bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of home detection algorithms using smartphone GPS data
Authors: Verma Rajat , Mittal Shagun , Lei Zengxiang , Chen Xiaowei , Ukkusuri Satish V.
Published: January 2024

Estimation of people’s home locations using location-based services data from smartphones is a common task in human mobility assessment. However, commonly used home detection algorithms (HDAs) are often arbitrary and unexamined. In this study, we review existing HDAs and examine five HDAs using eight high-quality mobile phone geolocation datasets. These include four commonly used HDAs as well as an HDA proposed in this work. To make quantitative comparisons, we propose three novel metrics to assess the quality of detected home locations and test them on eight datasets across four U.S. cities. We find that all three metrics show a consistent rank of HDAs’ performances, with the proposed HDA outperforming the others. We infer that the temporal and spatial continuity of the geolocation data points matters more than the overall size of the data for accurate home detection. We also find that HDAs with high (and similar) performance metrics tend to create results with better consistency and closer to common expectations. Further, the performance deteriorates with decreasing data quality of the devices, though the patterns of relative performance persist. Finally, we show how the differences in home detection can lead to substantial differences in subsequent inferences using two case studies—(i) hurricane evacuation estimation, and (ii) correlation of mobility patterns with socioeconomic status. Our work contributes to improving the transparency of large-scale human mobility assessment applications.
Cost-aware Service Placement and Scheduling in the Edge-Cloud Continuum
Authors: Rac Samuel , Brorsson Mats
Published: January 2024

The edge to data center computing continuum is the aggregation of computing resources located anywhere between the network edge (e.g., close to 5G antennas), and servers in traditional data centers. Kubernetes is the de facto standard for the orchestration of services in data center environments, where it is very efficient. It, however, fails to give the same performance when including edge resources. At the edge, resources are more limited, and networking conditions are changing over time.

In this article, we present a methodology that lowers the costs of running applications in the edge-to-cloud computing continuum. This methodology can adapt to changing environments, e.g., moving end-users. We are also monitoring some Key Performance Indicators of the applications to ensure that cost optimizations do not negatively impact their Quality of Service. In addition, to ensure that performances are optimal even when users are moving, we introduce a background process that periodically checks if a better location is available for the service and, if so, moves the service. To demonstrate the performance of our scheduling approach, we evaluate it using a vehicle cooperative perception use case, a representative 5G application. With this use case, we can demonstrate that our scheduling approach can robustly lower the cost in different scenarios, while other approaches that are already available fail in either being adaptive to changing environments or will have poor cost-effectiveness in some scenarios.
Characterization of mitochondria-associated ER membranes in the enteric nervous system under physiological and pathological conditions
Authors: Delfino Giada , Briand Jean Baptiste , Oullier Thibauld , Nienkemper Léa , Greig Jenny , Véziers Joëlle , Neunlist Michel , Derkinderen Pascal , Paillusson Sébastien
Published: January 2024

Our work shows for the first time the presence of contacts between endoplasmic reticulum and mitochondria in the enteric neurons and that the dynamic of these contacts is affected in these cells from an age-related neurodegeneration mouse model. It provides new insights into the potential role of enteric mitochondria-associated endoplasmic reticulum membrane in neurodegenerative disorders.
Circulating biomarker analyses in a longitudinal cohort of patients with IPF
Authors: Ebert Christina , Walsh Alice M. , Sereda Larisa , Wilson Carole L. , Schafer Peter H. , Fischer Aryeh , Zhao Lei , Ramirez-Valle Francisco , Gordon David , Schnapp Lynn M.
Published: January 2024

In this study, we confirmed protein expression differences in only a subset of predicted biomarkers from IPF and control subjects. Most differentially expressed proteins were predicted to be secreted from lung cells. However, a significant minority of the proteins are not known to be transcriptionally expressed by lung cells, suggesting an ongoing systemic response. The contributions of the systemic response in IPF may be important as new therapeutics are developed.
Organizational Culture and Trust Affect the Team-BasedPractice and Job Satisfaction of Nurse Practitioners in Acute Care Hospitals: A National Survey
Authors: Huang Sheng-Shiung , Jen Hsiu-Fang , Tsay Shiow-Luan , Wang Ya-Jung , Tung Heng-Hsin
Published: January 2024

Background. The link between organizational culture, organizational trust, job satisfaction, and team-based practice among nurse practitioners (NPs) has not been examined simultaneously. Aim. To identify the effects of organizational culture, organizational trust, and other factors on NPs such as job satisfaction and team-based practice. Methods. We used a cross-sectional design with a national sample. Data were collected using an online survey of 1,100 NPs working in acute care settings. The survey included demographic and working characteristics, the Organizational Culture Scale, the Organizational Trust Scale, the Misener Nurse Practitioner Job Satisfaction Scale (MNPJSS), and the NP-physician relations (NP-PR) subscale of the Nurse Practitioner Primary Care Organizational Climate (NP-PCOCQ). Multiple regression analysis with a stepwise selection method explored potential factors that influence job satisfaction and team-based practice. Results. A learning environment, psychological safety, senior leadership support, commitment to the organization, and the organizational culture and trust were positively associated with higher job satisfaction, which accounted for 49.2% of the variance in NPs’ job satisfaction. Organizational trust, commitment to the organization, and learning environment promoted better team-based practice significantly. Also, NPs working a fixed shift pattern showed higher levels of team-based practice. These factors accounted for 23.66% of variances in team-based practice. Conclusion. Organizational culture and organizational trust affect the job satisfaction and team-based practice of NPs in acute care practices. Implications for Nursing Management. Acute care hospitals are encouraged to develop policies to enhance a learning environment, a supportive organizational culture, and trust in NPs’ practice.
Temporal and Spatial Evolution of Public–Private Partnership (PPP) Project Risks in China: 2003–2019
Authors: Wang Yanwei , Gong Lili , Zheng Shanfeng , Han Xiaoqing , Zhang Jiajin , Huang Yi
Published: January 2024

The implementation of public–private partnership (PPP) is perturbed by multiple factors, and it is difficult for the Chinese government to fully control the risks of PPP projects. Based on the DPSIR model, this study constructed the PPP projects risk evaluation index system by using the TOPSIS method. Then the spatial variation, standard deviation ellipse, and gray dynamic model were used to analyze the spatial–temporal dynamic evolution characteristics of the risk level of PPP projects from 2003 to 2019 and to make reasonable predictions of the future spatial distribution pattern. This study yielded the following five results: (1) the average risk level of China’s PPP projects is 0.722, with a decreasing trend of fluctuation and relatively stable risk; (2) high‐risk provinces for PPP projects decrease, medium‐risk provinces increase; (3) the spatial variability of risk is increasing, and the spatial differentiation is significant, showing a spatial evolution pattern of “west > central > east,” but areas with low‐risk values are clearly migrating to the east; (4) the spatial distribution pattern of risk has a north‐easterly orientation, with a “north‐west to north‐east” trend in the path of movement; (5) There are differences in the spatial distribution patterns in the east–west and north–south directions, and the spatial spillover effect is not obvious. Based on the above results, the risk center of China’s PPP projects will be shifted to the northeast in 2025–2035. Our study captures the evolution of PPP project risks in China in both temporal and spatial dimensions, which can provide lessons for optimizing global PPP project risk management.
Analysis of Traveling Wave and Combined Site Effect of Long‐Span Upper‐Bearing Concrete‐Filled Steel Tubular Arch Bridge
Authors: Li Zite , Wang Genhui , Fan Jiang , Jian Yue , Zhang Yongliang
Published: January 2024

In order to study the traveling wave effect and combined site effect of long‐span steel tube concrete‐filled arch bridge, a 400‐m span bridge of the same type is taken as an example, and a large‐mass time‐history analysis method with multipoint input of recorded seismic waves is used. A total of 11 kinds of traveling wave excitations and 9 kinds of combined site excitations under 4 types of typical sites are carried out to calculate the structural response, and the chord axial force ratio and displacement changes are compared and analyzed. The results show that the long‐span arch bridge also has nonuniform seismic excitation conditions in the lateral and vertical directions, and the spatial effect of the structural response is significant; under the traveling wave excitation, the change of the axial force ratio of the chord has a certain periodicity, and it is not the larger the axial force ratio is, the larger the axial force ratio is; the X direction has a significant influence, the maximum axial force ratio of the vault under the design condition is 6.26, and the changes in the Y and Z directions are relatively gentle, but there are still nearly two times the working condition; after the same amplitude modulation of different recorded waves, under the uniform excitation, the axial force is similar, but the displacement is quite different; under the unidirectional traveling wave excitation, the displacement in the X and Z directions shows an accelerating and increasing trend toward the vault. When it is relatively consistent under the unidirectional combined site excitation, and the axial force ratio changes under small and then increases, the L/4–3L/8 segment has a significant impact; the axial force ratio changes are the combined site excitation in different directions are spatially random; three under the combined site excitation. The axial force ratio in the orthogonal direction changes greatly. When the hard field is transformed into the soft field, the axial force ratio decreases, and the displacement increases continuously.
Few More Series of Reciprocals with Binomial Coefficients and Their Evaluations
Authors: Bhat Shruthi C. , Krithi M. , Srivatsa Kumar B. R.
Published: January 2024

In the present work, utilizing the known series, new series involving reciprocals of binomial coefficients, alternating positive, and negative binomial coefficients are constructed. Further, several new series of reciprocals of binomial coefficients with two odd terms in the denominator are obtained. In the end, we use these to establish the closed form evaluations of hypergeometric functions for the argument 1/16.
Metastatic Esophageal Adenocarcinoma Presenting as Neck Dermal Metastasis
Authors: Ibrahim-Shaikh Sara , Shaikh Noah , Daboul Nour , Alshaikhnassir Esra , Hafez Maria , Freiser Monika E.
Published: January 2024

Dermal metastasis is a rare manifestation of visceral disease, and esophageal adenocarcinomas represent around only 1% of primaries that present with cutaneous metastasis. In this case, we discuss a patient who presented with a painless submental mass and extensive right neck cutaneous induration and erythema. Core needle biopsy demonstrated poorly differentiated adenocarcinoma. Blood testing also demonstrated elevated carbohydrate antigen 19-9, carcinoembryonic antigen, and alkaline phosphatase. PET/CT followed by esophagoscopy led to the diagnosis of esophageal signet-cell adenocarcinoma primary with isolated dermal metastasis. The patient was started on palliative radiotherapy and passed away two months later from a suspected thoracic fistula and hydropneumothorax.
Enhancement of the Thermohydraulic Performance in a Double Passage Square Duct with the Use of Inclined Ribs of 45°: A Comparative Computational Study
Authors: Kaplan Mahmut
Published: January 2024

The modern gas turbines need to run at very high inlet temperature to promote their power output. Thus, improvements in cooling technologies play a significant role for enhancing the gas turbine blade life. In this paper, thermohydraulic performance (THP) of a two‐pass square channel with inclined ribs at 45° was scrutinized employing the k–ε realizable model with enhanced wall treatment in ANSYS Fluent. The calculations were performed for the rib pitch to height ratio (p/e) of 5‐10, rib height to hydraulic diameter ratio (e/Dh) of 0.1‐0.2, and Reynolds number (Re) of 20,000‐40,000. Detailed analysis of the flow structure in a double passage square duct was carried out to understand the interaction of the rib and bend‐induced secondary flows and its contribution to heat transfer enhancement for the rib configurations with distinct p/e and e/Dh, which was not available in any other existing numerical or experimental investigations. The results revealed that the ribs with higher e/Dh generated the stronger stream‐wise secondary flows which led to the augmentation of the cooling performance with the disadvantage of pressure loss increment. The maximum THP of 26.55% was achieved with the ribbed configuration having p/e = 5 and e/Dh = 0.1 at Re = 20,000. The new correlations were developed from the computational data to predict the normalized Nusselt number and friction factor (Nu/Nu0 and f/f0, where 0 is the correlation), taking the e/Dh and flow Re into consideration.
Supplementary Material and Methods from Metabolomic Rewiring Promotes Endocrine Therapy Resistance in Breast Cancer
Authors: Ahn Songyeon , Park Jun Hyoung , Grimm Sandra L. , Piyarathna Danthasinghe Waduge Badrajee , Samanta Tagari , Putluri Vasanta , Mezquita Dereck , Fuqua Suzanne A.W. , Putluri Nagireddy , Coarfa Cristian , Kaipparettu Benny Abraham
Published: January 2024

Supplementary Material and Methods
Table S9 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S9
Table S7 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S7
Table S5 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S5
Table S2 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S2
Data S5 from Erythroid Differentiation Enhances RNA Mis-Splicing in SF3B1-Mutant Myelodysplastic Syndromes with Ring Sideroblasts
Authors: Moura Pedro L. , Mortera-Blanco Teresa , Hofman Isabel J. , Todisco Gabriele , Kretzschmar Warren W. , Björklund Ann-Charlotte , Creignou Maria , Hagemann-Jensen Michael , Ziegenhain Christoph , Cabrerizo Granados David , Barbosa Indira , Walldin Gunilla , Jansson Monika , Ashley Neil , Mead Adam J. , Lundin Vanessa , Dimitriou Marios , Yoshizato Tetsuichi , Woll Petter S. , Ogawa Seishi , Sandberg Rickard , Jacobsen Sten Eirik W. , Hellström-Lindberg Eva
Published: January 2024

Seurat clustering and differential expression analysis between RS/NBM and MDS/NBM cell identity clusters in scRNAseq
Table S11 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S11
Table S10 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S10
Table S1 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S1
Supplementary Data from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

List of Supplementary Data
Figure S2 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Figure S2
Figure S1 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Figure S1
Figure S7 from Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment
Authors: Du Yanhua , Shi Jintong , Wang Jiaxin , Xun Zhenzhen , Yu Zhuo , Sun Hongxiang , Bao Rujuan , Zheng Junke , Li Zhigang , Ye Youqiong
Published: January 2024

Figure S7
Figure S2 from Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment
Authors: Du Yanhua , Shi Jintong , Wang Jiaxin , Xun Zhenzhen , Yu Zhuo , Sun Hongxiang , Bao Rujuan , Zheng Junke , Li Zhigang , Ye Youqiong
Published: January 2024

Figure S2
Supplementary Figure 7 from Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Ko Julie H. , Lambert Kyle E. , Bhattacharya Debadrita , Lee Myung Chang , Colón Caterina I. , Hauser Haley , Sage Julien
Published: January 2024

CUT&RUN analysis of FOXA1 binding in NFIBhigh and NFIBneg SCLC cells
Supplementary Figure 3 from Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Ko Julie H. , Lambert Kyle E. , Bhattacharya Debadrita , Lee Myung Chang , Colón Caterina I. , Hauser Haley , Sage Julien
Published: January 2024

NFIB and MYC mRNA levels in human SCLC cell lines
Supplementary Data 1 from Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Ko Julie H. , Lambert Kyle E. , Bhattacharya Debadrita , Lee Myung Chang , Colón Caterina I. , Hauser Haley , Sage Julien
Published: January 2024

TPM values from RNA-seq
Data from Erythroid Differentiation Enhances RNA Mis-Splicing in SF3B1-Mutant Myelodysplastic Syndromes with Ring Sideroblasts
Authors: Moura Pedro L. , Mortera-Blanco Teresa , Hofman Isabel J. , Todisco Gabriele , Kretzschmar Warren W. , Björklund Ann-Charlotte , Creignou Maria , Hagemann-Jensen Michael , Ziegenhain Christoph , Cabrerizo Granados David , Barbosa Indira , Walldin Gunilla , Jansson Monika , Ashley Neil , Mead Adam J. , Lundin Vanessa , Dimitriou Marios , Yoshizato Tetsuichi , Woll Petter S. , Ogawa Seishi , Sandberg Rickard , Jacobsen Sten Eirik W. , Hellström-Lindberg Eva
Published: January 2024

Abstract
Myelodysplastic syndromes with ring sideroblasts (MDS-RS) commonly develop from hematopoietic stem cells (HSC) bearing mutations in the splicing factor SF3B1 (SF3B1mt). Direct studies into MDS-RS pathobiology have been limited by a lack of model systems that fully recapitulate erythroid biology and RS development and the inability to isolate viable human RS. Here, we combined successful direct RS isolation from patient samples, high-throughput multiomics analysis of cells encompassing the SF3B1mt stem-erythroid continuum, and functional assays to investigate the impact of SF3B1mt on erythropoiesis and RS accumulation. The isolated RS differentiated, egressed into the blood, escaped traditional nonsense-mediated decay (NMD) mechanisms, and leveraged stress-survival pathways that hinder wild-type hematopoiesis through pathogenic GDF15 overexpression. Importantly, RS constituted a contaminant of magnetically enriched CD34+ cells, skewing bulk transcriptomic data. Mis-splicing in SF3B1mt cells was intensified by erythroid differentiation through accelerated RNA splicing and decreased NMD activity, and SF3B1mt led to truncations in several MDS-implicated genes. Finally, RNA mis-splicing induced an uncoupling of RNA and protein expression, leading to critical abnormalities in proapoptotic p53 pathway genes. Overall, this characterization of erythropoiesis in SF3B1mt RS provides a resource for studying MDS-RS and uncovers insights into the unexpectedly active biology of the “dead-end” RS.
Significance:
Ring sideroblast isolation combined with state-of-the-art multiomics identifies survival mechanisms underlying SF3B1-mutant erythropoiesis and establishes an active role for erythroid differentiation and ring sideroblasts themselves in SF3B1-mutant myelodysplastic syndrome pathogenesis.
Data from Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Ko Julie H. , Lambert Kyle E. , Bhattacharya Debadrita , Lee Myung Chang , Colón Caterina I. , Hauser Haley , Sage Julien
Published: January 2024

Abstract
Metastasis is a major cause of morbidity and mortality in patients with cancer, highlighting the need to identify improved treatment and prevention strategies. Previous observations in preclinical models and tumors from patients with small cell lung cancer (SCLC), a fatal form of lung cancer with high metastatic potential, identified the transcription factor NFIB as a driver of tumor growth and metastasis. However, investigation into the requirement for NFIB activity for tumor growth and metastasis in relevant in vivo models is needed to establish NFIB as a therapeutic target. Here, using conditional gene knockout strategies in genetically engineered mouse models of SCLC, we found that upregulation of NFIB contributes to tumor progression, but NFIB is not required for metastasis. Molecular studies in NFIB wild-type and knockout tumors identified the pioneer transcription factors FOXA1/2 as candidate drivers of metastatic progression. Thus, while NFIB upregulation is a frequent event in SCLC during tumor progression, SCLC tumors can employ NFIB-independent mechanisms for metastasis, further highlighting the plasticity of these tumors.
Significance:
Small cell lung cancer cells overcome deficiency of the prometastatic oncogene NFIB to gain metastatic potential through various molecular mechanisms, which may represent targets to block progression of this fatal cancer type.
Abstract A010: Evaluation of the Avantect Pancreatic Cancer Test for identifying high-risk pancreatic cysts
Authors: Bergamaschi Anna , Haan David , Friedl Verena , Guler Gulfem , Kesling Michael , Collins Micah , Hazen Kyle , Lopez Vanessa , Malta Roger , Nabiyouni Maryam , Riviere Michael , Leighton Anna , Peters Melissa , Chowdhury Shimul , Volkmuth Wayne , Levy Samuel
Published: January 2024

Background: Pancreatic cystic lesions are common incidental findings on imaging, but up to half may be precursors of pancreatic cancer. Current diagnostic methods cannot robustly identify cysts that have the highest probability to progress to cancer and require treatment. To address this gap, we evaluated the performance of a non-invasive epigenomic based test employing cell-free DNA, the Avantect Pancreatic Cancer test, in a cohort of patients with pancreatic cysts to identify those at higher risk of malignancy. Methods: In this study, we investigated the use of Avantect in a cohort of patients with pancreatic cysts. Whole blood was collected from 44 patients with cysts: 18 patients with high/moderate and 26 patients with low grade dysplasia/benign cysts. In parallel, demographic information, imaging results, surgical reports, and histological findings were collected for analysis and clinical annotation of patients. Results: Avantect was successfully run on all 44 pancreatic cysts. 16 out of the 18 (89%) patients with cysts of moderate/high grade dysplasia were detected having an abnormal pancreatic signal associated with pancreatic cancer. Of the 26 patients with cysts with low grade/benign features 8 (31%) were detected by Avantect as abnormal. This nearly three-fold higher detection rate for abnormal pancreatic signals in patients with cysts with medium/high grade dysplasia suggests the detection of epigenomic changes as precursors to pancreatic cancer. Conclusions: The Avantect Pancreatic Cancer test shows initial promise in distinguishing between low grade/benign and moderate/high grade dysplasia cysts. Larger studies have been commenced to enable prospective evaluation of Avantect for the management and surveillance of individuals with pancreatic cysts.

Citation Format: Anna Bergamaschi, David Haan, Verena Friedl, Gulfem Guler, Michael Kesling, Micah Collins, Kyle Hazen, Vanessa Lopez, Roger Malta, Maryam Nabiyouni, Michael Riviere, Anna Leighton, Melissa Peters, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy. Evaluation of the Avantect Pancreatic Cancer Test for identifying high-risk pancreatic cysts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A010.
Abstract A013: Uptake and predictors of Covid-19 vaccination among United States’ cancer populations
Authors: Greene Tayla , Olaosebikan Kikelomo , Idolor Osahon , Appiah-Pippim James
Published: January 2024

The COVID-19 pandemic led different stakeholders to call for measures to reduce the morbidity and mortality associated with it. However, following the development of a vaccine, United States adults were reluctant to get vaccinated against COVID-19. Our objective was to evaluate the uptake of COVID-19 vaccination among at risk adults with cancer, and to analyze the predictors of vaccination. Using 2021 data from the National Health Interview Survey, COVID-19 vaccination uptake among 2703 respondents representing 150 million United States adults with any type of cancer was explored, as well as the sociodemographic and comorbid predictors of the vaccination. Chi-square analysis was used to analyze differences between the vaccinated and unvaccinated respondents, and a multiple logistic regression analysis was used to determine the predictors of COVID-19 vaccination. Among 2703 respondents with any type of cancer, 2317 (83.8%) of them reported vaccination against COVID-19. As compared to those who were unvaccinated, those who were vaccinated were mostly 65+ years and above (88.7% vs 11.4%), females (81.9% vs 18.1%), whites (84.0% vs 16.0%), insured (84.7% vs 15.3%), and educated (92.0% vs 8.0%). With regards to the sociodemographic and comorbid predictors of COVID-19 vaccination. As compared to those less than 40 years of age, those between 40-64 years (AOR 2.55, CI 1.45 – 4.48; p=0.001) and 65 years and above (AOR 4.82, CI 2.65 – 8.79; p=<.001) were more likely to be vaccinated, the insured were more likely be vaccinated as compared to the uninsured (AOR 2.85, CI 1.42 – 5.71; p=0.003), and those who were educated were more likely to be vaccinated (AOR 3.10, CI 2.22 - 4.32; p=<.001) as compared to those who were uneducated. However, being a current smoker of cigarettes was associated with reduced odds of being vaccinated against COVID-19 infection compared to non-smokers (AOR 0.67, 0.47 – 0.97; p=0.035) While there appears to be a reasonable uptake of the COVID-19 vaccine among US adults with any type of cancer, efforts are needed to increase vaccine uptake among those who smoke cigarettes. In addition, younger, uninsured, and less educated adults with any type of cancer may be at a higher risk of contracting COVID-19 infection, and therefore measures to increase uptake in these groups are also.

Citation Format: Tayla Greene, Kikelomo Olaosebikan, Osahon Idolor, James Appiah-Pippim. Uptake and predictors of Covid-19 vaccination among United States’ cancer populations [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A013.
Abstract A020: Molecular basis of immune suppressive microenvironment specified by cancer-associated fibroblasts in pancreatic cancer
Authors: Aoki Kazunori , Fukuda Hironori , Hashimoto Eri , Arai Kosuke
Published: January 2024

Despite constant efforts to improve treatment, the prognosis remains poor, with an overall survival rate of 6% (ranges from 2% to 9%) due to lack of efficient chemotherapy, radiotherapy, and targeted therapy. Immune checkpoint inhibitors (ICIs) has been reported to be effective in various solid cancers, such as melanoma, lung cancer, and renal cell carcinoma. However, pancreatic ductal adenocarcinoma (PDAC) is resistant against ICIs. The responsiveness of immune therapy is mainly determined by immune tumor microenvironment (TME) composed of tumor-infiltrating lymphocytes (TIL) and stromal cells. PDAC possesses unique TME, which is abundant of fibrosis, termed of desmoplasia, and the role of fibrosis in constructing immune suppressive TME remains unclear. First, in this study, to examine the immunological characteristics of TME, we constructed an integrated data base of TIL profiling, RNA-seq and whole exome seq using 31 fresh resected tissues of PDAC. An unsupervised clustering of based on numbers and percentages of 12 TIL types analyzed by flow cytometry showed that PDAC was divided into 2 types of cluster (myeloid cell-, T cell-dominant type), and the prognosis of myeloid type was significantly poorer than T cell-type. Myeloid type contained the high frequency of myeloid cell lineage including monocytes, macrophages and myeloid-derived suppressor cells (MDSC). Only MDSCs were significantly associated with poor prognosis among various immune cell types. Furthermore, gene enrichment analysis identified activated and suppressed pathways in each immune type, and the immune-related pathways were significantly down-regulated in myeloid cell-dominant type. Then, to understand the characteristics of MDSCs infiltrated into pancreatic cancer tissues, single cell RNA-seq with surgical specimens was performed, and the analysis showed that a specific subtype of MDSCs infiltrated into cancer tissues. In addition, activation status of cancer-associated fibroblasts (CAFs) was related with MDSC recruitment and activation, indicating that the interaction between MDSCs and CAFs is crucial to create MDSC-rich TME. Inhibition of interaction between MDSCs and CAFs is expected to overcome immunosuppressive TME can be a novel immunotherapy in PDAC.

Citation Format: Kazunori Aoki, Hironori Fukuda, Eri Hashimoto, Kosuke Arai. Molecular basis of immune suppressive microenvironment specified by cancer-associated fibroblasts in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A020.
Abstract A022: Novel nanoparticle delivery of toll like receptor agonists alters the tumor immune landscape and improves response to standard of care therapy in preclinical PDAC models
Authors: Beals Nathan , Sorrentino Anthony , Bar-Sagi Dafna
Published: January 2024

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is becoming an increasingly complex system, driven by the interactions between multiple different cell types. These drivers of cancer progression can suppress local immune responses, promote resistance to therapies, and reinforce a pro-tumorigenic TME. Despite advances in other tumor types with immune checkpoint blockade, minimal progress has been made in the treatment of PDAC with immunotherapies targeted at adaptive responses. As such, with a majority of the TME being made up of innate immune cells being skewed towards immunosuppressive phenotypes, there remains an underutilized immunologic target. Of the potential subset of targets, toll like receptors (TLR) have garnered significant interest given the key role they have in controlling the innate immune response in a number of different immune cells. On their own, agonists of these family of receptors lack efficacy, either through poor tumor penetration, lack of target specificity or toxicity. To address this unmet need, we have developed a nano-delivery approach for TLR agonists for target immune cell uptake. Thus far, we have established two conjugates, a protein-based nanoparticle termed FN-TLR7 for the delivery of a CL307-based conjugate and a DNA nanoparticle termed CAGE-TLR9 for the delivery of a CpG-based agonist. We have found that these conjugates can activate target immune cells within the TME via an advantageous pharmacokinetic profile which significantly reduces nonspecific toxicities compared to free agonists. When paired with the current standard of care options in PDAC, we see significant improvements in tumor control. The implications of nano-delivery of TLR agonists for treating PDAC tumors will be discussed.

Citation Format: Nathan Beals, Anthony Sorrentino, Dafna Bar-Sagi. Novel nanoparticle delivery of toll like receptor agonists alters the tumor immune landscape and improves response to standard of care therapy in preclinical PDAC models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A022.
Abstract A024: B cells facilitate lymph node colonization in pancreatic ductal adenocarcinoma
Authors: Bertocchi Alice , Hoffman Megan T. , Qiang Li , Hsu Lauren , Dougan Michael , Agudo Judith , Dougan Stephanie K.
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate. Several factors contribute to its dismal prognosis, including resistance to available therapies and high invasiveness. Lymph nodes act as an early systemic source of circulating malignant cells in PDAC, allowing their dissemination to other organs early in disease progression. Lymphatic colonization is linked to worse prognosis. Therefore, a better understanding of mechanisms regulating lymph node metastasis is clinically needed. To study each step in the metastatic cascade to the lymph nodes, we have developed a mouse co-clinical model of resectable pancreatic cancer. This model consists of subcutaneous injection of highly metastatic pancreatic cancer cells, followed by surgical resection of the primary tumor. Following resection, mice spontaneously develop lymph nodes metastasis at a comparable frequency to human PDAC post-surgical recurrence, on a similar time scale relative to the lifespans of mice and humans. Expression of nuclear tdTomato allows detection of single cancer cells seeding the draining lymph nodes early in disease progression, even before metastases are histological detectable. Using this model, we are gaining insights into the first steps of metastatic seeding of lymph nodes, and have identified a pro-metastatic role for B cells. These findings will enhance our understanding of lymphatic colonization in PDAC and potentially inform immunotherapeutic interventions to disrupt the metastatic cascade.

Citation Format: Alice Bertocchi, Megan T. Hoffman, Li Qiang, Lauren Hsu, Michael Dougan, Judith Agudo, Stephanie K. Dougan. B cells facilitate lymph node colonization in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A024.
Abstract A031: Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma
Authors: Christopher Benjamin N. , Reyes Lety , Robinson Reeder , Golick Lena , Dolloff Nathan
Published: January 2024

Pancreatic Ductal Adenocarcinoma (PDAC) has a 5-year survival rate of only 10%, and limited treatment options exist. Immune checkpoint inhibitors are effective in a variety of cancer types; however, the complex immunosuppressive tumor microenvironment (TME) of PDAC is a significant barrier to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors from humans and mouse models. MDSCs suppress effector T cell function and promote the expansion of other immunosuppressive cell types. This led us to hypothesize that targeting tumor MDSCs would be an effective therapeutic strategy for PDAC and enhance the efficacy of T cell based immunotherapy. Our preliminary data and the work from others shows that CXCR2 ligands such as CXCL8/IL-8, CXCL5/ENA78, and CXCL1/GROα are the most abundant soluble factors secreted by PDAC cells. CXCR2 ligands are critical for the homing of myeloid cells to sites of injury in cutaneous wound healing, suggesting that dysregulated secretion of CXCR2 chemokines in PDAC may mimic a wound healing response that attracts myeloid cells and promotes the expansion of MDSCs and an immunosuppressive TME. To test this hypothesis, we have designed and produced multiple drug-conjugated CXCR2 ligand-based engineered proteins to target and eliminate MDSCs from PDAC tumors. We are referring to these novel biotherapeutic molecules as Ligand Drug Conjugates (LDCs). We have demonstrated binding, internalization, induction of signaling, and cytotoxicity of these LDCs to CXCR2 expressing myeloid cells. Our data suggests that our engineered proteins are superior binders and activators of CXCR2 axis signaling compared to WT CXCR2 ligands. Utilizing CXCR2 knockin models we demonstrated that the cytotoxicity of our LDCs is CXCR2 dependent. In vivo, we are utilizing the KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) mouse model of PDAC, which we've shown in preliminary studies to, like human PDAC, support an abundance of MDSCs in tumors as well as secondary lymphoid organs such as the spleen. We anticipate that this study will demonstrate the therapeutic potential and actionability of targeting MDSCs and will provide novel biotherapeutic drug candidates that will ultimately improve immunotherapy outcomes in patients with PDAC.

Citation Format: Benjamin N. Christopher, Lety Reyes, Reeder Robinson, Lena Golick, Nathan Dolloff. Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A031.
Abstract A033: Blocking TNF-a producing macrophage activates antitumor immunity in pancreatic cancer via IL33
Authors: Dixit Ajay , Provenzano Paolo , Sarver Aaron , Zettervall Jon , Huang Huocong , Zheng Kexin , Brekken Rolf
Published: January 2024

Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely due to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance and recent studies targeting macrophages in combination with checkpoint blockade have demonstrated promising preclinical results. Yet, our understanding of tumor-associated macrophage (TAM) function, complexity, and diversity in PDA remains limited. Here, analysis of human PDA single cell sequencing data revealed significant macrophage heterogeneity, with bone marrow-derived monocytes serving as the primary source for immunosuppressive TAMs. These bone marrow derived macrophages also served as a primary source of TNF-a. Deletion of Ccr2 in genetically engineered KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice decreased monocyte recruitment resulting in decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) renders PDA susceptible to checkpoint blockade therapy (CTLA-4 and PD-L1) resulting in reduced metastatic burden and increased survival in KPC mice. Additionally, TNF-a suppresses the expression of alarmin IL-33 in cancer cells, thereby hindering dendritic cell and cytotoxic T cell anti-tumor activity. When put together our data indicate that interventions to disrupt infiltration of immunosuppressive macrophages lead to decreased TNF-a, decreased metastasis and increased survival in two different models suggesting its potential role to overcome barriers to effective immunotherapeutics for PDA.

Citation Format: Ajay Dixit, Paolo Provenzano, Aaron Sarver, Jon Zettervall, Huocong Huang, Kexin Zheng, Rolf Brekken. Blocking TNF-a producing macrophage activates antitumor immunity in pancreatic cancer via IL33 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A033.
Abstract A058: Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis
Authors: Chen Ziheng , Ho I-Lin , Draetta Giulio , Ying Haoqiang
Published: January 2024

Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The essential contributions of mitochondrial metabolism to fuel tumor growth and resistance to therapy are now evident in multiple contexts. However, targeting of mitochondrial metabolism in the clinical setting has repeatedly failed, owing to a narrow therapeutic window and the remarkable ability of tumor cells to activate compensatory metabolic programs. Thus, it is essential to uncover additional mechanisms that may render cancer cells selectively susceptible to treatment and those that enable them to survive when exposed to mitochondrial metabolism-targeted drugs. Here, using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we report that cellular and, in particular, mitochondrial lipid composition affects the sensitivity of cancer cells to pharmacological inhibition of electron transport chain complex I. Metabolomic, including lipidomic, analyses of patient-derived PDAC models uncovered a critical role for monosaturated fatty acids (MUFAs) and demonstrated that MUFA-linked ether phospholipids have a critical role to sustain homeostasis of mitochondrial reactive oxygen species (ROS). Blocking de novo ether phospholipid biosynthesis in the peroxisomes, sensitized PDAC cells to mitochondrial complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. Biochemical analysis revealed a role of ether phospholipids in the assembly of mitochondrial supercomplexes and ROS production. Together, our data identify an ether phospholipid-dependent mechanism that regulates mitochondrial redox control and contributes to the sensitivity of PDAC cells to complex I inhibition. These findings might lead to novel approaches to target mitochondrial metabolism in cancer cells.

Citation Format: Ziheng Chen, I-Lin Ho, Giulio Draetta, Haoqiang Ying. Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A058.