Sci投稿第二次修改意见 miRNA

投稿了一个四区的sci，第一次编辑让我修改了之后，现在是审稿人意见，各位大侠能不能帮我看看该怎么回，是不是被录用的机会很小很小了……

Dear  Li,

Reviewers have now commented on your paper.  You will see that they are advising that you revise your manuscript.  If you are prepared to undertake the work required, I would be pleased to reconsider my decision.  

For your guidance, reviewers' comments are appended below.

If you decide to revise the work, please submit a list of changes or a rebuttal against each point which is being raised when you submit the revised manuscript.

Your revision is due by Jun 27, 2021.

To submit a revision, go to 
                https://www.editorialmanager.com/jtim/
               and log in as an Author.  You will see a menu item call Submission Needing Revision.  You will find your submission record there. 

Yours sincerely

Wilson Zhang
Managing Editor 2
Journal of Translational Internal Medicine

Reviewers' comments:

Reviewer #1: In this study, the authors found that serum miR-421, miR-223, miR-25 and miR-21 were up-regulated in gastric cancer patients, and were associated with the disease progression. However, several questions should be refined.
1. In figure2, the expression level of miRs should be showed in Scatter plot but not histogram, to show the distribution of different patients.
2. As the authors compared the AUC of miRs and CEAs, the expression level of CEA, CA199, CA724 should be showed.
3. How about the miRs expression level in other cancers, such as hepatocellular carcinama, colon cancer...? sometimes, miRs showed non-specificity upregulated in all types of cancers, therefore, it is important to valuate the specificity, besides the ROC curve.
4. It is necessory to discuss the limitaions in the discussion.


Reviewer #2: In this manuscript, the authors aimed to investigate the role of serum miR-421, miR-223, miR-25 and miR-21 as a panel of potential noninvasive biomarkers for early diagnosis of GC. However, the data is too little to prove the conclusion and there are some defects in this research. Hence, I think that the manuscript should be rejected.
Reasons:
1.	The detection reason for selecting these four miRNAs is so weak. There are still many other dysregulated miRNAs, which play important roles in the diagnosis, treatment, and prognosis of cancers？. This may lead to biased conclusions.
2.	It is no necessary to show the amplification curves in the official results. So please deleted Figure 1 or put them into supplymentry data.
3.	The authors detected the expression of these four target miRNAs in early gastric cancer (EGC) and GC, but did not show their expression in advanced gastric cancer alone. Whether there was no differences in advanced gastric cancer compared to control group? Figure 2 and 3 should be combined together to show the expression of these four target miRNAs in the control group, in early gastric cancer and in advanced gastric cancer. Is there a gradual upward trend among control group, early gastric cancer and advanced gastric cancer?
4.	The authors did not apply the method of combination of these four target miRNAs. Please provide the calculation fomula. 
5.	The authors only showed the AUC of GC and EGC. Please show the AUC in advanced GC too.
6.	It is lack of validation dataset to verify the conclusion. You could divide your own samples into training set and validation set according to the principles.
7.	There are no specific mechanisms in the paper, which leads to the article too