Dear PhD Yan,

Thank you very much for submitting your manuscript "Effect of aberrant fructose metabolism following SARS-CoV-2 infection on colorectal cancer patients' poor prognosis" for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We apologize for the long delay. It was very hard to find expert referees on this topic. We now secured two referee reports that both provide constructive comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Rob J De Boer

Section Editor

PLOS Computational Biology

Rob De Boer

Section Editor

PLOS Computational Biology

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We apologize for the long delay. It was very hard to find expert referees on this topic. We now secured two referee reports that both provide constructive comments.

We therefore invite you to resubmit a revision addressing these suggestions by the referees.

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: SARS-CoV-2-induced cancer patients have a poor prognosis, which may be related to fructose metabolism. In order to improve clinical practice, a composite predictive nomogram is presented in this work. It includes characteristics of the aberrant fructose metabolism brought on by this novel coronavirus, together with age and tumor stage. The genes with the best possible prognostic values were found using LASSO regression analysis. This work lays the theoretical foundation for future customized treatment of fructose metabolism in these patients, while also optimizing dietary advice and therapeutic care for patients with colorectal cancer in the context of the COVID-19 pandemic.

The manuscript is well written. Furthermore, there are other issues that need to be clarified in a revised version.

More detailed comments are provided below.

1. The images are of very poor quality, can’t even understandable. Please re-upload all the images with proper legends and titles.

2. For 1b image, consider the cut-off in log2(FC) so that selected number of genes can be identified properly.

3. Accuracy can not be observed properly as the ROC curve is not clear to view. So that the results can be verified.

4. Here, authors mentioned that they have splitted the dataset into 4:1 ratio for training and validation purpose randomly. Please verify that this ratio performing best or not.

5.Here Lasso regression technique has been implemented. It would be great to compare this regression model with some other techniques? please add one comparison table.

Reviewer #2: This study aims to use a bioinformatics approach to predict fructose metabolism genes that are altered in response to COVID-19 infection and also in tissues from CRC patients, and are linked to CRC prognosis. They developed a prognostic risk score based on a number of these genes, and used this to examine correlations to immune responses and CRC treatment efficacy. The aims of the research have been performed well, there are multiple areas in which the rationale could be explained clearer. The discussion does not discuss any of the results generated in the paper. Therefore, the significance of their findings is not clear, or what their findings will lead to, or how they will be followed up. The outcome of the research is observational, but an interesting hypothesis has been generated.

Major Comments: In most cases, the rationale for performing each type of analysis is not mentioned, there is also no summary of findings in each section which would help link the results to the next analysis. Also, the discussion could be reorganized to discuss the results of the study, it is currently a review of fructose metabolism. There is no mention of any of the findings, or limitations of their work.

Minor Comments:

1. Language in abstract needs improvement

2. The statement “SARS-CoV-2 is more prevalent among cancer patients treated with anticancer therapy than those without anticancer therapy” as a supporting argument needs more thought as this could be due to their increased exposure when not distancing vs anything biological.

3. The supporting citations for the statement the fructose can make cancer worse are for breast and prostate cancers, not CRC. As metabolism differs even by stage and genetic mutations in CRC it is difficult to translate the findings in other cancers to CRC. So this statement should express that limitation.

4. Information on the sex, age, stage and types of tissues analyzed and method of analysis (for example GSE41258 is microarray) in the 3 CRC datasets would be helpful, perhaps as a supplementary table. The lung covid dataset (GSE183533) as generated by RNA-Seq, perhaps this could be mentioned, it’s possible some transcripts are missed in the microarray?

5. Fig 2, It is not clear why the OS time is different between each plot on Figs 2. Typically this is set to 5 years, or in some cases 10 years for CRC, which is the timeframe in which recurrence may occur. This should be more clinically relevant.

6. The rationale for examining immune infiltration was not explained, is this linked to fructose metabolism?

7. Fig 3. A – the risk groups should be labelled in the legend. B, it is not clear which 2 groups are being compared, are these high and low risk groups again?

8. Gender should be changed to sex in text and on figures.

9. Fig 4, what was the rationale for performing univariate and multivariate analysis.

10. There is no information provided on the antibodies used for immunohistochemistry, or their authentication

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: None

Reviewer #2: No: Codes not provided

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Reviewer #1: No

Reviewer #2: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

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Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear PhD Yan,

Thank you very much for submitting your manuscript "Effect of aberrant fructose metabolism following SARS-CoV-2 infection on colorectal cancer patients' poor prognosis" for consideration at PLOS Computational Biology. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Rob J De Boer

Section Editor

PLOS Computational Biology

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A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

The two referees agree that the manuscript has improved considerably, and have a few more recommendations.

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have addressed my previous comments satisfactorily,

My only remaining comments are:

1. The authors conducted various computational analyses for this study; however, the script for these analyses is not included in the manuscript.

2. The authors have included links to various databases throughout the manuscript. Instead of providing these links, please cite the original papers associated with each database.

Reviewer #2: The authors have been responsive to the recommendations made, however the discussion still mostly discusses research from other studies, and not the results of their own study. The discussion is also very long and given that the research from the paper is not really discussed in any detail, there is room for improvement here.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: None

Reviewer #2: None

**********

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Amit Ghosh

Reviewer #2: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References:

Review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Dear PhD Yan,

We are pleased to inform you that your manuscript 'Effect of aberrant fructose metabolism following SARS-CoV-2 infection on colorectal cancer patients' poor prognosis' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Rob J De Boer

Section Editor

PLOS Computational Biology

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