المؤلفون: Wenjia Feng, Jack F. Shern, R. Taylor Sundby, Divya Srihari, Noah Earland, Yi Huang, Paul Jones, David D. Roberts, Melissa Spencer, Faridi Qaium, Brigitte C. Widemann, Leah Hoffman, Jamie Bell, Peter K. Harris, Li Ding, Aadel A. Chaudhuri, Jeffrey J. Szymanski, Matthew B. Spraker, Michele Landeau, Haiyan Lei, Angela C. Hirbe

المصدر: PLoS Medicine
PLoS medicine, 18(8):e1003734
PLoS Medicine, Vol 18, Iss 8, p e1003734 (2021)

مصطلحات موضوعية: Male, Pathology, Physiology, Biopsy, DNA Mutational Analysis, Cancer Treatment, Lung and Intrathoracic Tumors, Malignant transformation, Medical Conditions, CDKN2A, Basic Cancer Research, Medicine and Health Sciences, Neurofibroma, medicine.diagnostic_test, Soft tissue sarcoma, Genomics, General Medicine, Middle Aged, Body Fluids, Blood, Cell-free fetal DNA, Oncology, Neurofibrosarcoma, Genetic Diseases, Medicine, Female, Anatomy, Cell-Free Nucleic Acids, Research Article, Adult, medicine.medical_specialty, Copy number analysis, Surgical and Invasive Medical Procedures, Malignant peripheral nerve sheath tumor, Malignancy, Blood Plasma, Young Adult, Malignant Tumors, Cancer Genomics, Genomic Medicine, Genetics, medicine, Humans, Neurofibromatosis, Malignant tumors, Neurofibromatosis type 1, Nerves, Blood plasma, Lesions, Cancer genomics, Cancers and neoplasms, Neurofibroma, Plexiform, Clinical Genetics, Whole Genome Sequencing, business.industry, Autosomal Dominant Diseases, Cancers and Neoplasms, Biology and Life Sciences, Cancer, medicine.disease, Minimal residual disease, Neurofibromatosis Type 1, business

الوصف: Background The leading cause of mortality for patients with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the development of malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma. In the setting of NF1, this cancer type frequently arises from within its common and benign precursor, plexiform neurofibroma (PN). Transformation from PN to MPNST is challenging to diagnose due to difficulties in distinguishing cross-sectional imaging results and intralesional heterogeneity resulting in biopsy sampling errors. Methods and findings This multi-institutional study from the National Cancer Institute and Washington University in St. Louis used fragment size analysis and ultra-low-pass whole genome sequencing (ULP-WGS) of plasma cell-free DNA (cfDNA) to distinguish between MPNST and PN in patients with NF1. Following in silico enrichment for short cfDNA fragments and copy number analysis to estimate the fraction of plasma cfDNA originating from tumor (tumor fraction), we developed a noninvasive classifier that differentiates MPNST from PN with 86% pretreatment accuracy (91% specificity, 75% sensitivity) and 89% accuracy on serial analysis (91% specificity, 83% sensitivity). Healthy controls without NF1 (participants = 16, plasma samples = 16), PN (participants = 23, plasma samples = 23), and MPNST (participants = 14, plasma samples = 46) cohorts showed significant differences in tumor fraction in plasma (P = 0.001) as well as cfDNA fragment length (P < 0.001) with MPNST samples harboring shorter fragments and being enriched for tumor-derived cfDNA relative to PN and healthy controls. No other covariates were significant on multivariate logistic regression. Mutational analysis demonstrated focal NF1 copy number loss in PN and MPNST patient plasma but not in healthy controls. Greater genomic instability including alterations associated with malignant transformation (focal copy number gains in chromosome arms 1q, 7p, 8q, 9q, and 17q; focal copy number losses in SUZ12, SMARCA2, CDKN2A/B, and chromosome arms 6p and 9p) was more prominently observed in MPNST plasma. Furthermore, the sum of longest tumor diameters (SLD) visualized by cross-sectional imaging correlated significantly with paired tumor fractions in plasma from MPNST patients (r = 0.39, P = 0.024). On serial analysis, tumor fraction levels in plasma dynamically correlated with treatment response to therapy and minimal residual disease (MRD) detection before relapse. Study limitations include a modest MPNST sample size despite accrual from 2 major referral centers for this rare malignancy, and lack of uniform treatment and imaging protocols representing a real-world cohort. Conclusions Tumor fraction levels derived from cfDNA fragment size and copy number alteration analysis of plasma cfDNA using ULP-WGS significantly correlated with MPNST tumor burden, accurately distinguished MPNST from its benign PN precursor, and dynamically correlated with treatment response. In the future, our findings could form the basis for improved early cancer detection and monitoring in high-risk cancer-predisposed populations.
Jeffrey J. Szymanski and colleagues investigate the use of cell-free DNA ultra-low-pass whole genome sequencing to distinguish the malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion in patients with Neurofibromatosis type 1 in United States.
Author summary Why was this study done? Neurofibromatosis type 1 (NF1) is the most common inherited cancer predisposition syndrome. The leading cause of mortality in NF1 is malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma that arises from a benign plexiform neurofibroma (PN) precursor lesion. Transformation from PN to MPNST is challenging to detect by imaging (due to difficulty in distinguishing PN from MPNST radiologically) or by biopsy (due to intralesional heterogeneity), which often delays the diagnosis of MPNST and results in a worsened prognosis. What did the researchers do and find? We conducted a multi-institutional study involving 2 large NF1 referral centers, the National Cancer Institute and Washington University in St. Louis, involving 53 patients from whom plasma cell-free DNA (cfDNA) was analyzed using ultra-low-pass whole genome sequencing (ULP-WGS). We found that cfDNA from patients with MPNST harbors a shorter fragmentation profile compared to patients with PN or healthy donors. Using sequencing reads from this fragmentation profile, we quantified genome-wide copy number alterations (CNAs) in cfDNA and used CNAs to estimate the fraction of plasma cfDNA originating from tumor. Tumor fraction in plasma cfDNA distinguished pretreatment MPSNT from PN with 86% accuracy. Plasma cfDNA from MPNST and PN patients harbored focal copy number loss of NF1 not found in healthy donors. Strikingly, MPNST patient cfDNA also had significantly greater tumor genomic instability compared to PN, with CNAs in key genomic loci previously observed in MPNST tissue (i.e., gain of chromosome arm 8q and loss of 9p), which enabled sensitive and specific liquid biopsy discrimination of MPNST from PN. Plasma-derived tumor fraction correlated with tumor size from imaging in MPNST patients, and serial cfDNA analysis demonstrated the potential for noninvasive detection of minimal residual disease, treatment response assessment, and the potential for even greater assay sensitivity. What do these findings mean? Our findings suggest that cfDNA fragment analysis followed by ULP-WGS has the potential to be developed as a biomarker for treatment response and as a screening assay for early detection of MPNST. This study provides, to our knowledge, the first evidence for the ability of liquid biopsy to distinguish between benign and malignant tumors in a heritable cancer predisposition syndrome.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::61e23e4617fd9614615fab2f5926f8b6Test
https://doi.org/10.1371/journal.pmed.1003734Test

المؤلفون: Mohammad A. Alabduljabbar, Deepak P. Edward, Diego Strianese, Rajiv Khandekar, Hind M. Alkatan, Azza Maktabi, Malak Abedalthagafi, Osama Al-Sheikh, Hailah Al-Hussain

المساهمون: Alabduljabbar, M., Strianese, D., Al-Sheikh, O., Alkatan, H. M., Al-Hussain, H., Maktabi, A. M. Y., Khandekar, R., Abedalthagafi, M., Edward, D. P.

المصدر: PLoS ONE, Vol 16, Iss 10 (2021)
PLoS ONE, Vol 16, Iss 10, p e0258802 (2021)
PLoS ONE

مصطلحات موضوعية: Male, Macroglial Cells, Pathology, Proliferation index, Medical Conditions, Diffuse Pattern, Retrospective Studie, Animal Cells, Medicine and Health Sciences, Neurofibroma, Child, Connective Tissue Cells, Staining, Multidisciplinary, biology, Cell Staining, Middle Aged, Prognosis, Oncology, Connective Tissue, Genetic Diseases, Child, Preschool, Immunohistochemistry, Medicine, Female, Anatomy, Cellular Types, Human, Research Article, Adult, medicine.medical_specialty, Histology, Adolescent, Prognosi, Science, Saudi Arabia, Surgical and Invasive Medical Procedures, Glial Cells, Research and Analysis Methods, Young Adult, Malignant Tumors, Plexiform neurofibroma, medicine, Humans, Neurofibromatosis, Retrospective Studies, Neurofibroma, Plexiform, Clinical Genetics, CD117, business.industry, Autosomal Dominant Diseases, Cancers and Neoplasms, Biology and Life Sciences, Cell Biology, Fibroblasts, medicine.disease, Biological Tissue, Specimen Preparation and Treatment, biology.protein, Schwann Cells, Neurofibromatosis Type 1, Neoplasm Recurrence, Local, business

الوصف: To evaluate and compare the clinical and histopathological profile of primary and recurrent orbital-periorbital plexiform neurofibromas (OPPN) in patients with neurofibromatosis type 1. We retrospectively evaluated 43 primary or recurrent neurofibroma (NF) specimens from 26 patients (2002 to 2018) at the King Khaled Eye Specialist Hospital, Saudi Arabia. Demographics, clinical presentation, and surgical intervention data were collected. Histopathological specimens were studied with hematoxylin-eosin, Alcian blue, and immunohistochemical markers; S-100, CD44, CD117, smooth muscle actin (SMA), neurofilament, and Ki-67. Of the 43 NFs specimens, 20 were primary and 23 recurrent tumors. For primary NF, the ratio of plexiform to the diffuse type was 13:7, however in recurrent tumors was 3:8 after the first recurrence, and 1:5 after multiple recurrences. Of the 17 patients with primary tumors that had paired recurrent tumors, 12/17 (70.6%) primary NFs were plexiform and 5/17 (29.4%) were diffuse. However, when tumors recurred, 13/17 tumors (76.5%) were diffuse and only 4/17 tumors (23.5%) had a plexiform pattern. The odds of a tumor having a diffuse pattern in recurrent NF was significantly higher than the plexiform pattern [OR = 7.8 (95% confidence interval 1.69:36.1) P = 0.008]. Primary plexiform NFs underwent an excision at a significantly younger age than the diffuse type. Recurrent NFs had significantly higher CD44, CD117, and neurofilament labeling (P = 0.02, P = 0.01 and P.001 respectively) but had significantly decreased Alcian blue, and S-100 labeling (P = 0.03, and P = 0.02 respectively) compared to primary tumors. SMA and Ki-67 proliferation index were not different between primary and recurrent NFs (P = 0.86, and P = 0.3 respectively). There appears to be a high risk for primary plexiform NFs to develop a diffuse histologic pattern when they recur. Immunohistochemical staining suggests a role of mast cells (CD117) and expression of infiltration makers (CD44) in the transformation of plexiform tumors to the diffuse phenotype.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4d0a5a52bb377e0c6a699ab91506a5ddTest
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530295/?tool=EBITest

المؤلفون: Olga Zapletalová, Pavel Hradílek, David Stejskal, Pavlína Kušnierová, David Zeman

المصدر: PLoS ONE, Vol 15, Iss 5, p e0233519 (2020)
PLoS ONE

مصطلحات موضوعية: Male, Central Nervous System, 0301 basic medicine, Pathology, Physiology, Nervous System, Biochemistry, White Blood Cells, 0302 clinical medicine, Cerebrospinal fluid, Animal Cells, Medicine and Health Sciences, Enzyme-Linked Immunoassays, Cerebrospinal Fluid, Aged, 80 and over, Multidisciplinary, Clinically isolated syndrome, biology, Neurodegenerative Diseases, Middle Aged, Prognosis, Body Fluids, medicine.anatomical_structure, Neurology, Peripheral nervous system, Medicine, Female, Anatomy, Cellular Types, Research Article, Adult, Immunofixation, medicine.medical_specialty, Multiple Sclerosis, Neurofilament, Inflammatory Diseases, Immune Cells, Science, Immunology, Research and Analysis Methods, CHI3L1, Autoimmune Diseases, Young Adult, 03 medical and health sciences, Diagnostic Medicine, medicine, Humans, Chitinase-3-Like Protein 1, Immunoassays, Neuroinflammation, Aged, Blood Cells, business.industry, Macrophages, Multiple sclerosis, Biology and Life Sciences, Cell Biology, medicine.disease, Demyelinating Disorders, 030104 developmental biology, Immunologic Techniques, biology.protein, Clinical Immunology, Clinical Medicine, business, Biomarkers, 030217 neurology & neurosurgery, Demyelinating Diseases

الوصف: Objectives Chitinase 3-like 1 (CHI3L1) is an extracellular monomeric single-chain glycoprotein expressed by many types of cells. Its elevated levels were found in cerebrospinal fluid in central nervous system (CNS) inflammatory diseases patients. The aim of the study was 1) to validate the reference interval of cerebrospinal fluid (CSF) CHI3L1 in a control group; 2) to measure the CHI3L1 concentration in different diagnosis groups .including multiple sclerosis (MS); and 3) to correlate those values with other biomarkers of axonal damage or neuroinflammation in different grous. Methods The study included 132 CSF samples sent to the Department of Clinical Biochemistry, Institute of Laboratory Diagnostics, University Hospital Ostrava. Concentrations of CHI3L1, CXCL13 chemokine, neurofilament light chains, and phosphorylated neurofilament heavy chains were determined by enzyme-linked immunosorbent assays. IgG oligoclonal bands were detected by isoelectric focusing in agarose gels followed by immunofixation. IgM and FLC oligoclonal bands were analyzed by IEF followed by affinity immunoblotting. The group consisted of 42 patients with multiple sclerosis, 14 with clinically isolated syndrome, 11 with other central nervous system inflammatory diseases, 46 with non-inflammatory diseases of the central nervous system, 4 with inflammatory diseases of the peripheral nervous system, and 15 controls. Results The estimated reference values of CHI3L1 were 28.6–182.5 μg.L-1. Statistically significant differences of CSF CHI3L1 concentrations were found among diagnosis groups (p < 0.0001), after age adjustment (p = 0.002). There was a statistically significant relationship between CHI3L1 and NFL in the MS group (rs = 0.460; P = 0.002), and between CHI3L1 and pNFH in the MS group (rs = 0.691; P < 0.001). No statistically significant difference was found in the categorical comparison of CHI3L1 in the MS group and other diagnostic groups as well as when using the Mann-Whitney U test for CHI3L1 with additional parameters with and without oligoclonal bands present. Conclusions CSF CHI3L1 values differ depending on diagnosis and correlate significantly with concentrations of the axonal damage markers CSF neurofilament light chains, and CSF phosphorylated neurofilament heavy chains, but not with CSF concentrations of the inflammatory marker CXCL13. Thus, CSF CHI3L1 could be another promising prognostic, albeit probably etiologically nonspecific, biomarker of MS.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::49242942945784015adfea13ee213f2bTest
https://doi.org/10.1371/journal.pone.0233519Test

المؤلفون: David F. Kallmes, Sylvain V. Costes, Tamara M. Hudson, Dana Schroeder, Jennifer S. McDonald, Philip M. Young, Jacob B. Ekins, Anthony S. Tin, Robert J. McDonald, Aiming Lu, Ramanathan Kadirvel, Scott H. Kaufmann, Kevin M. Kallmes

المصدر: PLoS ONE, Vol 13, Iss 1, p e0190890 (2018)
PLoS ONE

مصطلحات موضوعية: 0301 basic medicine, Male, Pathology, DNA Repair, Physiology, medicine.medical_treatment, lcsh:Medicine, Gadolinium, 030204 cardiovascular system & hematology, Biochemistry, Diagnostic Radiology, Histones, White Blood Cells, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Lymphocytes, Prospective Studies, Prospective cohort study, lcsh:Science, Multidisciplinary, medicine.diagnostic_test, Radiology and Imaging, Heart, Middle Aged, Magnetic Resonance Imaging, Body Fluids, Nucleic acids, Chemistry, Blood, Physical Sciences, Female, Cellular Types, Anatomy, Cardiomyopathies, Tumor Suppressor p53-Binding Protein 1, Research Article, Chemical Elements, Adult, medicine.medical_specialty, DNA damage, Imaging Techniques, Immune Cells, Immunology, Cardiology, Malignancy, Research and Analysis Methods, Drug Absorption, Peripheral blood mononuclear cell, 03 medical and health sciences, Diagnostic Medicine, medicine, Genetics, Humans, Clinical significance, Pharmacokinetics, Aged, Retrospective Studies, Pharmacology, Chemotherapy, Blood Cells, Biology and life sciences, business.industry, lcsh:R, Correction, Magnetic resonance imaging, DNA, Cell Biology, medicine.disease, Radiation therapy, 030104 developmental biology, lcsh:Q, business, Biomarkers, DNA Damage

الوصف: Magnetic resonance imaging is considered low risk, yet recent studies have raised a concern of potential damage to DNA in peripheral blood leukocytes. This prospective Institutional Review Board-approved study examined potential double-strand DNA damage by analyzing changes in the DNA damage and repair markers γH2AX and 53BP1 in patients who underwent a 1.5 T gadolinium-enhanced cardiac magnetic resonance (MR) exam. Sixty patients were enrolled (median age 55 years, 39 males). Patients with history of malignancy or who were receiving chemotherapy, radiation therapy, or steroids were excluded. MR sequence data were recorded and blood samples obtained immediately before and after MR exposure. An automated immunofluorescence assay quantified γH2AX or 53BP1 foci number in isolated peripheral blood mononuclear cells. Changes in foci number were analyzed using the Wilcoxon signed-rank test. Clinical and MR procedural characteristics were compared between patients who had a >10% increase in γH2AX or 53BP1 foci numbers and patients who did not. The number of γH2AX foci did not significantly change following cardiac MR (median foci per cell pre-MR = 0.11, post-MR = 0.11, p = .90), but the number of 53BP1 foci significantly increased following MR (median foci per cell pre-MR = 0.46, post-MR = 0.54, p = .0140). Clinical and MR characteristics did not differ significantly between patients who had at least a 10% increase in foci per cell and those who did not. We conclude that MR exposure leads to a small (median 25%) increase in 53BP1 foci, however the clinical relevance of this increase is unknown and may be attributable to normal variation instead of MR exposure.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a9f306e02fb700f124b332c39429b22bTest
http://europepmc.org/articles/PMC5757995?pdf=renderTest

المؤلفون: Georges Bellon, Caroline Fichel, Christelle Coquelet, Marie-Danièle Diebold, Lukshe Kanagaratnam, Aude Bressenot, Saviz Nasri, Christophe Schneider, Reza Kianmanesh, Thibaut Galissier, Camille Boulagnon-Rombi, Stéphane Dedieu

المصدر: PLoS ONE, Vol 11, Iss 4, p e0154326 (2016)
PLoS ONE

مصطلحات موضوعية: Male, 0301 basic medicine, Pathology, Necrosis, Colorectal cancer, medicine.medical_treatment, Gene Expression, lcsh:Medicine, medicine.disease_cause, Vascular Medicine, 0302 clinical medicine, Ischemia, Adenocarcinomas, Medicine and Health Sciences, RNA, Neoplasm, lcsh:Science, Colectomy, Aged, 80 and over, Multidisciplinary, Caspase 3, Anastomosis, Surgical, Cold Ischemia, Middle Aged, Immunohistochemistry, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Adenocarcinoma, Female, KRAS, Anatomy, medicine.symptom, Research Article, Adult, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Histology, Stromal cell, Colon, Surgical and Invasive Medical Procedures, Tissue Banks, Carcinomas, Specimen Handling, Proto-Oncogene Proteins p21(ras), Digestive System Procedures, 03 medical and health sciences, Genetics, medicine, Humans, Aged, business.industry, lcsh:R, Reproducibility of Results, Cancers and Neoplasms, Biology and Life Sciences, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Gastrointestinal Tract, 030104 developmental biology, Multivariate Analysis, RNA, Laparoscopy, lcsh:Q, business, Digestive System, Microsatellite Repeats

الوصف: Medical research projects become increasingly dependent on biobanked tissue of high quality because the reliability of gene expression is affected by the quality of extracted RNA. Hence, the present study aimed to determine if clinical, surgical, histological, and molecular parameters influence RNA quality of normal and tumoral frozen colonic tissues. RNA Quality Index (RQI) was evaluated on 241 adenocarcinomas and 115 matched normal frozen colon tissues collected between October 2006 and December 2012. RQI results were compared to patients’ age and sex, tumor site, kind of surgery, anastomosis failure, adenocarcinoma type and grade, tumor cell percentage, necrosis extent, HIF-1α and cleaved caspase-3 immunohistochemistry, and BRAF, KRAS and microsatellites status. The RQI was significantly higher in colon cancer tissue than in matched normal tissue. RQI from left-sided colonic cancers was significantly higher than RQI from right-sided cancers. The RNA quality was not affected by ischemia and storage duration. According to histological control, 7.9% of the samples were unsatisfactory because of inadequate sampling. Biobanked tumoral tissues with RQI ≥5 had lower malignant cells to stromal cells ratio than samples with RQI

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c6465ba9fcde50fbf562ae4ad288e529Test
http://europepmc.org/articles/PMC4849710?pdf=renderTest

المؤلفون: Yan Li, Liangliang Shen, Yuan Liu, Bolei Cai, Jin-Long Zhao, Bo Yu, Yanpu Liu, Jun-Zheng Wu

المصدر: PLoS ONE, Vol 11, Iss 2, p e0148223 (2016)
PLoS ONE

مصطلحات موضوعية: Male, 0301 basic medicine, Pathology, Cancer Treatment, lcsh:Medicine, Salivary Glands, Metastasis, 0302 clinical medicine, Cell Movement, Basic Cancer Research, Medicine and Health Sciences, Child, lcsh:Science, Multidisciplinary, Pharmaceutics, Middle Aged, Cell cycle, Prognosis, Cell Motility, medicine.anatomical_structure, Oncology, Child, Preschool, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Cancer Therapy, Immunohistochemistry, Female, Anatomy, Research Article, Adult, medicine.medical_specialty, Adolescent, Down-Regulation, Cell Migration, Biology, Carcinomas, Lymphatic System, Young Adult, 03 medical and health sciences, Exocrine Glands, Drug Therapy, Gentamicin protection assay, Downregulation and upregulation, Diagnostic Medicine, Mucoepidermoid carcinoma, Cell Line, Tumor, medicine, Chemotherapy, Humans, Neoplasm Invasiveness, MTT assay, ATP Binding Cassette Transporter, Subfamily B, Member 1, Aged, Cell Proliferation, Cell Nucleus, lcsh:R, Expression index, Biology and Life Sciences, Cancers and Neoplasms, Infant, Cell Biology, medicine.disease, Cell nucleus, 030104 developmental biology, Cancer research, Carcinoma, Mucoepidermoid, lcsh:Q, Lymph Nodes, Neoplasm Grading, Digestive System, Developmental Biology

الوصف: Objectives Multidrug resistance-related protein 1 (MRP1) overexpression is a well acknowledged predictor of poor response to chemotherapy, but MRP1 also correlated to better prognosis in some reports, especially for patients not pretreated with chemotherapy. In our previous study, we found nuclear translocation of MRP1 in mucoepidermoid carcinoma (MEC) for the first time. The purpose of this study was to further investigate the function of nuclear MRP1 in MEC. Materials and Methods Human MEC tissue samples of 125 patients were selected and stained using immunohistochemistry. The expression level of total MRP1/nuclear MRP1 of each sample was evaluated by expression index (EI) which was scored using both qualitative and quantitative analysis. The correlations between the clinicopathologic parameters and the EI of nuclear MRP1 were analyzed using Spearman’s rank correlation analysis, respectively. The effects of RNAi-mediated downregulation of nuclear MRP1 on MEC cells were assessed using flow cytometric analysis, MTT assay, plate colony formation assay, transwell invasion assay and monolayer wound healing assay. Results In this study, we found the EI of nuclear MRP1 was negatively correlated to the pathologic grading (r = -0.498, P

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::20315fe36214ed48fa9928df3068eeabTest
http://europepmc.org/articles/PMC4734599?pdf=renderTest

المؤلفون: Benjamin Levi, David Cholok, Thomas A. Davis, Shawn Loder, Ammar T. Qureshi, Yuji Mishina, Shailesh Agarwal, Kay Shigemori, James Drake, Jonathan A. Forsberg, Jonathan R. Peterson, Shuli Li

المصدر: PLoS ONE, Vol 11, Iss 8, p e0156253 (2016)
PLoS ONE

مصطلحات موضوعية: 0301 basic medicine, Male, Pathology, Critical Care and Emergency Medicine, Cellular differentiation, lcsh:Medicine, Core Binding Factor Alpha 1 Subunit, Rats, Sprague-Dawley, Mice, 0302 clinical medicine, Animal Cells, Osteogenesis, Medicine and Health Sciences, Morphogenesis, lcsh:Science, Trauma Medicine, Cells, Cultured, Connective Tissue Cells, Multidisciplinary, biology, Chemistry, Muscles, Cell Differentiation, Animal Models, Muscle Differentiation, Osteoblast Differentiation, Connective Tissue, Sp7 Transcription Factor, 030220 oncology & carcinogenesis, Osteocalcin, Cellular Types, Anatomy, Burns, Traumatic Injury, Research Article, Adult, Smad5 Protein, medicine.medical_specialty, Cell type, Soft Tissues, Mouse Models, Mice, Transgenic, Research and Analysis Methods, Bone and Bones, Smad1 Protein, 03 medical and health sciences, Young Adult, Model Organisms, Genetic model, medicine, Animals, Humans, Bone, Cell Proliferation, Osteoblasts, Cell growth, Ossification, Heterotopic, Mesenchymal stem cell, lcsh:R, Biology and Life Sciences, Mesenchymal Stem Cells, Cell Biology, medicine.disease, Molecular biology, In vitro, Rats, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Biological Tissue, biology.protein, Heterotopic ossification, lcsh:Q, Developmental Biology, Transcription Factors

الوصف: Heterotopic ossification (HO) is the pathologic formation of bone separate from the normal skeleton. Although several models exist for studying HO, an understanding of the common in vitro properties of cells isolated from these models is lacking. We studied three separate animal models of HO including two models of trauma-induced HO and one model of genetic HO, and human HO specimens, to characterize the properties of cells derived from tissue containing pre-and mature ectopic bone in relation to analogous mesenchymal cell populations or osteoblasts obtained from normal muscle tissue. We found that when cultured in vitro, cells isolated from the trauma sites in two distinct models exhibited increased osteogenic differentiation when compared to cells isolated from uninjured controls. Furthermore, osteoblasts isolated from heterotopic bone in a genetic model of HO also exhibited increased osteogenic differentiation when compared with normal osteoblasts. Finally, osteoblasts derived from mature heterotopic bone obtained from human patients exhibited increased osteogenic differentiation when compared with normal bone from the same patients. These findings demonstrate that across models, cells derived from tissues forming heterotopic ossification exhibit increased osteogenic differentiation when compared with either normal tissues or osteoblasts. These cell types can be used in the future for in vitro investigations for drug screening purposes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::08fa437ceed882406ccb54c413772acfTest
http://europepmc.org/articles/PMC4975503?pdf=renderTest

المؤلفون: Catherina Pfuhl, Klemens Ruprecht, Caroline Eberle, Lisa Heiserich, Klaus Lenz, Judith Bellmann-Strobl, Janina Behrens, Dirk Roggenbuck, Peter Bauer, René M. Gieß, Erik Freitag, Jan Dörr, Jens Wuerfel, Katharina Wakonig, Friedemann Paul, Ludwig Rasche

المصدر: PLoS ONE, Vol 11, Iss 1, p e0147968 (2016)
PLoS ONE

مصطلحات موضوعية: Male, 0301 basic medicine, Pathology, Focus (geometry), Physiology, Immunomodulatory Treatments, lcsh:Medicine, Pathology and Laboratory Medicine, Biochemistry, Diagnostic Radiology, Histones, 0302 clinical medicine, Medicine and Health Sciences, Public and Occupational Health, Lymphocytes, 10. No inequality, lcsh:Science, Multidisciplinary, Clinically isolated syndrome, Radiology and Imaging, Intracellular Signaling Peptides and Proteins, Neurodegenerative Diseases, Hematology, Middle Aged, Magnetic Resonance Imaging, Pathophysiology, Body Fluids, 3. Good health, Nucleic acids, Blood, Neurology, Female, Anatomy, Tumor Suppressor p53-Binding Protein 1, Research Article, Adult, medicine.medical_specialty, Multiple Sclerosis, Imaging Techniques, DNA damage, Disabilities, Immunology, Immunocytochemistry, Biology, Research and Analysis Methods, Peripheral blood mononuclear cell, Autoimmune Diseases, Young Adult, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, Genetics, medicine, Humans, Multiple sclerosis, Magnetic resonance imaging, Lesions, Immunomodulatory treatments, Diagnostic medicine, Expanded Disability Status Scale, lcsh:R, Biology and Life Sciences, DNA, medicine.disease, Demyelinating Disorders, 030104 developmental biology, Case-Control Studies, Clinical Immunology, lcsh:Q, Clinical Medicine, Biomarkers, 030217 neurology & neurosurgery

الوصف: Background: In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as {gamma}-H2AX. Formation of {gamma}-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. {gamma}-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS). Objective: To evaluate the significance of {gamma}-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated {gamma}-H2AX and 53BP1 foci detection. Methods: Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with {gamma}-H2AX and 53BP1 specific antibodies. Nuclear {gamma}-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of {gamma}-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. {gamma}-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls. Results: The median (range) number of {gamma}-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0–0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, {gamma}-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. {gamma}-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although {gamma}-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, {gamma}-H2AX values of both groups overlapped and {gamma}-H2AX did not correlate with the number or volume of CEL. Conclusion: {gamma}-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::99efbe298af26434076b1d69dc961b6bTest
http://europepmc.org/articles/PMC4731473?pdf=renderTest

المؤلفون: Takanori Himuro, Sei Sai, Yoshiya Horimoto, Noriko Sasahara, Mitsue Saito, Atsushi Arakawa, Masahiko Tanabe

المصدر: PLoS ONE, Vol 11, Iss 10, p e0165253 (2016)
PLoS ONE

مصطلحات موضوعية: 0301 basic medicine, Oncology, CA15-3, Pathology, Carcinogenesis, Cancer Treatment, lcsh:Medicine, Disease, Metastasis, 0302 clinical medicine, Animal Cells, Cancer Stem Cells, Breast Tumors, Basic Cancer Research, Medicine and Health Sciences, Neoplasm Metastasis, lcsh:Science, Staining, Multidisciplinary, biology, CD24, Stem Cells, Cell Staining, Middle Aged, Immunohistochemistry, Isoenzymes, Hyaluronan Receptors, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Cellular Types, Research Article, Adult, medicine.medical_specialty, Breast Neoplasms, Surgical and Invasive Medical Procedures, Research and Analysis Methods, Aldehyde Dehydrogenase 1 Family, 03 medical and health sciences, Breast cancer, Cancer stem cell, Internal medicine, Breast Cancer, Biomarkers, Tumor, medicine, Humans, Immunohistochemistry Techniques, Cytoplasmic Staining, Aged, business.industry, CD44, lcsh:R, CD24 Antigen, Retinal Dehydrogenase, Cancers and Neoplasms, Biology and Life Sciences, Cancer, Cell Biology, medicine.disease, Histochemistry and Cytochemistry Techniques, 030104 developmental biology, Specimen Preparation and Treatment, Immunologic Techniques, biology.protein, lcsh:Q, business

الوصف: The combination of CD44 and CD24, or aldehyde dehydrogenase 1 (ALDH1) alone, is a widely used cancer stem cell marker in breast cancer. However, no conclusion has yet been reached as to which marker is the best for characterizing cancer stemness. Immunohistochemical evaluation using cancer stem cell markers is clearly less common clinically than in basic experiments and how the expressions of these markers relate to patient outcomes remains controversial. To investigate whether combining these markers might improve the prediction of patient outcomes, we immunohistochemically examined clinical samples. Primary invasive breast cancer samples from 61 patients who eventually developed distant metastases after curative surgery were immunohistochemically examined. All patients were free of metastatic disease at the time of surgery and received standard adjuvant systemic treatments. CD44+/24- and ALDH1-positive rates in primary tumors differed according to intrinsic subtype. ER-positive patients with CD44+/24- tumors had significantly longer disease-free-survival than all other ER-positive patients (p = 0.0047). On the other hand, CD44+/24- tumors were associated with poor outcomes of ER-negative patients (p = 0.038). Finally, expression patterns of CD44 and ALDH1 in single tumors were strikingly different and there were virtually no individual double-stained cells. Thus, this combination does not allow evaluation of relationships with patient outcomes. Our results raise the possibility of CD44+/24- being a good prognostic marker, one which would allow treatment effects and outcomes to be predicted in patients with recurrent breast cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1437eb975bd6ac0c8c8b98a17d292e9fTest
http://europepmc.org/articles/PMC5074575?pdf=renderTest

المؤلفون: Hugo ten Cate, Iris L.H. Knottnerus, Ellen C. van Overbeek, Robert J. van Oostenbrugge, Julie Staals

المساهمون: MUMC+: MA AIOS Neurologie (9), RS: CARIM - R3.03 - Cerebral small vessel disease, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: MA Alg Interne Geneeskunde (9), Interne Geneeskunde, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Biochemie

المصدر: PLoS ONE, Vol 11, Iss 3, p e0150740 (2016)
PLoS ONE
PLOS ONE, 11(3):e0150740. Public Library of Science

مصطلحات موضوعية: Central Nervous System, Male, Pathology, Physiology, lcsh:Medicine, Blood Pressure, 030204 cardiovascular system & hematology, Tissue plasminogen activator, Nervous System, Vascular Medicine, Diagnostic Radiology, chemistry.chemical_compound, 0302 clinical medicine, Mathematical and Statistical Techniques, Endocrinology, Medicine and Health Sciences, Longitudinal Studies, lcsh:Science, Stroke, Multidisciplinary, medicine.diagnostic_test, Radiology and Imaging, Brain, Hematology, Middle Aged, Magnetic Resonance Imaging, White Matter, Body Fluids, medicine.anatomical_structure, Blood, Neurology, Plasminogen activator inhibitor-1, Tissue Plasminogen Activator, Physical Sciences, Hypertension, Cardiology, Disease Progression, Regression Analysis, Female, Anatomy, Statistics (Mathematics), medicine.drug, Research Article, Adult, medicine.medical_specialty, Lacunar stroke, Imaging Techniques, Endocrine Disorders, Cerebrovascular Diseases, Research and Analysis Methods, behavioral disciplines and activities, Blood Plasma, White matter, Endothelial activation, 03 medical and health sciences, Diagnostic Medicine, Internal medicine, Plasminogen Activator Inhibitor 1, mental disorders, medicine, Diabetes Mellitus, Humans, Statistical Methods, Ischemic Stroke, Aged, Hemostasis, business.industry, lcsh:R, Biology and Life Sciences, Magnetic resonance imaging, medicine.disease, Hyperintensity, chemistry, Metabolic Disorders, Stroke, Lacunar, lcsh:Q, business, 030217 neurology & neurosurgery, Mathematics

الوصف: Introduction Tissue plasminogen activator (tPA)-activity and plasminogen activator inhibitor type 1 (PAI-1) antigen are considered to be haemostasis-related markers of endothelial activation and relate to presence of cerebral white matter hyperintensities (WMH) as was earlier shown in a cross-sectional study. We investigated whether tPA-activity and PAI-1 levels are associated with WMH progression in a longitudinal study. Methods In 127 first-ever lacunar stroke patients in whom baseline brain MRI and plasma levels of tPA-activity and PAI-1-antigen were available, we obtained a 2-year follow-up MRI. We assessed WMH progression by a visual WMH change scale. We determined the relationship between levels of tPA-activity and PAI-1 and WMH progression, by logistic regression analysis. Results Plasma tPA-activity was associated with periventricular WMH progression (OR 2.36, 95% CI 1.01–5.49, with correction for age and sex and baseline presence of WMH), but not with deep or any (periventricular and/or deep) WMH progression. PAI-1 levels were lower in patients with WMH progression, but these results were not significant. Conclusion We found a relationship between plasma tPA-activity and progression of periventricular WMH. More research is needed to determine whether there is a (direct) role of tPA in the development and progression of WMH.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::600f101fb62afee3dd1835e735f2fef5Test
http://europepmc.org/articles/PMC4778794?pdf=renderTest