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Thank you for completing those last few requested changes.
The Reviewers and Editorial Board are pleased to see your revision. Some minors issues to be corrected before we can formally accept for publication.
The authors have adequately addressed the points raised by the Editor and the Reviewers.
Much improved following revision. Th authors have addressed reviewers comments
Abstract Discussion . the sentence does not need 'of' in 'value of obtained'
Line 26: melanocytes are transplanted
Line 77: revise this phrase 'To alternate the heavy suction apparatus' as it is not clear what it means
Line 307-9: this statement is now repetitive - suggest delete or make any further additional point?
A recent study has reported a good correlation between total melanin content in the epidermis and melanosome size in these subjects, suggesting melanosome size may be correlated (at least in part) with the amount of melanin (Alaluf
et al., 2002a).
Thank you for addressing the reviewers comments
It is not yet clear whether the data actually helps predict a formula to derive skin color. Can you be more explicit why melanocyte ratio is important? What is the basis for the high variation of this within skin of same ethnic origin? Many studies relate spectral measurement of skin color to melanin content. What is the clinical significance application of relating L* to M x R?
Authors should explain rationale for choosing the product of R and M vs L*? Would the correlation of melanin content with the melanin ratio not be expected to show an increase in melanin with a higher ratio? Please note that the reviewers had some concern regarding the reproducibility of the data – how often were these measurements performed? For melanocyte ratio and melanin concentration. Finally if R does not correlate with M or L*, then how is R useful for manipulation in future studies?
Evaluating skin color by objective measurement is important clinically in dermatology. Huang et al. found a high correlation between L* value and the product of epidermal melanocyte ratio (R) and melanin content (M) in Asian young adult skins. The experiments yielded an equation L* = -0.095 x (M x R) + 55.872 for estimating skin color. This formula was validated on additional experiments using skin substituents. The study is technically sound and contains information on ethical consideration and reproducibility of the data. However, there are several points that should be improved before acceptance of this manuscript.
1) The authors did not make it clear why they thought the melanocyte ratio (R) important to study. This point is important because there are many studies relating spectral measurement of skin color to melanin content which is equal to R x M. Also, some comments on the rather high variation of the epidermal melanocyte ratio within the same ethnic origin will be welcome. Any similar findings in literature?
2) In relation to the above 1), discussion should be expanded to include some more literatures studying the objective measurements of human skin color. Examples are:
a) Alaluf et al. The impact of epidermal melanin on objective measurements of human skin colour. Pigment Cell Res. 15, 119-126, 2002.
b) Del Bino et al. Chemical analysis of constitutive pigmentation of human epidermis reveals constant eumelanin to pheomelanin ratio. Pigment Cell Melanoma Res. 28, 707-717, 2015.
3) The (clinical) significance of the above equation relating L* to M x R is not clearly written. How will the authors plan to use the formula clinically?
4) Reproducibility of the data: It is clear that skin color measurement was performed three times. But for the melanocyte ratio (n = 5?) and melanin concentration (n = 3?), how the reproducibility was assessed was not described.
1) Melanocyte ratio: This should be defined at the first appearance.
2) Table 1: I believe that n = 5 for epidermal melanocyte ratio.
3) Line 66, and could the influence: A verb is required here.
4) Line 129: The volume of 1 N NaOH should be given. Also, 1 M or 1 mol/L is better.
5) Line 160, SE: According to the raw data provided by the Authors, SD (standard deviation) is actually given instead of SE (standard error).
6) Lines 223 to 225, Arthur et al. and Kahn & Cohen : Arthur et al. is not listed in REFERENCES. Also, what Arthur et al. found and Kahn & Cohen found should be more clearly presented.
7) Lines 229 to 231, Geel et al., Mulekar, van Geel: Are Geel et al and van Geel et al. identical? What did Mulekar say?
8) Line 243, Alaluf et al.: This should be "Alaluf et al. (2002)".
9) Lines 285-287: The log values of eumelanin/pheomelanin ratio... This data was not presented in Ito & Wakamatsu (2003). Instead, a similar data on human hair was reported in: Naysmith et al. Quantitative measures of the effect of the melanocortin 1 receptor on human pigmentary status. J. Invest. Dermatol. 122, 423-428, 2004.
Quality of written English is mostly good. The manuscript would benefit from a final read-through by a native speaker of English.
Quite a lot of the information in the first part of the discussion might be better placed into the introduction to give the study its clinical context?
Line 239 - the comment and references cited seem not to reflect the wide range of work published in the last 10 years in the understanding of regulatory factors in skin pigmentation. Consider revising this sentence and use of references given the discussion goes onto discuss some examples?
Abstract background please state that the premise for the work is in the field of transplantation or tissue regeneration for e.g. vitiligo/burns.
minor language comments :
Line 41...the L* value correlated with the value obtained by ....ratio (R) with melanin....and that this correlation was much more statistically significant that either L* vs M or L* vs R. This suggests that a .....color can be achieved taking into account both R and M.
Line 45....not sure what is suggested here. Do the authors require a more substantial study to improve the predictive model or are they suggesting that each clinical case requires such data?
Line 50...color match for the purpose of?.....
Line 66....donation, thus the influence....
Line 69...and melanocyte number and activity.
Line 70..correlations between...
Line 282 - referencing style?
Line 285 - make it clear that the statement about L,a,b refers to data in the cited literature
Generally meets aims of the journal and is relevant to a clinical problem.
Can the authors be sure that the method of melanocyte quantification is not confounded by cell losses? The %ratio or M to E is lower than reported in the literature (1:16; appx 6%).
Some minor points noted below.
Line 80 HMGS spell out in full
Line 101; after how much time in culture was the media switch made?
Line 146 ;The ratios used in the skin equivalent should be mentioned.
Line 192...it is really no correlation not weak!
Line 193; was this correlation statistically significant? Why interestingly? Surely it is expected that L values that are lower indicate higher levels of melanin?
Line 195...product of
Can the authors explain their rationale for choosing the product of R and M vs L*?
The correlation of melanin content with the melanin ratio world be expected to show an increase in melanin with a higher ratio. Thus hypothesis that varying melanocyte number relates to associated degree of activity and thus to L* value is not proven by these data and the use of the product of M and R would seem to overcome/mask the differential contribution of either of these measured parameters to color. What would seem to be a negative correlation between M and R needs to be referred to and discussed. Normalising M to R (M/R) vs L* reveals no correlation.
However, the tissue engineering data presented does indicate that L* can be engineered using an appropriate R value, although a table of all Ratio's used vs L* measured would be helpful.
The conclusion would benefit from some suggestions on why there is little or negative relationship between total melanin and R and the significance especially as R is the only variable that can be adjusted in the future design?
The authors could consider including some more recent references on the genetic control of pigmentation within ethnicity that may underlie inter-individual and intra-racial differences.
Renee P. Stokowski, et al. A Genomewide Association Study of Skin Pigmentation in a South Asian Population,The American Journal of Human Genetics,Volume 81, Issue 6,2007,Pages 1119-1132,
Wilson S. et al. (2013) NCKX5, a Natural Regulator of Human Skin Colour Variation, Regulates the Expression of Key Pigment Genes MC1R and Alpha-MSH and Alters Cholesterol Homeostasis in Normal Human Melanocytes. In: Annunziato L. (eds) Sodium Calcium Exchange: A Growing Spectrum of Pathophysiological Implications. Advances in Experimental Medicine and Biology, vol 961. Springer, Boston, MA
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