bluuebunny/crossref_metadata_2025 huggingface dataset:
A Survey on Zero Trust Architecture: Challenges and Future Trends
Authors: He Yuanhang , Huang Daochao , Chen Lei , Ni Yi , Ma Xiangjie
Published: June 2022

The traditional perimeter-based network protection model cannot adapt to the development of current technology. Zero trust is a new type of network security model, which is based on the concept of never trust and always verify. Whether the access subject is in the internal network or the external network, it needs to be authenticated to access resources. The zero trust model has received extensive attention in research and practice because it can meet the new network security requirements. However, the application of zero trust is still in its infancy, and enterprises, organizations, and individuals are not fully aware of the advantages and disadvantages of zero trust, which greatly hinders the application of zero trust. This paper introduces the existing zero trust architecture and analyzes the core technologies including identity authentication, access control, and trust assessment, which are mainly relied on in the zero trust architecture. The main solutions under each technology are compared and analyzed to summarize the advantages and disadvantages, as well as the current challenges and future research trends. Our goal is to provide support for the research and application of future zero trust architectures.
Optimal Design of Sports Event Timer Structure Based on Ferroelectric Memory
Authors: Liu Jiannan , Chen Cailie
Published: June 2022

Sports events are an indispensable part of popularization and strong entertainment and can promote the physical and mental health of the people and the construction of cultural and spiritual civilization. Therefore, it is necessary to use a timer to record and analyze data during the game. In the traditional sense, the game timer is a fixed system. And now we can design sports event timer operations through mobile phones, computers, and other equipment to assist in the calculation of game time and competition. Ferroelectric memory is a kind of random access memory, which combines the fast read and write access of dynamic random access memory with the ability to retain data. Based on this, the ferroelectric memory timer proposed in this paper is intended to improve the accuracy and fairness of sports events. Therefore, this article has tested the function of the timer designed in this article by studying the ferroelectric memory and experimental construction and testing methods and finally concluded that the design is reasonable, but there is still a problem of data susceptibility. The experimental results show that there is a certain gap between the time interval measurement level of the timer and SR, the difference is 47 ps, the pulse width difference is controlled at 0.004, and the measurement uncertainty of timer interval is better than 60 ps. This shows that the timer can be applied, but it needs further improvement.
Cryptanalysis and Enhancement of an Authenticated Key Agreement Protocol for Dew-Assisted IoT Systems
Authors: Ma Yuqian , Ma Yongliu , Cheng Qingfeng
Published: June 2022

Real-time and high-efficient communication becomes a vital property for IoT-enabled equipment, since the application range of the Internet of Things has extended widely. At the same time, the centralized characterization of the cloud computing is gradually unable to meet the demand for both low latency and high computing efficiency. To resolve these issues, new computing paradigms have been introduced, such as edge, dew, and fog computing. Recently, Saurabh et al. introduced a mutual authentication protocol, which was claimed to resist various attacks without the requirement of a trusted server, for dew-assisted IoT devices. However, this paper will show that Saurabh et al.’s scheme lacks forward security and user anonymity. Then, a new authenticated key agreement (AKA) protocol, named e-SMDAS, will be put forward and formally proven secure under the eCK security model. Further, the analysis results of BAN logic and Scyther tool will also confirm the security of e-SMDAS. Finally, the comparative analysis of security features and computation efficiency between e-SMDAS and several recent schemes will be demonstrated at the end of this paper.
lncRNA FR215775 Regulates Th2 Differentiation in Murine Allergic Rhinitis
Authors: Ma Yue , Shi Le , Zhao Keqing , Zheng Chunquan
Published: June 2022

To identify the effect of long noncoding RNA (lncRNA) FR215775 in regulating CD4+ T cells on murine models of allergic rhinitis (AR), the expression of lncRNA FR215775 in primary Th2 cells was detected through qRT-PCR. After knocking down the expression of lncRNA FR215775 via Sh-FR215775-Ads, Cell Counting Kit-8, cytometric bead array, and fluorescence-activated cell sorting were performed to determine its functions in vitro. Moreover, lncRNA FR215775-silencing or nonsilencing cells were injected intravenously into AR mice. Then, hematoxylin and eosin, Alcian blue-periodic acid Schiff, and toluidine blue staining were performed, and the levels of IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A, IFN-γ, and TNF in the AR mice were also determined. We found that the expression of lncRNA FR215775 was specifically higher in the murine primary Th2 cells. After the knockdown of lncRNA FR215775, the proliferation of CD4+ T cells was inhibited, and the expressions of IL-4 and IL-5 in the cell culture supernatant were significantly decreased (

P
<
0.001

), along with the percentage of Th2 cells (

P
<
0.05

). The lncRNA FR215775-silencing AR group showed less serious allergic symptoms and a low level of ovalbumin-specific immunoglobulin E (

P
<
0.01

). Meanwhile, the eosinophilia inflammation, goblet cell hyperplasia, and mast cell inflammation in the nasal mucosa all decreased, which indicated attenuated allergic inflammation in the lncRNA FR215775-silencing AR group. In addition, the Th2-related cytokines IL-4 and IL-5 were downregulated in the serum and nasal lavage fluid of this group (

P
<
0.01

). In conclusion, lncRNA FR215775 may play a vital role in the function and differentiation of Th2 cells, which may encourage allergic inflammation. These results may provide significant insights into AR pathogenesis and offer new treatment targets for alleviating AR.
Research on the Sustainable Development Path of Folk Culture Village Tourism under the Background of “Internet + Industrial Resources”
Authors: Xiao Ying
Published: June 2022

Folk culture village has beautiful village scenery and rich national culture connotation. With the accelerated development of folk culture village tourism industry, traditional villages become popular. In view of the problems existing in the development of folk culture village tourism in Yunnan Province, from the perspective of “Internet + cultural industry,” this paper studies and analyzes the distribution status, tourism resources status and economic industry status of traditional folk villages in Yunnan Province, and uses grey correlation method to further analyze the relationship between culture, tourism industry and Internet industry. The results show that thanks to the construction of the Internet platform, the resources of Yunnan folk culture villages are known by more and more tourists. The number of tourists in Yunnan folk culture villages has increased from 1486.26 million to 3362.41, and the tourism income has also increased from 7.7 billion yuan to 21.697 billion yuan, reaching a sustained growth state. The results of the grey correlation analysis of folk culture village resources show that the correlation between cultural resources and various resources in Yunnan’s folk culture villages is greater than 0.7, indicating that there is a strong correlation between cultural resources, Internet resources, tourism resources and industrial resources, with sufficient potential for development. In order to strengthen the sustainable development of folk culture villages, the convenience of the Internet and the integration of tourism resources can be used to create an “online + offline” tourism system to further increase the popularity of the villages.
Deletion of Mettl3 at the Pro-B Stage Marginally Affects B Cell Development and Profibrogenic Activity of B Cells in Liver Fibrosis
Authors: Kang Xinmei , Chen Shuhan , Pan Lijie , Liang Xiaoqi , Lu Di , Chen Huaxin , Li Yanli , Liu Chang , Ge Mian , Zhang Qi , Liu Qiuli , Xu Yan
Published: June 2022

N6-methyladenosine (m6A) modification plays a pivotal role in cell fate determination. Previous studies show that eliminating m6A using Mb1-Cre dramatically impairs B cell development. However, whether disturbing m6A modification at later stages affects B cell development and function remains elusive. Here, we deleted m6A methyltransferase Mettl3 from the pro-B stage on using Cd19-Cre (Mettl3 cKO) and found that the frequency of total B cells in peripheral blood, peritoneal cavity, and liver is comparable between Mettl3 cKO mice and wild-type (WT) littermates, while the percentage of whole splenic B cells slightly increases in Mettl3 cKO individuals. The proportion of pre-pro-B, pro-B, pre-B, immature, and mature B cells in the bone marrow were minimally affected. Loss of Mettl3 resulted in increased apoptosis but barely affected B cells’ proliferation and IgG production upon LPS, CD40L, anti-IgM, or TNF-α stimulation. Different stimuli had different effects on B cell activation. In addition, B cell-specific Mettl3 knockout had no influence on the pro-fibrogenic activity of B cells in liver fibrosis, evidenced by comparable fibrosis in carbon tetrachloride- (CCl4-) treated Mettl3 cKO mice and WT controls. In summary, our study demonstrated that deletion of Mettl3 from the pro-B stage on has minimal effects on B cell development and function, as well as profibrogenic activity of B cells in liver fibrosis, revealing a stage-specific dependence on Mettl3-mediated m6A of B cell development.
A Method Applied in Anomaly Detection of Impurities Adhering to Pipes of Coriolis Mass Flowmeter
Authors: Ren Jianxin , Qin Yixin , Yang Peng , Zhang Peng
Published: June 2022

The Coriolis mass flowmeter (CMF) is widely used to measure mass flow, mainly in petrochemical, medical, pharmaceutical, food manufacturing, and other industries. The measuring tube is the crucial component of CMF, which affects the measurement accuracy and causes losses to the production of enterprises. Wall-mounted failure of the measuring tube affects measurement accuracy. A real-time detection method based on acceleration sensor array signal processing and pattern recognition are proposed to detect such failure. Two acceleration sensors are arranged outside the CMF to compose a five-channel sensor array. The signals of the multichannel array are decomposed through a blind source separation algorithm, and array signal features are extracted by a wavelet scattering network. Support vector data description (SVDD) is used to detect the hanging state of CMF at last. The experimental results show that the proposed method can be used to detect the CMF wall-mounted failure in real-time with an accuracy of 89.59%, and the method can reduce production losses.
Clinical Utility of the Prenatal Ultrasound Score of the Placenta Combined with Magnetic Resonance Imaging in Diagnosis of Placenta Accreta during the Second and Third Trimester of Pregnancy
Authors: Zhang Jing , Dong Pingping
Published: June 2022

Objective. The aim is to explore the clinical utility of the prenatal ultrasound score of the placenta combined with magnetic resonance imaging (MRI) in diagnosis of placenta accreta during the second and third trimester of pregnancy. Materials and Methods. A total of 108 pregnant women with suspected placenta accreta treated in Wuhan Hankou Hospital and Yantaishan Hospital of Yantai from January 2019 to January 2022 were retrospectively analyzed, the enrolled pregnant women received MRI examination because of suspected results of ultrasonic diagnosis, and by taking pathologic findings as the gold standard, the diagnostic efficacy of the ultrasound score, MRI, and their combination to placenta accreta during the second and third trimester of pregnancy was analyzed, and the diagnostic sensitivity, specificity, the positive predictive value, and the negative predictive value of these diagnostic modalities were evaluated. Results. Among 108 patients with suspected placenta accreta, 75 with pathologically confirmed placenta accreta were included in the accreta group, and 33 without placenta accreta were included in the non‐accreta group; no statistical between‐group differences in the patients’ age, gestational weeks, educational degree, and other general data were observed (P > 0.05), but the history of cesarean section, history of induced abortion, and incidence rate of placenta praevia were significantly higher in the accreta group than in the non‐accreta group (P < 0.05); the ultrasound score was significantly higher in the accreta group than in the non‐accreta group (P < 0.05); the incidence rates of signs of “placental heterogeneity” and “bulge of lower segment of the uterus and local thickening of the placenta” were obviously higher in the accreta group than in the non‐accreta group (P < 0.05); according to the comparison with pathologic findings, the accuracy rate, sensitivity, specificity, the positive predictive value, and the negative predictive value of combined diagnosis were significantly higher than those of single application of the ultrasound score and MRI diagnosis (P < 0.05); and ROC analysis found that the area under the curve of combined diagnosis was obviously larger than that of the ultrasound score and MRI diagnosis (P < 0.05). Conclusion. A combining prenatal ultrasound score of the placenta with MRI plays an important role in the diagnosis of placenta accreta during the second and third trimester of pregnancy, which can further improve the diagnostic accuracy rate of placenta accreta and provide significant guidance in preventing high‐risk complications during the perinatal period.
A Linear Regression Prediction Model of Infectious Disease Spread Based on Baidu Migration and Effective Distance
Authors: Zhou Tianqi
Published: June 2022

Objective. To analyze the relationship between effective distance and epidemic spread trajectory and between arrival time and scale based on the COVID-19 data outbreak in Wuhan and thus to improve the prediction ability of the spread of infectious disease. Methods. Up to January 28, 2020, the reporting date, the onset date, and the cumulative number of confirmed cases of COVID-19 in each province and city were collected. Baidu migration data was used to calculate the effective distance from Wuhan city to other regions. The reporting date and onset date of the first diagnosed patient were taken as the arrival time, respectively, to establish a linear regression model of effective distance and arrival time. In different provinces and cities, the logarithm of the cumulative number of confirmed cases with a base of 5 was taken as the criteria to determine the level of the cumulative confirmed cases. Based on this, the linear regression model of effective distance and the level of cumulative confirmed cases in the provincial and municipal units was established. Results. The linear correlation between the reporting date of the first confirmed patient and the effective distance was not strong. The coefficients of determination (

R

2

) for cities with and without the cities of Hubei Province were 0.36 and 0.44, respectively. And the linear correlation between the onset date of the first confirmed patient and the effective distance was strong. And the coefficients of determination (

R

2

) for cities with and without the cities of Hubei Province were 0.67 and 0.83, respectively. And the linear correlation between the level of cumulative confirmed cases in the provincial and municipal units and the effective distance was strong, with an

R

2

of 0.87 and 0.84, respectively. The regression coefficients of each linear model were statistically significant (

P
<
0.001

). Conclusion. The effective distance has a good fit with the model of the onset date of the first confirmed patient and the level of cumulative confirmed cases, which can predict the trajectory, time, and transmission range of the epidemic. It can be taken as the reference for the early warning, prevention, and control of sudden acute infectious diseases from a macro perspective.
PI3King the Environment for Growth: PI3K Activation Drives Transcriptome Changes That Support Oncogenic Growth
Authors: Claridge Sally E. , Hopkins Benjamin D.
Published: June 2022

PI3K signaling plays an integral role in cells, coordinating the necessary alterations in cellular metabolism and programs to support survival and proliferation. In the first genome-wide analysis of alternative splicing in PIK3CA-mutant breast cancer, Ladewig and colleagues show that activating mutations in PIK3CA alter the use of known exons and splice junctions, leading to changes in gene expression and transcription factor activity that promote an oncogenic phenotype. Their work reveals a novel mechanism underlying the functional impact of PI3K signal activation in the context of breast cancer, where PIK3CA mutations are common and PI3K inhibitors are part of the standard of care. Their studies uncover a feedforward mechanism by which PI3K signaling enables a shift in the spectrum of translated splice variants as another method through which the PI3K pathway has evolved to regulate its own activity, thereby modifying the cellular response to upstream activation based on the signaling that has come before. These findings have profound implications for understanding the evolution of the PI3K pathway and the rewiring of cells in response to prolonged or repeated signal activation.

See related article by Ladewig et al., p. 2269
Abstract 104: Targeting NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic ductal adenocarcinoma: An in silco, in vitro and in vivo approach
Authors: Ganji Purnachandra N. , Lesinski Gregory B. , El-Rayes Bassel F.
Published: June 2022

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme. NQO1 is important for catalyzation, detoxification, and reduction of organic compounds including quinone. Elevated NQO1 expression is associated with increased pancreatic ductal adenocarcinoma (PDAC) growth, and metastasis as well as poor prognosis. BBI 608 is a small molecule that exhibits potential therapeutic properties for PDAC due to its powerful anti-inflammatory and antioxidant properties and ability to regulate multiple signaling pathways. The current study explores the binding capacity and ligand efficacy of BBI608 against NQO1 in PDAC. To observe the molecular properties of BBI608 and to analyze the exact mechanism of NQO1 on PDAC, computational approaches were applied, including molecular docking. This investigation provides a detailed understanding of the interaction between NQO1 and BBI608 and its implication in PDAC therapy. To support this computational analysis, we performed in vitro and in vivo studies. The combination of BBI608 with gemcitabine plus irradiation creates higher cytotoxicity (decreased proliferation, clonogenicity and increased Annexin V positive cells; p<0.001) in PDAC cell lines and the mice bearing subcutaneous PANC-02 and MIA PaCa-2 model. Collectively, this investigation offers mechanistic insight into the cytotoxicity initiated by BBI608 and suggests further investigation of its utility for PDAC therapy is warranted.

Citation Format: Purnachandra N. Ganji, Gregory B. Lesinski, Bassel F. El-Rayes. Targeting NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic ductal adenocarcinoma: An in silco, in vitro and in vivo approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 104.
Abstract 1041: HBI-2376, HUYABIO clinical stage SHP2 inhibitor, possess robust in vitro potency and in vivo efficacy in several preclinical tumor models carrying KrasG12C or EGFR mutations
Authors: Shojaei Farbod , Shojaei Farbod , Ricono Jill M. , Fang Che , Kabbinavar Fairooz , Goodenow Bob , Gillings Mireille
Published: June 2022

SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) is an attractive target in oncology drug development due to its dual roles on the direct growth and proliferation of cancer cells and also acting as an immune checkpoint molecule to suppress tumor immunity. HBI-2376 is an orally bioavailable selective SHP2 inhibitor that is being developed for the treatment of solid tumors harboring KRAS or EGFR mutations, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Additionally, HBI-2376 has the potential to suppress tumor growth via induction of the activity of immune infiltrating cells in the TME (tumor microenvironment). In a head-to-head comparison, in vitro studies showed greater potency of HBI-2376 to inhibit cell proliferation in a variety of cancer cell lines compared to other SHP2 inhibitors such as TNO-155 (Novartis AG) and RMC-4550 (Revolution Medicines). Consistently, HBI-2376 found to be more efficacious in tumor growth inhibition than TNO-155 and RMC-4550 in NCI-H1975L858R_T790M_C797S osimertinib-resistant cell line and other tumor models. In addition to xenograft models, we tested efficacy of HBI-2376 as single agent or in combination with anti-PD1 mAb in MC38 CRC syngeneic model. Consistent with xenograft data, HBI-2376 showed greater efficacy in tumor growth inhibition vs. TNO-155 and RMC-4550 both as single agent and in combination therapy. IHC data showed reduction in infiltration of M2 macrophages (F4/80+Arg1+) in the HBI-2376 treated tumors suggesting a MoA for its greater efficacy in MC38 model. Furthermore, Western blotting showed inhibition of p-ERK and DUSP6 in HBI-2376 treated cells indicative of a biomarker of response to the therapy. These findings, along with a positive safety profile led to HBI-2376 IND clearance by FDA and suggested promising responses in NSCLC or CRC patients in the forthcoming clinical studies.

Citation Format: Farbod Shojaei, Farbod Shojaei, Jill M. Ricono, Che Fang, Fairooz Kabbinavar, Bob Goodenow, Mireille Gillings. HBI-2376, HUYABIO clinical stage SHP2 inhibitor, possess robust in vitro potency and in vivo efficacy in several preclinical tumor models carrying KrasG12C or EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1041.
Abstract 1127: Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines
Authors: Hernandez-Pedro Norma Yanet , Lucio-Lozada Jose , Barrios-Bernal Pedro , Ramos-Ramírez Maritza , Arrieta Oscar
Published: June 2022

KRAS is the most frequently mutated oncogene in lung adenocarcinoma, in which is related to poor treatments response and worse survival rates than other driver mutations. KRAS activates MAPK and mTOR pathways, and even after sotorasib treatment, a novel KRAS inhibitor, the duration of responses to this monotherapy are excessively short. In this context, metformin is able to inhibit PI3K and mTOR pathways; therefore, combined use of metformin with sotorasib aids to diminish the activity of both signaling pathways. We performed a dose-effect curve to determine IC50 of sotorasib, and IC10 of metformin to treat lung cancer cell lines harboring different mutational profiles: A549 (KRAS G12S), and H522 (TP53) in order to study the effects of the combination compared to the monotherapy of each drug at MTT assay and western blot analysis. In detail, we evaluated drug-induced cytotoxicity, apoptosis, and activity of MAPK and mTOR pathways. Our results show a synergic effect in cytotoxicity by MTT assay, as well as increased inhibition of MAPK pathway inhibition at combinational treatment, compared to monotherapies in A549 cell lines; conversely, we did not find significant effects on cytotoxicity and signaling inhibition in H522 cell line. In conclusion, the combined treatment of metformin and sotorasib show synergistic effects in drug-induced cytotoxicity and inhibition of MAPK pathways in lung cancer cell lines.

Citation Format: Norma Yanet Hernandez-Pedro, Jose Lucio-Lozada, Pedro Barrios-Bernal, Maritza Ramos-Ramírez, Oscar Arrieta. Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1127.
Abstract 1274: Prognostic relevance of ZnF 649 in clear cell carcinoma
Authors: Reams Renee , Heyliger Simone O. , Saulsbury marilyn , Soliman Karam F.
Published: June 2022

Clear cell renal carcinoma (ccRCC) is the most common form of neoplastic disease affecting the kidneys that accounts for at least 70% of all kidney cancers. Given its resistance to medications and high mortality at later stages, there is a need to identify biomarkers that can detect ccRCC. KRAB Zinc finger proteins (KRAB-ZFPs) are the largest family of mammalian transcription regulators. They are differentially expressed in various tissues during cellular development and phenotypic differentiation. Though poorly understood, these transcription factors, are also differentially expressed in several cancers though very few have been reported to be implicated in ccRCC. Using bioinformatics techniques, we have demonstrated that ZNF649 and its paralog ZNF613 are suppressed in clear cell renal carcinomas (p<0.001) relative to normal tissues. Moreover, The ZNF649 and ZNF613 transcripts were downregulated across all histological grades and pathological stages (p<0.001). In addition, both ZNF649 and ZNF613 downregulation was associated with metastasis and unsatisfactory patient survival (p<0.001). Univariate and multivariante Cox regression analysis of age, gene expression, gender, pathological stage, histological grade, and pathological N in relationship to overall survival in ccRCC patients revealed that ZNF649 expression was predictive of overall survival. Gene Set Enrichment Analysis of the Gene Ontology Biological Processes database indicate that the top pathways enriched with genes correlated to ZNF649 expression were associated with angiogenesis, cellular motility and mitochondrial regulation (p<0.001 and FDR <0.05). Taken collectively, our observations indicate that ZNF649 is a prognostic marker and is a putative tumor suppressor gene in clear cell renal carcinoma.

Citation Format: Renee Reams, Simone O. Heyliger, marilyn Saulsbury, Karam F. Soliman. Prognostic relevance of ZnF 649 in clear cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1274.
Abstract 1297: Chemotherapy-induced senescence activates robust, parallel programs of immune checkpoint expression that can be targeted with immunotherapy
Authors: Shahbandi Ashkan , Chiu Fang-Yen , Ungerleider Nathan A. , Anderson Ashlyn Y. , Machado Heather L. , Pursell Zachary F. , Kvadas Raegan , Rao Sonia G. , Jackson James G.
Published: June 2022

We and others have previously shown that the breast cancers most difficult to eradicate with chemotherapy are TP53 wild-type, and these are among the most lethal breast cancers. For instance, chemotherapy-treated TNBC patients with TP53 wild-type tumors have a median overall survival of 45 months, vs 263 months for TP53 mutant tumors. Treatments fail to eradicate these cancers for two reasons: the tumor cells 1) avoid intrinsic cell death, and 2) escape immune clearance. We have shown that p53 drives a program of senescence that arrests the cell cycle to prevent intrinsic modes of cell death such as mitotic catastrophe, apoptosis and nutrient deprivation. However, it is not currently understood how breast cancer cells that enter senescence to survive chemotherapy escape immune clearance.

Here, we show tumor cells from mice and human patients that survive chemotherapy activate complex programs of immune modulation. Surprisingly, the surviving, senescent tumor cells are highly enriched for many antigen presentation genes and positive regulators of T cell activation, suggesting they have switched from immunologically “cold” to “hot”. Unfortunately, these senescent tumors concurrently upregulate redundant expression of many T cell inhibitory checkpoint genes, including CD80 and PD-L1. scRNA-seq and cell imaging revealed that CD80 and PD-L1 each mark unique populations of cells in the treated tumor, typified by p53 signaling or interferon signaling, respectively.

In p53 wild-type, syngeneic, orthotopic mouse mammary tumor models that recapitulate human breast cancer response to chemotherapy, treatment of tumors with chemotherapy followed by targeting of the PD-L1 and/or CD80 axes improved response, including complete eradication in some instances. Unfortunately, however, even combination strategies failed to elicit a cure in the majority of cases. Our findings reveal the formidable challenge of eliminating residual disease populated by senescent cells that express multiple redundant immune inhibitory pathways and suggest rational strategies are needed based on the specific checkpoint pathways expressed in residual disease.

Citation Format: Ashkan Shahbandi, Fang-Yen Chiu, Nathan A. Ungerleider, Ashlyn Y. Anderson, Heather L. Machado, Zachary F. Pursell, Raegan Kvadas, Sonia G. Rao, James G. Jackson. Chemotherapy-induced senescence activates robust, parallel programs of immune checkpoint expression that can be targeted with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1297.
Abstract 1301: T cell intrinsic androgen receptor activity regulates response to immunotherapy
Authors: Moran Amy E. , Polesso Fanny , Xia Zheng , Thomas George , Graff Julie
Published: June 2022

Immune checkpoint blockade has revolutionized the field of oncology inducing durable anti-tumor immunity in many solid tumors. In advanced prostate cancer patients, immunotherapy treatments have largely failed. Androgens have pleiotropic functions in prostate cancer; they are potent drivers of cancer cell growth and can suppress T cell function. In metastatic prostate cancer, intratumor androgen levels can remain high. Androgen deprivation therapy, the backbone of clinical care in prostate cancer, is classically administered to inhibit tumor cell growth. We postulated that this therapy also impacts tumor associated T cells. To test this hypothesis, we performed transcriptome profiling of individual leukocytes isolated from metastatic prostate cancer lesions resistant to androgen deprivation therapy (ADT) and androgen receptor (AR) antagonism and prior to treatment with a PD-1 inhibitor. We reveal that inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. Notably, AR directly bound to Ifng and eviction of this transcription factor with a small molecule significantly increased cytokine production in CD8 T cells. Furthermore, genomic deletion of Ar prevented chronically stimulated CD8 T cells from losing their ability to make IFNγ upon restimulation. Finally, we demonstrate that AR blockade sensitizes multiple tumor mouse models to effective checkpoint blockade by directly enhancing CD8 T cell function. Together, our findings establish T cell specific AR activity as one mechanism of immunotherapy resistance and show that targeting AR can improve immunotherapy outcomes.

Citation Format: Amy E. Moran, Fanny Polesso, Zheng Xia, George Thomas, Julie Graff. T cell intrinsic androgen receptor activity regulates response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1301.
Abstract 1337: Pan-cancer analysis of immune-associated genes and pathways dysregulated by tobacco reveals osteopontin as a key mediator of smoking-associated carcinogenesis
Authors: Chakladar Jaideep , Shende Neil , Li Wei Tse , Ongkeko Weg M.
Published: June 2022

Background: Smoking remains a primary etiological agent of 12 different cancers. However, current understanding of the pathogenesis and progression of these smoking-induced cancers remains unclear. Though vaping has been proposed as a safer alternative to cigarette smoking, more research is needed to fully understand its potential to cause cancer. In particular, the chemicals in e-cigarette (e-cig) vapor have previously been demonstrated to cause immune dysregulation, similar to conventional cigarette smoke. In this study, we aimed to investigate the immune-associated (IA) genomic and transcriptomic landscapes of a panel of smoking-induced cancers in order to identify common and unique elements among these cancers and to determine whether certain immune dysregulations may be shared between smoking and vaping.

Methods: Whole genome sequencing data from tumors and adjacent normal samples was obtained from The Cancer Genome Atlas (TCGA) to compare the IA landscapes of 5 different smoking-induced cancers: head and neck squamous cell carcinoma (HNSCC), esophageal carcinoma (ESCA), bladder urothelial carcinoma (BLCA), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). Differentially expressed genes were identified and correlated to tumor stage and patient survival. Gene Set Enrichment Analysis and ReactomeFi were used to correlate IA gene expression to cancer pathway enrichment. The REVEALER algorithm was used to correlate gene expression to copy number variations and mutations.

Results: We found that the genomic landscapes of smoking-induced cancers were largely unique. However, Osteopontin (OPN), an IA gene capable of regulating the EGFR and CD44 signaling cascades, was found to be upregulated along with its downstream targets in HNSCC, LUAD, LUSC, and ESCA smoking patients. Such upregulation was correlated to poorer prognosis for all 4 cancers. In vitro study indicated an upregulation of OPN and its downstream targets in cell lines exposed to both e-cig vapor and cigarette smoke.

Conclusions: Despite few similarities among the IA landscapes of these smoking-induced cancers, we suggest the importance of OPN upregulation in HNSCC, LUSC, LUAD, and ESCA pathogenesis caused by smoking and, potentially, vaping.

Citation Format: Jaideep Chakladar, Neil Shende, Wei Tse Li, Weg M. Ongkeko. Pan-cancer analysis of immune-associated genes and pathways dysregulated by tobacco reveals osteopontin as a key mediator of smoking-associated carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1337.
Abstract 1343: CD8+ resident memory T (TRM) cells in tumors
Authors: Mami-Chouaib Fathia
Published: June 2022

Tumor-resident memory T (TRM) cells play an important role in cancer diseases. Accumulating evidence indicates that subpopulations of CD3+CD8+ tumor-infiltrating lymphocytes (TIL) are TRM cells, and are emerging as activated tumor-specific T cells. These TRM cells are characterized by expression of CD103 integrin and identify tumor-reactive cytotoxic T lymphocytes (CTL). Human lung tumor CD103+CD8+ TRM cells co-express CD49a and CD69, and are associated with a favorable prognosis. They also express a panel of T-cell inhibitory receptors, including PD-1, and are able to kill autologous tumor cells upon blockade of PD-1 with neutralizing antibodies. This CD103+CD8+ TRM subset also emerges as a predictive biomarker of response to PD-1 blockade and expands during anti-PD-1 treatment in responder, but not in non-responder lung cancer patients. It is now widely admitted that expression of CD103 on activated CD8+ T lymphocytes and persistence of TRM cells in epithelial tissues requires transforming growth factor (TGF)-β. This cytokine is secreted in the tumor microenvironment in its inactive form bound to latency-associated protein (LAP), and is activated by αV integrins on tumor cells and immune cells. Using multiplex immunofluorescence staining on cohorts of anti-PD-(L)1-treated lung cancer patients, we recently showed that decreased expression of tumor αV is associated with improved immunotherapy-related-progression-free survival (PFS) and correlates with an increased density of CD8+CD103+ TIL. Cancer cell αV activates autocrine TGF-β and participates in inducing CD103 on activated CD8+ T cells. Our more recent studies in mouse tumor models and human cancers demonstrate that different CD8+ TRM subsets participate to response different immune checkpoint inhibitors and therapeutic cancer vaccines.

Citation Format: Fathia Mami-Chouaib. CD8+ resident memory T (TRM) cells in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1343.
Abstract 1391: PBMC humanized mouse model for ImmunoOncology drug evaluation
Authors: Xie Bin , Chen Hongkui , Hou Xin , Wen Danyi
Published: June 2022

Since the first immune checkpoint blocker Ipilimumab was approved by US FDA in 2011, more and more immune therapeutic drugs popped up. Humanized PBMC reconstitution in immune deficient mice is becoming a good model for evaluating therapeutic antibodies, especially the BsAb with one arm of anti-CD3 that mediates immune cells and another arm targeting a tumor antigen. However, limited window of dosing regimen triggered by graft-versus-host-disease (GvHD) after 30-40 days of reconstitution, and insufficient tumor-infiltrated immune cells naturally from reconstituted circulatory system hindered the widely application of the model in immunotherapy in development of multiple immune checkpoint inhibitors or immune agonists. To overcome this, LIDE has developed a unique human PBMC-cancer cells co-inoculated model instead. In our platform, cancer-priming PBMCs were mixed with the fresh cancer cells in MatriGel, co-inoculated into NCG mice to form a huPBMC well-infiltrated tumor tissue for immunotherapy. Our platform has been successfully helped evaluate biological function of PD1, Tigit, PVRIG, CD73, CD47, CD38, CD40, GITR Antibodies, Tgfb1/PDL1 BsAb, DLL3/CD3 BsAb in multiple cancers, such as melanoma, breast cancer and lung cancer.

Citation Format: Bin Xie, Hongkui Chen, Xin Hou, Danyi Wen. PBMC humanized mouse model for ImmunoOncology drug evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1391.
Abstract 1399: Discovery and development of PARP inhibitor senaparib
Authors: Cai Sui Xiong , Ma Ning , Wang Xiaozhu , Jiang Yangzhen , Guo Mingchuan , Hsieh Chih-Yi , Tian Ye Edward
Published: June 2022

Poly (ADP-ribose) polymerase (PARP) is a key enzyme for DNA repair. PARP inhibitors have been shown to be effective against cancers with DNA repair defects, such as with BRCA1 or BRCA2 mutations. Several PARP inhibitors, including olaparib, rucaparib, niraparib, talazoparib, fluzoparib and pamiparib have been approved for the treatment of several types of cancer. In this presentation, we will report our discovery and development of senaparib (IMP4297) as a potent PARP inhibitor. We will present studies led to the identification of senaparib as a clinical candidate, as well as IND enabling in vitro and in vivo characterization of senaparib. Preclinical data indicated that senaparib had a wide therapeutic window (single agent effective dose of 2.5-21 mg/kg QD, in a BRCA1 mutated MDA-MB-436 human breast cancer xenograft model), which was confirmed in clinical studies (effective dose of 20-120 mg QD, and no DLT was found up to 150 mg QD). Senaparib is currently in several phase I/II, phase II and phase III clinical studies for the treatment of multiple tumor types either as single agent or in combination with temozolomide (TMZ). The most advanced study of senaparib is a phase III study as maintenance therapy in platinum-sensitive advanced ovarian cancer patients following first-line chemotherapy (ClinicalTrials.gov Identifier: NCT04169997).

Citation Format: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Mingchuan Guo, Chih-Yi Hsieh, Ye Edward Tian. Discovery and development of PARP inhibitor senaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1399.
Abstract 1454: Interaction of obesity loci with energy intake and physical activity on the risk of colorectal cancer: Evidence from UK Biobank
Authors: Cho Sooyoung , Shin Aesun
Published: June 2022

Colorectal cancer is one of the common cancers worldwide. Obesity and physical activity are well-established risk factors for colorectal cancer. Studies have shown that as a consequence of energy metabolism, imbalance between energy intake and physical activity can lead to obesity. In order to precisely examine the close interrelationship between obesity, energy intake, and physical activity, we conducted a genome-wide interaction study of obesity with energy intake and physical activity. We also evaluated the interaction between obesity susceptibility loci with energy intake and physical activity for colorectal cancer using the nested case-control design. We analyzed data on participants in the UK Biobank. Genome-wide interaction analyses of obesity with energy intake and physical activity was performed on 65,514 and 250,369 participants who have information on genotype, body mass index, and energy intake/physical activity, respectively. We assessed the effect of obesity loci in the participants comprised 3523 colorectal cancer cases and 10,522 matched controls. The logistic regression model was used for finding obesity loci under a p-value threshold of 10-4. Odds ratios (ORs) and 95% confidence intervals (CIs) for colorectal cancer were estimated using a conditional logistic regression model. We found 21 loci and 44 loci of obesity with energy intake and physical activity, respectively. We also observed significant interaction of obesity loci with energy intake and physical activity for colorectal cancer. The obesity loci interacting with energy intake, including rs10828896 and rs7099260, were significantly interacted with physical activity for colorectal cancer. Rs426345 and rs12551684, which were the obesity loci interacting with physical activity, were significantly interacted with energy intake for colorectal cancer. The results of this study may provide evidence for bioenergetics in colorectal cancer carcinogenesis.

Citation Format: Sooyoung Cho, Aesun Shin. Interaction of obesity loci with energy intake and physical activity on the risk of colorectal cancer: Evidence from UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1454.
Abstract 1459: Identification of transcription factor enrichments in HPV+ head and neck cancer using ChIP-seq and cistrome analysis
Authors: Zamuner Fernando , Chan Spencer S. , Kessler Michael , Vorontsov Ilya , Danilova Ludmila , Erbe Rossin , Kelley Dylan , Guo Theresa , Imada Eddie , Fertig Elana J. , Kulakovskiy Ivan , Favorov Alexander , Gaykalova Daria A.
Published: June 2022

The subset of head and neck squamous cell carcinomas (HNSCC) that are driven by infection with the Human Papilloma Virus (HPV+ HNSCC) are increasing in prevalence and are defined by distinct biological signatures and mechanisms, such as abnormal transcriptional regulation. Here, we use optimized protocols to perform ChIP-seq and RNA-seq on patient surgical samples, which we use to define promoter, typical-enhancer, and super-enhancer (SE) regulatory regions with differential chromatin states (i.e. H3K27ac signal) between tumor and normal samples. We then leverage publicly available transcription factor (TF) cistrome data to test 372 TFs for tumor or normal specific enrichment across these differential regulatory regions. We identify 31 tumor-specific TF enrichments, such as TP53/63/73, NKX2-1, JUNB/D, FOSL1/2, E2F1/3, KLF3/4/5, SMAD3/4, TEAD1/4, TFAP2A/C, HIF1A, PPARG, GRHL2, EPAS1, and SNAI2. A number of these enriched TFs, including TP63, TP73, FOSL1, and E2F1, show both significantly increased expression in tumors and significant transcriptional reductions after JQ1 treatment. These results provide novel insight into the regulatory biology of HPV+ HNSCC, and suggest that the transcriptional networks and feedback loops governing TF expression and dysregulation in HPV+ HNSCC can be targeted using JQ1 treatment.

Citation Format: Fernando Zamuner, Spencer S. Chan, Michael Kessler, Ilya Vorontsov, Ludmila Danilova, Rossin Erbe, Dylan Kelley, Theresa Guo, Eddie Imada, Elana J. Fertig, Ivan Kulakovskiy, Alexander Favorov, Daria A. Gaykalova. Identification of transcription factor enrichments in HPV+ head and neck cancer using ChIP-seq and cistrome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1459.
Abstract 1520: Replication stress and the inability to repair damaged DNA, the potential “Achilles' heel” of ecDNA+ tumor cells
Authors: Chowdhry Sudhir , Garcia Salvador , Nguyen Nam-Phuong , Celeste Anthony , Tse Edison , Milutinovic Snezana , Wilkinson Deepti , Hassig Christian , Kasibhatla Shailaja
Published: June 2022

Replication stress (RS) is a primary source of genomic instability, tumorigenesis, and cancer progression. RS is defined as an uncoupling of the replicative helicase and DNA polymerase, resulting in long stretches of fragile single stranded DNA (ssDNA) that is prone to damage. Excessive RS can result in replication catastrophe and cell death, which could be leveraged as a therapeutic strategy to treat high-RS cancers. While overexpression of certain oncogenes has been implicated as a driver of RS in cancer, the precise cellular conditions that result in RS have been difficult to predict. Here we demonstrate that high copy number amplification of genes on non-native extrachromosomal DNA (ecDNA) is associated with elevated RS in comparison to the same amplification on linear chromosomes. The ecDNA bearing cells display heightened basal levels of phosphorylated RPA, a hallmark of ssDNA, and decreased replication fork velocities. Consistent with this finding, the ecDNA amplified cells display greater sensitivity to inhibitors of deoxyribonucleotide production relative to cells harboring chromosomal gene amplification and to normal cells. Moreover, ecDNA bearing cells demonstrate a dramatic vulnerability to reduction in the conditionally essential amino acid glutamine, the primary nitrogen source for de novo nucleotide biosynthesis. The enhanced sensitivity to glutamine starvation is directly correlated with a reduction in ecDNA in tumor cells, and a corresponding selection for chromosomally integrated gene amplification in the surviving population. These phenotypes are rescued with nucleoside supplementation but not anaplerotic TCA cycle intermediates, further reinforcing a link between ecDNA and RS biology. Collectively, observations made here support a novel mechanism for oncogene-induced RS shaped by ecDNA driven oncogene amplification, revealing a novel molecular strategy to identify high-RS tumors and a therapeutic approach to target this “Achilles heel” of tumor biology.

Citation Format: Sudhir Chowdhry, Salvador Garcia, Nam-Phuong Nguyen, Anthony Celeste, Edison Tse, Snezana Milutinovic, Deepti Wilkinson, Christian Hassig, Shailaja Kasibhatla. Replication stress and the inability to repair damaged DNA, the potential “Achilles' heel” of ecDNA+ tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1520.