bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multifaceted effects of soluble human CD6 in experimental cancer models
Authors: Simões Inês T , Aranda Fernando , Casadó-Llombart Sergi , Velasco-de Andrés María , Català Cristina , Álvarez Pilar , Consuegra-Fernández Marta , Orta-Mascaró Marc , Merino Ramón , Merino Jesús , Alberola-Ila José , González-Aseguinolaza Gloria , Carreras Esther , Martínez Vanesa , Lozano Francisco 
Published: March 2020

BackgroundCD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6-mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor.MethodsHigh sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckEμTg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins.ResultsThrough a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells.ConclusionsEvidence is provided for the disruption of CD6 receptor–ligand interactions as a feasible immunomodulatory approach in cancer.
CD244 represents a new therapeutic target in head and neck squamous cell carcinoma
Authors: Agresta Laura , Lehn Maria , Lampe Kristin , Cantrell Rachel , Hennies Cassandra , Szabo Sara , Wise-Draper Trisha , Conforti Laura , Hoebe Kasper , Janssen Edith M 
Published: March 2020

BackgroundDeveloping novel strategies to overcome the immunosuppressive tumor microenvironment is a critically important area of cancer therapy research. Here, we assess the therapeutic potential of CD244 (2B4/signaling lymphocyte activation molecule family 4), an immunoregulatory receptor found on a variety of immune cells, including exhausted CD8+T cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs).MethodsUsing de-identified human tumor and blood samples from patients with head and neck squamous cell carcinoma (HNSCC) and HNSCC models in WT and CD244-/-mice, we assessed the therapeutic potential of CD244 using flow cytometry, RT-PCR, Luminex immunoassays and histopathological analyses.ResultsCompared with healthy tissues, tumor infiltrating CD8+T cells from HNSCC patients and a HNSCC mouse model showed significant increased expression of CD244 expression that correlated with PD1 expression. Moreover, CD244 was increased on intratumoral DC and MDSC and high CD244 expression correlated with PD-L1 expression and increased spontaneous expression of immune-suppressive mediators. In addition, CD244 activation inhibited production of proinflammatory cytokines in human DC in vitro. Importantly, CD244-/-mice showed significantly impaired tumor growth of HNSCC and interventional treatment of WT mice with anti-CD244 monoclonal antibody significantly impaired the growth of established HNSCC tumors and increased tumor-infiltrating CD8+T cells.ConclusionsTogether these data suggest that CD244 contributes to the overall immune-suppressive environment and therefore has potential as a new immunotherapy target in the treatment of malignancies.
Cellular cytotoxicity is a form of immunogenic cell death
Authors: Minute Luna , Teijeira Alvaro , Sanchez-Paulete Alfonso R , Ochoa Maria C , Alvarez Maite , Otano Itziar , Etxeberrria Iñaki , Bolaños Elixabet , Azpilikueta Arantza , Garasa Saray , Casares Noelia , Luis Perez Gracia Jose , Rodriguez-Ruiz Maria E , Berraondo Pedro , Melero Ignacio 
Published: March 2020

BackgroundThe immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown.MethodsIn this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient inBatf3,Ifnar1andSting1were used to study mechanistic requirements.ResultsWe observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient inBatf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+T lymphocytes.ConclusionThese results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.
Characterization of human cancer xenografts in humanized mice
Authors: Rios-Doria Jonathan , Stevens Christina , Maddage Christopher , Lasky Kerri , Koblish Holly K 
Published: March 2020

BackgroundPreclinical evaluation of drugs targeting the human immune system has posed challenges for oncology researchers. Since the commercial introduction of humanized mice, antitumor efficacy and pharmacodynamic studies can now be performed with human cancer cells within mice bearing components of a human immune system. However, development and characterization of these models is necessary to understand which model may be best suited for different agents.MethodsWe characterized A375, A549, Caki-1, H1299, H1975, HCC827, HCT116, KU-19–19, MDA-MB-231, and RKO human cancer cell xenografts in CD34+humanized non-obese diabetic-scid gamma mice for tumor growth rate, immune cell profiling, programmed death ligand 1 (PD-L1) expression and response to anti-PD-L1 therapy. Immune cell profiling was performed using flow cytometry and immunohistochemistry. Antitumor response of humanized xenograft models to PD-L1 therapy was performed using atezolizumab.ResultsWe found that CD4+and CD8+T-cell composition in both the spleen and tumor varied among models, with A375, Caki-1, MDA-MB-231, and HCC827 containing higher intratumoral frequencies of CD4+and CD8+T cells of CD45+cells compared with other models. We demonstrate that levels of immune cell infiltrate within each model are strongly influenced by the tumor and not the stem cell donor. Many of the tumor models showed an abundance of myeloid cells, B cells and dendritic cells. RKO and MDA-MB-231 tumors contained the highest expression of PD-L1+tumor cells. The antitumor response of the models to atezolizumab was positively associated with the level of CD4+and CD8+tumor-infiltrating lymphocytes (TILs).ConclusionsThese data demonstrate that there are tumor-intrinsic factors that influence the immune cell repertoire within tumors and spleen, and that TIL frequencies are a key factor in determining response to anti-PD-L1 in tumor xenografts in humanized mice. These data may also aid in the selection of tumor models to test antitumor activity of novel immuno-oncology or tumor-directed agents.
Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study
Authors: Martinez Chanza Nieves , Xie Wanling , Issa Majd , Dzimitrowicz Hannah , Tripathi Abhishek , Beuselinck Benoit , Lam Elaine , Zakharia Yousef , Mckay Rana , Shah Sumit , Mortazavi Amir , R. Harrison Michael , Sideris Spyridon , Kaymakcalan Marina D , Abou Alaiwi Sarah , Nassar Amin H , Nuzzo Pier Vitale , Hamid Anis , K Choueiri Toni , C Harshman Lauren 
Published: March 2020

BackgroundThere is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations.MethodsThis multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months.ResultsOf 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%).ConclusionsPatients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.
Incorporation of transradial approach in neuroendovascular procedures: defining benchmarks for rates of complications and conversion to femoral access
Authors: Almallouhi Eyad , Al Kasab Sami , Sattur Mithun G , Lena Jonathan , Jabbour Pascal M , Sweid Ahmad , Chalouhi Nohra , Gooch M Reid , Starke Robert M , Peterson Eric C , Yavagal Dileep R , Chen Stephanie H , Li Yangchun , Gross Bradley A , Tonetti Daniel A , Zussman Benjamin M , Stone Jeremy G , Jadhav Ashutosh P , Jankowitz Brian T , Young Christopher C , Lim Do H , Levitt Michael R , Osbun Joshua W , Spiotta Alejandro M 
Published: March 2020

BackgroundThe transradial approach (TRA) has gained increasing popularity for neuroendovascular procedures. However, the experience with TRA in neuroangiography is still in early stages in most centers, and the safety and feasibility of this approach have not been well established. The purpose of this study is to report the safety and feasibility of TRA for neuroendovascular procedures.MethodsWe reviewed charts from six institutions in the USA to include consecutive patients who underwent diagnostic or interventional neuroendovascular procedures through TRA from July 2018 to July 2019. Collected data included baseline characteristics, procedural variables, complications, and whether there was a crossover to transfemoral access.ResultsA total of 2203 patients were included in the study (age 56.1±15.2, 60.8% women). Of these, 1697 (77%) patients underwent diagnostic procedures and 506 (23%) underwent interventional procedures. Successfully completed procedures included aneurysm coiling (n=97), flow diversion (n=89), stent-assisted coiling (n=57), balloon-assisted coiling (n=19), and stroke thrombectomy (n=76). Crossover to femoral access was required in 114 (5.2%). There were no major complications related to the radial access site. Minor complications related to access site were seen in 14 (0.6%) patients.ConclusionIn this early stage of transforming to the ‘radial-first’ approach for neuroendovascular procedures, TRA was safe with low complication rates for both diagnostic and interventional procedures. A wide range of procedures were completed successfully using TRA.
Cost-effectiveness of positive airway pressure modalities in obesity hypoventilation syndrome with severe obstructive sleep apnoea
Authors: Masa Juan F , Mokhlesi Babak , Benítez Iván , Gómez de Terreros Caro Francisco Javier , Sánchez-Quiroga M-Ángeles , Romero Auxiliadora , Caballero Candela , Alonso-Álvarez Maria Luz , Ordax-Carbajo Estrella , Gómez-García Teresa , González Mónica , López-Martín Soledad , Marin Jose M , Martí Sergi , Díaz-Cambriles Trinidad , Chiner Eusebi , Egea Carlos , Barca Javier , Vázquez-Polo Francisco-José , Negrín Miguel Angel , Martel-Escobar María , Barbé Ferran , Corral-Peñafiel Jaime 
Published: March 2020

BackgroundObesity hypoventilation syndrome (OHS) is treated with either non-invasive ventilation (NIV) or CPAP, but there are no long-term cost-effectiveness studies comparing the two treatment modalities.ObjectivesWe performed a large, multicentre, randomised, open-label controlled study to determine the comparative long-term cost and effectiveness of NIV versus CPAP in patients with OHS with severe obstructive sleep apnoea (OSA) using hospitalisation days as the primary outcome measure.MethodsHospital resource utilisation and within trial costs were evaluated against the difference in effectiveness based on the primary outcome (hospitalisation days/year, transformed and non-transformed in monetary term). Costs and effectiveness were estimated from a log-normal distribution using a Bayesian approach. A secondary analysis by adherence subgroups was performed.ResultsIn total, 363 patients were selected, 215 were randomised and 202 were available for the analysis. The median (IQR) follow-up was 3.01 (2.91–3.14) years for NIV group and 3.00 (2.92–3.17) years for CPAP. The mean (SD) Bayesian estimated hospital days was 2.13 (0.73) for CPAP and 1.89 (0.78) for NIV. The mean (SD) Bayesian estimated cost per patient/year in the NIV arm, excluding hospitalisation costs, was €2075.98 (91.6), which was higher than the cost in the CPAP arm of €1219.06 (52.3); mean difference €857.6 (105.5). CPAP was more cost-effective than NIV (99.5% probability) because longer hospital stay in the CPAP arm was compensated for by its lower costs. Similar findings were observed in the high and low adherence subgroups.ConclusionCPAP is more cost-effective than NIV; therefore, CPAP should be the preferred treatment for patients with OHS with severe OSA.Trial registration numberNCT01405976
Duration of neonatal oxygen supplementation, erythropoiesis and blood pressure in young adults born preterm
Authors: Flahault Adrien , Girard-Bock Camille , Fernandes Rafael Oliveira , Cloutier Anik , Pastore Yves D , Luu Thuy Mai , Nuyt Anne Monique 
Published: March 2020

BackgroundAlthough erythropoiesis is impaired and anaemia frequent in neonates born preterm, haematopoiesis in adults born preterm has not been previously studied.ObjectiveWe, thus, aimed to evaluate haemoglobin and erythropoietin levels in young adults born preterm, to identify neonatal events associated with erythropoiesis in adulthood and to examine the relationships of haemoglobin levels with respiratory function and blood pressure.MethodsWe assessed a cohort of 101 young adults (ages 18–29) born preterm (≤29 weeks of gestation), in comparison to 105 full-term controls. We measured haemoglobin, erythropoietin levels and blood pressure. We also assessed respiratory function using spirometry.ResultsCompared with controls, tobacco use and sex-adjusted haemoglobin levels were 5.3 (95% CI 2.9 to 7.7) g/L higher in preterm-born individuals, but erythropoietin levels were similar. Duration of oxygen supplementation in the neonatal period was independently associated with higher haemoglobin levels in the preterm group. In young adults born preterm with bronchopulmonary dysplasia, airflow limitation was associated with higher haemoglobin levels. Both systolic (SBP) and diastolic (DBP) blood pressure were increased in individuals born preterm (p=0.042 and p=0.0008, respectively). Higher haemoglobin levels were associated with higher SBP and DBP, independently of term or preterm status. Mediation analysis suggests that haemoglobin increase contributes to 37% and 32% of the effect of preterm birth on SBP and DBP, respectively.ConclusionsHaemoglobin levels are higher in young adults born preterm, while erythropoietin levels are similar, especially in case of bronchopulmonary dysplasia and airflow limitation, and haemoglobin increase is associated with elevated blood pressure in this population.
Structural state and thermodynamic stability of Al–Cu alloys
Authors: Filonenko Nataliia 
Published: March 2020

It is known that processes occurring in binary system melts affect the crystallization process and the phase composition of alloys. To predict these processes, we should determine the region of thermodynamic stability of the melt. In this paper, the structural properties of hypoeutectic and hypereutectic alloys in Al–Cu system are studied depending on the heating temperature above the liquidus line and aftercooling rate. It is shown that overheating of Al–Cu melts to 150 K above the liquidus line and further cooling leads to complete suppression of the process of formation of primary aluminum crystals in hypoeutectic alloys and [Formula: see text] phase in hypereutectic alloys. For the first time, by accounting in Gibbs energy of binary Al–Cu alloy for the first degree approximation of high-temperature expansion of thermodynamic potential, the dependence of temperature of line of the melt thermodynamic stability on copper content in alloy is obtained.
App in the Middle
Authors: Zhang Lei , Yang Zhemin , He Yuyu , Li Mingqi , Yang Sen , Yang Min , Zhang Yuan , Qian Zhiyun 
Published: March 2020

Customizability is a key feature of the Android operating system that differentiates it from Apple's iOS. One concrete feature that gaining popularity is called "app virtualization''. This feature allows multiple copies of the same app to be installed and opened simultaneously (e.g., with multiple accounts logged in). Virtualization frameworks are used by more than 100 million users worldwide. As with any new system features, we are interested in two aspects: (1) whether the feature itself introduces security risks and (2) whether the feature is abused for unintended purposes. This paper conducts a systematic study on the two aspects of the app virtualization techniques.
With a thorough study of 32 popular virtualization frameworks from Google Play, we identify seven areas of potential attack vectors and find that most of the frameworks are susceptible to them. By deeply investigating their ecosystem, we show, with demonstrations, that attackers can easily distribute malware that takes advantage of these attack vectors. In addition, we show that the same virtualization techniques are also abused by malware as an alternative and easy-to-use repackaging mechanism. To this end, we design and implement a new app repackage detector. After scanning 250,145 apps from app markets, it finds 164 repackaged apps that attempt to steal user credentials and private data.
CircFOXK2 Promotes Growth and Metastasis of Pancreatic Ductal Adenocarcinoma by Complexing with RNA-Binding Proteins and Sponging MiR-942
Authors: Wong Chi Hin , Lou Ut Kei , Li Youjia , Chan Stephen L. , Tong Joanna HM , To Ka-Fai , Chen Yangchao 
Published: March 2020

Abstract

The detailed biological functions of circular RNA (circRNA) are largely unexplored. Using circRNA sequencing, we identified 169 differentially expressed circRNA in pancreatic ductal adenocarcinoma (PDAC) cells compared with nontumor human pancreatic ductal epithelial cells. Among them, circFOXK2 was validated with significant upregulation in PDAC cells and 63% of primary tumors (53 of 84). circFOXK2 promoted cell growth, migration, and invasion and was involved in cell-cycle progression and apoptosis. circFOXK2 contained multiple miRNA binding sites, functioning as a sponge for miR-942, which in turn promoted expression of ANK1, GDNF, and PAX6. A novel and highly specific circRNA-pulldown followed by mass spectrometry analysis identified 94 circFOXK2-interacting proteins, which were involved in cell adhesion, mRNA splicing, and structural molecule activity. Of these, circFOKX2 interactions with YBX1 and hnRNPK enhanced expression of oncogenes NUF2 and PDXK. Knockdown of circFOXK2 reduced binding of YBX1 and hnRNPK to NUF2 and PDXK, in turn decreasing their expression. Collectively, our findings demonstrate that circFOXK2 in complex with YBX1 and hnRNPK promotes expression of oncogenic proteins that contribute to PDAC progression.

Significance:
This study reveals a prominent role for the circRNA circFOXK2 in PDAC progression, suggesting that circFOXK2 might be a novel diagnostic marker for PDAC.