bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arctic coastal erosion: UAV-SfM data collection strategies for planimetric and volumetric measurements
Authors: Clark Andrew , Moorman Brian , Whalen Dustin , Fraser Paul 
Published: February 2021

Above average warming in the Arctic is leading to increasing permafrost temperatures and a reduction in sea ice cover, which are expected to contribute to increasing rates of Arctic coastal erosion and sediment release. We studied a 1.5 km stretch of coastline off Richard’s Island, Northwest Territories, Canada, consisting of multiple retrogressive thaw slumps (RTSs) with varying degrees of activity over a one-year period. Multi-temporal 2D and 3D geomorphic analysis was based on unmanned aerial vehicle-Structure-from-Motion (UAV-SfM) data sets collected in 2018 and 2019. Over the observation period, −3.9 m and −1.1 m of planimetric cliff edge and toe retreat occurred, respectively, and corresponded to an average volumetric change of 8.1 m3 m−1. The accuracy of UAV-SfM-derived digital elevation models was tested using 12 data collection and processing scenarios, testing the influence of off-nadir camera angle, flight pattern, and georeferencing strategy. We found that oblique imaging and georeferencing strategy had a large influence on vertical accuracy and variability across the study site and has implications for studying volumetric changes in RTSs. This study furthers the geomorphological understanding of RTS processes by highlighting the complex relationship between planimetric and volumetric change along rapidly retreating Arctic coasts, and demonstrates advancements in measurement practices for UAV-SfM data sets.
High energy QCD: multiplicity dependence of quarkonia production
Authors: Gotsman E. , Levin E. 
Published: February 2021

AbstractIn this paper we propose an approach which demonstrates the dependence of quarkonia production on the multiplicity of the accompanying hadrons. Our approach is based on the three gluon fusion mechanism, without assuming the multiplicity dependence of the saturation scale. We show, that we describe the experimental data, which has a dependence that is much steeper than the multiplicity of the hadrons.
Gain of HIF1 Activity and Loss of miRNA let-7d Promote Breast Cancer Metastasis to the Brain via the PDGF/PDGFR Axis
Authors: Wyss Christof B. , Duffey Nathalie , Peyvandi Sanam , Barras David , Martinez Usatorre Amaïa , Coquoz Oriana , Romero Pedro , Delorenzi Mauro , Lorusso Girieca , Rüegg Curzio 
Published: February 2021

Abstract

Early detection and adjuvant therapies have significantly improved survival of patients with breast cancer over the past three decades. In contrast, management of metastatic disease remains unresolved. Brain metastasis is a late complication frequently observed among patients with metastatic breast cancer, whose poor prognosis calls for novel and more effective therapies. Here, we report that active hypoxia inducible factor-1 (HIF1) signaling and loss of the miRNA let-7d concur to promote brain metastasis in a recently established model of spontaneous breast cancer metastasis from the primary site to the brain (4T1-BM2), and additionally in murine and human experimental models of breast cancer brain metastasis (D2A1-BM2 and MDA231-BrM2). Active HIF1 and let-7d loss upregulated expression of platelet-derived growth factor (PDGF) B/A in murine and human brain metastatic cells, respectively, while either individual silencing of HIF1α and PDGF-A/B or let-7d overexpression suppressed brain metastasis formation in the tested models. Let-7d silencing upregulated HIF1α expression and HIF1 activity, indicating a regulatory hierarchy of the system. The clinical relevance of the identified targets was supported by human gene expression data analyses. Treatment of mice with nilotinib, a kinase inhibitor impinging on PDGF receptor (PDGFR) signaling, prevented formation of spontaneous brain metastases in the 4T1-BM2 model and reduced growth of established brain metastases in mouse and human models. These results identify active HIF1 signaling and let-7d loss as coordinated events promoting breast cancer brain metastasis through increased expression of PDGF-A/B. Moreover, they identify PDGFR inhibition as a potentially actionable therapeutic strategy for patients with brain metastatis.

Significance:
These findings show that loss of miRNA let-7d and active HIF1 signaling promotes breast cancer brain metastasis via PDGF and that pharmacologic inhibition of PDGFR suppresses brain metastasis, suggesting novel therapeutic opportunities.
Abstract IA004: Challenges for future adjuvant studies and the role of immunotherapy in endometrial cancer
Authors: Nout Remi A. 
Published: February 2021

Abstract
Adjuvant therapy for endometrial cancer (EC) is recommended based on risk factors. In current clinical practice these are mainly based on classical pathological factors such as stage, grade and presence of LVSI. The Cancer Genome Atlas Group demonstrated that EC can be divided in four distinct subgroups with impact on prognosis. This has now been shown to be feasible using surrogate markers in multiple large cohorts. Analysis of the intratumoral immune infiltrate using a machine learning image-based algorithm, found that low intraepithelial density of CD8+ cells was an independent prognostic factor for recurrence free survival. Combining intraepithelial CD8+ cell density with molecular and pathological factors improved the risk stratification model. Exploratory analysis found a significant impact within the p53abnormal and no specific molecular profile subgroups. While in intermediate to high-intermediate risk the majority has no specific molecular profile, in high risk there are more patients with POLE hypermutated tumors, p53abnormal and mismatch repair deficient tumors. The question is how to bring these molecular factors to the clinic? Molecular stratification does present additional subgroups with a rationale for targeted approaches. It does however present a challenge for trial design and feasibility, An overview of current ongoing studies using targeted therapies is provided, with a focus on immune checkpoint inhibition.
Citation Format: Remi A. Nout. Challenges for future adjuvant studies and the role of immunotherapy in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA004.
Abstract PO011: Spatial immune cell and transcriptome profiling uncover differential cellular and molecular signatures in primary and metastatic tumor sites in patients with advanced uterine serous cancer
Authors: Zhang Li , Rynne-Vidal Angela , Lu Karen H. , Mok Samuel C. 
Published: February 2021

Abstract
Uterine serous carcinoma (USC) is the most aggressive and lethal subtype of endometrial cancer with a low overall patient survival rate of 18%-27%. Extra-uterine metastasis is frequently found in lymph nodes and omentum. The high lethality and poor understanding of the underneath mechanisms that drives USC progression lead to an urgency to develop novel therapeutic tools for the treatment of USC patients. Metastasis is proven to be the leading cause of death from USC and the immune system plays a vital role for this process. However, differential cellular and molecular profiles in the primary and metastatic tumor microenvironment have not been thoroughly examined. To identify the immune cell profile of USC, a panel of 7 immune cell markers together with functional markers granzyme B and Ki-67 were used to examine the spatial localization of a variety of tumor-infiltrating immune cells by multiplex immunofluorescence IHC assay using OpalTM immunology detection kit (Perkin Elmer). Formalin fixed paraffin embedded (FFPE) tissue sections from both primary and metastasis sites (lymph node metastasis) of 10 USC patients were used. Vetra 3.0 microscope was used to take photos of stained slides. Images were quantified and analyzed by inForm software. Transcriptome profiling of microdissected tumor cells from the same tissue samples was performed using the human Clariom D assay platform. Our results demonstrated that primary USC sites had significantly higher density of intratumoral activated tumor-infiltrating cytotoxic T cells (CD8+granzyme B+), and CD8 and LCK double positive T cell subpopulation (CD8+LCK+) than the metastatic sites in lymph nodes. In addition, we found that the density and spatial distribution of activated CD8+ T cells correlate with the overall survival of USC patients. Furthermore, differentially expressed genes and signaling networks associated immune cell activation and tumor cell metastasis were identified in primary sites compared with those in the metastatic sites. Taken together, our study suggested that the immune cell and molecular phenotypes in the lymph nodes provide a permissive niche that support USC progression, which may lead to poor survival rates in patients with advanced USC. Targeting these altered signaling networks may provide novel therapeutic strategies in the treatment of USC patients.
Citation Format: Li Zhang, Angela Rynne-Vidal, Karen H. Lu, Samuel C. Mok. Spatial immune cell and transcriptome profiling uncover differential cellular and molecular signatures in primary and metastatic tumor sites in patients with advanced uterine serous cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO011.
Abstract PO014: Clinicopathologic evaluation of CTNNB1 gene mutations in high-intermediate risk endometrial cancer
Authors: Haag Jennifer G. , Wolsky Rebecca J. , Moroney Marisa R. , Sheren Jamie , Sheeder Jeanelle , Bitler Benjamin G. , Corr Bradley R. 
Published: February 2021

Abstract
Background: CTNNB1 mutations convey increased risk of recurrence in low risk endometrioid endometrial cancers. However, sub-analyses of high-intermediate risk (HIR) endometrioid endometrial cancers in other cohorts have not demonstrated a clearly increased recurrence risk and have often been equivocal. The objective of this study is to perform a clinicopathologic evaluation of patients with HIR endometrioid endometrial cancer in relation to CTNNB1 mutational status.
Methods: A single-institution chart review of patients diagnosed with endometrioid endometrial cancer between 2006 and 2018 was undertaken. Patients were classified as HIR according to GOG249 criteria. Mutational status was determined by Sanger sequencing of exon 3 of the CTNNB1 gene in primary tumor specimens. Immunohistochemical (IHC) analysis of B-catenin was performed to evaluate for the presence of nuclear staining. Factors associated with recurrence were assessed by logistic regression; recurrence-free (RFS) and overall survival (OS) were assessed by Kaplan-Meier survival analysis.
Results: 93 cases of HIR endometrioid endometrial cancer were identified, of which 23 (24.7%) were CTNNB1 mutant and 70 (75.3%) were wild type. Median follow-up was 54.7 months. Recurrence occurred in 14/93 (15.1%) patients. Recurrence rates were not significantly different between patients with CTNNB1 mutant and wild type tumors (13.0% vs. 15.9%, p=0.76). In both univariable and multivariable analyses, RFS and OS were not significantly different (RFS HR 0.88, p=0.85, 95% CI 0.24 – 3.17; OS HR 0.20, p=0.12, 95% CI 0.03 – 1.54). Predicted oncogenic mutations comprised 87% of all identified mutations and were present in 100% of recurrent tumors and 85% of non-recurrent tumors (p=0.47). Nuclear B-catenin expression by IHC demonstrated a sensitivity of 87% and a specificity of 83% for CTNNB1 mutations.
Conclusions: CTNNB1 mutations have a prevalence of 25% in HIR endometrioid endometrial cancer. In this single institution retrospective study, there were no differences in RFS or OS in patients with CTNNB1 mutant compared to wild-type tumors.
Citation Format: Jennifer G. Haag, Rebecca J. Wolsky, Marisa R. Moroney, Jamie Sheren, Jeanelle Sheeder, Benjamin G. Bitler, Bradley R. Corr. Clinicopathologic evaluation of CTNNB1 gene mutations in high-intermediate risk endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO014.
Abstract PO018: PAX8 represents a potential novel therapeutic target in copy number high uterine serous carcinoma
Authors: Read Susan H. , Anderson Matthew L. , Rutherford Thomas J. , Jonnalagadda Venkata A. , Dou Yongchao , Zhang Bing 
Published: February 2021

Abstract
Purpose: Assess the suitability of PAX8 as a therapeutic target in copy number (CNV)-high uterine cancers. Methods: Patterns of gene expression and somatic mutations were evaluated across 97 specimens of uterine cancers characterized by the National Institute of Health’s Clinical Proteomics Tumor Analysis Consortium. Three established USC cell lines (ARK1, ARK2, ARK4) were transfected with small interfering RNAs (siRNAs) targeting PAX8 or a non-targeting siRNA control. Proliferation and apoptosis were evaluated using MTS and Caspase 3/7 assays, respectively. Migration and invasion were evaluated using Boyden chamber assays. PAX8 expression was evaluated using semi-quantitative rtPCR and Western blot. Statistical significance was evaluated using two-tailed t-tests. Results: Our analyses revealed that PAX8 is highly expressed in a subset of uterine cancers and correlates with advanced clinical stage, serous histology and inactivating TP53 mutations. In vitro, knockdown of PAX8 expression resulted in significantly decreased rates of proliferation and apoptosis when compared to cells transfected with non-targeting controls. Decreased proliferation was seen most profoundly at the 72- and 96-hour time points. Enforced reductions in PAX8 expression also decreased rates of tumor migration and invasion. Invasion was significantly decreased in ARK1 (p = 0.05). Migration was significantly decreased in ARK2 (p = 0.002), and the decrease in invasion approached statistical significance (p=0.07). In ARK4, both migration (p = 0.02) and invasion (p = 0.02) were significantly decreased. Knockdown of PAX8 was confirmed using rtPCR for all in vitro experiments. Conclusion: High levels of PAX8 expression are a key feature of a CNV-high uterine cancers that drive tumor proliferation, invasion and migration. These results indicate that PAX8 overexpression contributes to the aggressive clinical behavior of these cancers. They also establish that agents targeting PAX8 activity or expression could ultimately prove to be effective therapeutically.
Citation Format: Susan H. Read, Matthew L. Anderson, Thomas J. Rutherford, Venkata A. Jonnalagadda, Yongchao Dou, Bing Zhang. PAX8 represents a potential novel therapeutic target in copy number high uterine serous carcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO018.
Abstract PO041: Everolimus and MK-2206 reverse P4-resistant endometrial hyperplasia in Mig-6 mutant mice
Authors: Kim Tae Hoon , Jeong Jae-Wook 
Published: February 2021

Abstract
Endometrial cancer is the most frequent type of gynecological tumor in the United States. Hysterectomy, the surgical removal of the uterus, is the main therapy for endometrial cancer, but this is not an option for women seeking to preserve their fertility. In cases of early-stage endometrial cancer and endometrial hyperplasia, hormonal therapy is a vital nonsurgical option. However, progesterone (P4) resistance robs women of the option to choose hormone therapy to preserve their uterus. Therefore, developing nonsurgical treatments for endometrial cancer remains an essential goal for women who wish to maintain endometrial functions and women in high-risk surgical conditions. Mitogen-inducible gene 6 (MIG-6) acts as a tumor suppressor during endometrial tumorigenesis and as a P4 target gene in humans and mice. We developed mice with the conditional knockout of Mig-6 in all uterine compartments (Pgrcre/+Mig-6f/f; Mig-6KO) and endometrial epithelial cell-specific Mig-6 knockout (Sprr2fcre/+Mig-6f/f; Mig-6Ep-KO) mice. P4 treatment abated the development of endometrial hyperplasia and restored morphological and histological characteristics of the uterus of Mig-6Ep-KO mice, but Mig-6Ep-KO mice showed P4 resistance. P4 treatment reduced cell proliferation which was accompanied by decreased AKT signaling. In order to investigate the inhibition effect of AKT/mTOR signaling as non-surgical treatment on P4-resistant endometrial hyperplasia, we treated Mig-6KO and Mig-6Ep-KO mice with either: 1) vehicle (PBS); 2) MK-2206 (360 mg/kg, once a week); or 3) everolimus (10mg/kg daily) at 10 weeks old (n=6/treatment/genotype) for 1 month. MK-2206 has completed phase II trials and inhibits AKT phosphorylation. Everolimus is FDA-approved mTOR inhibitor. The vehicle group of Mig-6KO and Mig-6Ep-KO mice manifested the endometrial hyperplasia phenotype. In contrast, IHC analysis showed that the groups receiving MK-2206 or everolimus experienced significantly decreased AKT phosphorylation and phosphorylated S6 levels, respectively, and decreased epithelial proliferation, resulting in restoration of normal uterine histology. These data suggest that everolimus and MK-2206 may be new non-surgical treatment options for P4-resistant endometrial hyperplasia. This information may help guide more effective non-surgical interventions in the future. The project described was supported by Grant Number P50CA098258 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Citation Format: Tae Hoon Kim, Jae-Wook Jeong. Everolimus and MK-2206 reverse P4-resistant endometrial hyperplasia in Mig-6 mutant mice [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO041.
Increased Serum Complement C3 Levels Are Associated With Adverse Clinical Outcomes After Ischemic Stroke
Authors: Yang Pinni , Zhu Zhengbao , Zang Yuhan , Bu Xiaoqing , Xu Tian , Zhong Chongke , Wang Aili , Peng Hao , Guo Daoxia , Zheng Xiaowei , Xu Tan , Chen Jing , Zhang Yonghong , He Jiang 
Published: February 2021

Background and Purpose:
Complement C3 has been implicated in inflammation and ischemia/reperfusion injury, but its impact on the prognosis of ischemic stroke remains unclear. Aim of this study was to prospectively investigate the association between serum complement C3 and adverse clinical outcomes after ischemic stroke.

Methods:
We measured serum complement C3 levels for 3474 patients with ischemic stroke in 26 participating hospitals and collected data of clinical outcomes at 3 months after ischemic stroke. The primary outcome was composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset and secondary outcomes included major disability, death, and vascular events.

Results:

During 3 months of follow-up, 866 participants (25.4%) developed primary outcome. After multivariate adjustment, elevated serum complement C3 levels were associated with increased risk of primary outcome (odds ratio, 1.30 [95% CI, 1.02–1.65];
P
trend
=0.038) when 2 extreme tertiles were compared. Each SD increase of log-transformed complement C3 was associated with 13% (95% CI, 2%–25%) increased risk of primary outcome. Multivariable-adjusted spline regression model showed a linear relationship between serum complement C3 and the risk of primary outcome (
P
linearity
=0.022). Addition of serum complement C3 to conventional risk factors significantly improved the risk prediction of primary outcome (net reclassification index: 8.87%,
P
=0.028; integrated discrimination index: 0.19%,
P
=0.029).

Conclusions:
High serum complement C3 levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that serum complement C3 may be a valuable prognostic biomarker for ischemic stroke.
Neutrophil-to-Lymphocyte Ratio Predicts Cerebral Edema and Clinical Worsening Early After Reperfusion Therapy in Stroke
Authors: Ferro Daniela , Matias Margarida , Neto Joana , Dias Rafael , Moreira Goreti , Petersen Nils , Azevedo Elsa , Castro Pedro 
Published: February 2021

Background and Purpose:
The mechanisms linking systemic inflammation to poor outcome in ischemic stroke are not fully understood. The authors investigated if peripheral inflammation following reperfusion therapy leads to an increase in cerebral edema (CED), thus hindering the clinical recovery.

Methods:
We designed a single-center study conducted at Centro Hospitalar Universitário São João between 2017 and 2019. Inclusion criteria were being adult, having an anterior circulation acute ischemic stroke, and receiving reperfusion therapy. Neutrophil-to-lymphocyte, platelet-to-lymphocyte ratios, and the systemic inflammatory response syndrome criteria were determined. The presence and grade of CED were evaluated on the computed tomography performed 24 hours following event. The clinical outcomes included early neurological deterioration and functional dependence at 90 days. Adjusted odds ratio and 95% CI were obtained by ordinal and logistic regression models. Optimal cutoff values were defined using receiver operating characteristic analysis in the training cohort and validated in an independent data set.

Results:

Five hundred fifty-three patients were included. Neutrophil-to-lymphocyte increased with higher degrees of CED at 24 hours (adjusted odds ratio, 1.34 [1.09–1.68],
P
<0.01) and was associated with early neurological deterioration (adjusted odds ratio, 1.30 [1.04–1.63],
P
<0.05) and poor functional status at 90 days (adjusted odds ratio, 1.79 [1.28–2.48],
P
<0.01). Platelet-to-lymphocyte was not associated with the outcomes. Systemic inflammatory response syndrome was related to CED due to altered white blood cell counts. Neutrophil-to-lymphocyte was the best predictor with an area under the curve around 0.7. Neutrophil-to-lymphocyte ≥7 had and accuracy, sensitivity, and specificity around 60%.

Conclusions:
Increased systemic inflammation is linked to the severity of CED early after reperfusion therapy in stroke. Easily obtained inflammatory markers convey early warning alerts for patients at risk of severe neurological complications with an impact on long-term functional outcome. CED quantification should be included as an end point in proof-of-concept trials in immunomodulation in stroke.