bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5194: BALB/c mice with humanized VISTA: A novel GEMM for preclinical evaluation of therapeutic antibodies against VISTA
Authors: Yu Weiwei , Bao Honghong , Li Shuai , Ju Chao , Sun Hongyan , Qi Hao , Ju Cunxiang , Zhao Jing , Gao Xiang 
Published: June 2022

Abstract
VISTA, also known as PD1H, is an immune-checkpoint receptor mainly expressed in immune cells, including macrophages, conventional dendritic cells, monocytes and circulating neutrophils. As a negative regulator of T cell activation, VISTA inhibits T cell proliferation and attenuates the production of cytokines. Studies have shown that VISTA expression is increased in infiltrating immune cells found in the tumor microenvironment and that blocking pathways that lead to VISTA activation can enhance antitumor immune responses in mice. Based on this, antibodies targeting VISTA are promising leads for cancer therapy. Preclinical efficacy evaluation of antibodies again human VISTA requires the expression of human VISTA in animal models, since difference in extracellular domains may affect antibody recognition while the overall homology between the two proteins is only 77%.
To meet this need, we established a humanized mouse model in which the extracellular domain of mVISTA is replaced with that of hVISTA while the trans-membrane and cytoplasmic domains remain intact. In order to confirm the activity of the chimeric protein in our mice, we evaluated the anti-tumor effect of proven VISTA antibodies in homozygous hVISTA mice engrafted with CT26 tumor subcutaneously. Consistent with previous studies, the growth of CT26 tumor was inhibited after VISTA antibody treatment, indicating the humanized VISTA mice are suitable for efficacy evaluation of human VISTA antibodies.
Moreover, we evaluated the anti-tumor effect of a combination of PD-L1 antibody and VISTA antibody in these mice. Interestingly, the combined use of PD-L1 antibody and VISTA antibody led to significantly enhanced tumor regression than either antibody. Taken together, BALB/c-hVISTA mouse is a novel non-human animal model appropriate for preclinical efficacy study of human VISTA antibodies.
Citation Format: Weiwei Yu, Honghong Bao, Shuai Li, Chao Ju, Hongyan Sun, Hao Qi, Cunxiang Ju, Jing Zhao, Xiang Gao. BALB/c mice with humanized VISTA: A novel GEMM for preclinical evaluation of therapeutic antibodies against VISTA [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 5194.
Abstract 5241: p38 MAPK/EGR1/PD-L1 axis promotes radiation resistance of nasopharyngeal carcinoma by enhancing immune evasion
Authors: Meng Dong-Fang 
Published: June 2022

Abstract
Radiation resistance is the main reason for treatment failure. Till present, the underlying molecular mechanism of NPC radiation resistance remains poorly understood. Recent clinical trials have demonstrated that PD-1/PD-L1 inhibitors have achieved better efficacy in the treatment of recurrent or metastatic NPC. Further studies are needed to better understand the molecular mechanisms underlying PD-1/PD-L1 inhibitors enhance response to radiation in NPC. We performed RNA-seq analysis in NPC radioresistant and wild-type cells. We identified EGR1 promotes NPC radiation resistance and is significantly correlated with NPC recurrence. We further found that EGR1 upregulated PD-L1 expression at transcriptional level in a p38 MAPK dependent manner. Moreover, EGR1 participated in CD8+T cell mediated immune evasion in NPC radioresistant cells. We therefore propose a hypothesis that p38 MAPK/EGR1 axis induced PD-L1 expression promotes radiation resistance of NPC by enhancing immune evasion. This study aims to identify the key regulatory factors in p38 MAPK/EGR1/PD-L1 axis, especially PD-L1, as a new target to improve radiosensitivity of NPC, provide theoretical basis for PD-1/PD-L1 inhibitors plus radiotherapy in the treatment of NPC. Meanwhile, this study also provides the possibility for predicting the radiosensitivity of NPC.
Citation Format: Dong-Fang Meng. p38 MAPK/EGR1/PD-L1 axis promotes radiation resistance of nasopharyngeal carcinoma by enhancing immune evasion [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 5241.
Abstract 5252: In colorectal cancer (CRC), neuroendocrine carcinoma (NEC) is contaminated in the cancer given a confirmed diagnosis of poorly differentiated adenocarcinoma (P-ad-ca)
Authors: Rong Yuhan , Takeda Yuma , Okubo Naoki , Suzuki Akihiro , Tokuhisa Motohiko , Kobayashi Noritoshi , Ishibe Atsushi , Kato Ikuma , Yamanaka Shoji , Fujii Satoshi , Endo Itaru , Ichikawa Yasushi 
Published: June 2022

Abstract
Background: Most of CRC were well or moderately differentiated adenocarcinoma and P-ad-ca is very rare. In Japan, P-ad-ca was reported to be only 4-6% of all CRC. NEC is also rare. The incidence of that were reported to be less than 1%. One of their points of common is morphological poorly differentiated appearance. In this study, we evaluated the incidence of NEC contaminated in the CRC given a confirmed diagnosis as P-ad-ca.
Material and Method: From 2009 to 2019, 816 CRCs were resected in department of Yokohama City University Hospital and 74 cases showing P-ad-ca or having a small region of P-ad-ca with well or moderately differentiated ad-ca (W-ad-ca, M-ad-ca). Among the 74 cases, there were 8 of P-ad-ca, 4 of W-ad-ca with P-ad-ca, 44 of M-ad-ca with P-ad-ca, and 18 W-ad-ca and M-ad-ca with P-ad-ca. Immunohistochemistry (IHC) using neuroendocrine markers (NM) including chromogranin A, synaptophysin and insulinoma-associated protein 1 (INSM1) was performed to identified NEC. Recently, a high incidence of Rb protein loss was reported in NEC of several organs, then IHC using Rb monoclonal antibody was also performed. The cancers showing immunohistochemically positive of at least one of the three NM and negative of Rb were identified as true NEC in this study.
Results: At least one of the three NM was positive in the 39 cases. In these 39 cases, 3 cases were also Rb negative. Two of the three cases were region of P-ad-ca. These 2 P-ad-ca regions showed positive of NM. Interestingly, in the other one case, region of W-ad-ca showed positive of NM and negative of Rb. Region of P-ad-ca of the case showed positive of all three NM and Rb. From morphological appearance, this case was quite unlikely to true NEC.
Conclusion: In 74 P-ad-ca, 2 cases might be true NEC in our small evaluation. NEC might be contaminated in the P-ad-ca of CRC which is difficult to be distinguished by only pathological findings of HE staining.
Citation Format: Yuhan Rong, Yuma Takeda, Naoki Okubo, Akihiro Suzuki, Motohiko Tokuhisa, Noritoshi Kobayashi, Atsushi Ishibe, Ikuma Kato, Shoji Yamanaka, Satoshi Fujii, Itaru Endo, Yasushi Ichikawa. In colorectal cancer (CRC), neuroendocrine carcinoma (NEC) is contaminated in the cancer given a confirmed diagnosis of poorly differentiated adenocarcinoma (P-ad-ca) [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 5252.
Abstract 5332: Prostate cancer targeting therapy using PSA promoter-driven perforin expression vector encapsulated in liposomes conjugated with anti-PSMA antibody
Authors: Mizutani Kosuke , Kawakami Kyojiro , Fujita Yasunori , Kato Taku , Takai Manabu , Kato Daiki , Iinuma Koji , Koie Takuya , Ito Masafumi 
Published: June 2022

Abstract
Perforin secreted from cytotoxic T cells and natural killer cells play important roles in anti-tumor immunoreaction leading to cancer cell apoptosis. The aim of this study is to investigate whether perforin-rich tumor microenvironment could inhibit tumor growth. Advanced prostate cancer (PC) expresses high amount of prostate-specific antigen (PSA) that is a possible therapeutic target, therefore, we constructed a PSA promoter-driven perforin expression vector for its predominant expression in tumor microenvironment of PC. Prostate membrane-specific antigen (PSMA) expressed on PC cell surface is also an attractive therapeutic target. To deliver perforin expression vector to PC, it was encapsulated in liposomes conjugated with anti-PSMA antibody (PSMA-pLipo), then the anti-tumor effect of PSMA-pLipo was evaluated using docetaxel-resistant PC cell line, 22Rv1DR, expressing both PSA and PSMA. The conjugated anti-PSMA antibody on PSMA-pLipo recognized recombinant PSMA protein, and incubation with PSMA-pLipo induced perforin expression in 22Rv1DR cells but not in PC-3 cells not expressing both PSA and PSMA. Growth of 22Rv1DR and PC-3 cells was barely inhibited by PSMA-pLipo alone. Perforin functions in concert with cytotoxic lymphocytes, therefore anti-tumor effect of PSMA-pLipo was analyzed in the presence of human peripheral blood mononuclear cells (PBMCs). Low concentration of PSMA-pLipo with human PBMCs significantly inhibited growth of 22Rv1DR cells but not PC-3 cells. High concentration of PSMA-pLipo with human PBMCs showed nearly complete inhibition of 22Rv1DR cell growth. In a mouse xenograft model implanted with 22Rv1DR cells, PSMA-pLipo was intravenously administrated via tale vein and tumor volume was monitored. PSMA-pLipo inhibited growth of 22Rv1DR cells compared to injection of anti-PSMA antibody alone. The data presented here suggest that gene therapy expressing perforin specifically in PC cells could be a novel therapy for advanced PC.
Citation Format: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Taku Kato, Manabu Takai, Daiki Kato, Koji Iinuma, Takuya Koie, Masafumi Ito. Prostate cancer targeting therapy using PSA promoter-driven perforin expression vector encapsulated in liposomes conjugated with anti-PSMA antibody [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 5332.
Abstract 5367: DNA-PKcs inhibitors impair OCT4-mediated MYC transcriptional activation in small cell lung cancer
Authors: Yang Inhyoung , Mohiuddin Ismail , Wei Sung-Jen , Gloria Martinez , Kang Min H. 
Published: June 2022

Abstract
Small cell lung cancer (SCLC) is a disease found almost exclusively in smokers and is a highly aggressive cancer with incredibly poor outcomes. Initially, most patients diagnosed with SCLC respond to platinum + etoposide (PE)-based therapy, but relapse occurs in nearly all patients and is fatal. SCLC is a cancer with a heavy mutational burden, and loss-of-function mutations of the tumor suppressor genes RB1 and TP53 are nearly ubiquitous in SCLC tumors. Amplification and overexpression of the MYC of oncogene occurs in a subset of SCLC tumors that are associated with tumor progression, treatment resistance, and poor outcomes, therefore we pursued the inhibition of the MYC activation. The purpose of this study is to inhibit a novel pathway of MYC transcriptional activation via DNA-PKcs-mediated phosphorylation of OCT4 at its Ser93 residue in SCLC, a MYC transcriptional activation pathway that we discovered. We identified OCT4 being a transcription factor that primarily induce MYC activation. Subsequently, Serine 93 residue of OCT4, a new OCT-4 binding site, was phosphorylated by DNA-PKcs that was a critical step for OCT4-induced MYC activation. In a panel of 19 small cell lung cancer, DNA-PKcs, phosphorylation of OCT4 at Ser93, and c-MYC were positively correlated. We confirmed the binding of DNA-PKcs to OCT4 and identified novel OCT4-binding sites in the MYC promoter/enhancer region that regulated MYC expression via phosphorylation by DNA-PKcs, and DNA-PKcs or OCT4 knockdown decreased c-MYC expression. DNA-PKcs inhibitors also reduced phosphorylation of OCT4 at Ser93 leading to decreases in c-MYC and showed cytotoxic effects via inducing apoptosis by DNA-PKcs inhibitors. DNA-PKcs inhibitors augments antitumor activity of Bcl-2 inhibitors cell lines and xenograft models of small cell lung cancer. In conclusion, report here that DNA-PKcs-mediated phosphorylation of OCT4 at Ser93 is a novel mechanism for activating the MYC oncogene in SCLC, and that DNA-PKcs is a viable target to decrease c-MYC expression in these highly aggressive tumors.
Citation Format: Inhyoung Yang, Ismail Mohiuddin, Sung-Jen Wei, Martinez Gloria, Min H. Kang. DNA-PKcs inhibitors impair OCT4-mediated MYC transcriptional activation in small cell lung 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 5367.
Abstract 5392: Magnolol induces apoptosis and inhibits invasion ability via suppression of STAT3 signaling in glioblastoma multiforme cells
Authors: Lee Sin-Rong , Chang Yuan , Chiang I-Tsang , Hsu Fei-Ting 
Published: June 2022

Abstract
Magnolol is a phenolic compound extracted from magnolia officinalis, exhibited anti-tumor potential against many types of cancers. Magnolol has also recognized as an anti-inflammation agent which can downregulate several inflammation signals transduction. Glioblastoma multiforme (GBM) is the most common central nervous system (CNS) tumor and associated with poor prognosis among adults due to rapid growth and aggressive invasion. However, the treatment efficacy of current standard therapy for GBM is remaining unsatisfied. Nevertheless, whether magnolol may suppress GBM progression and its underlying mechanism has not been elucidated. Thus, the purpose of this study was to investigate the mechanism and therapeutic efficacy of magnolol on GBM.First of all, we validated the potential treatment targets of GBM with the GEPIA (Gene Expression Profiling Interactive Analysis) analysis and Western blotting assay. GEPIA data indicated the PKCδ/STAT3 signaling pathway as a potential target of GBM that may affect patient survival. In our results, magnolol can effectively suppress the phosphorylation and the nuclear translocation of STAT3 in GBM cells. Then, we used the MTT assay to investigate the cytotoxicity of GBM cells after various dose of magnolol treatment. We also detected the extrinsic/intrinsic apoptosis induction ability of magnolol on GBM cells. This study also demonstrated that magnolol may significantly trigger the loss of mitochondrial membrane potential, and the activation of cleaved caspase-3, -8 and -9. Transwell invasion and wound healing assays was used to identify the suppression of migration and invasion effects of magnolol on glioblastoma cells. Meanwhile, tumor invasion and migration ability and the associated genes, including MMP9 and uPA, were all diminished by magnolol treatment. In sum, our results demonstrated that magnolol suppressed GBM progression may be associated with the inactivation of PKCδ/STAT3 signaling transduction.
Citation Format: Sin-Rong Lee, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Magnolol induces apoptosis and inhibits invasion ability via suppression of STAT3 signaling in glioblastoma multiforme cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5392.
Abstract 5402: Urothelial carcinomas in different anatomical positions exhibit distinct genomic and immunological characteristics
Authors: Li Ruiqian , Zhang Hushan , Wang Qilin , Yang Hong , Bai Yu , Hu Chen , Wu Hongyi , Zhang Chongjian , Wang Ziyong , Wang Qiwei , Xu Pengjie , Li Jun 
Published: June 2022

Abstract
Background Human bladder cancers were recently suggested to be grouped into different molecular subtypes. However, little is known about the difference in gene landscape between upper tract urothelial carcinoma (UTUC) and lower tract urothelial carcinoma (LTUC) of Chinese patients. Herein, we analyzed the genomic characteristics of primary UTUC and LTUC in China.
Methods The formalin-fixed paraffin-embedded specimens of 250 LTUC and 121 UTUC patients have been consecutively collected and have underwent next-generation sequencing (NGS) from 2018 to 2021 in 3DMed Clinical Laboratory Inc. Gene mutation and TMB level were analyzed by NGS, detected PD-L1 expression by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1.
Results NGS analysis showed that, in the samples of UTUC, the top ten gene mutations were CDKN2A/2B 6.6% (8/121), TP53 5.8% (7/121), FGF19 5.8% (7/121), TERT 3.3% (4/121), PREX2 3.3% (4/121), FRS2 3.3% (4/121), KDM6A 2.5% (3/121), PIK3CA 2.5% (3/121), EGFR 2.5% (3/121), MYCL 2.5% (3/121); while in the LTUC, the top gene mutations were TP53 44.4% (111/250), TERT 31.6% (79/250), CDKN2A/2B 25.7% (64/250), FGF3 18% (45/250), KDM6A 17.6% (44/250), PIK3CA 16.4% (41/250), RB1 14.0%(35/250), DGFR3 13.6% (34/250), ARID1A 12.4% (31/250). Furthermore, TMB level and PD-L1 expression in the UTUC and LTUC were also analyzed, and results showed that although the gene mutation was totally different, but no significant difference was found on TMB level (p&gt;0.05). However, among these patients, higher PD-L1 expression level were found in UTUC than LTUC (p&lt;0.05).
Conclusion UTUC and LTUC in Chinese patients hold different gene landscape and PD-L1 expression, this suggested these patients may have different prognosis and response differently to targetable therapy and immunotherapy.
Citation Format: Ruiqian Li, Hushan Zhang, Qilin Wang, Hong Yang, Yu Bai, Chen Hu, Hongyi Wu, Chongjian Zhang, Ziyong Wang, Qiwei Wang, Pengjie Xu, Jun Li. Urothelial carcinomas in different anatomical positions exhibit distinct genomic and immunological characteristics [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 5402.
Abstract 5405: Expression of cathepsin D in early-stage breast cancer and its prognostic and predictive value
Authors: Alhudiri Inas M. , Nolan Christopher C. , Ellis Ian O. , Rakha Emad A. , Elzagheid Adam , Green Andrew R. , Chapman Caroline J. 
Published: June 2022

Abstract
Purpose: Cathepsin D is a proteolytic enzyme that is normally localized in the lysosomes and is involved in the malignant progression of breast cancer. The expression of Cathepsin D is regulated by steroid hormones including oestrogen and growth factors. There are conflicting results between different studies regarding Cathepsin D significance as prognostic and predictor marker in breast cancer. Furthermore, Cathepsin D has not been recommended for clinical use by the American Society of Clinical Oncology because of insufficient evidence. This study was aimed to fill the gap in the lack of recent and large studies on prognostic significance of Cathepsin D expression by studying a large well-characterized series of primary breast cancer for cathepsin D expression using immunohistochemistry.
Methods: Expression of Cathepsin D was assessed by immunohistochemical staining of tissue microarrays, in a large well-characterized series of early-stage operable breast cancer (n=954) from Nottingham Primary Breast Carcinoma Series between the period of 1988 and 1998 who underwent primary surgery. Correlation of cathepsin D expression with clinicopathological parameters and prognosis was evaluated.
Results: Cathepsin D expression was positive in 28.8% (275/954) of breast cancer tumors. Positive expression of cathepsin D was significantly associated with high histological grade (p=0.007), pleomorphism (p=0.002), poor Nottingham Prognostic Index score (NPI) (p&lt;0.002), recurrence (p=0.005) and distant metastasis (p&lt;0.0001). Kaplan-Meier analysis showed that Cathepsin D expression was significantly associated with shorter breast cancer specific survival (BCSS) (p=0.001), higher risk of recurrence (p=0.001) and distant metastasis (p&lt;0.0001). Cathepsin D positive tumors with ER positive staining who were treated with tamoxifen were associated with lower BCSS and higher risk of developing distant metastasis (p=0.001).
Conclusion: This study shows Cathepsin D expression as a promising prognostic biomarker for early operable invasive breast cancer. Our results indicate that Cathepsin D expressing tumors are associated with shorter breast cancer specific survival and higher risk of recurrence and metastasis. Cathepsin D could be clinically useful to predict response to tamoxifen treatment. Targeting Cathepsin D either through inhibition of action or interference with the proteolytic pathway could be used to treat metastatic breast cancers expressing Cathepsin D.
Citation Format: Inas M. Alhudiri, Christopher C. Nolan, Ian O. Ellis, Emad A. Rakha, Adam Elzagheid, Andrew R. Green, Caroline J. Chapman. Expression of cathepsin D in early-stage breast cancer and its prognostic and predictive value [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 5405.
Abstract 5425: Quantitative determination of fibroblast growth factor receptor inhibitor-AZD4547 using HPLC analysis in a mouse model of ultraviolet B (UVB)-induced skin carcinogenesis
Authors: Kandula Rema Anisha , Babin Katherine Claire , Latimer Brian , Martin Kenneth Mc , Linquest Lauren , Moore-Medlin Tara , Thakur Megha A. , Khandelwal Alok R. , DiGiovanni John , Nathan Cherie-Ann O. 
Published: June 2022

Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer affecting more than two million Americans annually. Cumulative sun exposure plays a leading role in the pathogenesis of cSCC. In our previous studies, topical application of Fibroblast growth factor receptor (FGFR) inhibitor AZD4547 was associated with a significant reduction in Ultraviolet B-induced (UVB)-induced acute skin changes such as epidermal hyperplasia and hyperproliferation. Further, chronic, topical application of AZD4547 was associated with significant inhibition in UVB-induced tumor incidence and multiplicity. Unfortunately, oral administration of FGFR inhibitors in clinical trials for solid tumors is associated with notable side effects such as hyperphosphatemia, diarrhea, decreased appetite, fatigue, and liver dysfunction. Therefore, our objective was to investigate whether topical administration of AZD4547 could potentially circumvent systemic absorption, leading to a low toxicity profile. Accordingly, mice were topically administered AZD4547 (400ug/200ul acetone) followed by exposure to UVB three times a week for two weeks. Blood was collected at the end of the study. AZD4547 was extracted using methanol extraction and concentrated using a Savant SpeedVac system. Samples were reconstituted in 25% acetone/75% water solution and analyzed using Reverse-phase HPLC (Shimadzu) with a Zorbax Eclipse C18 3.5-µm 4.6x100mm analytical column operated at ambient temperature and gradient elution using trifluoroacetic acid (TFA) (Mobile A) and 0.1% TFA in Acetonitrile. Data from HPLC analysis demonstrated non-appreciable absorption of AZD4547 (blood levels only from 108-358nM) suggesting that the topical application of AZD4547 was not systemically absorbed and the effect of treatment was restricted to the local skin tissue. Based on the efficacy and low systemic absorption profile, AZD4547 could potentially be utilized as a topical agent to both prevent and treat UVB-induced cSCC.
Citation Format: Rema Anisha Kandula, Katherine Claire Babin, Brian Latimer, Kenneth Mc Martin, Lauren Linquest, Tara Moore-Medlin, Megha A. Thakur, Alok R. Khandelwal, John DiGiovanni, Cherie-Ann O. Nathan. Quantitative determination of fibroblast growth factor receptor inhibitor-AZD4547 using HPLC analysis in a mouse model of ultraviolet B (UVB)-induced skin carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5425.