bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells
Authors: Masterman Kelly-Anne , Haigh Oscar L , Tullett Kirsteen M , Leal-Rojas Ingrid M , Walpole Carina , Pearson Frances E , Cebon Jonathon , Schmidt Christopher , O'Brien Liam , Rosendahl Nikita , Daraj Ghazal , Caminschi Irina , Gschweng Eric H , Hollis Roger P , Kohn Donald B , Lahoud Mireille H , Radford Kristen J 
Published: July 2020

BackgroundDendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs.MethodsHuman anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, tumor necrosis factor and CD107a and by lysis of target tumor cells.ResultsCLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro.ConclusionsThese data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.
Oropharyngeal
Chlamydia trachomatis
in women; spontaneous clearance and cure after treatment (FemCure)
Authors: Dukers-Muijrers Nicole H T M , Wolffs Petra , Lucchesi Mayk , Götz Hannelore M , De Vries Henry , Schim van der Loeff Maarten , Bruisten Sylvia M , Hoebe Christian J P A 
Published: July 2020

Objectives

Women attending STI clinics are not routinely tested for oropharyngeal
Chlamydia trachomatis
(CT) infections. We aimed to assess spontaneous clearance of oropharyngeal CT and cure after antibiotic treatment in women.

Methods
Women with vaginal or rectal CT (n=560) were recruited at STI clinics in 2016–2017, as part of the FemCure study (prospective cohort study). We included participants’ data from week −1, that is, the diagnosis at initial visit, when clinics applied selective oropharyngeal testing. At week −1, a total of 241 women were oropharyngeally tested (30 positive) and 319 were untested. All FemCure participants provided nurse-collected oropharyngeal samples at study enrolment, that is, week 0, just prior to treatment (n=560), and after treatment at weeks 4 (n=449), 8 (n=433) and 12 (n=427). Samples were tested by nucleic acid amplification test, and at week 0 also by viability testing by viability PCR. Proportions of oropharyngeal CT test results were presented to represent spontaneous clearance and cure.

Results
Of 30 women diagnosed with oropharyngeal CT at week −1, fifteen (50%) were negative at week 0 after a median of 9 days, that is, ‘spontaneous clearance’. At week 0, a total of 560 participants were tested, and 46 (8.8%) were oropharyngeal CT positive; 12 of them (26.1%) had viable CT. Of the 46 positive, 36 women had an oropharyngeal test after treatment; 97.2% (35/36) were negative at week 4, that is, ‘cure’. Of all women with follow-up visits, the proportion of oropharyngeal CT positive was between 0.5% and 1.6% between weeks 4 and 12. Of those not tested at week −1 (n=319), 8.5% (n=27) were oropharyngeal positive at week 0.

Conclusions
The clinical importance of oropharyngeal CT in women is debated. We demonstrated that spontaneous clearance of oropharyngeal CT among women is common; of those who did not clear for CT, three-quarters had non-viable CT. After regular treatment with azithromycin or doxycycline, cure rate (97%) of oropharyngeal CT is excellent.

Trial registration number

NCT02694497
.
Load-Carrying Capacities of Fully Clamped RC Slab Accompanying Compressive-Tensile Membrane Actions: A Theoretical Approach
Authors: Chen Wanxiang , Luo Lisheng , Guo Zhikun , Wang Yingjie 
Published: July 2020

Fully clamped reinforced concrete (RC) slab is a common structural component possessing better load-carrying capacity over simply supported slab. Currently, typical yield line theory is a popular approach to estimate the bearing capacity of fully clamped RC slab, although it would greatly underestimate the actual ultimate resistance. This paper is devoted to enriching the knowledge of membrane action and its contribution to the load-carrying capacity of the clamped slab. The resistance trajectory of fully clamped RC slab from loading to failure undergoes three phases: the ascending branch raised by outward movement prevention, the descending branch due to crushed concrete and the re-ascending branch caused by reinforcement strain. Applied load–deflection curves of RC slab accompanying compressive-membrane actions are achieved according to the bending theory of normal cross-section. The reserve capacities accompanying tensile-membrane actions in the condition of large deformations are further derived. The whole load–deflection curves that considered compressive-tensile membrane effects are finally presented, where the mid-span displacements are revised by the deflection equations and the softening coefficient of flexural rigidity. It is indicated that the load–deflection relationships of fully clamped RC slabs can be reasonably depicted by taking compressive-tensile membrane effects into account, which are fairly different from yield line approaches. Comparative analysis shows that analytical results are in good agreement with experimental data reported by Park et al. and illustrates that the proposed model is capable of predicting the bearing capacity of fully clamped RC slab with very good accuracy.
ANXA1 Binds and Stabilizes EphA2 to Promote Nasopharyngeal Carcinoma Growth and Metastasis
Authors: Feng Juan , Lu Shan-Shan , Xiao Ta , Huang Wei , Yi Hong , Zhu Wei , Fan Songqing , Feng Xue-Ping , Li Jiao-Yang , Yu Zheng-Zheng , Gao Song , Nie Guo-Hui , Tang Yao-Yun , Xiao Zhi-Qiang 
Published: July 2020

Abstract

Overexpression of ANXA1 and EphA2 has been linked to various cancers and both proteins have attracted considerable attention for the development of new anticancer drugs. Here we report that ANXA1 competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC). Binding of ANXA1 to EphA2 promoted NPC cell growth and metastasis in vitro and in vivo by elevating EphA2 levels and increasing activity of EphA2 oncogenic signaling (pS897-EphA2). Expression of ANXA1 and EphA2 was positively correlated and both were significantly higher in NPC tissues than in the normal nasopharyngeal epithelial tissues. Patients with high expression of both proteins presented poorer disease-free survival and overall survival relative to patients with high expression of one protein alone. Furthermore, amino acid residues 20-30aa and 28-30aa of the ANXA1 N-terminus bound EphA2. An 11 amino acid–long ANXA1-derived peptide (EYVQTVKSSKG) was developed on the basis of this N-terminal region, which disrupted the connection of ANXA1 with EphA2, successfully downregulating EphA2 expression and dramatically suppressing NPC cell oncogenicity in vitro and in mice. These findings suggest that ANXA1 promotes NPC growth and metastasis via binding and stabilization of EphA2 and present a strategy for targeting EphA2 degradation and treating NPC with a peptide. This therapeutic strategy may also be extended to other cancers with high expression of both proteins.

Significance:
These findings show that EphA2 is a potential target for NPC therapeutics and an ANXA1-derived peptide suppresses NPC growth and metastasis.
Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guérin Therapy for Bladder Cancer via Modulating Rab27b-Induced Exocytosis
Authors: Mizushima Taichi , Jiang Guiyang , Kawahara Takashi , Li Peng , Han Bin , Inoue Satoshi , Ide Hiroki , Kato Ikuma , Jalalizadeh Mehrsa , Miyagi Etsuko , Fukuda Mitsunori , Reis Leonardo O. , Miyamoto Hiroshi 
Published: July 2020

Abstract
Although intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard for nonsurgical management of non–muscle-invasive bladder cancer, a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in bladder cancer. AR knockdown or overexpression in bladder cancer lines resulted in induction or reduction, respectively, in intracellular BCG quantity and its cytotoxic activity. Microarray screening identified Rab27b, a small GTPase known to mediate bacterial exocytosis, which was upregulated in BCG-resistant cells and downregulated in AR-shRNA cells. Knockdown of Rab27b, or its effector SYTL3, or overexpression of Rab27b also induced or reduced, respectively, BCG quantity and cytotoxicity. In addition, treatment with GW4869, which was previously shown to inhibit Rab27b-dependent secretion, induced them and reduced Rab27b expression in bladder cancer cells. Meanwhile, AR expression was upregulated in BCG-resistant lines, compared with respective controls. In a mouse orthotopic xenograft model, Rab27b/SYTL3 knockdown or GW4869 treatment enhanced the amount of BCG within tumors and its suppressive effect on tumor growth. Moreover, in non–muscle-invasive bladder cancer specimens from patients subsequently undergoing BCG therapy, positivity of AR/Rab27b expression was associated with significantly higher risks of tumor recurrence. AR activation thus correlates with resistance to BCG treatment, presumably via upregulating Rab27b expression. Mechanistically, it is suggested that BCG elimination from urothelial cells is induced by Rab27b/SYTL3-mediated exocytosis. Accordingly, Rab27b inactivation, potentially via antiandrogenic drugs and/or exocytosis inhibition are anticipated to sensitize the efficacy of BCG therapy, especially in patients with BCG-refractory AR/Rab27b-positive bladder cancer.
Targeting the Synthetic Vulnerability of PTEN-Deficient Glioblastoma Cells with MCL1 Inhibitors
Authors: Chen Chao , Zhu Sichao , Zhang Xia , Zhou Tingting , Gu Jing , Xu Yurong , Wan Quan , Qi Xiao , Chai Yezi , Liu Xiaorong , Chen Lukui , Yan Jie , Hua Yunfen , Lin Fan 
Published: July 2020

Abstract
PTEN deletion or mutation occurs in 30% to 60% of patients with glioblastoma (GBM) and is associated with poor prognosis. Efficacious therapy for this subgroup of patients is currently lacking. To identify potential target(s) to selectively suppress PTEN-deficient GBM growth, we performed a three-step synthetic lethal screen on LN18 PTEN wild-type (WT) and knockout (KO) isogeneic GBM cell lines using a library containing 606 target-selective inhibitors. A MCL1 inhibitor UMI-77 identified in the screen exhibited excellent suppression on the proliferation, colony formation, 3D spheroid, and neurosphere formation of PTEN-deficient GBM cells. Mechanistically, loss of PTEN in GBM cells led to upregulation of MCL1 in posttranslational level via inhibition of GSK3β, and consequently confer cells resistance to apoptosis. Pharmacologic inhibition or knockdown of MCL1 blocked this PI3K–GSK3β–MCL1 axis and caused reduction of several antiapoptotic proteins, finally induced massive caspase-3 cleavage and apoptosis. In both subcutaneous and orthotopic GBM models, knockdown of MCL1 significantly impaired the in vivo growth of PTEN-deficient xenografts. Moreover, the combination of UMI-77 and temozolomide synergistically killed PTEN-deficient GBM cells. Collectively, our work identified MCL1 as a promising target for PTEN-deficient GBM. For future clinical investigations, priority should be given to the development of a selective MCL1 inhibitor with efficient brain delivery and minimal in vivo toxicity.
Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles
Authors: Marchini Julio F. , Manica Andre , Crestani Paulo , Dutzmann Jochen , Folco Eduardo J. , Weber Heinz , Libby Peter , Croce Kevin 
Published: July 2020

Background
Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage‐derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production.

Methods and Results

We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low‐density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration‐dependent manner (293% increase;
P
<0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (
P
<0.05), and oxLDL‐induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL‐induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (
P
<0.01) and caspase 3/7 activation increased MΦMP production by 208% (
P
<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL‐induced caspase 3/7 activation and attenuated oxLDL‐stimulated MΦMP production and tissue factor content by 60% (
P
<0.01) and 43% (
P
<0.05), respectively.

Conclusions
OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.
Optimal Revascularization Strategy in Non–ST‐Segment–Elevation Myocardial Infarction With Multivessel Coronary Artery Disease: Culprit‐Only Versus One‐Stage Versus Multistage Revascularization
Authors: Kim Min Chul , Hyun Ju Yong , Ahn Youngkeun , Bae SungA , Hyun Dae Young , Cho Kyung Hoon , Sim Doo Sun , Hong Young Joon , Kim Ju Han , Jeong Myung Ho , Kim Hyo‐Soo , Gwon Hyeon Cheol , Seong In Whan , Hwang Kyoung‐Kook , Chae Shung Chull , Hur Seung Ho , Cha Kwang Soo , Oh Seok Kyu 
Published: July 2020

Background
Few studies have investigated optimal revascularization strategies in non–ST‐segment–elevation myocardial infarction with multivessel disease. We investigated 3‐year clinical outcomes according to revascularization strategy in patients with non–ST‐segment–elevation myocardial infarction and multivessel disease.

Methods and Results

This retrospective, observational, multicenter study included patients with non–ST‐segment–elevation myocardial infarction and multivessel disease without cardiogenic shock. Data were analyzed at 3 years according to the percutaneous coronary intervention strategy: culprit‐only revascularization (COR), 1‐stage multivessel revascularization (MVR), and multistage MVR. The primary outcome was major adverse cardiac events (MACE: a composite of all‐cause death, nonfatal spontaneous myocardial infarction, or any repeat revascularization). The COR group had a higher risk of MACE than those involving other strategies (COR versus 1‐stage MVR; hazard ratio, 0.65; 95% CI, 0.54–0.77;
P
<0.001; and COR versus multistage MVR; hazard ratio, 0.74; 95% CI, 0.57–0.97;
P
=0.027). There was no significant difference in the incidence of MACE between 1‐stage and multistage MVR (hazard ratio, 1.14; 95% CI, 0.86–1.51;
P
=0.355). The results were consistent after multivariate regression, propensity score matching, inverse probability weighting, and Bayesian proportional hazards modeling. In subgroup analyses stratified by the Global Registry of Acute Coronary Events score, 1‐stage MVR lowered the risk of MACE compared with multistage MVR in low‐to‐intermediate risk patients but not in patients at high risk.

Conclusions
MVR reduced 3‐year MACE in patients with non–ST‐segment–elevation myocardial infarction and multivessel disease compared with COR. However, 1‐stage MVR was not superior to multistage MVR for reducing MACE except in low‐to‐intermediate risk patients.
Clinical Course and Mortality of Stroke Patients With Coronavirus Disease 2019 in Wuhan, China
Authors: Zhang Lijuan , Sun Wenwu , Wang Yujun , Wang Xiaopin , Liu Yanli , Zhao Su , Long Ding , Chen Liangkai , Yu Li 
Published: July 2020

Background and Purpose:
No studies have reported the effect of the coronavirus disease 2019 (COVID-19) epidemic on patients with preexisting stroke. We aim to study the clinical course of COVID-19 patients with preexisting stroke and to investigate death-related risk factors.

Methods:
We consecutively included 651 adult inpatients with COVID-19 from the Central Hospital of Wuhan between January 2 and February 15, 2020. Data on the demography, comorbidities, clinical manifestations, laboratory findings, treatments, complications, and outcomes (ie, discharged or death) of the participants were extracted from electronic medical records and compared between patients with and without preexisting stroke. The association between risk factors and mortality was estimated using a Cox proportional hazards regression model for stroke patients infected with severe acute respiratory syndrome coronavirus 2.

Results:
Of the 651 patients with COVID-19, 49 with preexisting stroke tended to be elderly, male, had more underlying comorbidities and greater severity of illness, prolonged length of hospital stay, and greater hospitalization expenses than those without preexisting stroke. Cox regression analysis indicated that the patients with stroke had a higher risk of developing critical pneumonia (adjusted hazard ratio, 2.01 [95% CI, 1.27–3.16]) and subsequent mortality (adjusted hazard ratio, 1.73 [95% CI, 1.00–2.98]) than the patients without stroke. Among the 49 stroke patients, older age and higher score of Glasgow Coma Scale or Sequential Organ Failure Assessment were independent risk factors associated with in-hospital mortality.

Conclusions:
Preexisting stroke patients infected with severe acute respiratory syndrome coronavirus 2 were readily predisposed to death, providing an important message to individuals and health care workers that preventive measures must be implemented to protect and reduce transmission in stroke patients in this COVID-19 crisis.
Headline Indicators for Global Climate Monitoring
Authors: Trewin Blair , Cazenave Anny , Howell Stephen , Huss Matthias , Isensee Kirsten , Palmer Matthew D. , Tarasova Oksana , Vermeulen Alex 
Published: July 2020

AbstractThe World Meteorological Organization has developed a set of headline indicators for global climate monitoring. These seven indicators are a subset of the existing set of essential climate variables (ECVs) established by the Global Climate Observing System and are intended to provide the most essential parameters representing the state of the climate system. These indicators include global mean surface temperature, global ocean heat content, state of ocean acidification, glacier mass balance, Arctic and Antarctic sea ice extent, global CO2 mole fraction, and global mean sea level. This paper describes how well each of these indicators are currently monitored, including the number and quality of the underlying datasets; the health of those datasets; observation systems used to estimate each indicator; the timeliness of information; and how well recent values can be linked to preindustrial conditions. These aspects vary widely between indicators. While global mean surface temperature is available in close to real time and changes from preindustrial levels can be determined with relatively low uncertainty, this is not the case for many other indicators. Some indicators (e.g., sea ice extent) are largely dependent on satellite data only available in the last 40 years, while some (e.g., ocean acidification) have limited underlying observational bases, and others (e.g., glacial mass balance) with data only available a year or more in arrears.
The Post-Wildfire Impact of Burn Severity and Age on Black Carbon Snow Deposition and Implications for Snow Water Resources, Cascade Range, Washington
Authors: Uecker Ted M. , Kaspari Susan D. , Musselman Keith N. , McKenzie Skiles S. 
Published: July 2020

AbstractWildfires in the snow zone affect ablation by removing forest canopy, which enhances surface solar irradiance, and depositing light absorbing particles [LAPs, such as black carbon (BC)] on the snowpack, reducing snow albedo. How variations in BC deposition affects post-wildfire snowmelt timing is poorly known and highly relevant to water resources. We present a field-based analysis of BC variability across five sites of varying burn age and burn severity in the Cascade Range, Washington State, United States. Single particle soot photometer (SP2) analyses of BC snow concentrations were used to assess the impact of BC on snow albedo, and radiative transfer modeling was used to estimate the radiative effect of BC on snowmelt. Results were compared to Snowpack Telemetry (SNOTEL) data from one site that burned in 2012 and another in a proximal unburned forest. We show that post-wildfire forests provide a significant source of BC to the snowpack, and this effect increases by an order of magnitude in regions of high versus low burn severity, and decreased by two orders of magnitude over a decade. There is a shift in the timing of snowmelt, with snow disappearance occurring on average 19 ± 9 days earlier post-wildfire (2013–19) relative to pre-wildfire (1983–2012). This study improves understanding of the connection between wildfire activity and snowmelt, which is of high relevance as climate change models project further decreases in snowpack and increases in wildfire activity in the Washington Cascades.