COVID-19 and Cancer最新文献

{"title":"Abstract 704: Sex and age differences in telomere length and susceptibility to COVID-19","authors":"Manar Ahmed Kamal, Kareem Reda Alamiry, Mahmoud Zaki","doi":"10.1158/1538-7445.AM2021-704","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-704","url":null,"abstract":"Background: Telomeres are the ends of a chromosome and play a fundamental role as vanguards contra the chromosomal decay. Due to the inability of DNA polymerase to replicate chromosomal ends, a reduction in telomeres length happens after each cell division. The existence of shorter telomeres in older people is related to diminished immune functions. Viral infections able to stimulate remodeling of cells, stress responses, and telomere shortening. Moreover, telomere shortening can be caused by extrinsic environmental variables which induce oxidative stress under conditions of inflammation. Aim: To identify the correlation between telomere shortening and susceptibility to Novel Coronavirus Disease 2019 (COVID-19). In addition to clarifying changes in telomere length according to the viral infection, the effect of sex and age differences in telomere length in confirmed positive COVID-19 cases are also reviewed. Conclusion: There is a correlation between telomere length and COVID-19 infection with higher susceptibly of elderly patients and males due to shortening in their telomere length. Approximately 53% of (111,428) infected cases (≥50) years old are males, and 47% of (111,428) infected cases (≥50) years old are females. Citation Format: Manar Ahmed Kamal, Kareem Reda Alamiry, Mahmoud Zaki. Sex and age differences in telomere length and susceptibility to COVID-19 [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 704.","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"55 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127466971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 712: Anticancer natural compounds as potential inhibitors of novel coronavirus (COVID19) main protease: An in-silico study","authors":"A. Mishra, Yamini Pathak, G. Choudhir, Anuj Kumar, Surabhi Kirti Mishra, V. Tripathi","doi":"10.1158/1538-7445.AM2021-712","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-712","url":null,"abstract":"Introduction: Severe acute respiratory syndrome coronavirus identified as the root cause of the Coronavirus disease 2019 (COVID-19) has spread all over the world. The pandemic situation caused by SARS-CoV-2 currently challenging the world. Given that the COVID-19 disease has no vaccine or therapeutic drugs to prevent the infection. In contrast, the key protease (Mpro) of SARS CoV-2 is involved in replication and proliferation of the virus and hence represents a crucial drug for the inhibition of COVID-19. Recent development shows the antiviral and anti-cancerous potential of natural products in the drug development process against various diseases which resulted in the screening of such agents to combat emergent mutants of SARS-CoV-2. Herein, we have applied a bioinformatics approach including molecular docking and a combination of molecular dynamics simulations and Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations to identify the inhibitory potency of candidates against SARS‐CoV2 main protease. Methods: In-Silico molecular docking analysis was performed for all selected anti-cancerous natural compounds with the potential drug target, PDB Id: 6W63 COVID-19 main protease in complex with a noncovalent inhibitor X77 using molecular docking and a combination of molecular dynamics simulations and Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations. Absorption, Distribution, Metabolism, and Excretion (ADME) property as well as Lipinski9s rule of five was also predicted for all the selected compounds. Among the 20 natural compounds, four natural metabolites namely, amentoflavone, guggulsterone, puerarin, and piperine were found to have strong interaction with Mpro of COVID-19. During MD simulations, all four natural compounds bound to Mpro at 50ns and MM/G/P/BSA free energy calculations showed that all four shortlisted ligands have stable and favorable energies causing strong binding with the binding site of Mpro protein. Conclusion: Although the anti-cancerous natural compounds show high binding affinity with the active site of SARS-CoV-2 main protease. Among these Amentoflavone and Guggulsterone were the top two leads showing the lowest binding energy and satisfying our studied parameters. Guggulsterone of Indian traditional ayurvedic medical plant Commiphoramukul was found to be the most suitable based on comprehensive pharmacokinetic parameters, drug-likeness, and docking analysis. Therefore, we propose anti-cancerous natural compound Guggulsterone may further be validated as potential inhibitors of COVID-19 main protease Mpro. Citation Format: Amaresh Mishra, Yamini Pathak, Gourav Choudhir, Anuj Kumar, Surabhi Kirti Mishra, Vishwas Tripathi. Anticancer natural compounds as potential inhibitors of novel coronavirus (COVID19) main protease: An in-silico study [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","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"86 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116135457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 722: The hallmark of COVID-19 cancer disparities: Cellular sequelae","authors":"E. McGhee, Mengtao Li, Yi-Ling Lin, Nefertari Carr, Chinelo Njubigbo, Rohun Sadeghi, Brooke M Su-Velez, Julian Handler, Adin Handler, Judith Okoro, S. Afework, J. Vadgama","doi":"10.1158/1538-7445.AM2021-722","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-722","url":null,"abstract":"Coronavirus disease-19 (COVID-19). Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus resulting in a severe threat to safety and public health. Genetic analyses suggest that SARS-COV-2 belongs to the Betacoronavirus group and Middle East respiratory syndrome coronavirus (MERS-CoV). Like most viruses, some are oncogenic, and genetic instability is involved in the initiating factor for tumor progression that is known to lead to malignancy, resulting in disease sequelae. Genomic instability is characterized by the increased rate of acquisition of alterations in the mammalian genome. These changes encompass a diverse set of biological end points including gene mutation and amplification, cellular transformation, clonal heterogeneity and delayed reproductive cell death. The loss of stability of the genome is becoming accepted as one of the most important aspects of viral induced carcinogenesis, and the numerous genetic changes associated with cancer cell implicate genomic stability as contributing to the neoplastic phenotype. The aim of this study is to analyze the influence of COVID-19 cancer related diseases and determine the epigenetic-genomic profiles in these diseases. In our experimental procedures, we will use oral epithelium cells as a model for this cancer study. We proposed a novel approach to study COVID-19-induced genetic changes with oral epithelium cells. We used these cells with COVID-19 co treatment to determine mechanisms that lead cells into crisis. Preliminary data using oral viral infected cells show that the viral infection can trigger certain gatekeeper proteins like p53 and pRB to be degraded and forcing cells to go into crises, and telomerase is turned on. In this study we will determine if COVID-19 transfected cells can follow the process using the Hayflick model, which show cells that are in crises, and some may progress to cancer. In summary, preliminary data show that viral infected cells that are none cancerous and are telomerase positive, may use a similar mechanism to send cells into crisis that turn telomerase on resulting in cellular malignancy. Citation Format: Eva McGhee, Mengtao LI, Yi-Ling Lin, Nefertari Carr, Chinelo Njubigbo, Rohun Sadeghi, Brooke Su-Velez, Julian Handler, Adin Handler, Judith Okoro, Sebhat Afework, Jay Vadgama. The hallmark of COVID-19 cancer disparities: Cellular sequelae [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 722.","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129231807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 707: Detection of SARS-CoV-2 co-infections with seasonal respiratory viruses using a multiplexed amplicon NGS panel","authors":"Lucie S. Lee, Rounak Feigelman, D. Debruyne, J. Spencer, Chenyu Li, Zhitong Liu, Guoying Liu","doi":"10.1158/1538-7445.AM2021-707","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-707","url":null,"abstract":"The ongoing COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected everyone around the world. Most symptoms of COVID-19 overlap with symptoms of the flu and the common cold. With the approaching flu season, early and accurate detection of these viruses are critical not only to slow the spread of SARS-CoV-2, but also to ensure that patients receive the appropriate care based on their diagnosis, and to keep the healthcare system from becoming overloaded. We designed a next-generation sequencing (NGS) assay to detect the SARS-CoV-2, influenza A H1N1, influenza A H3N2, influenza B, RSV A, and RSV B viruses, and to allow for surveillance and subtype identification. The primers for this multiplex PCR-based method interrogate nearly every gene of each virus. Subsequent sequencing enables not only virus detection but also co-infection detection for these respiratory viruses. In addition, sequencing of virus-positive samples makes it possible to use this assay for mutation and strain analysis. Using the CleanPlex target enrichment technology, we prepared targeted amplicon libraries with human total RNA (50ng) spiked with SARS-CoV-2 synthetic RNA, influenza A synthetic RNA, influenza B synthetic RNA, RSV A RNA, and RSV B RNA (100-10,000 viral genome copies), either individually or in combination. The NGS library preparation protocol includes a reverse transcription step to generate cDNA, followed by a multiplexed PCR step for specific amplification of viral targets. A critical subsequent background cleaning step removes non-specific PCR products, and a final PCR adds sample indices and Illumina sequencing adapters to complete the NGS library preparation. Libraries were sequenced on the Illumina iSeq100 platform, and sequencing metrics as well as virus characterization were determined using Paragon Genomics9s bioinformatics pipeline. Each sample was sequenced at 1,000 average paired-end reads per amplicon. After aligning sequencing reads to each viral genome, we were able to detect nearly every gene of each virus with high specificity. At viral loads of 10,000 copies, 96-100% of amplicons were covered at >100X, and mapped to the intended virus species as well as to the intended subtypes for influenza A and RSV. The assay also accurately identified co-infected samples, which contained equal copies of SARS-CoV-2 and influenza (either A H1N1, A H3N2, or B). In summary, the assay detects multi-target respiratory viruses with high accuracy and specificity. We plan to expand on our findings for this assay9s performance with additional targets, co-infection studies and mutational analysis studies. Citation Format: Lucie S. Lee, Rounak Feigelman, David Debruyne, Julia Spencer, Chenyu Li, Zhitong Liu, Guoying Liu. Detection of SARS-CoV-2 co-infections with seasonal respiratory viruses using a multiplexed amplicon NGS panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"127 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115248313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 718: The Impact of COVID-19 on breast oncology care practices during the pandemic in New York City: A single center retrospective study","authors":"D. Seidman, B. Zimmerman, Lauren Margetich, S. Tharakan, Natalie F. Berger, R. Patel, Michelle Nezolosky, H. Joshi, K. Cascetta, A. Tiersten","doi":"10.1158/1538-7445.AM2021-718","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-718","url":null,"abstract":"Background: In early March of 2020, New York City (NYC) became the epicenter of the COVID-19 (SARS-CoV-2) pandemic in the United States. Early reports suggested that cancer patients who received chemotherapy prior to diagnosis with COVID-19 were at risk for more severe disease. In an effort to limit patient exposure to COVID-19, modifications to the delivery of cancer care were made at our large NYC outpatient practice. This study aimed to assess the impact of the COVID-19 pandemic on breast oncology practice patterns. Methods: Patients with appointments scheduled, postponed, or changed to virtual visits with medical oncology between March 1 and June 30, 2020 at our outpatient center were identified. Demographic and clinical data were abstracted through a review of the electronic medical record. Raw data from RedCap was preprocessed and analysis was performed in R statistical environment. Results: Records for 359 patients were reviewed. Median age was 59.6 and 98% were female. 305 (85%) were receiving systemic therapy at the time of review, with 181 (50.4%) receiving hormone therapy alone and 65 (18.1%) receiving chemotherapy. Of 319 patients receiving or planned to receive systemic therapy, 28 (8.8%) had treatment delayed. 58 patients (17.1%) had a change in their treatment plan, with the most common being extension of ovarian suppression to long-acting leuprolide administration (administered every 10 weeks) from monthly administration (N=23, 37.7% of patients with changes to their plan). 11 patients (18%) received neoadjuvant therapy with delay of surgery, 8 patients (13.1%) were treated with a different systemic therapy, 8 patients (13.1%) had systemic therapy held, and 4 patients (6.6%) were not offered any systemic therapy. Estradiol levels were checked among patients treated with long-acting leuprolide and 100% were found to be in the menopausal range. 116 of the 359 patients (32.3%) had telemedicine visits during the study period. Of all patients reviewed, 28 (7.8%) received diagnoses of COVID-19 during the study period. Eight of the 28 patients (28.6%) were asymptomatic, 16 (57.1%) had mild symptoms that did not require hospitalization, 2 (7.1%) required emergency room visits only, and 2 (7.1%) died from COVID-19 related illness. Conclusions: Among a large sample of breast oncology patients, the vast majority did not have any interruption or change to their treatment during the study period. The most common deviation from the standard of care was the use of longer acting leuprolide and estradiol levels remained in the menopausal range. While the long-term effects of the COVID-19 pandemic on the clinical outcomes of breast oncology patients are unknown, patients treated at our center received largely uninterrupted care. The COVID-19 infection rate among our patient population (7.8%) was significantly lower than the general infection rate in NYC during the same time period (20%). Citation Format: Danielle Seidman, Brittney S. Zimmerman, Lau","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"53 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123801695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 717: Rapid transformation of TTFields care-delivery during COVID-19 pandemic to optimize treatment of patients with glioblastoma (GBM)","authors":"Peggy M. Frongillo, M. Shackelford, Lindsay Rain","doi":"10.1158/1538-7445.AM2021-717","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-717","url":null,"abstract":"INTRODUCTION: Due to the unprecedented, COVID-19 pandemic and resulting health/safety guidelines, rapid-adjustments to treatment plans for patients battling glioblastoma (GBM; debilitating, aggressive cancer) were critical. Tumor Treating Fields (TTFields; FDA-approved for GBM; antimitotic device) are alternating electric fields (200 kHz) delivered through scalp-placed transducer arrays to target rapidly dividing GBM cells. Visitor restrictions at cancer-centers created obstacles to cancer therapy. Health and safety of patients/caregivers, healthcare providers (HCPs), and patient Device Support Specialists (DSS) were prioritized. We evaluated the impact of Novocure® (device manufacturer) implemented strategies on overcoming limitations/restrictions to treatment-access during COVID-19. TREATMENT/PROTOCOL: TTFields (Optune) offers a viable noninvasive, built-in-care system for convenient at-home use. TTFields provides survival benefit with continuous, portable-usage and is tolerable (no-related systemic effects) without overall impact on quality-of-life (except itchy skin). Novocure adopted/amended protocols to meet health guidance/regulation (ie, World Health Organization, Centers for Disease Control and Prevention, local, hospital/clinic directives). PERSPECTIVES: COVID-19 forced a change in treatment patterns imposed by quarantine limitations. This, coupled with the vulnerabilities of immunocompromised patients with GBM, necessitated new-access to TTFields. A COVID-19 task force was created to monitor developments, providing directives to minimize risks to patients/caregivers and employees. Hygiene-practices/full-personal protective equipment were applied for live patient-appointments with DSS. Virtual education appointments were executed to guide patients/caregivers through treatment-initiation. New, no-contact, monthly-usage data downloads captured through the MyLink system, a remote modem allowed data from the patient9s device to upload directly to Novocure. MyLink increases Novocure9s virtual support capability and enables the Novocure team to quickly access patients9 usage data. Communication measures were implemented, informing HCPs of process changes impacting patients. To date, no observed differences were noted for virtual versus in-person patient starts, demographics, time-to-start, treatment discontinuations, percentage continuing therapy and overall complaints. No new safety signals were observed utilizing new approaches. CONCLUSIONS: Care-delivery of TTFields has been transformed during COVID-19. Adoption of virtual-platforms/protocols, resulting in enhanced access and education for patients/caregivers, as well as healthcare teams, has helped bridge the access gap created by the pandemic. Citation Format: Peggy M. Frongillo, Melissa Shackelford, Lindsay Rain. Rapid transformation of TTFields care-delivery during COVID-19 pandemic to optimize treatment of patients with glioblastoma (GBM) [abstract]. In: Proceedings of the American As","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"10 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122450416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB073: The growth inhibitory effect of paclitaxel on gefitinib-resistant non-small cell lung cancer (NSCLC) cells during the COVID-19 pandemic","authors":"Mohiuddin, H. Kimura, T. Sone, S. Watanabe, Hiroki Matsuoka, K. Saeki, Nanao Terada, M. Abo, K. Kasahara","doi":"10.1158/1538-7445.AM2021-LB073","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB073","url":null,"abstract":"Background: Coronavirus disease 2019 (COVID-19) has posed a great challenge for the treatment of cancer patients. COVID-19 presents as a severe respiratory infection in aging individuals, including lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. Conversely, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence could worsen COVID-19. Considering the above-mentioned facts, our present work aimed to investigate the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant NSCLC cells (PC9-MET) and to reveal the underlying mechanisms. Methods: PC9-MET cells were treated with paclitaxel for 72 h and were then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, ROS assay, SA-β-Gal staining, TUNEL assay and Western blotting.Results: Our results revealed that paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3, cleaved caspase-9 and cleaved PARP. Additionally, paclitaxel increased ROS production, leading to DNA damage. Importantly, paclitaxel eliminated cellular senescence, which was observed by SA-β-Gal staining.Conclusion: In light of these findings, paclitaxel could be a promising anticancer drug and could offer a new therapeutic strategy for gefitinib-resistant NSCLC during the COVID-19 pandemic. Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. The growth inhibitory effect of paclitaxel on gefitinib-resistant non-small cell lung cancer (NSCLC) cells during the COVID-19 pandemic [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 LB073.","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"114 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128148997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 709: Estrogen and androgen receptor inhibitors: Unexpected allies in the fight against COVID-19","authors":"S. Bravaccini, Eugenio Fonzi, M. Tebaldi, D. Angeli, G. Martinelli, F. Nicolini, P. Parrella, M. Mazza","doi":"10.1158/1538-7445.AM2021-709","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-709","url":null,"abstract":"","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"119 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125189848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 702: Single-cell expression landscape of SARS-CoV-2 receptorACE2and host proteases in human lung adenocarcinoma","authors":"Guangchun Han, Ansam Sinjab, K. Hara, Warapen Treekitkarnmongkol, Patrick M Brennan, K. Chang, Elena Bokatenkova, B. Sánchez-Espiridión, C. Behrens, L. Solis, B. Gao, L. Girard, Jianjun Zhang, B. Sepesi, T. Cascone, L. Byers, D. Gibbons, Jichao Chen, S. Moghaddam, E. Ostrin, P. Scheet, J. Fujimoto, J. Shay, J. Heymach, J. Minna, S. Dubinett, I. Wistuba, Christopher S. Stevenson, A. Spira, Linghua Wang, H. Kadara","doi":"10.1158/1538-7445.AM2021-702","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-702","url":null,"abstract":"The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-asociated mortality among lung cancer patients. Angiotensin converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. Yet, the single-cell expression landscape of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. To fill these voids, we leveraged our ongoing efforts in single-cell transcriptomic analysis of 186,916 cells including a large number of epithelial cells (n=70,030) derived from 5 LUADs and 14 matching uninvolved normal lung tissues, to delineate expression levels and cellular distribution of ACE2 and SARS-CoV-2 priming proteases TMPRSS2 and TMPRSS4. Single-cell RNA sequencing of 186,916 cells revealed epithelial-specific expression of ACE2, TMPRSS2 and TMPRSS4. Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that ACE2 levels were highest in normal alveolar type 2 (AT2) cells and that TMPRSS2 was expressed in 65% of normal AT2 cells. Conversely, expression of TMPRSS4 was highest and most frequently detected (75%) in malignant lung cells. ACE2-positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated HHIP, and the scavengers CD36 and DMBT1. Notably, the viral scavenger DMBT1 was significantly positively correlated with ACE2 expression in AT2 cells. In conclusion, we describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, and that thus comprise potential treatment targets for COVID-19 particularly among lung cancer patients. Citation Format: Guangchun Han, Ansam Sinjab, Kieko Hara, Warapen Treekitkarnmongkol, Patrick Brennan, Kyle Chang, Elena Bokatenkova, Beatriz Sanchez-Espiridion, Carmen Behrens, Luisa M. Solis, Boning Gao, Luc Girard, Jianjun Zhang, Boris Sepesi, Tina Cascone, Lauren A. Byers, Don L. Gibbons, Jichao Chen, Seyed Javad Moghaddam, Edwin J. Ostrin, Paul Scheet, Junya Fujimoto, Jerry Shay, John V. Heymach, John D. Minna, Steven Dubinett, Ignacio I. Wistuba, Christopher S. Stevenson, Avrum E. Spira, Linghua Wang, Humam Kadara. Single-cell expression landscape of SARS-CoV-2 receptor ACE2 and host proteases in human lung adenocarcinoma [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 702.","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"52 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121562317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB075: Development of SARS-CoV-2 neutralizing protein by ACE2 receptor engineering for severe infection and patients with underlying diseases","authors":"B. Kwon, Seunghyung Lee, J. Choi, Bora Hwang, Sun-Woo Im, Y. Lim, Bumseok Kim, S. Hwang, HoonSung Jeh","doi":"10.1158/1538-7445.AM2021-LB075","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB075","url":null,"abstract":"Since the Spike protein on the surface of SARS coronavirus 2 (SARS-CoV-2) binds to the ACE2 receptor in human cells, the development of neutralizing proteins or antibodies targeting the receptor binding domain (RBD) of the spike protein is an important strategy for SARS-COV-2 therapy. We chose to develop molecularly-evolved soluble ACE2 protein on three grounds; 1) it can trap and neutralize the SARS-CoV-2 as neutralizing antibodies do, 2) it can supplement angiotensin II-converting enzyme activities that protect lung, heart, and kidneys of severe cases of infections and patients with underlying diseases, and 3) it may trap effectively SARS-CoV-2 mutants even though the mutations compromise the protection by neutralizing antibodies or vaccine. For the enhancement of ACE2 binding affinity to RBD, we used the 3D complex structure between ACE2 and RBD to select the major contributing ACE2 amino acids, a library targeting selected amino acids and random mutations were constructed and screened using yeast surface display. The engineered ACE2, EU129, was fused with the human IgG1 Fc for long half-life and viral clearance. The binding affinity of EU129 to RBD was increased by about 500-folds compared to ACE2 wild-type in SPR analysis, and the neutralizing activity was also increased by about 130-folds compared to ACE2 wild-type in surrogate virus neutralization test (sVNT). In addition, it was confirmed that the enzymatic activity of ACE2, which prevents organ damage due to SARS-CoV-2 infection in the human, is maintained at a level similar to that of ACE2 wild-type. In vitro assays using live SARS-CoV-2 virus and Vero E6 cells, EU129 was shown to be more effective in inhibiting viral infection and amplification than ACE2 wild-type, which was confirmed through protein and RNA level and cell morphology change of the live virus. In vivo stability assays using BALB/c mice, EU129 showed enhanced binding to the RBD and maintained enzymatic activity similar to ACE2 wild-type. We generated EU129 with the improved binding affinity and neutralizing activity through ACE2 receptor engineering. It has angiotensin II-converting enzymatic activity for organ protection, thus EU129 is a better therapeutic candidate for severe cases of SARS-CoV-2 infection and patients with underlying diseases such as cancers. Citation Format: Byoung S. Kwon, Seunghyun Lee, Jin-Kyung Choi, Bora Hwang, Sun-Woo Im, Yun-Sook Lim, Bumseok Kim, Soon B. Hwang, HoonSung Jeh. Development of SARS-CoV-2 neutralizing protein by ACE2 receptor engineering for severe infection and patients with underlying diseases [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 LB075.","PeriodicalId":417728,"journal":{"name":"COVID-19 and Cancer","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134147551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}