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INTRODUCTION: Gastric cancer (GC) is the fifth most diagnosed neoplasia and the third leading cause of cancer-related deaths. A substantial number of patients exhibit an advanced GC stage once diagnosed. Therefore, the search for biomarkers contributes to the improvement and development of therapies. OBJECTIVE: This study aimed to identify potential GC biomarkers making use of in silico tools. METHODS: Gastric tissue microarray data available in Gene Expression Omnibus and The Cancer Genome Atlas Program was extracted. We applied statistical tests in the search for differentially expressed genes between tumoral and non-tumoral adjacent tissue samples. The selected genes were submitted to an in-house tool for analyses of functional enrichment, survival rate, histological and molecular classifications, and clinical follow-up data. A decision tree analysis was performed to evaluate the predictive power of the potential biomarkers. RESULTS: In total, 39 differentially expressed genes were found, mostly involved in extracellular structure organization, extracellular matrix organization, and angiogenesis. The genes SLC7A8, LY6E, and SIDT2 showed potential as diagnostic biomarkers considering the differential expression results coupled with the high predictive power of the decision tree models. Moreover, GC samples showed lower SLC7A8 and SIDT2 expression, whereas LY6E was higher. SIDT2 demonstrated a potential prognostic role for the diffuse type of GC, given the higher patient survival rate for lower gene expression. CONCLUSION: Our study outlines novel biomarkers for GC that may have a key role in tumor progression. Nevertheless, complementary in vitro analyses are still needed to further support their potential.

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Neoplasias Gástricas/diagnóstico , Biomarcadores de Tumor , Biología Computacional , Pronóstico , Simulación por Computador , Expresión Génica , Análisis de Matrices Tisulares

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BACKGROUND AND AIMS: Deafferentation and compensatory neural plastic changes in the inferior colliculus (IC) have been suggested following single-sided deafness (SSD). We explored related miRNA changes in the IC of SSD rats using miRNA microarray analyses. METHODS: Eight-week-old rats were divided into control and SSD rats (n = 8 for each group). SSD rats underwent right-side cochlear ablation surgery, with the IC harvested two weeks post-surgery. miRNA microarray analysis was performed using GeneChip miRNA 4.0, microarray (Affymetrix Inc.). miRNAs whose expression levels differed between SSD and control rats with a fold-change ≥ 1.5 and P < 0.05 were examined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target genes of differentially expressed miRNAs were predicted using TargetScan software. The pathways related to predicted target genes were analyzed. mRNA levels of predicted target genes were estimated using qRT-PCR. RESULTS: The expression of miR-15b-5p, miR-202-5p, and miR-212-3p was lower in the contralateral (left) IC of SSD rats than that of control rats. In SSD rats, miRNA expression levels in the contralateral IC were 0.45-, 0.25-, and 0.50-fold lower for miR-15b-5p, miR-202-5p, and miR-212-3p, respectively (P < 0.05). The expression of predicted target genes (Spred1, Rasa1, Lsm11, and Srsf1) was higher in the contralateral IC of SSD rats than in control rats. The targets were predicted to be related with cleavage of growing transcripts in the termination region, mitogen-activated protein kinase family signaling cascades, RAF/AMP kinase cascade, regulation of RAS by GTPase activating proteins (GAPs), and RNA polymerase II transcription termination. For ipsilateral ICs, miR-425-3p, miR-199a-5p, and miR-134-3p showed lower expressions in SSD rats than in control rats, which were 0.55-, 0.61-, and 0.69-fold lower, respectively (P < 0.05). The expression of predicted target genes (Atp2b2, Grin2b, Foxp1, Ztbt20, Zfp91, and Strn) was higher in the ipsilateral IC of SSD rats; the regulation of synaptic plasticity, cAMP signaling pathway, metal ion binding, and calcium ion transport can be associated with these target genes. CONCLUSION: Adult rats with unilateral auditory deprivation showed miRNA changes in the IC. The contralateral IC showed decreased miRNA expression predicted to be related to MAPK and RAS signaling, whereas the ipsilateral IC revealed decreased miRNA expression predicted to be associated with synaptic plasticity and calcium ion transport.

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Sordera , Colículos Inferiores , MicroARNs , Adenilato Quinasa , Animales , Calcio , Factores de Transcripción Forkhead/genética , Proteínas Activadoras de GTPasa/genética , Perfilación de la Expresión Génica , Colículos Inferiores/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Plásticos/metabolismo , ARN Polimerasa II/metabolismo , ARN Mensajero/genética , Ratas , Proteínas Represoras/genética

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Bladder cancer (BC) ranks as the ninth most commonly diagnosed cancer worldwide. The presence of a transcription factor (TF) has been uncovered as a significant contributor to the pathophysiological changes of cancers. In present study, we elucidated the expression and clinical significance of Homeobox A11 (HOXA11) in BC for the first time, and originally investigated HOXA11 as a TF. Employing in-house immunohistochemistry (IHC), we incorporated 137 BC and 34 non-BC cases to detect the expression of HOXA11 protein in BC tissues. HOXA11-related RNA-sequencing (RNA-seq) expression and RNA microarrays were collected from public databases, the "sva" and "limma" R packages were implemented to integrate and normalize the RNA-seq data and microarrays separately. Integration expression was carried out to further evaluate the HOXA11 expression by utilizing the standard mean difference (SMD). The expression level of HOXA11 in various BC cell lines was also evaluated. We further systematically analyzed the downstream target genes of HOXA11 in BC by utilizing Chromatin Immunoprecipitation Sequencing (ChIP-seq) profiles, differentially expressed genes (DEGs), and HOXA11-related genes. Modification of histone marks on the promoter region of target genes were also discovered by histone ChIP-seq data. Results of the IHC and RNA-seq revealed the protein and mRNA expression of HOXA11 was significantly decreased in BC tissues compared to non-BC tissues (2.98 ± 1.48 vs. 8.23 ± 2.64; 6.87 ± 1.54 vs. 8.38 ± 1.42). Five platforms significantly revealed the down-regulation of HOXA11 expression in BC (GPL96, GPL570, GPL6102, GPL6884, and GPL13497). A similar decreased trend was discovered in BC tissues in expression integration with the incorporated SMD reaching -0.843 (-1.362 ~ -0.325, p = 0.001) and -1.051 (-1.674 ~ -0.428, p = 0.001). Expression of HOXA11 was down-regulated in most of the BC cell lines. COL1A1 was considered as a final HOXA11 target gene and positively related to HOXA11 with the correlation coefficient as 0.584 (95% CI: 0.371-0.739, p < 0.001). HOXA11 regulates COL1A1 expression in BC via H3K27ac modification. The expression of COL1A1 was down-regulated with the SMD reached -0.312 (p < 0.001). In conclusion, HOXA11 expression is markedly decreased and might promote the transcription of COL1A1 to inhibit BC.

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Genes Homeobox , Neoplasias de la Vejiga Urinaria , Regulación de la Expresión Génica , Proteínas de Homeodominio , Humanos , ARN , Factores de Transcripción/genética , Neoplasias de la Vejiga Urinaria/genética

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INTRODUCTION: Immune-checkpoint inhibitors have demonstrated a significant survival benefit in metastatic and non-resectable head and neck squamous cell carcinoma (HNSCC). Patients with a combined positivity score (CPS) of 20 and higher benefit the most from therapy. Inaccurate definition of the CPS category might lead to the incorrect stratification of patients to immunotherapy. This study's main aim was to investigate programmed death-ligand 1 (PD-L1) antigen expression in HNSCC in diverse clinical situations and histological settings. MATERIALS AND METHODS: This is a prospective cohort study conducted in a tertiary referral medical center. Tissues were investigated for PD-L1 expression using the FDA-approved 22C3 immunohistochemistry assay (Dako). We analyzed potential associations between the CPS category and meaningful demographic, clinical, and outcome metrics. Furthermore, we investigated morphologically separate sites for CPS scores in whole surgical tissue specimens and matched preoperative biopsies. RESULTS: We analyzed 36 patients, of whom 26 had oral cavity SCC and 10 had laryngeal SCC. The overall, disease-specific, and progression-free survival of the HNSCC group of patients were not associated with the CPS category (p = 0.45, p = 0.31, and p = 0.88, respectively). There was a significant (18%, 95% CI 0.65-0.9) inconsistency between the CPS category determined in biopsies versus whole carcinoma analyses. We also found an uneven distribution of whole-tumor CPS attributed to spatial carcinoma invasiveness, tumor differentiation, and inflammatory cell infiltration heterogeneity. DISCUSSION AND CONCLUSIONS: Our data suggest that careful selection of tumor area for CPS analysis is important. PD-L1 antigen expression, clinically represented by CPS, may be up- or down-categorized in different clinical and pathological circumstances. The high whole-tissue CPS category scatter may clinically result in potential treatment modifications. We argue that CPS analysis requires not only adequacy (at least 100 viable tumor cells), but also correct representation of the tumor microenvironment.

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Antígeno B7-H1/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Biopsia , Femenino , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Microambiente Tumoral

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OBJECTIVE: To evaluate the evidence reporting gene expression array data of human in vitro cultured periodontal ligament cells (PDLCs) submitted to static mechanical loading compared to a control group. DESIGN: Systematic searches were performed in MEDLINE/PubMed, Scopus, Web of Science, Virtual Health Library, The Cochrane Library and the System for Information on Grey Literature in Europe up to June 2019. A narrative synthesis was performed to summarize differentially expressed genes (DEGs). These were grouped according to the culture method (2D or 3D), force type (compression or tension) and observation time. Additionally, gene ontology (GO) analysis was performed using the Database for Annotation Visualization and Integrated Discovery. The risk of bias (RoB) and certainty of evidence (CoE) were assessed using a modified CONSORT checklist and the GRADE tool, respectively. RESULTS: Of eight studies included (all rated as having moderate RoB), only two provided the complete list of DEGs and four studies performed GO, gene network or pathways analysis. "Cell proliferation", "cell-cell signaling", "response to hypoxia and to mechanical stimulus" were among the significantly enriched biological processes in 3D-cultured compressed PDLCs (moderate CoE); while "collagen catabolic process", "extracellular matrix organization" and "cell proliferation" were associated with DEGs of 3D-cultured PDLCs submitted to tension (very low CoE). Biological processes significantly enriched in 2D-cultured PDLCs under compression were "extracellular matrix organization", "canonical glycolysis" and "glycolytic process" (very low CoE). CONCLUSION: Genes such as NR4A2, NR4A3, NAMPT, PGK1, and REDD1 are suggested as novel biomarkers for orthodontic tooth movement. Limited amount of evidence on the complete gene expression profile and the high heterogeneity in methodologies make it impossible to obtain definite conclusions. New studies following standardized and well-designed in vitro model and reporting complete gene expression datasets are needed.

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Ligamento Periodontal , Estrés Mecánico , Transcriptoma , Células Cultivadas , Humanos , Técnicas de Movimiento Dental

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BACKGROUND: Prognosis among patients with differentiated thyroid cancer is widely variable. Better understanding of biologic subtypes is necessary to stratify patients and improve outcomes. METHODS: In patients diagnosed with classic histology papillary thyroid cancer treated from 1973 to 2009, BRAF V600E mutation status was determined on surgical tumor specimens by restriction fragment length polymorphism analysis. A tissue microarray (TMA) was constructed from tumor specimens in triplicate and stained by immunohistochemistry for RET, phospho-MEK, MAPK(dpERK), PPARγ, and phospho-AKT(pAKT). Stained slides were scored independently and blindly by two investigators and compared to tumor and patient characteristics and outcomes. RESULTS: A total of 231 patients had archived formalin-fixed, paraffin-embedded tumor tissue available and were included on the TMA. Mean age at diagnosis was 44 years (range 6-82 years); proportion of patients with female sex was (72%); 2015 American Thyroid Association (ATA) risk stratification was low (26%), intermediate (32%), and high (42%). BRAF V600E mutation was found in 74% of specimens, and IHC was scored as positive for RET (61%), MAPK (dpERK) (14%), PPARγ (27%), and pAKT (39%). Positive RET staining was associated with a lower risk of recurrence (HR = 0.46, 95% CI 0.22-0.96). No other molecular biomarkers were independent predictors of recurrence on univariable analysis. On RPA, patients with RET-negative and either MAPK(dpERK)-positive or pAKT-positive tumors were identified to have a high risk of recurrence (HR = 5.4, 95%CI 2.5-11.7). This profile remained associated with recurrence in a multivariable model including ATA risk stratification (HR = 2.8, 95% CI 1.3-6.0). CONCLUSION: Characterization of molecular pathways involved in cPTC tumorigenesis may add further risk stratification for recurrence beyond the 2015 ATA risk categories alone.

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Recurrencia Local de Neoplasia/genética , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/mortalidad , PPAR gamma/genética , PPAR gamma/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas c-ret/metabolismo , Riesgo , Cáncer Papilar Tiroideo/metabolismo , Cáncer Papilar Tiroideo/mortalidad , Cáncer Papilar Tiroideo/cirugía , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Adulto Joven

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BACKGROUND The expression of aldehyde dehydrogenase 1A1 (ALDH1A1) is increased in several human tumors, including colorectal carcinoma (CRC). The aim of this study was to compare the expression ALDH1A1 in CRC tumor tissue compared with non-tumor adjacent tissue (NAT), using immunohistochemistry (IHC), and to determine whether the expression of the ALDH1A1 protein was associated with prognostic factors in CRC. MATERIAL AND METHODS Formalin-fixed paraffin-embedded (FFPE) tissue from 424 patients diagnosed with CRC, and 196 matched NATs were used to prepare tissue microarrays (TMAs). IHC was performed using an immunoperoxidase method with a primary polyclonal rabbit anti-ALDH1A1 antibody. The IHC scores by light microscopy were the staining intensity (scored from 0-3) multiplied by the percentage area of positive immunostaining within the visual field (scored from 0-4). Associations between tumor expression levels of ALDH1A1 and patient clinicopathological characteristics, including tumor grade, size, and TNM stage at surgery were analyzed. RESULTS ALDH1A1 protein expression was significantly increased in CRC tissues compared with matched NATs. In patients with CRC, increased expression of the ALDH1A1 protein was significantly associated with the presence of lymph node metastasis: 64.28% in N0 cases; 75.49% in N1 cases; and 82.14% in N2 cases, (P=0.002). Univariate and multivariate analysis showed that ALDH1A1 expression was an independent prognostic marker for CRC (P<0.001). CONCLUSIONS Using IHC, the expression of the ALDH1A1 protein in CRC tissues was significantly associated with the presence of lymph node metastases and might be a potential prognostic marker in patients with CRC.

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Aldehído Deshidrogenasa/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Familia de Aldehído Deshidrogenasa 1 , Neoplasias Colorrectales/patología , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Retinal-Deshidrogenasa

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Sialyl Lewisx (SLX) is a carbohydrate ligand for endothelial selectin that participates in cell adhesion, proliferation and scattering. It plays an important role in cancer cell adhesion to vascular endothelial cells, leading to hematogenous metastasis. The prognostic significance of SLX expression level at the invasive front in patients with stage II colorectal cancer (CRC) was examined. A total of 209 patients with stage II CRC curatively resected between 1997 and 2000 were enrolled. The preoperative serum SLX levels measured by radioimmunoassay and SLX immunoexpression levels at the invasive front, and at the non-invasive frontal region determined by tissue microarray were analyzed. SLX expression at the invasive front was positively associated with tumor invasion depth (P=0.007) and tumor budding grade (P=0.038). Disease-free survival curves differed between the high and low SLX-expression groups (5-year survival rates, 77.0 and 89.7%, respectively; P=0.036). Liver cancer recurrence was more frequent in the high-expression group than in the low-expression group (15.9 and 2.4%; P=0.002). Multivariate analysis revealed that its expression (hazard ratio, 5.26; P=0.015) and venous invasion (hazard ratio, 4.14; P=0.040) were independent predictive markers of liver cancer recurrence. Neither the preoperative serum SLX level nor SLX expression at the non-invasive frontal region showed any association with histopathological features or disease-free survival. SLX expression level at the invasive front is a promising marker for identifying patients with stage II CRC with a high risk of liver cancer recurrence.

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BACKGROUND: The amount of time available to pathologists with which to perform research is becoming limited due to an increasing manpower shortage in pathology, decreased reimbursement, and increased workload. This is occurring at the same time as demands escalate for pathologists to develop new companion tests, correlate the molecular findings with traditional methods, and assist in the development of individualized medicine. This study examined whether cytotechnologists may be integrated into a research team that uses their expertise in understanding pathology and clinical disease to provide interpretations of experiments that traditionally were performed by pathologists. METHODS: Cytotechnologists worked with pathologists to choose blocks for tissue microarrays (TMAs) and to interpret immunohistochemically stained TMA slides. The pathologist met with the cytotechnologist to review the study design. The cytotechnologists reviewed the slides and blocks and chose the most appropriate blocks for the TMA. Either 10% or all of the slides/blocks selected for TMA construction were reviewed by the supervising pathologist. The final selections were given to the TMA technologist to make the TMA. A minimum of 10% of the immunohistochemically stained TMA slides were reviewed by the supervising pathologist. RESULTS: A total of 32 TMAs were created with 6 cytotechnologists collaborating with 6 pathologists. Immunohistochemical stains of 190 TMAs were interpreted by 4 cytotechnologists collaborating with 3 pathologists. All the TMAs and TMA interpretation data were used successfully for the research for which they were designed. CONCLUSIONS: The collaboration of cytotechnologists and pathologists in research can improve the quality of effort and increase satisfaction and productivity. Cancer Cytopathol 2018;126:232-5. © 2018 American Cancer Society.

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Investigación Biomédica , Patología Clínica , Conducta Cooperativa , Humanos , Inmunohistoquímica , Análisis de Matrices Tisulares

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BACKGROUND: Aquaporin 1 (AQP1) overexpression has been shown to be associated with uncontrolled cell replication, invasion, migration, and tumor metastasis. We aimed to evaluate AQP1 expression in lung adenocarcinomas and to examine its association with clinicopathological features and prognostic significance. We also investigated the association between AQP1 overexpression and epithelial-mesenchymal transition (EMT) markers. METHODS: We examined AQP1 expression in 505 cases of surgically resected lung adenocarcinomas acquired at the Seoul National University Bundang Hospital from 2003 to 2012. Expression of AQP1 and EMT-related markers, including Ecadherin and vimentin, were analyzed by immunohistochemistry and tissue microarray. RESULTS: AQP1 overexpression was associated with several aggressive pathological parameters, including venous invasion, lymphatic invasion, and tumor recurrence. AQP1 overexpression tended to be associated with higher histological grade, advanced pathological stage, and anaplastic lymphoma kinase (ALK) translocation; however, these differences were not statistically significant. In addition, AQP1 overexpression positively correlated with loss of E-cadherin expression and acquired expression of vimentin. Lung adenocarcinoma patients with AQP1 overexpression showed shorter progression-free survival (PFS, 46.1 months vs. 56.2 months) compared to patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter PFS (hazard ratio, 1.429; 95% confidence interval, 1.033 to 1.977; p=.031). CONCLUSIONS: AQP1 overexpression was thereby concluded to be an independent factor of poor prognosis associated with shorter PFS in lung adenocarcinoma. These results suggested that AQP1 overexpression might be considered as a prognostic biomarker of lung adenocarcinoma.

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PURPOSE: Transducer-like enhancer of split 1 (TLE1) is a member of the Groucho/TLE family of transcriptional co-repressors that regulate the transcriptional activity of numerous genes. TLE1 is involved in the tumorigenesis of various tumors. We investigated the prognostic significance of TLE1 expression and its association with clinicopathological parameters in gastric cancer (GC) patients. MATERIALS AND METHODS: Immunohistochemical analysis of six tissue microarrays was performed to examine TLE1 expression using 291 surgically resected GC specimens from the Soonchunhyang University Cheonan Hospital between July 2006 and December 2009. RESULTS: In the non-neoplastic gastric mucosa, TLE1 expression was negative. In GC, 121 patients (41.6%) were positive for TLE1. The expression of TLE1 was significantly associated with male gender (P=0.021), less frequent lymphatic (P=0.017) or perineural invasion (P=0.029), intestinal type according to the Lauren classification (P=0.024), good histologic grade (P<0.001), early pathologic T-stage (P=0.012), and early American Joint Committee on Cancer stage (P=0.022). In the Kaplan-Meier analysis, the TLE1 expression was significantly associated with longer disease-free (P=0.022) and overall (P=0.001) survival rates. CONCLUSIONS: We suggested that TLE1 expression is a good prognostic indicator in GCs.

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Myoferlin is a protein that is associated with cellular repair following injury. The expression of myoferlin in breast cancer and pancreatic adenocarcinoma has been reported to correlate with tumor invasiveness, epithelial to mesenchymal transition and an adverse prognosis. In the present study, myoferlin expression was investigated in non-small cell lung carcinoma (NSCLC), along with its association with patient prognosis and the expression of a number of other proteins. A total of 148 patients exhibiting NSCLC were enrolled in the present study. The survival data of all patients was examined, and myoferlin, vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor, E-cadherin, ß-catenin, thyroid transcription factor-1 and tumor protein p63 expression was investigated via immunohistochemical staining of tissue microarrays. Myoferlin expression was detected in the cytoplasm of 75/148 (50.7%) of the NSCLC cases. In the adenocarcinoma cases, myoferlin-positive patients possessed a poorer prognosis (odds ratio, 2.94; P=0.339). In the squamous cell carcinoma cases, myoferlin expression was significantly associated with VEGFR-2 expression (P=0.001). Immunohistochemical staining for VEGFR-2 and myoferlin expression indicated similar features and cytoplasmic staining in tumor cells. As VEGFR-2 is a significant target for novel anticancer therapies, it is anticipated that myoferlin may also possess the potential to become a novel clinical target for the treatment of NSCLC.

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BACKGROUND: Immunohistochemical demonstration of CD20 in diffuse large B-cell lymphoma (DLBCL) is prerequisite not only for the diagnosis but also for assigning patients to rituximab-containing chemotherapy. However, little is known about the impact of abundance of CD20 expression assessed by immunohistochemistry on the clinical outcome of DLBCL. We performed a semi-quantitative immunohistochemical analysis of CD20 expression in DLBCL to examine the prognostic implication of the level of CD20 expression. METHODS: Pre-treatment diagnostic tissue samples from 48 DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen were represented in a tissue microarray and immunostained for CD20. The relative abundance of CD20 expression was semi-quantitatively scored using a web-based ImmunoMembrane plug-in. Receiver operating characteristic curve analysis was used to determine a prognostically relevant cut-off score in order to dichotomize the patients into CD20-high versus CD20-low groups. RESULTS: The levels of CD20 expression were heterogeneous among the patients, with a wide and linear distribution of scores. Patients in CD20-low group showed significantly poor clinical outcome. CONCLUSIONS: The levels of CD20 expression in DLBCL are heterogeneous among the patients with DLBCL. A subgroup of the patients with CD20 expression levels below the cut-off score showed poor clinical outcome.

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PURPOSE: Existing data regarding the expression of estrogen receptors (ERs) and prostate cancer outcomes have been limited. We evaluated the relationship of expression profiles of ERß subtypes and the ER GPR30 (G-protein-coupled receptor-30) with patient factors at diagnosis and outcomes following radical prostatectomy. MATERIALS AND METHODS: Tissue microarrays constructed using samples from 566 men with long-term clinical followup were analyzed by immunohistochemistry targeting ERß1, ERß2, ERß5 and GPR30. An experienced pathologist scored receptor distribution and staining intensity. Tumor staining characteristics were evaluated for associations with patient characteristics, recurrence-free survival and prostate cancer specific mortality following radical prostatectomy. RESULTS: Prostate cancer cells had unique receptor subtype staining patterns. ERß1 demonstrated predominantly nuclear localization while ERß2, ERß5 and GPR30 were predominantly cytoplasmic. After controlling for patient factors intense cytoplasmic ERß1 staining was independently associated with time to recurrence (HR 1.7, 95% CI 1.1-2.6, p = 0.01) and prostate cancer specific mortality (HR 6.6, 95% CI 1.8-24.9, p = 0.01). Intense nuclear ERß2 staining was similarly independently associated with prostate cancer specific mortality (HR 3.9, 95% CI 1.1-13.4, p = 0.03). Patients with cytoplasmic ERß1 and nuclear ERß2 co-staining had significantly worse 15-year prostate cancer specific mortality than patients with expression of only cytoplasmic ERß1, only nuclear ERß2 and neither ER (16.4%, 4.3%, 0.0% and 2.0 %, respectively, p = 0.001). CONCLUSIONS: Increased cytoplasmic ERß1 and nuclear ERß2 expression is associated with worse cancer specific outcomes following radical prostatectomy. These findings suggest that tumor ERß1 and ERß2 staining patterns provide prognostic information on patients treated with radical prostatectomy.

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Receptor beta de Estrógeno/metabolismo , Próstata/metabolismo , Prostatectomía/métodos , Neoplasias de la Próstata/metabolismo , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adulto , Anciano , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Pronóstico , Próstata/patología , Próstata/cirugía , Prostatectomía/efectos adversos , Neoplasias de la Próstata/cirugía , Estudios Retrospectivos , Análisis de Supervivencia , Análisis de Matrices Tisulares

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BACKGROUND: Aquaporin 1 (AQP1) overexpression has been shown to be associated with uncontrolled cell replication, invasion, migration, and tumor metastasis. We aimed to evaluate AQP1 expression in lung adenocarcinomas and to examine its association with clinicopathological features and prognostic significance. We also investigated the association between AQP1 overexpression and epithelial-mesenchymal transition (EMT) markers. METHODS: We examined AQP1 expression in 505 cases of surgically resected lung adenocarcinomas acquired at the Seoul National University Bundang Hospital from 2003 to 2012. Expression of AQP1 and EMT-related markers, including Ecadherin and vimentin, were analyzed by immunohistochemistry and tissue microarray. RESULTS: AQP1 overexpression was associated with several aggressive pathological parameters, including venous invasion, lymphatic invasion, and tumor recurrence. AQP1 overexpression tended to be associated with higher histological grade, advanced pathological stage, and anaplastic lymphoma kinase (ALK) translocation; however, these differences were not statistically significant. In addition, AQP1 overexpression positively correlated with loss of E-cadherin expression and acquired expression of vimentin. Lung adenocarcinoma patients with AQP1 overexpression showed shorter progression-free survival (PFS, 46.1 months vs. 56.2 months) compared to patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter PFS (hazard ratio, 1.429; 95% confidence interval, 1.033 to 1.977; p=.031). CONCLUSIONS: AQP1 overexpression was thereby concluded to be an independent factor of poor prognosis associated with shorter PFS in lung adenocarcinoma. These results suggested that AQP1 overexpression might be considered as a prognostic biomarker of lung adenocarcinoma.

Asunto(s)

Humanos , Adenocarcinoma , Acuaporina 1 , Cadherinas , Supervivencia sin Enfermedad , Transición Epitelial-Mesenquimal , Inmunohistoquímica , Pulmón , Linfoma , Análisis Multivariante , Metástasis de la Neoplasia , Fosfotransferasas , Pronóstico , Recurrencia , Seúl , Análisis de Matrices Tisulares , Vimentina

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PURPOSE: Although the influence of Notch signaling on several types of malignancies has been studied, the role of Notch signaling in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we evaluated the levels of Notch1 and Jagged1 and their significance in ccRCC. MATERIALS AND METHODS: Tumor tissue and matched normal adjacent kidney tissue from 49 ccRCC cases were obtained. The expression of Notch1 and Jagged1 was analyzed using real-time polymerase chain reaction (PCR) and Western blotting. Tissue samples were divided into several groups according to clinicopathological features, and the relative expression of Notch1 and Jagged1 was assessed. RESULTS: Real-time PCR revealed increased Notch1 expression in tumor tissues compared with that in adjacent normal tissues (p=0.044). Based on the pathological stage, a significant difference in Notch1 expression was observed between tumor and normal kidney tissues in pT2 and pT3 ccRCC (pT2, p=0.041; pT3, p=0.001). Notch1 expression in ccRCC relative to that in normal tissue was higher in later-stage ccRCC and larger ccRCC. Notch1 expression showed significant positive correlation with the maximal diameter of the primary renal tumor (mRNA, p<0.001; protein, p=0.001). High Notch1 expression was associated with recurrence and disease-specific death, although the difference was not significant. Jagged1 level was not significantly correlated with any of the factors examined. CONCLUSIONS: Notch1 may play a significant role in the tumorigenesis and progression of ccRCC. Notch signaling may be a potential target for chemopreventive or adjuvant therapeutics for ccRCC.

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Biomarcadores , Western Blotting , Carcinogénesis , Carcinoma de Células Renales , Riñón , Reacción en Cadena en Tiempo Real de la Polimerasa , Recurrencia , Análisis de Matrices Tisulares

RESUMEN

PURPOSE: Transducer-like enhancer of split 1 (TLE1) is a member of the Groucho/TLE family of transcriptional co-repressors that regulate the transcriptional activity of numerous genes. TLE1 is involved in the tumorigenesis of various tumors. We investigated the prognostic significance of TLE1 expression and its association with clinicopathological parameters in gastric cancer (GC) patients. MATERIALS AND METHODS: Immunohistochemical analysis of six tissue microarrays was performed to examine TLE1 expression using 291 surgically resected GC specimens from the Soonchunhyang University Cheonan Hospital between July 2006 and December 2009. RESULTS: In the non-neoplastic gastric mucosa, TLE1 expression was negative. In GC, 121 patients (41.6%) were positive for TLE1. The expression of TLE1 was significantly associated with male gender (P=0.021), less frequent lymphatic (P=0.017) or perineural invasion (P=0.029), intestinal type according to the Lauren classification (P=0.024), good histologic grade (P<0.001), early pathologic T-stage (P=0.012), and early American Joint Committee on Cancer stage (P=0.022). In the Kaplan-Meier analysis, the TLE1 expression was significantly associated with longer disease-free (P=0.022) and overall (P=0.001) survival rates. CONCLUSIONS: We suggested that TLE1 expression is a good prognostic indicator in GCs.

Asunto(s)

Humanos , Masculino , Carcinogénesis , Clasificación , Proteínas Co-Represoras , Mucosa Gástrica , Articulaciones , Estimación de Kaplan-Meier , Neoplasias Gástricas , Tasa de Supervivencia , Análisis de Matrices Tisulares

RESUMEN

BACKGROUND: Immunohistochemical demonstration of CD20 in diffuse large B-cell lymphoma (DLBCL) is prerequisite not only for the diagnosis but also for assigning patients to rituximab-containing chemotherapy. However, little is known about the impact of abundance of CD20 expression assessed by immunohistochemistry on the clinical outcome of DLBCL. We performed a semi-quantitative immunohistochemical analysis of CD20 expression in DLBCL to examine the prognostic implication of the level of CD20 expression. METHODS: Pre-treatment diagnostic tissue samples from 48 DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen were represented in a tissue microarray and immunostained for CD20. The relative abundance of CD20 expression was semi-quantitatively scored using a web-based ImmunoMembrane plug-in. Receiver operating characteristic curve analysis was used to determine a prognostically relevant cut-off score in order to dichotomize the patients into CD20-high versus CD20-low groups. RESULTS: The levels of CD20 expression were heterogeneous among the patients, with a wide and linear distribution of scores. Patients in CD20-low group showed significantly poor clinical outcome. CONCLUSIONS: The levels of CD20 expression in DLBCL are heterogeneous among the patients with DLBCL. A subgroup of the patients with CD20 expression levels below the cut-off score showed poor clinical outcome.

Asunto(s)

Humanos , Antígenos CD20 , Linfocitos B , Ciclofosfamida , Diagnóstico , Doxorrubicina , Quimioterapia , Inmunohistoquímica , Linfoma de Células B , Prednisona , Curva ROC , Análisis de Matrices Tisulares , Vincristina , Rituximab

RESUMEN

Biomarker is defined as biological variables that correlate with biologic outcome. This review will discuss investigations into gastric cancer (GC) biomarkers by proteomic analysis. Proteomic analysis consists of 3 steps. The first step is the digestion and separation process using 2-dimensional electrophoresis gel or liquid chromatography. The second step is mass analysis using mass spectrometry. The third step is protein identification using databases. Clinical validation of proteins identified can help estimate expressions of cancer tissue and cancer cell line using Western blot and immunohistochemistry. Researchers can validate the association between protein expression and clinical data (tumor stage, cell type, survival, and recurrence), which helps identify the possibility of biomarkers for GC. After clinical validation, the next step is functional analysis in vitro and in vivo. This step is commonly performed by knock-in and knock-out studies on the proliferation, migration, and invasion using the cancer cell line. Animal studies also provide indirect evidence for the role of the proteins in tumor growth and metastasis in vivo. In conclusion, the proteomic analysis is one of the useful methods for detecting biomarkers for GC. Multidisciplinary approaches to protein, DNA, RNA, and epigenetics are crucial to the investigation for molecular biomarkers for GC.

Asunto(s)

Animales , Biomarcadores , Western Blotting , Línea Celular , Cromatografía Liquida , Digestión , ADN , Electroforesis , Epigenómica , Inmunohistoquímica , Técnicas In Vitro , Espectrometría de Masas , Métodos , Metástasis de la Neoplasia , Proteómica , ARN , Neoplasias Gástricas , Análisis de Matrices Tisulares

RESUMEN

Objective To investigate the expression of sodium-coupled neutral amino acid transporter 1 (SNAT1) in esophageal squamous cell carcinoma (ESCC) tissues, and to evaluate its prognostic value in patients with ESCC. Methods The tissue microarray including 183 ESCC tissues and their corresponding adjacent tissues was subjected to immunohistochemistry detection and Western blotting analysis of SNAT1 expression, and their correlation with the clinicopatho logical parameters and overall survival time was analyzed. Results SNAT1 was highly expressed in ESCC tissues, with the positive rate being 45. 4% (83/183); we also noticed that t was not expressed in normal squamous epithelium tissues. Our analysis results indicated that overexpression of SNAT1 was significantly correlated with tumor size (P=0.023), lymph node metastasis (P=0.007) and tumor stage (P=0.003). The Kaplan-Meier analysis showed that patients with overexpression of SNAT1 had significantly worse outcome than those with negative SNAT1 expression (P=0.001). Cox regression analysis revealed that over expression of SNAT1 was an independent factor for prognostic of patients with ESCC (P=0.004). Conclusion The expression of SNAT1 is abnormally increased in ESCC tissue, indicating that SNAT1 expression may serve as an important biomarker for prognosis evaluation in patients with ESCC.