bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB009: Dynamic changes in the compositions of cancer associated-fibroblasts correlate with clinical outcome in breast cancer
Authors: Friedman Gil , Levi-Galibov Oshrat , David Eyal , Bornstein Chamutal , Giladi Amir , Dadiani Maya , Mayo Avi , Halperin Coral , Pevsner-Fischer Meirav , Lavon Hagar , Mayer Shimrit , Nevo Reinat , Stein Yaniv , Balint-Lahat Nora , Barshack Iris , Ali H. Raza , Caldas Carlos , Gal-Yam Einav Nili , Alon Uri , Amit Ido , Scherz-Shouval Ruth 
Published: July 2021

Abstract
Cancer associated fibroblasts (CAFs) are prevalent in carcinomas. CAFs are also heterogeneous and perform various tumor-promoting tasks. Understanding whether distinct CAF-subsets exert specific functions, and how the composition of CAFs changes as tumors evolve could improve the accuracy of cancer treatment. Here, we analyzed thousands of CAFs by single-cell RNA-sequencing and index-sorting at several timepoints along breast tumor progression in mice, revealing distinct CAF-subsets. We discovered that the transcriptional programs of these subsets change over time, shifting from an immune-regulatory program at earlier timepoints to wound-healing and antigen-presenting programs at later timepoints, indicating that the composition and functions of CAFs are dynamic. We also found the two main CAF subsets in human breast tumors, wherein their ratio was associated with disease outcome. This association was particularly correlated with BRCA mutations in triple-negative breast cancer. Our findings indicate that the diverse composition of CAFs in breast cancer changes over time as tumors progress, and that these changes are linked to disease outcome.
Citation Format: Gil Friedman, Oshrat Levi-Galibov, Eyal David, Chamutal Bornstein, Amir Giladi, Maya Dadiani, Avi Mayo, Coral Halperin, Meirav Pevsner-Fischer, Hagar Lavon, Shimrit Mayer, Reinat Nevo, Yaniv Stein, Nora Balint-Lahat, Iris Barshack, H. Raza Ali, Carlos Caldas, Einav Nili Gal-Yam, Uri Alon, Ido Amit, Ruth Scherz-Shouval. Dynamic changes in the compositions of cancer associated-fibroblasts correlate with clinical outcome in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB009.
Abstract LB018: Cloud-based biological domain knowledge derived gene expression classifier to predict the cancer clinical outcome
Authors: Papineni Rao V. , Gupta Seema , Natarajan Aravindan , Papineni Ram , Kasinathan Chandra 
Published: July 2021

Abstract
We report the advances of a cloud-based software utilizing advanced algorithms to identify the molecular cancer drivers and its signal transduction. To test, a classifier based on the NFκB signaling pathway gene expression profiles that predicts the clinical therapeutic response to chemo-radiation therapy of Squamous Cell Carcinomas of the Head and Neck (SCCHN) patients are described here. Expression of HPV16, p16 and 84 NFκB signaling pathway genes were determined using real time RT PCR in SCCHN patient samples and SCCHN cell lines. Gene expression was correlated to chemo-radiation response in cell lines and the model was blindly tested in SCCHN patients to predict their clinical outcome to chemo-radiation. This tool intends to fuse biological domain knowledge by way of integrating disease targets, cell line experiments towards creating a gene expression classifier for clinical outcome. The gene expression-based predicted clinical outcome compared with patients actual observed clinical outcome correctly identified the clinical response in 73% of the cases. Such work will allow design of tailored individualized clinical treatment strategies to target NFκB inhibition using biological modifying agents with or without chemo/radiation therapy. This will help to develop several targets to directly inhibit the NFκB activity or inhibit the downstream pivotal targets. The significance of the classifier would be the ability to use the biologic attributes of a tumor to tailor specific treatment protocols for each individual patient. This would not only spare the chemo-radiation resistant patients the ill effects of the therapy but will also decrease the delay in effective treatment among the resistant patients. The long-term objective is to use such pro-survival driver genes in other cancers; SMAD, TGFβ in pancreatic cancer, and AR in prostate cancer. This tool (MeghaOncomine) intends to fuse biological domain knowledge by way of integrating cancer targets, cell line experiments towards creating a gene expression classifier for clinical outcome.
Citation Format: Rao V. Papineni, Seema Gupta, Aravindan Natarajan, Ram Papineni, Chandra Kasinathan. Cloud-based biological domain knowledge derived gene expression classifier to predict the cancer clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB018.
Abstract LB057: Whole exome sequencing of tumor tissue and circulating tumor DNA ingastrointestinal stromal tumors (GIST)
Authors: Coleman Niamh , Abbot Charles , Somaiah Neeta , Piha-Paul Sarina , Pant Shubham , Rodon Jordi , Call S. Greg , Boyle Sean , Meric-Bernstam Funda , Janku Filip 
Published: July 2021

Abstract
Background: The discovery of oncogenic mutations as potential targets for cancer therapy has revolutionized the treatment of GIST and other cancers. However, adaptive resistance ultimately develops in nearly all patients, which emphasizes the need for a more detailed understanding of the underlying molecular profile. Methods: Using the Personalis ImmunoID NeXT Platform® (Personalis, Inc.; Menlo Park, CA), an augmented exome/transcriptome platform and analysis pipeline, we performed whole exome sequencing (WES) and whole transcriptome total RNA sequencing (RNA-Seq) of paired baseline tumor and normal tissue. NeXT Liquid Biopsy™ (Personalis, Inc.) was used for WES of plasma-derived ctDNA from serially collected samples collected at baseline, after 1 month and at progression to experimental systemic therapies in 15 patients with advanced/metastatic GIST. Results: WES of tumor tissue samples from all 15 patients confirmed underlying KIT mutation in all patients. There was large heterogeneity of other molecular alterations, which included therapeutically relevant molecular alterations, such as microsatellite instability-high (MSI-high) in 1 sample. RNA-Seq of tumor tissue revealed recurrent overexpression of GALR2, NY-ESO-1 and other genes involved in cancer progression, angiogenesis and anticancer immunity. Patients with response to systemic therapies demonstrated lower levels of cytolytic activity measured by CYT score in tumor tissue compared to patients without response (P=0.04). KIT mutations were detected in serially collected ctDNA samples from 12 (80%) of 15 patients. Quantity of KIT and other mutant ctDNA dynamically tracked the clonal evolution and clinical course during systemic therapy. Conclusions: Comprehensive genomic profiling (WES and RNA-Seq) of tumor tissue and WES of serially collected ctDNA is feasible and detects underlying druggable KIT mutations and other molecular alterations.
Citation Format: Niamh Coleman, Charles Abbot, Neeta Somaiah, Sarina Piha-Paul, Shubham Pant, Jordi Rodon, S. Greg Call, Sean Boyle, Funda Meric-Bernstam, Filip Janku. Whole exome sequencing of tumor tissue and circulating tumor DNA ingastrointestinal stromal tumors (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB057.
Abstract LB066: Assessing the safety liability of t-cell bispecific (TCB) antibodies using Ogans-on-Chips technology
Authors: Kerns S. Jordan , Kujala Ville , Kanellias Marianne , Sauld John , Tien-Street William , Grant Heather S. , Karalis Katia A. , Hamilton Geraldine A. , Ewart Lorna , Roth Adrian B. , Moisan Annie , Gjorevski Nikolche 
Published: July 2021

Abstract
T-cell bispecific antibodies (TCBs) are a promising class of immunotherapeutic agents that promote tumor cell killing by physical crosslinking of effector T-cells to target expressing cells.
While TCBs are effective in targeting less-immunogenic tumors, they are subject to safety liabilities in normal tissues, which may express low levels of the target. Preclinical assessment of safety risks is crucial but species differences between human and rodent immune responses necessitate the development of advanced human cell-based models for TCB safety profiling. While conventional killing assays are experimentally tractable, they lack physiological organization and cytoarchitecture and often fail to accurately predict efficacy and off-tumor cytotoxicity. Here, we show the robustness of our Intestine-Chip to capture variability in immune cell activation at physiologically relevant TCB concentrations when immune cells are directly applied to the apical epithelium. With increased confidence in the predictive capabilities of the model, we then confirmed expected regional dependence to gastrointestinal (GI) toxicity of the TCB by showing elevated immune cell activation in the large- versus small-intestine. Further, we have demonstrated vascular recruitment and transmigration of circulating immune cells to the intestinal epithelium to more accurately capture the in vivo mechanisms of TCB-mediated toxicity. Together, these data show that our models are suitable for safety profiling of novel engineered immunotherapies and provide clinically relevant results.
Citation Format: S. Jordan Kerns, Ville Kujala, Marianne Kanellias, John Sauld, William Tien-Street, Heather S. Grant, Katia A. Karalis, Geraldine A. Hamilton, Lorna Ewart, Adrian B. Roth, Annie Moisan, Nikolche Gjorevski. Assessing the safety liability of t-cell bispecific (TCB) antibodies using Ogans-on-Chips technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB066.
Abstract LB071: Tuning the tumor myeloid microenvironment (TME) by targeting TREM2+ tumor-associated macrophages to overcome resistance to immune checkpoint inhibitors
Authors: Jahchan Nadine S. , Binnewies Mikhail , Pollack Joshua L. , Mehta Ranna , Dash Subhadra , Tun Christine , Lu Erick , Du Xiaoyan , Baker Kevin P. , Reyno Len , Sriram Venkataraman 
Published: July 2021

Abstract
The tumor microenvironment (TME) often contains high levels of suppressive myeloid cells that may contribute to innate checkpoint inhibitor (CPI) resistance. Pionyr's Myeloid Tuning approach involves altering the composition and/or the function of myeloid cells in the TME. To this end, therapeutic targeting of tumor-associated macrophages (TAMs) is a promising strategy to increase CPI response rates in solid tumor indications, as well as to overcome resistance to CPI therapies. Pionyr and others identified the transmembrane protein triggering receptor expressed on myeloid cells-2 (TREM2) as a highly enriched TAMs target. Furthermore, TREM2 mRNA expression negatively correlates with patient survival in a variety of tumor types, supporting the involvement of TAMs in tumor progression. Pionyr developed a lead anti-TREM2 monoclonal antibody (mAb), termed PY314, as well as a murinized version of PY314, termed PY314m. PY314m demonstrated significant anti-tumor activity either as single agent in CPI-sensitive syngeneic tumor models or in combination with anti-PD-1 in CPI-resistant syngeneic tumor models. Mechanistically, PY314m reduced the pro-tumorigenic MHC class II-low, M2-like TAMs, induced pro-inflammatory cytokine production, significant increased CD8+ T cell infiltration into the TME. These findings suggest that PY314 therapy could be used to overcome CPI resistance in humans. To select patients most likely to benefit from PY314 therapy, Pionyr developed a qualitative IHC assay that detects TREM2 expression levels in formalin-fixed, paraffin-embedded human tumor tissues. Screening for TREM2 expression in tumor tissues demonstrated that TREM2+ TAMs were present in multiple solid tumor indications and their number increased with disease grade in a selected set of indications. Ongoing efforts are aimed at better understanding localization of TREM2+ TAMs within the TME, and spatial relationship of the TREM2+ TAMs to other immune cells present in the TME. The TREM2 IHC assay will be used to test our hypothesis that patients with tumors with high level of TREM2+ TAMs are most likely to benefit from PY314 treatment.
Citation Format: Nadine S. Jahchan, Mikhail Binnewies, Joshua L. Pollack, Ranna Mehta, Subhadra Dash, Christine Tun, Erick Lu, Xiaoyan Du, Kevin P. Baker, Len Reyno, Venkataraman Sriram. Tuning the tumor myeloid microenvironment (TME) by targeting TREM2+ tumor-associated macrophages to overcome resistance to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB071.
Abstract LB072: SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus
Authors: Qin Zhiqiang , Chen Jungang , Dai Lu , Barrett Lindsey , Post Steven 
Published: July 2021

Abstract
An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected over 75,000,000 people since the end of 2019, killed over 1,600,000, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, such as Kaposi's sarcoma (KS) and Primary effusion lymphoma (PEL), mostly seen in immunosuppressed patients especially people with HIV infection. In the current study, we for the first time report that SARS-CoV-2 encoded spike (S) and nucleocapsid (N) proteins and some currently used anti-COVID-19 drugs (especially Azithromycin and Nafamostat mesylate) are able to induce lytic reactivation of KSHV from virus infected normal and tumor cells, through manipulation of intracellular signaling pathways. In addition, we found the obvious upregulation of ACE2 expression, the major receptor of SARS-CoV-2, in AIDS-KS tissues, indicating that KSHV may potentially increase SARS-CoV-2 co-infection. Together, our data indicate that those KSHV+ patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop these virus-associated cancers, even after they have fully recovered from COVID-19.
Citation Format: Zhiqiang Qin, Jungang Chen, Lu Dai, Lindsey Barrett, Steven Post. SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB072.
Abstract LB077: Adrenergic signaling induces neuroendocrine differentiation of prostate adenocarcinoma cells
Authors: Krishnan Anand , Dwivedi Shubham , Bautista Maricris , Iftikhar Tauqeer 
Published: July 2021

Abstract
Prostate cancer is the leading cancer diagnosed among men worldwide. The prostate cancer-associated mortality is due to the development of aggressive neuroendocrine prostate cancer (NEPC). Unfortunately, there is no effective treatment available for NEPC at present. This is due to the lack of proper understanding of the molecular switch that triggers neuroendocrine changes in prostate adenocarcinoma cells. Recent research demonstrated that peripheral nerves promote prostate cancer progression and metastasis. However, there is no clear understanding of the involvement of sympathetic nerves or their signaling in facilitating NEPC. In this work, we examined the effect of the sympathetic neurotransmitter norepinephrine (NE) in inducing neuroendocrine differentiation (NED) of prostate cancer cells in vitro. We used androgen-sensitive LNCaP and androgen-insensitive DU145 cells for the study. We examined the dose and time-dependent effect of NE in inducing NED-related phenotypic alterations in these cells using bright field and fluorescence imaging. NED-related molecular alterations were assessed using real-time PCR, western bot and immunocytochemistry. We found that NE induces characteristic NEPC morphological changes, such as compact cell bodies and neurite-like extensions, in both DU145 and LNCaP cells. At the mRNA level, NE induced the expression of the NED markers chromogranin B, synaptophysin and βIII tubulin in both cell types. Further immunoblot and immunostaining showed the upregulation of chromogranin B in these cells. We repeated the experiments in growth factor deprived conditions by avoiding fetal bovine serum in the cultures to mimic growth deprivation to prostate cancer cells, which they experience during androgen deprivation therapy. Surprisingly, the NE induced NED changes were more pronounced in the growth factor deprived conditions. Overall, our result indicates the potential of NE in inducing NED in prostate cancer cells and point towards a critical role for this sympathetic neurotransmitter in facilitating the development of NEPC.
Citation Format: Anand Krishnan, Shubham Dwivedi, Maricris Bautista, Tauqeer Iftikhar. Adrenergic signaling induces neuroendocrine differentiation of prostate adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB077.
Abstract LB093: Incident heart failure among young adult cancer survivors
Authors: Tanaka Yoshihiro , Greenland Phlip , Khan Sadiya , Hibler Elizabeth A. 
Published: July 2021

Abstract
Background: Risk of heart failure (HF) is known to be higher among childhood cancer survivors as well as older adult cancer survivors who may already have cardiovascular disease risk factors. However, the risk of HF among young adult cancer survivors is not known. Aim: To examine incident HF in adult cancer survivors between 18-39 years of age. Methods: We identified patients who were aged 18-39 years when diagnosed with cancer based on the International Classification of Diseases (ICD) 9 and 10 at an integrated multisite single health system (Northwestern Medicine) between January 2000 and January 2019. We stratified by cancer types predominantly linked with anthracycline exposure (leukemia, lymphoma, sarcoma, breast, kidney, and bone cancers) compared with those less likely to have anthracycline exposure. We estimated the cumulative incidence of HF using the Kaplan-Meier method then calculated unadjusted and adjusted hazard ratios (HRs) for incident HF using Cox proportional hazard models. HRs were adjusted for demographic factors and cardiovascular risk factors. Results: Of 12,879 eligible patients, 35% were men and 68% White. The mean age was 31.5±5.7 years. Cardiovascular comorbidities were present in &lt;5% of cancer survivors. During a median follow-up period of 3.4 (IQR, 1.3-7.1) years, 180 incident HF events were observed. Five-year cumulative incidence of HF was significantly higher in those cancer types more likely to have anthracycline exposure compared without (2.5% vs 0.6%, Log-rank p-value &lt;0.01) with an adjusted HR for incident HF of 3.31 (95% confidence of interval 2.36-4.64, p&lt;0.01). Conclusion: While cardiovascular comorbidities and HF are rare in the young adult population, undergoing cancer treatment with anthracycline exposure is associated with significantly higher risk for HF in young adult cancer survivors.
Citation Format: Yoshihiro Tanaka, Phlip Greenland, Sadiya Khan, Elizabeth A. Hibler. Incident heart failure among young adult cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB093.
Abstract LB101: Mechanism of the growth inhibitory effect of pemetrexed disodium heptahydrate in human PC9 cells (EGFR exon 19 deletion)
Authors: Mohiuddin Md , Kimura Hideharu , Sone Takashi , Watanabe Satoshi , Matsuoka Hiroki , Saeki Keigo , Terada Nanao , Abo Miki , Kasahara Kazuo 
Published: July 2021

Abstract
Background: Pemetrexed disodium heptahydrate (pemetrexed) in combination with another drug, is recommended for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). However, the mechanisms of its anticancer activities have not yet been analyzed. We examined the in vitro effects of pemetrexed and further elucidated a potential underlying molecular mechanism.Methods: PC9 cells were treated with pemetrexed and then evaluated with a cell viability assay, Giemsa staining, DAPI staining, flow cytometry (FCM), SA-β-Gal staining, and Western blotting.Results: We found that pemetrexed reduced the proliferation of PC9 cells. The cells treated with pemetrexed showed morphological signs of apoptosis. The apoptotic effect of pemetrexed was related to the generation of ROS and the loss of mitochondrial membrane potential. A cell cycle analysis showed that pemetrexed arrested PC9 cells in the G1 phase. Cellular senescence was associated with pRb hyperphosphorylation and the overexpression of CDK. Regarding the molecular mechanism of this apoptosis, pemetrexed can induce the phosphorylation of p53 at ser 15 and ser 46. Moreover, the expression of extrinsic apoptotic pathway proteins, such as Fas/FasL, DR4/TRAIL, and FADD, was elevated after pemetrexed treatment. Conclusion: In addition to apoptosis, pemetrexed can also cause specific adverse reactions, thus providing a new target for reducing lung toxicity.
Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. Mechanism of the growth inhibitory effect of pemetrexed disodium heptahydrate in human PC9 cells (EGFR exon 19 deletion) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB101.