- SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis. [Journal Article]
- EMExp Mol Pathol 2017 Jan 18
- SIRT1, a NAD dependent histone and protein deacetylase, is a member of the histone deacetylase class III family. We previously showed that SIRT1 mRNA expression is significantly lower in peripheral b...
SIRT1, a NAD dependent histone and protein deacetylase, is a member of the histone deacetylase class III family. We previously showed that SIRT1 mRNA expression is significantly lower in peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients during relapses than in stable patients. We have now investigated SIRT1 as a possible biomarker to predict relapse as well as responsiveness to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2years, a cohort of 15 GA-treated RRMS patients were clinically monitored using the Expanded Disability Status Scale and assessed for MS relapses. Blood samples collected from MS patients were analyzed for levels of SIRT1 and histone H3 lysine 9 (H3K9) acetylation and dimethylation. During relapses, MS patients had a lower expression of SIRT1 mRNA than did stable MS patients. In addition, there was a significant decrease in H3K9 dimethylation (H3K9me2) during relapses in MS patients when compared to stable patients (p=0.01). Responders to GA treatment had significantly higher SIRT1 mRNA (p=0.01) and H3K9me2 levels than did non-responders (p=0.018). Receiver operating characteristic analysis was used to assess the predictive power of SIRT1 and H3K9me2 as putative biomarkers: for SIRT1 mRNA, the predictive value for responsiveness to GA treatment was 70% (p=0.04) and for H3K9me2 was 71% (p=0.03). Our data suggest that SIRT1 and H3K9me2 could serve as potential biomarkers for evaluating patients' responsiveness to GA therapy in order to help guide treatment decisions in MS.
- CDK3 is a major target of miR-150 in cell proliferation and anti-cancer effect. [Journal Article]
- EMExp Mol Pathol 2017 Jan 17
- MiR-150, a member of small non-coding RNAs, has been proven to dysregulate in different types of tumor and bear on carcinogenesis and cancer prognosis by regulating the expression of a series of gene...
MiR-150, a member of small non-coding RNAs, has been proven to dysregulate in different types of tumor and bear on carcinogenesis and cancer prognosis by regulating the expression of a series of gene including utrophin. Given that utrophin can compensate for dystrophin's absence and be regarded as a promising therapeutic target for Duchenne Muscular Dystrophy (DMD), we further detected the deep role of miR-150 in dystrophic muscle. Using a range of bioinformatic, molecular and cell biology techniques, we declared that miR-150 directly targets cyclin-dependent kinase 3 (CDK3) and leads to the regulation of CDK3 gene expression in both muscle-derived and non-muscle cells. The results indicated the expression of miR-150 was upregulated in mdx muscle and closely related to the lower level of CDK3. Transient transfection of miR-150 into cultured C2C12 cells led to significant decrease in cell proliferation, which is partly mediated via the 3'-UTRs of CDK3 mRNA. Targeting of CDK3 could also play a role, at least in part, in the anti-cancer activity suggested for miR-150 in previous studies. Consistently, the analysis of tumor and matched normal lung tissues indicates that miR-150 downregulation in lung tumors correlates with higher CDK3 levels. In addition, miR-150 transfection experiments with cancer-derived cell lines reveal that miR-150-mediated CDK3 suppression directly induces to growth inhibition. Collectively, our results highlight a novel activity for CDK3 in myoblast cell proliferation and confirm CDK3 as a key target that further enhances the tumor suppressor function proposed for miR-150.
- The phenomenon of atherosclerosis reversal and regression: Lessons from animal models. [Review]
- EMExp Mol Pathol 2017 Jan 17; 102(1):138-145
- Studies in non-rodent and murine models showed that atherosclerosis can be reversed. Atherosclerosis progression induced by high-fat or cholesterol-rich diet can be reduced and reversed to plaque reg...
Studies in non-rodent and murine models showed that atherosclerosis can be reversed. Atherosclerosis progression induced by high-fat or cholesterol-rich diet can be reduced and reversed to plaque regression after switching to a normal diet or through administration of lipid-lowering agents. The similar process should exist in humans after implementation of lipid-lowering therapy and as a result of targeting of small rupture-prone plaques that are major contributors for acute atherosclerotic complications. Lowering of low density lipoprotein (LDL) cholesterol and the activation of reverse cholesterol transport lead to a decline in foam cell content, to the depletion of plaque lipid reservoirs, a decrease in lesional macrophage numbers through the activation of macrophage emigration and, probably, apoptosis, dampening plaque inflammation, and the induction of anti-inflammatory macrophages involved in clearance of the necrotic core and plaque healing. By contrast, plaque regression is characterized by opposite events, leading to the retention of atherogenic LDL and oxidized LDL particles in the plaque, an increased flux of monocytes, the immobilization of macrophages in the intimal vascular tissues, and the propagation of intraplaque inflammation. Transfer of various apolipoprotein (apo) genes to spontaneously hypercholesterolemic mice deficient for either apoE or LDL receptor and, especially, the implementation of the transplantation murine model allowed studying molecular mechanisms of atherosclerotic regression, associated with the depletion of atherogenic lipids in the plaque, egress of macrophages and phenotypic switch of macrophages from the proinflammatory M1 to the anti-inflammatory M2.
- HBXIP over expression as an independent biomarker for cervical cancer. [Journal Article]
- EMExp Mol Pathol 2017 Jan 16; 102(1):133-137
- CONCLUSIONS: HBXIP over-expression appears to associate with cervical cancer progression, and may potentially be used as a cervical cancer biomarker for the early diagnosis, prognostic evaluation and therapeutic target for cervical cancer.
- Spectrum of Mutations in Leiomyosarcomas Identified By Clinical Targeted Next-Generation Sequencing. [Journal Article]
- EMExp Mol Pathol 2017 Jan 13
- Recurrent genomic mutations in uterine and non-uterine leiomyosarcomas have not been well established. Using a next generation sequencing (NGS) panel of common cancer-associated genes, 25 leiomyosarc...
Recurrent genomic mutations in uterine and non-uterine leiomyosarcomas have not been well established. Using a next generation sequencing (NGS) panel of common cancer-associated genes, 25 leiomyosarcomas arising from multiple sites were examined to explore genetic alterations, including single nucleotide variants (SNV), small insertions/deletions (indels), and copy number alterations (CNA). Sequencing showed 86 non-synonymous, coding region somatic variants within 151 gene targets in 21 cases, with a mean of 4.1 variants per case; 4 cases had no putative mutations in the panel of genes assayed. The most frequently altered genes were TP53 (36%), ATM and ATRX (16%), and EGFR and RB1 (12%). CNA were identified in 85% of cases, with the most frequent copy number losses observed in chromosomes 10 and 13 including PTEN and RB1; the most frequent gains were seen in chromosomes 7 and 17. Our data show that deletions in canonical cancer-related genes are common in leiomyosarcomas. Further, the spectrum of gene mutations observed shows that defects in DNA repair and chromosomal maintenance are central to the biology of leiomyosarcomas, and that activating mutations observed in other common cancer types are rare in leiomyosarcomas.
- Over expression of proteins that alter the intracellular signaling pathways in the cytoplasm of the liver cells forming Mallory-Denk bodies. [Journal Article]
- EMExp Mol Pathol 2017 Jan 13; 102(1):106-114
- In this study, liver biopsy sections fixed in formalin and embedded in paraffin (FFPE) from patients with alcoholic hepatitis (AH) were used. The results showed that the expression of the SYK protein...
In this study, liver biopsy sections fixed in formalin and embedded in paraffin (FFPE) from patients with alcoholic hepatitis (AH) were used. The results showed that the expression of the SYK protein was up regulated by RNA-seq and real time PCR analyses in the alcoholic hepatitis patients compared to controls. The results were supported by using the IHC fluorescent antibody staining intensity morphometric quantitation. Morphometric quantification of fluorescent intensity measurement showed a two fold increase in SYK protein in the cytoplasm of the cells forming MDBs compared to surrounding normal hepatocytes. The expression of AKT1 was also analyzed. AKT1 is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. The AKT protein was also increased in hepatocyte balloon cells forming MDBs. This observation demonstrates the role of SYK and its subsequent effect on the internal signaling pathways such as PI3K/AKT as well as p70S6K, as a potential multifunctional target in protein quality control mechanisms of hepatocytes when ER stress is activated.
- ERCC1 and ERCC2 as predictive biomarkers to oxaliplatin-based chemotherapy in colorectal cancer patients from Egypt. [Journal Article]
- EMExp Mol Pathol 2017 Jan 12; 102(1):78-85
- CONCLUSIONS: ERCC1 expression levels may help in selecting patients who benefit from oxaliplatin chemotherapy in stage III & IV CRC. Further large trials are needed to validate these data.
- Correlation of the HPV detection, protein expression and DNA content in cutaneous pre-invasive and invasive carcinoma among Croatian patients. [Journal Article]
- EMExp Mol Pathol 2017 Jan 12; 102(1):123-127
- Development of cutaneous carcinomas has been associated with HPV infection. There have been various reports on p16, p53 and pRb expression in cutaneous carcinomas and on its linkage to HPV status. As...
Development of cutaneous carcinomas has been associated with HPV infection. There have been various reports on p16, p53 and pRb expression in cutaneous carcinomas and on its linkage to HPV status. Association of protein expression and HPV infection with DNA content is not clear. The aim of this study was to determine a possible correlation between HPV type, protein expression and DNA content in both pre-invasive and invasive squamous cell carcinoma, as well as differences between studied groups in these parameters. Sections of formalin fixed paraffin-embedded tumor tissue from 54 cases of Morbus Bowen (preinvasive cutaneous carcinoma) and 41 cases of invasive squamous cell carcinoma of the skin were subjected to HPV genotyping using Lipa (Line imuno probe assay), immunohistochemical staining for p16(INK4A), p53, pRb and prepared for flow cytometry DNA content analysis. Obtained data were analyzed in SPSS using Chi square test. Only p16 expression showed statistically significant differences in studied groups. Statistically significant correlations were found only in MB between parameters HPV-p53, p53-pRb and p53-p16. Our results suggest different virus-induced pathobiology pathways for different cutaneous carcinoma groups.
- Predictors and mechanisms of epilepsy occurrence in cerebral gliomas: What to look for in clinicopathology. [Journal Article]
- EMExp Mol Pathol 2017 Jan 11; 102(1):115-122
- Gliomas, especially low-grade gliomas, are highly epileptogenic brain tumors. Histopathological information is valuable in evaluating the diagnosis and/or biologic behavior of various gliomas. Here w...
Gliomas, especially low-grade gliomas, are highly epileptogenic brain tumors. Histopathological information is valuable in evaluating the diagnosis and/or biologic behavior of various gliomas. Here we explored the clinical data and histopathological predictors of the occurrence of epilepsy in patients with gliomas. A retrospective study examined 310 consecutive patients who had undergone surgical treatment for gliomas in our institution from January 2013 to January 2015. Clinical data and pathological examination results were analyzed. Literatures regarding the predictors and etiology of glioma associated epileptic seizures in the period of 1995-2015 were also reviewed. A total of 234 (75.5%) astrocytic tumors and 76 (24.5%) oligodendrial tumors were included. At diagnosis, 33.6% of patients had epileptic seizures. Multivariate analysis revealed cortex involvement (OR=7.991, 95%CI=1.599-39.926), lower World Health Organization grade (OR=3.584, 95%CI=1.032-12.346) and topoisomerase II (TopoII) positivity (OR=0.943, 95%CI=0.903-0.982) were strong predictors for preoperative epileptic seizures. Gender, disease course, tumor classification, location or volume did not significantly affect epileptic seizure occurrence. Forty-three publications involved glioma-associated epilepsy were found in PubMed online database and key data were extracted and summarized. The present studies on glioma-related epilepsy are relatively limited and inconsistent. Low-grade gliomas, cortex involvement and TopoII positivity were independent predictors of a history of epileptic seizures at diagnosis. Further studies to examine the underlying mechanism of topoisomerase II as well as other molecules in epilepsy occurrence in brain gliomas are needed in the future.
New Search Next
- Clonal cytogenetic abnormalities are predictor in developing non-Hodgkin lymphomas? [Journal Article]
- EMExp Mol Pathol 2017 Jan 11; 102(1):146-155
- Pathological analysis is the cornerstone for diagnosing malignant lymphoma. Status of cytogenetic abnormalities is frequently left unexamined if no evidence of malignancy is found in pathological ana...
Pathological analysis is the cornerstone for diagnosing malignant lymphoma. Status of cytogenetic abnormalities is frequently left unexamined if no evidence of malignancy is found in pathological analysis. In this study, we presented 3 cases in which clonal cytogenetic abnormalities were detected but morphological alterations of the same tissue did not support malignant non Hodgkin lymphoma at the first lymph node biopsy. Case 1 is a 55-year-old female with lymphadenopathy neoplastic process confirmed by flow cytometry and polymerase chain reaction (PCR). Chromosome analysis revealed 47,XX,t(3;22)(q27;q11),+del(9)(p12)/46,XX. The pathological analysis of subsequent lymph node biopsy indicated diffuse large B-cell lymphoma (DLBCL). Case 2, a 74-year-old female, for whom the pathological analysis, molecular studies and flow cytometric analysis of the first lymph node biopsy found no evidence of clonal cell. Cytogenetic analysis demonstrated a terminal deletion of chromosome 7 and 1, and the patient received a second lymph node biopsy and splenectomy. A pathological diagnosis of splenic marginal zone lymphoma (SMZL) was made. In Case 3 who was a 66-year-old female with right cervical and axillary lymph node enlargement. Cytogenetic analysis showed clonal karyotypic abnormalities: 48,XX, t(14;18)(q32;q21) /46, XY . The diagnosis of follicular lymphoma was rendered by the second biopsy of axillary lymph node according to the analysis of morphology and immunohistochemistry. We propose that clonal cytogenetic abnormalities may be a high potential risk for developing non-Hodgkin lymphomas. Follow-up and rebiopsy must be performed in patients who are cytogenetically abnormal but morphologically benign.