bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5505: ADAM10-targeting CAR-T cells inhibit colon cancer cell growth in vivo
Authors: Rad Elaheh Rohani , Foeng Jade , McPeak Dylan , Tyllis Timona , Abbott Caitlin , bandara Veronika , Napoli Silvana , gundsambuu Batjargal , Barry Simon , Sadlon Timothy , McColl shaun 
Published: June 2022

Abstract
Chimeric antigen receptor (CAR) T cell therapy has demonstrated a high degree of efficacy in patients with hematological malignancies such as acute lymphatic leukemia. However, its efficacy in solid tumors remains to be demonstrated. There are a number of issues currently limiting therapeutic treatment of solid tumors with CAR-T cells, none more important than target antigen selection. This is a major challenge in solid tumors due to their heterogenous characteristics and the potential for off-cancer effects. ADAM10, A Disintegrin And Metalloproteinase 10, plays critical roles in a wide range of pathophysiological processes during development and inflammation. These proteolytically active multifunctional proteins act as sheddases by cleaving transmembrane-bound proteins such as growth factors, adhesion molecules and chemokine receptors, which can then contribute to migration and invasion of cancer cells. An active form of ADAM10 that has undergone a conformational change has been identified in several cancer types, particularly colorectal cancer. In this study, a novel CAR was generated based on a previously characterized cancer-specific ADAM10 antibody. ADAM-10-targeting CAR-T cells were manufactured using T cells from the peripheral blood of the healthy donors. The CAR-T cells displayed the naïve and central memory phenotype that has been shown to differentiate and proliferate within tumor microenvironments, with little expression of exhaustion markers. These CAR-T cells were capable of killing several human colorectal tumor cell lines in vitro, assessed in a bioluminescence-based cytotoxicity assay. Furthermore, treatment of NSG mice bearing human LoVo colon cancer cell tumors with ADAM-10-targeting CAR-T cells led to significant inhibition of tumor growth compared with either untransduced control T cells or PBS treatment. Overall, these data suggest that targeting ADAM-10 via CAR-T cell therapy is a promising novel avenue of treatment of colorectal cancer.
Citation Format: Elaheh Rohani Rad, Jade Foeng, Dylan McPeak, Timona Tyllis, Caitlin Abbott, Veronika bandara, Silvana Napoli, Batjargal gundsambuu, Simon Barry, Timothy Sadlon, shaun McColl. ADAM10-targeting CAR-T cells inhibit colon cancer cell growth in vivo [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 5505.
Abstract 590: Humanized PD-1/LAG-3 mice for preclinical evaluation of combination therapy
Authors: Duan Feifei , Yang Xiaoliu , Ju Cunxiang , Zhao Jing , Gao Xiang , Chen Santi Suryani 
Published: June 2022

Abstract
Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily which shares homolog with CD4 and binds to MHC II with higher affinity. It is expressed on activated T cells, regulatory T cells (Tregs), natural killer cells and plasmacytoid dendritic cells, and inhibits their activation. Blocking LAG-3 activity is expected to provide therapeutic benefits in the treatment of cancer, especially when combined with PD-1 blockade. Due to the low homology between human and mouse LAG-3 and PD-1 and in order to enable increased translatability of preclinical in-vivo efficacy evaluation of immune checkpoint antibodies, we generated double humanized mice by replacing the extracellular domain of mouse LAG-3 and PD-1 with the corresponding human sequences.
Homozygous double humanized mice express chimeric LAG-3 and PD-1 at comparable levels to mouse LAG-3 and PD-1 respectively in wildtype mice. When treated with human LAG-3 antibody (anti-LAG-3) or human PD-1 antibody (anti-PD-1), CT26 tumor growth was inhibited in a dose-dependent manner, proving that both humanized proteins are functional. However, not all tumor types respond to anti-LAG-3 or anti-PD-1 the same. To identify the suitable tumor models for preclinical efficacy evaluation of anti-LAG-3 and anti-PD-1 combo therapy, we engrafted several syngeneic tumor models onto our mice. The growth of subcutaneously engrafted MC38 colon tumor was mildly inhibited by anti-PD-1, but strongly inhibited in the presence of anti-LAG-3. Similarly, B16F10 melanoma tumor showed modest growth inhibition when treated with anti-PD-1 or anti-LAG-3 separately, while combination therapy significantly repressed tumor growth. However, neither monotherapies of anti-LAG-3 and anti-PD-1 nor combination treatment effectively inhibited tumorigenesis of LLC1 derived lung cancer, indicating that this tumor is likely insensitive to PD-1 and LAG-3 blockade. Collectively, these data indicate that double humanized PD-1 and LAG-3 mice are a powerful tool to evaluate the therapeutic efficacies of anti-hPD-1 and anti-hLAG-3 treatment in different types of tumor in vivo.
Citation Format: Feifei Duan, Xiaoliu Yang, Cunxiang Ju, Jing Zhao, Xiang Gao, Santi Suryani Chen. Humanized PD-1/LAG-3 mice for preclinical evaluation of combination therapy [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 590.
Abstract 5911: Soybean products consumption decreases risk for gastric cancer: Results from the Health Examinees study
Authors: Shin Woo-Kyoung , Lee Hwi-Won , Huang Dan , De la Torre Katherine , Min Sukhong , Shin Aesun , Lee Jong-koo , Lee Jung Eun , Kang Daehee 
Published: June 2022

Abstract
Background: Twenty percent of soy production is consumed directly by humans worldwide. However, epidemiological findings on the association between soybean products consumption and gastric cancer risk remain inconsistent. We evaluated the relationship between soybean products consumption and the risk of gastric cancer in a prospective cohort study in Korea.
Methods: This prospective cohort study included a total of 139,267 participants (men 46,953 and women 92,314) aged 40-69 years from the Health Examinees-Gem (HEXA-G) study between 2004 and 2013. Information on cancer diagnosis was retrieved from the Korea Central Cancer Registry until 31 December 2018. Multivariate hazard ratios (HRs) and 95% of confidence intervals (CIs) for the risk of gastric cancer according to the consumption of soybean products were estimated using Cox proportional hazards models with age as the time scale.
Results: A total of 884 incident cases of gastric cancer (men 480 and women 404) occurred over an average follow-up period of 9.20 years (men 9.18 years and women 9.21 years). We found that soybean products consumption is associated with the lower risk of gastric cancer among Koreans (the multivariate HRs for tofu consumption of more than two servings/week were 0.93 (95% CI: 0.68, 1.26; NS) among women and 0.63 (95% CI: 0.45, 0.89) among men). Among men with a body mass index of less than 25kg/m2, increased consumption of soybean paste (p for trend = 0.0188) and tofu (more than two servings/week vs. almost never consumed; HR 0.51 (0.32, 0.82) p for trend = 0.0095) was associated with decreased risk for gastric cancer.
Conclusion : Our results suggest that a high consumption of soybean products has a protective effect against gastric cancer
Citation Format: Woo-Kyoung Shin, Hwi-Won Lee, Dan Huang, Katherine De la Torre, Sukhong Min, Aesun Shin, Jong-koo Lee, Jung Eun Lee, Daehee Kang. Soybean products consumption decreases risk for gastric cancer: Results from the Health Examinees study [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 5911.
Abstract 6070: Functional natural killer cells derived from engineered hiPSC with hypoimmunity gene combo demonstrate hypoimmunity features in evading host attacks
Authors: Hu Jiabiao , He Xiangjun , Xu Jing , Zhou Yixuan , Yue Yanan , Gao Yangbin , Church George , Yang Luhan 
Published: June 2022

Abstract
Engineered human induced pluripotent stem cells (hiPSC)-derived allogeneic Natural Killer (NK) cells are emerging as promising safe and effective off-the-shelf cell therapy drugs. Repeated dosing of NK cells can partly compensate the relatively shorter persistence of NK cells compared with chimeric antigen receptor T cells (CAR-T); However, with each repeat, the persistence and efficacy are increasingly challenged by activation of host innate and adaptive immunity. Thus, reducing immunogenicity of allogeneic NK cells holds promise for better efficacy. In this study, we report a combination of “hypoimmunity” gene edits including multiple transgene knock-ins and both class I and class II MHC knockouts (2KO). We show that hiPSC engineered by the hypoimmunity combo can be efficiently differentiated into NK cells, comparable to the non-engineered ones. This is contrary to the notion from mouse studies that NK cells devoid of class I molecules are hypo-responsive, these engineered NK cells can be expanded by aAPC (artifitial Antigen Presenting Cells, a K562 cell line with surface expression of mbIL-21 and CD137L) and are capable of killing tumor cells, Additionally, we show that the engineered NK cells can evade T cell immunity, as examined by in vitro T cell proliferation and cytotoxicity assays. A humanized mouse model with transplanted CD34-positive human hematopoietic stem cells confirmed that the engineered NK cells can persist longer than WT and 2KO NK cells. Hypoimmune-QN-019 NK cells are generated by incorporating hypoimmunity gene combo edits into our hiPSC-derived NK cell clinical candidate QN-019 which has 3 transgenes including membrane-bound IL-15, high affinity non-cleavable CD16 and CAR targeting CD19. Comparing to QN-019, hypoimmune-QN-019 displayed better efficacy in humanized CDX mouse model in clearing CD19-positive cancer cells. Taken together, we have engineered hiPSC-derived allogeneic NK cells with hypoimmunity features, which hold great promise in becoming an off-the-shelf drug with improved in vivo persistence and efficacy for repeated dosing.
Citation Format: Jiabiao Hu, Xiangjun He, Jing Xu, Yixuan Zhou, Yanan Yue, Yangbin Gao, George Church, Luhan Yang. Functional natural killer cells derived from engineered hiPSC with hypoimmunity gene combo demonstrate hypoimmunity features in evading host attacks [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 6070.
Abstract 6077: Mammalian adipose has many tumor features, which suggests the possible way of its evolutionary origin
Authors: Kozlov Andrei P. 
Published: June 2022

Abstract
Adipose expansion during obesity has remarkable similarities with the growth of solid tumors. These similarities are the following: the capability to unlimited expansion; reversible plasticity; induction of angiogenesis; chronic inflammation; remodeling and disfunction; systemic influence on the organism; hormone production; production of miRNAs that influence other tissues; immunosuppression; DNA damage and resistance to apoptosis; infiltration in other organs and tissues. The existing similarities between adipose and tumors suggest the possible evolutionary origin of mammalian adipose from some ancestral benign mesenchymal hereditary tumors.
Transgenic inducible zebrafish tumor model was used to verify the above hypothesis.
We described several genes, which originated in fish and were expressed in fish tumors. Their human orthologs LEP, SPRY1, PPARG, ID2, and CIDEA acquired functions connected with human adipose. They are also involved in tumor development in humans.
If the hypothesis of the evolutionary origin of mammalian adipose from the ancestral benign hereditary tumors is correct, it may open new opportunities to resolve the oncological problem and the problem of the obesity epidemic. New interventions targeting LEP, SPRY1, PPARG, ID2, and CIDEA gene network, in addition to what already is going on, can be designed for treatment and prevention of both obesity and tumors.
Citation Format: Andrei P. Kozlov. Mammalian adipose has many tumor features, which suggests the possible way of its evolutionary origin [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 6077.
Abstract 6230: Loss of ALK4 function promotes cancer progression by regulating cell surface TGF-β receptor stability
Authors: Zhang Manqi , Chen Jian , Blobe Gerard Conrad 
Published: June 2022

Abstract
Pancreatic cancer is a lethal disease. More than 50% of pancreatic cancer patients are diagnosed with metastatic disease with a dismal 3% five-year survival rate. There is clearly an urgent need to identify novel targets to treat pancreatic cancer patients. Transforming growth factor-β (TGF-β) signaling is dysregulated during cancer progression, inhibiting tumorigenesis while promoting metastasis. Approximately half of pancreatic cancer patients have mutations of genes in the TGF-β signaling pathway, including SMAD4, SMAD3, TGFBR1, TFGBR2, ACVR1B, and ACVR2A. ALK4 (Activin receptor-like kinase 4), which is encoded by ACVR1B, is a type I receptor in the TGF-β superfamily. Mutation or copy number loss of ALK4 occurs in 34% of pancreatic cancer patients, while ALK4 expression is significantly down-regulated in many cancers, including pancreatic cancer, with low ALK4 expression associated with poor clinical outcomes. Here we demonstrate that loss of ALK4 increases cell migration and invasion, induces epithelial to mesenchymal transition (EMT), and promotes local and distal metastasis in pancreatic cancer models. Loss of ALK4 unexpectedly increases activation of the canonical TGF-β signaling pathway and significantly induces TGF-β-mediated expression of EMT mediators and effectors. Moreover, ALK4 loss increases the cell surface expression of TβRs (TGFβ receptor type I and II), without changing the receptor gene expression, by increasing N-linked glycosylation of TβRs, potentially by altering Golgi morphology and function. Proteomic analysis of newly synthesized proteins induced by ALK4 loss identified galectin-3 (Gal-3) as upregulated. Gal-3 is known to be upregulated by MGAT5 (Alpha-1,6-Mannosylglycoprotein 6-Beta-N-Acetylglucosaminyltransferase) and cross-links MGAT5-modified N-glycans on TβRs at the cell surface, suppressing TβRs endocytosis. Consistent with this observation, loss of ALK4 increased MGAT5 mRNA expression and induced Gal-3 protein expression, suggesting that ALK4 might regulate TβRs stability by promoting lattice formation with Gal-3 and preventing internalization. Taken together, our results suggest that the loss of ALK4 increases TβR receptor stability through regulating receptor glycosylation, activating TGF-β signaling, promoting the EMT transition and cancer progression.
Citation Format: Manqi Zhang, Jian Chen, Gerard Conrad Blobe. Loss of ALK4 function promotes cancer progression by regulating cell surface TGF-β receptor stability [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 6230.
Abstract 6247: Evaluation of AS-10, identified based on SAR studies of newly generated organoselenium compounds, as a potential colorectal cancer therapeutic acting potentially by acetylating histones
Authors: Johnson Hannah , Singh Amandeep , Raza Asif , Karelia Deepkamal , Plano Daniel , Amin Shantu , Sharma Arun 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the third most common form of cancer diagnosed in the United States. Standard treatment for CRC utilizes a combination therapy composed of 5-fluorouracil, oxaliplatin, and folinic acid, known as FOLFOX. It has been established that patients with CRC tend to develop drug resistance to FOLFOX leading to a need for new chemotherapeutic treatments. Recent work has established that AS-10, a small molecule established for its promising role in treating pancreatic cancer, to be capable of inhibiting the growth of a range of CRC cell lines, including FOLFOX resistant CRC cells. Twenty-four cyclic and open chain analogs of AS-10 were synthesized and evaluated for their activity in inhibiting the viability of different cancer cells in vitro. The cell viability of these compounds was compared to AS-10 in the cell lines of pancreatic carcinoma (MiaPaCa2), lung carcinoma (H460), colorectal adenocarcinoma (HT29), colorectal carcinoma (HCT116), and FOLFOX resistant HT29 and HCT116 cells. Based on the IC50 values observed from these initial studies, only ASA-7, an open-chain alkyl selenocyanate, could treat all cancer cell lines in a similar concentration range of AS-10. Dose-response curves completed in 6 CRC cell lines indicated IC50 values in the range of 1-2 µM for AS-10 and 3.3-6.6µM for ASA-7. Cell viability evaluation in normal kidney (HEK293T) and colon (FHC) cell lines indicated AS-10 to be less toxic as compared to ASA-7. A similar trend was observed in vivo - AS-10 was 4 times more tolerable in mice as compared to ASA-7. A HCT116 xenograft study demonstrated the ability of AS-10 to significantly inhibit tumor growth in vivo without any apparent systemic toxicity. Moreover, AS-10 was assessed for its ability to act as an acetyl donor for histone acetyltransferase (HAT) and was found to initiate HAT activity in the absence of Acetyl-CoA in pancreatic epithelioid carcinoma (Panc-1) and colorectal carcinoma (HCT116) cells. In conclusion, AS-10 was identified as the best among the 24 analogs, in vitro and in vivo, when treating CRC and found to be capable of inducing HAT activity in both pancreatic and colorectal carcinoma elucidating a possible mechanism of action.
Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Deepkamal Karelia, Daniel Plano, Shantu Amin, Arun Sharma. Evaluation of AS-10, identified based on SAR studies of newly generated organoselenium compounds, as a potential colorectal cancer therapeutic acting potentially by acetylating histones [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 6247.
Abstract 6263: A pilot study to survey the exposure to secondhand smoke at home and at the workplace in Pakistan
Authors: Rehmat Shagufta , Khan Faisal F. 
Published: June 2022

Abstract
Globally over 7 million deaths are attributed to direct tobacco consumption whereas about 1.2 million people die due to the exposure to secondhand smoke (SHS). The health complications and mortalities caused by SHS exposure in Pakistan are also very prominent as it causes more than 33 thousand annual deaths. In this pilot study, we wanted to evaluate the exposure to secondhand smoke at work and at home, and its association with the prevalence of diseases through a survey based cross-sectional study. An online questionnaire was designed and developed using Google Forms and a short link was distributed using social media channels (i.e., WhatsApp groups and Facebook). Respondents were young adults from all cities of Pakistan who had access to internet and were digitally literate. Exposure to secondhand smoke at home, during childhood (from 0-18 year of age), adulthood exposure (after 18 years of age), and exposure at work was evaluated. The data was analyzed using Microsoft Excel and R.A total of 438 respondents participated in this survey with representation of male (54%) and female (46%) belonging to major cities in Pakistan, including Peshawar (38%), Islamabad (10.4%), Lahore (7.2%), and Karachi (6%). Overall, 75% of the study cohort were exposed to SHS, with the highest exposure noticed during adulthood with 70.3% of people being exposed to SHS after 18 years of age. Amongst those who were exposed daily at home, 63% had chronic bronchitis while 60% had cardiac diseases as self-reported health issues. Those exposed to SHS during childhood for 2 or more than 2 hours per week, 80% had self-reported chronic bronchitis in the survey. During adulthood, universities dominated as a location that offered highest exposure to SHS for 2 or more than 2 hours/week. One-year exposure history at workplace revealed that of those who were exposed to SHS at work ‘several times a day’, 60% had high blood pressure, 55% had asthma, while 50% had chronic bronchitis. At home ‘the father’ was identified as the main source of secondhand smoke and during adulthood universities are identified as place of highest exposure. At workplaces although the percentage of people exposed to secondhand smoke is lesser than those reported in previous studies but the correlation with medical complications was revealing. Overall throat irritation, gastric issues, and eye irritations were highly reported medical conditions amongst exposed individuals.
Citation Format: Shagufta Rehmat, Faisal F. Khan. A pilot study to survey the exposure to secondhand smoke at home and at the workplace in Pakistan [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 6263.
Abstract 733: Adolescent dietary patterns in relation to later prostate cancer risk and mortality in the NIH-AARP diet and health study
Authors: Lan Tuo , Park Yikyung , Colditz Graham A. , Liu Jingxia , Wang Molin , Wu Kana , Giovannucci Edward , Sutcliffe Siobhan 
Published: June 2022

Abstract
Background: Although adolescent diet has been proposed to contribute to prostate cancer (PCa) development, no studies have investigated the relation between adolescent dietary patterns and PCa risk or mortality.
Method: Using data from the NIH-AARP Diet and Health Study, we performed factor analysis to identify dietary patterns at ages 12-13 years. We further used Cox proportional hazards regression to examine hazard ratios (HRs) and 95% confidence intervals (CIs) of total, non-advanced, advanced, and fatal PCa.
Results: During 1,878,681 person-years of follow-up, 17,861 men were diagnosed with PCa, including 15,499 non-advanced, 2,362 advanced, and 832 fatal cancers. Three adolescent dietary patterns were identified: a Western modern pattern characterized by greater intake of sweets, processed meat, beef, cheese, and pizza; a plant-based pattern characterized by greater intake of vegetables, fruits, and dark bread; and a Western traditional pattern characterized by greater intake of gravy, bacon, and chicken, eggs, potatoes, green beans, legumes, and white bread. Although not entirely consistent across analyses, a higher adolescent plant-based pattern score was associated with reduced risks of total PCa (fully-adjusted HRQ5vs.Q1=0.93, 95% CI: 0.89-0.98, p-trend=0.003) and non-advanced PCa (HR=0.91, 95% CI: 0.87-0.96, p-trend&lt;0.001), whereas no associations were observed for Western modern or Western traditional patterns.
Conclusions: In the first study, to our knowledge, to investigate adolescent dietary patterns and PCa risk, we found some evidence to support a protective role for a plant-based diet during adolescence on PCa risk. Our findings may inform the development of new, primary prevention strategies for PCa.
Citation Format: Tuo Lan, Yikyung Park, Graham A. Colditz, Jingxia Liu, Molin Wang, Kana Wu, Edward Giovannucci, Siobhan Sutcliffe. Adolescent dietary patterns in relation to later prostate cancer risk and mortality in the NIH-AARP diet and health study [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 733.