bluuebunny/crossref_metadata_2025_split huggingface dataset:
291 Dual-specific antibodies blocking both PD-L1 and PD-L2 engagement of PD-1 restore anti-tumor immunity
Authors: Couillault Coline , Srinivasamani Anupallavi , Hedge Shweta , Liu Qinying , Jaiswal Ashwin , Zha Dongxing , Curran Michael 
Published: November 2021

BackgroundInhibition of T cell activation and effector function via engagement of the co-inhibitory receptor PD-1 is a critical mechanism enabling tumors to evade host immunity. The two ligands for PD-1, PD-L1 and PD-L2, can be expressed by a variety of immunosuppressive stromal cells, particularly of the myeloid lineage, endothelial cells, and by tumors themselves. In addition to PD-1, PD-L1 engages B7-1 in an additional co-inhibitory interaction. Blocking only PD-1 or only PD-L1 thus does not relieve all inhibitory components of this pathway. We hypothesized that bispecific antibodies blocking both PD-L1 and PD-L2 could more fully restore tumor-specific T cell activation and potentiate anti-cancer immunotherapy. Furthermore, we speculated that enhancing the cytotoxic effector function of these antibodies might further enhance their efficacy through the depletion of tumor cells and supportive stroma.MethodsWe investigated the capacity of monoclonal antibodies capable of bivalent binding to both PD-L1 and PD-L2 to restore the function of PD-1-suppressed T cells in vitro. To assess the in vivo therapeutic efficiency of bispecific PD-Ligand antibodies with ADCC capacities, mouse IgG2a and modified human IgG1 versions were generated. We assessed their ADCC activity in vitro using a bioluminescent reporter assay, and their therapeutic efficiency in vivo in syngeneic or human-cell derived tumors.ResultsThe bispecific antibodies we generated restore the function of PD-1-suppressed T cells in vitro with equivalent efficiency to the FDA approved PD-1 antibody Pembrolizumab. Moreover, our modified human bispecific antibodies lead to significantly higher FcγRIIa activation than FDA-approved clinical human IgG1 PD-L1 antibodies in vitro. In vivo, ADCC-capable PD-Ligand bispecific antibodies suppress the growth of U2940 lymphoma in immunodeficient mice more efficiently than Rituximab, and in a syngeneic model of PD-L1/PD-L2 double positive colon carcinoma, these antibodies demonstrate superiority to PD-1 blocking antibodies to limit tumor growth and increase survival. Furthermore, treatment with our bispecific antibodies increases T cell proliferation and cytotoxicity and reduces density of immunosuppressive myeloid stroma in vivo.ConclusionsADCC-capable PD-Ligand bispecific antibodies display higher therapeutic potential than existing anti-PD-1 antibodies and represent a new class of PD-1 pathway therapeutics with significant potential for the treatment of a variety of human cancers.AcknowledgementsI would like to thank Anupallavi Srinivasamani, PhD student in Michael Curran’s lab, who performed a considerable amount of the work on this project before I joined.
309 Visualizing the immunotherapy-induced spatial reorganization of the tumor-immune microenvironment by CODEX multiplex imaging
Authors: Medrano Ruan , Han Fei , Cheikh Bassem Ben , Leinert Patrick , Leinert Wm Pat , Braubach Oliver , Schreiber Robert 
Published: November 2021

BackgroundTumors contain spatially organized microenvironments in which the location and composition of the cellular components ultimately determine tumor fate. We previously characterized CD45+ cells infiltrating T3 sarcomas using complementary forms of high-dimensional profiling (scRNAseq and CyTOF) and identified key immune cell populations that became associated either with growing tumors in mice treated with control antibody (cmAb) or rejecting tumors in mice treated with immune-checkpoint therapy (ICT) i.e., anti-PD-1 and/or anti-CTLA-4. To better understand the effects of the intratumoral immune cell populations on one another and on the tumor itself, we used CODEX multiplex imaging to simultaneously characterize expression of 35 distinct immune cell markers on tumor tissue sections thereby maintaining the spatial relationships between effector cells and their cognate tumor cell targetsMethodsT3 tumor bearing syngeneic mice were treated with cmAb or a-PD-1/a-CTLA-4 on days 6,9 and 12, harvested on different days, fresh frozen, cut in 8µM sections, transferred to coverslips, and stained with a panel of commercially available and custom-made CODEX antibodies following optimized staining conditions using the manufacturer’s protocol. Whole tumor tissue raw TIFF images were subjected to an image processing pipeline developed by Akoya Biosciences, Inc, where dapi+ cells used for cell segmentation by the Startdist method. Unsupervised clustering using Scanpy toolkit based on normalized marker expression profiles identified and validated 12 unique cell clustersResultsWhen compared to the cmAb group, a-PD-1/a-CTLA-4 tumors harvested on day 10 displayed a marked increase in percentage as well as density of CD4+ and CD8+ T cells, Ly6G neutrophils, MHC-II+cd11c+cd24+DCs and a decrease of CD140a+ tumor cells. Spatial analysis indicated statistically significant differences in the organization of these cell types upon treatment with a-PD-1/a-CTLA-4 compared to cmAb treatment. Specifically, immune cells were found at the border of the tumor in cmAb treated mice and heavily infiltrated tumors following ICT. Neighborhood identification analysis revealed changes in the composition of the main neighborhood clusters, of which the top three clusters present in cmAb treated tumors (macrophage, tumor, and other immune cells) were substituted by clusters of CD4+ and CD8+ T cells, neutrophils, and macrophages.ConclusionsThese results not only confirm the remodeling of both the lymphoid and myeloid compartments previously observed with scRNAseq and CyTOF but also suggest that changes in the spatial organization of immune cells are drivers of the tumor rejection process upon treatment with ICT.
Clinical ethics support services during the COVID-19 pandemic in the UK: a cross-sectional survey
Authors: Dittborn Mariana , Cave Emma , Archard David 
Published: November 2021

BackgroundThe COVID-19 pandemic highlighted the need for clinical ethics support provision to ensure as far as possible fair decision making and to address healthcare workers’ moral distress.PurposeTo describe the availability, characteristics and role of clinical ethics support services (CESSs) in the UK during the COVID-19 pandemic.MethodA descriptive cross-sectional online survey was developed by the research team. The survey included questions on CESSs characteristics (model, types of support, guidance development, membership, parent and patient involvement) and changes in response to the pandemic. Invitations to participate were widely circulated via National Health Service institutional emails and relevant clinical ethics groups known to the research team.ResultsBetween October 2020 and June 2021, a total of 53 responses were received. In response to the pandemic, new CESSs were established, and existing provision changed. Most took the form of clinical ethics committees, groups and advisory boards, which varied in size and membership and the body of clinicians and patient populations they served. Some services provided moral distress support and educational provision for clinical staff. During the pandemic, services became more responsive to clinicians’ requests for ethics support and advice. More than half of respondents developed local guidance and around three quarters formed links with regional or other local services. Patient and/or family members’ involvement in ethics discussions is infrequent.ConclusionsThe pandemic has resulted in an expansion in the number of CESSs. Though some may disband as the pandemic eases, the reliance on CESSs during the pandemic demonstrates the need for additional research to better understand the effectiveness of their various forms, connections, guidance, services and modes of working and for better support to enhance consistency, transparency, communication with patients and availability to clinical staff.
Predictors of unfavorable outcome in stent-assisted coiling for symptomatic unruptured intracranial spontaneous vertebral artery dissecting aneurysms (uis-VADAs): results from a multicenter study
Authors: Zhao Kaijun , Zhao Rui , Yang Xinjian , Guan Sheng , Liang Guobiao , Wang Hong-Lei , Wang Donghai , Feng Wenfeng , Li Zhenbao , Wang Weiwei , Peng Ya , Xu Jing , Wang Lei , Zhong Ming , Mao Guohua , Li Tianxiao , Zhang Yang , Chen Dong , Cai Chuwei , Sun Xiaochuan , Shi Huaizhang , Yu Jianjun , Wang Yang , Gu Zhen , Zhu Gang , Zhu Qing , Wan Jieqing , Li Qiuping , Yang Hua , Li Gang , Chai Erqing , Li Qiang , Yang Pengfei , Fang Yibin , Dai Dongwei , Hong Bo , Huang Qinghai , Xu Yi , Liu Jianmin , Xu Jinyu 
Published: November 2021

ObjectiveTo evaluate predictors of unfavorable outcome in stent-assisted coiling for symptomatic unruptured intracranial spontaneous vertebral artery dissecting aneurysms (uis-VADAs) based on 608 reconstructed lesions in 30 medical centres.MethodsA total of 608 patients (male:female=479:129; mean age, 53.26±10.26 years) with 608 symptomatic uis-VADAs underwent reconstructive treatments using stent(s) with coils between January 2009 and December 2015. Treatments and predictors of unfavorable outcomes were retrospectively analyzed.ResultsMainly, three methods were used to treat patients with uis-VADAs, including routine single-stent in 208 patients (such as Enterprise and others), new low-profile LVIS single stent in 107 patients, and multiple stents in 293 patients. During the median 66 months of clinical follow-up, 14 patients died, and 16 of the remaining 594 survivors had unfavorable outcomes (modified Rankin Scale score 3–5). The overall mortality rate was 2.3% (14/608), and the unfavorable outcome (mRS score 3–6) rate was 4.9% (30/608). Multivariate logistic regression analysis indicated that preprocedural ischemic infarctions (OR=3.78; 95% CI 1.52 to 9.40; p<0.01), diabetes mellitus (OR=3.74; 95% CI 1.31 to 10.68; p=0.01), and procedural complications (OR=14.18; 95% CI 5.47 to 36.80; p<0.01) were predictors of unfavorable outcome in the reconstructed VADAs.ConclusionsThis multicenter study indicated that preprocedural ischemic infarctions, diabetes mellitus, and procedural complications were related to unfavorable clinical outcomes in the reconstructed uis-VADAs.
Multimodal MRI Analysis of Cervical Cancer on the Basis of Artificial Intelligence Algorithm
Authors: Wang Bin , Zhang Yuanyuan , Wu Chunyan , Wang Fen 
Published: November 2021

The purpose of this study is to explore the application value of artificial intelligence algorithm in multimodal MRI image diagnosis of cervical cancer. Based on the traditional convolutional neural network (CNN), an artificial intelligence 3D-CNN algorithm is designed according to the characteristics of cervical cancer. 70 patients with cervical cancer were selected as the experimental group, and 10 healthy people were selected as the reference group. The 3D-CNN algorithm was applied to the diagnosis of clinical cervical cancer multimodal MRI images. The value of the algorithm was comprehensively evaluated by the image quality and diagnostic accuracy. The results showed that compared with the traditional CNN algorithm, the convergence rate of the loss curve of the artificial intelligence 3D-CNN algorithm was accelerated, and the segmentation accuracy of whole-area tumors (WT), core tumor areas (CT), and enhanced tumor areas (ET) was significantly improved. In addition, the clarity of the multimodal MRI image and the recognition performance of the lesion were significantly improved. Under the artificial intelligence 3D-CNN algorithm, the Dice values of WT, ET, and CT regions were 0.78, 0.71, and 0.64, respectively. The sensitivity values were 0.92, 0.91, and 0.88, respectively. The specificity values were 0.93, 0.92, and 0.9 l, respectively. The Hausdorff (Haus) distances were 0.93, 0.92, and 0.90, respectively. The data of various indicators were significantly better than those of the traditional CNN algorithm (

P

< 0.05). In addition, the diagnostic accuracy of the artificial intelligence 3D-CNN algorithm was 93.11 ± 4.65%, which was also significantly higher than that of the traditional CNN algorithm (82.45 ± 7.54%) (

P

< 0.05). In summary, the recognition and segmentation ability of multimodal MRI images based on artificial intelligence 3D-CNN algorithm for cervical cancer lesions were significantly improved, which can significantly enhance the clinical diagnosis rate of cervical cancer.
Oncogenic circRNA C190 Promotes Non–Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway
Authors: Ishola Afeez Adekunle , Chien Chian-Shiu , Yang Yi-Ping , Chien Yueh , Yarmishyn Aliaksandr A. , Tsai Ping-Hsing , Chen Jerry Chieh-Yu , Hsu Po-Kuei , Luo Yung-Hung , Chen Yuh-Min , Liang Kung-Hou , Lan Yuan-Tzu , Huo Teh-Ia , Ma Hsin-I. , Chen Ming-Teh , Wang Mong-Lien , Chiou Shih-Hwa 
Published: November 2021

Abstract

Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non–small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR–MAPK–ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC.

Significance:
The circRNA C190 is identified as a mediator of multiple pro-oncogenic signaling pathways in lung cancer and can be targeted to suppress tumor progression.
HER3 Is an Actionable Target in Advanced Prostate Cancer
Authors: Gil Veronica , Miranda Susana , Riisnaes Ruth , Gurel Bora , D’Ambrosio Mariantonietta , Vasciaveo Alessandro , Crespo Mateus , Ferreira Ana , Brina Daniela , Troiani Martina , Sharp Adam , Sheehan Beshara , Christova Rossitza , Seed George , Figueiredo Ines , Lambros Maryou , Dolling David , Rekowski Jan , Alajati Abdullah , Clarke Matthew , Pereira Rita , Flohr Penny , Fowler Gemma , Boysen Gunther , Sumanasuriya Semini , Bianchini Diletta , Rescigno Pasquale , Aversa Caterina , Tunariu Nina , Guo Christina , Paschalis Alec , Bertan Claudia , Buroni Lorenzo , Ning Jian , Carreira Suzanne , Workman Paul , Swain Amanda , Califano Andrea , Shen Michael M. , Alimonti Andrea , Neeb Antje ,   PCF/SU2C International Prostate Cancer Dream Team, Welti Jonathan , Yuan Wei , de Bono Johann 
Published: November 2021

AbstractIt has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting ERBB receptors as a therapeutic strategy for prostate cancer has been ineffective clinically. However, we show here that membranous HER3 protein is commonly highly expressed in lethal prostate cancer, associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated that the HER3 ligand NRG1 is detectable primarily in tumor-infiltrating myelomonocytic cells in human prostate cancer; this observation was confirmed using single-cell RNA sequencing of human prostate cancer biopsies and murine transgenic prostate cancer models. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids with high HER3 expression as well as mouse prostate cancer organoids, recombinant NRG1 enhanced proliferation and survival. Supernatant from murine bone marrow–derived macrophages and myeloid-derived suppressor cells promoted murine prostate cancer organoid growth in vitro, which could be reversed by a neutralizing anti-NRG1 antibody and ERBB inhibition. Targeting HER3, especially with the HER3-directed antibody–drug conjugate U3-1402, exhibited antitumor activity against HER3-expressing prostate cancer. Overall, these data indicate that HER3 is commonly overexpressed in lethal prostate cancer and can be activated by NRG1 secreted by myelomonocytic cells in the tumor microenvironment, supporting HER3-targeted therapeutic strategies for treating HER3-expressing advanced CRPC.Significance:HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.
Mogamulizumab in Combination with Nivolumab in a Phase I/II Study of Patients with Locally Advanced or Metastatic Solid Tumors
Authors: Hong David S. , Rixe Olivier , Chiu Vi K. , Forde Patrick M. , Dragovich Tomislav , Lou Yanyan , Nayak-Kapoor Asha , Leidner Rom , Atkins James N. , Collaku Agron , Fox Floyd E. , Marshall Margaret A. , Olszanski Anthony J. 
Published: November 2021

Abstract

Purpose:
The aim of the study was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-CCR4 monoclonal antibody targeting effector regulatory T cells (Treg) in combination with the checkpoint inhibitor nivolumab in patients with locally advanced or metastatic solid tumors.

Patients and Methods:
This was a multicenter, dose-finding (phase I), and dose expansion (phase II) study (NCT02705105) in patients with locally advanced or metastatic solid tumors. There were no dose-limiting toxicities in phase I with mogamulizumab 1 mg/kg every week for cycle 1 followed by 1 mg/kg every 2 weeks plus nivolumab 240 mg every 2 weeks intravenously, and cohort expansion occurred at this dose level.

Results:
All 114 patients treated with mogamulizumab 1 mg/kg plus nivolumab 240 mg in phases I (n = 4) and II (n = 110) were assessed for safety and efficacy. Mogamulizumab plus nivolumab showed acceptable safety and tolerability. Objective response rate was 10.5% [95% confidence interval (CI), 5.6–17.7; 3 complete and 9 partial responses]. Disease control rate was 36.8%. Median duration of response was 14.4 months. Median progression-free survival was 2.6 (95% CI, 2.3–3.1) months, and median overall survival was 9.5 (95% CI, 5.9–13.5) months.

Conclusions:
Combination of mogamulizumab with nivolumab for treatment of patients with locally advanced or metastatic solid tumors did not result in enhanced efficacy. Tolerability of mogamulizumab 1 mg/kg plus nivolumab 240 mg was acceptable.
Exosomal lncRNA-Mediated Intercellular Communication Promotes Glioblastoma Chemoresistance
Authors: Zhao Weixi , Xie Qi 
Published: November 2021

Abstract
Standard treatment for glioblastoma (GBM) is surgery followed by radiotherapy and chemotherapy, often with the chemotherapeutic agent temozolomide. However, this treatment is not curative. In this issue, Li and colleagues uncover a novel circuit regulating GBM cell resistance to temozolomide that involves exosome-mediated transfer of the long noncoding RNA (lncRNA) lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence) to microglial cells. The results provide new targets for therapeutics that could help overcome resistance to temozolomide.
See related article by Li et al., p. 1383. (3).
Blood Affairs: Racial Blood Group Research and Nation Building in Greece, 1920s–1940s
Authors: Lefkaditou Ageliki 
Published: November 2021

Abstract
This paper examines the transnational exchanges associated with the emergence of racial blood group studies in Greece. It explores the overlap between anthropological and medical perspectives as well as the concurrences and tensions between national and transnational concerns. By following the work of the main Greek physical anthropologist of the interwar period, the paper asks how politics interpenetrates into this case study in a scientifically consequential way and conversely how innovation in research allows anthropologists to intervene with politically timely questions. It showcases how wartime mobilities generated anthropological data that weaved and strengthened the fabric of the Greek national narrative.
The Word “Woman” in Pre-Modern Arabic Lexicons
Authors: Paraskeva Tsampika 
Published: November 2021

Abstract
In all languages, lexicons constitute a valuable source of information on femininities and women. This assertion is enhanced in the case of pre-modern Arabic lexicography, due to the diversity of its contents. However, the picture of women in lexicons has always received more attention in the field of lexicography in Western languages than in Arabic. This paper aims to fill a minor part of this noteworthy gap, by shedding light on all semantical, lexical, and orthographic elements which concern the word “woman” (imraʾa/al-marʾa) in pre-modern Arabic lexicons, more specifically, under the root m-r-ʾ.
The Outcomes of Fifth-Grade Emergent Bi/Multilinguals’ Introduction to a Visual Metalanguage When Constructing Scientific Explanations in Hong Kong
Authors: Williams Melanie , Tang Kok-Sing 
Published: November 2021

Abstract
The visual mode provides emergent bi/multilinguals an essential resource to construct scientific explanations. Yet, while a metalanguage is used to describe the written mode of scientific language such as, claim, evidence, reason; there is little research that makes students aware of the metalanguage of a visual mode. We propose an introduction to the visual metalanguage will ensure emergent bi/multilinguals better access to the visual mode. This study employs an instrumental case study to examine the introduction of visual metalanguage to a fifth-grade science class. Two cameras record ten emergent bi/multilinguals as they construct scientific explanations in nine lessons. We use a framework informed by social semiotics to analyse the meanings made. The data revealed that an awareness of the visual metalanguage led to an enhanced commitment to illustrate the explanation of the phenomenon, illuminated key concepts and provided more context to the audience. In addition, teacher questioning became more focused.