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Valsamo K Anagnostou,
Anastasios T Dimou,
Taxiarchis Botsis,
Elizabeth J Killiam,
Mark D Gustavson,
Robert J Homer,
Daniel Boffa, Vassiliki Zolota,
Dimitrios Dougenis,
Lynn Tanoue,
Scott N Gettinger,
Frank C Detterbeck,
Konstantinos N Syrigos,
Gerold Bepler,
David L Rimm
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ABSTRACT: The importance of definitive histological subclassification has increased as drug trials have shown benefit associated with histology in nonsmall-cell lung cancer (NSCLC). The acuity of this problem is further exacerbated by the use of minimally invasive cytology samples. Here we describe the development and validation of a 4-protein classifier that differentiates primary lung adenocarcinomas (AC) from squamous cell carcinomas (SCC).
Quantitative immunofluorescence (AQUA) was employed to measure proteins differentially expressed between AC and SCC followed by logistic regression analysis. An objective 4-protein classifier was generated to define likelihood of AC in a training set of 343 patients followed by validation in 2 independent cohorts (n = 197 and n = 235). The assay was then tested on 11 cytology specimens.
Statistical modeling selected thyroid transcription factor 1 (TTF1), CK5, CK13, and epidermal growth factor receptor (EGFR) to generate a weighted classifier and to identify the optimal cutpoint for differentiating AC from SCC. Using the pathologist's final diagnosis as the criterion standard, the molecular test showed a sensitivity of 96% and specificity of 93%. Blinded analysis of the validation sets yielded sensitivity and specificity of 96% and 97%, respectively. Our assay classified the cytology specimens with a specificity of 100% and sensitivity of 87.5%.
Molecular classification of NSCLC using an objective quantitative test can be highly accurate and could be translated into a diagnostic platform for broad clinical application.
Cancer 03/2012; 118(6):1607-18. · 4.77 Impact Factor
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ABSTRACT: Estrogen receptors alpha (ERα) and beta (ERβ) and their co-regulatory proteins are key components of complex signaling networks that specifically regulate the growth and development of various tissues and tumors. Still, their protein expression profiles and possible role in the pathogenesis of astrocytic tumors remain largely unknown. The purpose of the present study is to evaluate the differential protein expression of ΕRα, ERβ, and their co-activators, AIB1, TIF2, and PELP1 in astrocytic tumors of World Health Organization (WHO) grade II-IV, using immunohistochemistry. Potential correlations with clinicopathological parameters and patient prognosis were also explored. ERα protein expression was undetectable while ERβ levels were significantly decreased with progression of tumor grade (P < 0.001). High expression of ERβ was an independent favorable prognostic factor on multivariate analysis (P = 0.003). Expression of AIB1, TIF2, and PELP1 was not correlated with ERβ expression and followed an opposite trend, with increasing levels in high-grade relative to low-grade tumors (P < 0.001). Univariate survival analysis revealed that high AIB1, TIF2, and PELP1 expression was associated with worse prognosis (P = 0.049, P = 0.033, and P = 0.020, respectively). ERβ and ER co-activators AIB1, TIF2, and PELP1 appear to play an important role in the pathogenesis and progression of astrocytic tumors and might have prognostic significance. The mechanisms underlying their involvement in astrocytic tumorigenesis, as well as their utility for prognostic and therapeutic purposes merit further investigation.
Journal of Neuro-Oncology 07/2011; 106(1):23-31. · 3.21 Impact Factor
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ABSTRACT: Challenges in measurement of epidermal growth factor receptor (EGFR) protein expression have led to conflicting data on its prognostic value and discontinuation of its use for prediction of response. Herein is described a quantitative standardized assay for EGFR and its use in a series of retrospective cohorts of patients with non-small cell lung cancer (NSCLC). The AQUA technology of quantitative immunofluorescence was used in conjunction with Western blot analysis to calculate the absolute concentration of EGFR in two independent NSCLC cohorts (170 from Yale New Haven Hospital and 335 from Sotiria and Patras Hospitals in Greece). EGFR and mutated EGFR were measured using D38B1 antibody and two mutation-specific antibodies. All patients positive or borderline for mutation-specific antibody were genotyped. A threshold for reproducible detection of EGFR was defined as 0.85 ng/μg total protein. EGFR expression demonstrated no prognostic value in either cohort. The mutation rate was 1.79% in the Yale cohort, and 1.52% in the Sotiria/Patras cohort, with no antibody detection-based false-positive cases. No mutations were detected for EGFR concentrations <1.46 ng/μg total protein. In summary, accurate measurement of EGFR still shows no prognostic value in NSCLC. In these two population-based cohorts, the antibody-based EGFR mutation rate was lower than has been frequently reported.
American Journal Of Pathology 06/2011; 179(2):580-9. · 4.89 Impact Factor
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ABSTRACT: Phosphorylation of p27(Kip1) at threonine 187 (pThr187-p27(Kip1)) occurs frequently in the development of human tumors, directing protein polyubiquitination and subsequent proteasomal degradation. We investigated the immunoexpression of p27(Kip1) and pThr187-p27(Kip1) in 126 B-cell lymphomas and their relation to proliferative activity and clinical parameters. Increased levels of p27(Kip1) and pThr187-p27(Kip1) were significantly correlated with indolent and aggressive lymphomas, respectively (p < 0.001). pThr187-p27(Kip1) expression showed a strong positive correlation with proliferation index in aggressive (p = 0.01) and indolent (p < 0.001) subgroups. Survival analysis revealed that pThr187-p27(Kip1) was an unfavorable prognostic factor for disease-free (p = 0.019) and overall survival (p = 0.003) in aggressive lymphomas. Cox regression analysis demonstrated that the prognostic value of pThr187-p27(Kip1) was independent of the international prognostic index (IPI) score, tumor stage, patient age, and serum lactate dehydrogenase (LDH) level. Overall, our results suggest that high levels of pThr187-p27(Kip1) may predict a worse clinical outcome in patients with aggressive lymphomas.
Leukemia & lymphoma 02/2011; 52(5):814-22. · 2.40 Impact Factor
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ABSTRACT: The aim of this study was to assess the antitumour effect of an anti-VEGFR (sunitinib) and the anti-EGFR multi-targeted agent (lapatinib), applied either alone or in combination on the migration capacity of two glioma cell lines. Furthermore, this study sought to evaluate the effect of lapatinib in the formation of EGFR-integrin β(1) complex, as well as the effect of sunitinib in the VEGFR-integrin β(3) and PDGFR-integrin β(3) complexes formation.
U87 and M059K cells were cultured as recommended by the American Type Culture Collection (ATCC). Migration assays were performed in Boyden chambers, using uncoated polycarbonate membranes. Immunoprecipitation and Western blot analysis were used for studying the complex formation of EGFR, PDGFR and VEGFR with integrins. The protein localisation was evaluated using immunofluorescence assay.
It was found that both agents, administered either alone or in combination, reduced the ability of U87 and M059K cells to migrate four h after their application. The time course study of the effect of lapatinib on EGFR-integrin β(1) complex revealed an inhibition in complex formation up to 30 min after the application of the agent. Likewise, sunitinib inhibited complex formation of VEGFR-integrin β(3) complex within two h after its application without affecting PDGFR-integrin β(3) complex. The previously described interruption of complexes formation was confirmed with an immunofluorescence assay.
The preliminary results of this study are the first to support the implication of a dual anti-EGFR/HER-2 agent, lapatinib and a multi-targeted agent, sunitinib in glioma cell migration, through a mechanism implying interruption of growth factor receptor integrin complexes formation.
Anticancer research 12/2010; 30(12):4987-92. · 1.73 Impact Factor
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Valsamo Anagnostou,
Frank Lowery, Vassiliki Zolota,
Vassiliki Tzelepi,
Arun Gopinath,
Camil Liceaga,
Nikolaos Panagopoulos,
Konstantina Frangia,
Lynn Tanoue,
Daniel Boffa,
Scott Gettinger,
Frank Detterbeck,
Robert Homer,
Dimitrios Dougenis,
David Rimm,
Konstantinos Syrigos
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ABSTRACT: Abstract
Background
Bcl-2 promotes cell survival by inhibiting adapters needed for the activation and cleavage of caspases thus blocking the proteolytic cascade that ultimately dismantles the cell. Bcl-2 has been investigated as a prognostic factor in non small cell lung cancer (NSCLC) patients with conflicting results.
Methods
Here, we quantitatively assessed Bcl-2 expression in two large and independent cohorts to investigate the impact of Bcl-2 on survival. AQUA<sup>®</sup>, a fluorescent-based method for analysis of in situ protein expression, was used to measure Bcl-2 protein levels and classify tumors by Bcl-2 expression in a cohort of 180 NSCLC patients. An independent cohort of 354 NSCLC patients was used to validate Bcl-2 classification and evaluate outcome.
Results
Fifty % and 52% of the cases were classified as high expressers in training and validation cohorts respectively. Squamous cell carcinomas were more likely to be high expressers compared to adenocarcinomas (63% vs. 45%, p = 0.002); Bcl-2 was not associated with other clinical or pathological characteristics. Survival analysis showed that patients with high BCL-2 expression had a longer median survival compared to low expressers (22 vs. 17.5 months, log rank p = 0.014) especially in the subset of non-squamous tumors (25 vs. 13.8 months, log rank p = 0.04). Multivariate analysis revealed an independent lower risk for all patients with Bcl-2 expressing tumors (HR = 0.53, 95% CI 0.37-0.75, p = 0.0003) and for patients with non-squamous tumors (HR = 0.5, 95% CI 0.31-0.81, p = 0.005).
Conclusions
Bcl-2 expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of NSCLC patients.
BMC Cancer. 01/2010;
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Valsamo K Anagnostou,
Frank J Lowery, Vassiliki Zolota,
Vassiliki Tzelepi,
Arun Gopinath,
Camil Liceaga,
Nikolaos Panagopoulos,
Konstantina Frangia,
Lynn Tanoue,
Daniel Boffa,
Scott Gettinger,
Frank Detterbeck,
Robert J Homer,
Dimitrios Dougenis,
David L Rimm,
Konstantinos N Syrigos
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[hide abstract]
ABSTRACT: Bcl-2 promotes cell survival by inhibiting adapters needed for the activation and cleavage of caspases thus blocking the proteolytic cascade that ultimately dismantles the cell. Bcl-2 has been investigated as a prognostic factor in non small cell lung cancer (NSCLC) patients with conflicting results.
Here, we quantitatively assessed Bcl-2 expression in two large and independent cohorts to investigate the impact of Bcl-2 on survival. AQUA(R), a fluorescent-based method for analysis of in situ protein expression, was used to measure Bcl-2 protein levels and classify tumors by Bcl-2 expression in a cohort of 180 NSCLC patients. An independent cohort of 354 NSCLC patients was used to validate Bcl-2 classification and evaluate outcome.
Fifty % and 52% of the cases were classified as high expressers in training and validation cohorts respectively. Squamous cell carcinomas were more likely to be high expressers compared to adenocarcinomas (63% vs. 45%, p = 0.002); Bcl-2 was not associated with other clinical or pathological characteristics. Survival analysis showed that patients with high BCL-2 expression had a longer median survival compared to low expressers (22 vs. 17.5 months, log rank p = 0.014) especially in the subset of non-squamous tumors (25 vs. 13.8 months, log rank p = 0.04). Multivariate analysis revealed an independent lower risk for all patients with Bcl-2 expressing tumors (HR = 0.53, 95% CI 0.37-0.75, p = 0.0003) and for patients with non-squamous tumors (HR = 0.5, 95% CI 0.31-0.81, p = 0.005).
Bcl-2 expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of NSCLC patients.
BMC Cancer 01/2010; 10:186. · 3.01 Impact Factor
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ABSTRACT: Several studies have implicated leptin in the pathophysiology of neoplasias. We investigated the direct effect of leptin on malignant hematopoietic tissue that included: primary acute myeloid leukemia (AML) cells, leukemic cell lines and bone marrow biopsies from multiple myeloma (MM) patients. PBMC, T-cells, B-cells and monocytes from healthy subjects served as controls. We defined the patterns of OB-R isoform expression in AML cells and leukemic cell lines in comparison to control cells by RT-PCR. rLeptin upregulated the expression of OB-R and endogenous leptin in AML blasts and certain cell lines but not in control cells. Cytometric Bead Array analysis of pro- and anti-inflammatory cytokines showed that rleptin upregulates IL-6 secretion by AML cells, various cytokines by the leukemic cell lines tested and IL-10 secretion by control PBMC, contributed by monocytes. Western immunoblotting revealed that the effect of rleptin was independent of JAK-2/phospho-JAK-2 protein levels. Finally, MM biopsies stained positive for leptin and, to a lesser extend, OB-R. Immunoreactivity was confined mostly to the nucleus of the myeloma cells. Normal myelocytes, promyelocytes and megakaryocytes stained weakly positive, and erythroid cells were constantly negative. We propose that the leptin/OB-R system is strongly and directly involved in supporting the growth of hematopoietic malignancies.
Cytokine 09/2009; 48(3):203-11. · 3.02 Impact Factor
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ABSTRACT: This study investigated the presence of apoptosis and proliferation in gastric cancer and assesses their possible correlation with classic prognostic markers and patients' survival.
The study comprised 110 patients with gastric carcinoma who underwent gastrectomy for therapeutic reasons, and did not receive any pre- or postoperative treatment. Patients were followed up for 3.5-140 months. Thick paraffin sections (4 microm) were subjected to immunohistochemistry using anti-Bcl-2 and anti-Ki-67 antibodies and to in situ hybridization [TUNEL method-apoptotic body index (ABI)]. Morphological and immunohistochemical results were correlated with clinicopathologic parameters.
Bcl-2 protein was detected in 67% of adenocarcinomas with increased expression in low-grade and early-stage tumors. Bcl-2 expression did not correlate with Ki-67 index, ABI or patients' survival. Ki-67 expression was correlated with a poorer survival rate. Apoptosis was more frequently observed in advanced stage and high-grade tumors. Cox analysis revealed that tumor stage and grade, as well as Ki-67 index, constituted independent prognostic factors.
This study included patients with gastric cancer none of whom received any additional pre- or post-operative treatment. Thus the prognostic value of each marker studied was not affected by additional treatments. Bcl-2 expression in advanced-stage and high-grade gastric carcinomas, indicate that Bcl-2 is involved in early stage of tumor development. Ki-67 expression constitutes an independent prognostic factor regarding the outcome of patients with gastric cancer. The positive association between apoptosis and proliferation suggests that apoptosis might reflect not only cell loss but also the proliferative activity. However, further research is required in order to determine if these markers may provide useful information for the prediction of prognosis in patients with colorectal carcinoma.
Anticancer research 03/2009; 29(2):703-9. · 1.73 Impact Factor
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ABSTRACT: Bone metastases depend on reciprocal interactions between malignant cells and bones that will determine the homing and growth
of malignant cells in the bone microenvironment. Additionally, the final step of bone metastasis (bone destruction or production)
that determines the clinical phenotype of the metastatic foci (osteolytic or osteoblastic metastasis, respectively) is actually
mediated by the bone cells under the influence of various factors secreted by malignant cells. In fact, metastatic lesions
are the result of disruption of the normal bone remodeling process. Thus, understanding of the normal histology and physiology
of the bone is fundamental in the elucidation of bone metastasis mechanisms and the development of therapeutic interventions.
This chapter presents a description of the normal structure, physiology and function of the bone, emphasizing the aspects
that are most relevant to the metastatic process. It begins with a description of the anatomy and histology of normal bone
and continues with a detailed discussion on the microscopic and functional characteristics of bone cells and non-cellular
matrix. Finally, a discussion on embryological development of bones, comments on bone functions and a conclusion on how the
different constituents of bones are involved in the highly coordinated processes of bone remodeling, mechanotransduction and
mineral homeostasis, are presented. By reviewing the structure, physiology and function of the bone, the reader will be able
to understand the mechanisms implicated in bone metastasis, the pathobiologic basis of the clinical phenotype and the mechanism
of action of the therapeutic strategies used in clinical practice.
12/2008: pages 3-30;
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ABSTRACT: To investigate the potential involvement of apoptosis and its regulators Bcl-2, Bax, and Fas within the retina in Staphylococcus epidermidis experimental endophthalmitis.
Endophthalmitis was induced in 48 male Lewis rats by unilateral 25-mircrol intravitreal injection of 7,000 viable organisms of slime-producing S. epidermidis strain ATCC 35983 (experimental group). Forty-eight other Lewis rats received a similar sterile normal saline injection (control group). The injected eyes were graded for clinical inflammation and were removed in groups at 6, 12, 24, 48, 72, and 168 hours post-injection. After surgical separation, retinal tissue specimens were fixed, and paraffin sections underwent hematoxylin-eosin staining, immunohistochemistry against Bcl-2, Bax, and Fas, and TUNEL assay for detection of apoptotic cells. Following morphometric analysis, the apoptotic body index (ABI) was calculated.
While Bcl-2 expression was absent, Bax and Fas expression and apoptosis in ganglion cells, bipolar cells, and photoreceptors, were significantly higher in the experimental group compared to the control group (P < 0.05). In the experimental group, inflammation peaked at 24 hours, Bax and Fas expression at 48 hours and the ABI at 72 hours post-injection.
Apoptosis is increased within the retina in S. epidermidis experimental endophthalmitis through upregulation of Bax and Fas, peaking soon after peak inflammation.
Albrecht von Graæes Archiv für Ophthalmologie 12/2008; 247(5):667-74. · 2.17 Impact Factor
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ABSTRACT: Recent knowledge indicates that neurotrophins play a significant role in neuroendocrine systems through their specific receptors TrkA, TrkB, TrkC and low-affinity p75(NTR) receptor. TrkA and TrkB receptors have been previously detected in numerous endocrine cells in human anterior pituitary and adenomas. In the present study, the localization of p75(NTR) and TrkC along with TrkA and TrkB receptors was investigated.
Semi-serial paraffin-embedded sections of 5 human normal pituitaries and 30 adenomas were immunostained using specific antibodies.
Expression of p75(NTR) receptor was demonstrated in the intricate capillary and reticulin network in the anterior pituitary and in the pericapillary tissue and pituicytes in the posterior lobe. p75(NTR) immunoreactivity was absent from all adenomas. In normal anterior pituitary, a few scattered cells showed weak TrkC immunoreactivity in contrast to a high percentage of endocrine cells distributed throughout the pars distalis and pars intermedia which exhibited strong TrkA and/or intermediate TrkB immunoreactivity. Double immunohistochemistry demonstrated TrkA immunoreactivity in more than 80% of lactotropes and 70% of corticotropes and to a lesser extent in other cell types. Furthermore, in the majority of adenomas, independently of type, sex and age, a high percentage of TrkA- and/or TrkB-positive cells was detected. Interestingly, TrkC expression appeared to be increased in some adenomas compared to normal pituitary. Endothelial cells and perivascular connective tissue were always TrkB-immunostained.
The above findings support a potential role of all neurotrophins, through their different receptors, in pituitary functions.
Neuroendocrinology 04/2008; 88(2):127-34. · 2.38 Impact Factor
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ABSTRACT: Gliomas are among the most aggressive and treatment-refractory of all human tumors. The aim of the present study is to evaluate the role of the expression of cell cycle molecules as prognostic indicators in gliomas. We immunohistochemically analyzed the expression of p21, p27, p14, p16, p53 and proliferation marker Ki67, in 67 low and high grade astrocytic tumors. High grade tumors exhibited higher labeling indices for Ki67 (P = 0.004), p53 (P = 0.039) and slightly higher index for p21 (P = 0.07) compared to low grade tumors. p14 and p16 were more frequently present in low grade tumors (P = 0.001 and P = 0.052, respectively). Worse survival was correlated with high grade tumors (P < 0.0001) and higher Ki67 index (P < 0.0001). Cox regression analysis revealed that only age, grade and marginally Ki67 index were independent prognostic factors. Cell cycle alterations are involved in the malignant progression of astrocytomas, but only age, tumor grade and proliferating index can predict the outcome of the patients with glioma.
Neuropathology 02/2008; 28(1):35-42. · 2.02 Impact Factor
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ABSTRACT: Cell cycle control is a crucial event in normal hematopoiesis, and abnormalities of regulatory cell cycle genes have been found to contribute to the development of many hematologic malignancies. The present study investigates the immunohistochemical expression of seven essential cell cycle proteins (p21, p27, p14, p16, p53, mdm2, and cyclin E) in paraffin-embedded sections from 42 bone marrow biopsies obtained from an equal number of patients with newly diagnosed acute myeloid leukemia (AML). This study revealed (i) a high frequency of p53+/mdm2-/p21-phenotype, which is probably a result of p53 gene mutation and/or inhibition of mdm2 action by p14(ARF); (ii) expression of p27+/cyclinE-phenotype in most cases, suggesting that p27 may act as a potent cyclin-dependent kinase inhibitor; (iii) expression of p16 only in very few cases; and (iv) no relationship between the expression of any of the above proteins and survival as well as histologic subtype.
Pathology - Research and Practice 01/2007; 203(4):199-207. · 1.21 Impact Factor
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Athanassios C Tsamandas,
Ioulia Syrokosta,
Konstantinos Thomopoulos, Vassiliki Zolota,
Dimitra Dimitropoulou,
Anna Liava,
Anna Antona Coupoulou,
Dimitrios Siagris,
Theodore Petsas,
Chrisoula Karatza,
Charalambos A Gogos
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ABSTRACT: This study investigates the correlation of hepatic progenitor cells (HPC) expression with treatment response in patients with chronic hepatitis C.
The study comprised 77 liver biopsies with chronic hepatitis C (HCV). All patients were PCR-HCV (+) and received antiviral therapy with interferon or pegylated interferon alpha-2b and ribavirin. Twenty-nine patients were assigned as responders (group A), 29 as nonresponders (group B) and 19 as relapsers (group C). Ten normal liver biopsies were used as controls. Liver paraffin sections were subjected (a) to immunohistochemistry using antibodies for cytokeratins 19 (CK19) and 7 (CK7), alpha-fetoprotein (AFP), leukocyte common antigen (LCA) and CD34 antigen (b) to in situ hybridization for AFP mRNA and (c) to immunohistochemistry+in situ hybridization. Results were expressed as % of positive cells following morphometric analysis.
HPC expression was present in all 87 specimens. In the control biopsies, rare HPC were detected. In the CH cases and according to AFP mRNA expression, the grade for % HPC expression was: group B: 53.2+/-2.6> group C: 48.37+/-1.8> group A: 31.4+/-1.6 (group A vs B P<0.01, group A vs C P<0.01, group B vs C P>0.05. Double stain revealed that HPC coexpressed CK19/AFP mRNA, CK7/AFP mRNa and AFP protein/AFP mRNA. HPC-percentages were directly correlated with total HAI score (P<0.01), fibrosis stage (P<0.01), and transaminase values (P<0.05).
This study demonstrates that in cases of chronic hepatitis C, the significant association of HPC expression with the severity of disease and more specifically with the response to treatment implies that HPC development and proliferation may provide additional prognostic information and predict prognosis in such cases.
Liver international: official journal of the International Association for the Study of the Liver 09/2006; 26(7):817-26. · 3.82 Impact Factor
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ABSTRACT: Rhabdomyomas are benign tumors in which at least some cells are differentiated as skeletal muscle cells with cytoplasmic cross-striations. Extracardiac adult rhabdomyoma is an extremely uncommon benign neoplasm that usually involves the head and neck region. Rare cases have been reported to involve other sites of the body including mediastinum. We report the fourth case of mediastinal adult rhabdomyoma.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 08/2006; 449(1):124-8. · 2.49 Impact Factor
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ABSTRACT: We present a new case of leiomyosarcoma, a very rare clinical entity, arising from the renal pelvis. The primary diagnosis, based on asymptomatic gross hematuria and imaging findings, was tumor of the left kidney. After a left radical nephro-ureterectomy, histology confirmed a leiomyosarcoma of the renal pelvis. No adjuvant treatment was provided and the patient remains healthy 3 years after surgery.
International Urology and Nephrology 02/2006; 38(2):211-3. · 1.47 Impact Factor
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ABSTRACT: Groups of sea bass (Dicentrarhus labrax L.) were surgically implanted in the abdominal cavity with dialysis tubing of different pore size containing either live Photobacterium damsela subsp. piscicida cells or sterile phosphate-buffered saline, in order to grow the pathogen in vivo. During the course of the experiment mortalities, not due to microbial infection, occurred, that prompted the use of histology in order to identify the lesions caused by molecules released from the dialysis bags during in vivo growth of the pathogen. Collected tissues from moribund fish were processed for light microscopy. Fish implanted with the 2 kD molecular weight cut-off (MWCO) bags suffered very minor histological changes whereas fish with 12 kD MWCO membranes showed severe lesions varying upon the time post operation. Moreover, inflammatory cells appeared in all tissues from fish implanted with 12 kD MWCO especially 48 h after infection. Spleen, liver, intestine and gills showed necrotic changes appearing 60 h post infection. Since no bacteria were isolated after microbiological sampling of tissue, the inflammatory-necrotic changes observed in the tissues were attributed to the toxicity of extracellular products.
Aquaculture Research 06/2004; 35(10):931 - 936. · 1.20 Impact Factor
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Athanassios C Tsamandas,
Dimitrios Kardamakis,
Panagiota Ravazoula, Vassiliki Zolota,
Stavroula Salakou,
Konstantinos Tepetes,
Cristina Kalogeropoulou,
Irene Tsota,
Theodore Kourelis,
Thomas Makatsoris,
Dionissios Karavias,
Chrisoula D Scopa,
Dionysis S Bonikos,
Haralambos P Kalofonos,
Theodore Petsas
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ABSTRACT: This study investigates the expression of tumor growth factors TGFbeta1, TGFbeta2 and TGFbeta3 in tissue material from patients with colorectal carcinoma and evaluates their correlation with known prognostic markers and patient survival.
The study included 124 patients with colorectal carcinoma. According to the TNM classification of malignant tumors, 26 tumors were identified as being stage I, 30 stage II, 48 stage III, and 20 stage IV, whereas 106 tumors were low-grade and 18 high-grade malignancies. On paraffin sections, the streptavidin-biotin technique using antibodies against TGFbeta1, TGFbeta2 and TGFbeta3 was applied. Morphological and immunohistochemical results were correlated with clinicopathologic parameters.
TGFbeta1 protein was expressed in 88 out of 124 (71%) carcinomas, whereas TGFbeta2 and TGFbeta3 proteins were detected in all tumors examined. Normal colonic mucosal epithelial cells expressed TGFbeta2 (significantly less as compared to neoplastic cells; p < 0.01) and TGFbeta3 (p > 0.05 compared to neoplastic cells), but not TGFbeta1. Statistical analysis revealed a higher expression of TGFbeta1 in low-grade carcinomas (p = 0.009) and a higher presence of TGFbeta2 in advanced tumors (p = 0.008). TGFbeta1 expression was related with increased disease-free and overall survival (p < 0.05 each). The presence of TGFbeta2 was correlated with worse prognosis (p < 0.05). Cox analysis revealed that besides tumor grade and stage, TGFbeta1 expression constituted an independent prognostic factor.
This study shows that in adenocarcinomas of the colon, there is a differential expression of TGFbeta1, TGFbeta2 and TGF3. TGFbeta1 may be implicated in the pathogenesis of these tumors, since it is expressed only in neoplastic but not in normal cells. TGFbeta1 is related with an increased disease-free and overall survival and constitutes an independent prognostic factor. In advanced stages, TGFbeta2 seems to be involved in tumor progression and is related with worse prognosis.
Strahlentherapie und Onkologie 04/2004; 180(4):201-8. · 3.56 Impact Factor
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AthanassiosC. Tsamandas,
Dimitrios Kardamakis,
Panagiota Ravazoula, Vassiliki Zolota,
Stavroula Salakou,
Konstantinos Tepetes,
Cristina Kalogeropoulou,
Irene Tsota,
Theodore Kourelis,
Thomas Makatsoris,
Dionissios Karavias,
ChrisoulaD. Scopa,
DionysisS. Bonikos,
HaralambosP. Kalofonos,
Theodore Petsas
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ABSTRACT: Purpose:This study investigates the expression of tumor growth
factors TGF1, TGF2 and TGF3 in tissue material from patients
with colorectal carcinoma and evaluates their correlation with
known prognostic markers and patient survival.Patients and
Methods:The study included 124 patients with colorectal carcinoma.
According to the TNM classification of malignant tumors, 26
tumors were identified as being stage I, 30 stage II, 48 stage
III, and 20 stage IV, whereas 106 tumors were low-grade and 18
high-grade malignancies. On paraffin sections, the
streptavidin-biotin technique using antibodies against TGF1,
TGF2 and TGF3 was applied. Morphological and
immunohistochemical results were correlated with
clinicopathologic parameters.Results:TGF1 protein was expressed in 88 out of 124 (71%)
carcinomas, whereas TGF2 and TGF3 proteins were detected in
all tumors examined. Normal colonic mucosal epithelial cells
expressed TGF2 (significantly less as compared to neoplastic
cells; p < 0.01) and TGF3 (p > 0.05 compared to
neoplastic cells), but not TGF1. Statistical analysis revealed
a higher expression of TGF1 in low-grade carcinomas (p = 0.009)
and a higher presence of TGF2 in advanced tumors (p = 0.008).
TGF1 expression was related with increased disease-free and
overall survival (p < 0.05 each). The presence of TGF2 was
correlated with worse prognosis (p < 0.05). Cox analysis
revealed that besides tumor grade and stage, TGF1 expression
constituted an independent prognostic factor.Conclusion:This study shows that in adenocarcinomas of the colon,
there is a differential expression of TGF1, TGF2 and TGF3.
TGF1 may be implicated in the pathogenesis of these tumors,
since it is expressed only in neoplastic but not in normal
cells. TGF1 is related with an increased disease-free and
overall survival and constitutes an independent prognostic
factor. In advanced stages, TGF2 seems to be involved in tumor
progression and is related with worse prognosis.Ziel:Diese Studie untersuchte die Expression der
Tumorwachstumsfaktoren TGF1, TGF2 and TGF3 in Gewebeproben
von Patienten mit kolorektalen Karzinomen und prfte ihre
Korrelation mit bekannten prognostischen Markern und mit dem
berleben der Patienten.Patienten und
Methodik:Die Studie umfasste 124 Patienten mit kolorektalen
Karzinomen. Nach der TNM-Klassifikation wurden 26 Tumoren als
Stadium I, 30 als Stadium II, 48 als Stadium III und 20 als
Stadium IV eingeordnet, whrend 106 Tumoren Low-Grade- und 18
High-Grade-Malignome waren. Paraffinschnittprparate wurden nach
der Streptavidin-Biotin-Methode mit Antikrpern gegen TGF1,
TGF2 und TGF3 behandelt. Die morphologischen und
immunhistochemischen Befunde wurden mit klinisch-pathologischen
Parametern korreliert.Ergebnisse:TGF1 wurde in 88 von 124 (71%) Karzinomen exprimiert,
whrend TGF2 und TGF3 in allen untersuchten Tumoren gefunden
wurden. Normale Epithelzellen der Dickdarmschleimhaut
exprimierten TGF2 (signifikant weniger verglichen mit
neoplastischen Zellen; p < 0,01) und TGF3 (p > 0,05
verglichen mit neoplastischen Zellen), aber kein TGF1. Die
statistische Analyse ergab strkere TGF1-Expression in
Low-Grade-Karzinomen (p = 0,009) und eine verstrkte Prsenz von
TGF2 in fortgeschrittenen Tumoren (p = 0,008). Die
TGF1-Expression korrelierte mit verlngertem krankheitsfreien
und Gesamtberleben (jeweils p < 0,05). Das Vorliegen von
TGF2 korrelierte mit schlechterer Prognose (p < 0,05). Die
Cox-Analyse ergab, dass neben Tumorgrad und -stadium die
TGF1-Expression einen unabhngigen prognostischen Faktor
darstellte.Schlussfolgerung:Diese Studie zeigt fr Adenokarzinome des Kolons und
Rektums Unterschiede in der Expression von TGF1, TGF2 und
TGF3. TGF1 knnte in der Pathogenese dieser Tumoren eine Rolle
spielen, da es nur in neoplastischen, nicht aber in normalen
Zellen exprimiert wird. TGF1 geht mit verlngertem
krankheitsfreien und Gesamtberleben einher und ist ein
unabhngiger prognostischer Faktor. In fortgeschrittenen Stadien
scheint TGF2 fr die Tumorprogression relevant zu sein und ist
mit einer schlechteren Prognose verbunden.
Strahlentherapie und Onkologie 03/2004; 180(4):201-208. · 3.56 Impact Factor
