bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5089: Small molecule Bax activator enhances immunotherapy against lung cancer
Authors: Anisuzzaman Abu Syed Md , Talukdar Muhammad Waliul , Deng Xingming 
Published: April 2023

Abstract
Induction of apoptosis is a critical mechanism underlying the durable efficacy of cancer treatment agents. Bax is a major proapoptotic protein whose activation is required for apoptotic cell death. We have recently discovered that small molecule Bax activator CYD-2-11 targets the S184 structural pocket in the c-terminal tail of Bax, directly activates its proapoptotic activity via conformational change and formation of Bax homo-oligomers in mitochondrial membranes. CYD-2-11 has potent anti-tumor activity against lung cancer in various animal models. Here we found that CYD-2-11 in combination with radiation, cisplatin or BH3 mimetic Bcl2 inhibitor venetoclax (ABT-199) synergistically suppressed tumor growth in non-small cell lung cancer (NSCLC) xenograft models. It is known that LKB1 mutations or deficiency are associated with therapeutic resistance to PD-1/PD-L1 checkpoint blockade immunotherapy. To test whether Bax activator CYD-2-11 reverses resistance to immunotherapy in immunologically “cold” genetically engineered LSL-KRASG12D LKB1 fl/fl (KL) mouse model, KL mice were treated with CYD-2-11, PD-L1 antibody or in combination. Results indicate that PD-L1 antibody alone has no significant anti-tumor effect in KL mice. CYD-2-11 alone can reduce tumor burden, but combination of CYD-2-11 with PD-L1 antibody has very strong synergistic effect and produces maximum efficacy in tumor burden reduction and significantly prolongs survival of KL mice. Mechanistically, combined treatment with CYD-2-11 and PD-L1 antibody enhances T cell infiltration in tumor tissues. These findings provide preclinical evidence for pharmacologic combinations of small molecule Bax activator with chemoradiotherapy, Bcl-2 inhibitor or PD-L1 antibody as novel strategies to treat lung cancer more effectively.
Citation Format: Abu Syed Md Anisuzzaman, Muhammad Waliul Talukdar, Xingming Deng. Small molecule Bax activator enhances immunotherapy against lung 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 5089.
Abstract 5202: NCG-M humanized mice: an excellent model for human immune reconstitution of myeloid lineages
Authors: Wang Huiyi , Fan Jialu , Guo Shiying , Zhang Mingkun , Li Shuai , Chen Santi Suryani , Li Zhiying , Moore Mark Wade , Zhao Jing , Gao Xiang , Ju Cunxiang 
Published: April 2023

Abstract
Severe immunodeficient mice engrafted with human hematopoietic stem cells (HSC) have been extensively used in immuno-oncology related studies to evaluate the efficacy of cancer therapies. However, because of species differences, murine cytokines provide limited support to human immune cells, thus immunodeficient mice have limited engraftment of human immune cells. Increasing evidence has shown that myeloid cells, especially macrophages and dendritic cells, are critical for the induction of anti-tumor immunity. We developed a mouse model, NCG-M, that can support human T, B, NK and myeloid cells such that in vivo evaluation of agents that require the interplay between these immune cells can be examined. This model was genetically engineered on the severe immunodeficient strain NCG and can produce human granulocyte/macrophage colony stimulating factor 2 (GM-CSF, also known as CSF2), interleukin-3 (IL-3) and stem cell factor (SCF, also known as KITLG). Upon human CD34+ HSC cell engraftment, increased myeloid lineage cells, such as granulocytes, monocytes, neutrophils, macrophages, and dendritic cells, were observed in the NCG-M cohort compared to NCG mice. The NCG-M mouse also supports the development of human T cells, and preliminary data showed increased B and NK cells. The NCG-M is an appropriate mouse model for studying the efficacy of therapeutic agents that require human T cells and myeloid cells.
Citation Format: Huiyi Wang, Jialu Fan, Shiying Guo, Mingkun Zhang, Shuai Li, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju. NCG-M humanized mice: an excellent model for human immune reconstitution of myeloid lineages. [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 5202.
Abstract 5206: A novel mouse model for preclinical efficacy evaluation of anti-CD3/GPRC5D bispecific antibodies
Authors: Yang Xiaoliu , Liang Xinyuan , Zhang Mingkun , Chen Santi Suryani , Li Zhiying , Trujillo Erica , Moore Mark Wade , Zhao Jing , Gao Xiang , Ju Cunxiang 
Published: April 2023

Abstract
The FDA has granted Breakthrough Therapy Designation (BTD) for talquetamab, which targets both GPRC5D on multiple myeloma cells and CD3 on T-cells, for treating adult patients with relapsed or refractory multiple myeloma. Results showed that patients who received talquetamab experienced adverse events, including cytokine release syndrome (CRS), neutropenia, skin-related adverse events and dysgeusia. To allow preclinical in vivo evaluation of anti-human CD3/GPRC5D bispecific antibodies, we developed a BALB/c-hCD3EDG mouse model and a human GPRC5D-expressing A20 murine lymphoma cell line. The BALB/c-hCD3EDG cohort (6-8 weeks old) was subcutaneously inoculated with A20-hGPRC5D cells and then treated with anti-CD3/GPRC5D bispecific antibodies. As expected, anti-CD3/GPRC5D bispecific antibody treatment strongly inhibited the growth of A20-hGPRC5D tumors in BALB/c-hCD3EDG mice.
To allow a comprehensive safety evaluation of anti-CD3/GPRC5D candidates, including the possibility of CRS and target organ toxicity, we engineered BALB/c-hCD3EDG mice that express hGPRC5D, denoted BALB/c-hCD3EDG/hGPRC5D. Human GPRC5D was detected in the liver, lung, thymus, adipose tissue, and thyroid. In vivo evaluation of anti-CD3/GPRC5D therapy in this mice is currently underway.
In conclusion, BALB/c-hCD3EDG/hGPRC5D and BALB/c-hCD3EDG mice bearing A20-hGPRC5D tumors are suitable models for preclinical studies testing anti-CD3/GPRC5D bispecific antibodies.
Citation Format: Xiaoliu Yang, Xinyuan Liang, Mingkun Zhang, Santi Suryani Chen, Zhiying Li, Erica Trujillo, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju. A novel mouse model for preclinical efficacy evaluation of anti-CD3/GPRC5D bispecific antibodies. [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 5206.
Abstract 5223: Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium
Authors: Liu Lili , Wen Wanqing , Long Jirong , Assimes Themistocles L , Bujanda Luis , Gruber Stephen B , Küry Sébastien , Lynch Brigid , Qu Conghui , Thomas Minta , White Emily , Woods Michael O. , Peters Ulrike , Zheng Wei 
Published: April 2023

Abstract
Background Conventional observational studies have reported conflicting results regarding the association between low density lipoprotein cholesterol (LDL-C) and risk of colorectal cancer (CRC). We conducted a Mendelian randomization analysis to address this association.
Methods Single-nucleotide polymorphisms (SNPs) associated with five blood lipids (total cholesterol, HDL-C, high-density lipoprotein cholesterol [HDL-C], non-HDL-C, and triglyceride) were obtained from a genome-wide association study (GWAS) meta-analysis of European ancestry in the Global Lipids Genetics Consortium (GLGC, N ≤ 1 319 982), and two lipids (apolipoprotein A1 and apolipoprotein B) from a GWAS in the UK Biobank (UKB, N ≤ 441 016). Summary statistics were obtained for these SNPs from a GWAS of CRC in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) including 34,869 cases and 29,051 controls. Associations with CRC risk per one standard deviation increase in the genetically predicted lipids level were generated using inverse-variance weighted random-effects models.
Results No overall association was observed between genetically predicted levels of blood lipids and CRC risk. However, increased risks were observed for all LDL-C related traits among women, including total cholesterol (OR = 1.10; 95%CI = 1.02, 1.18), LDL-C (1.07; 1.00, 1.14), non-HDL-C (1.09; 1.02, 1.16), and apolipoprotein B (1.11; 1.02, 1.21); whereas no significant association was found among men. Similar but ostensibly stronger associations of these traits
were seen with distal colon cancer cases, with no significant association showing on proximal colon or rectum cancer cases. We also observed similar positive associations of LDL-C related traits among those having CRC before their 50 years. Of note, risk reduction was found for apolipoprotein A1, a major component of HDL-C, in these early-onset cases (0.87; 0.78, 0.98).
Conclusion Results from this study suggest that high circulating LDL-C levels may increase the risk of CRC, particularly cancer of the distal colon, and the association may differ by sex and age at CRC onset.
Key words: Blood lipids; colorectal cancer; Mendelian randomization.
Citation Format: Lili Liu, Wanqing Wen, Jirong Long, Themistocles L Assimes, Luis Bujanda, Stephen B Gruber, Sébastien Küry, Brigid Lynch, Conghui Qu, Minta Thomas, Emily White, Michael O. Woods, Ulrike Peters, Wei Zheng. Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium. [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 5223.
Abstract 5252: Salsolinol suppresses the STAT3-EMT axis in liver carcinogenesis
Authors: Oh Hyeon Jeong , Park Seah , Yang Hong-Kyung , Ryu Hoon , Surh Young-Joon , Kim Dae-Yong , Na Hye-Kyung 
Published: April 2023

Abstract
Liver cancer is one of the most common malignancies and a leading cause of death worldwide. However, it is still very difficult to treat and prevent liver cancer. Salsolinol (SAL) is an endogenous catechol isoquinoline generated by the condensation of dopamine with acetaldehyde, a major metabolite of ethanol. In the present study, we found that SAL inhibited the phosphorylation, dimerization, and subsequent nuclear translocation of STAT3 in a concentration-dependent manner in SK-Hep1 cells, a hepatic carcinoma cell line. SAL suppressed the expression of Cdk 4 and Cyclin D1, the major target protein of STAT3, and induced the cell cycle arrest at Go/G1 phase. However, SAL induced the expression of STAT1 in SK-Hep1 cells. In addition, SAL enhanced the expression of the cell cycle regulators such as p53 and p21 in SK-Hep1 cells. Epithelial-mesenchymal transition (EMT) promotes tumor invasion and metastasis in malignancies through STAT3 activation. SAL induced the expression of E-cadherin while suppressing the expression of Snail, N-cadherin, and Slug, which are related to EMT. SAL inhibited the migration of SK-Hep1 cells by suppressing the expression of MMP-9 and MMP-2. Furthermore, intraperitoneal injection of SAL reduced the number of tumors in the diethylnitrosamine (DEN)-induced liver carcinogenesis model without affecting the body weight change. Proliferative markers PCNA and KI-67 and p-STAT3 were down-regulated in the SAL-injected mice liver cancer tissue. The plasma level of alpha-fetoprotein, a tumor marker in the blood, was also reduced in the SAL-injected mice. Interestingly, SAL injection significantly reduced the anxiety-like behavior without affecting the locomotive activities in the DEN-induced hepatocellular carcinoma mouse model. Moreover, SAL injection recovered tyrosine hydroxylase, a key enzyme for producing dopamine from tyrosine in the substantia nigra compacta of DEN-treated mice. Together, SAL inhibits STAT3 signaling, thereby suppressing the cell cycle progression and EMT in SK-Hep1 cells, which may account for its anti-depressant and anti-carcinogenic activity in DEN-induced liver carcinogenesis.
Citation Format: Hyeon Jeong Oh, Seah Park, Hong-Kyung Yang, Hoon Ryu, Young-Joon Surh, Dae-Yong Kim, Hye-Kyung Na. Salsolinol suppresses the STAT3-EMT axis in liver carcinogenesis. [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 5252.
Abstract 5313: The expression of phospho-Rb S249, N-cadherin, E-cadherin, and B-catenin as a prostate proteomic score for the risk classification of prostate cancer tumors
Authors: Cortes Sheila M. Valle , Cardona Pedro Santiago , Osterman Carlos Diaz , Morales Jaileene Perez , Maldonado Darielys Maldonado , Deya Gilberto Ruiz 
Published: April 2023

Abstract
Prostate cancer (PCa) ranks as the second leading cause of cancer-related deaths in American men. Most PCa deaths occur due to aggressive, fast-growing tumors that develop into metastasis when cancer cells spread to other body parts, including the lymph nodes, bones, etc. However, men could also be affected by indolent, slow-growing tumors, which may exist for an extended period without causing any symptoms or death. Current prognostic methods, such as Prolaris, or Oncotype, do not precisely specify how aggressive cancer might be, resulting in overtreating patients with indolent PCa. Therefore, improved ways to differentiate indolent from aggressive tumors are needed. In the presented study, we have validated the clinical potential of phospho-Rb S249, N-cadherin, B-catenin, and E-cadherin to discriminate between indolent and aggressive PCa tumors. We hypothesize that the biomarkers phospho-Rb S249, N-cadherin, E-cadherin, and B-catenin expression in PCa will be a clinical tool for the risk classification of PCa tumors when used as part of a prostate proteomic (PPS) that can predict the risk of the tumor of evolving into an aggressive phenotype. We conducted immunohistochemistry staining of these biomarkers on PCa tumor microarrays and correlated it with the patient’s clinical parameters, such as tumor size, lymph node invasion, metastasis, etc. Also, we correlated it with the PSA levels and created a PPS. The combination of our proteomic biomarkers predicts patient staging by 53.83%. Adding clinical data such as the tumor size, lymph node invasion, and metastasis (TNM) increases the precision of the prediction to 83.21%. In addition, the PSA levels increased as the phospho-Rb S249 expression and N-cadherin rise, accompanied by up-regulation of E-cadherin. Also, the PPS showed to distinguish between normal prostate tissue, hyperplasia, and PCa. Results suggest that these biomarkers could serve as a tool for the risk classification of indolent and aggressive PCa tumors.
Citation Format: Sheila M. Valle Cortes, Pedro Santiago Cardona, Carlos Diaz Osterman, Jaileene Perez Morales, Darielys Maldonado Maldonado, Gilberto Ruiz Deya. The expression of phospho-Rb S249, N-cadherin, E-cadherin, and B-catenin as a prostate proteomic score for the risk classification of prostate cancer tumors. [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 5313.
Abstract 5413: AIVE, an artificial intelligence protein miner based on omics data to discover new cancer druggable candidates
Authors: Hong Dongwan 
Published: April 2023

Abstract
Recently, AI software including Alphafold, RoseTTAFold and ESMFold, can predict protein structures based on amino acid sequences, and DeepMind (Alphafold2) and Meta (ESMFold) opened hundreds of millions of protein structures to world-wide clinical researchers. These tools are possible to generate protein structures in a shorter time and less cost than traditional protein study methods. Finally, they can lead to the advent of the protein rush generation. To evaluate accurately and quickly the prediction of structures of mutations embedding in protein sequences, we developed an Artificial Intelligence analytics toolkit for predicting Virus mutation in protEin (AIVE; http://ai-ve.org) that clinical researchers can use easily on web. An amino acid property eigen selection score (APESS) defined in AIVE is a comprehensive mathematical analysis model, andit was calculated basically by below: 1 artificial intelligence base clustering (AIBC) using predicted aligned error (PAE) and per-residue confidence (pLDDT) values, 2 base level change rate (BLCR)using the probability of occurrence of mutation in each amino acid sequence or nucleotide sequence, 3chemical property eigen score (CPES) using amino acid properties (PH, Residue and Hydrophobic),and 4polarity based feature selection (PBFS) using continuous position of polar amino acids including S, C, N, Q, T, and Y [APESS = AIBC ´ BLCR ´ CPES ´ PBFS]. AIVE also calculated the docking score using AlphaFold to estimate protein to protein interaction (PPI) among hosts (or mutations) and provided a graph as final report showing APESS distribution among mutation group, and evaluation of APESS and docking score. For example, according to APESS score in lung cancer, we can find out the feasibility of structure transformation of H-bond in EGFR protein (L858R) tyrosine kinase and also show the differences of tyrosine kinase affinity between each lung cancer patients. However, for the T790M mutation of EGFR protein, there was no significant difference compared with the wild type (790). The execution time of AIVE (GPU based web server platform) depends on the length of the input sequence, and it completes such an example case in an average of 2-3 hours. AIVE can suggest anti-cancer candidates in protein-level and present a precision medicine model which is available to implement close to real time.
Citation Format: Dongwan Hong. AIVE, an artificial intelligence protein miner based on omics data to discover new cancer druggable candidates. [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 5413.
Abstract 5421: Constructing the largest-scale knowledge graph using all PubMed abstracts and its application for highly specific and accurate knowledge retrieval
Authors: Sui Xin , Zhang Yuan , Pan Feng , Sun Donghu , Chung Menghan , Zhang Jinfeng 
Published: April 2023

Abstract
Most of the biomedical knowledge the research community has acquired during the past few decades has been deposited in scientific literature as unstructured text. Converting the unstructured text into the structured form will enable novel methodologies and applications for scientific discovery that can fully harness the power of the existing knowledge. To this end, two fundamental questions need to be addressed: named entity recognition (NER) and relation extraction (RE). NER deals with identifying the concepts or entities in texts, such as diseases, genes/proteins, chemical compounds, etc. while RE aims to extract the relations among these entities. Together, the extracted information forms a knowledge graph (KG) where the nodes are entities in the texts and the edges represent their relationships. KGs can link concepts within existing research to allow researchers to find connections that may have been difficult to discover without them. The LitCoin Natural Language Processing (NLP) Challenge was recently organized by NCATS of NIH and NASA to spur innovation by rewarding the most creative and high-impact uses of biomedical text to create KGs. Our team participated in the challenge and ranked first place. We have applied the methods we developed for the LitCoin NLP challenge to all PubMed abstracts and constructed the largest-scale biomedical KG to date. We show that powerful and versatile query functions can be implemented on top of the KG to enable highly specific and accurate knowledge retrieval and inference of causal and indirect relationships.
Citation Format: Xin Sui, Yuan Zhang, Feng Pan, Donghu Sun, Menghan Chung, Jinfeng Zhang. Constructing the largest-scale knowledge graph using all PubMed abstracts and its application for highly specific and accurate knowledge retrieval. [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 5421.
Abstract 5490: Combination of the PI3k inhibitor Paxalisib with the nucleoside analog Gemcitabine over-activates the integrated stress response and induces atypical teratoid/rhabdoid tumor cell death
Authors: Findlay Tyler , Malebranche Kristen , Geethadevi Anupa , Raabe Eric , Eberhart Charles , Rubens Jeffrey 
Published: April 2023

Abstract
We have previously identified high activation of both mTORC1 and mTORC2 in the aggressive infantile brain tumor, atypical teratoid/rhabdoid tumor (AT/RT). Paxalisib is a highly brain penetrant PI3k inhibitor which acts upstream of mTOR to simultaneously inhibit mTORC1/2. Paxalisib is well-tolerated in ongoing pediatric clinical trials. In murine orthotopic xenograft models of AT/RT, Paxalisib significantly extended survival (CHLA-06: 40 to 54 days, p=0.001; BT12: 21 to 35 days, p=0.02). However, to improve the durability of this single agent therapy, we evaluated the efficacy of rational therapeutic partners. Analysis of RNAseq following mTOR inhibition (mTORi) of 4 cell lines representative of AT/RT showed an upregulation of genes associated with the integrated stress response (ISR), (ATF4: CHLA-06, t-test p&lt;0.05; CHOP: CHLA-02, CHLA-06 t-test p&lt;0.001). The activation of the ISR is further suggested through induction of PPP1R15A, a gene whose activation is closely associated with stress events and leads to downstream cell growth arrest and apoptosis (BT37 t-test p&lt;0.001, CHLA-02, CHLA-06, CHLA-266, t-test p&lt;0.01). Gemcitabine is a pyrimidine nucleoside prodrug, which inhibits DNA synthesis and induces DNA damage. As a result, Gemcitabine also induces phosphorylation of eIF2α and the activation of the ISR. While the ISR can be protective, intense or prolonged activation leads to cell death. We therefore hypothesized that Paxalisib would combine with Gemcitabine to hyper-activate the ISR and drive AT/RT cell death. Through Western blot analysis, we demonstrate that combination therapy increases phospho-eIF2α, ATF4, and CHOP compared to DMSO control. Furthermore, we demonstrate that combination therapy increases apoptosis (Western blot cPARP, MUSE Annexin V Assay) and synergizes to decrease AT/RT cell growth (SynergyFinder BLISS score CHLA-06: 16.8, BT12: 14.3, CHLA-266: 13.9, BT37: 11.4, CHLA-05: 10.4). Ongoing treatment of mice bearing CHLA06 orthotopic tumors demonstrate that combination therapy further extends median survival. Our studies suggest that pharmacologically activating the ISR may be an effective strategy to target AT/RT and combination of Paxalisib and Gemcitabine may be an effective treatment to help extend survival in this deadly disease.
Citation Format: Tyler Findlay, Kristen Malebranche, Anupa Geethadevi, Eric Raabe, Charles Eberhart, Jeffrey Rubens. Combination of the PI3k inhibitor Paxalisib with the nucleoside analog Gemcitabine over-activates the integrated stress response and induces atypical teratoid/rhabdoid tumor cell death. [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 5490.