bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody-Mediated Endocytosis of Polysialic Acid Enables Intracellular Delivery and Cytotoxicity of a Glycan-Directed Antibody–Drug Conjugate
Authors: Cox Emily C. , Thornlow Dana N. , Jones Michaela A. , Fuller Jordan L. , Merritt Judith H. , Paszek Matthew J. , Alabi Christopher A. , DeLisa Matthew P. 
Published: February 2019

Abstract

The specific targeting of differentially expressed glycans in malignant cells has emerged as an attractive anticancer strategy. One such target is the oncodevelopmental antigen polysialic acid (polySia), a polymer of α2,8-linked sialic acid residues that is largely absent during postnatal development but is re-expressed during progression of several malignant human tumors, including small-cell and non–small cell lung carcinomas, glioma, neuroblastoma, and pancreatic carcinoma. In these cancers, expression of polySia correlates with tumor progression and poor prognosis and appears to modulate cancer cell adhesion, invasiveness, and metastasis. To evaluate the potential of PolySia as a target for anticancer therapy, we developed a chimeric human polySia-specific mAb that retained low nanomolar (nmol/L) target affinity and exhibited exquisite selectivity for polySia structures. The engineered chimeric mAb recognized several polySia-positive tumor cell lines in vitro and induced rapid endocytosis of polySia antigens. To determine whether this internalization could be exploited for delivery of conjugated cytotoxic drugs, we generated an antibody–drug conjugate (ADC) by covalently linking the chimeric human mAb to the tubulin-binding maytansinoid DM1 using a bioorthogonal chemical reaction scheme. The resulting polySia-directed ADC demonstrated potent target-dependent cytotoxicity against polySia-positive tumor cells in vitro. Collectively, these results establish polySia as a valid cell-surface, cancer-specific target for glycan-directed ADC and contribute to a growing body of evidence that the tumor glycocalyx is a promising target for synthetic immunotherapies.

Significance:
These findings describe a glycan-specific antibody-drug conjugate that establishes polySia as a viable cell surface target within the tumor glycocalyx.
Retinoic Acid–Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer
Authors: Cao Dalong , Qi Zihao , Pang Yangyang , Li Haoran , Xie Huyang , Wu Junlong , Huang Yongqiang , Zhu Yao , Shen Yijun , Zhu Yiping , Dai Bo , Hu Xin , Ye Dingwei , Wang Ziliang 
Published: February 2019

Abstract

Retinoic acid–related orphan receptor C (RORC) is a member of the nuclear orphan receptor family and performs critical regulatory functions in cell proliferation, metastasis, and chemoresistance in various types of malignant tumors. Here we showed that expression of RORC is lost in tumor tissues of bladder cancer patients. Enhanced expression of RORC suppressed cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis in vitro and in vivo. RORC bound the promoter region of programmed death ligand-1 (PD-L1) and negatively regulated PD-L1 expression. PD-L1 directly interacted with integrin β6 (ITGB6) and activated the ITGB6/FAK signaling pathway. RORC prevented the nuclear translocation of STAT3 via suppression of the PD-L1/ITGB6 signaling pathway, which further inhibited bladder cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis. These findings reveal that RORC regulates bladder cancer cell proliferation, glucose metabolism, and chemoresistance by participating in the PD-L1/ITGB6/STAT3 signaling axis. Moreover, this new understanding of PD-L1 signaling may guide the selection of therapeutic targets to prevent tumor recurrence.

Significance:
These findings suggest that RORC-mediated regulation of a PD-L1/ITGB6/FAK/STAT3 signaling axis in bladder cancer provides several potential therapeutic targets to prevent tumor progression.
B7-H3 Expression in Merkel Cell Carcinoma–Associated Endothelial Cells Correlates with Locally Aggressive Primary Tumor Features and Increased Vascular Density
Authors: Aung Phyu P. , Parra Edwin Roger , Barua Souptik , Sui Dawen , Ning Jing , Mino Barbara , Ledesma Debora Alejandra , Curry Jonathan L. , Nagarajan Priyadharsini , Torres-Cabala Carlos A. , Efstathiou Eleni , Hoang Anh G. , Wong Michael K. , Wargo Jennifer A. , Lazar Alexander J. , Rao Arvind , Prieto Victor G. , Wistuba Ignacio , Tetzlaff Michael T. 
Published: February 2019

Abstract

Purpose:
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease.
Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid.

Results:
Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC.

Conclusions:
Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.
Large-scale Circulating microRNA Profiling for the Liquid Biopsy of Prostate Cancer
Authors: Urabe Fumihiko , Matsuzaki Juntaro , Yamamoto Yusuke , Kimura Takahiro , Hara Tomohiko , Ichikawa Makiko , Takizawa Satoko , Aoki Yoshiaki , Niida Shumpei , Sakamoto Hiromi , Kato Ken , Egawa Shin , Fujimoto Hiroyuki , Ochiya Takahiro 
Published: February 2019

Abstract

Purpose:
The high false-positive rate of prostate-specific antigen (PSA) may lead to unnecessary prostate biopsies. Therefore, the United States Preventive Services Task Force recommends that decisions regarding PSA-based screening of prostate cancer should be made with caution in men ages 55–69 years, and that men ≥70 years should not undergo PSA screening. Here, we investigated the potential of serum miRNAs as an accurate diagnostic method in patients with suspected prostate cancer.

Experimental Design:
Serum samples of 809 patients with prostate cancer, 241 negative prostate biopsies, and 500 patients with other cancer types were obtained from the National Cancer Center, Japan. Forty-one healthy control samples were obtained from two other hospitals in Japan. Comprehensive microarray analysis was performed for all samples. Samples were divided into three sets. Candidate miRNAs for prostate cancer detection were identified in the discovery set (n = 123). A diagnostic model was constructed using combinations of candidate miRNAs in the training set (n = 484). The performance of the diagnostic model was evaluated in the validation set (n = 484).

Results:
In the discovery set, 18 candidate miRNAs were identified. A robust diagnostic model was constructed using the combination of two miRNAs (miR-17-3p and miR-1185-2-3p) in the training set. High diagnostic performance with a sensitivity of 90% and a specificity of 90% was achieved in the validation set regardless of the Gleason score and clinical tumor–node–metastasis stage.

Conclusions:
The model developed in this study may help improve the diagnosis of prostate cancer and reduce the number of unnecessary prostate biopsies.
Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
Authors: Oh Ji Hoon , Kim Myeong Joon , Choi Seong Jin , Ban Young Ho , Lee Heung Kyu , Shin Eui-Cheol , Lee Kyung-Mi , Ha Sang-Jun 
Published: February 2019

AbstractThe importance of natural killer (NK) cells in the early immune response to viral or bacterial infection is well known. However, the phenotype, function, and physiologic role of NK cells during the late stage of persistent viral infection have not been extensively studied. Here, we characterized NK cells in mice persistently infected with lymphocytic choriomeningitis virus clone 13 and showed that in contrast to NK cells from acutely infected or uninfected mice, NK cells from chronically infected mice expressed a terminally differentiated phenotype, stronger cytotoxicity, and reduced inhibitory receptor expression. In an in vivo tumor model, chronically infected mice exhibited significantly delayed tumor progression in an NK cell–dependent manner. NK cells from chronically infected mice also expressed high STAT1, and blocking the type I interferon (IFN) receptor revealed that type I IFN signaling directly regulated NK cell cytotoxicity. Our findings indicate that sustained type I IFN signaling during chronic viral infection potentiates the cytolytic function of NK cells and contributes to NK cell–dependent host immune surveillance.
Characterization of dorsal guard hair of the wild goats and sheep (Bovidae: Caprinae) occurring in the Himalaya and Western Ghats of India
Authors: Kamalakannan Manokaran 
Published: February 2019

The morphological and microscopic characteristics of dorsal guard hair of six species of the Indian goat-antelopes are described. Although the cuticular characteristics of hair of all the six species studied are similar, the morphological, medulla and transverse section characteristics of hair are varied between the species. The hair of Indian caprines can easily be identified on the basis of their unique medulla and transverse section. The high-resolution microphotographs and key characteristics of hair are presented here and can be used as an appropriate reference for species identification of the wild goats and sheep occurring in the Himalaya and Western Ghats of India.
New record of Low’s Flatfaced Longhorn Beetle Sarothrocera lowii White, 1846 (Coleoptera: Cerambycidae: Lamiinae: Lamiini) in Nagaland, India, along with first-time descriptions of male and female genitalia
Authors: Kolla Sreedevi , Sharma Manisha , Ghate Hemant Vasant 
Published: February 2019

Sarothrocera lowii White, 1846 is the only species belonging to the genus Sarothrocera (Coleoptera: Cerambycidae: Lamiinae). Both the sexes of S. lowii were collected from Medziphema, Nagaland, northeastern India, during surveys in 2016. Earlier, Ghate et al. (2012) and Kumawat et al. (2015) reported this species from Manipur and Arunachal Pradesh, respectively, based on female specimens. This paper describes detailed characters of male S. lowii with comments on the female, along with the genitalia descriptions of both sexes for the first time. The species is a new report from Nagaland, India, adding to the known distribution.
‘Non-protected’ primates as bushmeat, pets and pests in southeastern Democratic Republic of Congo
Authors: Kazaba Paul Kaseya 
Published: February 2019

This article reports the uses of primates in a fast-expanding city, and human-primate interactions in the vicinity of a protected area in southeastern Democratic Republic of Congo (DRC). Surveys in markets, households and restaurants suggested that primate meat is frequently sold and consumed in the city of Lubumbashi. Carcasses of diurnal monkeys accounted for almost 10% of the total weight of smoked bushmeat sold between March and July 2016 in urban markets, and in 21% of households the last bushmeat consumed prior the date of the survey was of a primate species. Kinda Baboons Papio kindae, Malbrouck Monkeys Chlorocebus cynosuros and Blue Monkeys Cercopithecus mitis were found illegally kept as pets. Occasional observations and questionnaire surveys carried out in both the Sector North of Upemba National Park and its neighboring areas, indicated wild populations of these species which were mentioned as “pest primates” by 73% of respondents. There is no compensation scheme for damages caused by wildlife to crops, and culling problematic animals was listed by a majority (70%) of respondents as the most effective way to repel crop-raiding primates. Given the current population growth, and considering the increasing spatial overlap between human activities and wildlife, wild populations of these primates are no doubt at risk, but all the three species belong to the Least Concern category on the latest version of the IUCN Red List. The Blue Monkey is a ‘partially protected’ species in DRC, while the two other benefit from less strict conservation measures and their legal status of ‘non-protected’ remains. This situation illustrates the necessity of updating legal status and establishing a Red List of species at the country level.
Substantial Cardiovascular Morbidity in Adults With Lower-Complexity Congenital Heart Disease
Authors: Saha Priyanka , Potiny Praneetha , Rigdon Joseph , Morello Melissa , Tcheandjieu Catherine , Romfh Anitra , Fernandes Susan M. , McElhinney Doff B. , Bernstein Daniel , Lui George K. , Shaw Gary M. , Ingelsson Erik , Priest James R. 
Published: February 2019

Background:
Although lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors.

Methods:
A multitiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison among >500 000 British adults in the UK Biobank. ACHD diagnoses were subclassified as isolated aortic valve and noncomplex defects. Time-to-event analyses were conducted for the primary end points of fatal or nonfatal acute coronary syndrome, ischemic stroke, heart failure, and atrial fibrillation and a secondary combined end point for major adverse cardiovascular events. Maximum follow-up time for the study period was 22 years with retrospectively and prospectively collected data from the UK Biobank.

Results:

We identified 2006 individuals with lower-complexity ACHD and 497 983 unexposed individuals in the UK Biobank (median age at enrollment, 58 [interquartile range, 51–63] years). Of the ACHD-exposed group, 59% were male, 51% were current or former smokers, 30% were obese, and 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes mellitus, respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary end points, with hazard ratios ranging from 2.0 (95% CI, 1.5–2.8;
P
<0.001) for acute coronary syndrome to 13.0 (95% CI, 9.4–18.1;
P
<0.001) for heart failure. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of major adverse cardiovascular events, in contrast to 13% in individuals without ACHD with ≥5 risk factors.

Conclusions:
Individuals with lower-complexity ACHD had a higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.
Tactical Decision-Making Support Information for Aircraft Lightning Avoidance: Feasibility Study in Area of Winter Lightning
Authors: Yoshikawa Eiichi , Ushio Tomoo 
Published: February 2019

AbstractDid you know that aircraft can cause lightning? Researchers began investigating aircraft-triggered lightning after several cases were observed of aircraft receiving lightning strikes from lightning-inactive clouds. The phenomenon of aircraft-triggered lightning was subsequently confirmed by a UHF radar, and today, it is known that most aircraft lightning strikes are aircraft triggered. However, aviation weather support for aircraft lightning avoidance has not been well developed. This is probably because aircraft lightning strikes have been somewhat avoided by using other information such as thunderstorm nowcasting, and have hardly ever caused serious accidents. In fact, today’s aircraft are designed, manufactured, and certified so as not to be seriously affected by lightning. In actual aircraft operations, however, lightning strikes can still cause minor damage to an aircraft’s body and instruments and result in time and expense being incurred by airlines to check for and repair any damage. Moreover, such checks and repairs can sometimes lead to the delay or cancellation of following services. Aircraft lightning strike is therefore recognized as an important issue in aviation weather. The Japan Aerospace Exploration Agency and Tokyo Metropolitan University carried out a feasibility study on providing tactical support information for aircraft lightning avoidance. In this study, weather and flight data were collected from actual cases of aircraft lightning strikes, and their analysis yielded information on trends regarding the relationship between aircraft lightning strikes and weather conditions. A prototype tactical support system was then developed based on the analyzed trends, and its evaluation showed that it could be used to avoid potentially 60%–80% of current aircraft lightning strikes.
A Composite Perspective on Bore Passages during the PECAN Campaign
Authors: Loveless David M. , Wagner Timothy J. , Turner David D. , Ackerman Steven A. , Feltz Wayne F. 
Published: February 2019

AbstractAtmospheric bores have been shown to have a role in the initiation and maintenance of elevated convection. Previous observational studies of bores have been case studies of more notable events. However, this creates a selection bias toward extraordinary cases, while discussions of the differences between bores that favor convective initiation and maintenance and bores that do not are lacking from the literature. This study attempts to fill that gap by analyzing a high-temporal-resolution thermodynamic profile composite of eight bores observed by multiple platforms during the Plains Elevated Convection at Night (PECAN) campaign in order to assess the impact of bores on the environment. The time–height cross section of the potential temperature composite displays quasi-permanent parcel displacements up to 900 m with the bore passage. Low-level lifting is shown to weaken the capping inversion and reduce convective inhibition (CIN) and the level of free convection (LFC). Additionally, low-level water vapor increases by about 1 g kg−1 in the composite mean. By assessing variability across the eight cases, it is shown that increases in low-level water vapor result in increases to convective available potential energy (CAPE), while drying results in decreased CAPE. Most cases resulted in decreased CIN and LFC height with the bore passage, but only some cases resulted in increased CAPE. This suggests that bores will increase the potential for convective initiation, but future research should be directed toward better understanding cases that result in increased CAPE as those are the types of bores that will increase severity of convection.
A dynamic reference change value model applied to ongoing assessment of the steady state of a biomarker using more than two serial results
Authors: Lund Flemming , Hyltoft Petersen Per , Fraser Callum G 
Published: February 2019

Background Reference change values are used to assess the significance of a difference in two consecutive results from an individual. Reference change value calculations provide the limits for significant differences between two results due to analytical and inherent biological variations. Often more than two serial results are available. Using the reference change value concept on more than two measurements results in an increased number of false-positive results. This problem has been solved for both uni- and bidirectional differences through use of wider limits when additional results are included. Methods Based on normally (Gaussianly) distributed simulated data, a dynamic reference change value model was developed using more than two results and total coefficients of variation. The dynamic reference change value model includes validation of a set-point as the mean of the four first serial results and additional results are assessed for compliance to the steady state with the same set-point. Furthermore, the dynamic reference change value model compensates for increasing false-positive results with subsequent results. The dynamic reference change value model was designed to calculate significant limits for bidirectional differences. Results Reference change factors were calculated for multiplication of the mean of previous results to create the limits for significant differences. The reference change factors are provided as a function of number of results and total coefficients of variation both in tables and in figures. Conclusions The dynamic reference change value model is appropriate for ongoing assessment of the steady state of a biomarker using more than two serial results.
Challenges in enacting occupation-based social transformative practices: A critical dialogical study
Authors: Farias Lisette , Rudman Debbie Laliberte 
Published: February 2019

Background.Globally, occupational therapists are taking up the transformative potential of occupation to mobilize the profession’s commitment to social change.Purpose.This study examined ideal constructions of occupation-based social transformative practices and challenges that may arise when enacting these practices.Method.Five participants with experiences developing practices aligned with social transformative goals in diverse locations were recruited. In this critical dialogical study, three dialogical interviews were conducted with each participant. Critical reflexivity was enacted through the exchange of transcripts and critical reflections with participants. A critical discourse analysis was conducted to examine how such practices are shaped within discourses and other contextual features.Findings.The findings address constructions of ideal practice and three threads that provide critical insights into ways discourses shape possibilities to enact social transformation through occupation.Implications.This study brings together experiential and theoretical knowledge to advance social transformative practices by problematizing underexamined discourses in occupational therapy.