bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of very high dose rates on the radiolysis of supercritical water at 400 °C and 25 MPa
Authors: Sultana Abida , Meesungnoen Jintana , Jay-Gerin Jean-Paul 
Published: November 2022

Monte Carlo multitrack chemistry simulations were used in combination with a cylindrical, “instantaneous pulse” irradiation model to study the effect of high dose rates on the early, transient yields ( G values) of the “primary products” ([Formula: see text], H•, H2,•OH, H2O2, H3O+, OH−, …) of the radiolysis of supercritical water (SCW) at 400 °C and 25 MPa pressure. Our simulation model consisted of randomly irradiating SCW with single pulses of N incident 300-MeV protons, which mimic the low linear energy transfer of60Co γ/fast electron irradiations. The effect of dose rate was studied by varying N. Generally, high dose rates were found to favor radical–radical reactions, which increases the proportion of the molecular products at the expense of the radical products. However, as an exception, G(H•) increases with increasing dose rate in the track stage of radiolysis, predominantly due to the reaction of hydrated electrons with hydronium ions (H3O+). In addition, the generation of acidic spikes due to proton transfer reactions in the physicochemical stage was also examined. Interestingly, an early, transient, very acidic (pH ∼ 3.5) response was observed at high radiation dose rates across the entire irradiated volume. The present work raises the question of whether the potential oxidizing species•OH and H2O2and these highly acidic pH spikes at high dose rates could promote a corrosive environment under proposed Generation IV SCW-cooled reactor or small modular reactor operating conditions that would lead to progressive degradation of materials.
Immunogenetic Determinants of Susceptibility to Head and Neck Cancer in the Million Veteran Program Cohort
Authors: Liu Yanhong , Kramer Jennifer R. , Sandulache Vlad C. , Yu Robert , Li Guojun , Chen Liang , Yusuf Zenab I. , Shi Yunling , Pyarajan Saiju , Tsavachidis Spyros , Jiao Li , Mierzwa Michelle L. , Chiao Elizabeth , Mowery Yvonne M. , Shuman Andrew , Shete Sanjay , Sikora Andrew G. , White Donna L. 
Published: November 2022

Abstract

Increasing rates of human papillomavirus (HPV)–driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk.

Significance:
Several inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.
A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer
Authors: Jones Robert , Plummer Ruth , Moreno Victor , Carter Louise , Roda Desamparados , Garralda Elena , Kristeleit Rebecca , Sarker Debashis , Arkenau Tobias , Roxburgh Patricia , Walter Harriet S. , Blagden Sarah , Anthoney Alan , Klencke Barbara J. , Kowalski Mark M. , Banerji Udai 
Published: November 2022

Abstract

Purpose:
This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737.

Patients and Methods:
Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors.

Results:
The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer.

Conclusions:
SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors.
Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma
Authors: Tobin Richard P. , Cogswell Dasha T. , Cates Victoria M. , Davis Dana M. , Borgers Jessica S.W. , Van Gulick Robert J. , Katsnelson Elizabeth , Couts Kasey L. , Jordan Kimberly R. , Gao Dexiang , Davila Eduardo , Medina Theresa M. , Lewis Karl D. , Gonzalez Rene , McFarland Ross W. , Robinson William A. , McCarter Martin D. 
Published: November 2022

AbstractPurpose:A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma.Patients and Methods:Anti–PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS).Results:Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs.Conclusions:With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation.See related commentary by Olson and Luke, p. 1167
Abstract A006: Integrating single cell and spatial transcriptomics define gene signature for pancreatic ductal adenocarcinoma pre-neoplastic lesion
Authors: Elhossiny Ahmed M. , Carpenter Eileen , Kadiyala Padma , Zhang Yaqing , Bednar Filip , Rao Arvind , Frankel Timothy , Di Magliano Marina Pasca 
Published: November 2022

Abstract
Pancreatic Cancer Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers with 5-year survival of 11%. Understanding the intratumor heterogeneity is a pivotal piece to unravel the complexity of PDAC. While single cell RNASeq identifies the heterogeneous cell populations within the tumor tissue, spatially characterizing the transcriptomic profile of neoplastic and pre-neoplastic populations within the tissue remains a challenge, as the spatial dimension is usually lost upon tissue dissociation. We identified an approach to integrate spatial transcriptomics data with single cell RNASeq data. To characterize the cell populations within the tissue we performed single cell RNASeq on disease pathology-free pancreas tissue and primary PDAC samples. We profiled the transcriptomic profile of Acinar, Ductal, Acinar-to-Ductal (ADM), and Pancreatic Intraepithelial Neoplasia (PanINs) regions of interest (ROIs) across the tissue using the Nanostring GeoMx platform. Differential gene expression analysis using linear mixed-effect models of the cell-type specific ROIs defined pan-marker gene sets for each cell type, which were mapped to UMAP projections of single cell RNA sequencing data using AUCell scoring. As expected, the acinar pan-markers gene set derived from the spatial transcriptomics mapped to the manually annotated acinar population in the single cell data. On the other hand, Ductal, ADM, and PanIN pan-marker gene sets were mapped to distinct clusters that previously were not well-defined by single cell sequencing. The analysis coupled with orthogonal validation using RNAScope revealed gene signatures uniquely specific to ADM lesions and PanINs, respectively. Interestingly, our list included known markers as well as novel findings, supporting the validity of the findings. Furthermore, RNA velocity analysis using scVelo revealed a trajectory of cell evolution originating from acinar cells passing through the newly-defined ADM population and ending towards the ductal population derived from tumor samples. Overall, this integration approach of spatial and single cell transcriptomics can further define the characteristics that differentiate neoplastic and pre-neoplastic populations, as well as the potential drivers for tumorigenesis that could be therapeutically targeted.
Citation Format: Ahmed M. Elhossiny, Eileen Carpenter, Padma Kadiyala, Yaqing Zhang, Filip Bednar, Arvind Rao, Timothy Frankel, Marina Pasca Di Magliano. Integrating single cell and spatial transcriptomics define gene signature for pancreatic ductal adenocarcinoma pre-neoplastic lesion [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A006.
Abstract A008: PanCAN SPARK: A cloud-based health data integration platform for pancreatic cancer data
Authors: Abdilleh Kawther , Khalid Omar , Ladnier Dennis , Wan Wenshuai , Seepo Sara , Rupp Garrett , Corelj Valentin , Worman Zelia F. , Press Bruce , DiGiovanna Jack , Chandrashekhar Satty , Collisson Eric , Cui Karen , Maitra Anirban , Rejto Paul A. , White Kevin , Matrisian Lynn , Doss Sudheer 
Published: November 2022

Abstract
The Pancreatic Cancer Action Network (PanCAN) is leading large-scale research initiatives that will help transform the way pancreatic cancer is detected and treated including the Know Your Tumor precision medicine service, the Precision Promise adaptive clinical trial platform, the Early Detection Initiative, and the Patient Registry. Combined, these initiatives will generate a wide range of patient health data including molecular, multi-omic, clinical, patient-reported, treatment, outcomes, and imaging data. Here we introduce SPARK, a cloud-based data and analytics platform powered by Seven Bridges. SPARK integrates patient health data from PanCAN’s research initiatives and serves to accelerate research by making pancreatic cancer data easier to access and use. The platform supports the full spectrum of clinical data analysis with PanCAN patient health data as well as bioinformatics and analytical tools designed to leverage clinico-genomic data in a centralized location. SPARK fills an unmet need in pancreatic cancer research by providing researchers rapid and secure access to a wide range of pancreatic cancer patient health data on a platform backed by a robust cloud-based analytical infrastructure. The pilot release of the PanCAN SPARK platform brings qualified researchers closer to identifying novel treatments and ultimately improving patient outcomes.
Citation Format: Kawther Abdilleh, Omar Khalid, Dennis Ladnier, Wenshuai Wan, Sara Seepo, Garrett Rupp, Valentin Corelj, Zelia F. Worman, Bruce Press, Jack DiGiovanna, Satty Chandrashekhar, Eric Collisson, Karen Cui, Anirban Maitra, Paul A. Rejto, Kevin White, Lynn Matrisian, Sudheer Doss. PanCAN SPARK: A cloud-based health data integration platform for pancreatic cancer data [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A008.
Abstract A056: Epithelial hyaluronan synthase 2 expression promotes pancreas cancer metastasis
Authors: Tu Bo , Wright Heather Wright T. , Dufort Christopher C. , Whittle Martin C. , Feng Libing , Thorsen Shelley M. , Hingorani Sunil R. 
Published: November 2022

Abstract
A defining characteristic of pancreatic ductal adenocarcinoma (PDA) is its robust desmoplastic reaction that promotes tumor progression and protects PDA from treatment. As a major component of the extreme microenvironment, hyaluronan (HA) is synthesized by the hyaluronan synthase (Has) family of enzymes and secreted in excess by both epithelial cells and cancer-associated fibroblasts (CAFs). We have previously described the role of HA in binding water and swelling to create vessel-crushing interstitial gel-fluid pressures and its function as a biophysical barrier. However, HA also acts by signaling through a wide range of specific receptors that can drive proliferation, migration and invasion. In an effort to understand the role of HA in PDA development and pathogenesis, we developed a KPC mouse model of autochthonous pancreas cancer in which Has2 is conditionally deleted in tumor epithelial cells (TECs). We demonstrate that Has2-deficient epithelial cells produce little to no HA and altered the dense microenvironment. We also found that deletion of Has2 leads to an increase in overall survival and a striking reduction in metastasis. We have further investigated the cell autonomous functions of Has2, associated with 3D invasion and activation of oncogenic signaling pathways in TECs. These data implicate a potential Achilles’ heel in PDA, whereby HAS2 is required to maintain a highly metastatic phenotype involving both non-cell and cell autonomous mechanisms.
Citation Format: Bo Tu, Heather Wright T. Wright, Christopher C. Dufort, Martin C. Whittle, Libing Feng, Shelley M. Thorsen, Sunil R. Hingorani. Epithelial hyaluronan synthase 2 expression promotes pancreas cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A056.
Abstract A057: Therapeutic efficacy of selective CDK7 inhibition in pancreatic cancer mediated by induction of R-loop formation, DNA replication stress and genomic instability
Authors: Yang Annan , Jiang Jie , Li Ziyue , Kapner Kevin S. , Feng Hanrong , Lowder Kristen E. , Kuljanin Miljan , Johnson Whiteny , Uribe Giselle , Neggers Jasper E. , Liu Shengwu , Zhang Tinghu , Decaprio James , Sicinska Ewa , Wolpin Brian M. , Kwiatkowski Nicholas P. , Dougan Stephanie K. , Mancias Joseph D. , Gray Nathanael S. , Aguirre Andrew J. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with 5-year overall survival of less than 10% and few effective therapies. Here, we demonstrate that cyclin dependent kinase 7 (CDK7) is essential for the proliferation and viability of PDAC cells by showing potent anti-tumor efficacy for the CDK7-specific inhibitor YKL-5-124 in preclinical PDAC models. Selective CDK7 inhibition leads to G2/M cell cycle arrest and apoptosis in PDAC, while mediating a more modest transcriptional response compared with multi-targeted CDK7 inhibitors. YKL-5-124 treatment impairs DNA damage repair pathways in PDAC cells and evokes genomic instability by inducing R-loop formation and DNA replication stress in telomeric regions leading to chromosomal bridging and micronuclei formation. Furthermore, we demonstrate that selective CDK7 inhibition has in vitro and in vivo combinatorial efficacy with gemcitabine chemotherapy through pronounced induction of replication stress and apoptosis. Collectively, these findings support selective CDK7 inhibition as a promising therapeutic strategy for PDAC.
Citation Format: Annan Yang, Jie Jiang, Ziyue Li, Kevin S. Kapner, Hanrong Feng, Kristen E. Lowder, Miljan Kuljanin, Whiteny Johnson, Giselle Uribe, Jasper E. Neggers, Shengwu Liu, Tinghu Zhang, James Decaprio, Ewa Sicinska, Brian M. Wolpin, Nicholas P. Kwiatkowski, Stephanie K. Dougan, Joseph D. Mancias, Nathanael S. Gray, Andrew J. Aguirre. Therapeutic efficacy of selective CDK7 inhibition in pancreatic cancer mediated by induction of R-loop formation, DNA replication stress and genomic instability [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A057.
Abstract A066: 5z-7-oxozeaenol as an epithelial mesenchymal transition plasticity inhibitor in PDAC
Authors: You Eunae , Phillips Ildiko Phillips E. , Ebright Richard Y. , Desai Niyati , Raabe Michael J. , Lang Evan R. , Nieman Linda T. , Hajizadeh Soroush , Kreuzer Johannes , Haas Wilhelm , Ting David T. 
Published: November 2022

Abstract
Transcriptional profiling has defined PDAC into distinct classical epithelial (E) or quasi-mesenchymal (QM) subtypes, and these subtypes exist on a continuum of interconverting cell states. This epithelial to mesenchymal transition (EMT) plasticity is thought to be important for the metastatic dissemination and intrinsic resistance to chemotherapy. Our prior work identified TAK1 as an important driver of EMT in mouse circulating tumor cells, and we had identified a compound (5z)-7-oxozeaenol (Oxo) as a small molecule inhibitor of TAK1. Here, we have expanded upon this prior work by evaluating Oxo in 3 human patient derived PDAC cell lines as an EMT plasticity inhibitor. Treatment with Oxo induced a shift of all PDAC cell lines towards an E phenotype in both E and QM PDAC cell lines using RNA-seq and quantitative RNA in situ hybridization. This was associated with increased FFX sensitivity, loss of migratory abilities of all cell lines by Boyden chamber, and decreased invasion in matrigel. Interestingly, genetic TAK1 knockout via CRISPR/Cas9 in these PDAC cell lines showed different effects from Oxo. We found that TAK1 knockout decreased E PDAC cell line migratory behavior and increased FFX sensitivity, but QM PDAC cell lines were not affected by TAK1 knockout. This suggests that QM PDAC cell lines have additional signaling cascades that compensate for TAK1 loss and that Oxo effects across PDAC cell lines are not solely TAK1 dependent. Using phospho-proteomics, in FFX treated PDAC cell lines, we have identified potential candidate pathways in RNA splicing and viral processes that may be additional processes affected by Oxo that merits further investigation. Altogether, we have identified Oxo as a potential broad EMT plasticity inhibitor across PDAC subtypes, and there is a potential role of selective TAK1 inhibitors for E PDAC tumors.
Citation Format: Eunae You, Ildiko Phillips E. Phillips, Richard Y. Ebright, Niyati Desai, Michael J. Raabe, Evan R. Lang, Linda T. Nieman, Soroush Hajizadeh, Johannes Kreuzer, Wilhelm Haas, David T. Ting. 5z-7-oxozeaenol as an epithelial mesenchymal transition plasticity inhibitor in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A066.
Abstract A068: Investigation of changes in epithelial cell states in pancreatic cancer using human organoids
Authors: Huang Ling , Muthuswamy Senthil 
Published: November 2022

Abstract
Pancreatic cancer is among the deadliest cancers in the US. The low survival rates of pancreatic cancer are mainly due to late diagnosis and a lack of effective treatments. To improve the clinical management of pancreatic cancer, we need better understand the biological mechanisms underlying the initiation and progression of this disease. With a focus on elucidating pancreatic cancer biology in human patients, we have developed organoid models for pancreatic normal physiology and malignancy using pluripotent stem cells or patient tumor tissues. Using stem cell-derived organoids, we investigated the interactions between pancreatic epithelial cell states, oncogenic signaling pathways, and cytokines. In this study, we discovered that human acinar organoids, compared to ductal organoids, were more sensitive to KRasG12D oncogenic signaling in vitro and in vivo, which supported acinar cells as the main cell of origin for pancreatic cancer in human patients. We have also developed working pipelines using organoid models to identify biomarkers and predict patient drug responses. Based on those successful studies, we now focus on investigating biological principles underlying racial disparities in pancreatic cancer using human cell models.
Citation Format: Ling Huang, Senthil Muthuswamy. Investigation of changes in epithelial cell states in pancreatic cancer using human organoids [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A068.