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Abnormal Differentiation (abnormal + differentiation)
Selected AbstractsAbnormal differentiation of memory T cells in systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 7 2006Ruth D. Fritsch Objective The chemokine receptor CCR7 and the tumor necrosis factor receptor family member CD27 define 3 distinct, progressively more differentiated maturational stages of CD4 memory subpopulations in healthy individuals: the CCR7+,CD27+, the CCR7,, CD27+, and the CCR7,,CD27, populations. The goal of this study was to examine maturational disturbances in CD4 T cell differentiation in systemic lupus erythematosus (SLE), using these phenotypic markers. Methods Phenotypic analysis by flow cytometry, in vitro stimulation experiments, telomere length measurement, and determination of inducible telomerase were carried out. Results In SLE patients, significant increases of CCR7,,CD27, and CCR7,,CD27+ and a reduction of CCR7+,CD27+ CD4 memory T cells were found. In vitro stimulation of SLE T cells showed a stepwise differentiation from naive to CCR7+,CD27+ to CCR7,,CD27+ to CCR7,,CD27,; telomere length and inducible telomerase decreased in these subsets in the same progressive sequence. The in vitro proliferative response of these populations progressively declined as their susceptibility to apoptosis increased. Interestingly, a significant reduction in inducible telomerase was noted in SLE naive and CCR7+,CD27+ CD4+ memory T cells. Additionally, SLE CCR7,,CD27+ and CCR7,, CD27, CD4 memory T cells proliferated poorly in response to in vitro stimulation and underwent significantly more apoptosis than their normal counterparts. Finally, expression of CXCR4 was significantly reduced in all SLE subsets compared with normal. Conclusion Together these data indicate an increased degree of in vivo T cell stimulation in SLE, resulting in the accumulation of terminally differentiated memory T cells with a decreased proliferative capacity and an increased tendency to undergo apoptosis upon stimulation. [source] Gs, Mutations in Fibrous Dysplasia and McCune-Albright Syndrome,JOURNAL OF BONE AND MINERAL RESEARCH, Issue S2 2006Lee S Weinstein Abstract Fibrous dysplasia (FD) is a focal bone lesion composed of immature mesenchymal osteoblastic precursor cells. Some FD patients also have hyperpigmented skin lesions (café-au-lait spots), gonadotropin-independent sexual precocity, and/or other endocrine and nonendocrine manifestations (McCune-Albright syndrome [MAS]). MAS results from somatic mutations occurring during early development, resulting in a widespread mosaic of normal and mutant-bearing cells, which predicts that the clinical presentation of each patient is determined by the extent and distribution of abnormal cells. These mutations encode constitutively active forms of Gs,, the ubiquitously expressed G protein ,-subunit that couples hormone receptors to intracellular cAMP generation. These mutations lead to substitution of amino acid residues that are critical for the intrinsic GTPase activity that is normally required to deactivate the G protein. This leads to prolonged activation of Gs, and its downstream effectors even with minimal receptor activation. This explains why MAS patients have stimulation of multiple peripheral endocrine glands in the absence of circulating stimulatory pituitary hormones and increased skin pigment, which is normally induced by melanocyte-stimulating hormone through Gs,/cAMP. Similar mutations are also present in 40% of pituitary tumors in acromegaly patients and less commonly in other endocrine tumors. FD results from increased cAMP in bone marrow stromal cells, leading to increased proliferation and abnormal differentiation. Parental origin of the mutated allele may also affect the clinical presentation, because Gs, is imprinted and expressed only from the maternal allele in some tissues (e.g., pituitary somatotrophs). [source] Defective ,1 -integrins expression in arsenical keratosis and arsenic-treated cultured human keratinocytesJOURNAL OF CUTANEOUS PATHOLOGY, Issue 2 2006Chih-Hung Lee Background:, ,1 -integrins, which localize to the basolateral surface of basal keratinocytes, are important in the differentiation control and proliferation of the epidermis. Many cutaneous diseases with perturbed differentiation, including arsenical keratosis, show altered patterns of integrin distribution and expression. Arsenic may induce arsenical keratosis through the differentiation and apoptosis aberration by integrins. The purpose of this study is to investigate the role of integrin and arsenic in the pathogenesis of arsenical keratosis. Methods:, Twenty-five specimens obtained from 25 patients with arsenical keratosis disease were studied. Immunohistochemistry staining to ,1, ,2,1, or ,3,1 integrins was performed in arsenical keratosis and clinically normal perilesional skin. Western blotting was used to assess the expression of integrin ,1 and focal adhesion kinase (FAK) in arsenic-treated cultured keratinocytes. Results:, A decreased expression of ,1, ,2,1, or ,3,1 integrins was demonstrated in arsenical keratosis and clinical normal perilesional skin in a large proportion of arsenical keratosis cases studied. The expressions of integrin ,1 and FAK were both decreased in arsenic-treated keratinocytes. Conclusions:, Our results suggest that arsenic induces abnormal differentiation in arsenical keratosis via the effects of integrin expression in keratinocytes. [source] Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2PATHOLOGY INTERNATIONAL, Issue 8 2001Hiroshi Maruyama Tuberous sclerosis (TSC) is a rare, genetically determined disorder / familial tumor syndrome, currently diagnosed using specific clinical criteria proposed by Gomez, including the presence of multiorgan hamartomas. Pulmonary involvement in TSC is well known as pulmonary lymphangioleiomyomatosis (LAM), which has an incidence of 1,2.3% in TSC patients. LAM has immunohistochemical expression of both smooth-muscle actin and a monoclonal antibody specific for human melanoma, HMB-45. It has recently been reported that multifocal micronodular pneumocyte hyperplasia (MMPH) associated with TSC should be considered as a distinct type of lung lesion, whether it occurs with or without LAM. Two predisposing genes have been found in families affected by TSC; approximately half of the families show linkage to TSC1 at 9q34.3, and the other half show linkage to TSC2 at 16p13.3. TSC genes are considered to be tumor suppressor genes, and mutations in them may lead to abnormal differentiation and proliferation of cells. Tuberin, the TSC2 gene product, has recently been found to be expressed in LAM and MMPH. In this article we discuss the histogenesis and genetic abnormalities of neoplastic lesions associated with TSC, and we review the current understanding of the pathogenesis of pulmonary hamartomatous lesions such as LAM and MMPH in TSC. [source] Alpha-fetoprotein producing uterine corpus carcinoma: A hepatoid adenocarcinoma of the endometriumPATHOLOGY INTERNATIONAL, Issue 10 2000Hiroshi Toyoda A case of alpha-fetoprotein (AFP) producing endometrial carcinoma in a 60-year-old Japanese woman is presented. The patient complained of abnormal vaginal bleeding of 10 days' duration. On admission a uterine corpus mass and high serum AFP concentration (31950 ng/mL) was noted. There was no tumorous lesion in any other organ radiographically and endoscopically. Histologically, the biopsy specimen taken from the uterine mass showed a poorly differentiated endometrial carcinoma and a radical hysterectomy was subsequently performed. The postoperative serum AFP value transiently decreased with chemotherapy, however, lung metastases were found and the patient died 12 months following surgery. The resected uterus had a necrotic tumor, 6 × 5 × 4 cm in size, filling the endometrial cavity, characterized by exophytic growth with infiltration in the myometrium. Histologically, the tumor was composed of the main medullary carcinoma area with microcysts and admixed small areas of well-differentiated endometrioid adenocarcinoma, accompanied by a smooth transition with one another. In both the areas, the tumor cells had immunoreactive AFP, alpha-1-antitripsin, albumin, transferrin, carcinoembryonic antigen, CA19-9, and epithelial membrane antigen. There was no histologic evidence for a germ cell tumor. Based on these findings, this uterine corpus tumor was regarded as hepatoid variant of endometrial carcinoma. Although the histogenesis remains controversial, we assume the hypothesis that the tumor may arise in the endometrium per se in association with abnormal differentiation of muellerian duct elements. [source] Restoration of DWF4 expression to the leaf margin of a dwf4 mutant is sufficient to restore leaf shape but not size: the role of the margin in leaf developmentTHE PLANT JOURNAL, Issue 6 2007Beate Reinhardt Summary The role of the margin in leaf development has been debated over a number of years. To investigate the molecular basis of events in the margin, we performed an enhancer trap screen to identify genes specifically expressed in this tissue. Analysis of one of these lines revealed abnormal differentiation in the margin, accompanied by an abnormal leaf size and shape. Further analysis revealed that this phenotype was due to insertion of the trap into DWF4, which encodes a key enzyme in brassinolide biosynthesis. Transcripts for this gene accumulated in a specific and dynamic pattern in the epidermis of young leaf primordia. Targeted expression of DWF4 to a subset of these cells (the leaf margin) in a dwf4 mutant background led to both restoration of differentiation of a specific group of leaf cells (margin cells) and restoration of wild-type leaf shape (but not leaf size). Ablation of these cells led to abrogation of leaf development and the formation of small round leaves. These data support the hypothesis that events in the margin play an essential role in leaf morphogenesis, and implicate brassinolide in the margin as a key mediator in the control of leaf shape, separable from a general function of this growth factor in the control of organ size. [source] Elevated serum levels of calcium-binding S100 proteins A8 and A9 reflect disease activity and abnormal differentiation of keratinocytes in psoriasisBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2006S. Benoit Summary Background, The expression of calcium-binding S100 molecules organized within the epidermal differentiation complex on chromosome 1q21 is disturbed in hyperproliferative skin diseases such as psoriasis. Objectives, We studied whether serum levels of S100 proteins A8 (S100A8) and A9 (S100A9) are elevated in psoriasis, correlated their amounts with disease activity and identified potential cellular sources. Methods, Serum obtained from psoriasis patients or from healthy individuals was studied for S100A8 and S100A9 levels by enzyme-linked immunosorbent assay. Data were correlated to disease activity as reflected by the Psoriasis Area and Severity Index (PASI). Cellular sources of S100A8 and S100A9 were identified by in situ hybridization and immunohistochemistry of lesional psoriatic and nonlesional, nonpsoriatic skin. Results, A significant increase of S100A8/S100A9 serum levels was found in patients with psoriasis compared with healthy controls. Grading the patients into two groups of severity, individuals with a PASI of <15 showed serum levels of 705 ± 120 ng mL,1 (mean ± SEM, n = 18), those with a PASI of ,15 showed levels of 1315 ± 150 ng mL,1 (n = 32) while controls presented with 365 ± 50 ng mL,1. Performing in situ hybridization of lesional psoriatic skin we detected a dramatic induction of both S100A8 and S100A9 mRNA and protein primarily in the suprabasal layers of the epidermis while expression was negligible in nonlesional, nonpsoriatic interfollicular epidermis. Conclusions, Our data demonstrate that hyperproliferation and abnormal differentiation of psoriatic skin is associated with a massive upregulation and secretion of S100A8 and S100A9, suggesting not only a prominent role of these molecules during intracellular calcium-dependent signalling but also implying distinct extracellular functions. [source] The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skinBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2005C. Johansen Summary Background, Alterations in specific signal transduction pathways may explain the hyperproliferation and abnormal differentiation of the keratinocytes as well as the increased expression of inflammatory cytokines seen in psoriasis. Major signalling pathways used by eukaryotic cells to transduce extracellular signals into cellular responses impinge on the mitogen-activated protein kinases (MAPKs). Objectives, To investigate the expression of the MAPK p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2 -terminal kinase (JNK) in psoriatic skin. Methods, Keratome biopsies were taken from patients with plaque-type psoriasis. Western blot analysis was used to determine p38, ERK and JNK activity and protein levels, whereas kinase assays were used to examine the kinase activity of p38. Results, We demonstrated increased levels of the phosphorylated forms of p38 and ERK1/2 in lesional psoriatic skin compared with nonlesional psoriatic skin. No abnormality was found in the activation and expression of JNK1/2. Ex vivo kinase assays confirmed the increased activation of p38, and furthermore demonstrated increased kinase activity of the p38 isoforms p38,, p38, and p38, in lesional compared with nonlesional psoriatic skin. p38, was not detected in the psoriatic skin. Clearance of the psoriatic lesions, induced by climatotherapy at the Dead Sea for 4 weeks, led to a normalization in the activity of both p38 and ERK1/2. Conclusions, Taken together, our results demonstrate that the activity of the MAPKs p38,, p38, and p38, and ERK1/2 are increased in lesional psoriatic skin compared with nonlesional psoriatic skin, and that clearance of psoriasis normalizes the p38 and ERK1/2 activity. Thus, p38 and ERK1/2 might be potential targets in the treatment of psoriasis. [source] Stem cells and gastric cancer: Role of gastric and intestinal mixed intestinal metaplasiaCANCER SCIENCE, Issue 2 2003Masae Tatematsu All of the different types of stomach epithelial cells are known to be derived from a single progenitor cell in each gland. Similarly, cancers develop from single cells, based on data from clonality analysis in C3H/HeN , BALB/c chimeric mice. Using gastric and intestinal epithelial cell markers, intestinal metaplasia (IM) can be divided into two major types: a gastric and intestinal (GI) mixed type, and a solely intestinal (I) type. Ectopic expression of Cdx genes and down-regulation of Sox2 in isolated single GI mixed IM glands suggests abnormal differentiation of stem cells that can produce both gastric (G) and I type cells. Similarly, phenotypic expression of gastric cancer cells of each histological type can be clearly classified into G and I type epithelial cells. The heterogeneity of phenotypic expression of gastric cancer cells in individual cancers is assumed to reflect this intrinsic potential for differentiation in two directions. Gastric cancers at early stages, independent of the histological type, mainly consist of G type cells, and phenotypic shift from G to I type expression is clearly observed with progression. The data thus suggest IM may not be a preneoplastic change in gastric carcinoma, but rather that cells of the I type may appear independently in the gastric mucosa in IM and in gastric cancers. Intestinalization of gastric mucosa and cancer cells may represent a kind of homeotic transformation. Whether disturbance of the regulation of Sox2 and Cdx genes may be of importance to the biological behavior of gastric cancers should therefore be clarified in future studies. (Cancer Sci 2003; 94: 135,141) [source] A comprehensive review of biomarkers in psoriasisCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 6 2009R. Rashmi Summary Psoriasis is a common, chronic skin disorder, the pathogenesis of which is incompletely understood. Results from various clinical and experimental studies indicate that psoriasis is a complex, multifactorial disease with a genetic predisposition. Factors such as climate, physical trauma, drug, stress and infections (Streptococcus, human immunodeficiency virus) are known to trigger psoriasis. The success of treatment of psoriasis with T-cell depletion and antitumour necrosis factor (TNF)-, treatment is explained by the involvement of T cells and TNF- , in the pathogenesis of psoriasis. The biochemical basis for the pathogenesis of psoriasis can be attributed to both overexpression and underexpression of certain proteins in psoriatic lesions. The anomalies in protein expression can be classified as abnormal keratinocyte differentiation, keratinocyte hyperproliferation and inflammation. Oxidative stress (OS) and increased free-radical generation have been linked to skin inflammation in psoriasis. The review presents evidence for various markers of psoriasis that can be targeted for effective treatment, including biomarkers of inflammation, keratinocyte hyperproliferation and abnormal differentiation, and stress. [source] | ||||||||||