bluuebunny/crossref_metadata_2025 huggingface dataset:
Overlap in habitat use and activity patterns between sika deer (Cervus nippon) and Japanese serows (Capricornis crispus) in subalpine habitats: exploitative competition rather than direct interference?
Authors: Takada Hayato , Nakamura Keita
Published: June 2023

Examining multiple niche relationships, such as habitat use and activity patterns, between sympatric species contributes to an understanding of the mechanisms of coexistence and competition. Sika deer ( Cervus nippon Temminck, 1838) and Japanese serows ( Capricornis crispus (Temminck, 1836)) often show different habitat use, and diversity in vegetation and topography seems to facilitate their coexistence. Conversely, their habitat use may overlap in areas with low-diversity habitats; however, this remains unstudied. Moreover, whether they spatiotemporally avoid each other to reduce direct interference is unclear. We examined the fine-scale patterns of habitat use and activity of deer and serows in the subalpine forests of Mount Fuji, which have low-diversity habitats, using camera trapping data over 3 years. Deer and serow habitat niches largely overlapped, especially in summer (92%–94%) and autumn (89%–91%), suggesting that low-diversity habitats facilitate overlapping habitat use. Both species selected areas frequently used by the other during spring to autumn and their temporal niches largely overlapped, especially in summer (88%) and autumn (83%), suggesting that they do not spatiotemporally avoid each other (i.e., there is no direct interference). Rapid range expansion of deer into these subalpine habitats may exclude native serows through resource exploitative competition rather than interference competition.
Dynamical stability in presence of non-minimal derivative dependent coupling of k-essence field with a relativistic fluid
Authors: Bhattacharya Kaushik , Chatterjee Anirban , Hussain Saddam
Published: June 2023

In this paper we investigate a non-minimal, space-time derivative dependent, coupling between the k-essence field and a relativistic fluid using a variational approach. The derivative coupling term couples the space-time derivative of the k-essence field with the fluid 4-velocity via an inner product. The inner product has a coefficient whose form specifies the various models of interaction. By introducing a coupling term at the Lagrangian level and using the variational technique we obtain the k-essence field equation and the Friedmann equations in the background of a spatially flat Friedmann–Lemaitre–Robertson–Walker (FLRW) metric. Explicitly using the dynamical analysis approach we analyze the dynamics of this coupled scenario in the context of two kinds of interaction models. The models are distinguished by the form of the coefficient multiplying the derivative coupling term. In the simplest approach we work with an inverse square law potential of the k-essence field. Both of the models are not only capable of producing a stable accelerating solution, they can also explain different phases of the evolutionary universe.
Discrete Symmetry Transformations on Non-Abelian Gauge Fields
Authors: Lahiri Amitabha , Pal Palash B. , Shokova Marina
Published: June 2023

All gauge bosons of a non-Abelian gauge theory do not transform the same way under the discrete transformations of time-reversal and charge-conjugation. Moreover, the transformation rules depend on how the generators are chosen. We show how well-defined rules pertain only to specific choices of generators, and then show how unified rules can be constructed, using matrix forms of the gauge bosons, which are completely independent of the choice of generators.
Knowledge Graph Based Recommendation by Adversarial Learning Algorithm in Application of Lifelong Education Data Classification
Authors: Xue Yunlan
Published: June 2023

Students can improve their capacity to learn continuously and work together to achieve a common goal through cooperative and explorative coursework in personalized learning. This article presents an effective method for clustering people by preference and a strategy for developing course suggestions for different organizations. This lets us consider student characteristics and courses in a statistically and semantically clear way. First, this article uses specific word articles and Word2Vec to extract factors efficiently. Optimizing efficiency. After that, a slightly modified K-means algorithm and perceptron adversarial learning method classify students into interest-based study clusters. The knowledge graph is created and saved to achieve this. In conclusion, the opinion-based deep learning algorithm used for subject recommendation system design provides advice for appropriate and high-quality results based on the degree of similarity between recommendation results and expert scoring. To do this, the proposed method is approximated against existing machine learning methods and compared to their prediction performance metrics.
IronNetInjector: Weaponizing .NET Dynamic Language Runtime Engines
Authors: Rose Anthony , Graham Scott , Krasnov Jacob
Published: June 2023

As adversaries evolve their Tactics, Techniques, and Procedures (TTPs) to stay ahead of defenders, Microsoft’s .NET Framework emerges as a common component found in the tradecraft of many contemporary Advanced Persistent Threats (APTs), whether through PowerShell or C#. Because of .NET’s ease of use and availability on every recent Windows system, it is at the forefront of modern TTPs and is a primary means of exploitation. This article considers the .NET Dynamic Language Runtime as an attack vector, and how APTs have utilized it for offensive purposes. The technique under scrutiny is Bring Your Own Interpreter (BYOI), which is the ability of developers to embed dynamic languages into .NET using an engine. The focus of this analysis is an adversarial use case in which APT Turla utilized BYOI as an evasion technique, using an IronPython .NET Injector named IronNetInjector. This research analyzes IronNetInjector and how it was used to reflectively load .NET assemblies. It also evaluates the role of Antimalware Scan Interface (AMSI) in defending Windows. Due to AMSI being at the core of Windows malware mitigation, this article further evaluates the memory patching bypass technique by demonstrating a novel AMSI bypass method in IronPython using Platform Invoke (P/Invoke).
Efficiently Making Cross-Engine Transactions Consistent
Authors: Zhang Jianqiu , Huang Kaisong , Wang Tianzheng , Lv King
Published: June 2023

Database systems are becoming increasingly multi-engine. In particular, a main-memory engine may coexist with a traditional storage-centric engine in a system to support various applications. It is desirable to allow applications to access data in both engines using cross-engine transactions. But existing systems are either only designed for singleengine accesses, or impose many restrictions by limiting crossengine transactions to certain isolation levels and operations. The result is inadequate cross-engine support in terms of correctness, performance and programmability.
Threshold Queries
Authors: Bonifati Angela , Dumbrava Stefania , Fletcher George , Hidders Jan , Hofer Matthias , Martens Wim , Murlak Filip , Shinavier Joshua , Staworko Slawek , Tomaszuk Dominik
Published: June 2023

Threshold queries are an important class of queries that only require computing or counting answers up to a specified threshold value. To the best of our knowledge, threshold queries have been largely disregarded in the research literature, which is surprising considering how common they are in practice. We explore how such queries appear in practice and present a method that can be used to significantly improve the asymptotic bounds of their state-of-the-art evaluation algorithms. Our experimental evaluation of these methods shows order-of-magnitude performance improvements.
Technical Perspective: (Pre-) Semirings Come to the Recursion Party
Authors: Rudra Atri
Published: June 2023

(This article is an imagined conversation with my U. at Buffalo UG algorithms class students.)
Convergence of Datalog over (Pre-) Semirings
Authors: Abo Khamis Mahmoud , Ngo Hung Q. , Pichler Reinhard , Suciu Dan , Remy Wang Yisu
Published: June 2023

Recursive queries have been traditionally studied in the framework of datalog, a language that restricts recursion to monotone queries over sets, which is guaranteed to converge in polynomial time in the size of the input. But modern big data systems require recursive computations beyond the Boolean space. In this paper we study the convergence of datalog when it is interpreted over an arbitrary semiring. We consider an ordered semiring, define the semantics of a datalog program as a least fixpoint in this semiring, and study the number of steps required to reach that fixpoint, if ever. We identify algebraic properties of the semiring that correspond to certain convergence properties of datalog programs. Finally, we describe a class of ordered semirings on which one can generalize the semi-na¨ve evaluation algorithm to compute their minimal fixpoints.
Technical Perspective: Revisiting Runtime Dynamic Optimization for Join Queries in Big Data Management Systems
Authors: Kipf Andreas
Published: June 2023

Query optimization is the process of finding an efficient query execution plan for a given SQL query. The runtime difference between a good and a bad plan can be tremendous. For example, in the case of TPC-H query 5, a query with 5 joins, the difference between the best and the worst plan is more than 10,000×. Therefore, it is vital to avoid bad plans. The dominating factor which differentiates a good from a bad plan is their join order and whether this join order avoids large intermediate results.
Repurposing Drugs in Controlling Recurrent Platinum-Resistant Clear-Cell Ovarian Cancer
Authors: Sinsuwan Woraporn , Norchai Phawit
Published: June 2023

Background. Recurrent platinum-resistant clear-cell ovarian cancer has a low overall survival duration of 7-8 months, making it a fatal disease. Currently, chemotherapy is the major kind of treatment, but it offers little advantage. Repurposed conventional drugs have recently been found to offer the ability to control cancer with few side effects and at a reasonable cost to healthcare organizations. Case Presentation. In this case report, we present the case of a 41-year-old Thai female patient diagnosed with recurrent platinum-resistant clear-cell ovarian cancer (PRCCC) in the year 2020. After undergoing chemotherapy for two courses and failing to respond to treatment, she began alternative medicine with repurposing drugs in November 2020. Simvastatin, metformin, niclosamide, mebendazole, itraconazole, loratadine, and chloroquine were also administered. Two months after therapy, a computerized tomography (CT) scan revealed a conflict between a decline in tumor marker levels (CA 125, CA 19-9) and an increase in the number of lymph nodes. However, after continuing all medications for 4 months, the CA 125 level decreased from 303.6 to 54 U/ml, and the CA 19-9 level decreased from 1210.3 to 386.10 U/ml. The patient’s EQ-5D-5L score increased from 0.631 to 0.829 (abdominal pain and depression), indicating improved quality of life. Overall survival was 8.5 months, and progression-free survival was 2 months. Conclusion. The response to drug repurposing is demonstrated by a four-month-long improvement in symptoms. This work introduces a novel strategy for the management of recurrent platinum-resistant clear-cell ovarian cancer that needs further evaluation in large-scale studies.
Coordination Control of Active Steering and Direct Yaw Control for the Articulated Steering Vehicle
Authors: Huang Bin , Yuan Zhijun , Peng Dengzhi , Wei Xiaoxu , Wang Yongsheng
Published: June 2023

Lateral stability is vital to vehicle handling stability and traffic safety. It is also a crucial factor for the path-tracking ability of the vehicle in the intelligent transportation system (ITS). Most of the research focuses on vehicles with an Ackerman steering system. The ASV (articulated steering vehicle) has a lower steering radius. Thus, it is widely used in some special vehicles, such as mining and construction vehicles. The ASV has weaker lateral stability than the vehicle with an Ackerman steering system. To improve the stability of an ASV, the nonlinear lateral dynamic model is established and validated by field test. With the lateral dynamic model, the steering characteristic of the ASV is analyzed. Based on the stability criteria analysis, the vehicle sideslip angle and angular velocity phase portrait are chosen as the stability indicator. An integrated AASS (active articulated steering system) DYC (direct yaw control) controller based on the adaptive MPC (model predictive control) method is designed according to the track on the phase plane. The double lane-change and 0.7 Hz sine with dwell maneuver are initiated based on the integrated vehicle dynamic model. The results suggest that the provided controller has a better stability performance than the current antiwindup PID control algorithm. It lays a good foundation for the vehicle safety and path tracking of ASV in the ITS.
The Complex-Typek-Pell Numbers and Their Applications
Authors: Aküzüm Yeşim
Published: June 2023

In this study, a new sequence called the complex-typek-Pell number is defined. Also, we give properties of this sequence such as the generating matrix, the generating function, the combinatorial representations, the exponential representation, the sums, the permanental and determinantal representations, and the Binet formula. Then, we determine the periods of the recurrence sequence according to the moduloυand produce cyclic groups with the help of the generating matrices of the sequence. We also get some findings about the ranks and periods of the complex-typek-Pell sequence. Additionally, we create relations between the orders of the cyclic groups produced and the periods of the sequence. Then, this sequence is moved to groups and examined in detail in finite groups. As an application, we get the periods of the complex-type2-Pell numbers in the polyhedral groupsυ,2,2,2,υ,2, and2,2,υand the quaternion groupQ2υ.
Green Spectrophotometric Determination of Organophosphate in Selected Fruits and Vegetables
Authors: Sharma Hemraj , Sapkota Hari Prasad , Paudel Kanchan , Raila Anusha , Kandel Sujata , Chaudhary Pramod , Bhattarai Kritika
Published: June 2023

A simple, sensitive, precise, and environmentally safe spectrophotometry method was developed and validated for the determination of organophosphate in various fruits and vegetables using a UV-Visible spectrophotometer using a magnesia mixture. The volume of reagent used for analysis and the stability of the color complex were also optimized. The drug showed a stable white color complex at 420 nm. The greenness of the methods was estimated using an ecoscale (84), the Green Analytical Procedure Index, and AGREE (0.89), which were found to be excellent green method based on spectrophotometric determination. The method was validated using ICH guidelines and has acceptable values for linearity (0.5–2.5 mg/ml), accuracy (98.5–102.5%), precision, robustness, limit of detection (0.16 mg), and limit of quantification (0.486 mg). The concentration of the organophosphate in the analyzed sample was in the range of 0.003 to 2.45 mg. Altogether, the proposed green analytical method was found to be a simple, selective, sensitive, accurate, and ecofriendly method for the analysis of organophosphate in various fruits and vegetables.
In Vitro Antidiabetic, Antioxidant, and Cytotoxic Evaluation of Honeybush Tea (Cyclopia genistoides) Extracts
Authors: Cele Nkosinathi D. , Mthimunye Ntokozo E. , Mkhwanazi Qiniso B. , Nxumalo Seluleko , Tshabuse Freedom , Pooe Ofentse J. , Chellan Nireshni , Mthembu Matthew S. , Opoku Andy R.
Published: June 2023

Background. This study evaluated in vitro antidiabetic and antioxidant properties of different extracts (n-hexane, dichloromethane (DCM), and 70% ethanol) of honeybush tea (Cyclopia genistoides). Over a period of 28 days, antiprotein glycation was evaluated and some antidiabetic indicators (α-amylase, α-glucosidase, and pancreatic lipase inhibitory effects) and antioxidant activities (DPPH, ABTS, hydroxyl radical, metal ion chelating, and reducing power) for each of the crude extracts were also investigated. The results showed that all of the tested C. genistoides extracts had strong α-amylase and lipase inhibitory activity in a concentration-dependent manner with IC50 values from 0.018 μg/ml (DCM extract) to 9.93 μg/ml (n-hexane extract), respectively. The extracts also displayed inhibitory effects on protein glycation between the 14th and 28th days. The DCM and ethanolic extracts further exhibited strong antioxidant activities as they effectively scavenged most of the radicals tested, with IC50 values ranging from 0.014–0.048 mg/ml to 0.019–0.043 mg/ml. Two hundred and seventy-four chemical constituents had been identified by GC-MS, with the n-hexane extract having the highest number of peaks (127) followed by the DCM extract (107). Six compounds were identified across all the following three extracts: decane (RT: 6.4), undecane (RT: 7.7), dodecane (RT: 9.00), phytol (RT: 21.32), heptadecanoic acid, 9-methyl, methyl ester (RT: 21.65), and 9-octadecenamide (RT: 24.30). The cytotoxicity of the extracts against C3A cell lines was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay, which demonstrated that honeybush tea had a toxicity effect ranging from 66.3–88.4 μg/ml on C3A cell lines. The results showed that honeybush has antioxidant and antidiabetic activities, which could be partially attributed to the phytochemical compounds identified within the extracts.
Data from Proteogenomic Analysis of Salivary Adenoid Cystic Carcinomas Defines Molecular Subtypes and Identifies Therapeutic Targets
Authors: Ferrarotto Renata , Mitani Yoshitsugu , McGrail Daniel J. , Li Kaiyi , Karpinets Tatiana V. , Bell Diana , Frank Steven J. , Song Xingzhi , Kupferman Michael E. , Liu Bin , Lee J. Jack , Glisson Bonnie S. , Zhang Jianhua , Aster Jon C. , Lin Shiaw-Yih , Futreal P. Andrew , Heymach John V. , El-Naggar Adel K.
Published: June 2023

AbstractPurpose:
Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard-of-care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications.
Experimental Design:
RNA/DNA sequencing of 54 flash-frozen salivary ACCs and reverse phase protein array (RPPA) in 38 specimens were performed, with validation by Western blotting and/or IHC. Three independent ACC cohorts were used for validation.
Results:
Both unbiased RNA sequencing (RNA-seq) and RPPA analysis revealed two molecular subtypes: ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH-activating mutations, and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, and EGFR) and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNA-seq. Furthermore, IHC staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggest a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II, producing unique therapeutic vulnerabilities for each subtype.
Conclusions:
Cooccurrence of multiple actionable protein/pathways alterations in each subtype indicates unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.
Abstract 1008: A novel biomarker and therapeutic target for early pancreatic cancer
Authors: Park Min Seok , Jung Kyung Hee , Kim Sang Eun , Lee Yun Ji , Park Sunghyouk , Hong Soon-Sun
Published: June 2023

Purpose: Pancreatic cancer (PC) has a grim prognosis, and an early diagnostic biomarker has been highly desired. The molecular link between diabetes and PC has not been well established.

Methods: Bioinformatics screening was performed for a serum PC marker. Experiments in cell lines (5 PC and 1 normal cell lines), mouse models, and human tissue staining (37 PC and 10 normal cases) were performed to test asprosin production from PC. Asprosin’s diagnostic performance was tested with serums from multi-center cohorts (347 PC, 209 normal, and 55 additional diabetic patients) and evaluated according to PC status and stages which was compared with that of CA19-9.

Results: Asprosin, a diabetes-related hormone, was found from the bioinformatics screening, and its production from PC was confirmed. Serum asprosin levels from multi-center cohorts yielded an age-adjusted diagnostic area under the curve (AUC) of 0.987 (95% confidence interval [CI] = 0.961 to 0.997), superior to that of CA19-9 (AUC = 0.876, 95% CI = 0.847 to 0.905), and a cut-off of 7.18 ng/mL, at which the validation set exhibited a sensitivity of 0.957 and a specificity of 0.924. Importantly, the performance was maintained in early stage PC, consistent with the tissue staining. A slightly lower performance against additional diabetic patients (n = 55) was restored by combining asprosin and CA19-9 (AUC = 0.985, 95% CI = 0.975 to 0.995).

Conclusion: Asprosin is presented as an early-stage PC serum marker that may provide clues for PC-induced diabetes. Larger prospective clinical studies are warranted to solidify its utility.

Citation Format: Min Seok Park, Kyung Hee Jung, Sang Eun Kim, Yun Ji Lee, Sunghyouk Park, Soon-Sun Hong. A novel biomarker and therapeutic target for early pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1008.
Abstract 1106: A novel cancer therapy using proton beam; an integrated proton dynamic therapy, iPDT
Authors: Matsui HIrofumi
Published: June 2023

A super-aged society, the prime example of which is Japan, is being flooded with increasing in numerous numbers of aged cancer patients, who often take anti-coagulant medicines to prevent the attacks of ischemic heart diseases and/or strokes. Since they show bleeding tendency induced by the medicines, it’s hard for them to receive surgical operations. Thus, low invasive cancer treatments without bleedings are abundantly desired. In this study, the applicant will establish a new proton therapy, in which a resonance nuclear reaction (RNR) induced by collision of a proton with a stable nitrogen isotope (15N), can be a clue to injure cancer-cells specifically. The LET of the product ions (12C6+, 4He2+) of the 15N RNR is above 50 times in comparison with the LET of proton. To establish the cancer-specific 15N delivery, 15N-aminolevulinic acid (15N-ALA) will be used. This reagent has been already used and obtained regulatory approvals as a diagnostic medicine for the location of the glioblastoma in Japan. In this study, a pair of rat gastric epithelial cells, one is normal cell, and another is cancerous characteristics cells were used. 15N-ALA treated porphyrin fluorescent intensity of these cells will be compared with 14N-ALA treatment. The cells will be irradiated with a proton beam generated by an electrostatic accelerator and 4.43 MeV gamma-rays will be measured to demonstrate the amount of 15N collected specifically in the tumor cells. Such quantitative analysis of 15N in the tumor cells can be a new pre-diagnosis of iPDT.

Citation Format: HIrofumi Matsui. A novel cancer therapy using proton beam; an integrated proton dynamic therapy, iPDT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1106.
Abstract 1175: Systematic profiling of conditional pathway activation as a new class of cancer dependency
Authors: Chang Liang , Jung Nancy Y. , Atari Adel , Kesar Devishi , Rodriguez Diego J. , Rees Matthew A. , Ronan Melissa , Sellers William R.
Published: June 2023

The paradigm of cancer dependencies and targeted therapies has been nearly exclusively focused on inhibiting critical pathways or nodes in cancer. However, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been systematically characterized. In this study, we sought to systematically identify context-specific gene activation lethalities in cancer. We performed lineage-specific mutual-exclusivity (ME) analysis using 69,393 cancer patient genomes in cohorts of AACR-GENIE, TCGA, and Foundation One, across 12 cancer lineages, and identified ME mutation pairs within MAPK, PI3K and WNT pathways indicative of evolutionarily negative selection. To functionally test whether mutual exclusive genetic alterations likely create negative selection pressures in cancer, we developed a lentiviral method to achieve simultaneous ectopic ORF expression ~500 barcoded cancer cell lines for large-scale gain-of-function genetic perturbation. Using this technology, we systematically profiled the pan-cancer vulnerability landscape upon activating 10 key pathway nodes, revealing selective activation dependencies associated with specific biomarkers. We validated the anti-tumor effect of PI3K hyperactivation in PIK3CA/PTEN double-mutant endometrial cancer cell lines. Notably, we find that subsets of APC-mutant colorectal cancers retain active destruction complexes. Upon further depletion of APC or direct expression of β-catenin, the resulting WNT pathway hyperactivation impairs the viability of APC-mutant colorectal cancers in in vitro cell lines and organoids and in in vivo tumor models. Together, our study reveals a new class of conditional gene activation dependencies in cancer.

Citation Format: Liang Chang, Nancy Y. Jung, Adel Atari, Devishi Kesar, Diego J. Rodriguez, Matthew A. Rees, Melissa Ronan, William R. Sellers. Systematic profiling of conditional pathway activation as a new class of cancer dependency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1175.
Abstract 1266: MYC mediated HIF-2α modulates the altruistic stemness reprogramming in leukemia stem cells
Authors: Mitra Shirsajit , Pathak Lekhika , Saikia Partha Jyoti , Pal Bidisha , Das Bikul
Published: June 2023

Potential cell surface markers specifically enriching the leukemia stem cell (LSC) subfraction based on stemness genes expression have not yet been identified. Previously, we reported ABCG2, a drug efflux pump, enriches a subpopulation of cells exhibiting a very high level of stemness genes expression in ES cells. These ABCG2+ ES cells exhibited high HIF-2α, which in cooperation with MYC-regulated Nanog and Sox-2. ABCG2+ cells demonstrated highly cytoprotective altruistic behavior by secreting high levels of glutathione. In the present study, we evaluated whether ABCG2+ subfraction of human LSCs exhibits high level of stemness genes and altruistic behavior. We isolated the ABCG2+ cell subfraction from cervical lymph node and blood of human T-ALL(n=5) and CML(n=7) patients exhibiting high levels of stemness genes in addition to MYC and HIF-2α. We investigated the altruistic stemness phenotype of the ABCG2+ cells by studying the molecular signature of MYC binding to HIF-2α. siRNA HIF-2α treatment led to ABCG2+ cell loss of proliferative capacity and reduced GSH levels, suggesting reduction of cytoprotective altruistic behavior in vitro. Treatment of ABCG2+ cell harboring mice with FM19G11 led to marked loss in the secondary engraftment in NOD/SCID mice, indicating loss of ABCG2+ cell self-renewal capacity. We found siRNA MYC inhibition led to loss of HIF-2α expression, suggesting that MYC might be regulating HIF-2α mediated altruistic stemness program in the ABCG2+ cells. Overall, we found that ABCG2 can be a probable marker to enrich the LSC subfraction having high expression of stemness genes and altruistic stemness phenotype.

Citation Format: Shirsajit Mitra, Lekhika Pathak, Partha Jyoti Saikia, Bidisha Pal, Bikul Das. MYC mediated HIF-2α modulates the altruistic stemness reprogramming in leukemia stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1266.
Abstract 1477: TICRR is a prognosis biomarker associated with RNA epigenetic modification, DDR pathway, and RNA metabolism of lung adenocarcinoma
Authors: Zheng Xunbo , Guan Jun , Chen Chenteng , Han Li , Huang Hanxing
Published: June 2023

Background: TOPBP1 interacting checkpoint and replication regulator (TICRR), a hub gene of the Cdk2-mediated initiation step of DNA replication, has been identified as a prognostic biomarker in papillary renal cell carcinoma (PRCC). Nevertheless, there are few studies on the comprehensive analysis between mRNA expression of TICRR and lung adenocarcinoma (LUAD).

Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database of LUAD were acquired to analyze the mRNA expression between tumor and normal tissues, survival prognosis, and clinicopathology characters. The GO, KEGG, and gene set enrichment analysis (GSEA) were performed using the R package. The correlation of TICRR with immune cell infiltration, RNA epigenetic modification, DDR pathway, and RNA metabolism of LUAD were further explored using TCGA and GEO database.

Results: TICRR was confirmed significantly upregulated in several cancers, like LUAD, Lung squamous cell carcinoma (LUSC), Uterine Corpus Endometrial Carcinoma (UCEC), except for Prostate adenocarcinoma (PRAD), Thyroid carcinoma (THCA), which was downregulated in tumor tissues. Cox analysis indicated the overexpression of TICRR was related to poor survival in several cancers. The KEGG enrichment showed TICRR expression positively related to cell cycle, homologous recombination, mismatch repair, DNA replication, and cysteine metabolism in LUAD. Pathway enrichment showed a close relationship with spliceosome, oxidative phosphorylation, and ubiquitin-mediated proteolysis. Immune infiltration analysis revealed TICRR expression was negatively correlated with B cell expression, immune score, stromal score, and immunostimulators like IL2 (P<0.001), and positively correlated with neutrophil cell expression, immune inhibitors like PD-L1 and CTLA4. Interestingly, high mRNA expression of TICRR correlates with DDR pathway signature (37 genes), 37 m6A/m5C regulated genes, and some metabolism-regulated genes. Single-cell analysis of six LUAD samples showed that TICRR was significantly enriched in macrophage and T cells.

Conclusions: TICRR has been identified to be a prognosis biomarker in LUAD, which is involved in immune activation, pathway transportation, RNA modification, and tumor energy metabolism. TICRR can be used as a promising therapeutic target and prognosis indicator for LUAD.

Citation Format: Xunbo Zheng, Jun Guan, Chenteng Chen, Li Han, Hanxing Huang. TICRR is a prognosis biomarker associated with RNA epigenetic modification, DDR pathway, and RNA metabolism of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1477.
Abstract 1583: Bcl-6 as a potential therapeutic target for bladder cancer
Authors: Furuya Hideki , Murakami Kaoru , Kim Nari , Rosser Charles J.
Published: June 2023

Introduction and Objectives: B-cell lymphoma 6 (Bcl-6) is known to be a nuclear protein and a master transcription factor for regulation of T follicular helper cells (TFH cells) proliferation. Previously, we reported on the increased angiogenic potential of human prostate cancer cells that overexpressed the Bcl-2. Comparative genomic profiling of the endothelial cells treated with/without conditioned media from Bcl-2-overexpressing human prostate cancer cells revealed approximately 250 differentially expressed genes. Interestingly, bioinformatics analysis identified Bcl-6 as one of several secreted proteins on the list. In this study, we first confirmed that Bcl-6 exists in liquid biopsy, and secondly evaluate the effect of Bcl-6 neutralization on angiogenesis and tumor growth in in vitro and in vivo models.

Methods: We first analyzed Bcl-6 levels in serum and urine by ELISA. Then we tested the effect of Bcl-6 antibody for the following: ability to inhibit in vitro and in vivo angiogenesis, ability to inhibit cellular proliferation, and tumor growth in cell line-derived xenograft model.

Results: First, we found that Bcl-6 exists in urine and serum. Interestingly, Bcl-6 level was significantly higher in cancer patients than healthy subjects. Next, we identified the effective clone tube formation assay. Then we further tested the effect of the antibody and exogenous Bcl-6 on cell proliferation, tube formation, and tube disruption in HUVEC. The exogenous Bcl-6 did not enhance cell proliferation of HUVEC. On the other hand, the Bcl-6 antibody significantly inhibited tube formation in HUVEC, but not tube disruption. Subsequently, we performed Matrigel plug assay to evaluate the effect on angiogenesis in vivo. The CD31 positive cells in Matrigel plug were significantly reduced by the Bcl-6 antibody treatment. To evaluate the effect on tumor growth, we first performed the cell proliferation assay to evaluate the effect on tumor growth in vitro. The Bcl-6 antibody significantly inhibited the cell proliferation of T24 and UM-UC-3 cell lines highly expressing Bcl-6. Finally, we tested the effect of the Bcl-6 antibody on tumor growth in an animal model. Intratumoral injection of Bcl-6 antibody (15 μg/tumor, twice weekly) significantly inhibited the tumor growth.

Conclusions: This is the first time to identify that Bcl-6 may be a secreted protein and found that neutralization of Bcl-6 by antibody inhibits angiogenesis and tumor growth in both in vitro and in vivo. The results suggest that neutralizing Bcl-6 by antibody could be a promising therapeutic agent in bladder cancer.

Citation Format: Hideki Furuya, Kaoru Murakami, Nari Kim, Charles J. Rosser. Bcl-6 as a potential therapeutic target for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1583.
Abstract 1589: Characterization of polyaminohydroxamic acids and polyaminobenzamides as inhibitors of HDAC10
Authors: Stewart Tracy Murray , Foley Jackson R. , Woster Patrick M. , Casero Robert A.
Published: June 2023

Elevated polyamine levels are essential for continual proliferation of cancer cells. Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd), of which extracellular sources can be abundant, particularly in the colonic lumen. We previously demonstrated that exogenously supplied N8-AcSpd can support tumor cell growth through HDAC10-mediated deacetylation into spermidine, which is then redistributed within the polyamine interconversion pathway to maintain homeostasis.In the current study, we investigate the utility of polyamine-based hydroxamic acids (PAHAs) and benzamides (PABAs) as pharmacological inhibitors of HDAC10-mediated polyamine deacetylation. Incorporation of the polyamine moiety enables these compounds to enter the cell selectively through the polyamine transport system, which is upregulated in cancer cells. A total of 42 compounds, including 21 PAHAs and 21 PABAs, were screened for HDAC10 inhibition using a cell-based growth assay in which polyamine-depleted, growth-arrested cells are exposed to N8-AcSpd: in the presence of HDAC10 activity, this polyamine is deacetylated and proliferation is restored. Several compounds in our screen inhibited HDAC10 activity in this assay, as indicated by a lack of growth rescue, and were selected for further analysis in which treatment was expanded over a range of doses, thereby allowing a dose-dependent evaluation and comparison of sensitivity. HPLC-based analysis of cell lysates functionally confirmed that deacetylation of N8-AcSpd into spermidine was inhibited by the test compounds. Finally, specificity of the selected PAHAs and PABAs for HDAC10 was evaluated by immunoblotting for increased acetylation of the substrates of related HDACs, including histones H3 and H4, and alpha-tubulin. These studies provide a basis for future drug design strategies targeting the polyamine deacetylase activity of HDAC10 as an antitumor strategy, which may be particularly important in the context of polyamine-blocking therapies.

Citation Format: Tracy Murray Stewart, Jackson R. Foley, Patrick M. Woster, Robert A. Casero. Characterization of polyaminohydroxamic acids and polyaminobenzamides as inhibitors of HDAC10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1589.
Abstract 169: Leveraging space to advance terrestrial cancer research
Authors: Pham Jessica , Ladel Luisa , Wu Christina , Jamieson Catriona
Published: June 2023

The International Space Station (ISS) offers a unique macroenvironment to study biology. The effects of microgravity in low earth orbit (LEO) can be leveraged to study pre-cancer and cancer transformation in an accelerated timeframe. Thus, we launched two cancer cell types into space as a proof of concept and to establish an innovative model for studying cancer. The two cell types are TF1a, an erythroleukemia cell line, and Caco-2, a colon cancer cell line that was cultured as organoids. These studies were performed in collaboration with Axiom Space and were launched as part of the Ax-1 mission on April 8, 2022. To study these tumor organoids in space, cells were transduced with two lentiviral reporters, ADAR1 NanoLuciferase reporter, an A-to-I editing reporter, and Fucci2BL, a cell-cycle transit reporter. Fluorescent imaging at days 5 and 6 of the mission, courtesy of KEyence Research MIcroscope Testbed (KERMIT), allowed us to receive and assess the development of these tumor models in real-time. Caco-2 organoids in flight grew 3-5 times bigger than their ground counterparts. Preliminary whole genome sequencing (WGS) analysis showed that telomere length is shortened in flight samples compared to asynchronous ground control samples. In summary, research done in LEO has the capacity to strengthen terrestrial research. As we follow-up with these studies as part of the Ax-2 mission in May of 2023, we hope to gain more insight into the pathogenesis of cancer and develop strategies to mitigate cancer progression.

Citation Format: Jessica Pham, Luisa Ladel, Christina Wu, Catriona Jamieson. Leveraging space to advance terrestrial cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 169.
Abstract 1694: Loss ofZNF251stimulates NHEJ resulting in PARP inhibitor resistance inBRCA1-mutated cancer cells
Authors: Huang Jian , Skorski Tomasz
Published: June 2023

The poly (ADP-ribose) polymerases (PARPs) inhibitors are an exciting new class of agents that have shown efficacy in treating various cancers, especially those harboring BRCA1/2 mutations. The cancer associated BRCA1/2mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPi) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, PARPi resistance is common and develops through multiple mechanisms. Restoring HR and/or stabilizing replication forks are two major mechanisms of PARPi resistance in BRCA1/2-mutated cells. To further understand the mechanisms of drug resistance to PARPi, we took an unbiased approach with a CRISPR-pooled genome-wide library to screen new genes whose loss-of-function confers resistance to PARPi olaparib. We identified ZNF251, a transcription factor, and found that its loss-of-function led to the PARPi resistance in multipleBRCA1-mutated breast and ovarian cancer lines. Elevated activities of both HR and non-homologous end joining (NHEJ) repair were detected in cancer cells harboring BRCA1 mutation and ZNF251 deletion (BRCA1mut+ZNF251del) and were associated with enhanced expression of RAD51 and Ku70/Ku80, respectively. Furthermore, we showed that a DNA-PKcs inhibitor restored sensitivity of BRCA1mut+ZNF251del cells to PARPi ex vivo and in vivo. Taken together, our study discovered a novel gene ZNF251 whose loss-of-function conferred resistance to PARPi in BRCA1-mutated breast and ovarian cancers and identified DNA repair pathway responsible for this effect.

Citation Format: Jian Huang, Tomasz Skorski. Loss ofZNF251stimulates NHEJ resulting in PARP inhibitor resistance inBRCA1-mutated cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1694.
Abstract 2309: Unlocking the proteome of metastatic prostate cancer circulating tumor cells
Authors: Drake Justin M. , Sychev Zoi , Horrmann Alec , Smith Kaylee J. , Galeano-Garces Catalina , Arafa Ali , Heller Nicholas , Ahmadi Mahdi , Hong Jiarong , Ludwig Megan , Hwang Justin , Antonarakis Emmanuel S. , Parthasarathy Jayant
Published: June 2023

In recent years, liquid biopsies have emerged to provide improved insights on the current disease state of a patient, but they generally rely on a small number of protein markers from immunofluorescent staining or cell-free DNA, which provides limited information especially around drug targets. As more targeted and immune therapies enter the market, selecting the optimal drug target could improve patient outcomes drastically. One way to achieve this goal is to generate multi-omic datasets from the cancer cells in circulation, known as circulating tumor cells (CTCs). In this study, Astrin Biosciences’ patented isolation technology was used to enrich CTCs with high purity from the blood of metastatic castration resistant prostate cancer (mCRPC) patients. The enriched CTCs and a patient matched control sample consisting primarily of white blood cells were divided such that RNA and protein could be interrogated from the same patient. Label free unbiased mass spectrometry was used to identify proteins and marks the first time a global proteomic assessment has been performed in CTCs from cancer patients. Initial analysis identified over 1,500 peptides corresponding to greater than 500 proteins with increased epithelial cell markers in the CTC-enriched sample and increased WBC markers in the control sample. Hallmarks of androgen response and detection of the androgen receptor were also identified in the CTC proteome. In addition to the proteome, RNA sequencing will also be performed to generate a multi-omic platform to detect cancer signaling mechanisms and biomarkers. Overall, this study was designed to show the feasibility of obtaining multi-omic data from a liquid biopsy and future studies will provide more insight into the clinical utility of such data. As we analyze more patients, we plan to compare the protein and RNA signatures across mCRPC patients and eventually be able to map patient outcomes and correlate them with drug response with the overall goal to improve treatment selection and patient outcomes.

Citation Format: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee J. Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy. Unlocking the proteome of metastatic prostate cancer circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2309.
Abstract 2736: Locoregional modified vaccinia ankara (MVA) encoding a single-chain IL-12 achieves efficacy antitumor immune response in peritoneal carcinomatosis
Authors: Bella Ángela , Arrizabalaga Leire , Trani Claudia Augusta Di , González-Gomariz José , Cirella Assunta , Olivera Irene , Alvarez Maite , Teijeira Álvaro , Langbein Cigdem Atay , Medina-Echeverz José , Hinterberger Maria , Hochrein Hubertus , Melero Ignacio , Berraondo Pedro , Aranda Fernando
Published: June 2023

Peritoneal carcinomatosis is an advanced stage of cancer developed in the peritoneal cavity without effective treatment. In order to restore antitumor immunity subverted by tumor cells, we evaluated in this study intraperitoneal administration of vaccinia virus Ankara (MVA) genetically modified to express the proinflammatory cytokine single-chain interleukin 12. MVA encoding scIL-12 was evaluated in peritoneal carcinomatosis models based on intraperitoneal administration of tumor cells. The immune response was evaluated by ELISpot, flow cytometry, intravital microscopy, and depleting monoclonal antibodies. Safety was assessed by measuring body weight and a hemogram test. Tissue tropism after intravenous or intraperitoneal administration was determined by bioluminescence analysis after the administration of MVA encoding luciferase.

Intraperitoneal or locoregional administration, but not other routes of administration, elicited a potent immune response characterized by increased levels of tumor-specific T CD8 lymphocytes. The antitumor immune response was detectable not only in the peritoneal cavity but also systemically. As a result, a single intraperitoneal administration of MVA encoding scIL-12 completely eradicates MC38 cells implanted in the peritoneum, protecting cured mice from a subcutaneous rechallenge with MC38 cells. The safety profile of intraperitoneal administration was also superior to that of intravenous administration since there was no weight loss or hematological toxicity when the vector was infused into the peritoneal cavity.

In conclusion, intraperitoneal administration of MVA vectors encoding scIL-12 induces a potent tumor-specific immune response that leads to the eradication of peritoneal metastasis.

Citation Format: Ángela Bella, Leire Arrizabalaga, Claudia Augusta Di Trani, José González-Gomariz, Assunta Cirella, Irene Olivera, Maite Alvarez, Álvaro Teijeira, Cigdem Atay Langbein, José Medina-Echeverz, Maria Hinterberger, Hubertus Hochrein, Ignacio Melero, Pedro Berraondo, Fernando Aranda. Locoregional modified vaccinia ankara (MVA) encoding a single-chain IL-12 achieves efficacy antitumor immune response in peritoneal carcinomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2736.