PAD4 and Its Inhibitors in Cancer Progression and Prognosis
Round 1
Reviewer 1 Report
This is a comprehensive and detailed review of the research progression of PAD4 in cancers. In my opinion, this is useful for researchers working in this field.
Minor issues:
1. Many typos in line 143 need to be fixed. Such as "cancer", "expression" and others.
2. The gene name, for example "PADI4", must be itallic to be distinguished with the protein PAD4.
3. Line 49-51 need a reference to indicate that this is an effect of PAD2.
Author Response
- Many typos in line 143 need to be fixed. Such as "cancer", "expression" and others.
Response: Thanks for your kind reminding, we have corrected the typos in line 143.
- The gene name, for example "PADI4", must be italic to be distinguished with the protein PAD4.
Response: Thanks for your comments. We have revised the gene name to italics.
- Line 49-51 need a reference to indicate that this is an effect of PAD2.
Response: Thanks for your suggestion. We have added reference 13 in line 52.
Author Response File: 
Author Response.docx
Reviewer 2 Report
This is a very interesting in-depth review describing various roles of PAD4 in cancer. The abstract is concise. The authors provide very comprehensive review that includes basic chemical structure, distribution, various biological functions, mechanism of actions. They have intelligently incorporated all the Tables to highlight major roles and the design of inhibitors flows logistically. Overall, the body of work presented is highly commendable.
Minor: It will be good to add a comprehensive schematic figure showing the mechanisms of PAD4 including its dependence on Ca and NETosis and may be a figure for cancer associated thrombosis.
Author Response
Minor: It will be good to add a comprehensive schematic figure showing the mechanisms of PAD4 including its dependence on Ca and NETosis and may be a figure for cancer associated thrombosis.
Response: Thanks for your suggestion. We have added a comprehensive schematic figure (Figure 1)
Figure 1. PAD4 and its inhibitors in cancer progression and prognosis. PAD4 mediates citrullination, NET and MET formation in a calcium-dependent manner. The elevated activity of PAD4 contributes to diseases including cancer metastasis, relapse as well as cancer-associated thrombosis. As such, PAD4 inhibitor drugs to be developed will be beneficial for patients suffering these illnesses.
Author Response File: Author Response.docx
Reviewer 3 Report
The present paper is a well written review attempting to clarify the multiple roles of PAD4 in cancer progression. Emphasis is also laid on cancer-associated thrombosis and the critical role played by PAD4 in NET formation. Overall, I find this a timely and interesting review that represents a lot of work. The paper is scientifically accurate, complete and fully comprehensive to the reader. The reference section is adequate, up-to-date and appropriate to back up the points made by the Authors. The study conveys a clear-cut message and highlights the need to further elucidate the potential role played by PAD4 in cancer to develop novel PAD4 inhibitors with antitumor and/or antithrombotic functions. Overall, I have no major comment on this well presented review. Minor points that should be taken into consideration are:
- Paragraph 7.9. Cancer Biomarker H3Cit; this should follow the general discussion of PAD4 involvement in cancer and not be included within the description of specific tumor types
- The manuscript should be carefully revised for typos and minor linguistic inconsistencies (e.g., PAD Epression in Cncer and Asociated Trombosis on page 5)
Author Response
Minor points that should be taken into consideration are:
- Paragraph 7.9. Cancer Biomarker H3Cit; this should follow the general discussion of PAD4 involvement in cancer and not be included within the description of specific tumor types
Response: Thanks for your comments. We have moved “Cancer Biomarker H3Cit” to the general discussion in part 7 (line 654-672).
- The manuscript should be carefully revised for typos and minor linguistic inconsistencies (e.g., PAD Epression in Cncer and Asociated Trombosis on page 5)
Response: Thanks for your kind reminding. We have corrected these typos.
Reviewer 4 Report
The authors review too extensively the functions of PAD4 and its involvement in cancer. Numerous reviews have addressed the role of PAD4 in gene regulation, protein citrullination, and NET formation, so I consider it unnecessary to include it in this review. However, it is more interesting to address the role of PAD4 in cancer progression and prognosis, as well as the discussion of the role of PAD4 in cancer-associated thrombosis and potential treatment with its inhibitors, as the title indicates. Therefore, I recommend that the authors consider rewriting the manuscript with these considerations.
Author Response
Response: Thanks for this reviewer's comments. We do agree a short review of the role of PAD4 and NETs in cancer progression and prognosis with a focus on recent literature could be useful to the field. However, as other three reviewers have pointed out: the extensive coverage of PAD4 related literature in this review is also a strength and a helpful resource for researchers new to this field to get a comprehensive picture. We hope you will agree with us and the other reviewers' points.
Author Response File: Author Response.docx
Round 2
Reviewer 4 Report
The review is very good but I still believe that it should focus mainly on what is specified in the title which is the involvement of PAD4 and its inhibitors in cancer progression and prognosis. The rest of the information should be much more summarized.
Author Response
Dear Reviewer,
Thanks for your comments. After combining the opinions of other three reviewers and discussing with the editor, we still decided to retain this part. We hope you will agree with us and the other reviewers' points.
