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      Cancer at the time of the COVID-19 hurricane

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      Journal of Experimental & Clinical Cancer Research : CR
      BioMed Central

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          Abstract

          Dear Editor, The World Health Organization (WHO) reported 18.1 million new cancer cases with 9.6 million cancer deaths in 2018. As of April 13th 2020, there are over 2.0 million cases of COVID-19 and over 100 thousands deaths from this worsening pandemic. These numbers provide testimony to the progression of two devastating “pandemic” illnesses affecting humans. While cancer is a longstanding challenge for thousands of basic, translational and clinical scientists worldwide, COVID-19 has entered the arena with an unprecedented virulence which has turned life upside down [1]. Virologists, epidemiologists, biostatisticians, immunologists, molecular biologists, modellers and infectious disease experts have joined forces to estimate the COVID-19 peak of infection, to predict its evolution, to come up with rapid and effective therapies and to prepare vaccines [2, 3]. Many of them are asked to comment on government policies, to inform authorities and to deal with the media. In that context, they must carefully weigh the statements they release to national and international communities. I believe that fighting COVID-19 under this enormous pressure that is exacerbated by the dramatic increase of deaths is extremely difficult. This might render the coordination of national and global efforts more difficult, thereby prolonging instead of shortening, the time required until we are able to defeat successful the COVID-19 pandemic. Coordinated and spontaneous fund raising is increasing worldwide; governmental agencies, private foundations, companies are launching calls for grant applications as it has never been done before. Often, deadlines or applications are within 1 month and both the review process and release of funds may be as short as a month. Unlike typical biomedical research grants, most calls for COVID-19 research projects ask for completion within 1 year, emphasizing the demand for rapid and urgent therapeutic discoveries. Those of us who have been engaged for decades in the fight against cancer appreciate that patient stratification is critical for successful treatment. Precise cancer patient stratification also implies the identification of specific biomarkers to distinguish high and low risk subjects, to either prevent or prolong cancer insurgence, to monitor the efficacy of the treatment [4, 5]. However, the perfect cancer biomarkers have not yet been identified. One could argue that deciphering cancer, due to its high complexity, is much more difficult than SARS-CoV-2 infection which exerts its most devastating effects on the lungs. While we need to cure symptomatic COVID-19 patients, we should at the same time also study asymptomatic infected people and investigate whether any of their genetic and/or epigenetic determinants make them refractory to the emergence of clinical symptoms. Devoted and systematic biological repositories of body fluids derived from symptomatic and asymptomatic infected people will be of paramount importance for patient risk stratification and for allowing epidemiologists to exclude confounding factors and firmly identify those that drive the COVID-19 pandemic. As cancer researchers, we should be concerned about the fact that COVID-19 is severely impacting cancer treatment and slowing down the efforts to find cures for cancer [6]. Indeed, this pandemic brought the activity of many research laboratories and oncological clinical units to a standstill. It halted patient enrolment into active clinical trials, it disabled new clinical studies and it delayed all in-person cancer meetings by almost 1 year. Consequently, cancer Centres reduced their overall patient management. This is surely the greatest problem, because cancer patients who undergo to chemo or radiotherapy are part of the fragile population that is most likely to be severely affected by SARS-CoV-2 infection and the resultant respiratory illness. “ To be or not to be ” performing COVID-19 related research activities circulates within the cancer scientific community. Each of us ponders seriously and debates passionately with colleges what to do, and whether it’s correct and, most importantly, useful to reprogram their own laboratories from cancer research to COVID-19 research activities. What to do with cancer research projects that are already funded by public and private agencies. There is no consensus on these issues. While some investigators have already re-shaped their research objectives in order to contribute to discovering COVID-19 therapeutic vulnerabilities and design vaccine production strategies, others, despite the reduced laboratory activities are continuing to pursue their own research on cancer. It’s not a matter of who is doing right or wrong; it’s time for concerted actions. COVID-19 infection might blunt social globalization. At the same time, it might frame a worldwide research platform that will not only share scientific data, but will hopefully represent also a unique occasion to act together as a global human community for both COVID-19 and cancer research.

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          Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations

          Dear Editor, The ACE2 gene encodes the angiotensin-converting enzyme-2, which has been proved to be the receptor for both the SARS-coronavirus (SARS-CoV) and the human respiratory coronavirus NL63. Recent studies and analyses indicate that ACE2 could be the host receptor for the novel coronavirus 2019-nCoV/SARS-CoV-2 1,2 . Previous studies demonstrated the positive correlation of ACE2 expression and the infection of SARS-CoV in vitro 3,4 . A number of ACE2 variants could reduce the association between ACE2 and S-protein in SARS-CoV or NL63 5 . Therefore, the expression level and expression pattern of human ACE2 in different tissues might be critical for the susceptibility, symptoms, and outcome of 2019-nCoV/SARS-CoV-2 infection. A recent single-cell RNA-sequencing (RNA-seq) analysis indicated that Asian males may have higher expression of ACE2 6 . Currently, the clinical reports of 2019-nCoV/SARS-CoV-2 infection from non-Asian populations for comparison are very limited. A study from Munich reported four German cases, all of which showed mild clinical symptoms without severe illness 7 . However, the genetic basis of ACE2 expression and function in different populations is still largely unknown. Therefore, genetic analysis of expression quantitative trait loci (eQTLs) 8 and potential functional coding variants in ACE2 among populations are required for further epidemiological investigations of 2019-nCoV/SARS-CoV-2 spreading in East Asian (EAS) and other populations. To systematically investigate the candidate functional coding variants in ACE2 and the allele frequency (AF) differences between populations, we analyzed all the 1700 variants (Supplementary Table S1) in ACE2 gene region from the ChinaMAP (China Metabolic Analytics Project, under reviewing) and 1KGP (1000 Genomes Project) 9 databases. The AFs of 62 variants located in the coding regions of ACE2 in ChinaMAP, 1KGP, and other large-scale genome databases were summarized (Supplementary Table S2). All of the 32 variants potentially affecting the amino acid sequence of ACE2 in databases were shown (Fig. 1a). Previous study showed that the residues near lysine 31, and tyrosine 41, 82–84, and 353–357 in human ACE2 were important for the binding of S-protein in coronavirus 5 . The mutations in these residues were not found in different populations in our study. Only a singleton truncating variant of ACE2 (Gln300X) was identified in the ChinaMAP (Fig. 1a). These data suggested that there was a lack of natural resistant mutations for coronavirus S-protein binding in populations. The effects of low-frequency missense variants in populations for S-protein binding could be further investigated. The distributions of seven hotspot variants (Lys26Arg, Ile468Val, Ala627Val, Asn638Ser, Ser692Pro, Asn720Asp, and Leu731Ile/Leu731Phe) in different populations were shown (Fig. 1b). Six low-frequency loci (rs200180615, rs140473595, rs199951323, rs147311723, rs149039346, and rs73635825) were found to be specific in 1KGP database, the AFs of which were also low in the gnomAD and TopMed 10 database. Only two of these six variants (rs200180615 and rs140473595) could be found in CHB (Han Chinese in Beijing) population with the AF   0.05) and 1 rare variant (rs143695310) in the 15 eQTLs are associated with high expression of ACE2 in tissues (Supplementary Table S3). For instance, the eQTL variant rs4646127 (log allelic fold change = 0.314), which locates in the intron of ACE2 gene, has the highest AFs in both of the ChinaMAP (0.997) and EAS (0.994) populations. Comparatively, the AFs of rs4646127 in EUR (0.651) and AMR (0.754) populations are much lower. These findings suggested the genotypes of ACE2 gene polymorphism may be associated higher expression levels of ACE2 in EAS population. Recent reports of the ACE2 expression analysis in lung tissues from Asian and Caucasian populations are still controversial. The single-cell RNA-seq analysis reported that the Asian donor had much higher ACE2 expression cell ratio than white and African-American donors 6 . In contrast, the ACE2 expression analysis using the RNA-seq and microarray datasets from control lung tissues indicated there were no significant differences between Asian and Caucasian, or male and female 11 . The ACE2-expressing cells are a very small part of cells in lung tissues 6 . The sample size and the purity of ACE2-positive cells in the selected samples would influence the conclusions. Our analysis showed the differences in distribution and AFs of eQTLs for ACE2 in different populations, indicating the diversity of ACE2 expression pattern in populations (Supplementary Table S3). Large-scale and multiple tissue-level analysis of single-cell RNA-seq would be more accurate for the expression analysis of ACE2 in different populations. In addition, our data showed the moderate difference in AFs of eQTLs between South Asian and EAS, which suggests the potential difference of ACE2 expression in different populations and ethnics in Asia (Fig. 1c). In summary, we systematically analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Our findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations (Fig. 1a). The data of variant distribution and AFs may contribute to the further investigations of ACE2, including its roles in acute lung injury and lung function 12 . The East Asian populations have much higher AFs in the eQTL variants associated with higher ACE2 expression in tissues (Fig. 1c), which may suggest different susceptibility or response to 2019-nCoV/SARS-CoV-2 from different populations under the similar conditions. Supplementary information Supplementary Table S1 Supplementary Table S2 Supplementary Table S3
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            Virus against virus: a potential treatment for 2019-nCov (SARS-CoV-2) and other RNA viruses

            The novel coronavirus, 2019-nCov (named as SARS-CoV-2 by ICTV Coronaviridae Study Group on February 12, 2020), causes severe respiratory illness 1 and has been spreading around the world rapidly. 2 As of February 14, 2020, there are over 64,000 confirmed cases with 1,384 deaths. This raises an urgent need for an effective treatment of the deadly disease. However, current antiviral drugs have limited effects on 2019-nCov (SARS-CoV-2). Although Gilead’s NUC (nucleoside) inhibitor, which previously failed to treat Ebola, seemed to benefit a 2019-nCov (SARS-CoV-2) patient in Washington, USA, it remains unknown whether the drug will be effective against the virus in other patients, who may have been infected by different variants of the virus. Our analysis of 2019-nCov (SARS-CoV-2) RNA genome from 19 patients in China, USA and Australia reveals that these viruses have differences in sequence (Fig. 1a). These differences are mostly single nucleotide variations. Fig. 1b shows an example of single nucleotide variations that result in changes in amino acids 62 and 84 of ORF8 of 2019-nCov (SARS-CoV-2), a polypeptide implicated in driving coronavirus transition from bat to human. 3 The evidence from patient samples suggests that 2019-nCov (SARS-CoV-2) is actively acquiring new mutations that may enable it to escape antiviral drugs. This raises a serious challenge to the development of conventional drugs and of vaccines. The same limitations apply to other deadly RNA viruses such as SARS or MERS. Fig. 1 Analysis of genomic variations between 2019-nCov(SARS-CoV-2) viruses from infected patients in different countries and a flexible CRISPR/Cas13d strategy for treating 2019-nCov(SARS-CoV-2) virus infection and countering its evolution. a, b Sequence analysis of 2019-nCov(SARS-CoV-2) virus RNA genome with available complete sequences from 19 infected patients in China, USA and Australia. Lineage tree (a) and peptide sequence alignment (b) for a portion of the polypeptide ORF8 of 2019-nCov (SARS-CoV-2), showing sequence variation between the 2019-nCov (SARS-CoV-2) viruses from different patients. The sequences were extracted from GenBank then aligned with MUSCLE algorithm and visualized with Jalview. Red arrows in (b) indicate regions with variants. Geographical locations and GenBank IDs of the 19 patients are shown. c A model for Cas13d cleavage of 2019-nCov (SARS-CoV-2) RNA genome. d Number of guide RNAs that can be designed to cleave each peptide-encoding region of 2019-nCov (SARS-CoV-2) RNA genome without affecting the human genome. All possbile guide RNAs (gRNAs) containing 22 nt spacer sequences were generated for peptide-encoding regions of 2019-nCov (SARS-CoV-2) RNA genome then mapped to human genome with Bowtie. Guide RNAs with no alignment to human genome allowing up to 2 mismatches were considered to be specific to the 2019-nCov (SARS-CoV-2) RNA genome without human genome recognition. e Schematic for AAV design carrying Cas13d effector and a three-gRNA array for treatment of patients with 2019-nCov (SARS-CoV-2) infection. ITR inverted terminal repeats. Our group has implemented a flexible and efficient approach for targeting RNA in the laboratory using CRISPR/Cas13d technology (under review), and here we propose that this system can be used to specifically chew up 2019-nCov (SARS-CoV-2) RNA genome, hence limiting its ability to reproduce. To functionally disrupt the virus, we will specifically use guide RNAs (gRNAs) that concomitantly target ORF1ab and S, which represent the replicase-transcriptase (ORF1ab) and the spike (S) of the virus. The Gilead’s NUC inhibitor, remdesivir, having a similar chemical structure to HIV reverse-transcriptase inhibitors, is currently being tested in clinical trials for 2019-nCov (SARS-CoV-2), while a drug targeting the spike glycoprotein has also been tested in phase I trials for the treatment of HIV and SARS-CoV. 4 CRISPR/Cas13d is an RNA-guided, RNA-targeting CRISPR system. 5 To cleave the 2019-nCov (SARS-CoV-2) RNA genome, a Cas13d protein and guide RNAs-containing spacer sequences specifically complementary to the virus RNA genome are used (Fig. 1c). One advantage of the CRISPR/Cas13d system is its flexibility with respect to designing guide RNAs, because the RNA-targeting cleavage activity of Cas13d does not depend on the presence of specific adjacent sequences such as the NGG motif for the DNA-editing effector, Cas9. 5 This unique feature of the system meets the requirement for rapid development of guide RNAs to target different virus variants that evolve and may escape traditional drugs. In total, we have designed 10,333 guide RNAs to specifically target 10 peptide-coding regions of the 2019-nCov (SARS-CoV-2) virus RNA genome, without affecting the human transcriptome (Fig. 1d). Due to its desirable safety profile, adeno-associated virus (AAV) can serve as a vehicle to deliver the Cas13d effector to patients infected with 2019-nCov (SARS-CoV-2). The small size of the Cas13d effector makes it suitable for an ‘all-in-one’ AAV delivery with a guide-RNA array (Fig. 1e). Up to three guide RNAs targeting different peptide-encoding regions of 2019-nCov (SARS-CoV-2) RNA genome can be packaged into one AAV vector (Fig. 1e), making the system more efficient for virus clearance and resistance prevention. The expression of Cas13d can be driven by tissue-specific promoters to achieve precise treatment of infected organs. Additionally, AAV has serotypes highly specific to the lung, the main organ infected by 2019-nCov (SARS-CoV-2), and thus can be exploited for targeted delivery of the CRISPR system. A similar strategy is applicable to other types of RNA viruses. Taken together, we propose that CRISPR/Cas13d system is potentially a straightforward, flexible, and rapid novel approach for the treatment and prevention of RNA virus infection. Future studies determining the safety and efficacy of this system in eliminating 2019-nCov (SARS-CoV-2) and other viruses in animal models are needed before its therapeutic application to patients. If proven to be effective, this therapeutic approach will provide patients worldwide with more options to fight against life-threatening viruses that have the potential to evolve and develop resistance rapidly.
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              Snapshot: Trial Types in Precision Medicine

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                Author and article information

                Contributors
                giovanni.blandino@ifo.gov.it
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                29 April 2020
                29 April 2020
                2020
                : 39
                : 74
                Affiliations
                GRID grid.417520.5, ISNI 0000 0004 1760 5276, Oncogenomic and Epigenetic Unit, , IRCCS Regina Elena National Cancer Institute, ; Rome, Italy
                Article
                1575
                10.1186/s13046-020-01575-1
                7189172
                32349775
                7941ce3f-3973-43ad-a7fd-496f4bd941a8
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 14 April 2020
                : 16 April 2020
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                © The Author(s) 2020

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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