bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
Authors: Hwang Bin-Jin , Tsao Li-Chung , Acharya Chaitanya R , Trotter Timothy , Agarwal Pankaj , Wei Junping , Wang Tao , Yang Xiao-Yi , Lei Gangjun , Osada Takuya , Lyerly Herbert Kim , Morse Michael A , Hartman Zachary Conrad 
Published: March 2022

BackgroundThe majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression.MethodsWe first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo.ResultsMAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs.ConclusionThese data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers.
Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL
Authors: Zhang Tingting , Liu Hengqi , Jiao Lei , Zhang Zhenzhen , He Jin , Li Lanfang , Qiu Lihua , Qian Zhengzi , Zhou Shiyong , Gong Wenchen , Meng Bin , Ren Xiubao , Zhang Huilai , Wang Xianhuo 
Published: April 2022

BackgroundTargeting the PD-1/PD-L1/L2 (programmed cell death protein 1/programmed cell death ligand 1/ligand 2) pathway combined with other immunosuppressive signalings, such as CD73/A2aR (A2a adenosine receptor) adenosine signaling, has emerged as a promising strategy for cancer treatment. The genetic characteristics of these immune checkpoints need to be further investigated in diffuse large B-cell lymphoma (DLBCL).MethodsWe performed whole-exome sequencing/targeted deep sequencing to investigate the genetic characteristics of PD-1/PD-L1/L2 and CD73/A2aR. The immunosuppressive effect of these two pathways on the tumor microenvironment was evaluated via RNA sequencing. Single-cell RNA sequencing was further applied to investigate the dysfunctional CD8+ T cells. In addition, multiplex immunofluorescence staining was used to quantitatively assess the expression of dysfunctional CD8+T cells in DLBCL.ResultsSP140 was identified as a novel translocation partner for PD-L1, and a new inversion was detected between PD-L1 and PD-L2, both leading to the upregulation of PD-L1 expression. CD73 genetic mutations did not increase mRNA and protein expression. Patients with genetically altered CD73 tended to have a better overall survival than patients with wild-type CD73. Both PD-1/PD-L1 and CD73/A2aR signaling mediated the immunosuppressive microenvironment in DLBCL. The numbers of CD8+T cells with PD-1 and A2aR expression were positively correlated with the number of dysfunctional CD8+T cells (R2=0.974, p=0.013). According to the grades of dysfunctional CD8+T cells we defined,grade1 dysfunctional CD8+T cells, with either PD-1+or A2aR+, were significantly associated with poorer survival thangrade0 dysfunctional CD8+T cells, with both PD-1−and A2aR−; and patients withgrade2 dysfunctional CD8+T cells showed the worst clinical outcomes.ConclusionsThis study describes the additional genetic basis of PD-L1 overexpression and characterizes certain genetic alterations of CD73/A2aR in DLBCL. The degree of T-cell dysfunction is correlated with clinical outcomes. Strategies that reverse T-cell dysfunction by inhibiting PD-1/PD-L1/L2, particularly in combination with CD73/A2aR, may show potential as effective therapeutic options for DLBCL.
Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center
Authors: Rosenbaum Evan , Antonescu Cristina R , Smith Shaleigh , Bradic Martina , Kashani Daniel , Richards Allison L , Donoghue Mark , Kelly Ciara M , Nacev Benjamin , Chan Jason E , Chi Ping , Dickson Mark A , Keohan Mary L , Gounder Mrinal M , Movva Sujana , Avutu Viswatej , Thornton Katherine , Zehir Ahmet , Bowman Anita S , Singer Samuel , Tap William , D’Angelo Sandra 
Published: April 2022

BackgroundAngiosarcoma is a histologically and molecularly heterogeneous vascular neoplasm with aggressive clinical behavior. Emerging data suggests that immune checkpoint blockade (ICB) is efficacious against some angiosarcomas, particularly cutaneous angiosarcoma of the head and neck (CHN).MethodsPatients with histologically confirmed angiosarcoma treated with ICB-based therapy at a comprehensive cancer center were retrospectively identified. Clinical characteristics and the results of targeted exome sequencing, transcriptome sequencing, and immunohistochemistry analyses were examined for correlation with clinical benefit. Durable clinical benefit was defined as a progression-free survival (PFS) of ≥16 weeks.ResultsFor the 35 patients included in the analyses, median PFS and median overall survival (OS) from the time of first ICB-based treatment were 11.9 (95% CI 7.4 to 31.9) and 42.5 (95% CI 19.6 to 114.2) weeks, respectively. Thirteen patients (37%) had PFS ≥16 weeks. Clinical factors associated with longer PFS and longer OS in multivariate analyses were ICB plus other therapy regimens, CHN disease, and white race. Three of 10 patients with CHN angiosarcoma evaluable for tumor mutational burden (TMB) had a TMB ≥10. Five of six patients with CHN angiosarcoma evaluable for mutational signature analysis had a dominant mutational signature associated with ultraviolet (UV) light. No individual gene or genomic pathway was significantly associated with PFS or OS; neither were TMB or UV signature status. Analyses of whole transcriptomes from nine patient tumor samples found upregulation of angiogenesis, inflammatory response, and KRAS signaling pathways, among others, in patients with PFS ≥16 weeks, as well as higher levels of cytotoxic T cells, dendritic cells, and natural killer cells. Patients with PFS <16 weeks had higher numbers of cancer-associated fibroblasts. Immunohistochemistry findings for 12 patients with baseline samples available suggest that neither PD-L1 expression nor presence of tumor-infiltrating lymphocytes at baseline appears necessary for a response to ICB-based therapy.ConclusionsICB-based therapy benefits only a subset of angiosarcoma patients. Patients with CHN angiosarcoma are more likely to have PFS ≥16 weeks, a dominant UV mutational signature, and higher TMB than angiosarcomas arising from other primary sites. However, clinical benefit was seen in other angiosarcomas also and was not restricted to tumors with a high TMB, a dominant UV signature, PD-L1 expression, or presence of tumor infiltrating lymphocytes at baseline.
“There’s so much to be done”: a qualitative study to elucidate research priorities in childhood-onset systemic lupus erythematosus
Authors: Cannon Laura , Caliendo Anne , Hersh Aimee , Knight Andrea M 
Published: March 2022

ObjectiveThere is a pressing need for high-quality, comprehensive research to describe the natural history, best treatments, access to care and disparities in care for patients with childhood-onset SLE (cSLE). Building on a previously published survey study of cSLE clinicians and researchers to describe research priorities in cSLE, the primary objective of this study was to conduct expert interviews to define high-priority areas for cSLE research.MethodsIndividuals with identified multidisciplinary expertise in cSLE were recruited worldwide using purposive sampling technique. Experts participated in open-ended, semistructured qualitative interviews. Interviews were designed to elicit expert perspectives on research priorities, optimal research approaches, and factors that facilitate and hinder advancing cSLE research. Interviews were digitally recorded, transcribed and de-identified for analysis. Analysis for underlying themes of cSLE expert perspectives was performed using a constant comparative approach.ResultsTwenty-nine experts with diverse clinical and research backgrounds participated. Themes emerged within five domains: (1) expanding disease knowledge; (2) investigator collaboration; (3) partnering with patients and families; (4) improving care to optimise research; and (5) overcoming investigator barriers. Choosing a singular area of focus was difficult; experts identified many competing priorities. Despite the numerous priorities that emerged, experts described several existing and potential opportunities for advancing cSLE research.ConclusionsIn addition to the priorities identified by cSLE experts in this study, the opportunities for advancing cSLE research and care that were proposed should be used as a foundation for creation of a cSLE research agenda for both research and funding allocation.
Nitrogen use efficiency of wheat and canola from urea treated with different types of double inhibitors
Authors: Lasisi Ahmed A. , Akinremi Olalekan O. , Kumaragamage Darshani 
Published: March 2022

Urease inhibitor (specifically, N-( n-butyl) thiophosphoric triamide, NBPT) and nitrification inhibitors (NIs) have been used to minimize nitrogen (N) loss from urea. However, their effects on improving crop N use efficiency (NUE) are usually inconsistent. A 2-year study was conducted to determine the best combination of NBPT and different NIs on urea that will maximize NUE while reducing nitrate leaching. Treatments consisted of untreated urea, NBPT-treated urea, and six types of (NBPT + NI)-treated urea that were surface applied at 80 kg N ha−1 on plots seeded to canola (2019) and wheat (2020) at Carman and Portage in Manitoba, Canada. Plots at Carman had lysimeters installed to measure leached water and nitrate. The sites had at least 35% lesser rainfall than climate normal during each growing season. At each site, average grain yields, N removal, and residual nitrate were not significantly different between untreated urea and inhibitor-treated urea. Over the 2 years, there was no significant benefit of NBPT or NBPT + NI on crop NUE at each site. Cumulative leached nitrate (19–40 kg N ha−1) did not differ significantly among urea treated with and without inhibitors. This is because >50% of the precipitation occurred when the effectiveness of NI had elapsed. Although NBPT and NI are known to reduce N losses to the atmosphere, this study suggests that the agronomic benefit and nitrate leaching prevention by NI applied in the spring may be limited in regions where large precipitation occurs later in the growing season or during non-growing season.
GREENPEG – exploration for pegmatite minerals to feed the energy transition: first steps towards the Green Stone Age
Authors: Müller Axel , Reimer Wolfgang , Wall Frances , Williamson Ben , Menuge Julian , Brönner Marco , Haase Claudia , Brauch Klaus , Pohl Claudia , Lima Alexandre , Teodoro Ana , Cardoso-Fernandes Joana , Roda-Robles Encarnación , Harrop John , Smith Kate , Wanke Dietrich , Unterweissacher Thomas , Hopfner Mario , Schröder Mathias , Clifford Brendan , Moutela Paulo , Lloret Carla , Ranza Luigi , Rausa Andrea 
Published: April 2022

Abstract

The GREENPEG project, which is funded by the European Commission Horizon 2020 ‘Climate action, environment, resource efficiency and raw materials’ programme, aims to develop multimethod exploration toolsets for the identification of European, buried, small-scale (0.01–5 million m
3
) pegmatite ore deposits of the Nb–Y–F (NYF) and Li–Cs–Ta (LCT) chemical types. The project is being coordinated by the Natural History Museum of the University of Oslo and involves four exploration services/mining operators, one geological survey, one non-profit helix association of administration, industry and academia, two consulting companies and five academic institutions from eight European countries. The target raw materials are Li, high-purity quartz for silica and metallic Si, ceramic feldspar, rare earth elements, Ta, Be and Cs, which are naturally concentrated in granitic pegmatites. Silicon and Li are two of the most sought-after green technology metals as they are essential for photovoltaics and Li-ion batteries for electric cars, respectively. GREENPEG will change the focus of exploration strategies from large-volume towards small-volume, high-quality ores and overcome the lack of exploration technologies for pegmatite ore deposits by developing toolsets tailored to these ore types. This contribution focuses on the methods applied in the GREENPEG project and as such provides a potential pathway towards the ‘Green Stone Age’ from the perspective of pegmatite-sourced minerals.
Cervical Cancer and Its Screening: Assessing the Knowledge, Awareness, and Perception among Health and Allied Students
Authors: Aga Syed Sameer , Yasmeen Nusrath , Khan Muhammad Anwar 
Published: April 2022

Background. Cervical cancer (CC) is the fourth most common cancers affecting women. It being preventable, a robust and effective national education cum screening program is the key to curb its increasing incidence. Objectives. This cross-sectional study was designed to investigate the knowledge, awareness, and perceptions (KAP) towards CC etiology, its signs and symptoms and risk factors among Health Professions Students’ (HPSs) in King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah Campus. Methods. Data was collected using predesigned and validated study questionnaire. The respondents’ KAP were compared across gender, colleges, and levels of education. Data analysis was done using SPSS v 20.0 (IBM Corporation) at 95% CI. Results. A total of 580 HPS responded to the survey, 128 (22.1%) were males, while 452 (77.9%) were females with the

mean

age
±
SD

20.36
±
1.74

years. Although 70% of the respondents had heard about CC, but only 27.9% and 18.6% knew that CC is common among women and it is transmissible, respectively. Additionally, the knowledge of relationship between viral infection and vaccination was also dismal (34.1%) and only 18.6% of the students had knowledge that CC was a transmissible disease. Interestingly, students from college of medicine had more knowledge and awareness about CC (

p
<
0.05

). Conclusions. Since HPSs had considerable low knowledge about CC, we identify the dire need to implement an effective education programs, curricular activities, and awareness campaigns for HPSs as well as general population to augment the learning process effectively.
Aberrant RNA Splicing Is a Primary Link between Genetic Variation and Pancreatic Cancer Risk
Authors: Tian Jianbo , Chen Can , Rao Meilin , Zhang Ming , Lu Zequn , Cai Yimin , Ying Pingting , Li Bin , Wang Haoxue , Wang Lu , Li Yao , Huang Jinyu , Fan Linyun , Cai Xiaomin , Ning Caibo , Li Yanmin , Zhang Fuwei , Wang Wenzhuo , Jiang Yuan , Liu Yizhuo , Wang Min , Li Heng , Huang Chaoqun , Yang Zhiyong , Chang Jiang , Zhu Ying , Yang Xiaojun , Miao Xiaoping 
Published: April 2022

AbstractUnderstanding the genetic variation underlying transcript splicing is essential for fully dissecting the molecular mechanisms of common diseases. The available evidence from splicing quantitative trait locus (sQTL) studies using pancreatic ductal adenocarcinoma (PDAC) tissues have been limited to small sample sizes. Here we present a genome-wide sQTL analysis to identify SNP that control mRNA splicing in 176 PDAC samples from TCGA. From this analysis, 16,175 sQTLs were found to be significantly enriched in RNA-binding protein (RBP) binding sites and chromatin regulatory elements and overlapped with known loci from PDAC genome-wide association studies (GWAS). sQTLs and expression quantitative trait loci (eQTL) showed mostly nonoverlapping patterns, suggesting sQTLs provide additional insights into the etiology of disease. Target genes affected by sQTLs were closely related to cancer signaling pathways, high mutational burden, immune infiltration, and pharmaceutical targets, which will be helpful for clinical applications. Integration of a large-scale population consisting of 2,782 patients with PDAC and 7,983 healthy controls identified an sQTL variant rs1785932-T allele that promotes alternative splicing of ELP2 exon 6 and leads to a lower level of the ELP2 full-length isoform (ELP2_V1) and a higher level of a truncated ELP2 isoform (ELP2_V2), resulting in decreased risk of PDAC [OR = 0.83; 95% confidence interval (CI), 0.77–0.89; P = 1.16 × 10−6]. The ELP2_V2 isoform functioned as a potential tumor suppressor gene, inhibiting PDAC cell proliferation by exhibiting stronger binding affinity to JAK1/STAT3 than ELP2_V1 and subsequently blocking the pathologic activation of the phosphorylated STAT3 (pSTAT3) pathway. Collectively, these findings provide an informative sQTL resource and insights into the regulatory mechanisms linking splicing variants to PDAC risk.Significance:In pancreatic cancer, splicing quantitative trait loci analysis identifies a rs1785932 variant that contributes to decreased risk of disease by influencing ELP2 mRNA splicing and blocking the STAT3 oncogenic pathway.
Novel Anti-LY6G6D/CD3 T-Cell–Dependent Bispecific Antibody for the Treatment of Colorectal Cancer
Authors: Wang Peiyin , Sun Liping L. , Clark Robyn , Hristopoulos Maria , Chiu Cecilia P.C. , Dillon Michael , Lin WeiYu , Lo Amy A. , Chalsani Sreedevi , Das Thakur Meghna , Zimmerman Savill Kristin M. , Rougé Lionel , Lupardus Patrick , Piskol Robert , Husain Bushra , Ellerman Diego , Shivva Vittal , Leong Steven R. , Ovacik Meric , Totpal Klara , Wu Yan , Spiess Christoph , Lee Genee , Leipold Douglas D. , Polson Andrew G. 
Published: April 2022

Abstract
New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair–deficient or microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell–dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB–mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.
Cerebrovascular Ischemic Events in Patients With Takayasu Arteritis
Authors: Mirouse Adrien , Deltour Sandrine , Leclercq Delphine , Squara Pierre-Alexandre , Pouchelon Clara , Comarmond Cloé , Kahn Jean-Emmanuel , Benhamou Ygal , Mirault Tristan , Mekinian Arsène , Lambert Marc , Chiche Laurent , Koskas Fabien , Cluzel Philippe , Redheuil Alban , Cacoub Patrice , Biard Lucie , Saadoun David ,   for the French Takayasu Network
Published: March 2022

Background:
Takayasu arteritis (TA) is a large vessel vasculitis that may complicate with cerebrovascular ischemic events. The objective was to describe clinical and vascular features of TA patients with cerebrovascular ischemic events and to identify risk factors for these events.

Methods:
We analyzed the prevalence and type of stroke/transient ischemic attack (TIA), factors associated with cerebrovascular ischemic events, and stroke-free survival in a large cohort fulfilling the American College of Rheumatology or Ishikawa criteria of TA.

Results:

Among 320 patients with TA (median age at diagnosis, 36 [25–47] years; 261 [86%] women), 63 (20%) had a stroke (n=41; 65%) or TIA (n=22; 35%). Ischemic event localized in the carotid territory for 55 (87%) patients and the vertebral artery territory in 8 (13%) patients. Multiple stenosis were observed in 33 (52%) patients with a median number of stenosis of 2 (minimum, 0 to maximum, 11), and aneurysms were observed in 10 (16%) patients. A history of stroke or TIA before TA diagnosis (hazard ratio [HR], 4.50 [2.45–8.17];
P
<0.0001), smoking (HR, 1.75 [1.01–3.02];
P
=0.05), myocardial infarction history (HR, 0.21 [0.05–0.89];
P
=0.039), thoracic aorta involvement (HR, 2.05 [1.30–3.75];
P
=0.023), time from first symptoms to diagnosis >1 year (HR, 2.22 [1.30–3.80];
P
=0.005), and aspirin treatment (HR, 1.82 [1.04–3.19];
P
=0.035) were associated with cerebrovascular ischemic event. In multivariate analysis, time from first symptoms to TA diagnosis >1 year (HR, 2.16 [1.27–3.70];
P
=0.007) was independently associated with cerebrovascular ischemic events in patients with TA. The HR for cerebrovascular ischemic event in patients who already experienced a stroke/TIA was 5.11 (2.91–8.99;
P
<0.0001), compared with those who had not.

Conclusions:
Carotid stroke/TIA is frequent in TA. We identified factors associated with cerebrovascular ischemic events.
A Study in Early Māturīdite Theology: Abū l-Yusr al-Bazdawī (d. 493/1100) and His Discourse on God’s Speech
Authors: Polinsky Sheridan 
Published: April 2022

Abstract
Abū l-Yusr al-Bazdawī (d. 493/1100) was a notable early Māturīdite theologian who made an important contribution to the formation of his school by embracing kalām and promoting the image of al-Māturīdī (d. 333/944) as a Sunnite leader when the science was not yet popular in his region of Transoxania. This produced some tension in his thought as he negotiated rationalist and traditionalist doctrines and their adherents. Indications of this are found in his discussion of God’s speech in which he argues for the Sunnite doctrine of eternal divine speech while effectively affirming the createdness of scriptures; at the same time, he defends those who assert the uncreatedness of the Quran and maintains that God’s speech is truly written, memorized, recited, and heard.