropes from practical ethics and hagiographies and discusses Ebn ʿArabi’s al-Tadbirāt al-elāhiyya fi eslāh al-mamlaka al-ensāniyya for current notions on the responsibility of individuals and kings.
Changing Conservative Thinking in a Jesuit University
Authors: Engelbrechtová Jana 
Published: December 2019

This paper attempts to give a survey of the origin of the present collection of some forty works of Grotius in the present Scientific Library of Olomouc. After a short introduction about education in the Czech lands and especially in Olomouc, the present works of Grotius are discussed in connection with their origin. Most works were added to the collection due to the Josephine abolition of monasteries in the 1780s. Premonstratensian and Cistercian monasteries were the most important former possessors. A couple of Grotiana were donated by noblemen. A look is given to some course books that have been preserved. A complete list of all works of Grotius printed before 1800, present in the Scientific Library with an identification of their owners, is given in the annex.
Differential item functioning of the Arm function in Multiple Sclerosis Questionnaire (AMSQ) by language, a study in six countries
Authors: Kalkers Nynke F , Galan Ingrid , Kerbrat Anne , Tacchino Andrea , Kamm Christian P , O’Connell Karen , McGuigan Chris , Edan Gilles , Montalban Xavier , Uitdehaag Bernard MJ , Mokkink Lidwine B 
Published: December 2019

Background: The Arm function in Multiple Sclerosis Questionnaire (AMSQ) has been developed as a self-reported measure of arm and hand functioning for patients with multiple sclerosis (MS). The AMSQ was originally developed in Dutch and to date translated into five languages (i.e. English, German, Spanish, French, and Italian). Objective: The aim of this study was to evaluate differential item functioning (DIF) of the AMSQ in these languages. Methods: We performed DIF analyses, using “language” as the polytomous group variable. To detect DIF, logistic regression and item response theory principles were applied. Multiple logistic regression models were evaluated. We used a pseudo R2 value of 0.02 or more as the DIF threshold. Results: A total of 1733 male and female patients with all subtypes of MS were included. The DIF analysis for the whole dataset showed no uniform or non-uniform DIF on any of the 31 items. All R2 values were below 0.02. Conclusion: The AMSQ is validated in six languages. All items have the same meaning to MS patients in Dutch, English, German, Spanish, French, and Italian. This validation study enables use of the AMSQ in international studies, for monitoring treatment response and disease progression.