bluuebunny/crossref_metadata_2025 huggingface dataset:
The evolution of submarine slope-channel systems: Timing of incision, bypass, and aggradation in Late Cretaceous Nanaimo Group channel-system strata, British Columbia, Canada
Authors: Englert R.G. , Hubbard S.M. , Matthews W.A. , Coutts D.S. , Covault J.A.
Published: December 2019

Submarine channel systems convey terrestrially derived detritus from shallow-marine environments to some of the largest sediment accumulations on Earth, submarine fans. The stratigraphic record of submarine slope channels includes heterogeneous, composite deposits that provide evidence for erosion, sediment bypass, and deposition. However, the timing and duration of these processes is poorly constrained over geologic time scales. We integrate geochronology with detailed stratigraphic characterization to temporally constrain the stratigraphic evolution recorded by horizontally to vertically aligned channel-fill stacking patterns in a Nanaimo Group channel system exposed on Hornby and Denman Islands, British Columbia, Canada. Twelve detrital zircon samples (n = 300/sample) were used to calculate maximum depositional ages, which identified a new age range for the succession from ca. 79 to 63 Ma. We document five phases of submarine-channel evolution over 16.0 ± 1.7 m.y. including: an initial phase dominated by incision, sediment bypass, and limited deposition (phase 1); followed by increasingly shorter and more rapid phases of deposition on the slope by laterally migrating (phase 2) and aggrading channels (phase 3); a long period of deep incision (phase 4); and a final rapid phase of vertical channel aggradation (phase 5). Our results suggest that ∼60% of the evolutionary history of the submarine channel system is captured in an incomplete, poorly preserved record of incision and sediment bypass, which makes up <20% of outcropping stratigraphy. Our findings are applicable to interpreting submarine channel-system evolution in ancient and modern settings worldwide and fundamentally important to understanding long-term sediment dispersal in the deep sea.
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

The 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.
Generalised papular variant of elastolytic giant cell granuloma
Authors: Caldas Regina , Guimarães Maria José , Rodrigues Ana Patrícia , Araújo Catarina
Published: December 2019

Elastolytic giant cell granuloma (EGCG), also known as actinic granuloma, is an uncommon granulomatous dermatosis usually characterised by asymptomatic annular plaques on sun-exposed skin. Its aetiology is not fully elucidated, but actinic damage has been considered the main causal factor. Atypical variants with lesions in a non-photodistributed pattern are rare and often related to a systemic disorder, suggesting a more complex pathogenesis and demanding for a screening work-up. Herein, we report a case of an adult obese, diabetic woman presenting with a generalised pruritic papular eruption, histologically revealing an elastolytic giant cell granuloma, with a good response to treatment. In this case, the dermatosis was probably associated with her metabolic comorbidities.
Meglumine antimoniate combination treatment for relapsing Kala-azar after treatment and secondary prophylaxis failure with liposomal amphotericin B in two HIV-coinfected patients
Authors: Camara Lara , Queirós João , Ribeiro Rita , Teófilo Eugénio
Published: December 2019

Visceral leishmaniasis (VL) is a protozoan infection caused byLeishmania infantumandL. donovaniwith a higher incidence and severity in HIV-infected patients due to its synergistic effect on hampering the immune response, often leading to death after treatment failure. Literature regarding the management of relapsing VL in HIV-coinfected patients is lacking. Many experts recommend a combined therapy with liposomal amphotericin B and miltefosine. The use of pentavalent antimonials is often discouraged due to their toxicity. We report two cases of successful response to treatment with combined therapy with meglumine antimoniate followed by secondary prophylaxis with miltefosine and atovaquone on relapsing VL in two HIV-coinfected patients despite treatment and monthly prophylaxis with appropriate doses of liposomal amphotericin B.
Cu2ZnSnS4 (CZTS) thin films prepared by sol–gel spin-coating technique
Authors: Xiong Chao , Gao Min , Gao Wei
Published: December 2019

The [Formula: see text] (CZTS) thin film is a photovoltaics material with excellent photoelectric properties and has good potential applications. The CZTS thin films with different spin-coated layers and sulfurized temperatures were successfully prepared by a sol–gel spin-coating technique. The relationships of microstructure, surface morphology and processing parameters were studied using XRD, SEM and EDS. The results indicate that the grain size of the sample sulfurized at [Formula: see text]C was larger than that of the sample sulfurized at [Formula: see text]C. With increasing layers of spin, coatings, the films showed better crystalline structure. The sulfureted CZTS thin films prepared by six spin-coating possess uniform elemental distribution.
A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic β-cells
Authors: Chaudhry Ahsen , Shi Rocky , Luciani Dan S.
Published: December 2019

Live-cell imaging of mitochondrial function and dynamics can provide vital insights into both physiology and pathophysiology, including of metabolic diseases like type 2 diabetes. However, without super-resolution microscopy and commercial analysis software, it is challenging to accurately extract features from dense multilayered mitochondrial networks, such as those in insulin-secreting pancreatic β-cells. Motivated by this, we developed a comprehensive pipeline and associated ImageJ plugin that enables 2D/3D quantification of mitochondrial network morphology and dynamics in mouse β-cells and by extension other similarly challenging cell types. The approach is based on standard confocal microscopy and shareware, making it widely accessible. The pipeline was validated using mitochondrial photolabeling and unsupervised cluster analysis and is capable of morphological and functional analyses on a per-organelle basis, including in 4D ( xyzt). Overall, this tool offers a powerful framework for multiplexed analysis of mitochondrial state/function and provides a valuable resource to accelerate mitochondrial research in health and disease.
H-M Bearing Capacity of Cone-Shaped Foundation for Onshore Wind Turbine under Monotonic Horizontal Loading
Authors: Xing GuoQi , Liu ChangJiang , Li ShanShan , Xuan Wei
Published: December 2019

In this paper, monotonic horizontal loading tests were carried out to study the bearing capacity of the cone-shaped foundation in marine fine sand. With load-controlled methods, the horizontal load was applied to the rod of cone-shaped foundation at loading eccentricity ratios of 5.0, 6.0, and 7.0. In addition, theoretical analysis was used to investigate the horizontal ultimate bearing capacity, and finite element analysis was also used in this paper to investigate the influence factors of the bearing capacity of cone-shaped foundation. Based on the theoretical analysis, the formula for horizontal ultimate bearing capacity was deduced. Test results show that, at the same loading eccentricity, cone-shaped foundation can provide higher H-M bearing capacity as well as lower lateral deflection compared to regular circular foundation for wind turbines. In addition, the deflection-hardening behavior of load-deflection curve for cone-shaped foundation is also observed. Numerical analysis results show that the H-M bearing capacity of the cone-shaped foundation increases with increasing aspect ratio and buried depth, however, and decreases with increasing loading eccentricity. Based on the results from finite element analyses, several equations to calculate the maximum moment bearing capacities are put forward, which take the aspect ratio, loading eccentricity, and embedded depth into account.
Changes in the Management of Patients with Crohn’s Disease Based on Magnetic Resonance Enterography Patterns
Authors: Chinem Evelyn Sayuri S. , Esberard Barbara C. , Moreira Andre da L. , Barbassa Tatiana G. , da Cunha Guilherme M. , Carneiro Antonio Jose de V. , de Souza Heitor S. , Carvalho Ana Teresa P.
Published: December 2019

Background and Aims. Magnetic resonance enterography (MRE) has become an important modality of radiological imaging in the evaluation of Crohn’s disease (CD). The aim of this study was to investigate the impact of MRE in the assessment of disease activity and abdominal complications and in the making of therapeutic decisions for patients with CD. Methods. In a cross-sectional retrospective study, we selected 74 patients with CD who underwent MRE and ileocolonoscopy with an interval between the two exams of up to 30 days between January 2011 and December 2017. We assessed the parameters of the images obtained by MRE and investigated the agreement with the level of disease activity and complications determined by a clinical evaluation, inflammatory biomarkers, and endoscopy, as well as the resulting changes in medical and surgical management. Results. Changes in medical management were detected in 41.9% of patients. Significant changes in medical decisions were observed in individuals with a purely penetrating (P=.012) or a mixed (P=.024) MRE pattern. Patients with normal MRE patterns had a correlation with unchanged medical decisions (P=.001). There were statistically significant agreements between the absence of inflammatory criteria on MRE and remission according to the Harvey and Bradshaw index (HBI) (P=.037), the presence of inflammatory criteria on MRE and positive results for calprotectin (P=.005), and penetrating criteria on MRE and the scoring endoscopic system for Crohn’s disease (SES-CD), indicating active disease (P=.048). Finally, there was significant agreement between the presence of fibrostenotic criteria and a long disease duration (P=.027). Conclusion. MRE discloses disease activity and complications not apparent with other modalities and results in changes in therapeutic decisions. In addition to being used for diagnosis, MRE should be routinely used in the follow-up of CD patients.
Ship Steering Control Based on Quantum Neural Network
Authors: Guan Wei , Zhou Haotian , Su Zuojing , Zhang Xianku , Zhao Chao
Published: December 2019

During the mission at sea, the ship steering control to yaw motions of the intelligent autonomous surface vessel (IASV) is a very challenging task. In this paper, a quantum neural network (QNN) which takes the advantages of learning capabilities and fast learning rate is proposed to act as the foundation feedback control hierarchy module of the IASV planning and control strategy. The numeric simulations had shown that the QNN steering controller could improve the learning rate performance significantly comparing with the conventional neural networks. Furthermore, the numeric and practical steering control experiment of the IASV BAICHUAN has shown a good control performance similar to the conventional PID steering controller and it confirms the feasibility of the QNN steering controller of IASV planning and control engineering applications in the future.
Scheimpflug Camera-Based Stereo-Digital Image Correlation for Full-Field 3D Deformation Measurement
Authors: Sun Cong , Liu Haibo , Shang Yang , Chen Shengyi , Yu Qifeng
Published: December 2019

To further extend the scope of stereo-digital image correlation (stereo-DIC) to more challenging environments, a novel Scheimpflug camera-based stereo-DIC is developed for full-field 3D deformation measurement, wherein the Scheimpflug condition, consisting of tilting the sensor plane with respect to the lens plane for the sake of larger depth of field (DOF) of the camera, is employed. The geometric imaging model of the Scheimpflug camera is described, on the basis of which a robust and effective stepwise calibration strategy is performed to calculate the intrinsic and extrinsic parameters of the stereo Scheimpflug rig. With the aid of a specially tailored stereo triangulation method and well-developed subset-based DIC algorithms, the three-dimensional shape and displacement of the specimen can be retrieved. Finally, practical experiments, including rigid motion tests and three-point bending tests, demonstrate the effectiveness and accuracy of the proposed approach.
Labial Adhesions Causing Recurrent Urinary-Tract Infections in an Elderly Woman
Authors: Takemaru Masashi , Aramaki-Hattori Noriko , Tsue Chisato , Kishi Kazuo
Published: December 2019

A 91-year-old postmenopausal woman with a prior history of two labial-adhesion separations suffered from recurrent urinary-tract infections. We were able to successfully treat her labial adhesions using surgery.
A Brush‐Type Tire Model with Nonsmooth Representation
Authors: Kikuuwe Ryo
Published: December 2019

This paper proposes a brush‐type tire model with a new mathematical representation. The presented model can be seen as a generic model that describes the distributed viscoelastic force and Coulomb‐like friction force, which are balancing each other at each point, in the contact patch. The model is described as a partial differential algebraic inclusion (PDAI), which involves the set‐valuedness to represent the static friction. A numerical integration algorithm for this PDAI is derived through the implicit Euler discretization along both space and time. Some numerical comparisons with Magic Formula and a LuGre‐based tire model are presented. The results show that, with appropriate choice of parameters, the proposed model is capable of producing steady‐state characteristics similar to those of Magic Formula. It is also shown that the proposed model realizes a proper static friction state, which is not realized with a LuGre‐based tire model.
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

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

Mitochondria 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

Background:

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 < 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

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

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

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

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

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

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.
Medication-Induced Repigmentation of Gray Hair: A Systematic Review
Authors: Yale Katerina , Juhasz Margit , Atanaskova Mesinkovska Natasha
Published: December 2019

Hair graying is a common sign of aging resulting from complex regulation of melanogenesis. Currently, there is no medical treatment available for hair repigmentation. In this article we review the literature on medication-induced hair repigmentation, discuss the potential mechanisms of action, and review the quality of the literary data. To date, there have been 27 studies discussing medication-induced gray hair repigmentation, including 6 articles on gray hair repigmentation as a primary objective, notably with psoralen treatment or vitamin supplementation, and 21 reports on medication-induced gray hair repigmentation as an incidental finding. Medications noted in the literature include anti-inflammatory medications (thalidomide, lenalidomide, adalimumab, acitretin, etretinate, prednisone, cyclosporin, cisplatinum, interferon-α, and psoralen), stimulators of melanogenesis (latanoprost, erlotinib, imatinib, tamoxifen, and levodopa), vitamins (calcium pantothenate and para-amino benzoic acid), a medication that accumulates in tissues (clofazimine), and a medication with an undetermined mechanism (captopril). Diffuse repigmentation of gray hair can be induced by certain medications that inhibit inflammation or stimulate melanogenesis. There is also low-quality evidence that some vitamin B complex supplementation can promote gray hair darkening. While these compounds are not currently indicated for the treatment of gray hair, their mechanisms shed light on targets for future medications for hair repigmentation.
Duration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific Mortality
Authors: Heianza Yoriko , Ma Wenjie , Li Xiang , Cao Yin , Chan Andrew T. , Rimm Eric B. , Hu Frank B. , Rexrode Kathryn M. , Manson JoAnn E. , Qi Lu
Published: December 2019

Rationale:

The overuse of antibiotics has been an important clinical issue, and antibiotic exposure is linked to alterations in gut microbiota, which has been related to risks of various chronic diseases such as cardiovascular disease and cancer. Also, duration of antibiotic exposure may be a risk factor of premature death.

Objective:

We investigated associations of life-stage and duration of antibiotic use during adulthood with risks of all-cause and cause-specific mortality.

Methods and Results:

This prospective cohort study included 37 516 women aged ≥60 years who were free of cardiovascular disease or cancer from the Nurses’ Health Study. Participants reported a total amount of time they used antibiotics (none, <15 days, 15 days to <2 months, or ≥2 months) in the middle- (age, 40–59) and late adulthood (age, 60 or older). We estimated hazard ratios for all-cause mortality and deaths from cardiovascular disease or cancer over 10 years according to duration of antibiotic use. During 355 918 person-years of follow-up, we documented 4536 deaths from any cause (including 728 cardiovascular deaths and 1206 cancer deaths). As compared with women who did not use antibiotics, those who used them for ≥2 months in late adulthood had increased risks of all-cause mortality (hazard ratio, 1.16 [95% CI, 1.01–1.33]) and cardiovascular mortality (hazard ratio, 1.49 [95% CI, 1.04–2.13]), but not cancer mortality (hazard ratio, 0.85 [95% CI, 0.65–1.12]) after adjustment for chronic metabolic diseases, antibiotic use during middle adulthood, indication for use, demographic factors, and lifestyle/dietary factors. The association was more evident among women who also used antibiotics in middle-adulthood than among those who did not use during this life-stage.

Conclusions:

Long-term use of antibiotics in late adulthood may be a risk factor for all-cause and cardiovascular mortality. The unfavorable effect of antibiotic exposure for subsequent risks of deaths due to chronic diseases needs to be considered.
“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

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.
Observations on the Biology of Afrotropical Hesperiidae (Lepidoptera). Part 8. Hesperiinae incertae sedis: Dracaena Feeders
Authors: COCK MATTHEW J. W. , CONGDON T. COLIN E. , COLLINS STEVE C.
Published: December 2019

The Afrotropical genera Gamia and Artitropa are only known to feed on species of Dracaena (Asparagaceae), and together with Leona lissa Evans, which may require a new genus, they are the only Afrotropical Hesperiidae that feed on this unusual host genus. We present partial life histories of two species of Gamia, 22 taxa of Artitropa (of at least 12 species, and including several undescribed taxa), and notes on the life history of L. lissa. Based on life history information, Gamia and Artitropa are considered likely to form a monophyletic group, probably most closely related to some of the palm-feeding genera currently placed incertae sedis, but formerly in Evans’ 1937 Ploetzia group of genera. Notes on natural enemies of A. erinnys (Trimen) and A. milleri Evans are included.
Cymbiodyta lishizheni sp. nov., the second species of the genus from China
Authors: JIA FENGLONG , LIN RENCHAO
Published: December 2019

The water scavenger beetle genus Cymbiodyta Bedel contains 30 species (Jia & Short 2010, Short & Fikáček 2011), most of which are distributed in North America. Only one species (Cymbiodyta orientalis Jia & Short, 2010) has been described since the worldwide revision of the genus by Smetana (1974). This taxon was the second species of the genus known from the Old World and the first species known from the Oriental Region. Subsequently, Jia (2014) described the male of C. orientalis Jia & Short and provided photographs of the aedeagus.
Phidon chanco sp. nov. of cockroach from the coastal forest of central Chile (Insecta: Blattaria)
Authors: VERA S. ALEJANDRO
Published: December 2019

Phidon chanco sp. nov. is the first species of the genus where both sexes are described Male and female genitalia are described and illustrated using SEM. The new species can be distinguished from the other members of the genus, by the existence of brachypterism in both sexes; in males the median triangle of the sternum IX is long, sclerotised, and its apex strongly armed with numerous denticles; in females the tergite X is emarginate. The new species is distributed exclusively in the coastal forests of central Chile, in association with remnants of native flora and protected areas.
Cognitive and Achievement Characteristics of Students From a National Sample Identified as Potentially Twice Exceptional (Gifted With a Learning Disability)
Authors: Maddocks Danika L. S.
Published: December 2019

It is important to identify cognitive and achievement characteristics that differentiate students who are twice exceptional because they are gifted and have a learning disability (2e-LD) from gifted and average ability peers because this information informs empirically-based identification and support systems for this population. In this study, I classified school-age participants ( N = 3,865) in the nationally representative standardization sample for the Woodcock-Johnson IV (WJ IV) Tests of Cognitive Abilities and Achievement as potentially gifted, 2e-LD, or of average ability based on their WJ IV performance. I compared mean levels of performance, strengths and weaknesses, and intraindividual heterogeneity across 2e-LD, gifted, and average-ability groups. The 2e-LD group demonstrated greater heterogeneity in performance, and their strengths and weaknesses were largely consistent with past research and writing on 2e-LD characteristics. Results support some 2e-LD identification recommendations from the literature and highlight the potential benefits of individualized assessment, dual differentiation, and a de-emphasis of speeded academic tasks.
In Response to Cultural Threat: Cultural Self-Awareness on Collective Movement Participation
Authors: Lu Chieh , Wan Ching , Hui Pamsy P. , Tong Yuk-yue
Published: December 2019

This study investigated the role of cultural self-awareness, an individual’s awareness of culture’s influence on the self, on collective movement participation. We posited that individuals who were highly aware of their culture’s influence on them would more likely perceive self-relevance of cultural circumstances. In the context of a cultural threat, such perception of self-relevance would lead to psychological and behavioral reactions that affirm one’s collective identity. We tested our predictions during a collective political movement in Hong Kong. Results showed that among Hong Kong university students, the higher the cultural self-awareness, the more they participated in the collective movement. The relationship was mediated by increased pride in Hong Kong and a more exclusive Hong Kong identity. The findings highlighted the importance of metacognitive reflection of the self in collective processes.
The Influence of Power on U.S. and Chinese Individuals’ Judgments and Reasoning About Intrasocietal Conflicts
Authors: Zhu Nan , Hawk Skyler T. , Smetana Judith G.
Published: December 2019

This study used a social domain theory framework to investigate Chinese and U.S. individuals’ evaluations of intrasocietal conflicts (defined as situations where some individuals’ rights clash with collective interests), and how those evaluations might be influenced by concepts of high versus low power. Undergraduate students in both the United States ( n = 92) and China ( n = 98) received either a high-power or a low-power prime and then evaluated (a) the acceptability of actions taken by different parties in hypothetical scenarios about intrasocietal conflicts, (b) moral and societal justifications for these actions, and (c) the appropriateness of actions by outside, third parties aimed at affirming individual rights. Results showed that moral justifications for individual actions were positively associated with pro-individual-rights judgments in both societies, regardless of power condition. In addition, U.S. individuals primed with high power and Chinese participants primed with low power showed lower support for third-party actions, based on societal concerns from the collective perspective. Chinese participants primed with high power also accepted collective actions based on moral and societal concerns. These results extend social domain theory by demonstrating how different power concepts affect the relative importance of moral versus societal concerns in individuals’ judgments, especially when evaluating third-party actions.
Making values explicit in evaluation practice
Authors: Gullickson Amy M , Hannum Kelly M
Published: December 2019

Values play a fundamental role in the evaluation process; however, evaluators and evaluation training have tended to focus on research methodology. Much less emphasis has been placed on explicit attention to values and valuing, and the steps necessary to justify those aspects of evaluation conclusions. In this article, we argue that to improve evaluation practice, we need to make values an explicit part of the evaluation process. Research done in other disciplines can offer assistance towards this end. We first provide a general discussion of basic practical applications of value theories. Then, we offer an example for how a particular individual values theory, Schwartz’s Theory of Basic Human Values, can inform our work and encourage further exploration of approaches for incorporating value theories into evaluation practice.