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Response to Reviewer Major Concerns: 1) The article did not distinguish the association of oncoapoptotic markers with the

types and stages of oral cancers. Authors Response: The clear association between oncoapoptotic markers and types sta!es o" oral cancers has not been worked out "or oral cancer# There are some studies which have tried to resolve this association albeit at broader level like disease severity$ T%M status$ tumor si&e etc# 'e have updated our manuscript with these "indin!s in the revised manuscript# For Anubhav (You can either add following text as a separate heading or add them under Part 2 in the manuscript): The e(pression o" p)* in oral leukoplakia is hi!her than in cancer o" the ton!ue and should probably be considered an early event in tumour pro!ression +1,# -n their study o" ./CC in Taiwan$ 0in et al# "ound no si!ni"icant correlation between survivin e(pression and patient a!e$ !ender$ oral habits$ cancer location$ or T%M status$ but the patients with hi!h survivin e(pression$ an advanced sta!e$ a lar!er tumour si&e or positive lymph node metastases had a si!ni"icantly shorter overall survival than the others +1,# -n oral cancer$ 2cl31 is observed "rom the initial sta!es o" carcino!enesis up to the appearance o" metastasis +*$ 4$ ),# 2cl31 over3e(pression is associated with a!!ressive histopatholo!ic "eatures and advanced initial T%M tumor sta!in! +5$ 6$ 7,# 8i!h e(pression o" 9as0 was "ound to be associated with !reater tumor si&e and advanced sta!es o" oral cancer +:,# Re"erence: 1# 8# 8# ;ora$ T# -# Trivedi$ /# %# /hukla$ %# <# /hah$ =# ;# <oswami$ and ># M# /hah$ ?p)* e(pression in leukoplakia and carcinoma o" the ton!ue$@ -nternational =ournal o" 2iolo!ical Markers$ vol# 11$ no# 1$ pp# 64A7B$ 1BB5# 1# C#3C# 0in$ 8#3C# 8un!$ R#3C# Duo$ C#3># Chian!$ and M# C#3># Duo$ ?/urvivin e(pression predicts poorer pro!nosis in patients with areca Euid chewin!3related oral sEuamous cell carcinoma in Taiwan$@ .ral .ncolo!y$ vol# 41$ no# 5$ pp# 54)A 5)4$ 1BB)# *# <omes CC$ 2ernardes ;9$ Fini& M<$ Fe Marco 0$ <ome& RC# Anti3apoptotic !ene transcription si!nature o" salivary !land neoplasms# 2MC Cancer 1B11G 11: 51# 4# /ulkowska M$ 9amulski '$ Chyc&ewski 0$ /ulkowski /# Hvaluation o" p)* and bcl31 oncoprotein e(pression in precancerous lesions o" the oral cavity# %eoplasma 1BB1G 47I1)::437#

)# Duropkat C$ ;enkatesan TD$ Caldarelli FF$ et al# Abnormalities o" molecular

re!ulators o" proli"eration and apoptosis in carcinoma o" the oral cavity and oropharyn(# Auris %asus 0aryn( 1BB1G 1::15)364# 5# >i!nataro$ 0#$ Carboni$ %#$ >a!liari$ A# ;#$ Capaccio$ >#$ .ttaviani$ 9#$ J >runeri$ <# I1::6)# 2cl31 e(pression is related to poor di""erentiation and advanced clinical sta!e in laryn!eal sEuamous cell carcinoma# = Chemother$ 6I:)$ 11)35# 6# /harma$ 8#$ /en$ /#$ Mathur$ M#$ 2ahadur$ /#$ J /in!h$ %# I1BB4)# Combined evaluation o" e(pression o" telomerase$ survivin$ and anti3apoptotic 2cl31 "amily members in relation to loss o" di""erentiation and apoptosis in head and neck cancers# 8ead %eck$ 15I7)$ 6**34B# 7# =ordan$ R#$ Cat&avelos$ <#$ 2arrett$ J A#$ /pei!ht$ ># I1::5)# Fi""erential e(pression o" bcl31 and ba( in sEuamous cell carcinomas o" the oral cavity# Hur = Cancer$ *12$ *:434BB#
:# Fas /%$ Dhare >$ /in!h MD$ /harma /C# 9as receptor ICF:)) J 9as li!and

ICF167) e(pression in patients with tobacco3related intraoral sEuamous cell carcinoma# -nd = Med Res 1B11G 1*4:)435B#

1) Part 3 (Apoptotic markers in Oral Cancer Therapeutics) should more focus on the finding of the oral cancer treatment, elucidating the relationship markers and oral cancers. Authors Response: The relationship between apoptotic markers and oral cancers has already been elaborated in >art 1$ there"ore it was not repeated a!ain in this section# As o" today$ oral cancer is clinically mana!ed throu!h tumor resection$ reconstructive sur!ery$ radiation therapy$ chemotherapy etc# Cetu(imab is the only approved tar!eted therapy available "or oral cancer# -n K>art * IApoptotic markers in .ral Cancer Therapeutics) we have discussed various therapeutic options which are either in research or clinical3trial sta!es and have !iven special emphasis to use o" apoptotic markers in these treatment options$ "or e#!# under !ene therapy section we have discussed K!ene addition therapy etween apoptotic

with e(ample o" how p)* is pursued as therapeutic molecule in research clinical3trial sta!es under !ene addition therapy treatment optionG we have discussed how .%CL3B1) is a promisin! treatment option# Tar!ets o" e(trinsic and intrinsic apoptotic pathway$ has also been discussed alon! with mention o" various attempts o" their therapeutic tar!etin!# /pecial section is devoted to elaborate tar!etin! strate!y "or key apoptotic markers like p)*$ survivin!$ and Mcl31#

*I missed information about the reasons behind the chosen factors. Why did the authors choose these factors and not others? Was a systematic literature search conducted? How was it done? This should be pointed out in the article.

The oncoapoptotic "actors discussed in this review were selected on the basis o" e(tensive e(perienced !ained by our !roup while workin! in the area o" elucidatin! role o" apoptosis$ and utili&in! apoptotic "actors "or dia!nostic and therapeutic intervention in oral cancer +134,# The "indin!s presented in this review is a result o" detailed online MHF0-%HM search o" the selected oncoapoptotic "actors by usin! relevant search terms Ilike ?p)*+T-A2, A%F Iapoptosis+T-A2, .R apoptotic+T-A2,) A%F IIdia!nostic+T-A2, .R dia!nosis+T-A2, .R pro!nosis+T-A2, .R pro!nostic+T-A2, .R therapeutic+T-A2, .R therapy+T-A2,) A%F Imarker+T-A2, .R tar!et+T-A2,) A%F mouth neoplasms+M8,@) and the subseEuent review o" relevant literature returned by %C2-3>ubMedTM search system# Re"erence: 1# /ah %D$ Dhan N$ Dhan <=$ 2isen >/# /tructural$ "unctional and therapeutic biolo!y o" survivin# Cancer 0ett# 1BB5 Fec 7G144I1):154361#
1# Dhan N$ Tiwari R>$ Mulherkar R$ /ah %D$ >rasad <2$ /hrivastava 2R$ 2isen >/#

Fetection o" survivin and p)* in human oral cancer: correlation with clinicopatholo!ic 1B#1BB1 hed#11B61# "indin!s# 8ead %eck# 1BB: Au!G*1I7):1B*:347# doi:

*# Dhan N$ Dhan %$ Tiwari R>$ >atro -D$ >rasad <2$ 2isen >/# Fown3re!ulation o"

survivin by o(aliplatin diminishes radioresistance o" head and neck sEuamous carcinoma cells# Radiother .ncol# 1B1B Au!G:5I1):15636*# doi: 1B#1B15 j#radonc#1B1B#B5#BB)#
4# Dhan N$ Tiwari R>$ Dhan %$ >rasad <2$ 2isen >/# -nduction o" apoptosis and

sensiti&ation o" head and neck sEuamous carcinoma cells to cisplatin by tar!etin! survivin !ene e(pression# Curr <ene Ther 1B11G 11:4443)*#