bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6320: Connecting TET2 deficiency with inflammation in CMML and anti-tumor responses
Authors: Singh Anup Kumar , Onodera Atsushi , Sepulveda Hugo , Angel Carlos , Rao Anjana 
Published: June 2022

Abstract
Chronic Myelomonocytic Leukemia (CMML) is a clonal hematologic disorder of older individuals characterized by monocytosis and increased risk of progression to acute myeloid leukemia (AML). Although CMML is characterized by relatively low genetic complexity consistent with clonal expansion, loss-of-function mutations in ten-eleven translocation 2 (TET2) protein are frequent and reported in almost 60% of CMML cases. Consistent with this finding, deletion of the Tet2 gene in mice leads to CMML-like disease. TET2 restrains inflammatory signals through various means, for instance by directly suppressing the expression of the IL6 gene in mouse myeloid cells by recruiting histone deacetylases. Conversely, the levels of pre-inflammatory cytokines including IL6 correlate with pre-leukemic proliferation of Tet2-deficient mouse monocytes and other myeloid cells, suggesting that Tet2 deficiency increases IL-6 expression and increased IL-6 expression in turn drives the proliferation of Tet2-deficient myeloid-lineage cells in a positive feedback loop. This scenario may operate in CMML patients, who show increased levels of inflammatory cytokines and increased expression of interferon-induced genes compared to age-matched healthy individuals. To gain insight into the connection between inflammation caused by TET deficiency and monocyte hyperproliferation, we set up cultures of bone marrow derived macrophages (BMDMs) from inducible TET deficient mice. Using this model, we found that TET-deficient BMDMs show increased proliferation compared to wild type controls; moreover, LPS stimulation leads to significantly increased expression of IL6 and IL1b in TET-deficient BMDMs. Our previous RNA sequencing of expanded TET-deficient myeloid cells in vivo showed that TET deficiency correlated with increased expression of transposable elements (TEs) and induced a DNA damage response, leading us to hypothesize that TET deficiency and increased TE expression may activate DNA and RNA sensing pathways and induce sterile inflammation. I am currently using several molecular approaches to delineate the potential connection of TET deficiency with endogenous inflammation in CMML. There is growing evidence that TET deficiency or non-specific inhibition of TET enzymes in CD8 T cells can potentiate anti-tumor responses. I am now asking whether the TET deficiency-inflammation axis I observe in BMDMs might also enhance anti-tumor responses by increasing proinflammatory responses and hence T cell recruitment and anti-tumor activity.
Citation Format: Anup Kumar Singh, Atsushi Onodera, Hugo Sepulveda, Carlos Angel, Anjana Rao. Connecting TET2 deficiency with inflammation in CMML and anti-tumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6320.
Abstract 6322: Dynamic, stage-course protein interaction network using high power CpG sites in head and neck squamous cell carcinoma
Authors: Riaz Arsalan , Khan Faisal 
Published: June 2022

Abstract
Head and neck cancer is the most incident and prevalent cancer in men in South Asian countries, especially Pakistan. Prediction of pathological stages of cancer can play a critical role in early diagnosis and personalized medicine. This project ventures into the prediction of different stages of head and neck squamous cell carcinoma (HNSCC) using prioritized DNA methylation patterns. DNA methylation profiles for each HNSCC stage (stage-I-IV) were used to extensively analyze 485,577 methylation CpG sites and prioritize them on the basis of the highest predictive power using a wrapper-based feature selection method, along with different classification models. We identified 68 high-power methylation sites which predicted the pathological stage of HNSCC samples with 90.62% accuracy using a Random Forest classifier. We set out to construct a protein-protein interaction network for the proteins encoded by the 67 genes associated with these sites to study its network topology and also undertook enrichment analysis of nodes in their immediate neighborhood for GO and KEGG Pathway annotations revealing their role in cancer-related pathways, cell differentiation, signal transduction, metabolic and biosynthetic processes. With information on the predictive power of each of the 67 genes in each HNSCC stage, we unveil a dynamic stage-course network for HNSCC that evolves over the course of the four cancer stages. We intend to further study these genes in light of functional datasets from CRISPR, RNAi, drug screens for their putative role in HNSCC initiation and/or progression.
Citation Format: Arsalan Riaz, Faisal Khan. Dynamic, stage-course protein interaction network using high power CpG sites in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6322.
Abstract 6323: Differential analysis of HPV16-human and EBV1-human protein interaction networks to identify new protein candidates in head and neck squamous cell carcinomas
Authors: Riaz Arsalan , Ilyas Yusra , Khan Faisal 
Published: June 2022

Abstract
Oro-pharyngeal squamous cell carcinoma (OPSCC) cases are rising worldwide specifically among young individuals with risk factors including smoking and alcohol. HPV infection specifically the subtype HPV16 is a significant risk factor in the initiation and progression of OPSCC, more prevalent in the western part of the world. This study carries out a computational analysis using protein interactions between HPV16 proteins and protein products of key OPSCC and Oral Squamous Cell Carcinoma (OSCC) cancer genes, which aims to investigate the influence of HPV16 on OPSCC and OSCC in terms of protein-protein interactions (PPIs).We created a protein interaction network of HPV16 and human proteins followed by retrieval of mutated genes in OPSCC and OSCC from online databases including COSMIC, cBioPortal and the GDC Portal, along with literature mining. We used MCODE and ClueGo tools for cluster and enrichment analysis, respectively. Drug candidates against the common interacted proteins were found using drug databases like PanDrugs and CLUE Repurposing. After annotating the HPV16-Human PPI network with proteins encoded by genes found to be mutated in both cancers, 31 proteins in OPSCC and 17 proteins in OSCC were in direct interaction with the viral proteins especially, E5, E6, and E7. The immediate network (of first neighbors only) appeared to be sparse, but after looking at the broader HPV16-Human network we found 5 highly connected modules, 4 of which were dominated by proteins encoded by genes mutated in OPSCC as compared to OSCC, indicating the influence of HPV16 on OPSCC. Based on module integrity and topological characteristics we identified 4 significant candidates for HPV16-driven OPSCC i.e. MYC, CREBBP, PML, and RB1 which are significantly enriched in cancer pathways. In the South Asian countries, Epstein Bar Virus type 1 (EBV-1) is a more prevalent risk factor for virus-driven Head and Neck Squamous Cell Carcinoma (HNSCC) as compared to HPV-16, however, knowledge regarding the EBV induced OPSCC and OSCC is scarce. We created a protein interaction network for EBV1 and Human proteins to analyze the topological characteristics especially of proteins encoded by genes mutated in HNSCC using the same methodology and we identified 5 candidate proteins i.e. EP300, CUL3, RB1, DDB1, and CREBBP for further in vitro validation.
Citation Format: Arsalan Riaz, Yusra Ilyas, Faisal Khan. Differential analysis of HPV16-human and EBV1-human protein interaction networks to identify new protein candidates in head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6323.
Abstract 6325: Identification of genes responsible for osteosarcomas metastatic evolution by active super enhancers profiling
Authors: Lavaud Mélanie , Tesfaye Robel , Charrier Céline , Thépault Rose Anne , Golias Maxime , Page Sarah Le , Mullard Mathilde , Brounais Bénédicte , Verrecchia Franck , Baud'huin Marc , Lamoureux François , Georges Steven , Ory Benjamin 
Published: June 2022

Abstract
Super enhancers are strong spatiotemporal transcriptional regulators. They can be mapped on genomes thanks to their astounding enrichment for well-known enhancers markers, such as acetylation of the lysine 27 of type 3 histones (H3K27Ac). Their target genes, confined in their so-called topologically associated domains, present exceptionally high expression levels, depending on associated super enhancers activation status, and are responsible for defining cells identity whether physiological or pathological. Osteosarcomas are the most common primary malignant bone tumors. Patients suffering from osteosarcomas, on average 15 years old, mostly develop pulmonary metastasis, responsible for drastic decrease in their survival. We have conducted chromatin immunoprecipitation sequencing against H3K27Ac and RNA sequencing experiments on osteosarcoma cells presenting high propensity to metastatic dissemination or devoid of this capacity, in order to unveil genes implicated in metastasis development through super enhancers genomic mapping. We have highlighted exclusive active super enhancers profiles between metastatic and non-metastatic osteosarcoma cells. Among target genes of spotted super enhancers, three of them caught our attention. Implication of these genes in metastatic development have already been demonstrated in various cancers evolution, except in osteosarcomas. Osteosarcoma cells having high capacity for metastatic development present identified genes over expressions compared to cells incompetent in this pathological process. Artificial down expressions of identified genes decrease osteosarcoma cells metastatic capacity in vitro. In vivo experiments, that correspond to paratibial implantation of modified osteosarcoma cells and analysis of primary tumor metastatic development, are currently under way. Our strategy may allow identification of new therapeutic targets to fight against osteosarcoma metastatic evolution and open new perspectives to improve patients prognostic.
This work is funded by Ligue contre le cancer, ANR, SFCE and Région Pays de la Loire.
Citation Format: Mélanie Lavaud, Robel Tesfaye, Céline Charrier, Rose Anne Thépault, Maxime Golias, Sarah Le Page, Mathilde Mullard, Bénédicte Brounais, Franck Verrecchia, Marc Baud'huin, François Lamoureux, Steven Georges, Benjamin Ory. Identification of genes responsible for osteosarcomas metastatic evolution by active super enhancers profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6325.
Abstract 6368: Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors
Authors: Sasmal Sanjita , Patra Sukanya , Boorgu Venkatesham , Yanamadra Mahesh , Ettam Ashok , Dunaboyina Nagaraju , Kummari Githavani , Yengala Ram Mohan , Lakhavath Balakrishna , Das Jayita , Sunkanapally Satheesh , Reddy Pravalika , Mathew Megha Mariam 
Published: June 2022

Abstract
KRAS is an oncogene implicated in a wide variety of tumors (~21% of solid tumors harbor KRAS mutations). KRAS interaction with Guanidine Exchange Factors (GEFs) is crucial for its activation, with SOS1 being the predominant GEF. SOS1 inhibition is thus expected to be an effective strategy for targeting the downstream signaling pathway, resulting in anti-proliferative activity in RAS-driven cancers. We have identified multiple potent and selective SOS1 inhibitors, demonstrating significant reduction of GEF activity in a dose-dependent manner. The lead compounds show anti-proliferative activity across a panel of WT and mutant KRAS cell lines, and are synergistic with MAPK pathway inhibitors including KRASG12C inhibitor Sotorasib. Correspondingly, significant reduction in PD biomarkers, pERK and pAKT is demonstrated in KRAS mutant cell lines. PK-PD correlation is also established in a tumor bearing mice model, with dose-dependent reduction of both pERK and pAKT. The lead compound shows good ADME properties, and is orally bioavailable, making it amenable for further in vivo profiling.
Citation Format: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Mahesh Yanamadra, Ashok Ettam, Nagaraju Dunaboyina, Githavani Kummari, Ram Mohan Yengala, Balakrishna Lakhavath, Jayita Das, Satheesh Sunkanapally, Pravalika Reddy, Megha Mariam Mathew. Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6368.
Abstract 6369: Discovery of potent, orally bioavailable, brain penetrant RAD51 inhibitor as an anti-cancer agent
Authors: Sasmal Sanjita , Patra Sukanya , Boorgu Venkatesham , Chithaluri Shankar , Yanamadra Mahesh , Hiremath Deepika , Pathange Hemashankar , Girme Sandeep M. , Pawar Amitkumar , Shinde Rutuja Narayan , Samanta Nilanjan 
Published: June 2022

Abstract
Proliferating cells undergo DNA damage, and this is more pronounced in cancer cells due to their high rate of proliferation. Cancer cells are thus more dependent on the DNA damage repair pathway for their survival. Double-strand breaks (DSBs) are amongst the most severe type of DNA damage and are predominantly repaired by homologous recombination (HR) in an error-free manner. RAD51 is a pivotal recombinase for DSB repair by the HR pathway. Binding of RAD51 with BRCA2 followed by its nuclear translocation, is one of the key repair mechanisms for RAD51 mediated DSB repair. We have identified novel and potent RAD51 inhibitors disrupting the RAD51:BRCA2 interaction, which can address BRCA2 WT patient population. Upon induction of exogenous DNA damage, our compounds inhibit nuclear RAD51 foci formation and demonstrate sustained γH2AX accumulation in the nucleus, suggesting persistent DNA damage. Our orally bioavailable & brain penetrant lead compound shows anti-proliferative activity in multiple BRCA2 WT cancer cell lines across various indications, and excellent synergy when combined with PARP1 inhibitors such as Olaparib. Further, in a wound healing assay, treatment with our lead compound inhibits cell migration in a dose-dependent manner. TNBC patients with extensive brain metastasis have limited treatment options. Thus, a brain penetrant RAD51 inhibitor could provide a novel treatment option in this setting.
Citation Format: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Shankar Chithaluri, Mahesh Yanamadra, Deepika Hiremath, Hemashankar Pathange, Sandeep M. Girme, Amitkumar Pawar, Rutuja Narayan Shinde, Nilanjan Samanta. Discovery of potent, orally bioavailable, brain penetrant RAD51 inhibitor as an anti-cancer agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6369.
Abstract 6372: Nanodrug delivery system for non-genotoxic p53 activator INZ-C
Authors: Bhattarai Nimisha , Wang Jieqiong , Nguyen Daniel , Yang Xiaoxiao , Helmers Linh , Paruch Jennifer , Li Li , Zhang Yiwei , Meng Kun , Wang Alun , Jayawickramarajah Janarthanan , Wang Binghe , Zeng Shelya , Lu Hua 
Published: June 2022

Abstract
p53 is a known tumor suppressor protein whose gene is altered in 50% of all human cancers, while its function is inactivated in the many cancers harboring wild type p53, making it an attractive target for targeted cancer therapies. In this regard, our lab had previously discovered a small molecule, Inauhzin (INZ C), as a potent non-genotoxic p53 activator. In an effort to improve the bioavailability and efficacy, we have now encapsulated the INZ C small molecule in a chitosan/cyclodextrin nanoparticle delivery system. Evaluation of in vitro/in vivo activity and protien expression suggests nanoparticle encapsulation of INZ-C (n-INZ-C) improved p53 induction and inhibition of cell growth in lung and colorectal cancers, while maintaining a minimal effect for MEF and Wi38 normal cells. These results are consistent with the significantly reduced cellular uptake observed for normal cells as compared to the cancer cells. H/E staining of tissues for mice treated with n-INZ-C reveals no toxicity to other organs as well. Additionally, n-INZ-C demonstrates the ability to block migration of cells in vitro as demonstrated by both wound healing and trans-well migration assays. Our in vivo pharmacokinetic evaluation suggests nanoparticle encapsulation doubles the half-life of INZ-C from 2.5 to 5 h. These results suggest that nanoparticle encapsulation improved activity and bioavailability of INZ-C while maintaining the non-toxic nature of INZ-C in normal cells. In addition, we unveiled GRP78 as a potential new target of INZ-C and found out that knockdown of GRP78 can alleviate the inhibitory effect of INZ-C on lung and colorectal cancer proliferation. Further studies now focus on revealing the mechanism of enhanced cellular uptake for INZ-C in cancer cells as comapred to normal cells. Thus, these results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic and also identified a novel target of INZ-C.
Citation Format: Nimisha Bhattarai, Jieqiong Wang, Daniel Nguyen, Xiaoxiao Yang, Linh Helmers, Jennifer Paruch, Li Li, Yiwei Zhang, Kun Meng, Alun Wang, Janarthanan Jayawickramarajah, Binghe Wang, Shelya Zeng, Hua Lu. Nanodrug delivery system for non-genotoxic p53 activator INZ-C [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6372.
Abstract 6397: Understanding the glioblastoma microenvironment with spatial resolution in PDX models
Authors: Abdelkareem Aly O. , Osz Katalin , Senger Donna , Chan Jennifer A. , Morrissy Sorana 
Published: June 2022

Abstract
Glioblastoma multiforme (GBM) is the most common adult brain tumour, and despite aggressive treatment, it recurs fatally. GBM tumours include diverse populations of malignant and non-neoplastic cells with distinct molecular capabilities and with differential levels of sensitivity to treatment. Understanding the cell dynamics that occur during the development of GBM resistance to therapy could reveal key aspects of this process, including how resistance is acquired in time and how the diverse cell types of the tumour microenvironment (TME) contribute to this phenotype. In addition to the role of the TME, GBM exhibits significant tumour heterogeneity with diverse genetic clones coexisting in the same tumor, as well as cells with similar genetic backgrounds capable of adopting distinct transcriptional states and subtypes. The complex and dynamic interactions between tumor and TME remain to be fully studied. This work focuses on the in vivo spatial organization in GBM during disease progression. We generated spatial transcriptomic data from a set of adult GBM samples grown as patient-derived xenograft (PDX) models, profiled at different time points of the disease. Three PDX lines from one GBM patient (derived from tumor core, vascularized area, and infiltrating front) were used to recapitulate the genetic and phenotypic heterogeneity observed in the human disease. Two replicates from each of 8 PDX mice were collected from early, mid, and late time points of tumour growth and data was generated using the 10X Genomics Visium platform. We developed a robust computational pipeline capable of distinguishing admixture of human (tumour) and mouse cells (TME), using state-of-the-art tools. Human and mouse cell types and states were identified using pooled and separate single-cell references of human GBM states, and mouse brain cells from both normal and tumour conditions. With this approach we observe spatially distinct patterns of both (a) tumour infiltration patterns specific to the each PDX line that includes non-random distribution of GBM transcriptional states and genetic clones, and (b) spatially distinct infiltration of TME components including microglial and macrophage populations. Overall, our approach addresses the challenge of understanding the tumor-TME relationship by application of spatial profiling in PDX models, and provides a computational pipeline complex multi-species analysis in the spatial transcriptomic field.
Citation Format: Aly O. Abdelkareem, Katalin Osz, Donna Senger, Jennifer A. Chan, Sorana Morrissy. Understanding the glioblastoma microenvironment with spatial resolution in PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6397.
Abstract 6399: SP in relation to NK1R and Ki67 predicts survival in hormone receptor negative breast cancer
Authors: Al-Keilani Maha S. , Elstaty Rana , Alqudah Mohammad A. 
Published: June 2022

Abstract
Background: Substance P (SP) is a tachykinin that has been implicated in carcinogenesis in several types of cancer through binding to neurokinin 1 receptor (NK1R). This study aimed to investigate the expression levels of SP and NK1R in hormone receptor negative (HR -ve) versus positive (HR +ve) breast cancer tissues and their relationship with clinicopathological characteristics of patients, Ki-67 index, and overall survival rate.
Methods: Immunohistochemical expression levels of SP, NK1R and Ki-67 were measured in 144 paraffin-embedded breast cancer tissues (77 HR -ve and 67 HR +ve). SP and NK1R were scored semiquantitatively, while Ki-67 was obtained by the percentage of total number of tumor cells with nuclear staining. The optimal cutoff value for SP, NK1R and Ki-67 were assessed by Cutoff Finder. Pearson Chi-square (χ2) and Fisher’s exact tests were used to compare the staining scores between groups. ANOVA and student’s t-test were used to compare group means. Kaplan-Meier method with log-rank test was used for survival analysis.
Results: High expression of SP, NK1R and Ki-67 was observed in 41%, 36.8% and 38.9% of cases, respectively. Association analyses revealed that SP expression in HR -ve breast cancer was higher in pN3 tumors (p=0.002), positive axillary lymph node metastasis (p=0.003), and high NK1R expression (p=0.010). In HR+ve breast cancer, SP was lower in HER2 positive tumors (p=0.001). Regarding NK1R, the association analysis showed that low NK1R expression level in HR +ve tumors was related to stage IV (p=0.023), pN1 (p=0.006), and low Ki-67 index (p=0.038). Survival analysis revealed that high SP level negatively impacted overall survival in HR-ve tumors that had low NK1R level (p=0.021). Moreover, high SP negatively impacted overall survival in HR-ve tumors that had low Ki-67 level (p=0.005). Nevertheless, NK1R expression did not impact survival in HR-ve or HR+ve cases despite stratification by SP and Ki-67 expression (p&gt;0.05).
Conclusion: Up to our knowledge, this is the first study to investigate the prognostic potential of SP and NK1R in breast cancer. Combined expression levels of SP and NK1R or Ki-67 could be used to predict survival in breast cancer patients with HR-ve tumors. Our findings suggest the potential role of SP and NK1R as therapeutic targets in breast cancer.
Citation Format: Maha S. Al-Keilani, Rana Elstaty, Mohammad A. Alqudah. SP in relation to NK1R and Ki67 predicts survival in hormone receptor negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6399.