bluuebunny/crossref_metadata_2025_split huggingface dataset:
CpG Island Methylator Phenotype Is a Strong Determinant of Poor Prognosis in Neuroblastomas
Authors: Abe Masanobu , Ohira Miki , Kaneda Atsushi , Yagi Yukiko , Yamamoto Seiichiro , Kitano Yoshihiro , Takato Tsuyoshi , Nakagawara Akira , Ushijima Toshikazu 
Published: June 2022

Abstract
Neuroblastoma, one of the most common pediatric solid tumors, is characterized by two extreme disease courses, spontaneous regression and life-threatening progression. Here, we conducted a genome-wide search for differences in DNA methylation that distinguish between neuroblastomas of the two types. Three CpG islands (CGI) and two groups of CGIs were found to be methylated specifically in neuroblastomas with a poor prognosis. By quantitative analysis of 140 independent cases, methylation of all the five CGI (groups) was shown to be closely associated with each other, conforming to the CpG island methylator phenotype (CIMP) concept. The presence of CIMP was sensitively detected by methylation of the PCDHB CGIs and associated with significantly poor survival (hazard ratio, 22.1; 95% confidence interval, 5.3-93.4; P &lt; 0.0001). Almost all cases with N-myc amplification (37 of 38 cases) exhibited CIMP. Even in 102 cases without N-myc amplification, the presence of CIMP (30 cases) strongly predicted poor survival (hazard ratio, 12.4; 95% confidence interval, 2.6-58.9; P = 0.002). Methylation of PCDHB CGIs, located in their gene bodies, did not suppress gene expression or induce histone modifications. However, CIMP was significantly associated with methylation of promoter CGIs of the RASSF1A and BLU tumor suppressor genes. The results showed that neuroblastomas with CIMP have a poor prognosis and suggested induction of silencing of important genes as an underlying mechanism.
Heterozygosity for p53 (Trp53
+/−) Accelerates Epithelial Tumor Formation in Fanconi Anemia Complementation Group D2 (Fancd2) Knockout Mice
Authors: Houghtaling Scott , Granville Laura , Akkari Yassmine , Torimaru Yumi , Olson Susan , Finegold Milton , Grompe Markus 
Published: June 2022

Abstract
Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure and an increased susceptibility to cancer. FA is genetically heterogeneous, consisting of at least 11 complementation groups, FA-A through L, including FA-D1 (BRCA2) and D2. We have previously reported an increased incidence of epithelial tumors in Fancd2 knockout mice. To further investigate the role of the FA pathway in tumor prevention, Fancd2 mutant mice were crossed to mice with a null mutation in the tumor suppressor gene, Trp53. The tumor spectrum in Fancd2−/−/Trp53+/− mice included sarcomas expected in Trp53 heterozygotes, as well as mammary and lung adenocarcinomas that occur rarely in Trp53 heterozygotes. These tumors occurred earlier than in Fancd2−/− control mice. Therefore, the Fancd2−/−/Trp53+/− mice represent an improved model for the study of adenocarcinoma in FA. In addition, it was found that Fancd2−/− mouse embryonic fibroblasts but not Fancd2−/−/Trp53−/− mouse embryonic fibroblasts arrest following DNA damage. Therefore, Trp53 is required for the S phase checkpoint activation observed in Fancd2 mutant cells. Fancd2−/−/Trp53−/− cells showed an increase in aneuploidy and had multiple gross chromosomal rearrangements.
Transcriptional Coactivator Drosophila Eyes Absent Homologue 2 Is Up-Regulated in Epithelial Ovarian Cancer and Promotes Tumor Growth
Authors: Zhang Lin , Yang Nuo , Huang Jia , Buckanovich Ronald J. , Liang Shun , Barchetti Andrea , Vezzani Cristina , O'Brien-Jenkins Ann , Wang Jennifer , Ward Michelle Renee , Courreges Maria C. , Fracchioli Stefano , Medina Angelica , Katsaros Dionyssios , Weber Barbara L. , Coukos George 
Published: June 2022

Abstract
Epithelial ovarian cancer is the most frequent cause of gynecologic malignancy-related mortality in women. To identify genes up-regulated in ovarian cancer, PCR-select cDNA subtraction was done and Drosophila Eyes Absent Homologue 2 (EYA2) was isolated as a promising candidate. The transcriptional coactivator eya controls essential cellular functions during organogenesis of Drosophila. EYA2 mRNA was found to be up-regulated in ovarian cancer by real-time reverse transcription–PCR, whereas its protein product was detected in 93.6% of ovarian cancer specimens by immunohistochemistry (n = 140). EYA2 was amplified in 14.8% of ovarian carcinomas, as detected by array-based comparative genomic hybridization (n = 88). Most importantly, EYA2 overexpression was significantly associated with short overall survival in advanced ovarian cancer (n = 99, P = 0.0361). EYA2 was found to function as transcriptional activator in ovarian cancer cells by Gal4 assay and to promote tumor growth in vivo in xenograft models. Therefore, this study suggests an important role of EYA2 in ovarian cancer and its potential application as a therapeutic target.
ARID1A Hypermethylation Disrupts Transcriptional Homeostasis to Promote Squamous Cell Carcinoma Progression
Authors: Luo Qingyu , Wu Xiaowei , Chang Wan , Zhao Pengfei , Zhu Xiaolin , Chen Hongyan , Nan Yabing , Luo Aiping , Zhou Xuantong , Su Dan , Jiao Wenjie , Liu Zhihua 
Published: June 2022

Abstract

Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complexes have a mutation rate of approximately 20% in human cancer, and ARID1A is the most frequently mutated component. However, some components of SWI/SNF complexes, including ARID1A, exhibit a very low mutation rate in squamous cell carcinoma (SCC), and their role in SCC remains unknown. Here, we demonstrate that the low expression of ARID1A in SCC is the result of promoter hypermethylation. Low levels of ARID1A were associated with a poor prognosis. ARID1A maintained transcriptional homeostasis through both direct and indirect chromatin-remodeling mechanisms. Depletion of ARID1A activated an oncogenic transcriptome that drove SCC progression. The anti-inflammatory natural product parthenolide was synthetically lethal to ARID1A-depleted SCC cells due to its inhibition of both HDAC1 and oncogenic signaling. These findings support the clinical application of parthenolide to treat patients with SCC with low ARID1A expression.

Significance:
This study reveals novel inactivation mechanisms and tumor-suppressive roles of ARID1A in SCC and proposes parthenolide as an effective treatment for patients with SCC with low ARID1A expression.
Therapeutic Targeting of Macrophage Plasticity Remodels the Tumor-Immune Microenvironment
Authors: Jang Hee-Jin , Lee Hyun-Sung , Yu Wendong , Ramineni Maheshwari , Truong Cynthia Y. , Ramos Daniela , Splawn Taylor , Choi Jong Min , Jung Sung Yun , Lee Ju-Seog , Wang Daniel Y. , Sederstrom Joel M. , Pietropaolo Massimo , Kheradmand Farrah , Amos Christopher I. , Wheeler Thomas M. , Ripley R. Taylor , Burt Bryan M. 
Published: June 2022

AbstractAlthough the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationship of LUAD histologic heterogeneity to response to immune checkpoint blockade could help identify biomarkers and potential combinational approaches to improve immunotherapy efficacy. Here, we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of preinvasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, complementary capabilities of time-of-flight mass cytometry (CyTOF) and imaging mass cytometry was leveraged to identify cellular and spatial immune contextures in LUAD. Comprehensive investigation of mouse and human LUAD using these single-cell proteomics platforms showed that LUAD progression is associated with spatiotemporal evolution of tumor-associated macrophages in the tumor-immune microenvironment, which governs tumor response to immunotherapy. PD-1 was expressed in a highly plastic tumor-promoting subtype of tumor-associated macrophages that develops during tumor progression from preinvasive to invasive adenocarcinoma, controls the lymphocyte-depleted niche of invasive tumors, and protects tumor cells in the solid histologic components of the tumor. Longitudinal, multidimensional single-cell analyses of LUAD tumorigenesis revealed dynamic alteration of immunoregulatory PD-1–expressing tumor-associated macrophages that can be targeted to overcome resistance to checkpoint immunotherapy.Significance:Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy.See related commentary by Lee et al., p. 2515
Human Papillomavirus Integration Strictly Correlates with Global Genome Instability in Head and Neck Cancer
Authors: Labarge Brandon , Hennessy Max , Zhang Lijun , Goldrich David , Chartrand Scott , Purnell Carson , Wright Sage , Goldenberg David , Broach James R. 
Published: June 2022

Abstract

Human papillomavirus (HPV)-positive head and neck cancers, predominantly oropharyngeal squamous cell carcinoma (OPSCC), exhibit epidemiologic, clinical, and molecular characteristics distinct from those OPSCCs lacking HPV. We applied a combination of whole-genome sequencing and optical genome mapping to interrogate the genome structure of HPV-positive OPSCCs. We found that the virus had integrated in the host genome in two thirds of the tumors examined but resided solely extrachromosomally in the other third. Integration of the virus occurred at essentially random sites within the genome. Focal amplification of the virus and the genomic sequences surrounding it often occurred subsequent to integration, with the number of tandem repeats in the chromosome accounting for the increased copy number of the genome sequences flanking the site of integration. In all cases, viral integration correlated with pervasive genome-wide somatic alterations at sites distinct from that of viral integration and comprised multiple insertions, deletions, translocations, inversions, and point mutations. Few or no somatic mutations were present in tumors with only episomal HPV. Our data could be interpreted by positing that episomal HPV is captured in the host genome following an episode of global genome instability during tumor development. Viral integration correlated with higher grade tumors, which may be explained by the associated extensive mutation of the genome and suggests that HPV integration status may inform prognosis.

Implications:
Our results indicate that HPV integration in head and neck cancer correlates with extensive pangenomic structural variation, which may have prognostic implications.
Preventing Cholesterol-Induced Perk (Protein Kinase RNA-Like Endoplasmic Reticulum Kinase) Signaling in Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation
Authors: Chattopadhyay Abhijnan , Guan Pujun , Majumder Suravi , Kaw Kaveeta , Zhou Zhen , Zhang Chen , Prakash Siddharth K. , Kaw Anita , Buja L. Maximillian , Kwartler Callie S. , Milewicz Dianna M. 
Published: June 2022

Background:
Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling.

Methods:

We generated an SMC-specific
Perk
knockout mouse model, induced hyperlipidemia in the mice by AAV-

PCSK9
DY

injection, and subjected them to a high-fat diet. We then assessed atherosclerotic plaque formation and performed single-cell transcriptomic studies using aortic tissue from these mice.

Results:

SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 clusters of modulated SMCs in hyperlipidemic mice, one of which is absent when
Perk
is deleted in SMCs. The 2 modulated SMC clusters have significant overlap of transcriptional changes, but the Perk-dependent cluster uniquely shows a global decrease in the number of transcripts. SMC-specific Perk deletion also prevents migration of both contractile and modulated SMCs from the medial layer of the aorta.

Conclusions:
Our results indicate that hypercholesterolemia drives both Perk-dependent and Perk-independent SMC modulation and that deficiency of Perk significantly blocks atherosclerotic plaque formation.
Outcomes After Intracranial Rescue Stenting for Acute Ischemic Stroke
Authors: Tschoe Christine , Coffman Stephanie , Kittel Carol , Brown Patrick , Kasab Sami Al , Almallouhi Eyad , Spiotta Alejandro , Howard Brian , Alawieh Ali , Arthur Adam , Goyal Nitin , Kan Peter , Kim Joon‐Tae , De Leacy Reade , Rai Ansaar , Park Min , Starke Robert , Jabbour Pascal , Crosa Roberto , Dumont Travis , Maier Ilko , Osbun Joshua , Fargen Kyle , Wolfe Stacey 
Published: June 2022

Background
In cases of failed recanalization despite modern mechanical thrombectomy (MT) techniques, intracranial rescue stenting (RS) may be beneficial. However, outcomes and complications of RS relative to the natural history of ongoing emergent large vessel occlusion are unknown. To evaluate whether RS for ongoing emergent large vessel occlusion after failed MT achieves superior outcomes to the natural history of persistent emergent large vessel occlusion.

Methods
Patients from the Stroke Thrombectomy and Aneurysm Registry who underwent RS after failed MT from 2014 to 2019 were analyzed. For outcome comparisons, patients were screened for inclusion/exclusion criteria of 3 major randomized, controlled MT trials.

Results

Over 5 years, 2827 patients underwent thrombectomy, of which 120 required RS for failed revascularization. RS resulted in reperfusion (Thrombolysis in Cerebral Infarction≥2B) in 85.8%. Good 90‐day clinical outcomes (modified Rankin scale 0–2) were achieved in 33.9% of patients. Inclusion/exclusion criteria was met in 50 patients for MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), 64 patients for ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke), and 45 patients for DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake‐Up and Late Presenting Strokes Undergoing Neurointervention). Of patients meeting trial criteria, 40.8% of the RS cohort achieved modified Rankin scale 0–2 versus 19% in the MR CLEAN medical arm (
P
<0.001) and 27% versus 13% in the RS versus DAWN medical arm (
P
=0.04). There was no difference in RS versus the ESCAPE medical arm (
P
=0.15). Symptomatic intracranial hemorrhage was not significantly increased after RS compared with MR CLEAN (
P
=0.06), but was increased compared with DAWN.

Conclusion
This large retrospective registry of RS for failed MT suggests that RS in trial‐eligible patients yields significantly improved outcomes over failed revascularization, with no significant increase in hemorrhagic events in early thrombectomy windows and comparable outcomes to successful thrombectomy at early and intermediate timeframes.
Preclinical Large Vessel Occlusion Stroke Model: Capybaras (
Hydrochoerus
hydrochoeris
)
Authors: Haussen Diogo C. , Rangaraju Srikant , Al‐Bayati Alhamza , Rolfes Christian , Mohammaden Mahmoud , Frankel Michael , Nogueira Raul G. 
Published: June 2022

Background

Existing preclinical large vessel occlusion stroke models have multiple limitations. We evaluated the capybara (
Hydrochoerus hydrochoeris
), the largest living rodent possessing sizable cerebral cortex with gyral complexity and large caliber vessels that share many intracranial vascular attributes as seen in humans, as a potential large vessel occlusion stroke model.

Methods
Conventional angiography was performed in an 18‐month‐old capybara. We (1) investigated the angiographic architecture, (2) evaluated the feasibility of microcatheter navigation and stent‐retriever deployment/retraction in the intracranial vessels and the associated arterial histological changes, (3) evaluated the leptomeningeal collateral pattern following transient large vessel occlusion stroke with coil occlusion, and (4) defined the infarct topography.

Results
The diagnostic portion of the conventional angiogram was uneventfully performed. Five passes of a 3 mm stent‐retriever were successfully performed in the right middle cerebral artery. Transient coil occlusion of the left carotid terminus/middle cerebral artery was then pursued for 45 minutes followed by coil removal. Finally, 5 passes of a 3 mm stent‐retriever were performed at the basilar artery with unchanged final angiography. The animal was euthanized 2.5 hours after extubation. The middle cerebral and basilar arteries were resected and histopathological sampling of their proximal, mid, and distal sections was pursued. In all vessel segments in which stent retriever devices were deployed, denudation and endothelial stripping of the intima (<5% coverage) but preserved internal elastic lamina, media, and adventitia were observed. Subarachnoid hemorrhage was noted at the right Sylvian cistern. Brain histology revealed neuronal nuclear pyknosis in the left frontal cortex, left thalamus, and left hippocampal CA1 regions on hematoxilin and eosin. Luxol fast blue staining showed pallor and less conspicuous gray–white delineation, particularly in the frontal lobe.

Conclusion
We evaluated a novel preclinical model for thrombectomy. Capybara is a promising animal model for neurointervention. Further validation is warranted.
Refugee Status for North Korean Dual Nationals: A Study of Recent Cases from New Zealand
Authors: Wolman Andrew 
Published: June 2022

Abstract
In recent years, asylum tribunals in the West have normally concluded that North Korean asylum seekers are also South Korean nationals; and therefore, must show a well-founded fear of persecution in both North and South Korea in order to be considered refugees. This has predictably presented a challenge for North Koreans seeking asylum in the West. In most cases, it has led to denials of protection. There are, however, some exceptions. In a pair of recent cases, North Korean asylum seekers have been granted refugee status and asylum in New Zealand, despite their acknowledged South Korean nationality and prior settlement in the South. After a review of the general challenges faced by North Korean asylum seekers, this article examines each case in detail, drawing out the reasoning underlying the Tribunals’ decisions and exploring the implication for future applicants.
Changes in Global Ocean Circulation due to Isopycnal Diffusion
Authors: Chouksey Ashwita , Griesel Alexa , Chouksey Manita , Eden Carsten 
Published: June 2022

Abstract
We investigate changes in the ocean circulation due to the variation of isopycnal diffusivity (κiso) in a global non-eddy-resolving model. Although isopycnal diffusion is thought to have minor effects on interior density gradients, the model circulation shows a surprisingly large sensitivity to the changes: with increasing κiso, the strength of the Atlantic residual overturning circulation (AMOC) and the Antarctic Circumpolar Current (ACC) transport weaken. At high latitudes, the isopycnal diffusion diffuses temperature and salinity upward and poleward, and at low latitudes downward close to the surface. Increasing isopycnal diffusivity increases the meridional isopycnal fluxes whose meridional gradient is equatorward, hence leading to a negative contribution to the flux divergence in the tracer equations and predominant cooling and freshening equatorward of 40°. The effect on temperature overcompensates the countering effect of salinity diffusion, such that the meridional density differences decrease, along with which ACC and AMOC decrease. We diagnose the adjustment process to the new equilibrium with increased isopycnal diffusion to assess how the other terms in the tracer equations react to the increased κiso. It reveals that around ±40° latitude, the cooling induced by the increased isopycnal flux is only partly compensated by warming by advection, explaining the net cooling. Overall, the results emphasize the importance of isopycnal diffusion on ocean circulation and dynamics, and hence the necessity of its careful representation in models.

Significance Statement
The effect of mixing by mesoscale eddies, represented as diffusion along surfaces of constant density in models, on the ocean circulation is not well understood. Here, we show that an increase in the eddy diffusivity in different setups of a global ocean model leads to a surprisingly large change of the ocean circulation. The strength of the Atlantic overturning circulation and the Antarctic Circumpolar Current decrease. We find that the interior ocean becomes cooler and fresher and that the temperature effect on density dominates over salinity, resulting in a decrease in the density gradients. Our results point out the importance of eddy diffusion on ocean circulation, and hence the necessity of its correct representation in ocean and climate models.
Genome-wide alternative splicing profile in the posterior kidney of brown trout (Salmo trutta) during proliferative kidney disease
Authors: Sudhagar Arun , El-Matbouli Mansour , Kumar Gokhlesh 
Published: June 2022

Abstract
Background
The cnidarian myxozoan parasite Tetracapsuloides bryosalmonae causes chronic proliferative kidney disease (PKD) in salmonids. This parasite is a serious threat to wild and cultured salmonids. T. bryosalmonae undergoes intra-luminal sporogonic development in the kidney of brown trout (Salmo trutta) and the viable spores are released via urine. We investigated the alternative splicing pattern in the posterior kidney of brown trout during PKD.

Results
RNA-seq data were generated from the posterior kidney of brown trout collected at 12 weeks post-exposure to T. bryosalmonae. Subsequently, this data was mapped to the brown trout genome. About 153 significant differently expressed alternatively spliced (DEAS) genes, (delta PSI = 5%, FDR P-value < 0.05) were identified from 19,722 alternatively spliced events. Among the DEAS genes, the least and most abundant alternative splicing types were alternative 5′ splice site (5.23%) and exon skipping (70.59%), respectively. The DEAS genes were significantly enriched for sodium-potassium transporter activity and ion homeostasis (ahcyl1, atp1a3a, atp1a1a.1, and atp1a1a.5). The protein-protein interaction network analysis enriched two local network clusters namely cation transporting ATPase C-terminus and Sodium/potassium ATPase beta chain cluster, and mixed inclusion of Ion homeostasis and EF-hand domain cluster. Furthermore, the human disease-related salmonella infection pathway was significantly enriched in the protein-protein interaction network.

Conclusion
This study provides the first baseline information about alternative splicing in brown trout during PKD. The generated data lay a foundation for further functional molecular studies in PKD - brown trout infection model. The information generated from the present study can help to develop therapeutic strategies for PKD in the future.