bluuebunny/crossref_metadata_2025 huggingface dataset:
Software Defined Network Enabled Fog-to-Things Hybrid Deep Learning Driven Cyber Threat Detection System
Authors: Ullah Ihtisham , Raza Basit , Ali Sikandar , Abbasi Irshad Ahmed , Baseer Samad , Irshad Azeem
Published: December 2021

Software Defined Network (SDN) is a next-generation networking architecture and its power lies in centralized control intelligence. The control plane of SDN can be extended to many underlying networks such as fog to Internet of Things (IoT). The fog-to-IoT is currently a promising architecture to manage a real-time large amount of data. However, most of the fog-to-IoT devices are resource-constrained and devices are widespread that can be potentially targeted with cyber-attacks. The evolving cyber-attacks are still an arresting challenge in the fog-to-IoT environment such as Denial of Service (DoS), Distributed Denial of Service (DDoS), Infiltration, malware, and botnets attacks. They can target varied fog-to-IoT agents and the whole network of organizations. The authors propose a deep learning (DL) driven SDN-enabled architecture for sophisticated cyber-attacks detection in fog-to-IoT environment to identify new attacks targeting IoT devices as well as other threats. The extensive simulations have been carried out using various DL algorithms and current state-of-the-art Coburg Intrusion Detection Data Set (CIDDS-001) flow-based dataset. For better analysis five DL models are compared including constructed hybrid DL models to distinguish the DL model with the best performance. The results show that proposed Long Short-Term Memory (LSTM) hybrid model outperforms other DL models in terms of detection accuracy and response time. To show unbiased results 10-fold cross-validation is performed. The proposed framework is so effective that it can detect several types of cyber-attacks with 99.92% accuracy rate in multiclass classification.
Flexural Behaviour of RC Beams with a Circular Opening at the Flexural Zone and Shear Zone Strengthened Using Steel Plates
Authors: Branesh Robert J. , Angeline Prabhavathy R. , Joanna P. S. , Christopher Ezhil Singh S. , Murugan Sivaraj , Rajkumar S. , Sharma Shubham
Published: December 2021

In this paper, an investigation on the behaviour of RC beams with circular openings in the flexural zone and shear zone strengthened using steel plates is presented. Totally seven beams were cast: a control beam, one beam with a circular opening of size of one‐third the depth of the beam (100 mmϕ) in the flexural zone, one beam with opening strengthened using the steel plate, one beam with a circular opening of size of 100 mmϕ in the shear zone, one beam with an opening in the shear zone strengthened using the steel plate, one beam with two circular openings of size of 100 mmϕ in the shear zone, and another beam with two openings in the shear zone strengthened using the steel plate. The experiments were conducted in a loading frame of 400 kN capacity. The beams were subjected to two‐point loading. The ultimate load carrying capacity reduced marginally by 1.78% and 2.8% compared to that of the control beam when a circular opening of 100 mmϕ was provided in the flexural zone and shear zone, respectively, and when the opening was strengthened with steel plates, it reduced by 3.04% and 25%, respectively, but the ductility increased when steel plates were provided. Beams with an opening of size of one‐third the depth of the beam (100 mmϕ) in the flexural zone strengthened with the steel plate can be provided, as the load carrying capacity is only marginally reduced compared to the control beam, and the ductility is more when compared with beams with unstrengthened openings.
CircRNF13 Promotes the Malignant Progression of Pancreatic Cancer through Targeting miR-139-5p/IGF1R Axis
Authors: Liu Xinyuan , Zhou Lei , Chen Yankun , Jiang Xueyi , Jiang Jianxin
Published: December 2021

Background. Mounting evidence has shown circular RNAs (circRNAs) play an important role in the initiation and progression of pancreatic cancer (PC). Meanwhile, circRNAs may serve as the biomarkers for the diagnosis, treatment, and prognosis of PC. Therefore, it is urgent to elucidate the function and underlying mechanism of circRNAs in the development of PC. Methods. The Cancer-Specific CircRNA Database (CSCD), Circular RNA Interactome database (circinteractome database), and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to verify the expression level of circRNF13 in PC cell lines. Fluorescence in situ hybridization (FISH) and RNase protection assay were used to detect the localization and structure of circRNF13. Then, cell functional experiments were employed to estimate the proliferated, migrated, and invasive abilities in PC. Furthermore, bioinformatic tools, luciferase dual reporter assay, and RT-qPCR were used to investigate the interaction among circRNF13, miR-139-5p, and IGF1R. Eventually, the rescue functional experiments were employed to confirm that circRNF13 targeted the miR-139-5p/IGF1R axis to participate in the development of PC. Results. CircRNF13 was overexpressed in PC cell lines compared with the normal pancreatic duct cell line. Additionally, inhibition of circRNF13 impaired the proliferation, migration, and invasion of PC cells. CircRNF13 could serve as the molecular sponge of miR-139-5p to inhibit its association with IGF1R that eventually accelerated the malignant progression of PC. Conclusion. CircRNF13 serves as a competitive endogenous RNA of IGF1R to inhibit the function of miR-139-5p that eventually reinforces the malignant phenotype of PC.
Correlation Evaluation of Pilots’ Situation Awareness in Bridge Simulations via Eye‐Tracking Technology
Authors: Jiang Shaoqi , Chen Weijiong , Kang Yutao
Published: December 2021

To maintain situation awareness (SA) when exposed to emergencies during pilotage, a pilot needs to selectively allocate attentional resources to perceive critical status information about ships and environments. Although it is important to continuously monitor a pilot’s SA, its relationship with attention is still not fully understood in ship pilotage. This study performs bridge simulation experiments that include vessel departure, navigation in the fairway, encounters, poor visibility, and anchoring scenes with 13 pilots (mean = 11.3 and standard deviation = 1.4 of experience). Individuals were divided into two SA group levels based on the Situation Awareness Rating Technology (SART‐2) score (mean = 20.13 and standard deviation = 5.83) after the experiments. The visual patterns using different SA groups were examined using heat maps and scan paths based on pilots’ fixations and saccade data. The preliminary visual analyses of the heat maps and scan paths indicate that the pilots’ attentional distribution is modulated by the SA level. That is, the most concerning areas of interest (AOIs) for pilots in the high and low SA groups are outside the window (AOI‐2) and electronic charts (AOI‐1), respectively. Subsequently, permutation simulations were utilized to identify statistical differences between the pilots’ eye‐tracking metrics and SA. The results of the statistical analyses show that the fixation and saccade metrics are affected by the SA level in different AOIs across the five scenes, which confirms the findings of previous studies. In encounter scenes, the pilots’ SA level is correlated with the fixation and saccade metrics: fixation count (p = 0.034 < 0.05 in AOI‐1 and p = 0.032 < 0.05 in AOI‐2), fixation duration (p = 0.043 < 0.05 in AOI‐1 and p = 0.014 < 0.05 in AOI‐2), and saccade count (p = 0.086 < 0.1 in AOI‐1 and p = 0.054 < 0.1 in AOI‐2). This was determined by the fixation count (p = 0.024 < 0.05 in AOI‐1 and p = 0.034 < 0.05 in AOI‐2), fixation duration (p = 0.036 < 0.05 in AOI‐1 and p = 0.047 < 0.05 in AOI‐2), and saccade duration (p = 0.05 ≤ 0.05 in AOI‐1 and p = 0.042 < 0.05 in AOI‐2) in poor‐visibility scenes. In the remaining scenes, the SA could not be measured using eye movements alone. This study lays a foundation for the cognitive mechanism recognition of pilots based on SA via eye‐tracking technology, which provides a reference to establish cognitive competency standards in preliminary pilot screenings.
A Comparative Study on the Thermal Conductivity of Concrete with Coal Bottom Ash under Different Drying Conditions
Authors: Yang In-Hwan , Park Jihun , Kim Kyoung-Chul , Yoo Sung-Won
Published: December 2021

The utilization of coal bottom ash (CBA) and fly ash in concrete has become more common. For CBA concrete, curing conditions would influence the thermal properties of the concrete due to the high water absorption capacity of the CBA aggregate. In addition, CBA and fly ash contents in concrete affect the thermal properties of the concrete. Therefore, the effects of the drying conditions and the CBA and fly ash contents on the thermal conductivity of CBA concrete were investigated in this study. The thermal conductivity of concrete was measured under two different curing and drying conditions: oven‐dried conditions and saturated surface‐dry (SSD) conditions, with curing times of 28 and 91 days. The concrete mixtures also contained different levels of CBA and fly ash. Crushed sand in the concrete mixtures was replaced by CBA with replacement ratios of 25%, 50%, 75%, and 100% by volume. In addition, cement in the concrete mixture was substituted by fly ash with replacement ratios of 20 and 40% by volume. The thermal conductivity of concrete under the oven‐dried conditions was much lower than that under the SSD conditions. Moreover, the thermal conductivity of the concrete decreased as the CBA content increased under both the oven‐dried and SSD conditions. The material properties of the concrete, including unit weight, compressive strength, and ultrasonic velocity, were also measured in the study. Compared with the SSD conditions, the compressive strength, unit weight, and ultrasonic velocity of CBA concrete were considerably lower under the oven‐dried conditions. Moreover, the relationships between the thermal conductivity and unit weight, compressive strength, and ultrasonic velocity were suggested.
N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells
Authors: Liu Xiaopeng , Lu Xufeng , Hu Zhixiong
Published: December 2021

Background. N-Acetylcysteine (NAC) had exerted antioxidation and anti-inflammation effects on chronic obstructive pulmonary disease (COPD) patients. However, its effect in regulating interleukin- (IL-) 18 was not fully understood. This study was designed to evaluate the specific mechanism of NAC regulating IL-18. Materials and Methods. A total of 112 COPD patients and 103 health individuals were recruited in the study. Cytokine level in patients’ serum was measured by enzyme-linked immunosorbent assay (ELISA). A COPD mouse model was established by administration of lipopolysaccharide (LPS) and cigarette smoke. The expression of cytokines was measured by ELISA and flow cytometry. Inflammasome-related protein was measured by Western blot. Result. NAC could effectively improve the immune status of COPD patients as well as the COPD mouse model by downregulating proinflammation and inflammation cytokines including IL-1β, interferon- (IFN-) γ, tumor necrosis factor- (TNF-) α, and IL-18. It also had the capability to suppress synthesis of IL-18 in macrophage to inhibit the secretion of IFN-γ from natural killer (NK) cells through influencing the inflammasome-related protein in macrophages. Conclusion. NAC could effectively inhibit the production of IL-18 by suppressing NLRP3 expression in macrophages to reduce the production of IFN-γ in NK cells.
Numerical Analysis of Dynamic Characteristics of Thermowell Based on Two‐Way Thermo‐Fluid‐Solid Coupling
Authors: Zhang Yongchao , Ding Lilin , Qi Mei , Bei Guangxia
Published: December 2021

Because thermowells are prone to fatigue damage in petroleum cracking gas pipelines, in this paper, the LES method is used to simulate the flow around thermowells through two‐way thermal‐fluid‐solid coupling, the internal causes of thermowell damage are explored, and measures for improving the thermowell safety are proposed. According to this study, when high‐speed, high‐temperature gas passes the thermocouple bushing, the main factors affecting the structural safety of the thermocouple bushing are the alternating stress caused by the vortex falling off, the thermal stress cycle due to the temperature gradient, and the pressure gradient impacted by the gas. Furthermore, this paper proposes improving the thermowell safety by installing the interference devices and optimizing the installation angle. The improvement measures were studied by conducting a two‐way thermal fluid‐structure coupling simulation. The results of this study show that after installing the interference device and optimizing the installation angle the displacement deformation of the thermowell and the equivalent stress is reduced by 57.2% and 72.1%, respectively, which indicates the safety improvement of the thermowell structure and the effectiveness of the method. The research contents of this paper can provide guidance for the installation and use of thermocouple bushing.
The Human Positive Cofactor 4 is a Promising Chemotherapeutic Target in Lung Adenocarcinoma
Authors: Sun Tianyu , Zhang Jingge , Fan Xiaoqing , Long Tan , Tao Shaolin , Kang Poming , Tan Qunyou
Published: December 2021

Reduced sensitivity to chemotherapeutic drugs is almost inevitable in lung adenocarcinoma patients. Thus, understanding the relevant mechanisms is urgent. Positive cofactor 4 (PC4) was at first revealed to be a coactivator of basal transcription. Previous research has shown that PC4 participates in various cellular processes in normal and malignant cells. However, it is still unknown whether PC4 participates in altering the lung adenocarcinoma cell sensitivity to chemotherapy, and the relevant mechanisms remain to be explained. In this study, we discovered that PC4 was overexpressed in cisplatin-resistant lung adenocarcinoma cells. PC4 decreased cisplatin’s cytotoxic effects on lung adenocarcinoma in vivo and in vitro. Furthermore, PC4 positively correlated with SOX9 in multiple cancers. PC4 was an upstream regulator of SOX9 in lung adenocarcinoma. Furthermore, PC4 mediated lung adenocarcinoma cell sensitivity to the HIF-PH inhibitor DMOG and the mTOR inhibitor rapamycin, and PC4 mediated the synergistic effect of DMOG and cisplatin. Finally, PC4 destabilized HIF-1α upon cisplatin treatment. Our research showed that PC4 participates in mediating lung adenocarcinoma cell sensitivity to multiple drugs. Mechanistically, PC4 governs multiple downstream pathways associated with chemotherapy resistance, including the SOX9 and HIF-1α pathways. Thus, PC4 is a promising chemotherapeutic target in lung adenocarcinoma.
Pensiones: ¿candidaturas con puntos en común?
Authors: González Pablo
Published: December 2021

Uno de los reclamos claros de los movimientos sociales que pacíficamente se manifestaron en los últimos meses de 2019 apuntaba directamente al sistema de pensiones. No todos con el mismo acento, algunos hablando simplemente de los bajos niveles de las jubilaciones, otros criticando al sistema de capitalización individual, otros en busca de refuerzo a criterios de solidaridad en el sistema. Distintas miradas y énfasis, pero todos aceptando que la situación y los resultados que el actual sistema de pensiones basado en el ahorro individual a través de las AFP no está entregando los resultados esperados. Continuar leyendo...
Abstract LBA011: Discovery of combination targets of CDK inhibitors from CRISPR screens
Authors: Kim Kimberly H , Almaden Jonathan , arunachalam vinu , VanArsdale Todd , liu chaoting
Published: December 2021

CRISPR/Cas9 functional genetic screens are a powerful tool to discover drug targets in cancer. While many screens have been performed for identification of intrinsic cancer vulnerabilities, synthetic lethalities of targeted therapies remain largely unexplored, despite the fact that they may provide a potential targets and pathways for potential combination therapies, advance understanding of target biology, and hone patient selection strategies. To discover novel combination targets of Palbociclib, a CDK2 inhibitor, and a CDK2,4,6 inhibitor, we have screened a genome-wide CRISPR library in priority tumors with genetic background of interest, including ER+ breast cancer (HCC1428, MCF7), cyclin E amplified breast (HCC1806) and/or ovarian cancer (OVCAR4), and pancreatic cancer cell lines (MIAPACA2, Hs766T, SU8686). We analyzed the samples by condition and compared using MAGeCK-MLE for gene-level drop out and enrichment to identify common sensitizers and resistors to different CDK inhibitors. Differential genes, complexes, and pathways were assessed, and we have found that genes involved in G1/S transition (CyclinE/CDK2) are top Palbo sensitizers and CDK1/CyclinA, CDC25A/B, MuvB complex (MYBL2 and FOXM1) are major CDK2 sensitizing genes. In addition to sensitizers, we have identified genes with strong signals of resistance to CDK inhibitors. Furthermore, we highlighted major mechanisms influencing response to CDK2 inhibitors; 1) Regulation of DREAM may influence response to CDK inhibitors, 2) Regulation of cell cycle check points mediated by CDC25. Our targeted CRISPR KO screens in different CDKi combinations have identified common sensitizers and mediators of resistance to CDK inhibitors, and highlighted biology worthy of deeper consideration and offers opportunities to consider new directions for therapeutic intervention into the cancer cell cycle

Citation Format: Kimberly H Kim, Jonathan Almaden, vinu arunachalam, Todd VanArsdale, chaoting liu. Discovery of combination targets of CDK inhibitors from CRISPR screens [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA011.
Abstract LBA015: Accelerating clinically-translatable discoveries using a network-and RNA-based precision-oncology framework
Authors: Vasciaveo Alessandro , Zou Min , Arriaga Juan Martín , De Almeida De Almeida Francisca Nunes , Douglass Eugene , Shen Michael , Califano Andrea , Abate-Shen Cory
Published: December 2021

Despite recent advances, prioritizing therapy at the individual patient level remains challenging. In fact, inter-patient tumor heterogeneity remains one of the major challenges in cancer therapy, making it difficult to optimize available treatments on an individual patient basis. Likewise, the systematic prediction of drug sensitivity in vivo is still a major challenge in translational biology, where targeted therapeutics are currently selected based on the presence of either actionable oncogene dependencies or aberrant cellular mechanisms. A further challenge is the limited availability of models that faithfully recapitulate the biology, complexity, and heterogeneity of human tumors, including their interaction with a competent immune system. To address these challenges, we introduce OncoLoop, a highly-generalizable, network-based precision medicine framework to triangulate between available mouse models, human tumors, and large-scale drug perturbational assays with in vivo validation to predict personalized treatment. OncoLoop requires only transcriptomic data (i.e., RNA-seq profiles) and leverages regulatory network analysis to (a) identify cognate models based on conservation of patient-specific Master Regulator (MR) proteins and (b) prioritize drugs based on their ability to invert the activity of MR proteins (MR-inverters), using drug perturbation profiles in cognate cell lines. As proof-of-concept, we applied OncoLoop to prostate cancer using a series of genetically engineered mouse models (GEMMs) that capture a broad range of phenotypes, including metastatic, castration-resistant and neuroendocrine disease. Indeed, ~70% of patients in published cohorts had at least one high-fidelity matched GEMM. Drugs targeting shared Master Regulator dependencies of a patient and its cognate GEMM(s) were predicted using perturbational profiles of >300 drugs in MR-matched cell lines, resulting in an 80% validation rate in GEMM allografts and human xenografts. This network-based approach is highly generalized and can be applied to both cancer and non-cancer-related contexts.

Citation Format: Alessandro Vasciaveo, Min Zou, Juan Martín Arriaga, Francisca Nunes De Almeida De Almeida, Eugene Douglass, Michael Shen, Andrea Califano, Cory Abate-Shen. Accelerating clinically-translatable discoveries using a network-and RNA-based precision-oncology framework [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA015.
Abstract LBA022: IMM20324, a first-in-class, anti-interleukin-38 monoclonal antibody, rescues myeloid cell activation in vitro and induces robust anti-tumor responses in vivo
Authors: Dowling John P , Nikitin Pavel A , Shen Fang , Finn James P , Patel Nirja , Swider Cezary , Steele Jamie , Shukla Halley , Robinson Matthew K , Lundgren Karen , Harman Benjamin C
Published: December 2021

Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer. However, therapies targeting innate immune cell subsets that orchestrate adaptive immune responses could significantly improve the incidence of clinical response by more effectively activating a multi-lineage response to the tumor. Here, we show that IMM20324, an antibody that binds and neutralizes IL-38, enhances innate immune cell function in vitro and inhibits tumor growth in vivo. IMM20324 binds human, mouse and cynomolgus IL-38 and inhibits the binding of IL-38 to its putative receptors, IL1RAPL1 and IL-36R. In vivo, IMM20324 administration leads to inhibition of tumor growth and improved survival in two different syngeneic tumor models. Importantly, while IMM20324 targets innate immune cells, antibody treatment leads to the induction of immunological memory responses that induce tumor rejection following tumor rechallenge. Together, our data support the hypothesis that IL-38 plays an important role in tumor immunity and that therapies targeting IL-38 could reverse suppressive mechanisms in tumor microenvironment. IMM20324 demonstrated favorable in vitro potency and in vivo efficacy and therefore represents a promising development candidate with the potential to treat multiple cancers.

Citation Format: John P Dowling, Pavel A Nikitin, Fang Shen, James P Finn, Nirja Patel, Cezary Swider, Jamie Steele, Halley Shukla, Matthew K Robinson, Karen Lundgren, Benjamin C Harman. IMM20324, a first-in-class, anti-interleukin-38 monoclonal antibody, rescues myeloid cell activation in vitro and induces robust anti-tumor responses in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA022.
Abstract LBA041: Identification and characterization of potent RAD51 inhibitors targeting RAD51-BRCA2 interaction
Authors: Sasmal Sanjita , Patra Sukanya , Boorgu Venkatesham , Yanamandra Mahesh , Chithaluri Shankar , Pathange Hema Sankar , Hiremath Deepika , Girme Sandeep M , Pawar Amit Kumar
Published: December 2021

The DNA damage response (DDR) is a complex cellular network that acts as a cell defense mechanism and exerts signal for repair of DNA lesions. It repairs different types of DNA damage such as single-strand (ssDNA) breaks, DNA inter-strand crosslinks and double strand breaks (DSB) caused by endogenous and exogenous factors. These damages are mainly repaired by homologous recombination (HR) repair, and non-homologous end joining (NHEJ). DNA double-strand breaks (DSBs) are the most severe DNA damage and predominantly repaired by HR. As the DDR pathway is critical for tumorigenesis, a high degree of interest has been generated in the recent past to target this network. RAD51 is one of the pivotal enzymes for DNA double-strand break repair by the HR pathway. While PARP inhibitors are extensively used for BRCA2 mutated cancers, their responses in BRCA2 WT is limited. Targeting RAD51 will open a new avenue to treat BRCA2 WT cancer patients. BRCA2 interaction with RAD51 is a prerequisite for RAD51 nuclear translocation to exert its function by binding to DNA. The disruption of this interaction leads to inhibition of DNA repair and in turn inhibits proliferation and tumor growth. As this leads to BRCAness in an otherwise BRCA2 WT background, it is expected to have synergy with PARP1 inhibitors. We report the identification of novel and potent RAD51 inhibitors which disrupt the RAD51:BRCA2 interaction. Our hit compounds show anticancer activity in relevant cancer cell lines across various indications. Further, our compounds inhibit RAD51 nuclear translocation upon induction of exogenous DNA damage. Multiple series have been identified, with a good SAR trend and correlating well with cell based and PD activity. Further profiling of these compounds is ongoing.

Citation Format: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Mahesh Yanamandra, Shankar Chithaluri, Hema Sankar Pathange, Deepika Hiremath, Sandeep M Girme, Amit Kumar Pawar. Identification and characterization of potent RAD51 inhibitors targeting RAD51-BRCA2 interaction [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA041.
Abstract P002: Metabolomic credentialling of murine chemical carcinogenesis model of urothelial cancer
Authors: Said Neveen A.
Published: December 2021

Bladder cancer (BCa) is the most common malignancy of urinary system with increasing incidence and mortality and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. We identified the enriched metabolic signatures that associate with premalignant and NMIBC. We found that enrichment of lipid metabolism is the forerunner of carcinogen-induced premalignant and NMIBC lesions. Cross-species analysis revealed the prognostic value of the enzymes associated with carcinogen-induced enriched metabolic in human disease. To date, this is the first study describing the global metabolomic profiles associated with early premalignant and NMIBC and provide evidence that these metabolomic signatures can be used for prognostication of human disease.

Citation Format: Neveen A. Said. Metabolomic credentialling of murine chemical carcinogenesis model of urothelial cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P002.
Abstract P008: myc Gene and cancer variant analysis and network interaction: An in-silico analysis
Authors: Kabrah Saeed
Published: December 2021

The myc is a proto-oncogene that regulates the cellular process like cell growth, proliferation, metabolism, apoptosis and malignancy pathologies. myc deregulation occurs in several cancers and plays a significant role in disease development, metastatic potential, and therapeutic resistance. Drug targeting myc in cancer remains highly desirable with substantial challenges, delaying the direct myc targeted drugs’s development. These drugs target the myc transcriptions deregulations in tumours cell by compound inhibiting the inducing of epigenetic silencing or regulation of G-quadruplex structures within the myc promoter. Proteins involved in myc's post-translational modulation have been identified as significant surrogate targets for lowering myc activity downstream of aberrant cell stimulatory signals.

Citation Format: Saeed Kabrah. myc Gene and cancer variant analysis and network interaction: An in-silico analysis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P008.
Abstract P012: Genomic and clinical correlates of overall survival (OS) in men with newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT)
Authors: Sayegh Nicolas , Peterson Bennet , Nussenzveig Roberto , Kessel Adam , McFarland Taylor Ryan , Hahn Andrew Warren , Sirohi Deepika , Kohli Manish , Maughan Benjamin Louis , Swami Umang , Yandell Mark , Agarwal Neeraj
Published: December 2021

Background: Despite recent advancements in systemic therapy in men with mCSPC, disease remains fatal. Identification of novel genomic and clinical correlates of survival in this setting remain a significant unmet need. Methods: Newly diagnosed mCSPC undergoing intensified ADT i.e., ADT plus docetaxel or novel hormonal therapy and available tumor comprehensive genomic profiling (CGP) were included in the analysis. CGP was performed by a CLIA certified Next Generation Sequencing panel (Foundation Medicine) and involved the following genes: FAS, KDM6A, MYC1, PTEN, RB1, TMPRSS2, and TP53. All variants of unknown significance were removed, and mutated genes present in ≥5 % patients were included. Cox proportional hazards was used to assess relationships between OS and multiple variables (age at diagnosis, Gleason score, baseline PSA, de-novo disease, volume of disease, presence of visceral metastases and presence of genetic aberrations on CGP). Results: 127 patients were eligible and included. Higher baseline PSA (HR 1.45, 95% CI 1.09-1.9, P=0.0097), presence of visceral metastases (HR 4.41, 95% CI 1.26-15.39, P=0.0199) and genomic aberrations in MYC1 (HR 5.23, 95% CI 1.05-26.04, P=0.0433) and RB1 (HR 32.72, 95% CI 5.35-200.2, P=0.0002) were significantly associated with inferior OS. High volume disease trended to associate with poor OS, but was not statistically significant (HR 1.63, 95% CI 0.56-4.71, P=0.367). PTEN loss and other genomic aberrations were not associated with OS. See Table. Conclusions: In this real-world patient population of men with mCSPC undergoing intensified ADT we identify clinical and genomic markers associated with poor OS. This study has limitations as expected in a retrospective analysis. These data, upon external validation, may aid with development of a risk stratification model, counseling of patients, treatment decision making in the clinic, as well as further drug development.

Citation Format: Nicolas Sayegh, Bennet Peterson, Roberto Nussenzveig, Adam Kessel, Taylor Ryan McFarland, Andrew Warren Hahn, Deepika Sirohi, Manish Kohli, Benjamin Louis Maughan, Umang Swami, Mark Yandell, Neeraj Agarwal. Genomic and clinical correlates of overall survival (OS) in men with newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P012.
Abstract P050: Trial in progress: A phase 2 multicenter study of autologous tumor-infiltrating lymphocyte (TIL, LN-145) cell therapy in patients with metastatic non-small cell lung cancer (mNSCLC)
Authors: Massarelli Erminia , Samakoglu Selda , Gontcharova Viktoria , Chen Guang , Jagasia Madan , Finckenstein Friedrich Graf , Sukari Ammar
Published: December 2021

Patients with mNSCLC without actionable driver mutation(s) who have progressed after cytotoxic chemotherapy plus immune checkpoint inhibitors (ICI) ± bevacizumab have limited treatment options and represent an unmet need. The safety and efficacy of TIL cell therapy for patients with mNSCLC who failed to respond or progressed on nivolumab has been evaluated in a Phase 1 clinical trial (Creelan B. AACR 2020), demonstrating an objective response rate (ORR) of 25% including 17% durable CR. This provides a clear rationale for initiation of IOV-LUN-202 study, evaluating TIL cell therapy with LN-145 in patients with mNSCLC without actionable driver mutation(s), who have progressed on or following a single line of approved systemic therapy consisting of combined ICI + chemotherapy ± bevacizumab. Trial Design IOV-LUN-202 (NCT04614103) is a prospective, open-label, multi-cohort, non-randomized, multicenter Phase 2 study. Cohorts 1 and 2 (each, n=40) are enrolling patients with mNSCLC based on tumor proportion score (TPS; Cohort 1, TPS <1%; Cohort 2, TPS ≥1%) at metastatic diagnosis prior to ICI use. Cohort 3 (TPS <1%; n=15) uses core biopsies for tumor acquisition in patients unable to undergo a surgical harvest, and Cohort 4 is designated for patients requiring retreatment. LN-145 is a cryopreserved infusion product generated at centralized GMP facilities in a 22 day manufacturing process. All patients receive TIL therapy consisting of nonmyeloablative lymphodepletion with cyclophosphamide (60 mg/kg × 2) + fludarabine (25 mg/m2 × 5), followed by a single infusion of autologous LN-145 (Day 0) and up to 6 doses of IL-2 (600,000 IU/kg). Key eligibility criteria include age ≥ 18 y, 1 prior line of therapy, ≥1 lesion(s) available for TIL generation and a remaining RECIST-measurable lesion, and ECOG PS 0–1. For each cohort the primary endpoint is ORR per RECIST 1.1. Secondary endpoints are safety, complete response rate, duration of response, disease control rate, progression-free survival, overall survival, and efficiency of generating LN-145 from tumor core biopsies (Cohort 3).

Citation Format: Erminia Massarelli, Selda Samakoglu, Viktoria Gontcharova, Guang Chen, Madan Jagasia, Friedrich Graf Finckenstein, Ammar Sukari. Trial in progress: A phase 2 multicenter study of autologous tumor-infiltrating lymphocyte (TIL, LN-145) cell therapy in patients with metastatic non-small cell lung cancer (mNSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P050.
Abstract P063: Novel prodrugs coupled with albumin nanoparticle encapsulation improves antitumor effects of the nucleoside analog gemcitabine
Authors: Raheja Neil , Kahana Jason , Jackman Robin , Monnig Curtis
Published: December 2021

Nucleoside analogs such as gemcitabine have been widely used to treat many solid tumors. Despite their near universal use and well understood mechanisms of action, this class of chemotherapeutic agents has notable shortcomings including rapid metabolism, limited systemic exposure, acquired resistance, and dose-limiting toxicities. Albumin-based nanoparticles offer several advantages for drug delivery including direct tumor targeting, low risk of immunogenicity, and ease of synthesis and manufacturing. We have modified numerous nucleoside drugs of clinical significance to form new prodrugs and use nanoparticle encapsulation in an attempt to improve the therapeutic index of the parent drugs. Different prodrugs of gemcitabine were designed to evade drug resistance mechanisms, and methods were developed to form stable lyophilized nanoparticle formulations. Nanoparticles were characterized by particle size (~40-65 nm) and polydispersity, and dose-dependent effects on the proliferation of human tumor cell lines were compared to the response to the parent drug gemcitabine. To evaluate effects in vivo, nanoparticle formulations were dosed intravenously (IV) to immunocompromised mice bearing patient-derived xenografts (PDx). The prodrug JTX-836 (IC50=0.46 nM) was ~10x more potent against BxPC-3 pancreatic adenocarcinoma cells than the parent gemcitabine (IC50 = 5.2 nM) in vitro. IV dosing of JTX-836 albumin nanoparticle formulation improved tumor growth inhibition in PDx models of both pancreatic ductal adenocarcinoma (CTG-0282 TumorGraft, Champions Oncology) and ovarian cancer (CTG-1180, Champions Oncology) when compared to IV gemcitabine dosing. These results demonstrate the potential for nanoparticle encapsulation of prodrugs to improve the antitumor activity of existing nucleoside analog therapeutics and support continued development of albumin-based delivery of gemcitabine for the treatment of human cancer.

Citation Format: Neil Raheja, Jason Kahana, Robin Jackman, Curtis Monnig. Novel prodrugs coupled with albumin nanoparticle encapsulation improves antitumor effects of the nucleoside analog gemcitabine [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P063.
Abstract P064: Novel engineering of therapeutic Fusobacterium nucleatum phage for colorectal cancer treatment
Authors: Ninio-Many Lihi , Zigelman Yael , Buchshtab Nufar , Elharar Yifat , Eylon Gal , Gidron Eliya , Berko-Ashur Dikla , Nicenboim Julian , Zelcbuch Lior , Gartman Einav Safyon , Kredo-Russo Sharon , Kowalsman Noga , Slutskin Ilya Vainberg , Weiner Iddo , Gahali-Sass Inbar , Zak Naomi , Puttagunta Sailaja , Bassan Merav
Published: December 2021

Fusobacterium nucleatum (FN) is enriched in human colorectal tumors [1] and its presence is correlated with poor prognosis [2]. Bacteriophages ("phages") are naturally occurring, self-amplifying viruses that are highly specific for particular bacterial species and strains and are recognized to have a high intrinsic safety. They offer a promising treatment strategy to both target FN associated with colorectal cancer (CRC) and, by phage engineering, to deliver an anti-tumoral immune-stimulating payload that may enhance the effectivity of other anti-cancer therapies such as checkpoint inhibitors in unresponsive colorectal cancer patients. The major challenge in engineering phages that target FN is the optimization of the eukaryotic payloads for high expression in this bacterial host. Since no data is available about codon usage and non-coding genetic sequences in the genome of FN bacteria, two computational approaches were used to optimize the codon usage for elevated payload expression of the first selected payload, murine IL-15. These approaches involved identifying ribosome binding sites and elongation speeds to optimize codon usage. Following design of an IL-15 expression vector, expression of this eukaryotic payload in FN bacteria was tested in vitro. For phage engineering, a plasmid containing the designed payload sequence was used to introduce the selected IL-15 encoding sequences into the phage genome. FN phage was successfully engineered to deliver a payload encoding the sequence of murine cytokine IL-15. Targeting of FN with engineered phage resulted in IL-15 protein expression in phage-infected bacteria in vitro. Given the specificity of FN for CRC tumors and the ability to locally express a eukaryotic protein by using FN targeting phage to deliver a payload, phage therapy may offer novel treatment approaches for patients with CRC.

Citation Format: Lihi Ninio-Many, Yael Zigelman, Nufar Buchshtab, Yifat Elharar, Gal Eylon, Eliya Gidron, Dikla Berko-Ashur, Julian Nicenboim, Lior Zelcbuch, Einav Safyon Gartman, Sharon Kredo-Russo, Noga Kowalsman, Ilya Vainberg Slutskin, Iddo Weiner, Inbar Gahali-Sass, Naomi Zak, Sailaja Puttagunta, Merav Bassan. Novel engineering of therapeutic Fusobacterium nucleatum phage for colorectal cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P064.
Abstract P080: Analysis of clinical BRCA1/2 reversions identifies hotspot mutations and predicted neoantigens associated with therapy resistance
Authors: Pettitt Stephen J. , Frankum Jessica , Punta Marco , Lise Stefano , Alexander John , Chen Yi , Haider Syed , Tutt Andre N. J. , Lord Christopher J.
Published: December 2021

Although PARP inhibitors and platinum salts form part of the standard-of-care for cancers with homologous recombination (HR) defects, drug resistance does emerge and is often caused by reversion mutations in BRCA1 or BRCA2. Reversion mutations are secondary mutations that restore functional protein or compensate for frameshift mutations. To better understand the nature and aetiology of these mutations, we collated, codified and analysed over 200 reversion mutations from 24 published studies. Most reversions have been reported as case reports or small clinical series – we have collected all published reports into a single freely-accessible database to which further cases can be submitted. The majority of reported reversion mutations are from BRCA1/2 mutant serous ovarian cancer, reflecting the longer use of platinum and PARP inhibitors in this disease. Our analysis identified reversion “hotspots” and “deserts” in the N- and C-terminal coding regions (respectively) of BRCA2, suggesting that pathogenic mutations in these domains may be at higher or lower chance of reversion, an effect not seen for BRCA1. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than frameshift-causing mutations. Unexpectedly, whilst most reversions were <100 bp “second site” deletions, microhomology use was not universal, especially in BRCA1-mutant cancers, suggesting that multiple DNA repair processes cause reversion and these vary in BRCA1 vs. BRCA2 mutant tumours. Reversions in BRCA1 mutant tumours were less likely to be mediated by deletions. Many reversions contain novel protein sequence not found in the wild type protein, for example where a stretch of out-of-frame protein sequence is retained between the pathogenic and reversion mutations. We modelled MHC binding affinities for these sequences and found that many reversions were predicted to encode potentially immunogenic neopeptides, suggesting a route to the treatment of reverted disease. These observations have implications for how drug resistance might be managed in BRCA-mutant cancers.

Citation Format: Stephen J. Pettitt, Jessica Frankum, Marco Punta, Stefano Lise, John Alexander, Yi Chen, Syed Haider, Andre N. J. Tutt, Christopher J. Lord. Analysis of clinical BRCA1/2 reversions identifies hotspot mutations and predicted neoantigens associated with therapy resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P080.
Abstract P095: Isogenic CRISPR anchor screens identified actionable nodes to CHK1/2 inhibitor prexasertib in TP53 mutant cancer
Authors: Teng Teng , Paik Stephen , Zhao Shan-chuan , Choi Ashley , Lombardo Steven A. , Liu Shangtao , Meier Samuel R. , Yu Yi , Anderson Jannik N. , Huang Alan , Li Fang , Pan Xuewen
Published: December 2021

TP53 is the most mutated tumor suppressor gene in human cancers and is a master regulator of a wide array of cellular processes including but not limited to cell cycle progression and DNA damage response. Due to its diverse functions, therapies specifically exploit the vulnerabilities created by TP53 loss remained elusive. We established a panel of TP53 isogenic pair cell line models by knocking out TP53 from WT cell lines and observed that CHK1/2 inhibitor prexasertib showed preferential selectivity toward TP53 KO cell lines. To thoroughly examine additional nodes which could further exploit this selective sensitivity, we carried out genome-wide prexasertib anchor screen in A549 isogenic lines employing CRISPRn, CRISPRi and CRISPRa platforms. From these functional genomics screens, we identified that targeting the anti-folate pathway genes (TYMS, DHFR) showed selective synergy with prexasertib specifically in TP53 KO cells. Secondly, a panel of iron metabolism genes was identified across different CRISPR platforms as candidate TP53 context specific synthetic lethal hits synergize with prexasertib. And lastly, additional sub-context was identified which may inform patient selection strategy for prexasertib as single agent.

Citation Format: Teng Teng, Stephen Paik, Shan-chuan Zhao, Ashley Choi, Steven A. Lombardo, Shangtao Liu, Samuel R. Meier, Yi Yu, Jannik N. Anderson, Alan Huang, Fang Li, Xuewen Pan. Isogenic CRISPR anchor screens identified actionable nodes to CHK1/2 inhibitor prexasertib in TP53 mutant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P095.
Abstract P096: Using CRISPR-Cas9 screens to identify microRNA involved in aggressive prostate cancer phenotypes
Authors: Chow Jonathan Tak-Sum , Lee Daniel K. C. , Gabra Martino Marco , Fu Norman , Chen Keyue , Salmena Leonardo
Published: December 2021

Background: Prostate cancer (PCa) is the most common cancer diagnosis in Canadian men. For many, the tumour can remain “dormant” negating a need for treatment, but if the tumour progresses and becomes metastatic, prognosis is poor. Despite the introduction of new treatments, metastatic PCa remains a lethal and incurable disease. This is invariably due to the onset of castration-resistance in advanced cases producing a more aggressive tumour with increased metastatic potential. We hypothesize that microRNA can promote these aggressive PCa phenotypes due to their ability to regulate diverse gene networks simultaneously. Methods: We have generated miRKOv2, the second version of our microRNA CRISPR Knockout library using the latest on- and off-target scoring algorithms and other microRNA-specific features for CRISPR-Cas9 guide RNA (gRNA) design. miRKOv2 will be used in three separate screens to identify microRNA that are essential for PCa growth, microRNA that are involved in PCa metastasis, and microRNA that can confer castration-resistance, respectively. Results: Next generation sequencing of the plasmid miRKOv2 library showed a median gRNA coverage of ~1100X. In silico comparisons to other microRNA libraries demonstrate that miRKOv2 is a superior sgRNA library. DU145 cells stably expressing Cas9 are highly active and proof of principle growth assays demonstrate that essential gene knockout and subsequent decrease in cell viability is detectable. Generation of a Cas9+ PCa cell line panel and screens are ongoing. Conclusion: miRKOv2 is an improved microRNA-focused CRISPR library with high gRNA coverage. Proof of principle assays demonstrate that knockout of essential genes results in a reduction in cell viability, indicating that a CRISPR dropout screen is appropriate for our in vitro model. This project aims to identify microRNA dependencies in metastatic and castration-resistant PCa that can be leveraged into new biomarkers and therapies.

Citation Format: Jonathan Tak-Sum Chow, Daniel K. C. Lee, Martino Marco Gabra, Norman Fu, Keyue Chen, Leonardo Salmena. Using CRISPR-Cas9 screens to identify microRNA involved in aggressive prostate cancer phenotypes [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P096.