bluuebunny/crossref_metadata_2025 huggingface dataset:
Macrophages in Microbial Pathogenesis: Commonalities of Defense Evasion Mechanisms
Authors: Pandey Saurabh , Kant Sashi , Khawary Masuma , Tripathi Deeksha
Published: November 2021

Macrophages are key arsenals of the immune system against invaders. After compartmental isolation of a pathogen in phagosomes, the host immune response attempts to neutralize the pathogen.
What support do young people affected by adverse childhood experiences need?
Authors: Saul Helen , Gursul Deniz
Published: November 2021

The study

Lester S, Khatwa M, Sutcliffe K. Service needs of young people affected by adverse childhood experiences (ACEs): A systematic review of UK qualitative evidence.
Child Youth Serv Rev
2020;118:105429.

To read the full NIHR Alert, go to
https://evidence.nihr.ac.uk/alert/support-needs-of-young-people-affected-by-adverse-childhood-experiences/
Prevalence of eating disorders on male team sports players
Authors: Baldó Vela Daniel , Villarino Marín Antonio Luis , Bonfanti Noelia , Lázaro Martínez José Luis
Published: November 2021

Objective

To determinate the prevalence of EDs in national adult male team sports players.

Methodology

An observational study was conducted with 124 football, rugby, volleyball, handball, water polo, baseball and hockey players ranging between 18 and 55 years old. All subjects signed the informed consent before participating in the study. Data were collected via an online form including four validated questionnaires: The Eating Habits Questionnaire for Athletes, the Eating Attitudes Test (EAT-40), the Eating Disorders Inventory-2 and the Body Shape Questionnaire. Data analysis was conducted with the software IBM SPSS V.23.0.0.

Results

18.5% of the population presented a clinical profile compatible with an ED diagnosis. We cannot confidently say that the prevalence of EDs within our sample is conditioned by the analysed variables.

Conclusion

Male team sports players may also be a high-risk group in the development of EDs. Risk factors such as young age, semiprofessional sporting status and body fat composition could influence its development.
Development and validation of the athletes’ rights survey
Authors: Tuakli-Wosornu Yetsa A , Goutos Demetri , Ramia Ioana , Galea Natalie R , Mountjoy Margo , Grimm Katharina , Bekker Sheree
Published: November 2021

A recognised imbalance of power exists between athletes and sporting institutions. Recent cases of systemic athlete abuse demonstrate the relationship between power disparities and harassment and abuse in sport. Embedding human rights principles into sporting institutions is a critical step towards preventing harassment and abuse in sport. In 2017, the World Players Association (WPA) launched the Universal Declaration of Player Rights. A year later, the International Olympic Committee (IOC) developed their Athletes’ Rights and Responsibilities Declaration. These two documents codify benchmarks ‘for international sporting organisations to meet their obligations to protect, respect and guarantee the fundamental rights of players’. This paper is the first project exploring athletes’ knowledge, understanding and awareness of rights in the sports context. This study presents the development and validation of a survey investigating athletes’ knowledge of these declarations, associated attitudes/beliefs and understanding of how these rights can be enacted in practice. The survey includes 10 statements of athlete rights based on the WPA and IOC declarations. Face validation was assessed by distributing the survey to 10 athletes and conducting qualitative interviews with a subgroup of four athletes. The survey was reworked into 13 statements, and the tool was validated with 611 responses through confirmatory factor analysis. Key findings include a weak correlation between athletes’ knowledge and their attitudes/beliefs, and challenges with the interpretation of words such as ‘pressure,’ ‘violence,’ ‘harassment’ and ‘intimidation.’ This validation puts forward the first survey instrument to directly test athletes’ knowledge, attitudes and beliefs about rights in sport.
Outcomes in patients with a first episode of chest pain undergoing early coronary CT imaging
Authors: Siegersma Klaske R , Onland-Moret N Charlotte , Appelman Yolande , van der Harst Pim , Tulevski Igor I , Somsen G Aernout , Narula Jagat , den Ruijter Hester M , Hofstra Leonard
Published: November 2021

Objectives

To investigate the impact of a CT-first strategy on all-cause and cardiovascular mortality in patients presenting with chest pain in outpatient cardiology clinics.

Methods

Patients with a first presentation of suspected angina pectoris were identified and their data linked to the registrations of Statistics Netherlands for information on mortality. The linked database consisted of 33 068 patients. CT-first patients were defined as patients with a CT calcium score and coronary CT angiography, within 6 weeks after their initial visit. Propensity score matching (1:5) was used to match patients with and without a CT-first strategy. After matching, 12 545 patients were included of which 2308 CT-first patients and 10 237 patients that underwent usual care.

Results

Mean age was 57 years, 56.3% were women and median follow-up was 4.9 years. All-cause mortality was significantly lower in CT-first patients (n=43, 1.9%) compared with patients without CT (n=363, 3.5%) (HR: 0.51, 95% CI 0.37 to 0.70). Furthermore, CT-first patients were more likely to receive cardiovascular preventative and antianginal medication (aspirin: 44.9% vs 27.1%, statins: 48.7% vs 30.3%, beta-blockers: 37.8% vs 25.5%, in CT-first and without CT-first patients, respectively) and to undergo downstream diagnostics and interventions (coronary interventions: 8.5% vs 5.7%, coronary angiography: 16.2% vs 10.6% in CT-first and without CT-first patients, respectively).

Conclusions

In a real-world regular care database, a CT-first strategy in patients suspected of angina pectoris was associated with a lowering of all-cause mortality.
Combination immunotherapy with nivolumab and ipilimumab in patients with rare gynecological malignancies: results of the CA209-538 clinical trial
Authors: Klein Oliver , Kee Damien , Gao Bo , Markman Ben , da Gama Duarte Jessica , Quigley Luke , Jackett Louise , Linklater Richelle , Strickland Andrew , Scott Clare , Mileshkin Linda , Palmer Jodie , Carlino Matteo , Behren Andreas , Cebon Jonathan
Published: November 2021

Background

Patients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers.

Methods

This multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB).

Results

The objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB.

Conclusions

Ipilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.
Test Oracle Generation Based on BPNN by Using the Values of Variables at Different Breakpoints for Programs
Authors: Ma Chunyan , Liu Shaoying , Fu Jinglan , Zhang Tao
Published: November 2021

Automatic test oracle generation is a bottleneck in realizing full automation of the entire software testing process. This study proposes a new method for automatically generating a test oracle for a new test input on the basis of several historical test cases by using a backpropagation neural network (BPNN) model. The new method is different from existing test oracle techniques. Specifically, our method has two steps. First, the values of variables are collected as training data when several historical test inputs are used to execute the program at different breakpoints. The test oracles (pass or fail) of these test cases are utilized to classify and label the training data. Second, a new test input is used to execute the program at different breakpoints, where the trained BPNN prediction model automatically generates its test oracle on the basis of the collected values of the variables involved. We conduct an experiment to validate our method. In the experiment, 113 faulty versions of seven types of programs are used as experimental objects. Results show that the average prediction accuracy rate of 74,651 test oracles is 95.8%. Although the failed test cases in the training data account for less than 5%, the overall average recall rate (prediction accuracy of test case execution failure) of all programs is 78.9%. Furthermore, the trained BPNN can reveal not only the impact of the values of variables but also the impact of the logical correspondence between variables in test oracle generation.
The number of oriented rational links with a given deficiency number
Authors: Diao Yuanan , Finney Michael Lee , Ray Dawn
Published: November 2021

Let [Formula: see text] be the set of un-oriented and rational links with crossing number [Formula: see text], a precise formula for [Formula: see text] was obtained by Ernst and Sumners in 1987. In this paper, we study the enumeration problem of oriented rational links. Let [Formula: see text] be the set of oriented rational links with crossing number [Formula: see text] and let [Formula: see text] be the set of oriented rational links with crossing number [Formula: see text] ([Formula: see text]) and deficiency [Formula: see text]. In this paper, we derive precise formulas for [Formula: see text] and [Formula: see text] for any given [Formula: see text] and [Formula: see text] and show that [Formula: see text] where [Formula: see text] is the [Formula: see text]th convolution of the convolved Fibonacci sequences.
Explainable AI: A Multispectral Palm-Vein Identification System with New Augmentation Features
Authors: Chen Yung-Yao , Jhong Sin-Ye , Hsia Chih-Hsien , Hua Kai-Lung
Published: November 2021

Recently, as one of the most promising biometric traits, the vein has attracted the attention of both academia and industry because of its living body identification and the convenience of the acquisition process. State-of-the-art techniques can provide relatively good performance, yet they are limited to specific light sources. Besides, it still has poor adaptability to multispectral images. Despite the great success achieved by
convolutional neural networks (CNNs)
in various image understanding tasks, they often require large training samples and high computation that are infeasible for palm-vein identification. To address this limitation, this work proposes a palm-vein identification system based on lightweight CNN and adaptive multi-spectral method with explainable AI. The principal component analysis on symmetric discrete wavelet transform (SMDWT-PCA) technique for vein images augmentation method is adopted to solve the problem of insufficient data and multispectral adaptability. The
depth separable convolution (DSC)
has been applied to reduce the number of model parameters in this work. To ensure that the experimental result demonstrates accurately and robustly, a multispectral palm image of the public dataset (CASIA) is also used to assess the performance of the proposed method. As result, the palm-vein identification system can provide superior performance to that of the former related approaches for different spectrums.
Environmental Efficiency Evaluation Method Based on Data Envelopment Analysis and Improved Neural Network
Authors: Yang Chao , He Feng , Ren Chang
Published: November 2021

Economic development in China requires lots of energy to support it, but how to acquire an adequate energy supply is a difficult problem. Meantime, environmental pollution caused by energy consumption is a problem that immediately needs to be solved. To adapt to China’s rapidly emerging economy, and based on existing policies, giving more consideration to energy saving and environmental safety is more important. Therefore, to investigate China’s regional environmental efficiency and its factors has key importance. In order to evaluate the environmental efficiency input in China, this study first selects some indexes of environmental efficiency and applies the Data Envelopment Analysis (DAE) method to measure the efficiency of input and output. Then, the relative index of environmental efficiency input is selected as the input variable and the efficiency value as the output variable. The Backpropagation neural network is employed to learn and establish the prediction model and achieve high prediction accuracy. The performance of the model is improved by optimizing the index of environmental efficiency investment, adopting the latest data, and increasing the learning samples. This method is not only suitable for the evaluation of macro-environmental efficiency investment, but also suitable for enterprises in specific industries.
The Value of CTA Based on Gold Nanorod Contrast Agent in Coronary Artery Diagnosis and Plaque Property Analysis
Authors: Bi Heyu , Wang Liangshi , Wang Shupeng , Huang Qicheng , Sun Yue
Published: November 2021

Coronary CT angiography (CTA) with the characteristics of noninvasive and simple operation is widely used in the diagnosis of coronary artery stenosis. The choice of contrast agent exerts an important impact on the imaging quality of CTA. Conventional iodine contrast agents are easily excreted by the kidneys, from which the imaging window is short, and the imaging quality is poor. Metal nanomaterials have unique optical properties and have broad application prospects in imaging. Our aim is to explore the value of gold nanorod contrast agent in the diagnosis of coronary heart disease. A gold nanorod suspension was first prepared, and the prepared gold nanorod was uniform and had good dispersibility. It can be seen from the light absorption curve that there are two obvious peaks on the UV absorption peak of the gold nanorods. The gold nanorods were cultured in different solutions, and it was found that the particle size of the gold nanorods did not change significantly within 72 hours, indicating that the prepared gold nanorods had good stability. When observing the damage degree of mouse kidney tissue, it was shown that the damage degree of gold nanorod contrast agent to mouse kidney tissue was less than that of iodine contrast agent. The above results indicate that the gold nanorod contrast agent has good stability and safety. Therefore, our study demonstrated that the gold nanorod contrast agent has high value in the diagnosis of coronary arteries and the analysis of plaque properties.
Generalized Interpolative Contractions and an Application
Authors: Nazam Muhammad , Aydi Hassen , Hussain Aftab
Published: November 2021

In this study, we introduce a property (P) and the generalized interpolative contractions of types I, II, III, and IV. We investigate certain conditions for the existence of fixed points of generalized interpolative contractions. We derive several new results from the main theorems. As an application, we resolve the Urysohn integral equation.
A Modified Proximal Point Algorithm and Some Convergence Results
Authors: Weng Shengquan , Wu Dingping , Chao Zengfu
Published: November 2021

In this paper, the convergence to minimizers of a convex function of a modified proximal point algorithm involving a single-valued nonexpansive mapping and a multivalued nonexpansive mapping in CAT(0) spaces is studied and a numerical example is given to support our main results.
From Spot Sign to Bleeding on the Spot: Classic and Original Signs of Expanding Primary Spontaneous Intracerebral Hematoma
Authors: Kanj Ali , Ayoub Abir , Aljoubaie Malak , Kanj Ahmad , Mohanna Assaad , Chehade Feras , Rouhana Georges
Published: November 2021

Expansion of a primary spontaneous intracranial hemorrhage (PSICH) has become lately of increasing interest, especially after the emergence of its early predictors. However, these signs lacked sensitivity and specificity. The flood phenomenon, defined as a drastic increase in the size of a PSICH during the same magnetic resonance study, was first described in this paper based on the data of a university medical center in Lebanon. Moreover, further review of this data resulted in 205 studies with presumed diagnosis of primary spontaneous intracranial hemorrhage within the last 10 years, of which 29 exams showed typical predictors of hematoma expansion on computed tomography. The intended benefit of this observation is to draw the radiologists’ attention towards minimal variations in the volume of the hematoma between the two extreme sequences of the same MRI study, in order to detect inconspicuous flood phenomena—a direct sign of hematoma expansion.
A Classical LTE Cellular System Simulator for Computer Network Education
Authors: Ludu Julius Yaw , Appati Justice Kwame , Owusu Ebenezer , Boakye-Sekyerehene Prince
Published: November 2021

The proposal of LTE in the standardization of cellular network systems has received considerable attention in the research domain, and most subscribers widely use it. Despite the enormous acceptance of the system, academia as an industry is usually disadvantaged in training students due to the cost implication in setting up a prototype. In bridging this gap, simulators are traditionally developed as a testbed to aid students appreciate how these systems work. Although there are several simulators available on the market, these simulators are quite expensive to acquire while others come with license restrictions. In this study, a classical LTE cellular system simulator is proposed as a testbed to aid the education of computer networks at college. The proposed simulator is an extension of the functionality of LTE-Sim frameworks. Usability testing of the proposed study reveals that the system is much easier to simulate the various scenarios in wireless communication.
Phenotypic Screening of Molecular Docking Enriched Chemical Libraries from Targets Identified in Ischemic Stroke Genome Data by Network-Based Method
Authors: Peng Xiaojiang , Xue Dao-jin
Published: November 2021

Cerebral ischemia (IS) is one of the main cardiovascular diseases threatening life and disability. Like most cardiovascular events, the disease progression of is affects a variety of signaling pathways and changes multiple overexpressed genes in the body. The use of new therapeutic agents to interfere with the disease progression of cardiovascular diseases (such as is) can be achieved by selectively regulating small molecules of the target set of different signal pathways, also known as selective multipharmacology. Phenotypic screening can be an effective method to solve this problem, but the lack of targeted methods for ischemic stroke limits its impact. Here, we aim to identify IS-specific targets by RNA sequencing data with a network-based approach. Molecular docking approach was applied to screen over 210,000 molecules from SPECS compound library. Screening of this enriched library resulted in 605 candidates that led to several potent active hits. The novelty analysis suggested that the structure scaffolds of the compounds were dissimilar to existing IKKB inhibitors, and further biological test result confirmed two identified compounds represented novel IKKB inhibitors. Further, docking exploration with IKKB (PDB id: 4KIK) showed that the three selective compounds were stable inside the binding pocket of IKKB which shared a homology of compound-protein interactions in comparison with the bioactive inhibitor of CHEMBL1762621. Our screening method is expected to produce selective multidrug lead compounds for the development of treatments for complex diseases, such as ischemic stroke.
mTOR-Dependent ARID1A Degradation: A New Twist in the Genetic–Epigenetic Interplay Driving Hepatocellular Carcinoma
Authors: Pease David R. , Fernandez-Zapico Martin E.
Published: November 2021

The importance of the cross-talk between the genetic and epigenetic alterations promoting cancer development is well understood; however, the molecular details underlying the mechanism of how oncogenic signaling remodels the epigenome to generate a procancer transcriptome require further elucidation. The study by Zhang and colleagues in this issue of Cancer Research reveals a novel role for oncogenic mTOR signaling leading to the degradation of a prominent chromatin remodeler, ARID1a, establishing an altered, protumor chromatin landscape in hepatocellular carcinoma (HCC) controlling tumor deve-lopment and treatment resistance. These findings highlight oncogenic effects on chromatin remodelers as an important factor in both HCC pathobiology and therapeutic response. As strategies for cancer therapy begin to move in an increasingly individualized direction, increased knowledge into the impact of restoring the function of chromatin remodelers on response to therapy is warranted.

See related article by Zhang et al., p. 5652
Abstract IA-001: Molecular subtypes and vulnerabilities in pancreatic cancer
Authors: Aguirre Andrew
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with few effective treatment options. Understanding the molecular underpinnings of PDAC is critical to developing new biomarker strategies and therapeutic approaches for patients. In this talk, I will review our understanding of the genetics and biology of PDAC, including the major genomic subtypes and transcriptional programs of the disease. I will discuss how single-cell RNA sequencing has refined our understanding of subtype heterogeneity and evolution in the context of therapy and PDAC model systems. Moreover, I will discuss new KRAS inhibitors, their mechanisms of resistance and their potential to impact the treatment landscape for pancreatic cancer patients. Lastly, I will discuss our recent efforts to use functional genetic screening approaches to define new therapeutic targets in pancreatic cancer, highlighting our work on the VPS4A ATPase as a potential new target in tumors with 18q/SMAD4 deletion.

Citation Format: Andrew Aguirre. Molecular subtypes and vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr IA-001.
Abstract IA-003: Proteogenomic characterizations of pancreatic ductal adenocarcinoma
Authors: Cao Liwei , Huang Chen , Zhou Daniel Cui , Hu Yingwei , Lih Mamie , Savage Sara R. , Krug Karsten , Clark David J. , Schnaubelt Michael , Chen Lijun , Leprevost Felipe da Veiga , Eguez Rodrigo Vargas , Nesvizhskii Alexey I. , Mani D.R. , Omenn Gilbert S. , Boja Emily S. , Mesri Mehdi , Robles Ana I. , Rodriguez Henry , Bathe Oliver F. , Chan Daniel W. , Hruban Ralph H. , Ding Li , Zhang Bing , Zhang Hui ,   Clinical Proteomic Tumor Analysis Consortium
Published: November 2021

Pancreatic cancer is one of the deadliest cancers and the five-year survival rate is less than 10%. Pancreatic ductal adenocarcinoma (PDAC) represents more than 90% of all pancreatic malignancies, and is responsible for the majority of pancreatic cancer-related deaths. Towards understanding the underlying molecular alterations that drive PDAC oncogenesis and identify therapeutic targets for personalized treatments, we comprehensively characterized 140 pancreatic cancers and 67 normal adjacent tissues. To ensure robust, downstream analyses, tumor neoplastic cellularity was assessed via multiple, orthogonal strategies using molecular features, and verified via pathological estimation of tumor cellularity based on histological review to select tumors with sufficient tumor cellularity. We also included the analysis of 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole genome sequencing, whole exome sequencing, methylation, RNA-seq, and miRNA-seq were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. These characterizations revealed functional impacts of genomic and epigenomic alterations on proteins and protein modifications, delineated PDAC cell microenvironment compositions and the immune signatures for immunotherapy, also uncovered putative kinase inhibitors that could be tested for therapy. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.

Citation Format: Liwei Cao, Chen Huang, Daniel Cui Zhou, Yingwei Hu, Mamie Lih, Sara R. Savage, Karsten Krug, David J. Clark, Michael Schnaubelt, Lijun Chen, Felipe da Veiga Leprevost, Rodrigo Vargas Eguez, Alexey I. Nesvizhskii, D.R. Mani, Gilbert S. Omenn, Emily S. Boja, Mehdi Mesri, Ana I. Robles, Henry Rodriguez, Oliver F. Bathe, Daniel W. Chan, Ralph H. Hruban, Li Ding, Bing Zhang, Hui Zhang, Clinical Proteomic Tumor Analysis Consortium. Proteogenomic characterizations of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr IA-003.
Abstract PO-004: Basal-like, Classical A, and Classical B subtypes of pancreatic cancer show distinct immuno-suppressive molecular profiles
Authors: LaPlante Emily L. , Liu Dongliang , Milosavljevic Aleksandar , Yao Qizhi
Published: November 2021

With recent advances in distinguishing Pancreatic Ductal Adenocarcinoma (PDAC) subtypes based on transcriptional profiles, it is becoming clear that different subtypes have distinct therapeutic responses– e.g. Basal-like tumors tend to show less response to chemotherapy than Classical tumors. Here, we asked if the Basal-like, Classical A, and Classical B PDAC subtypes show distinct immuno-suppressive molecular profiles of relevance for targeted immunotherapy of PDAC. Toward this goal, we leveraged two large, public sequencing cohorts – TCGA and ICGC. To accommodate the large variation in cell type composition among the tumors across these cohorts, we applied the novel expression deconvolution (XDec) method to computationally deconvolute the bulk RNA-seq profiles. The method identified cell-type composition of each tumor and identified distinct Basal-like, Classical A, and Classical B subtypes, thus allowing classification of each tumor based on the state of its constituent cancer cell fraction. We further extended the method to also infer cell-type specific gene expression for each tumor sample and to identify correlation of cell-type specific gene expression levels across cohorts. Using the extended method, we determined that Basal-like cancer cells are CD274 high, Classical B cancer cell CD274 expression correlated strongly with MSLN and RELA (a recently proposed mechanism controlling PD-L1), and Classical A cancer cells had low CD274 expression. Because heterotypic interactions may also contribute toward an immuno-suppressive microenvironment, we next correlated expression levels between cancer and stromal cell types. Cancer cell MSLN expression correlated strongly with stromal CD274 expression which also correlated with stromal IFNGR1 and IFNγ. Using co-culture experiments we validated the causative relationship between cancer cell MSLN and stromal INFGR1 and CD274. Taken together, our results suggest that PDAC subtypes have distinct therapeutic vulnerabilities, with Basal-like and MSLN-high Classical B patients more likely to respond to PD-L1 targeting therapies. Moreover, we provided a methodological advance by extending the XDec method and by making it web-accessible, thus allowing the community to derive hypotheses testable in cell line models by performing correlations of cell-type specific gene expression levels deconvoluted from bulk RNA-seq profiles of PDAC patient tumors.

Citation Format: Emily L. LaPlante, Dongliang Liu, Aleksandar Milosavljevic, Qizhi Yao. Basal-like, Classical A, and Classical B subtypes of pancreatic cancer show distinct immuno-suppressive molecular profiles [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-004.
Abstract PO-006: CircRTN4 promotes pancreatic cancer progression through a novel circRNA-miRNA-lncRNA pathway and stabilizing epithelial-mesenchymal transition protein
Authors: Wong Chi Hin , Lou Ut Kei , Fung Frederic Khe-Cheong , Tong Joanna H. M. , To Ka-Fai , Chan Stephen Lam , Chen Yangchao
Published: November 2021

Background & Aims: Circular RNAs (circRNAs) play important roles in many biological processes. However, the detailed mechanism underlying the critical roles of circRNAs in cancer remains largely unexplored. We aim to explore the molecular mechanisms of circRTN4 with critical roles in pancreatic ductal adenocarcinoma (PDAC). Methods: CircRTN4 expression level was examined in PDAC primary tumors. The oncogenic roles of circRTN4 in PDAC tumor growth and metastasis were studied in mouse tumor models. Bioinformatics analysis, luciferase assay and miRNA pulldown assay were performed to study the novel circRTN4-miRNA-lncRNA pathway. To identify circRTN4-interacting proteins, we performed circRNA-pulldown and mass spectrometry in PDAC cells. Protein stability assay and 3-Dimensional structure modeling were performed to reveal the role of circRTN4 in stabilizing RAB11FIP1. Results: circRTN4 was significantly upregulated in primary tumors from PDAC patients. In vitro and in vivo functional studies revealed that circRTN4 promoted PDAC tumor growth and liver metastasis. Mechanistically, circRTN4 interacted with tumor suppressor miR-497-5p in PDAC cells. CircRTN4 knockdown upregulated miR-497-5p to inhibit the oncogenic lncRNA HOTTIP expression. Furthermore, we identified critical circRTN4-intercting proteins by circRNA-pulldown in PDAC cells. CircRTN4 interacted with important epithelial-mesenchymal transition (EMT)- driver RAB11FIP1 to block its ubiquitination site. We found that circRTN4 knockdown promoted the degradation of RAB11FIP1 by increasing its ubiquitination. Also, circRTN4 knockdown inhibited the expression of RAB11FIP1-regulating EMT-markers Slug, Snai1, Twist, Zeb1 and N-cadherin in PDAC. Conclusion: The upregulated circRTN4 promotes tumor growth and liver metastasis in PDAC through the novel circRTN4-miR-497-5p-HOTTIP pathway. Also, circRTN4 stabilizes RAB11FIP1 to contribute EMT.

Citation Format: Chi Hin Wong, Ut Kei Lou, Frederic Khe-Cheong Fung, Joanna H. M. Tong, Ka-Fai To, Stephen Lam Chan, Yangchao Chen. CircRTN4 promotes pancreatic cancer progression through a novel circRNA-miRNA-lncRNA pathway and stabilizing epithelial-mesenchymal transition protein [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-006.
Abstract PO-019: Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity
Authors: Mirlekar Bhalchandra , Pylayeva-Gupta Yuliya
Published: November 2021

B cells frequently infiltrate human tumors, and the intra-tumoral abundance of plasma cells can correlate with improved patient prognosis. However, many tumors are devoid of plasma B cells, and strategies to enhance anti-tumor B cell responses are needed. We report the existence of a negative regulatory signaling network that reprograms naïve B cells in pancreatic cancer to antagonize anti-tumor plasma B cells. This network is driven by IL-35-mediated STAT3 activation, which directly stimulates upregulation of the pioneer transcription factors Pax5 and Bcl6 in naïve B cells and impedes plasma cell differentiation while simultaneously activating regulatory B cell phenotypes. Significantly, inhibition of Bcl6 reversed this tumor-associated reprogramming of naïve B cells, enabling intra-tumoral accumulation of plasma cells, and reduced tumor growth. Our data provide evidence that B cell dysfunction in cancer involves a potentially targetable suppression program that alters the differentiation potential of naïve B cells.

Citation Format: Bhalchandra Mirlekar, Yuliya Pylayeva-Gupta. Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-019.
Abstract PO-046: The effect of neoadjuvant therapy on immune profiling of pancreatic ductal adenocarcinoma: A prospective study of the PREOPANC-1 randomized controlled trial
Authors: Latifi Diba , de Koning Willem , Lau Sai ping , Grevers Frederiek , van Dam Coen , van Eijck Casper H. J. , Mustafa Dana A. M.
Published: November 2021

The randomized phase III trial (PREOPANC-1) that was performed in 16 centers in the Netherlands compared the effects of preoperative chemoradiotherapy (Gemcitabine and 2.4 Gy radiation) versus immediate surgery for resectable and borderline resectable pancreatic cancer. The outcomes of the secondary endpoints and predefined subgroup analyses suggest an advantage of the neoadjuvant approach. The aim of the present study was to investigate the changes in the immune microenvironment and infiltration caused by the neoadjuvant treatment. To that aim, we collected formalin-fixed, paraffin-embedded pancreatic cancer samples from all centers that participated in the PREOPANC -1 trial. We performed targeted gene expression using the PanCancer Immune Profiling panel of NanoString. Comparing 50 samples of the patient who were subjected to neoadjuvant treatment to 46 treatment-naïve samples showed a distinct genetic profile induced by the neoadjuvant therapy. More than 250 immune-related genes were significantly differentially expressed between the two groups of samples. The results indicate that neoadjuvant therapy resets the innate immune activation in the tissue samples. A significantly higher infiltration of CD14+, CD33+, CSF1R+, and CD163+, MRC1+ cells were found in samples of the neoadjuvant arm. In contrast, B cells and various subtypes of T cells like CD8+ and FOXP3+ showed a significant decrease in the same samples. Pathway analysis revealed that the neoadjuvant treatment stimulated the expression of genes related to the complement activation, chemotaxis, and wound repair, while genes related to lymphocyte activation and adaptive immune responses were dominant in the treatment-naïve arm. In conclusion, this is the first comprehensive study to describe the immune-molecular changes as a result of neoadjuvant therapy in a randomized clinical trial. The results reveal the enrichment of the myeloid compartment following neoadjuvant therapy which was significantly associated with a survival benefit for the patients. Studying the personalized effect of neoadjuvant therapy will guide choosing the appropriate combined therapy for pancreatic cancer.

Citation Format: Diba Latifi, Willem de Koning, Sai ping Lau, Frederiek Grevers, Coen van Dam, Casper H. J. van Eijck, Dana A. M. Mustafa. The effect of neoadjuvant therapy on immune profiling of pancreatic ductal adenocarcinoma: A prospective study of the PREOPANC-1 randomized controlled trial [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-046.
Abstract PO-082: Delineating the molecular basis of early dissemination of pancreatic cancer
Authors: Ekstrom Taelor J. , Grygoryev Dmytro , Morgan Terry , Zaret Kenneth S. , Kim Jungsun
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at advanced stages rendering the already limited therapeutic options ineffective for many patients. Earlier diagnosis permits for “curative” surgery; however, 95% of these patients experience recurrence locally or distally and die within ten years of treatment. One hypothesis that can explain high recurrence is the early dissemination of PDAC progression. At the time of surgery, systemic subclinical dissemination of predominantly dormant cells found ubiquitously within patient livers has already occurred prior to the development of overt metastatic disease or bona fide recurrent PDAC. However, remarkably little is known about early PDAC cell dissemination despite these dismal outcomes, mainly due to the lack of human models to study disease progression. We previously demonstrated the cellular reprogramming “proof-of-principle” to model human PDAC progression (designated “10-22 cells”) and its use as a discovery tool for early biomarkers by unveiling a marker for stage 1 PDAC in human patients. We further analyzed transcriptomes of genetically tagged 10-22 cells progressing from pancreatic intraepithelial neoplasia (PanIN) to PDAC in mice and validated the results using the TCGA PDAC dataset, human clinical PanIN, PDAC tissues, and a well-established murine PDAC model. We found that extracellular vesicle transport and neuronal cell differentiation pathways were derepressed in the progression of PanINs to PDAC. HMG-Box Transcription Factor 1 (HBP1) emerged as a potential master factor regulating dynamically expressed genes in neuronal cell differentiation and dissemination during PDAC progression. HBP1 expression are aberrantly regulated in human and murine PanINs and PDAC tissue samples, and their mRNA expressions are inversely correlated with PDAC patients' prognosis. Ectopic overexpression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells. Conversely, knocking out HBP1 in PDAC cells decreased proliferation and migration. Altogether, our data indicate that HBP1 may confer the cell dissemination capacity in early PDAC progression. We are on the way to further dissect the mechanisms by which HBP1 regulates pancreatic cell migration and confers neuronal migratory phenotypes and how these signaling influence PDAC progression and prognosis.

Citation Format: Taelor J. Ekstrom, Dmytro Grygoryev, Terry Morgan, Kenneth S. Zaret, Jungsun Kim. Delineating the molecular basis of early dissemination of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-082.
Abstract PO-103: Cellular origin influences immune microenvironment in a pancreatic cancer mouse model with loss of Pten and activation of Kras
Authors: Dou Yan , Hunt Wesley , Chhuor Justin , Taghizadeh Farnaz , Samani Atefeh , Sarai Karnjit , Dubois Claire , Schaeffer David F. , Sander Maike , Kopp Janel L.
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of merely 9%. Although mouse studies in the past decade have made progress towards a better understanding of how PDAC cellular origin affects tumorigenesis, there hasn’t been study on the immune microenvironment differences between precursor lesions and PDAC derived from acinar and ductal cells. Following our previous study that showed loss of Pten with oncogenic KrasG12D mutations in the ductal cells (KPtenDuct/+) resulted the formation of intraductal papillary mucinous neoplasias (IPMN) as the precursor lesion in mice, we further found siminar mutations in the acinar cells (KPtenAcinar/+) formed pancreatic intraepithelial neoplasia (PanIN) instead. We subsequently used the KPtenDuct/+ and KPtenAcinar/+ models to elucidate the effect of cellular origin on the immune microenvironment by performing immunohistochemistry. We looked at immune cell infiltration densities between precursor lesions and PDAC derived from KPtenDuct/+ and KPtenAcinar/+ models and will present the data during the conference. Additionally, macrophages polarized by conditioned media derived from KPtenDuct/+ and KPtenAcinar/+ PDAC cells showed distinctive polarization status, indicating cellular origin could result in PDAC with different cytokine and chemokine profiles that affect the immune microenvironment. Our study is the first to directly compare immune cell population between acinar- and ductal-derived PDAC originating from different types of precursor lesions with the same genetic background. Our study suggests the potential role of cellular origin on influencing PDAC immune heterogeneity.

Citation Format: Yan Dou, Wesley Hunt, Justin Chhuor, Farnaz Taghizadeh, Atefeh Samani, Karnjit Sarai, Claire Dubois, David F. Schaeffer, Maike Sander, Janel L. Kopp. Cellular origin influences immune microenvironment in a pancreatic cancer mouse model with loss of Pten and activation of Kras [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-103.
Abstract PO-107: Fibroblast differentiation trajectories elicit regional tissue states in pancreatic cancer
Authors: Grünwald Barbara T. , McCloskey Curtis , Devisme Antoine , Vyas Foram , Andrieux Geoffroy , Aliar Kazeera , Notta Faiyaz , O’Kane Grainne , Wilson Julie , Knox Jennifer , Fischer Sandra , Kislinger Thomas , Boerries Melanie , Gallinger Steven , Khokha Rama
Published: November 2021

Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. We recently deconvoluted regional heterogeneity in the human PDAC stroma to assess its role in disease progression and discovered two types of ‘sub-tumor microenvironments’ (subTMEs), called ‘reactive’ and ‘deserted’. These histologically definable tissue states exhibit strong regional relationships with tumor immunity, subtypes, differentiation, and treatment response. Here, we set out to define their cell biological underpinnings through a combination of subTME-specific cancer-associated fibroblast (CAF) models, integrative histopathology, quantitative image analysis, multiOMICs, scRNAseq, and controlled functional assays. Remarkably, the growth patterns of CAF cultures closely recapitulated the characteristic histomorphology of their originating subTMEs, and these distinct phenotypes were accompanied by behavioral differences. Unsupervised graph-based clustering of scRNAseq profiles showed that CAFs largely grouped by their originating subTME yet comprised up to 10 individual clusters. The subTME-specific multi-subpopulation CAF communities self-organized into distinct ‘coordinated states’, represented by cluster-overarching functional profiles and distinct morpho-histological and behavioral phenotypes. These differences originated in cellular differentiation trajectories, with an ‘intermediate’ transitory state evident both in single cell transcriptomics and in situ. Noticeably, this CAF differentiation potential was associated with distinct tumor-related functions and, similar to stem cells, was marked by RNA diversity and pluripotency markers. Therefore, regional TME programs in PDAC appear to result largely from transitions between subpopulation-overarching fibroblast differentiation states that guide multifaceted CAF and immune cell communities into recurrent tissue self-organizational units.

Citation Format: Barbara T. Grünwald, Curtis McCloskey, Antoine Devisme, Foram Vyas, Geoffroy Andrieux, Kazeera Aliar, Faiyaz Notta, Grainne O’Kane, Julie Wilson, Jennifer Knox, Sandra Fischer, Thomas Kislinger, Melanie Boerries, Steven Gallinger, Rama Khokha. Fibroblast differentiation trajectories elicit regional tissue states in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-107.
Abstract PO-114: STAT3 in cancer-associated fibroblasts promotes an immunosuppressive tumor microenvironment
Authors: Lefler Julia E. , Ostrowski Michael , MarElia-Bennett Catherine
Published: November 2021

One of the defining characteristics of pancreatic ductal adenocarcinoma (PDAC) is the formation of a dense stroma comprised of cancer associated fibroblasts (CAFs) and immune cell populations. This stroma is immunosuppressive and can act as a physical barrier against common therapeutic treatments. Attempts to therapeutically target the PDAC stroma have yielded contradictory results, suggesting both tumor promoting and tumor limiting roles for CAFs. These studies emphasize the need to understand important transsignaling pathways between CAFs, tumor cells, and the immune microenvironment. IL-6 is a pleiotropic cytokine involved in several physiological functions and its increased expression is strongly associated with poor survival rates in PDAC patients. STAT3 is a major downstream target of IL-6, and its aberrant activation has been implicated in PDAC tumor progression and immune evasion. IL-6 expression and the IL-6/STAT3 signaling axis in PDAC has been characterized in epithelial tumor cells, however its stromal-specific function on PDAC has yet to be elucidated. We hypothesized that the STAT3 signaling axis in pancreatic CAFs contributes to the immunosuppressive and fibrotic phenotype seen with disease progression. Employing CreLoxP technology, the fibroblast specific protein-1 (Fsp-Cre) transgene was used to conditionally delete STAT3 in fibroblasts in the PdxFlp; KrasG12D; p53frt/frt (KPF) PDAC mouse model developed by our lab. Deletion of STAT3 in fibroblasts significantly increased the survival in a cohort of KPF mice compared to those with intact STAT3. In preliminary investigations, we found an increase in CD8+ T cell infiltration but a decrease in regulatory T cells in the STAT3-deleted cohort. We also observed a decrease in immunosuppressive M2 macrophage populations and an increase in M1 macrophages in the STAT3-deleted cohort. These preliminary results demonstrate a previously unexplored role of IL-6/STAT3 signaling in fibroblasts during PDAC progression.

Citation Format: Julia E. Lefler, Michael Ostrowski, Catherine MarElia-Bennett. STAT3 in cancer-associated fibroblasts promotes an immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-114.