RESUMEN
Early detection of PDAC remains challenging due to the lack of early symptoms and the absence of reliable biomarkers. The aim of the present project was to identify miRNA and proteomics signatures discriminating PDAC patients with DM from nondiabetic PDAC patients. Proteomics analysis and miRNA array were used for protein and miRNA screening. We used Western blotting and Real-Time Quantitative Reverse Transcription polymerase chain reaction (qRT-PCR) for protein and miRNA validation. Comparisons between experimental groups with normal distributions were performed using one-way ANOVA followed by Tukey's post hoc test, and pairwise tests were performed using t-tests. p ≤ 0.05 was considered statistically significant. Protein clusters of differentiation 166 (CD166), glycoprotein CD63 (CD63), S100 calcium-binding protein A13 (S100A13), and tumor necrosis factor-ß (TNF-ß) were detected in the proteomics screening. The miRNA assay revealed a differential miRNA 1285 regulation. Previously described target proteins of miR-1285 cadherin-1 (CDH-1), cellular Jun (c-Jun), p53, mothers against decapentaplegic homolog 4 (Smad4), human transglutaminase 2 (TGM2) and yes-associated protein (YAP), were validated via Western blotting. miR-1285-3p was successfully validated as differentially regulated in PDAC + DM via qRT-PCR. Overall, our data suggest miRNA1285-3p, TGM2, CDH-1, CD166, and S100A13 as potential meaningful biomarker candidates to characterize patients with PDAC + DM. Data are available via ProteomeXchange with the identifier PXD053169.
RESUMEN
Electrochemotherapy (ECT) combines the reversible electroporation (rEP) with intravenous (i.v.) or intratumoral (i.t.) administration of chemotherapeutic drugs. We conducted this study to compare the efficacy of i.v., i.t., and i.v. + i.t. injection of bleomycin (BLM) in ECT treatment of colorectal hepatic metastases in a rat model. WAG/Rij rats were randomized into three groups and underwent ECT with i.v., i.t., or i.v. + i.t. injection of BLM. Tumor volumes and oxygenation were measured by means of ultrasound and photoacoustic imaging. Moreover, liver and tumor tissue were analyzed by histology and immunohistochemistry. The i.v. and i.v. + i.t. groups exhibited a 44.0% and 46.6% reduction in oxygen saturation of the tumor tissue when compared to pretreatment values, whereas the i.t. group only showed a reduction of 35.2%. The extent of tumor tissue necrosis did not statistically differ between the groups. However, the i.t. group showed a tendency towards a lower necrosis rate. Cell proliferation, apoptotic cell death, vascularization, and immune cell infiltration were comparable in the treated tumors of the three groups. ECT with i.v. administration of BLM should be preferred in clinical practice, as the combined i.v. + i.t. therapy did not show superior oncological outcomes in the present study.
Asunto(s)
Bleomicina , Neoplasias Colorrectales , Electroquimioterapia , Neoplasias Hepáticas , Animales , Bleomicina/administración & dosificación , Electroquimioterapia/métodos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Ratas , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Modelos Animales de Enfermedad , Antibióticos Antineoplásicos/administración & dosificación , Masculino , Administración Intravenosa , Terapia Combinada , Inyecciones IntralesionesRESUMEN
BACKGROUND: Anastomosis configuration is an essential step in treatment to restore continuity of the gastrointestinal tract following bowel resection in patients with Crohn's disease (CD). However, the association between anastomotic type and surgical outcome remains controversial. This retrospective study aimed to compare early postoperative complications and surgical outcome between stapler and handsewn anastomosis after bowel resection in Crohn's disease. METHODS: Between 2001 and 2018, a total of 339 CD patients underwent bowel resection with anastomosis. Patient characteristics, intraoperative data, early postoperative complications, and outcomes were analyzed and compared between two groups of patients. Group 1 consisted of patients with stapler anastomosis and group 2 with handsewn anastomosis. RESULTS: No significant difference was found in the incidence of postoperative surgical complications between the stapler and handsewn anastomosis groups (25% versus 24.4%, p = 1.000). Reoperation for complications and postoperative hospital stay were similar between the two groups. CONCLUSION: Our analysis showed that there were no differences in anastomotic leak, nor postoperative complications, mortality, reoperation for operative complications, or postoperative hospital stay between the stapler anastomosis and handsewn anastomosis groups.
Asunto(s)
Anastomosis Quirúrgica , Enfermedad de Crohn , Complicaciones Posoperatorias , Grapado Quirúrgico , Humanos , Enfermedad de Crohn/cirugía , Femenino , Masculino , Anastomosis Quirúrgica/métodos , Estudios Retrospectivos , Adulto , Grapado Quirúrgico/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Persona de Mediana Edad , Técnicas de Sutura , Reoperación/estadística & datos numéricos , Resultado del Tratamiento , Tiempo de Internación/estadística & datos numéricos , Fuga Anastomótica/epidemiología , Fuga Anastomótica/etiología , Adulto JovenRESUMEN
INTRODUCTION: The clinical role of lymphadenectomy (LAD) as part of hepatic resection for malignancies of the liver remains unclear. In this study, we aimed to report on the use cases and postoperative outcomes of liver resection and simultaneous LAD for hepatic malignancies (HM). MATERIALS AND METHODS: Clinicopathological data from patients who underwent surgery at 13 German centers from 2017 to 2022 (n = 3456) was extracted from the StuDoQ|Liver registry of the German Society of General and Visceral Surgery. Propensity-score matching (PSM) was performed to account for the extent of liver resection and patient demographics. RESULTS: LAD was performed in 545 (16%) cases. The most common indication for LAD was cholangiocarcinoma (CCA), followed by colorectal liver metastases (CRLM) and hepatocellular carcinoma (HCC). N+ status was found in 7 (8%), 59 (35%), and 56 cases (35%) for HCC, CCA, and CRLM, respectively (p < 0.001). The LAD rate was highest for robotic-assisted resections (28%) followed by open (26%) and laparoscopic resections (13%), whereas the number of resected lymph nodes was equivalent between the techniques (p = 0.303). LAD was associated with an increased risk of liver-specific postoperative complications, especially for patients with HCC. CONCLUSION: In this multicenter registry study, LAD was found to be associated with an increased risk of liver-specific complications. The highest rate of LAD was observed among robotic liver resections.
Asunto(s)
Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Colorrectales , Laparoscopía , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/secundario , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Hepatectomía/métodos , Colangiocarcinoma/cirugía , Laparoscopía/métodos , Escisión del Ganglio Linfático , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/cirugía , Sistema de Registros , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía , Puntaje de PropensiónRESUMEN
INTRODUCTION: Knowledge of the vascular anatomy is critical to performing safe gluteal surgery. To date, only the course of the main blood vessels within the muscles has been outlined. These findings are based on MRI and CTA images that do not conform to a topographically standardized and normalized probability distribution. OBJECTIVES: The aim of this study was to develop a three-dimensional mapping of the gluteal zones of high vascular density in relation to anatomical landmarks. MATERIALS AND METHODS: This single-center retrospective cohort analysis comprised all consecutive patients who underwent cone-beam computed tomography (CBCT) scans between January 2016 and October 2021. The location of blood vessels in the gluteal region was allometrically normalized in relation to anatomical landmarks. Moreover, the caliber and area of the blood vessels were assessed. RESULTS: CBCT scans of 32 patients with an average age of 64 ± 12 years (range 34-87 years) were included. Fifty-three percent were female. The median [IQR] caliber of the intramuscular gluteal vessels was 1.47 [1.15-1.88] mm, significantly greater than that of the subcutaneous vessels 1.09 [0.72-1.44] mm (p < 0.001). Vascular density was higher intramuscularly, as 4.5% of the area of the muscle was occupied by blood vessels, as opposed to 0.3% in the adipose tissue. CONCLUSION: The analysis of the CBCT scans showed a higher vascular density and larger vessels intramuscularly. We, therefore, recommend the injection of autologous fat merely to the subcutaneous plane. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Asunto(s)
Tejido Adiposo , Tomografía Computarizada de Haz Cónico , Humanos , Nalgas/irrigación sanguínea , Nalgas/cirugía , Nalgas/diagnóstico por imagen , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Masculino , Adulto , Anciano , Tomografía Computarizada de Haz Cónico/métodos , Tejido Adiposo/trasplante , Anciano de 80 o más Años , Estudios de Cohortes , Imagenología Tridimensional , Trasplante Autólogo/métodos , Medición de Riesgo , Seguridad del Paciente , Contorneado Corporal/métodos , Contorneado Corporal/efectos adversosRESUMEN
BACKGROUND & AIMS: Transforming growth factor-ß1 (TGF-ß1) plays important roles in chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD involves various biological processes including dysfunctional cholesterol metabolism and contributes to progression to metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma. However, the reciprocal regulation of TGF-ß1 signaling and cholesterol metabolism in MASLD is yet unknown. METHODS: Changes in transcription of genes associated with cholesterol metabolism were assessed by RNA sequencing of murine hepatocyte cell line (alpha mouse liver 12/AML12) and mouse primary hepatocytes treated with TGF-ß1. Functional assays were performed on AML12 cells (untreated, TGF-ß1 treated, or subjected to cholesterol enrichment [CE] or cholesterol depletion [CD]), and on mice injected with adenovirus-associated virus 8-control/TGF-ß1. RESULTS: TGF-ß1 inhibited messenger RNA expression of several cholesterol metabolism regulatory genes, including rate-limiting enzymes of cholesterol biosynthesis in AML12 cells, mouse primary hepatocytes, and adenovirus-associated virus-TGF-ß1-treated mice. Total cholesterol levels and lipid droplet accumulation in AML12 cells and liver tissue also were reduced upon TGF-ß1 treatment. Smad2/3 phosphorylation after 2 hours of TGF-ß1 treatment persisted after CE or CD and was mildly increased after CD, whereas TGF-ß1-mediated AKT phosphorylation (30 min) was inhibited by CE. Furthermore, CE protected AML12 cells from several effects mediated by 72 hours of incubation with TGF-ß1, including epithelial-mesenchymal transition, actin polymerization, and apoptosis. CD mimicked the outcome of long-term TGF-ß1 administration, an effect that was blocked by an inhibitor of the type I TGF-ß receptor. In addition, the supernatant of CE- or CD-treated AML12 cells inhibited or promoted, respectively, the activation of LX-2 hepatic stellate cells. CONCLUSIONS: TGF-ß1 inhibits cholesterol metabolism whereas cholesterol attenuates TGF-ß1 downstream effects in hepatocytes.
Asunto(s)
Hígado Graso , Factor de Crecimiento Transformador beta1 , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Hepatocitos/metabolismo , Células Estrelladas Hepáticas/patología , Línea Celular , Hígado Graso/metabolismoRESUMEN
BACKGROUND: The available ablative procedures for the treatment of hepatic cancer have contraindications due to the heat-sink effect and the risk of thermal injuries. Electrochemotherapy (ECT) as a nonthermal approach may be utilized for the treatment of tumors adjacent to high-risk regions. We evaluated the effectiveness of ECT in a rat model. METHODS: WAG/Rij rats were randomized to four groups and underwent ECT, reversible electroporation (rEP), or intravenous injection of bleomycin (BLM) eight days after subcapsular hepatic tumor implantation. The fourth group served as Sham. Tumor volume and oxygenation were measured before and five days after the treatment using ultrasound and photoacoustic imaging; thereafter, liver and tumor tissue were additionally analysed by histology and immunohistochemistry. RESULTS: The ECT group showed a stronger reduction in tumor oxygenation compared to the rEP and BLM groups; moreover, ECT-treated tumors exhibited the lowest levels of hemoglobin concentration compared to the other groups. Histological analyses further revealed a significantly increased tumor necrosis of >85% and a reduced tumor vascularization in the ECT group compared to the rEP, BLM, and Sham groups. CONCLUSION: ECT is an effective approach for the treatment of hepatic tumors with necrosis rates >85% five days following treatment.
RESUMEN
BACKGROUND: Immunosuppressants represent an effective pharmacological treatment for the remission and management of Crohn's disease (CD); however, it has not been well-defined if these medications are associated with an increased incidence of postoperative complications after intestinal surgery. This retrospective study evaluated the association between immunosuppressive treatment and complications following bowel resection in patients with CD. METHODS: A total of 426 patients with CD who underwent abdominal surgery between 2001 and 2018 were included in the study. The participants were divided into two groups. In the first group, patients were under immunosuppressive treatment at the time of surgical resection, while in the second group, patients had never received pharmacological therapy for CD before surgery. RESULTS: No statistically significant difference was found in the incidence of postoperative complications between the two groups. Double or triple immunosuppressive therapy was not associated with increased complications compared to monotherapy or no pharmacological treatment. Preoperative risk factors such as hypoalbuminemia, abscess, fistula, intestinal perforation, long duration of symptoms, and the intraoperative performance of more than one anastomosis were related to increased rates of postoperative complications. Factors affecting the occurrence of postoperative complications in the univariate analysis were included in the multivariate analysis using a stepwise logistic regression model, and these factors were also related to increased rates of postoperative surgical complications. CONCLUSION: Immunosuppressive therapy was not associated with increased rates of postoperative complications following bowel resection in patients with CD.
Asunto(s)
Enfermedad de Crohn , Procedimientos Quirúrgicos del Sistema Digestivo , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/cirugía , Enfermedad de Crohn/complicaciones , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Anastomosis Quirúrgica/efectos adversos , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Inmunosupresores/efectos adversosRESUMEN
BACKGROUND: Esophagectomy is associated with increased rate of postoperative complications, making it one of the procedures with the highest impact on patients' quality of life. Hybrid Ivor Lewis esophagectomy (HMIE) has been introduced in our clinic with the aim to reduce postoperative morbidity, without compromising on oncological outcomes. We conducted this survey to evaluate the perioperative morbidity of the new method during the introduction phase compared to open esophagectomy in two similarly matched groups of patients. METHODS: This study included the first 17 patients who underwent HMIE for esophageal cancer at a high-volume tertiary center. After generating propensity scores using the variables age, body mass index, pulmonary comorbidities, cardiac comorbidities, histologic type, and neoadjuvant treatment, 17 patients in the hybrid group were matched with 17 patients in the open group. Surgical outcomes, oncological outcomes, and postoperative complications according to the guidelines of the Esophageal Complications Consensus Group were compared between the two groups. RESULTS: Surgical and oncological outcomes were comparable between the two approaches. The rate of postoperative complications, including surgical, gastrointestinal, and pulmonary complications, were similar in the two groups. CONCLUSIONS: Our hypothesis that laparoscopy could reduce postoperative complications was not confirmed. HMIE is a safe procedure, resulting in radical oncological resection and similar morbidity with open esophagectomy. Surgeons, who are proficient in open approach and laparoscopic anti-reflux and gastric surgery, can safely adopt the hybrid approach without significant learning curve associated morbidity.
Asunto(s)
Neoplasias Esofágicas , Laparoscopía , Neoplasias Esofágicas/cirugía , Esofagectomía/métodos , Humanos , Laparoscopía/efectos adversos , Calidad de Vida , Estudios RetrospectivosRESUMEN
BACKGROUND: Utilization of preoperative biliary drainage prior to pancreatoduodenectomy for patients with pancreatic ductal adenocarcinoma and obstructive jaundice remains controversial. METHODS: All patients that underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma at the authors' institution were analyzed retrospectively to evaluate the effect of endoscopic biliary drainage on postoperative outcomes and long-term survival. Age, gender, ASA-Score, operative time, blood loss, intraoperative transfusion rate, and postoperative complications, including postoperative pancreatic fistula, delayed gastric emptying, bleeding, bile fistula, wound infections, sepsis, pulmonary and cardiac complications as well as the need for relaparotomy were analyzed. RESULTS: Two hundred eighty-five patients with similar baseline characteristics underwent pancreatoduodenectomy, 151 patients with biliary drainage (group 1) and 134 without drainage (group 2). More than 60% of patients had one or more postoperative complications, without significant difference between the two groups (P=0.140). The overall incidence of pancreatic fistula was 21.75% in both groups (group 1: 19.87% vs. group 2: 23.88%, P=0.659). Wound healing impairment was the only postoperative complication that differed significantly between the two groups (group 1: 24.50% vs. group 2: 8.96%, P<0.001). In multivariate risk analysis, biliary drainage was the only independent risk factor for wound healing impairment (OR 4.126; 95% CI: 1.295-13.143; P=0.017). The median overall survival was similar in both groups. CONCLUSIONS: Preoperative endoscopic biliary drainage is associated with an increased risk for wound healing impairment and wound infections. Therefore, biliary drainage should not be used routinely in patients with obstructive jaundice prior to pancreatoduodenectomy.
Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Ictericia Obstructiva , Neoplasias Pancreáticas , Infección de Heridas , Humanos , Pancreaticoduodenectomía/efectos adversos , Estudios Retrospectivos , Fístula Pancreática/epidemiología , Neoplasias Pancreáticas/cirugía , Ictericia Obstructiva/etiología , Adenocarcinoma/cirugía , Cuidados Preoperatorios/efectos adversos , Drenaje/efectos adversos , Carcinoma Ductal Pancreático/cirugía , Complicaciones Posoperatorias/epidemiología , Infección de Heridas/complicaciones , Neoplasias PancreáticasRESUMEN
Background: Evidence is lacking concerning a clear benefit of single-port laparoscopic cholecystectomy (SILC) and transvaginal cholecystectomy (TVC) over the classical laparoscopic cholecystectomy (CLC). In this study, we investigated the preferences of the operation techniques among female employees in a tertiary university clinic. Materials and Methods: Study participants in the department of general surgery and gynecology were interviewed regarding their personal felt preferences for the mentioned procedures using a standardized illustrated questionnaire. Results: A total of 111 participants were included in the study. In 70.3% of cases, the transvaginal approach was unknown. The classical techniques were preferred in 95.2% of respondents. Participants with a wish for children showed a higher preference for nontransvaginal techniques (P = .011). The acceptance rate of transvaginal techniques among employees of the department of gynecology was higher than those of the department of general surgery (P = .028). Conclusions: The overall acceptance rate for TVC is low. Especially in case of a wish for children, SILC and CLC represent the preferred techniques. The lack of popularity of TVC could be an explanation for the refusal of this technique. Among employees of the gynecologic department, a transvaginal approach was significantly more often accepted. The cosmetic outcome and the knowledge about an operation technique certainly influence the decision making for the preferred surgical method.
Asunto(s)
Colecistectomía Laparoscópica , Cirugía Endoscópica por Orificios Naturales , Niño , Colecistectomía/métodos , Colecistectomía Laparoscópica/métodos , Femenino , Hospitales , Humanos , Cirugía Endoscópica por Orificios Naturales/métodos , Vagina/cirugíaRESUMEN
BACKGROUND: Thermoablation is an attractive treatment of thyroid nodules for its minimal-invasiveness. It remains unclear whether results and morbidity meet the patients' expectations. OBJECTIVE: The aim of the presented study is to show data obtained after microwave thyroid ablation from a patients' perspective. METHODS: Indications and preoperative diagnosis were chosen according to international guidelines. Thermoablation was achieved using a CE certified microwave system. The procedures heeded the published recommendations of the European Federation of Societies for Ultrasound in Medicine and Biology. Follow-up included ultrasound, laboratory parameters and a standardized questionnaire. RESULTS: Thirty patients were enrolled into the study. All patients reported an improvement of complaints following the procedure. Scar formation occurred in 3 cases (10%) with 0.5 ± 1.3 mm length and 0.4 ± 1.0 mm width. No cosmetic, neurological, vocal or pharyngeal complication occurred. Energy required for non-functioning nodules (n= 15, 50%) was 2.56 ± 3.41 kJ/mL, for autonomous adenoma (n= 8, 27%) 0.96 kJ/mL (p< 0.05, t-test). CONCLUSION: The presented data summarize an initial experience in selected patients and resemble excellent patient reported outcome with minimal morbidity. These preliminary data indicate the majority of patients satisfied with the procedure. Further trials will be required to endorse these findings.
Asunto(s)
Ablación por Catéter , Nódulo Tiroideo , Humanos , Microondas , Morbilidad , Nódulo Tiroideo/cirugía , Resultado del Tratamiento , UltrasonografíaRESUMEN
BACKGROUND: Guidelines have reported that although microwave ablation (MWA) has potential advantages over radiofrequency ablation (RFA), superiority in efficacy and safety remain unclear. Aim of the study is to compare MWA with RFA in the treatment of liver cancer. METHODS: Meta-analysis was conducted according to the PRISMA guidelines for studies published from 2010 onwards. A random-effects model was used for the meta-analyses. Complete ablation (CA), local tumor progression (LTP), intrahepatic distant recurrence (IDR), and complications were analyzed. RESULTS: Four randomized trials and 11 observational studies with a total of 2,169 patients met the inclusion criteria. Although overall analysis showed no significant difference in LTP between MWA and RFA, subgroup analysis including randomized trials for patients with hepatocellular cancer (HCC) demonstrated statistically decreased rates of LTP in favor of MWA (OR, 0.40; 95% CI, 0.18-0.92; p = 0.03). No significant differences were found between the two procedures in CA, IDR, complications, and tumor diameter less or larger than 3 cm. CONCLUSIONS: MWA showed promising results and demonstrated better oncological outcomes in terms of LTP compared to RFA in patients with HCC. MWA can be utilized as the ablation method of choice in patients with HCC.
Asunto(s)
Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Microondas/uso terapéutico , Ablación por Radiofrecuencia/métodos , Sesgo , Carcinoma Hepatocelular/patología , Intervalos de Confianza , Progresión de la Enfermedad , Humanos , Neoplasias Hepáticas/patología , Microondas/efectos adversos , Recurrencia Local de Neoplasia , Estudios Observacionales como Asunto , Oportunidad Relativa , Ablación por Radiofrecuencia/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Carga TumoralRESUMEN
INTRODUCTION: The endoplasmic reticulum transmembrane proteins Sec61, Sec62, and Sec63 are responsible for the intracellular trafficking of precursor proteins and affect intracellular signaling. SEC62 overexpression has been linked to various human cancers. Our aim was to investigate SEC62 and SEC63 expression in hepatocellular carcinoma (HCC) and surrounding liver tissue. PATIENTS AND METHODS: Primary liver tissue was collected from 11 consecutive patients (70 ± 9 years; 10 men) who underwent HCC resection. In the HCC and the tumor-surrounding liver tissue we investigated SEC62 und SEC63 mRNA expression using quantitative real-time PCR. For Sec62, immunohistochemistry was performed. RESULTS: SEC62and SEC63 total mRNA contents were significantly (p = 0.001) higher in HCCs (CT 22.5 ± 0.4 and 22.6 ± 0.3) when compared to the surrounding tissue (CT 24.6 ± 0.6 and 25.1 ± 0.9). Using the comparative CTmethod, SEC62 and SEC63 expression in HCC was increased 5- and 8.1-fold, respectively, in comparison to surrounding tissue. For Sec62 immunohistochemistry, the mean immunoreactive scores (IRS) were 7.9 ± 2.9 for HCC and 4.8 ± 1.2 for non-tumorous liver (p = 0.027). The mean IRS in HCC were 5.7 ± 3.5 and 8.9 ± 2.3 for patients without (n = 3) and with tumor recurrence (n = 8), respectively. CONCLUSIONS: Overexpression of SEC62 and SEC63 is a common feature of HCC. The role of Sec62 as a prognostic marker for tumor recurrence after surgery and its potential role in treatment stratification must be addressed in future studies.
RESUMEN
Cellular senescence is an irreversible growth arrest that occurs as a result of damaging stimuli, including DNA damage and/or telomere shortening. Here, we investigate histone variant H2A.J as a new biomarker to detect senescent cells during human skin aging. Skin biopsies from healthy volunteers of different ages (18-90 years) were analyzed for H2A.J expression and other parameters involved in triggering and/or maintaining cellular senescence. In the epidermis, the proportions of H2A.J-expressing keratinocytes increased from ≈20% in young to ≈60% in aged skin. Inverse correlations between Ki67- and H2A.J staining in germinative layers may reflect that H2A.J-expressing cells having lost their capacity to divide. As cellular senescence is triggered by DNA-damage signals, persistent 53BP1-foci, telomere lengths, and telomere-associated damage foci were analyzed in epidermal keratinocytes. Only slight age-related telomere attrition and few persistent nuclear 53BP1-foci, occasionally colocalizing with telomeres, suggest that unprotected telomeres are not a significant cause of senescence during skin aging. Quantification of integrin-α6+ basal cells suggests that the number and function of stem/progenitor cells decreased during aging and their altered proliferation capacities resulted in diminished tissue renewal with epidermal thinning. Collectively, our findings suggest that H2A.J is a sensitive marker of epidermal aging in human skin.
RESUMEN
The process of aging has been associated with differential patterns of DNA methylation which relate to changes in gene expression. Hence, we aimed to identify genes with significant age-related methylation differences and to study their mRNA and protein expression profile. Genome-wide DNA methylation analysis was performed with the Illumina Infinium Methylation EPIC BeadChip Microarray on bisulfite-converted DNA prepared from monocytes derived from young (average age: 23.8 yrs) and old (average age: 81.5 yrs) volunteers that are separated by at least 50 years of age difference, n=4, respectively. Differentially methylated CpG sites were assigned to the associated genes and validated by deep sequencing analysis (n=20). Demonstrating an age-associated significant increase of methylation in the promoter region (p=1x10-8), Homeobox A5 (HOXA5), also known to activate p53, emerged as an interesting candidate for further expression analyses by Realtime PCR, ELISA and Western Blot Analysis (n=30, respectively). Consistent with its hypermethylation we observed significant HOXA5 mRNA downregulation (p=0.0053) correlating with significant p53 downregulation (p=0.0431) in the old cohort. Moreover, we observed a significant change in HOXA5 protein expression (p=3x10-5) negatively correlating with age and promoter methylation thus qualifying HOXA5 for an eligible p53-related aging marker.