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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;CSCC&#41; is emerging as the second most common non-melanoma skin cancer&#44; with an increasing incidence ranging from 20&#37; to 30&#37; of all cutaneous malignancy&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The progression of CSCC is determined by a combination of genetic susceptibility and environmental risk factors&#44; including exposure to ultraviolet radiation&#44; carcinogens and immunosuppressive drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Despite the relatively low risk of metastasis and favorable long-term survival after treatment&#44; the incidence of CSCC has increased proportionately in recent years&#44; resulting in significant long-term morbidity&#44; mortality&#44; and economic burden for patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a> Therefore&#44; a deeper understanding of the pathogenesis of CSCC is crucial for improved diagnosis and treatment efficacy&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Sirtuins&#44; which belong to the histone deacetylase family&#44; are involved in various cellular functions such as aging&#44; stress response&#44; metabolism&#44; and energy homeostasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a> Mammalian sirtuins consist of seven family members &#40;SIRT1-7&#41;&#44; which exhibit different subcellular localization&#44; catalytic activities&#44; and biological functions&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> SIRT6&#44; primarily located in the nucleus&#44; functions as a highly conserved NAD&#43;-dependent deacetylase and ADP-ribosyltransferase&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> SIRT6 has been implicated in diabetes&#44; cardiovascular disease&#44; aging&#44; and cancer&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;16</span></a> Emerging evidence suggests a strong link between SIRT6 and the initiation and progression of multiple myeloma &#40;MM&#41; and several tumor types&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> Its dual role of either suppressing or promoting cancer has been observed in different cancer types&#44; potentially influenced by signaling pathways and tissue-specific contexts&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a> However&#44; the precise impact of SIRT6 on CSCC remains largely elusive&#46; The authors hypothesize that SIRT6 plays a pivotal role in the pathogenesis and progression of CSCC&#44; prompting us to evaluate its expression patterns&#44; functional mechanisms&#44; and potential clinical implications&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Materials</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Reagents</span><p id="par0015" class="elsevierStylePara elsevierViewall">The following reagents were used&#58; A431 human cutaneous squamous cell carcinoma cell line &#40;Obtained from Zhongqiao Xinzhou&#44; Shanghai&#41; and SCL-1 cell line &#40;Enzyme Research&#44; Shanghai&#41;&#59; The normal immortalized human keratinocyte line HaCaT &#40;Shanghai Fuheng Biotechnology Co&#46;&#44; Ltd&#46;&#41;&#59;skim milk&#44; chloroform&#44; and isopropanol &#40;purchased from Shanghai Shenggong Co&#46;&#44; Ltd&#46;&#41;&#59; primary antibodies against SIRT6 and &#946;-tubulin&#44; secondary antibodies against mouse immunoglobulin IgG &#40;purchased from Abcam&#44; USA&#41;&#59; mouse anti-human N-cadherin monoclonal antibody and mouse anti-human Vimentin monoclonal antibody &#40;Proteintech&#44; Wuhan&#41;&#59; fetal bovine serum and high-glucose DMEM medium &#40;purchased from Gibco&#44; USA&#41;&#59; BCA analysis kit&#44; crystal violet&#44; and Lipofectamine 2000 &#40;purchased from Biyuntian Biotechnology Co&#46;&#44; Ltd&#46;&#41;&#59; Polyvinylidene Fluoride &#40;PVDF&#41; membrane &#40;purchased from Millipore&#44; USA&#41;&#59; Trizol reagent&#44; RNA prep pure Tissue Kit&#44; PrimeScript RT synthesis kit&#44; and SYBR Green qRT-PCR Master Mix kit &#40;purchased from Thermo&#44; USA&#41;&#59; CCK-8 assay kit &#40;Proteintech&#44; Wuhan&#41;&#59; matrix gel and 8-&#181;m transwell chambers &#40;Corning&#44; USA&#41;&#59; all primers were synthesized by Shanghai Shenggong Co&#46;&#44; Ltd&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Tissue samples</span><p id="par0020" class="elsevierStylePara elsevierViewall">Tissue blocks from 70 patients with CSCC&#44; 25 patients with BD &#40;Bowen Disease&#41;&#44; and 60 patients with AK &#40;Actinic Keratosis&#41; were collected from January 2017 to December 2022&#46; In addition&#44; 20 normal skin plastic surgery tissue pieces were collected as normal controls&#46; Fresh CSCC and NT samples were collected&#44; 20 cases each&#46; In addition&#44; none of the patients in this study received any treatment before surgery&#44; including chemotherapy or radiation&#46; All patients participating in the study obtained informed consent&#44; and this study was approved by the Ethics Committee of this hospital &#40;ethics approval number&#58; 2021KT085&#41;&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Immunohistochemistry for protein expression analysis</span><p id="par0025" class="elsevierStylePara elsevierViewall">CSCC tissue samples were deparaffinized and treated with hydrogen peroxide for 5&#160;minutes to inhibit endogenous peroxidase activity&#46; Goat serum blocking solution was added and antigen retrieval was performed with citrate solution&#46; CSCC tissue samples were incubated with mouse anti-SIRT6 antibody &#40;1&#58;200&#41; overnight at 4&#160;&#176;C&#46; After two washes with PBS for 3&#160;minutes each&#44; the samples were incubated with HRP-conjugated goat anti-mouse IgG &#40;1&#58;2000&#41; for 1&#46;5&#160;hours at room temperature&#46; After two washes with PBS for 3-minutes each&#44; the primary antibody was detected using a Diaminobenzidine &#40;DAB&#41; substrate kit&#46; Immunohistochemical staining images were observed under a microscope and several fields were randomly selected for observation at high magnification&#46; The immunohistochemical staining results were interpreted using a commonly used semi-quantitative scoring method<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Cell culture</span><p id="par0030" class="elsevierStylePara elsevierViewall">The cell lines used in this study included the human skin squamous cell cancer cell line &#40;A431&#44; SCL-1&#41; and the normal immortalized human keratinocyte line HaCaT&#46; The medium used for A431&#44; SCL-1 and HaCaT cells was DMEM high-glucose medium&#46; All cells were cultured at 37&#160;&#176; with 5&#37; CO and 10&#37; fetal bovine serum in the medium&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Western blot</span><p id="par0035" class="elsevierStylePara elsevierViewall">Cell lysis was performed using RIPA buffer and protein was extracted on ice&#46; Protein concentration was determined using a BCA assay kit&#46; Protein samples from each group were loaded onto a 12&#46;5&#37; gel and electrophoresed at 80&#160;V for 30&#160;minutes&#44; followed by 110&#160;V for 1&#160;hour&#46; PVDF membrane transfer was performed at 100&#160;V in an ice bath for 1&#46;5&#160;hours&#46; The membrane was then blocked with 5&#37; skim milk for 2&#160;hours&#44; followed by incubation with primary antibody at 4&#160;&#176;C overnight and incubation with secondary antibody for 2&#160;hours&#46; The secondary antibodies used were goat anti-mouse HRP &#40;1&#58;1000 dilution&#41; and goat anti-rabbit HRP &#40;1&#58;1000 dilution&#41;&#46; Finally&#44; images were captured and stored using a Bio-Rad chemiluminescence imaging system&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Real-time Reverse Transcription Polymerase Chain Reaction &#40;qRT-PCR&#41;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Cell pellets were collected and treated with Trizol reagent for lysis&#44; followed by chloroform&#47;isopropanol extraction to separate and precipitate RNA&#46; The total RNA was further extracted by ethanol precipitation&#46; Reverse transcription of 1&#160;&#956;g RNA into cDNA was performed using the PrimeScript RT synthesis kit&#46; qRT-PCR was performed using the SYBR Green qRT-PCR Master Mix kit&#44; with U6 used as an internal reference&#46; The primer sequences are listed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Cell infection and screening</span><p id="par0045" class="elsevierStylePara elsevierViewall">Lentiviral shSIRT6 and control shNC were provided by Youxi Weinan Biotechnology Company &#40;Sanming&#44; China&#41;&#46; The lentiviruses were packaged using a triple plasmid system&#46; The shRNA was inserted into the Doxycycline &#40;DOX&#41;-inducible gene expression vector Tet-pLKO&#46;1-puro&#46; After transfection for 36&#160;hours&#44; the lentiviruses were harvested&#46; A431 cells and SCL-1 cells were infected with the lentiviruses for 24&#160;hours and stable transduced cell lines were selected using puromycin &#40;0&#46;8&#160;&#956;g&#47;mL for A431 cells&#44; 0&#46;4&#160;&#956;g&#47;mL for SCL-1 cells&#41;&#46; Gene expression was induced with 1&#160;&#956;g&#47;mL DOX and empty vector-transfected cells served as Normal Control &#40;NC&#41; cells&#46; Cells were divided into four groups&#58; NC group&#44; NC&#160;&#43;&#160;DOX group&#44; shSIRT6 group&#44; and shSIRT6&#160;&#43;&#160;DOX group&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Cell Counting Kit-8 &#40;CCK-8&#41; assay for cell proliferation</span><p id="par0050" class="elsevierStylePara elsevierViewall">Cells were seeded at 2&#44;000 cells&#47;100&#160;&#956;L in a 96-well plate with 4 replicate wells per group&#46; The plate was incubated at 37&#160;&#176;C with 5&#37; CO<span class="elsevierStyleInf">2</span> and saturated humidity until the cells reached 80&#37; confluence&#46; Each group of cells was treated differently and incubated for a further 24&#160;hours under the same conditions&#46; The original culture medium in each well was discarded and 100&#160;&#181;L of culture medium containing 10&#37; CCK-8 was added&#46; The plate was incubated in a cell incubator for 1&#160;hour and the absorbance at 450&#160;nm was measured using a microplate reader&#46; Absorbance values &#40;OD&#41; were measured at 12&#44; 24&#44; 48 and 72&#160;hours to assess cell proliferation&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Transwell assay</span><p id="par0055" class="elsevierStylePara elsevierViewall">Transwell coated with Matrigel was used to perform cell invasion and migration assays for each group&#46; Fifty microliters of Matrigel &#40;2&#160;mg&#47;mL&#41; were added to the upper chamber of the transwell and incubated at 37&#160;&#176;C for 30&#160;minutes&#46; Then 4&#160;&#215;&#160;10<span class="elsevierStyleSup">3</span> cells were seeded in a serum-free DMEM medium&#46; The lower chamber was filled with 600&#160;&#956;L of medium containing 10&#37; fetal bovine serum as a chemoattractant&#46; After incubation for 24&#160;hours&#44; non-invading cells were removed with a cotton swab&#46; Invaded cells on the lower membrane were fixed with 4&#37; paraformaldehyde for 30&#160;minutes at room temperature and stained with 0&#46;1&#37; crystal violet for 20&#160;minutes&#46; The invaded and migrated cells were photographed and counted under a microscope &#40;Carl Zeiss&#44; Germany&#41;&#46; Three random fields were selected for cell counting and the average was calculated&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Cell scratch assay</span><p id="par0060" class="elsevierStylePara elsevierViewall">Log-phase cells were harvested&#44; centrifuged&#44; and resuspended in a culture medium&#46; Cells were counted and each group of cells was seeded in a 6-well plate &#40;6&#46;0&#160;&#215;&#160;10<span class="elsevierStyleSup">5</span> cells&#47;well&#41; for culture&#46; When cell confluence reached approximately 95&#37; the next day&#44; a scratch was made in the center of each well using a 200&#160;&#956;L pipette tip&#46; After washing with PBS&#44; a fresh culture medium was added&#46; The 0&#160;-h image was taken using an inverted light microscope and the cells were further incubated&#46; Images were taken at 24 and 48&#160;hours&#46; The healing rate was calculated using ImageJ software&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Flow cytometric analysis of cell apoptosis using annexin V&#47;propidium iodide &#40;PI&#41; double staining</span><p id="par0065" class="elsevierStylePara elsevierViewall">The culture supernatant was collected from each group of cells and the cells were washed with PBS&#44; trypsinized and collected&#46; The cells were double stained using the Annexin V-FITC Apoptosis Detection Kit&#46; Staining was performed in a dark chamber at room temperature for 10&#160;minutes&#46; Flow cytometry was used for quantitative analysis and the apoptosis rate was calculated&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Cell cycle analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">Human CSCC cell lines A431 and SCL-1 were maintained in a DMEM culture medium supplemented with 5&#37; FBS in a 10&#160;cm culture dish&#46; After treatment under the specified conditions&#44; the cells were collected and suspended in PBS&#46; They were fixed in 70&#37; cold ethanol overnight at 4&#160;&#176;C&#46; The cells were then incubated with 50&#160;&#956;g&#47;mL Propidium Iodide &#40;PI&#41; and 100&#160;&#956;g&#47;mL RNase A &#40;1&#58;1&#41; for 20&#160;minutes at room temperature in the dark&#46; Finally&#44; the staining signal of CSCC cells was evaluated using the FACSCalibur&#8482; flow cytometer &#40;BD Biosciences&#44; Franklin Lakes&#44; New Jersey&#44; USA&#41;&#44; and the distribution of cell cycle percentages was analyzed using Cell Quest software version 3&#46;3 &#40;BD Biosciences&#41; according to the manufacturer&#39;s instructions&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Statistical analysis</span><p id="par0075" class="elsevierStylePara elsevierViewall">Statistical analysis was performed using SPSS 23&#46;0 software&#46; Quantitative data were expressed as mean&#160;&#177;&#160;standard deviation&#46; The chi-Squared test was used to compare categorical data&#44; and Analysis of Variance &#40;ANOVA&#41; was used to compare positive rates between multiple groups&#46; Independent samples <span class="elsevierStyleItalic">t</span>-tests were used for pairwise comparisons&#46; A p-value &#60;0&#46;05 was considered statistically significant&#46;</p></span></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Results</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Elevated expression of SIRT6 in AK&#44; BD&#44; and CSCC tissues compared to normal skin tissue</span><p id="par0080" class="elsevierStylePara elsevierViewall">The expression of SIRT6 in different tissues was examined using immunohistochemical staining&#46; The results revealed that SIRT6 protein expression was predominantly observed in the cell nucleus&#44; exhibiting a range of hues from pale yellow to brownish-brown staining&#44; while no significant expression was observed in the cytoplasm &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">A quantitative assessment of the expression levels was conducted using a semi-quantitative scoring system&#46; The results demonstrated the following distribution in the examined tissues&#58; among 20 cases of Normal Skin Tissue &#40;NT&#41;&#44; there were no cases of strong positive&#44; positive&#44; weak positive&#44; or negative SIRT6 expression&#59; for 60 cases of AK tissue&#44; the distribution was 3-cases&#44; 31-cases&#44; 22-cases&#44; and 4-cases&#44; respectively&#59; in 25 cases of BD tissue&#44; the distribution was 9-cases&#44; 14-cases&#44; 2-cases&#44; and 0-cases&#44; respectively&#59; and among 70-cases of CSCC tissue&#44; there were 46-cases&#44; 18-cases&#44; 6-cases&#44; and 0-cases&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46; The high expression rates of SIRT6 in NT&#44; AK&#44; BD&#44; and CSCC tissues were 0&#37;&#44; 56&#46;67&#37;&#44; 92&#46;00&#37;&#44; and 91&#46;43&#37;&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Pairwise comparisons revealed statistically significant higher expression of SIRT6 in AK&#44; BD&#44; and CSCC tissues compared to NT tissues &#40;p&#160;&#60;&#160;0&#46;05&#41;&#44; while there was no statistically significant difference in SIRT6 expression between BD and CSCC tissues&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Correlation between SIRT6 expression and clinical pathological parameters in CSCC patients</span><p id="par0090" class="elsevierStylePara elsevierViewall">Analysis of the correlation between SIRT6 expression and clinical pathological parameters in CSCC patients revealed that high expression of SIRT6 was associated with cancerous tissue located in sun-exposed areas &#40;p&#160;&#60;&#160;0&#46;05&#41; and higher Broders&#39; grade &#40;p&#160;&#60;&#160;0&#46;05&#41;&#46; However&#44; no significant correlations were observed between SIRT6 expression and clinical pathological data such as gender&#44; age&#44; disease duration&#44; depth of invasion&#44; and tumor diameter &#40;p&#160;&#62;&#160;0&#46;05&#41;&#46; Please refer to <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> for details&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">High expression of SIRT6 in CSCC cells and tissues and suppression of CSCC cell proliferation by SIRT6 knockdown</span><p id="par0095" class="elsevierStylePara elsevierViewall">By WB and qRT-PCR analysis&#44; it was observed that the expression level of SIRT6 protein was higher in CSCC cell lines &#40;A431&#44; SCL-1&#41; compared to immortalized human keratinocytes &#40;HaCaT&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; Similarly&#44; the mRNA expression level of SIRT6 was higher in A431 and SCL-1 cells than in HaCaT cells&#46; qRT-PCR analysis of 20 pairs of CSCC and adjacent normal tissues confirmed the high expression of SIRT6 in CSCC tissues &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#44; consistent with the immunohistochemistry results&#46; To further investigate the functional role of SIRT6 in CSCC&#44; CSCC cell lines with SIRT6 gene knockdown were established by lentiviral transduction&#46; Negative control &#40;NC&#41;&#44; NC&#160;&#43;&#160;DOX group&#44; and shSIRT6 control group were included as negative controls&#46; The efficiency of SIRT6 knockdown in A431 and SCL-1 cells was validated by Western blot analysis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41; and qRT-PCR &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>D&#41;&#44; demonstrating downregulation of SIRT6 protein and mRNA expression in the shSIRT6 group compared to the control group&#46; Subsequent experiments were performed using the knockdown cell lines and control groups&#46; CCK-8 assay results showed that SIRT6 knockdown significantly inhibited the proliferation of A431 and SCL-1 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>E&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Inhibition of CSCC cell migration and invasion by SIRT6 knockdown</span><p id="par0100" class="elsevierStylePara elsevierViewall">The effects of SIRT6 on CSCC cell migration and invasion were further investigated using the Transwell assay and the scratch assay&#46; The results showed that compared to the control groups &#40;NC&#44; NC&#160;&#43;&#160;DOX and shSIRT6 control&#41;&#44; the shSIRT6&#160;&#43;&#160;DOX knockdown group exhibited reduced cell migration and invasion &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#41; and reduced wound healing rate &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41; in A431 and SCL-1 cells&#46; These results indicate that SIRT6 knockdown significantly inhibits the migration and invasion capabilities of CSCC cells&#46; Western blot analysis was performed to detect the expression of epithelial-Mesenchymal Transition &#40;EMT&#41; markers in CSCC cells&#46; Compared to the control groups &#40;NC&#44; NC&#160;&#43;&#160;DOX and shSIRT6 control&#41;&#44; the shSIRT6&#160;&#43;&#160;DOX group of A431 and SCL-1 cells showed downregulated expression of the mesenchymal markers N-cadherin and vimentin &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C&#41;&#46; These results indicate that SIRT6 knockdown promotes the expression of epithelial-mesenchymal transition markers N-cadherin and vimentin in CSCC cells&#44; suggesting that the inhibition of CSCC cell migration and invasion by SIRT6 knockdown may be associated with the suppression of the EMT process&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">SIRT6 knockdown enhances apoptosis and induces cell cycle arrest at the G0&#47;G1 phase in CSCC cells</span><p id="par0105" class="elsevierStylePara elsevierViewall">Using flow cytometry&#44; the authors further investigated the effect of SIRT6 on apoptosis and cell cycle progression in CSCC cells&#46; The results show that the shSIRT6&#160;&#43;&#160;DOX-treated A431 and SCL-1 cell groups exhibit increased apoptotic rates &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41; and blockage in the G0&#47;G1 phase of the cell cycle &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#41;&#44; indicating that downregulation of SIRT6 can enhance apoptosis and induce cell cycle arrest at the G0&#47;G1 phase in CSCC cells&#46; To assess the expression of apoptosis-related markers &#40;Bax&#44; cleaved-caspase3&#41; and cell cycle-related markers &#40;CyclinD1&#44; CDK4&#41; in CSCC cells&#44; Western blot analysis was performed&#46; Compared to the NC&#44; NC&#160;&#43;&#160;DOX and shSIRT6 control groups&#44; the shSIRT6&#160;&#43;&#160;DOX-treated A431 and SCL-1 cell groups exhibited increased levels of Bax and cleaved-caspase3 protein expression&#44; while the levels of CyclinD1 and CDK4 protein expression were decreased &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C&#41;&#46; These results indicate that the downregulation of SIRT6 promotes apoptosis and induces cell cycle arrest at the G0&#47;G1 phase in CSCC cells&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;CSCC&#41; is a malignant proliferative tumor originating from the keratinizing cells of the appendages or epidermis&#46; Although the majority of CSCCs can be successfully eradicated through surgical excision&#44; approximately 14&#37; to 15&#37; of primary CSCC patients still experience subclinical infiltration&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Invasive growth of CSCC can breach the basal membrane of the epidermis and invade the deeper dermis&#44; skin appendages&#44; blood vessels&#44; lymphatic vessels&#44; nerves&#44; etc&#46;&#44; leading to the development of high-risk CSCC&#46; Despite significant advancements in treatment options such as Mohs surgery&#44; cetuximab&#44; and panitumumab&#44; which have greatly improved the prognosis of CSCC patients&#44; the prognosis for high-risk and very high-risk CSCC remains poor&#44; with 5-year recurrence rates ranging from 30&#37; to 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Therefore&#44; it is necessary to further explore the mechanisms underlying the occurrence and progression of CSCC and identify more therapeutic targets&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">SIRT6 is dysregulated in various cancers&#44; and its role in tumorigenesis depends on the type and context of the tumor&#46; SIRT6 expression is upregulated in breast cancer&#44; pancreatic cancer&#44; primary melanoma&#44; and non-small cell lung cancer&#44;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a> suggesting a pro-oncogenic role in these cancers&#46; Conversely&#44; SIRT6 is downregulated in ovarian cancer tissues&#44; and its low expression is closely associated with tumor infiltration and metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Studies have shown that SIRT6 inhibits the growth of gastric cancer by suppressing the JAK2&#47;signal transducer and activator of the transcription-3 pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Furthermore&#44; it has been reported that SIRT6 can suppress the occurrence and development of pancreatic cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Therefore&#44; SIRT6 also plays a role in inhibiting the initiation and development of malignant tumors&#44; with strong heterogeneity in different tumor types&#46; The results of this study show that SIRT6 expression is increased in CSCC tumor tissues compared to normal skin tissues&#44; suggesting that high expression of SIRT6 may be involved in the occurrence and development of CSCC&#46; The protein expression level of SIRT6 in CSCC is higher than that in the precancerous lesion Actinic Keratosis &#40;AK&#41; and normal skin tissue&#44; suggesting that SIRT6 may play an important role in the progression from normal skin tissue to precancerous lesions and further to Cutaneous Squamous Cell Carcinoma&#46; However&#44; SIRT6 expression was slightly higher in Bowen Disease &#40;BD&#41; than in CSCC tissue&#44; which may be related to the limited number of BD tissue samples&#46; High expression of SIRT6 in CSCC tissues is associated with the location of the cancer tissue in sun-exposed areas and Broders&#39; grade&#44; but not with gender&#44; age&#44; tumor diameter&#44; etc&#46;&#44; consistent with findings in melanoma and non-small cell lung cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Furthermore&#44; the authors found that SIRT6 is highly expressed in CSCC cells and that silencing SIRT6 inhibits the proliferation&#44; migration&#44; and invasion abilities of CSCC cells&#46; Invasion and migration are critical features of malignant tumors&#44; and SIRT6 silencing significantly reduced the proliferation&#44; migration&#44; and invasion of CSCC cells&#44; providing evidence for the role of SIRT6 in CSCC cell growth and motility&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Silencing of SIRT6 induces cell apoptosis and inhibits the G1&#47;S cell cycle transition&#46; Cell apoptosis is a complex process involving multiple signaling pathways&#44; and the upregulation of apoptosis-related proteins &#40;including Bax&#44; cleaved-caspase3&#41; following SIRT6 knockdown confirms the involvement of SIRT6 in the regulation of CSCC apoptosis&#46; The authors also observed that SIRT6 knockdown leads to G0&#47;G1 cell cycle arrest as demonstrated by cell cycle analysis&#46; In addition&#44; the downregulation of cyclin D1 and CDK4&#44; which encode proteins that regulate the cell cycle&#44; is associated with tumor progression&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Cyclin D1 is a key protein in cell cycle regulation and is sufficient to drive cell cycle progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;32</span></a> This study demonstrates the involvement of SIRT6 in the regulation of apoptosis and cell cycle in CSCC cells&#44; thereby influencing the expression levels of apoptosis and cell cycle-related proteins&#46; Based on this&#44; the authors speculate that SIRT6 may be involved in the biological behavior of cutaneous squamous cell carcinoma cells as a functional molecule&#46; However&#44; there are several limitations to this study&#46; First&#44; the clinical tissue samples in this study are limited&#44; and future studies should increase the sample size and use multiple experimental methods to further clarify the expression pattern of SIRT6&#46; Secondly&#44; due to the complexity of tumor regulation and development&#44; the specific mechanisms are still subject to further investigation&#44; and subsequent in vivo experiments should be conducted to explore the impact of SIRT6 on the biological behavior of CSCC&#46; In addition&#44; tumors are complex entities with high heterogeneity&#44; and their occurrence and development are not determined by a single independent factor&#46; Therefore&#44; the identification of molecules in CSCC that may interact synergistically or antagonistically with SIRT6 remains a focus of future research&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conclusion</span><p id="par0125" class="elsevierStylePara elsevierViewall">In summary&#44; this study found that SIRT6 is highly expressed in CSCC&#44; which may play a role as a carcinogenic factor&#44; providing a certain theoretical basis for future treatment&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Financial support</span><p id="par0130" class="elsevierStylePara elsevierViewall">This work was supported by the project of <span class="elsevierStyleGrantSponsor" id="gs0005">Nantong Municipal Health Commission</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0005">MB2021019&#41;</span>&#44; the <span class="elsevierStyleGrantSponsor" id="gs0010">Basic Research Project of Nantong Science and Technology Bureau</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0010">JCZ2022021</span>&#41;&#44; and the <span class="elsevierStyleGrantSponsor" id="gs0015">Natural Science Foundation of Jiangsu Province</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0015">BK20211108</span>&#41;&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Authors&#8217; contributions</span><p id="par0135" class="elsevierStylePara elsevierViewall">Sai Chen&#58; Study conception and planning&#59; collection&#44; analysis&#44; and interpretation of data&#59; statistical analysis&#59; drafting and editing of the manuscript&#59; critical review of the manuscript&#59; approval of the final version of the manuscript&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Hongxia Chen&#58; Collection&#44; analysis&#44; and interpretation of data&#59; statistical analysis&#59; drafting and editing of the manuscript&#59; critical review of the manuscript&#59; approval of the final version of the manuscript&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Xu Wang&#58; Collection&#44; analysis&#44; and interpretation of data&#59; statistical analysis&#59; drafting and editing of the manuscript&#59; critical review of the manuscript&#59; approval of the final version of the manuscript&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Dongmei Zhang&#58; Effective participation in research orientation&#59; critical review of the literature&#59; approval of the final version of the manuscript&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Li Zhang&#58; Collection&#44; analysis&#44; and interpretation of data&#59; critical review of the literature&#59; approval of the final version of the manuscript&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Jiawei Cheng&#58; Collection&#44; analysis&#44; and interpretation of data&#59; critical review of the literature&#59; approval of the final version of the manuscript&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Qi Zhang&#58; Collection&#44; analysis&#44; and interpretation of data&#59; critical review of the literature&#59; approval of the final version of the manuscript&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Zhixiang Hua&#58; Effective participation in research orientation&#59; critical review of the literature&#59; approval of the final version of the manuscript&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Xu Miao&#58; Effective participation in research orientation&#59; critical review of the literature&#59; approval of the final version of the manuscript&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Jian Shi&#58; Effective participation in research orientation&#59; collection&#44; analysis&#44; and interpretation of data&#59; statistical analysis&#59; preparation and writing of the manuscript&#59; critical review of the manuscript&#59; approval of the final version of the manuscript&#46;</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Conflicts of interest</span><p id="par0185" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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                  "titulo" => "Immunohistochemistry for protein expression analysis"
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                  "titulo" => "Real-time Reverse Transcription Polymerase Chain Reaction &#40;qRT-PCR&#41;"
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                  "titulo" => "Transwell assay"
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              "titulo" => "Elevated expression of SIRT6 in AK&#44; BD&#44; and CSCC tissues compared to normal skin tissue"
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              "titulo" => "Correlation between SIRT6 expression and clinical pathological parameters in CSCC patients"
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              "titulo" => "High expression of SIRT6 in CSCC cells and tissues and suppression of CSCC cell proliferation by SIRT6 knockdown"
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              "titulo" => "Inhibition of CSCC cell migration and invasion by SIRT6 knockdown"
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              "titulo" => "SIRT6 knockdown enhances apoptosis and induces cell cycle arrest at the G0&#47;G1 phase in CSCC cells"
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    "fechaRecibido" => "2023-06-17"
    "fechaAceptado" => "2023-08-30"
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          "palabras" => array:4 [
            0 => "Biomarkers"
            1 => "Carcinoma&#44; squamous cell"
            2 => "Histology"
            3 => "Sirtuin-6"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;CSCC&#41; is one of the most common types of skin cancer worldwide&#46; Therefore&#44; the identification of biomarkers associated with CSCC progression could aid in the early detection of high-risk squamous cell carcinoma and the development of novel therapeutic strategies&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">This study aimed to investigate the expression patterns of silent mating type Information Regulation 2 homolog 6 &#40;SIRT6&#41; in CSCC and its clinical significance&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">The protein expression level of SIRT6 in tissues was detected by immunohistochemistry&#44; and the correlation between SIRT6 expression and clinicopathological parameters in CSCC patients was analyzed&#46; The relative expression of SIRT6 in CSCC cell lineage and tissue specimens was determined by western blotting and PCR&#46; The effect of SIRT6 silencing on cell proliferation was evaluated using cell counting kit 8&#46; Wound healing&#44; transwell method&#44; and flow cytometry were used to investigate the migration&#44; invasion&#44; and cell cycle distribution&#47;apoptosis of CSCC cells after SIRT6 silencing&#44; respectively&#46; Western blot was used to detect the expression of EMT &#40;Epithelial-Mesenchymal Transition&#41;&#44; cycle&#44; apoptosis&#44; and other related proteins&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">The high expression of SIRT6 was correlated with the location of cancer tissue and Broder staging in CSCC patients&#46; Knockdown of SIRT6 inhibited the proliferation&#44; migration&#44; invasion and EMT of CSCC cells&#44; and promoted their apoptosis&#44; with cells blocked in G1 phase&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Study limitations</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">No animal experiments were conducted to further verify the results&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusion</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Decreased expression of SIRT6 can inhibit the occurrence and development of CSCC&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Expression of SIRT6 in NT &#40;Normal skin Tissue&#41;&#44; AK &#40;Actinic Keratosis&#41;&#44; BD &#40;Bowen Disease&#41;&#44; and CSCC &#40;Cutaneous Squamous Cell Carcinoma&#41; tissues&#46; &#40;A&#41; Representative images &#40;magnified by &#215;100&#160;&#215;&#160;200&#41; of SIRT6 immunohistochemical staining in NT&#44; AK&#44; BD&#44; and CSCC tissues using the SP method&#46; &#40;B&#41; Bar graph illustrating the intensity of SIRT6 expression&#58; n&#40;NT&#41;&#160;&#61;&#160;20-cases &#40;0-cases of strong positive&#44; 0-cases of positive&#44; 13-cases of weak positive&#44; and 7-cases of negative&#41;&#59; n&#40;AK&#41;&#160;&#61;&#160;60-cases &#40;3-cases of strong positive&#44; 31-cases of positive&#44; 22-cases of weak positive&#44; and 4-cases of negative&#41;&#59; n&#40;BD&#41;&#160;&#61;&#160;25 cases &#40;9-cases of strong positive&#44; 14-cases of positive&#44; 2-cases of weak positive&#44; and 0-cases of negative&#41;&#59; n&#40;CSCC&#41;&#160;&#61;&#160;70-cases &#40;46-cases of strong positive&#44; 18-cases of positive&#44; 6-cases of weak positive&#44; and 0-cases of negative&#41;&#46; Note&#58; The full name of SP method is streptomycin peroxidase coupling method&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">SIRT6 knockdown can increase apoptosis and cell cycle arrest in G0&#47;G1 phase of CSCC cells&#46; &#40;A&#8211;B&#41; Flow cytomatics analysis showed the apoptosis rate and cell cycle distribution of A431 and SCL-1 cells transfected with shSIRT6&#160;&#43;&#160;DOX and NC&#44; NC&#160;&#43;&#160;DOX and shSIRT6 in the control group&#46; The apoptotic rate was measured by flow cytometry&#46; The upper right quadrant represented late apoptotic cells&#44; and the lower right quadrant represented early apoptotic cells&#46; The apoptotic rate&#160;&#61;&#160;late apoptotic ratio&#160;&#43;&#160;early apoptotic ratio&#46; &#40;C&#41; Western blots showed apoptosis-related proteins &#40;Bax&#44; Cleaved-caspase3&#41; and cyclins &#40;cyclinD1 and CDK4&#41; in A431 and SCL-1 cells transfected with shSIRT6&#160;&#43;&#160;DOX and control NC&#44; NC&#160;&#43;&#160;DOX&#44; shSIRT6 Flat&#44; &#42;p&#160;&#60;&#160;0&#46;05&#44; &#42;&#42;p&#160;&#60;&#160;0&#46;01&#46;</p>"
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive cell count</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#37;&#65374;25&#37;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&#37;&#65374;50&#37;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#37;&#65374;75&#37;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76&#37;&#65374;100&#37;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Staining intensity</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No coloring</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Faint yellow</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Claybank</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tan</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Expression intensity &#40;Positive cell count&#160;&#215;&#160;Dyeing strength&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low expression</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative &#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#65374;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weak Positive &#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#65374;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High expression</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive &#40;&#43;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#65374;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Strong Positive &#40;&#43;&#43;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#65374;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3599861.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">SIRT6 staining results evaluated using a 12-point semi-quantitative scoring method&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0030"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primer sequence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SIRT6</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&#58;5&#8242;- TGGCAGTCTTCCAGTGTGGTGT-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">R&#58;5&#8242;- CGCTCTCAAAGGTGGTGTCGAA-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">U6</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&#58;5&#8242;- CTCGCTTCGGCAGCACA -3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">R&#58; 5&#8242;- AACGCTTCACGAATTTGCGT-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab3599860.png"
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Primer sequences used for real-time fluorescence quantitative PCR&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0035"
            "detalle" => "Table "
            "rol" => "short"
          ]
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">NT&#44; Normal skin Tissue&#59; AK&#44; Actinic Keratosis&#59; BD&#44; Bowen Disease&#59; CSCC&#44; Cutaneous Squamous Cell Carcinoma&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Expression of SIRT6</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">High expression rate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Low expression &#40;-&#65374;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">High expression &#40;&#43;&#43;&#65374;&#43;&#43;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#46;67&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;00&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CSCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">91&#46;43&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3599859.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Differences in expression of SIRT6 in NT&#44; AK&#44; BD&#44; and CSCC tissues&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0040"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical features</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number of cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Low expression &#40;-&#65374;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">High expression &#40;&#43;&#43;&#65374;&#43;&#43;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P-value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gender</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;433</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8804;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;207</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Position</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exposure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;032&#42;</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-exposure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Course of disease</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;2-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;405</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8805;2-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Invasion depth</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8804;3-mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;128</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;3-mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diameter</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8804;2-cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;316</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;2-cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Broders classification</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8544;&#8210;&#8545;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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