sash-ka/mdpi_arguments_relation · Datasets at Hugging Face

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Naturalistic shapes and forms the shapes of plants on building facades and columns, animal facsimiles woven into fabrics and coverings.	null	null	If this was the case, perhaps this could be succinctly mentioned. In consideration to their response #8, I understood and agreed with why half the seven of the 14 papers were discarded, but it did not provide much insight into why the Patterns of Biophilic Design were still used. A more useful example, which may have elucidated this more, was whether are there too few frameworks available, and/or none others could have been used.	3	2	buildings12040417_makarova
Author Response Response to Reviewer 1 Comments I would like to thank the authors for taking all my comments into full consideration.	null	null	The introduction can be optimized appropriately.The introduction of the term "Biophilia" can be more detailed and easy to understand .By contrast, the introduction of “Biophilic Design”is very substantial.It may be better to find some literature to combine workplace design and “Biophilic Design”,and then to explore the relationship between them.	1	2	buildings12040417_makarova
These are not significant remarks, but nonetheless, might provide further improvements and clarity: #1: For their response to comment #6, while I generally agreed with the authors, I felt that it didn’t quite address what I tried to originally convey.	null	null	Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.	1	2	buildings12040417_makarova
Kent, M., Parkinson, T., Kim, J., Schiavon, S., 2021.	null	null	The result of biophilic design frameworks for specific workplace typology is of certain value. The location of the workplace selected in this article is limited, the related biophilic factors are scientifically screened, and the researchers have made a detailed classification study. However, the huge research scope has certain obstacles to the relevant results, and the general and targeted conclusions will be worse.	1	2	buildings12040417_makarova
The figures and pictures have been adjusted in the revised manuscript.	null	null	It is best to supplement and describe the necessity of research. At the same time, it will be more complete if the results are reflected in the summary.	1	2	buildings12040417_makarova
There are overlaps between the nine biophilic design attributes and these eight influential factors for the workplace.	null	null	The object of the questionnaire should be composed of people with different ages and genders, which is best explained in the article.	1	2	buildings12040417_makarova
Thermal & Air flow variability Subtle changes in air temperature, relative humidity, air ow across the skin, and surface temperatures that mimic natural environments.	null	null	Adding some explanations, examples and data comparison to the conclusion will be more intuitive and convincing, just as discussed earlier in the article. Perhaps this makes this article more complete and credible. At the same time, the conclusion only summarizes the article, and lasks discussions and explanations for the future research direction.	1	2	buildings12040417_makarova
We think it is not hard for the readers to understand, and the original percentages (round to one decimal place) is more accurate.	null	null	The theoretical part of the presentation is extensive, but the application part is relatively poorly described.	1	2	buildings12040417_makarova
Animals Re-presentation of nonhuman animal life 6.	null	null	It is better to supplement the temperature, humidity and other parameters of the selected office in the part of the experiment, so as to facilitate readers' reference rather than just giving the location.	1	2	buildings12040417_makarova
Yin, J., Yuan, J., Arfaei, N., Catalano, P.J., Allen, G.J., Spengler, J.D., 2020.	null	null	The author can think about the impact of such a pro biological design model on the psychology of different experimental personnel. I think psychological factors will also affect human physiological comfort.	1	2	buildings12040417_makarova
#2: P1, L39-41: Please provide references to these frameworks.	null	null	Figure 1 should be improved regarding the arrow.	3	2	buildings12040417_makarova
Instead, studies may elect to use, for example, other relatable scales, which may not have originally been designed for POE surveys (e.g.,	null	null	Photo in table 6 should check the copyright of these photo.	3	2	buildings12040417_makarova
Yin, J., Arfaei, N., MacNaughton, P., Catalano, P.J., Allen, J.G., Spengler, J.D., 2019.	null	null	Please bring strong relevance to the scope of journal "Buildings" by investigating most recent literature.	3	2	buildings12040417_makarova
Point 2: The illustrations in the article are small and a bit vague, some pictures can shrink a little, not to the top to the border, these can be optimized.	null	null	The definition of biophilia is described as an “inherent love” toward nature. While this is somewhat accurate, it might be more appropriate to elucidate this as an “inherent affinity”.	1	2	buildings12040417_perova
#3: P2, 47-53: Although in the past there were few guidelines, nowadays, there may be more standards that focus on nature integration within the built environment.	null	null	P1, L39-41: Please provide references to these frameworks. Reading further to page 3, I believe these are the 24 biophilic design attributes [ref. 25,39], and the 14 patterns of biophilic design [ref.40]. Further references around the biophilic concept could also be provided, e.g.: Bjørn et al., 2009. The latter reference reviewed many international standards that advocate nature and biophilic design for view and building spaces, with examples given to the Singapore context. This somewhat overlaps with my next comment.	1	2	buildings12040417_perova
Yin, J., Zhua, S., MacNaughton, P., Joseph, G., Allen, J.G., Spengler, J.D., 2018.	null	null	P2, 47-53: Although in the past there were few guidelines, nowadays, there may be more standards that focus on nature integration within the built environment. WELL v2 has several features for Nature and Mind, and Biophilia – Parts I and II, with quantitative assessment methods provided. Similarly, the Green Mark system uses the green plot ratio, assigning credits to greenery provision to enhance biodiversity and visual relief. Other standards likely incorporate biophilic elements in building architecture and could be worth highlighting. The general issue raised by the authors do not necessarily imply a lack of guidelines for biophilic design, since there are several readily available, but may point toward prioritization or emphasis of criteria to meet certain varying expectations, which was alluded to on lines 52-53. If the authors agree with this, perhaps this could be revised here to reflect this.	1	2	buildings12040417_perova
#11: Table 2: Please consider providing further explanations for this table.	null	null	P2, L63: Although I wouldn’t completely rule this out, POE surveys may not always provide feedback to the architect, since they are implemented post design-stage and the building would be operated by facility management or the owner. In my view, POE information had more utility diagnosing operation problems, which can be solved when running the building, identifying prominent sources of dissatisfaction that can prompt action to resolve these issues. Recently POE studies, also using office data, advocate this as benefit to their implementation, albeit not necessarily being the only reason: žGraham et al., 2020. Building & Cities. Kent et al., 2021. Building and Environment. Cheung et al. 2021.	1	2	buildings12040417_perova
Response 7: 1) The Conclusion is rewritten to highlight the relationship between biophilic design and occupant health and wellbeing: Revision in Page 23 Line 516-540: “The significant research outputs from the present scrutiny are shown as following: a) The authors develop a POE questionnaire for evaluating the biophilic design for workplace health and wellbeing.	null	null	P3, L92: I think refers to “has helped” given the five decades predating this.	1	2	buildings12040417_perova
Biophilia: Does Visual Contact with Nature Impact on Health and Well-Being?	null	null	P3, L106: While I generally agree with, questions could be raised to whether POE scales should be used to evaluate biophilic design evaluation. Biophilic design is known to elicit mental and physical health benefits, as stated by the authors on page 1, lines 29-32. Therefore, it would be more appropriate to use psychological scales (e.g., PANAS or psychological restoration), instead of design orientated question or survey. If the authors agree with this, this aspect could be revised.	1	2	buildings12040417_perova
When the occupants feel that they have a strong sense of relationship with nature, it is observed that the biophilic environment would have positive impacts on their health.	null	null	Something I felt would useful would at the beginning would be a clear definition for what “biophilic attributes” refers to. Figure 1 provides some insights into this, but these listed attributes span across different domains and the communal features are not that apparent. This becomes an issue later, since some aspects referring to biophilic design become unclear.	1	2	buildings12040417_perova
Thermal & Air flow variability Subtle changes in air temperature, relative humidity, air ow across the skin, and surface temperatures that mimic natural environments.	null	null	P4, L173-174: The authors state that seven of the patterns from the 14 patterns of biophilic design were discarded. If this was the case, then please better articulate its overarching utility in this study, considering that half of the patterns were not relevant to the research scope.	1	2	buildings12040417_perova
The theoretical part of the presentation is extensive, but the application part is relatively poorly described	null	null	P4, L180-183: In traditional POE studies and general building science research, daylight, thermal comfort, and air-quality, would be considered as indoor environment parameters (as examples, please see refs. in comment #4), while office layout and building form would be considered a physical and architectural parameters. Reading further to page 5, lines 189-192, the authors begin to suggest to this, but referred to them and others indoor environmental parameters as factors for the workplace. I would suggest better rationalizing the connections between the nine design parameters to biophilia to make these more overt.	1	2	buildings12040417_perova
Limitation and Future Studies is added in the revised version: Revision in Page 23 Line 542-551: “6.	null	null	Figure 1: The image presenting all the linkages is very interesting and is worth emphasizing, but contains an overwhelming degree of information, and the text and line sizes are too small for readership. Please consider simplifying the figure. For example, some text boxes many do not need further explanation (e.g., presence of water); also, the lines connecting column A to the same patterns in column 4 could be color coordinated.	1	2	buildings12040417_perova
Due to the reasonable size of the dataset collected, it may not change the interpretation, but would help improve the analytical rigour.	null	null	Table 2: Please consider providing further explanations for this table. It was not clear what the authors wanted to show.	1	2	buildings12040417_perova
Dimension Office A Office B Location Singapore Shenzhen, South China Climate Zone Tropical Monsoon climate Sub-tropical climate Coordinate 1°16′North, 103°5′East 22°55′North, 114.1°East Floor 8 10 Office Ventilation Type Central air conditioned Natural ventilation Temperature in the office 25 to 26° C 26 to 28°C No.	null	null	P8, L245: Please specify why these two offices were of interest (e.g., were they comparable or had specify architectural features worthy of study). If possible, please provide more characteristics (e.g., size, floor area, furniture layout (e.g., open-plan or enclosed), etc.) for each office. Later (P10, L299), it says 201 questionnaires were collected, with 161 occupants taking part in the Singaporean office. This led me to believe that this office was much larger than the building studied in China. An image showing the indoor conditions and outdoor façade for each might be beneficial. Many of the explanations found in section 3.1 could be moved into this part of the manuscript, since they many describe and show the existing office conditions and to do necessarily form part of the main results.	1	2	buildings12040417_perova
International Journal of Environmental Research and Public Health.	null	null	Section 3.3. Although I appreciated the thoroughness to which the descriptive statistical was explained, I wasn’t convinced the mean was the best indicator for the data, considering that evaluation scores were collected on a 5-point scale and not a continuous linear one. In-lieu of the mean, please consider using the median and inter-quartile range as the central tendency and dispersion indicators. Figures 1 and 4 can be removed, as the assumption of normality no longer applies (also on P15, L399-400), or replaced with boxplots.	1	2	buildings12040417_perova
Revision in Page 13 Line 381-383: “The Cronbach’s α coefficient value of the main scale is 0.72, while those of the sub-scales GH, NR, and BDE in order are obtained as 0.68, 0.79, and 0.63, indicating that the questionnaire is reliable (i.e., an acceptable reliability: Cronbach's α>0.6) [57, 58] (Table 8).” Citations are added in the Reference list: 57.	null	null	Table 8: Please consider applying benchmarks for what constitute reasonable levels for internal consistency, when using the Cronbach’s Alpha (e.g., α>0.7): Please see, for example: Taber, 2018. The use of Cronbach’s Alpha when developing and reporting research instruments in science education. Research in Science Education. Tavakol et al. Making sense of Cronbach’s Alpha. International Journal of Medical Education.	1	2	buildings12040417_perova
A Data-Driven Analysis of Occupant Workspace Dissatisfaction.	null	null	Figure 3. The plot is well presented. A few minor notes for improvement: 1) Please consider adding short or abbreviated labels referring to the actual question, instead of codes (e.g., GH3-Q10). This would make it easier for the reader; 2) Round the percentages to the nearest whole number.	1	2	buildings12040417_perova
Response 6: The different genders and different ages are included in the study.	null	null	P17, L434: Please correct the unfortunate citation error on this line.	1	2	buildings12040417_perova
The above contents have been corrected in the revised version.	null	null	P18, section 4.2: Similar to comment #13, the data may be more suited to a Spearman’s correlation test, instead of the Pearson’s correlation coefficient. Due to the reasonable size of the dataset collected, it may not change the interpretation, but would help improve the analytical rigor.	1	2	buildings12040417_perova
I think psychological factors will also affect human physiological comfort.	null	null	P18, L448-450: Please check whether the sentence is accurate and correct the table caption numbers; I believe these should be Tables 10 and 11 and 12, not 1, 2 and 3. The sentence reads: Homogenous subsets with significant discrepancies (differences?) across subsets, leading to no significant differences across subsets. The above is not easy to grasp. If the information is accurate, please consider amending this to make this clearer.	1	2	buildings12040417_perova
Physiological and cognitive performance of exposure to biophilic indoor environment.	null	null	While the conclusions were well structured, I felt the authors could have highlighted more the main takeaway messages from their endeavors, in particularly the relationship between biophilic design and occupant health and wellbeing. This seems to be a core aspect of their work but did really emerge from the final section of their work in the same way it was emphasized in the abstract.	1	2	buildings12040417_perova
A Review of Psychological Literature on the Health and Wellbeing Benefits of Biophilic Design.	null	null	The introduction can be optimized appropriately.The introduction of the term "Biophilia" can be more detailed and easy to understand .By contrast, the introduction of “Biophilic Design”is very substantial.It may be better to find some literature to combine workplace design and “Biophilic Design”,and then to explore the relationship between them.	1	2	buildings12040417_perova
Biophilia, biophobia, and natural landscapes.	null	null	The introduction can be optimized appropriately.The introduction of the term "Biophilia" can be more detailed and easy to understand .By contrast, the introduction of “Biophilic Design”is very substantial.It may be better to find some literature to combine workplace design and “Biophilic Design”,and then to explore the relationship between them.	1	2	buildings12040417_perova
Response 7: The method of selection of the biophilic design attributes/patterns for workplace is: Step one, find out the correlated biophilic design characteristics from the two mainstream biophilic design frameworks.	null	null	The introduction can be optimized appropriately.The introduction of the term "Biophilia" can be more detailed and easy to understand .By contrast, the introduction of “Biophilic Design”is very substantial.It may be better to find some literature to combine workplace design and “Biophilic Design”,and then to explore the relationship between them.	1	2	buildings12040417_perova
The major scale of the questionnaire consists of three parts (subscales): general health (GH), nature relatedness (NR), and biophilic design evaluation (BDE).	null	null	Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.	1	2	buildings12040417_perova
Although this I don’t believe this would be a large undertaking, the analysis would be better served by non-parametric tests due to the level of measurement used (i.e.	null	null	Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.	1	2	buildings12040417_perova
Apart from the design evaluation, POE is also one of the mainstream research methods that can effectively diagnosing operation problems.	null	null	Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.	1	2	buildings12040417_perova
Therefore, the weighting results of this experiment are not employed to deny the ranking in the 14 Patterns of Biophilic Design.	null	null	Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.	1	2	buildings12040417_perova
Please see the revised contents in the updated manuscript below: Revision in Page 5 Line 191-197: “For instance, the patterns “Presence of Water”, “Prospect”, “Refuge”, “Mystery”, and “Risk” (i.e., itemized patterns 5, 11, 12, 13, and 14 in Column B) are recommended because they are proofed that benefits health.	null	null	Figure 1 should be improved regarding the arrow.	3	2	buildings12040417_perova
Stacked graph with percentage responses for individually arranged items (from the bottom with a high percentage of disagreement to the top with high percentage of agreement) is reduced, because the illustrations are obvious in the figure.	null	null	Photo in table 6 should check the copyright of these photo.	3	2	buildings12040417_perova
#6: P3, L106: While I generally agree with, questions could be raised to whether POE scales should be used to evaluate biophilic design evaluation.	null	null	Please bring strong relevance to the scope of journal "Buildings" by investigating most recent literature.	3	2	buildings12040417_perova
Response We are grateful to the reviewer for their favorable review and constructive input 1-	null	null	How is subtotal resection defined in chordoma (% of volume remaining?)	1	2	cancers14040966_makarova
Thus it would be helpful for the authors to clarify this.	null	null	What means Pathology 0 in table 4?	1	2	cancers14040966_makarova
Response We are grateful to the reviewer for their favorable review and constructive input 1-	null	null	Thus it would be helpful for the authors to clarify this. The AMIGO suite has great capabilities, but when it comes to intraoperative imaging, it is CT and MRI scans that are made, and then using Brain Lab and possibly other software, that information is processed and redisplayed including 3D reconstructions.	1	2	cancers14040966_makarova
The authors are to be commended for pursing this approach in a small series of patients with difficult diagnoses.	null	null	This does not detract from the value of the technique, but it is important to clarify that what really is happening is a variety of preoperative imaging is imported and co-registered into the Brain Lab, and then intraoperative MR and occasionally CT data is again obtained and processed and analyzed.	1	2	cancers14040966_makarova
There is not much to add and publication can be recommended.	null	null	It is therefore difficult to state that the results were clearly improved or to even compare to other series, without larger numbers and direct comparison or classification of individual tumor locations and characteristics in differing series.	1	2	cancers14040966_makarova
All that is needed is easy intra-operative access to CT and MR imaging and the ability to import and reconstruct the data real time.	null	null	How is subtotal resection defined in chordoma (% of volume remaining?)	1	2	cancers14040966_perova
What means Volume reduction 0 and 0% in Table 4?	null	null	What means Pathology 0 in table 4?	1	2	cancers14040966_perova
With these caveats clarified in a modified version, the paper is valuable and could be published.	null	null	when one reads it initially it would appear that there are many different modalities available for intraoperative imaging. However, the PET scan does not appear to have actually been used for intraoperative repeat imaging to assess resection, and fluoroscopy and 3D reconstructions using Brain Lab software are standard fare in many operating rooms. Intraoperative angiography might have been used in the case of vascular injury but this also is available in many institutions. The authors appear to really only use CT and MRI intraoperatively, with the other modalities imported preoperatively into the Brain Lab navigational system. 3D reconstructions of newly acquired data is a capability of the software, and is available in many places. Thus it would be helpful for the authors to clarify this. The AMIGO suite has great capabilities, but when it comes to intraoperative imaging, it is CT and MRI scans that are made, and then using Brain Lab and possibly other software, that information is processed and redisplayed including 3D reconstructions. Making this clear is important for others who either use the technique or who want to do so. All that is needed is easy intra-operative access to CT and MR imaging and the ability to import and reconstruct the data real time. That is plenty and a challenge for many, but the other imaging modalities used are either standard fare in many centers (x-ray imaging, endoscopy) or do not need to be in adjacent rooms (PET scanning and angiography (can be done in the primary Or). This does not detract from the value of the technique, but it is important to clarify that what really is happening is a variety of preoperative imaging is imported and co-registered into the Brain Lab, and then intraoperative MR and occasionally CT data is again obtained and processed and analyzed.	1	2	cancers14040966_perova
The AMIGO suite has great capabilities, but when it comes to intraoperative imaging, it is CT and MRI scans that are made, and then using Brain Lab and possibly other software, that information is processed and redisplayed including 3D reconstructions.	null	null	The results, while admirable, cannot easily be compared to other series, as the numbers are small and each case has its own complex series of characteristics that make it unique. It is therefore difficult to state that the results were clearly improved or to even compare to other series, without larger numbers and direct comparison or classification of individual tumor locations and characteristics in differing series.	1	2	cancers14040966_perova
Minor Issues: [4] In Figures 3G and 3H, please specify p-values for untreated vs selumetinib in FLO-1/EV and OE33/shMACC1 respectively.	null	null	Based on the cell line RNA and protein data the expression level of MACC1 is highly variable rather than being present or not. Is there a similar variability present among the tissue samples? Please provide the distribution of the IRS scores of the patient cohort and explain how was IRS 5 chosen as cut off?	1	2	cancers14071773_makarova
[10] If the journal allows it, please break up the abstract into Introduction, Methods, Results, Conclusion.	null	null	The authors argue that MACC1 expression did not significantly influenced cell proliferation in the two cell line models. However, cell proliferation was analyzed only in a 24-hour long period even though most cancer cells have a doubling time around 24 hours. In order to draw a conclusion about the proliferation effect a longer (48 or 72 hours) measurement is necessary.	1	2	cancers14071773_makarova
[8] In line 274, please change "OR 1.51" to "OR 1.51 [... - ...]", i.e.	null	null	It would be nice to know the selumetinib sensitivity of the two used cell lines. The concentration used from selumetinib both for the cell line experiments (10 microM) and for the animal experiments (50mg/kg) are quite high. Please discuss how the applied concentrations are related to the clinicaly used dosage (75 mg administered orally twice https://clinicaltrials.gov/ct2/show/NCT02448290) and why not the more efficient MEK1 inhibitor trametinib was used for the experiments.	1	2	cancers14071773_makarova
In this study, the authors have shown that the same is also true for gastric/esophageal cancer.	null	null	The authors´answer regarding the cut off is sufficient, please include this argument either in the methods section or as supplementary information.	3	2	cancers14071773_makarova
should be after "Expression was correlated with survival and morphological characteristics."	null	null	The authors refer to a data "Proliferation of FLO1 EV and FLO1 MACC1 over 72 h", however I couldn´t find the figure either in the manuscript file or here in the answer.	3	2	cancers14071773_makarova
[3] Throughout the paper, 10^x wrongly displays as 10x (e.g.	null	null	[1] Figure 4 is missing. In the pdf I reviewed, the caption is there, but the figure is not.	1	2	cancers14071773_makarova
In the in vitro analysis they investigated MACC1 expression in five cell lines and generated a cell line with MACC1 overexpression and a MACC1 knock-down cell line.	null	null	[2] Abstract says 266 patients were analyzed (line 36), while result says 360 patients were analyzed (line 249). Please fix this inconsistency.	1	2	cancers14071773_makarova
The authors´answer regarding the cut off is sufficient, please include this argument either in the methods section or as supplementary information.	null	null	[3] Throughout the paper, 10^x wrongly displays as 10x (e.g. "105" instead of "10^5" in lines 152 and 170, "106" instead of "10^6" in line 217, "X2" instead of "X^2" in line 241, "108" instead of "10^8" in lines 353, 354, 365, 366, 367, 368, 370, 371).	1	2	cancers14071773_makarova
Based on these comments we herewith respond to all questions raised in a point-by-point manner, as follows: Reviewer 2 Major Issues:	null	null	[4] In Figures 3G and 3H, please specify p-values for untreated vs selumetinib in FLO-1/EV and OE33/shMACC1 respectively. If the difference is statistically significant, please briefly explain/speculate why.	1	2	cancers14071773_makarova
[5] If possible, please use a higher resolution version of Figures 3F and 3I (the legends are blurry and hard to read in the current version).	null	null	[5] If possible, please use a higher resolution version of Figures 3F and 3I (the legends are blurry and hard to read in the current version).	1	2	cancers14071773_makarova
The authors refer to a data "Proliferation of FLO1 EV and FLO1 MACC1 over 72 h", however I couldn´t find the figure either in the manuscript file or here in the answer.	null	null	[6] In line 306/307, please explain/speculate briefly why the control clone had higher MACC1 expression than the wildtype.	1	2	cancers14071773_makarova
The concentration used from selumetinib both for the cell line experiments (10 microM) and for the animal experiments (50 mg/kg) are quite high.	null	null	[7] In line 272/273: (i) please report median survival in each group (instead of mean survival), (ii) please specify Hazard ratio with 95% confidence interval (in addition to p values), (iii) please report both overall survival result and disease-specific survival result (since you showed both in Figures).	1	2	cancers14071773_makarova
Author Response Please see the attachment Author Response File: Author Response.pdf	null	null	[8] In line 274, please change "OR 1.51" to "OR 1.51 [... - ...]", i.e. specify the 95% confidence interval.	1	2	cancers14071773_makarova
Answer: We thank the reviewer for this comment.	null	null	[9] In line 277-279: (i) please report median survival in each group (instead of mean survival), (ii) please specify Hazard ratio with 95% confidence interval (in addition to p values). Same for lines 425/426.	1	2	cancers14071773_makarova
Based on these comments we herewith respond to all questions raised in a point-by-point manner, as follows: Reviewer 2 Major Issues:	null	null	[10] If the journal allows it, please break up the abstract into Introduction, Methods, Results, Conclusion. If the journal requires an unstructured abstract instead, please reorganize the current abstract so that the content flows uninterrupted (e.g. "MACC1 is an independent negative prognostic marker in AGE/S patients." should be after "Expression was correlated with survival and morphological characteristics." and before "To analyze the role of MACC1 in vitro the cell lines FLO-1 and OE33 were lentivirally manipulated." and so on).	1	2	cancers14071773_makarova
[6] In line 306/307, please explain/speculate briefly why the control clone had higher MACC1 expression than the wildtype.	null	null	The authors have satisfactorily addressed my comments.	3	2	cancers14071773_makarova
Based on these comments we herewith respond to all questions raised in a point-by-point manner, as follows: Reviewer 1: 1.	null	null	Based on the cell line RNA and protein data the expression level of MACC1 is highly variable rather than being present or not. Is there a similar variability present among the tissue samples? Please provide the distribution of the IRS scores of the patient cohort and explain how was IRS 5 chosen as cut off?	1	2	cancers14071773_perova
The results are interesting and may have clinical relevance.	null	null	The authors argue that MACC1 expression did not significantly influenced cell proliferation in the two cell line models. However, cell proliferation was analyzed only in a 24-hour long period even though most cancer cells have a doubling time around 24 hours. In order to draw a conclusion about the proliferation effect a longer (48 or 72 hours) measurement is necessary.	1	2	cancers14071773_perova
Please discuss how the applied concentrations are related to the clinically used dosage (75 mg administered orally twice https://clinicaltrials.gov/ct2/show/NCT02448290) and why not the more efficient MEK1 inhibitor trametinib was used for the experiments.	null	null	It would be nice to know the selumetinib sensitivity of the two used cell lines. The concentration used from selumetinib both for the cell line experiments (10 microM) and for the animal experiments (50mg/kg) are quite high. Please discuss how the applied concentrations are related to the clinicaly used dosage (75 mg administered orally twice https://clinicaltrials.gov/ct2/show/NCT02448290) and why not the more efficient MEK1 inhibitor trametinib was used for the experiments.	1	2	cancers14071773_perova
In order to draw a conclusion about the proliferation effect a longer (48 or 72 hours) measurement is necessary.	null	null	The authors´answer regarding the cut off is sufficient, please include this argument either in the methods section or as supplementary information.	3	2	cancers14071773_perova
It would be nice to know the selumetinib sensitivity of the two used cell lines.	null	null	The authors refer to a data "Proliferation of FLO1 EV and FLO1 MACC1 over 72 h", however I couldn´t find the figure either in the manuscript file or here in the answer.	3	2	cancers14071773_perova
Based on these comments we herewith respond to all questions raised in a point-by-point manner, as follows: Reviewer 1: 1.	null	null	[1] Figure 4 is missing. In the pdf I reviewed, the caption is there, but the figure is not.	1	2	cancers14071773_perova
In the in vitro analysis they investigated MACC1 expression in five cell lines and generated a cell line with MACC1 overexpression and a MACC1 knock-down cell line.	null	null	[2] Abstract says 266 patients were analyzed (line 36), while result says 360 patients were analyzed (line 249). Please fix this inconsistency.	1	2	cancers14071773_perova
Please discuss how the applied concentrations are related to the clinically used dosage (75 mg administered orally twice https://clinicaltrials.gov/ct2/show/NCT02448290) and why not the more efficient MEK1 inhibitor trametinib was used for the experiments.	null	null	[3] Throughout the paper, 10^x wrongly displays as 10x (e.g. "105" instead of "10^5" in lines 152 and 170, "106" instead of "10^6" in line 217, "X2" instead of "X^2" in line 241, "108" instead of "10^8" in lines 353, 354, 365, 366, 367, 368, 370, 371).	1	2	cancers14071773_perova
Previous studies in colorectal cancer have shown that MACC1 expression (which is associated with poor prognosis) induces cell migration in vitro and metastasis formation in vivo, and these effects can be inhibited by selumetinib.	null	null	[4] In Figures 3G and 3H, please specify p-values for untreated vs selumetinib in FLO-1/EV and OE33/shMACC1 respectively. If the difference is statistically significant, please briefly explain/speculate why.	1	2	cancers14071773_perova
In the in vitro analysis they investigated MACC1 expression in five cell lines and generated a cell line with MACC1 overexpression and a MACC1 knock-down cell line.	null	null	[5] If possible, please use a higher resolution version of Figures 3F and 3I (the legends are blurry and hard to read in the current version).	1	2	cancers14071773_perova
Minor Issues: [4] In Figures 3G and 3H, please specify p-values for untreated vs selumetinib in FLO-1/EV and OE33/shMACC1 respectively.	null	null	[6] In line 306/307, please explain/speculate briefly why the control clone had higher MACC1 expression than the wildtype.	1	2	cancers14071773_perova
I recommend the following edits before publication.	null	null	[7] In line 272/273: (i) please report median survival in each group (instead of mean survival), (ii) please specify Hazard ratio with 95% confidence interval (in addition to p values), (iii) please report both overall survival result and disease-specific survival result (since you showed both in Figures).	1	2	cancers14071773_perova
Author Response Dear Professor Mok, We appreciate that you give us the possibility to revise our manuscript and we thank the reviewers for their valuable comments.	null	null	[8] In line 274, please change "OR 1.51" to "OR 1.51 [... - ...]", i.e. specify the 95% confidence interval.	1	2	cancers14071773_perova
If the journal requires an unstructured abstract instead, please reorganize the current abstract so that the content flows uninterrupted (e.g.	null	null	[9] In line 277-279: (i) please report median survival in each group (instead of mean survival), (ii) please specify Hazard ratio with 95% confidence interval (in addition to p values). Same for lines 425/426.	1	2	cancers14071773_perova
If the difference is statistically significant, please briefly explain/speculate why.	null	null	[10] If the journal allows it, please break up the abstract into Introduction, Methods, Results, Conclusion. If the journal requires an unstructured abstract instead, please reorganize the current abstract so that the content flows uninterrupted (e.g. "MACC1 is an independent negative prognostic marker in AGE/S patients." should be after "Expression was correlated with survival and morphological characteristics." and before "To analyze the role of MACC1 in vitro the cell lines FLO-1 and OE33 were lentivirally manipulated." and so on).	1	2	cancers14071773_perova
In this study, the authors have shown that the same is also true for gastric/esophageal cancer.	null	null	The authors have satisfactorily addressed my comments.	3	2	cancers14071773_perova
This might be achieved by using the combination of so-called Tumor Treating fields (TTFields) with targeted drug, I have the following suggestions about this manuscript:	null	null	What is the rationale of using 150 kHz TTFields? TTFields at 100 kHz has also shown significant differences as cytotoxicity at p<0.01 and p<0.001 in HepG2 and Huh-7D12 cells which have around 60% and 50% of cell survival. Why did the authors use high frequency of TTFields though the cytotoxicity was also observed in lower dose (Fig 1A).	1	2	cancers14122959_makarova
Response 7: We thank the reviewer for this question.	null	null	What is the ‘n’ number of the samples and experiments in each group? Also mention the ‘n’ number in all the experiments involved for invitro and invivo.	1	2	cancers14122959_makarova
In the animal study we have now added IHC examination of beclin-1 and of GRP78, a marker for ER stress, as described in results sub-section 3.4.	null	null	LC3 is increased in all the groups except in control tissue, however, cell death was increased only in combined group. How can the authors correlate autophagy with apoptosis? It is not so trustworthy that the only expression of LC3B indicate the treated condition have increased autophagy in the tumor tissue. Other important autophagy and degradation markers like Beclin1 and P62 need to be shown to reflect the regulatory mechanism of TTFields, as well as for the combined treatment with Sorafenib.	1	2	cancers14122959_makarova
Response 6: We thank the reviewer for this comment.	null	null	Several data have shown very high error bars in each group (especially Fig Can the author provide the tumor images which were harvested from mice?	1	2	cancers14122959_makarova
p < 0.05, p < 0.01, p < 0.001, and **p < 0.0001 relative to time-respective control; two-way ANOVA.	null	null	In the IHC experiment for PARP, the authors have incubated with primary antibody only for 30 min? Is that timing enough to get protein expression? What source of secondary antibody was used? In addition to IHC, I suggest performing western blot using PARP antibody where the full length and cleaved bands are observed in the same blot.	1	2	cancers14122959_makarova
Other important autophagy and degradation markers like Beclin1 and P62 need to be shown to reflect the regulatory mechanism of TTFields, as well as for the combined treatment with Sorafenib.	null	null	The figure number is mislabeled in Fig 4D-LC3 Immunofluorescence.	1	2	cancers14122959_makarova
What are the p53 status and the apoptosis signaling pathway function in N1S1 cells?	null	null	Why there is no error bar in the control group of all bar graphs? Please include error bars and re-calculate the statistical analysis for all the data wherever missing.	1	2	cancers14122959_makarova
The manuscript is an interesting work related to a potential new therapy of hepatocellular carcinoma (HCC) by using TTFields in combination with a TKI (Sorafenib).	null	null	Figure legends of Fig2D is missing. Fig C is repeated in the legend. Please label the figures appropriately. It is so frustrating to understand.	1	2	cancers14122959_makarova
Point 8: Since sorafenib acts also on angiogenesis, did the authors investigate if TTFields may interfere with anti-angiogenic effect sorafenib-mediated?	null	null	There is no data in Fig 4A. Whole data is missing but have explained in the result section and in figure legends.??	1	2	cancers14122959_makarova
I thank the authors for their extensive work and comprehensive review of the manuscript.	null	null	Line 337 seems over statement since the data are not shown in the manuscript.	1	2	cancers14122959_makarova
Overall, the authors believe that this research demonstrates potential for concomitant TTFields and sorafenib application in the treatment of HCC.	null	null	Typos: Line 111, ‘invitro’ spelling is not correct. Double ‘and’ in Line 342. Need language and grammar check.	1	2	cancers14122959_makarova
p < 0.05, p < 0.01, p < 0.001, and **p < 0.0001 relative to time-respective control; two-way ANOVA.	null	null	This is an interesting scientific study, as it concerns the issue of hepatocellular carcinoma, it also has a clinical aspect. The materials and methods section are elaborated in the details. Therefore, I expect further additional examination in the future. References contain mostly publications printed in the last 10 years. The authors indicated that TTFields had potential to be a new treatment option of hepatocellular carcinoma. The present study was examined in terms of autophagy and apoptosis in the antitumor effects of TTFields and sorafenib. However, the exact mechanism of the combination therapy induced cell death is not yet known as the activation of autophagy in the combination therapy was not increased.	1	2	cancers14122959_makarova
Were the mice perfused before collecting the tumors?	null	null	In vitro experiments sub-section in Methods sections lacks many experimental details (e.g., type of plate/flask, plating overnight or not before experiment, number of plated cells). A very important missing is not showing the actual number of rats included in the final analyses (the ones who successfully received therapy for more than 18 hours/day). This must be added.	1	2	cancers14122959_makarova
Point 7: Why there is no error bar in the control group of all bar graphs?	null	null	What are the p53 status and the apoptosis signaling pathway function in N1S1 cells? Maybe the cytotoxicity data will reveal a different better frequency.	1	2	cancers14122959_makarova
Other important autophagy and degradation markers like Beclin1 and P62 need to be shown to reflect the regulatory mechanism of TTFields, as well as for the combined treatment with Sorafenib.	null	null	Another puzzling experiment is the schedule for the in vivo work. Since the authors missed to add Figure 4A for timeline, based on Methods section the rats were treated for 5 days with TTFields and or sorafenib and a day later the rays were sacrificed. While a short “acute” follow-up is welcome the most important experiment should allow the follow-up for much more days to indeed observe the effect of TTFields added to sorafenib. I could not find an explanation for not including a long term follow-up. In my opinion, this is a key therapeutically experiment which must be done and included in the study.	1	2	cancers14122959_makarova
Response 4: We thank the reviewer for this question.	null	null	There is no explanation why the most effective dose was 150 kHz and higher does actually decreases the killing. Can this dose observed in vitro on only tumor cells be translated to in vivo work where the tumor microenvironment is total different?	1	2	cancers14122959_makarova
p < 0.05, p < 0.01, p < 0.001, and **p < 0.0001 relative to time-respective control; two-way ANOVA.	null	null	Why the in vitro experiment was performed for 72 hours and in in vivo for 120 hours?	1	2	cancers14122959_makarova

Naturalistic shapes and forms the shapes of plants on building facades and columns, animal facsimiles woven into fabrics and coverings.

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If this was the case, perhaps this could be succinctly mentioned. In consideration to their response #8, I understood and agreed with why half the seven of the 14 papers were discarded, but it did not provide much insight into why the Patterns of Biophilic Design were still used. A more useful example, which may have elucidated this more, was whether are there too few frameworks available, and/or none others could have been used.

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Author Response Response to Reviewer 1 Comments I would like to thank the authors for taking all my comments into full consideration.

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The introduction can be optimized appropriately.The introduction of the term "Biophilia" can be more detailed and easy to understand .By contrast, the introduction of “Biophilic Design”is very substantial.It may be better to find some literature to combine workplace design and “Biophilic Design”,and then to explore the relationship between them.

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These are not significant remarks, but nonetheless, might provide further improvements and clarity: #1: For their response to comment #6, while I generally agreed with the authors, I felt that it didn’t quite address what I tried to originally convey.

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Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.

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Kent, M., Parkinson, T., Kim, J., Schiavon, S., 2021.

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The result of biophilic design frameworks for specific workplace typology is of certain value. The location of the workplace selected in this article is limited, the related biophilic factors are scientifically screened, and the researchers have made a detailed classification study. However, the huge research scope has certain obstacles to the relevant results, and the general and targeted conclusions will be worse.

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The figures and pictures have been adjusted in the revised manuscript.

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It is best to supplement and describe the necessity of research. At the same time, it will be more complete if the results are reflected in the summary.

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There are overlaps between the nine biophilic design attributes and these eight influential factors for the workplace.

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The object of the questionnaire should be composed of people with different ages and genders, which is best explained in the article.

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Thermal & Air flow variability Subtle changes in air temperature, relative humidity, air ow across the skin, and surface temperatures that mimic natural environments.

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Adding some explanations, examples and data comparison to the conclusion will be more intuitive and convincing, just as discussed earlier in the article. Perhaps this makes this article more complete and credible. At the same time, the conclusion only summarizes the article, and lasks discussions and explanations for the future research direction.

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We think it is not hard for the readers to understand, and the original percentages (round to one decimal place) is more accurate.

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The theoretical part of the presentation is extensive, but the application part is relatively poorly described.

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Animals Re-presentation of nonhuman animal life 6.

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It is better to supplement the temperature, humidity and other parameters of the selected office in the part of the experiment, so as to facilitate readers' reference rather than just giving the location.

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Yin, J., Yuan, J., Arfaei, N., Catalano, P.J., Allen, G.J., Spengler, J.D., 2020.

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The author can think about the impact of such a pro biological design model on the psychology of different experimental personnel. I think psychological factors will also affect human physiological comfort.

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#2: P1, L39-41: Please provide references to these frameworks.

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Figure 1 should be improved regarding the arrow.

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Instead, studies may elect to use, for example, other relatable scales, which may not have originally been designed for POE surveys (e.g.,

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Photo in table 6 should check the copyright of these photo.

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Yin, J., Arfaei, N., MacNaughton, P., Catalano, P.J., Allen, J.G., Spengler, J.D., 2019.

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Please bring strong relevance to the scope of journal "Buildings" by investigating most recent literature.

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Point 2: The illustrations in the article are small and a bit vague, some pictures can shrink a little, not to the top to the border, these can be optimized.

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The definition of biophilia is described as an “inherent love” toward nature. While this is somewhat accurate, it might be more appropriate to elucidate this as an “inherent affinity”.

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#3: P2, 47-53: Although in the past there were few guidelines, nowadays, there may be more standards that focus on nature integration within the built environment.

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P1, L39-41: Please provide references to these frameworks. Reading further to page 3, I believe these are the 24 biophilic design attributes [ref. 25,39], and the 14 patterns of biophilic design [ref.40]. Further references around the biophilic concept could also be provided, e.g.: Bjørn et al., 2009. The latter reference reviewed many international standards that advocate nature and biophilic design for view and building spaces, with examples given to the Singapore context. This somewhat overlaps with my next comment.

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Yin, J., Zhua, S., MacNaughton, P., Joseph, G., Allen, J.G., Spengler, J.D., 2018.

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P2, 47-53: Although in the past there were few guidelines, nowadays, there may be more standards that focus on nature integration within the built environment. WELL v2 has several features for Nature and Mind, and Biophilia – Parts I and II, with quantitative assessment methods provided. Similarly, the Green Mark system uses the green plot ratio, assigning credits to greenery provision to enhance biodiversity and visual relief. Other standards likely incorporate biophilic elements in building architecture and could be worth highlighting. The general issue raised by the authors do not necessarily imply a lack of guidelines for biophilic design, since there are several readily available, but may point toward prioritization or emphasis of criteria to meet certain varying expectations, which was alluded to on lines 52-53. If the authors agree with this, perhaps this could be revised here to reflect this.

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#11: Table 2: Please consider providing further explanations for this table.

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P2, L63: Although I wouldn’t completely rule this out, POE surveys may not always provide feedback to the architect, since they are implemented post design-stage and the building would be operated by facility management or the owner. In my view, POE information had more utility diagnosing operation problems, which can be solved when running the building, identifying prominent sources of dissatisfaction that can prompt action to resolve these issues. Recently POE studies, also using office data, advocate this as benefit to their implementation, albeit not necessarily being the only reason: žGraham et al., 2020. Building & Cities. Kent et al., 2021. Building and Environment. Cheung et al. 2021.

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Response 7: 1) The Conclusion is rewritten to highlight the relationship between biophilic design and occupant health and wellbeing: Revision in Page 23 Line 516-540: “The significant research outputs from the present scrutiny are shown as following: a) The authors develop a POE questionnaire for evaluating the biophilic design for workplace health and wellbeing.

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P3, L92: I think refers to “has helped” given the five decades predating this.

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Biophilia: Does Visual Contact with Nature Impact on Health and Well-Being?

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P3, L106: While I generally agree with, questions could be raised to whether POE scales should be used to evaluate biophilic design evaluation. Biophilic design is known to elicit mental and physical health benefits, as stated by the authors on page 1, lines 29-32. Therefore, it would be more appropriate to use psychological scales (e.g., PANAS or psychological restoration), instead of design orientated question or survey. If the authors agree with this, this aspect could be revised.

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When the occupants feel that they have a strong sense of relationship with nature, it is observed that the biophilic environment would have positive impacts on their health.

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Something I felt would useful would at the beginning would be a clear definition for what “biophilic attributes” refers to. Figure 1 provides some insights into this, but these listed attributes span across different domains and the communal features are not that apparent. This becomes an issue later, since some aspects referring to biophilic design become unclear.

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Thermal & Air flow variability Subtle changes in air temperature, relative humidity, air ow across the skin, and surface temperatures that mimic natural environments.

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P4, L173-174: The authors state that seven of the patterns from the 14 patterns of biophilic design were discarded. If this was the case, then please better articulate its overarching utility in this study, considering that half of the patterns were not relevant to the research scope.

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The theoretical part of the presentation is extensive, but the application part is relatively poorly described

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P4, L180-183: In traditional POE studies and general building science research, daylight, thermal comfort, and air-quality, would be considered as indoor environment parameters (as examples, please see refs. in comment #4), while office layout and building form would be considered a physical and architectural parameters. Reading further to page 5, lines 189-192, the authors begin to suggest to this, but referred to them and others indoor environmental parameters as factors for the workplace. I would suggest better rationalizing the connections between the nine design parameters to biophilia to make these more overt.

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Limitation and Future Studies is added in the revised version: Revision in Page 23 Line 542-551: “6.

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Figure 1: The image presenting all the linkages is very interesting and is worth emphasizing, but contains an overwhelming degree of information, and the text and line sizes are too small for readership. Please consider simplifying the figure. For example, some text boxes many do not need further explanation (e.g., presence of water); also, the lines connecting column A to the same patterns in column 4 could be color coordinated.

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Due to the reasonable size of the dataset collected, it may not change the interpretation, but would help improve the analytical rigour.

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Table 2: Please consider providing further explanations for this table. It was not clear what the authors wanted to show.

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Dimension Office A Office B Location Singapore Shenzhen, South China Climate Zone Tropical Monsoon climate Sub-tropical climate Coordinate 1°16′North, 103°5′East 22°55′North, 114.1°East Floor 8 10 Office Ventilation Type Central air conditioned Natural ventilation Temperature in the office 25 to 26° C 26 to 28°C No.

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P8, L245: Please specify why these two offices were of interest (e.g., were they comparable or had specify architectural features worthy of study). If possible, please provide more characteristics (e.g., size, floor area, furniture layout (e.g., open-plan or enclosed), etc.) for each office. Later (P10, L299), it says 201 questionnaires were collected, with 161 occupants taking part in the Singaporean office. This led me to believe that this office was much larger than the building studied in China. An image showing the indoor conditions and outdoor façade for each might be beneficial. Many of the explanations found in section 3.1 could be moved into this part of the manuscript, since they many describe and show the existing office conditions and to do necessarily form part of the main results.

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International Journal of Environmental Research and Public Health.

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Section 3.3. Although I appreciated the thoroughness to which the descriptive statistical was explained, I wasn’t convinced the mean was the best indicator for the data, considering that evaluation scores were collected on a 5-point scale and not a continuous linear one. In-lieu of the mean, please consider using the median and inter-quartile range as the central tendency and dispersion indicators. Figures 1 and 4 can be removed, as the assumption of normality no longer applies (also on P15, L399-400), or replaced with boxplots.

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Revision in Page 13 Line 381-383: “The Cronbach’s α coefficient value of the main scale is 0.72, while those of the sub-scales GH, NR, and BDE in order are obtained as 0.68, 0.79, and 0.63, indicating that the questionnaire is reliable (i.e., an acceptable reliability: Cronbach's α>0.6) [57, 58] (Table 8).” Citations are added in the Reference list: 57.

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Table 8: Please consider applying benchmarks for what constitute reasonable levels for internal consistency, when using the Cronbach’s Alpha (e.g., α>0.7): Please see, for example: Taber, 2018. The use of Cronbach’s Alpha when developing and reporting research instruments in science education. Research in Science Education. Tavakol et al. Making sense of Cronbach’s Alpha. International Journal of Medical Education.

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A Data-Driven Analysis of Occupant Workspace Dissatisfaction.

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Figure 3. The plot is well presented. A few minor notes for improvement: 1) Please consider adding short or abbreviated labels referring to the actual question, instead of codes (e.g., GH3-Q10). This would make it easier for the reader; 2) Round the percentages to the nearest whole number.

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Response 6: The different genders and different ages are included in the study.

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P17, L434: Please correct the unfortunate citation error on this line.

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The above contents have been corrected in the revised version.

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P18, section 4.2: Similar to comment #13, the data may be more suited to a Spearman’s correlation test, instead of the Pearson’s correlation coefficient. Due to the reasonable size of the dataset collected, it may not change the interpretation, but would help improve the analytical rigor.

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I think psychological factors will also affect human physiological comfort.

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P18, L448-450: Please check whether the sentence is accurate and correct the table caption numbers; I believe these should be Tables 10 and 11 and 12, not 1, 2 and 3. The sentence reads: Homogenous subsets with significant discrepancies (differences?) across subsets, leading to no significant differences across subsets. The above is not easy to grasp. If the information is accurate, please consider amending this to make this clearer.

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Physiological and cognitive performance of exposure to biophilic indoor environment.

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While the conclusions were well structured, I felt the authors could have highlighted more the main takeaway messages from their endeavors, in particularly the relationship between biophilic design and occupant health and wellbeing. This seems to be a core aspect of their work but did really emerge from the final section of their work in the same way it was emphasized in the abstract.

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A Review of Psychological Literature on the Health and Wellbeing Benefits of Biophilic Design.

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The introduction can be optimized appropriately.The introduction of the term "Biophilia" can be more detailed and easy to understand .By contrast, the introduction of “Biophilic Design”is very substantial.It may be better to find some literature to combine workplace design and “Biophilic Design”,and then to explore the relationship between them.

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Biophilia, biophobia, and natural landscapes.

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The introduction can be optimized appropriately.The introduction of the term "Biophilia" can be more detailed and easy to understand .By contrast, the introduction of “Biophilic Design”is very substantial.It may be better to find some literature to combine workplace design and “Biophilic Design”,and then to explore the relationship between them.

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Response 7: The method of selection of the biophilic design attributes/patterns for workplace is: Step one, find out the correlated biophilic design characteristics from the two mainstream biophilic design frameworks.

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The introduction can be optimized appropriately.The introduction of the term "Biophilia" can be more detailed and easy to understand .By contrast, the introduction of “Biophilic Design”is very substantial.It may be better to find some literature to combine workplace design and “Biophilic Design”,and then to explore the relationship between them.

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The major scale of the questionnaire consists of three parts (subscales): general health (GH), nature relatedness (NR), and biophilic design evaluation (BDE).

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Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.

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Although this I don’t believe this would be a large undertaking, the analysis would be better served by non-parametric tests due to the level of measurement used (i.e.

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Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.

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Apart from the design evaluation, POE is also one of the mainstream research methods that can effectively diagnosing operation problems.

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Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.

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Therefore, the weighting results of this experiment are not employed to deny the ranking in the 14 Patterns of Biophilic Design.

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Some of the results in the illustrations are obvious and can be reduced to less elaboration. Overall work of the article is sufficient, the results is has the certain significance, but its limitation is obvious to all.

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Please see the revised contents in the updated manuscript below: Revision in Page 5 Line 191-197: “For instance, the patterns “Presence of Water”, “Prospect”, “Refuge”, “Mystery”, and “Risk” (i.e., itemized patterns 5, 11, 12, 13, and 14 in Column B) are recommended because they are proofed that benefits health.

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Figure 1 should be improved regarding the arrow.

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Stacked graph with percentage responses for individually arranged items (from the bottom with a high percentage of disagreement to the top with high percentage of agreement) is reduced, because the illustrations are obvious in the figure.

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Photo in table 6 should check the copyright of these photo.

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#6: P3, L106: While I generally agree with, questions could be raised to whether POE scales should be used to evaluate biophilic design evaluation.

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Response We are grateful to the reviewer for their favorable review and constructive input 1-

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How is subtotal resection defined in chordoma (% of volume remaining?)

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Thus it would be helpful for the authors to clarify this.

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What means Pathology 0 in table 4?

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Response We are grateful to the reviewer for their favorable review and constructive input 1-

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Thus it would be helpful for the authors to clarify this. The AMIGO suite has great capabilities, but when it comes to intraoperative imaging, it is CT and MRI scans that are made, and then using Brain Lab and possibly other software, that information is processed and redisplayed including 3D reconstructions.

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The authors are to be commended for pursing this approach in a small series of patients with difficult diagnoses.

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This does not detract from the value of the technique, but it is important to clarify that what really is happening is a variety of preoperative imaging is imported and co-registered into the Brain Lab, and then intraoperative MR and occasionally CT data is again obtained and processed and analyzed.

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There is not much to add and publication can be recommended.

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It is therefore difficult to state that the results were clearly improved or to even compare to other series, without larger numbers and direct comparison or classification of individual tumor locations and characteristics in differing series.

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All that is needed is easy intra-operative access to CT and MR imaging and the ability to import and reconstruct the data real time.

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How is subtotal resection defined in chordoma (% of volume remaining?)

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What means Volume reduction 0 and 0% in Table 4?

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What means Pathology 0 in table 4?

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With these caveats clarified in a modified version, the paper is valuable and could be published.

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when one reads it initially it would appear that there are many different modalities available for intraoperative imaging. However, the PET scan does not appear to have actually been used for intraoperative repeat imaging to assess resection, and fluoroscopy and 3D reconstructions using Brain Lab software are standard fare in many operating rooms. Intraoperative angiography might have been used in the case of vascular injury but this also is available in many institutions. The authors appear to really only use CT and MRI intraoperatively, with the other modalities imported preoperatively into the Brain Lab navigational system. 3D reconstructions of newly acquired data is a capability of the software, and is available in many places. Thus it would be helpful for the authors to clarify this. The AMIGO suite has great capabilities, but when it comes to intraoperative imaging, it is CT and MRI scans that are made, and then using Brain Lab and possibly other software, that information is processed and redisplayed including 3D reconstructions. Making this clear is important for others who either use the technique or who want to do so. All that is needed is easy intra-operative access to CT and MR imaging and the ability to import and reconstruct the data real time. That is plenty and a challenge for many, but the other imaging modalities used are either standard fare in many centers (x-ray imaging, endoscopy) or do not need to be in adjacent rooms (PET scanning and angiography (can be done in the primary Or). This does not detract from the value of the technique, but it is important to clarify that what really is happening is a variety of preoperative imaging is imported and co-registered into the Brain Lab, and then intraoperative MR and occasionally CT data is again obtained and processed and analyzed.

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The AMIGO suite has great capabilities, but when it comes to intraoperative imaging, it is CT and MRI scans that are made, and then using Brain Lab and possibly other software, that information is processed and redisplayed including 3D reconstructions.

null

The results, while admirable, cannot easily be compared to other series, as the numbers are small and each case has its own complex series of characteristics that make it unique. It is therefore difficult to state that the results were clearly improved or to even compare to other series, without larger numbers and direct comparison or classification of individual tumor locations and characteristics in differing series.

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Minor Issues: [4] In Figures 3G and 3H, please specify p-values for untreated vs selumetinib in FLO-1/EV and OE33/shMACC1 respectively.

null

Based on the cell line RNA and protein data the expression level of MACC1 is highly variable rather than being present or not. Is there a similar variability present among the tissue samples? Please provide the distribution of the IRS scores of the patient cohort and explain how was IRS 5 chosen as cut off?

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[10] If the journal allows it, please break up the abstract into Introduction, Methods, Results, Conclusion.

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The authors argue that MACC1 expression did not significantly influenced cell proliferation in the two cell line models. However, cell proliferation was analyzed only in a 24-hour long period even though most cancer cells have a doubling time around 24 hours. In order to draw a conclusion about the proliferation effect a longer (48 or 72 hours) measurement is necessary.

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[8] In line 274, please change "OR 1.51" to "OR 1.51 [... - ...]", i.e.

null

It would be nice to know the selumetinib sensitivity of the two used cell lines. The concentration used from selumetinib both for the cell line experiments (10 microM) and for the animal experiments (50mg/kg) are quite high. Please discuss how the applied concentrations are related to the clinicaly used dosage (75 mg administered orally twice https://clinicaltrials.gov/ct2/show/NCT02448290) and why not the more efficient MEK1 inhibitor trametinib was used for the experiments.

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In this study, the authors have shown that the same is also true for gastric/esophageal cancer.

null

The authors´answer regarding the cut off is sufficient, please include this argument either in the methods section or as supplementary information.

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should be after "Expression was correlated with survival and morphological characteristics."

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The authors refer to a data "Proliferation of FLO1 EV and FLO1 MACC1 over 72 h", however I couldn´t find the figure either in the manuscript file or here in the answer.

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[3] Throughout the paper, 10^x wrongly displays as 10x (e.g.

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[1] Figure 4 is missing. In the pdf I reviewed, the caption is there, but the figure is not.

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In the in vitro analysis they investigated MACC1 expression in five cell lines and generated a cell line with MACC1 overexpression and a MACC1 knock-down cell line.

null

[2] Abstract says 266 patients were analyzed (line 36), while result says 360 patients were analyzed (line 249). Please fix this inconsistency.

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The authors´answer regarding the cut off is sufficient, please include this argument either in the methods section or as supplementary information.

null

[3] Throughout the paper, 10^x wrongly displays as 10x (e.g. "105" instead of "10^5" in lines 152 and 170, "106" instead of "10^6" in line 217, "X2" instead of "X^2" in line 241, "108" instead of "10^8" in lines 353, 354, 365, 366, 367, 368, 370, 371).

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Based on these comments we herewith respond to all questions raised in a point-by-point manner, as follows: Reviewer 2 Major Issues:

null

[4] In Figures 3G and 3H, please specify p-values for untreated vs selumetinib in FLO-1/EV and OE33/shMACC1 respectively. If the difference is statistically significant, please briefly explain/speculate why.

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[5] If possible, please use a higher resolution version of Figures 3F and 3I (the legends are blurry and hard to read in the current version).

null

[5] If possible, please use a higher resolution version of Figures 3F and 3I (the legends are blurry and hard to read in the current version).

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The authors refer to a data "Proliferation of FLO1 EV and FLO1 MACC1 over 72 h", however I couldn´t find the figure either in the manuscript file or here in the answer.

null

[6] In line 306/307, please explain/speculate briefly why the control clone had higher MACC1 expression than the wildtype.

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The concentration used from selumetinib both for the cell line experiments (10 microM) and for the animal experiments (50 mg/kg) are quite high.

null

[7] In line 272/273: (i) please report median survival in each group (instead of mean survival), (ii) please specify Hazard ratio with 95% confidence interval (in addition to p values), (iii) please report both overall survival result and disease-specific survival result (since you showed both in Figures).

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Author Response Please see the attachment Author Response File: Author Response.pdf

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[8] In line 274, please change "OR 1.51" to "OR 1.51 [... - ...]", i.e. specify the 95% confidence interval.

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Answer: We thank the reviewer for this comment.

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[9] In line 277-279: (i) please report median survival in each group (instead of mean survival), (ii) please specify Hazard ratio with 95% confidence interval (in addition to p values). Same for lines 425/426.

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Based on these comments we herewith respond to all questions raised in a point-by-point manner, as follows: Reviewer 2 Major Issues:

null

[10] If the journal allows it, please break up the abstract into Introduction, Methods, Results, Conclusion. If the journal requires an unstructured abstract instead, please reorganize the current abstract so that the content flows uninterrupted (e.g. "MACC1 is an independent negative prognostic marker in AGE/S patients." should be after "Expression was correlated with survival and morphological characteristics." and before "To analyze the role of MACC1 in vitro the cell lines FLO-1 and OE33 were lentivirally manipulated." and so on).

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[6] In line 306/307, please explain/speculate briefly why the control clone had higher MACC1 expression than the wildtype.

null

The authors have satisfactorily addressed my comments.

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Based on these comments we herewith respond to all questions raised in a point-by-point manner, as follows: Reviewer 1: 1.

null

Based on the cell line RNA and protein data the expression level of MACC1 is highly variable rather than being present or not. Is there a similar variability present among the tissue samples? Please provide the distribution of the IRS scores of the patient cohort and explain how was IRS 5 chosen as cut off?

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The results are interesting and may have clinical relevance.

null

The authors argue that MACC1 expression did not significantly influenced cell proliferation in the two cell line models. However, cell proliferation was analyzed only in a 24-hour long period even though most cancer cells have a doubling time around 24 hours. In order to draw a conclusion about the proliferation effect a longer (48 or 72 hours) measurement is necessary.

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Please discuss how the applied concentrations are related to the clinically used dosage (75 mg administered orally twice https://clinicaltrials.gov/ct2/show/NCT02448290) and why not the more efficient MEK1 inhibitor trametinib was used for the experiments.

null

It would be nice to know the selumetinib sensitivity of the two used cell lines. The concentration used from selumetinib both for the cell line experiments (10 microM) and for the animal experiments (50mg/kg) are quite high. Please discuss how the applied concentrations are related to the clinicaly used dosage (75 mg administered orally twice https://clinicaltrials.gov/ct2/show/NCT02448290) and why not the more efficient MEK1 inhibitor trametinib was used for the experiments.

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In order to draw a conclusion about the proliferation effect a longer (48 or 72 hours) measurement is necessary.

null

The authors´answer regarding the cut off is sufficient, please include this argument either in the methods section or as supplementary information.

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It would be nice to know the selumetinib sensitivity of the two used cell lines.

null

The authors refer to a data "Proliferation of FLO1 EV and FLO1 MACC1 over 72 h", however I couldn´t find the figure either in the manuscript file or here in the answer.

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Based on these comments we herewith respond to all questions raised in a point-by-point manner, as follows: Reviewer 1: 1.

null

[1] Figure 4 is missing. In the pdf I reviewed, the caption is there, but the figure is not.

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In the in vitro analysis they investigated MACC1 expression in five cell lines and generated a cell line with MACC1 overexpression and a MACC1 knock-down cell line.

null

[2] Abstract says 266 patients were analyzed (line 36), while result says 360 patients were analyzed (line 249). Please fix this inconsistency.

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Please discuss how the applied concentrations are related to the clinically used dosage (75 mg administered orally twice https://clinicaltrials.gov/ct2/show/NCT02448290) and why not the more efficient MEK1 inhibitor trametinib was used for the experiments.

null

[3] Throughout the paper, 10^x wrongly displays as 10x (e.g. "105" instead of "10^5" in lines 152 and 170, "106" instead of "10^6" in line 217, "X2" instead of "X^2" in line 241, "108" instead of "10^8" in lines 353, 354, 365, 366, 367, 368, 370, 371).

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Previous studies in colorectal cancer have shown that MACC1 expression (which is associated with poor prognosis) induces cell migration in vitro and metastasis formation in vivo, and these effects can be inhibited by selumetinib.

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[4] In Figures 3G and 3H, please specify p-values for untreated vs selumetinib in FLO-1/EV and OE33/shMACC1 respectively. If the difference is statistically significant, please briefly explain/speculate why.

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cancers14071773_perova

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In the in vitro analysis they investigated MACC1 expression in five cell lines and generated a cell line with MACC1 overexpression and a MACC1 knock-down cell line.

null

[5] If possible, please use a higher resolution version of Figures 3F and 3I (the legends are blurry and hard to read in the current version).

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Minor Issues: [4] In Figures 3G and 3H, please specify p-values for untreated vs selumetinib in FLO-1/EV and OE33/shMACC1 respectively.

null

[6] In line 306/307, please explain/speculate briefly why the control clone had higher MACC1 expression than the wildtype.

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I recommend the following edits before publication.

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[7] In line 272/273: (i) please report median survival in each group (instead of mean survival), (ii) please specify Hazard ratio with 95% confidence interval (in addition to p values), (iii) please report both overall survival result and disease-specific survival result (since you showed both in Figures).

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Author Response Dear Professor Mok, We appreciate that you give us the possibility to revise our manuscript and we thank the reviewers for their valuable comments.

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[8] In line 274, please change "OR 1.51" to "OR 1.51 [... - ...]", i.e. specify the 95% confidence interval.

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If the journal requires an unstructured abstract instead, please reorganize the current abstract so that the content flows uninterrupted (e.g.

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[9] In line 277-279: (i) please report median survival in each group (instead of mean survival), (ii) please specify Hazard ratio with 95% confidence interval (in addition to p values). Same for lines 425/426.

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If the difference is statistically significant, please briefly explain/speculate why.

null

[10] If the journal allows it, please break up the abstract into Introduction, Methods, Results, Conclusion. If the journal requires an unstructured abstract instead, please reorganize the current abstract so that the content flows uninterrupted (e.g. "MACC1 is an independent negative prognostic marker in AGE/S patients." should be after "Expression was correlated with survival and morphological characteristics." and before "To analyze the role of MACC1 in vitro the cell lines FLO-1 and OE33 were lentivirally manipulated." and so on).

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In this study, the authors have shown that the same is also true for gastric/esophageal cancer.

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The authors have satisfactorily addressed my comments.

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This might be achieved by using the combination of so-called Tumor Treating fields (TTFields) with targeted drug, I have the following suggestions about this manuscript:

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What is the rationale of using 150 kHz TTFields? TTFields at 100 kHz has also shown significant differences as cytotoxicity at p<0.01 and p<0.001 in HepG2 and Huh-7D12 cells which have around 60% and 50% of cell survival. Why did the authors use high frequency of TTFields though the cytotoxicity was also observed in lower dose (Fig 1A).

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Response 7: We thank the reviewer for this question.

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What is the ‘n’ number of the samples and experiments in each group? Also mention the ‘n’ number in all the experiments involved for invitro and invivo.

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In the animal study we have now added IHC examination of beclin-1 and of GRP78, a marker for ER stress, as described in results sub-section 3.4.

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LC3 is increased in all the groups except in control tissue, however, cell death was increased only in combined group. How can the authors correlate autophagy with apoptosis? It is not so trustworthy that the only expression of LC3B indicate the treated condition have increased autophagy in the tumor tissue. Other important autophagy and degradation markers like Beclin1 and P62 need to be shown to reflect the regulatory mechanism of TTFields, as well as for the combined treatment with Sorafenib.

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Response 6: We thank the reviewer for this comment.

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Several data have shown very high error bars in each group (especially Fig Can the author provide the tumor images which were harvested from mice?

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*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 relative to time-respective control; two-way ANOVA.

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In the IHC experiment for PARP, the authors have incubated with primary antibody only for 30 min? Is that timing enough to get protein expression? What source of secondary antibody was used? In addition to IHC, I suggest performing western blot using PARP antibody where the full length and cleaved bands are observed in the same blot.

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Other important autophagy and degradation markers like Beclin1 and P62 need to be shown to reflect the regulatory mechanism of TTFields, as well as for the combined treatment with Sorafenib.

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The figure number is mislabeled in Fig 4D-LC3 Immunofluorescence.

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What are the p53 status and the apoptosis signaling pathway function in N1S1 cells?

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Why there is no error bar in the control group of all bar graphs? Please include error bars and re-calculate the statistical analysis for all the data wherever missing.

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The manuscript is an interesting work related to a potential new therapy of hepatocellular carcinoma (HCC) by using TTFields in combination with a TKI (Sorafenib).

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Figure legends of Fig2D is missing. Fig C is repeated in the legend. Please label the figures appropriately. It is so frustrating to understand.

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Point 8: Since sorafenib acts also on angiogenesis, did the authors investigate if TTFields may interfere with anti-angiogenic effect sorafenib-mediated?

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There is no data in Fig 4A. Whole data is missing but have explained in the result section and in figure legends.??

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I thank the authors for their extensive work and comprehensive review of the manuscript.

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Line 337 seems over statement since the data are not shown in the manuscript.

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Overall, the authors believe that this research demonstrates potential for concomitant TTFields and sorafenib application in the treatment of HCC.

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Typos: Line 111, ‘invitro’ spelling is not correct. Double ‘and’ in Line 342. Need language and grammar check.

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*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 relative to time-respective control; two-way ANOVA.

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This is an interesting scientific study, as it concerns the issue of hepatocellular carcinoma, it also has a clinical aspect. The materials and methods section are elaborated in the details. Therefore, I expect further additional examination in the future. References contain mostly publications printed in the last 10 years. The authors indicated that TTFields had potential to be a new treatment option of hepatocellular carcinoma. The present study was examined in terms of autophagy and apoptosis in the antitumor effects of TTFields and sorafenib. However, the exact mechanism of the combination therapy induced cell death is not yet known as the activation of autophagy in the combination therapy was not increased.

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Were the mice perfused before collecting the tumors?

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In vitro experiments sub-section in Methods sections lacks many experimental details (e.g., type of plate/flask, plating overnight or not before experiment, number of plated cells). A very important missing is not showing the actual number of rats included in the final analyses (the ones who successfully received therapy for more than 18 hours/day). This must be added.

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Point 7: Why there is no error bar in the control group of all bar graphs?

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What are the p53 status and the apoptosis signaling pathway function in N1S1 cells? Maybe the cytotoxicity data will reveal a different better frequency.

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Other important autophagy and degradation markers like Beclin1 and P62 need to be shown to reflect the regulatory mechanism of TTFields, as well as for the combined treatment with Sorafenib.

null

Another puzzling experiment is the schedule for the in vivo work. Since the authors missed to add Figure 4A for timeline, based on Methods section the rats were treated for 5 days with TTFields and or sorafenib and a day later the rays were sacrificed. While a short “acute” follow-up is welcome the most important experiment should allow the follow-up for much more days to indeed observe the effect of TTFields added to sorafenib. I could not find an explanation for not including a long term follow-up. In my opinion, this is a key therapeutically experiment which must be done and included in the study.

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Response 4: We thank the reviewer for this question.

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There is no explanation why the most effective dose was 150 kHz and higher does actually decreases the killing. Can this dose observed in vitro on only tumor cells be translated to in vivo work where the tumor microenvironment is total different?

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*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 relative to time-respective control; two-way ANOVA.

null

Why the in vitro experiment was performed for 72 hours and in in vivo for 120 hours?

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