ADAM10 and ADAM17 as Biomarkers Linked to Inflammation, Metabolic Disorders and Colorectal Cancer

Round 1

Reviewer 1 Report

Sikora-Skrabaka et al report that ADAM10 and ADAM17, two of TNFα converting enzyme family, which act as biomarkers linked inflammation, metabolic disorders and colorectal cancer. There are some things need to be clarify.

1.     In abstract, line 23, “the [mean] concentration of ADAM10……”. You may just write “ the concentration of ADAM10…..” because you used statistics method to analysis.

2.     In introduction, line 42-43, “these pathways are dependent on the proteins of the ADAM family”. However, I did not see direct information of this pathway of CRC development. Is that jupping way to mention that? Please make it clear or cite a correct reference.

3.     Please define CVD in your patients’ population. Is that one vessel, two vessels diseases? Did those patient take any medicines that would decrease inflammation reaction? Please describe the type II DM patients treatment, with OHA or insulin injection? How long did those patients having DM? that will influence on inflammation status.

4.     Please add P value for each column/ parameters in Table 2. Please add P value in Figure 1-4.

5.     Please do multivariate analysis of cancer stage, DM, and CVD between tumors and normal surrounding tissues samples. That will be helpful to find out the real factor that related to ADAM10 and ADAM17 levels.

6.     In Discussion, first paragraph, the references you cited are talking about higher ADAM17 in cancer tissue or serum related to cancer progression. Why were there no significant difference between cancer and normal tissue? In your data, there were no change of ADAM17 levels from stage I to stage IV (advanced) CRC samples. Please explain that.

7.     In discussion, line 206, “…of the inflammatory process and, ….”although you cited references that informed ADAM17 related to inflammation pathway, there was no proof in your study design.

8.     Lin 217-220, although ADAM17 levels were higher in CRC tumor compare to normal samples, there was no statistics significance. And most of the references make conclusions that ADAM17 related to cancer, through inflammation. That is an environment. According to your data, ADAM17 in CRC tumors are higher than surrounding normal tissues. Do you mean that is “focal” infloammation” induced pathogenesis of CRC? If so, how to explain DM and CVD, systemic inflammation situation, increased ADAM17?

9.     Line 228-238, this paragraph is too confusing. Please make it more clear. By the way, we use stage I, instead of the first stage of tumor advancement (line 232-233).

10.  In conclusions part, please do not use point description. The first point, line 247-248, please discuss the phenomenon in discussion part before you conclusive that.  

11.  Overall, please include C-reactive protein (CRP) or other cytokine, eg IL-1, IL-6, TNF-alpha, and compare with ADAM10 and ADAM17.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

My remarks from Lines:

1 missing with

13 to big fonts for corresponding author

18 surgical margin is not easy to understand for non-specialists

19 ADAM protein - why not proteins?

26 results were not was

 

26 also:

In conclusion, results of our study indi-

cate that ADAM10 and ADAM17 may be potential biomarkers in cancer linked with inflammation.

This is not true.

More accurate sentence:

In conclusion, results of our study indi-

cate that ADAM10 and ADAM17 may be potential biomarkers in disease such as DMT2 linked with inflammation.

But it is not first discovering based on [10-11] citations. Hovever maybe you have different samples or procedures.

Maybe sentences meaning from lines 230-234 could give better vision of abstract realiability/representation.

 

31 According to the sounds better

33 while being better just and is

36 inter alia /italic suppose to be/?

39 ulcerative clitis as well as Crohn's disease capital first letters?

51 play

69 resections- why -

70 1 cm 3 were collected is it allowed - such big frgamnet based on bioetic rules?

75 histopathological result were divided into 4 groups it requires explanation for profivient readers especially or citation(s)

91  ° C why space after grade

93 Protein Quantitation Kit is there any katalog number allowed to write

108 double space before All

111 pg / µg maybe without spaces aroud dash

114 Katowice is it proper English name for the city?

121 normally distributed variables, otherwise nonparametric tests - did you try eliminate or judge somehow results thet were non-normally distributed? or transform them?

138 results were not was

140 dot after significant

203 from I would replace by in comparison to the

206 in diseases

223-224 ADAM17 cellular levels it requires to explain whether this protein can be extracellular also in what degree level or transmembrane maybe?

It may question biological/metabolic meaning of your measurements, indeed. Try to avoid such thinking for suspcious readers because topic is extremly serious.

230 dot after cancer

243 hope for their practical application think about may remarks to lines 223-224

If Editor allows I would like to give final remarks about novelty of your study after your answers.

 

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

This study analyses the potential role of  ADAM10 and ADAM17 as Biomarkers Linked Inflammation, Metabolic Disorders and Colorectal Cancer.

 The manuscript is well written, and the results are well discussed. The authors concluded that ADAM10 and ADAM17 may be potential biomarkers in cancer linked with inflammation.

Major comments:

1. Introduction section (lines 54-57)

please explain the potential mechanisms underling the involvement of ADAM17 with inflammatory diseases.

2. The authors should discuss on the available methodologies used for the determination of ADAM10 and ADAM17.

3. Could the authors discuss on the differences or similarities for ADAM10 and ADAM17 action?

Minor comments

1. Line 53: Please define the DMT2 since it is the first time appeared in the manuscript.

 2. The style used to write the abbreviations should be modified.  

 

Author Response

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Author Response File: Author Response.pdf

Reviewer 4 Report

The work presented is of great value given the relevance of the CRC. However, some aspects need to be clarified/corrected:

 

1 - The introduction should include information about ADAM7 and 10 related to cancer and metabolism s.

2 - The number of patients is relevant; however, since the analysis is divided into 4 groups, the number per group is very small, not allowing conclusions to be drawn from the work. In this sense, I ask if it is not possible to use another nomenclature (according to clinical information) to divide patients into fewer groups. Or to group the stages, p.ex. (state I-II, and Stage III-IV)?

3 - It is not described in the article because the "surgical margin" is used as a comparison. I guess it's because it is assumed that this tissue would be "normal", but often in this area, there are already pathological changes. This can influence the results. More information about the histopathology of this control tissue is needed to validate the work.

4- Table 2 should be more evident. The statistical information that is presented is not understood. The * shown refers to which comparison?

5. The graphics should also speak for themselves. What does yes/no mean on the X axis?

6. Please include in the graphs the statistical value.

7. The discussion should be improved to highlight the findings' relevance.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Excellent.

Reviewer 4 Report

All my concerns were addressed.