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1.
J Am Acad Dermatol ; 72(5): 801-8, 2015 May.
Article in English | MEDLINE | ID: mdl-25774013

ABSTRACT

BACKGROUND: Little is known about the frequency of clinical and dermoscopic patterns of lentigo maligna (LM) in relation to specific anatomic subsites and patients characteristics. OBJECTIVE: We sought to assess the frequency of clinical and dermoscopic features of LM and to correlate them to specific anatomic subsites, and patients' age and gender. METHODS: This was a retrospective analysis of clinical and dermoscopic images of a series of consecutive, histopathologically diagnosed, facial and extrafacial LM. RESULTS: A total of 201 cases from 200 patients (mean age 69.51 ± 12.26 years) including 120 women were collected. Most cases were located on the face (n = 192, 95.5%). In 102 cases, LM presented as clinically solitary facial macule (s/LM), whereas it was associated with multiple surrounding freckles in the remaining cases. s/LM were significantly smaller (<10 vs >10 mm; P = .020) and associated with younger age compared with LM associated with multiple surrounding freckles (mean age 67.73 ± 12.68 years vs 71.34 ± 11.59 years, respectively; P = .036). Dermoscopically, gray color irrespective of a specific pattern was the most prevalent finding seen in 178 (88.6%) cases. LIMITATIONS: This was a retrospective study. CONCLUSIONS: The knowledge about patient age, patient gender, and site-related clinical features of LM associated with gray color upon dermoscopy may enhance the clinical recognition of LM.


Subject(s)
Hutchinson's Melanotic Freckle/pathology , Skin Neoplasms/pathology , Age Factors , Aged , Dermoscopy , Facial Neoplasms/epidemiology , Facial Neoplasms/pathology , Female , Humans , Hutchinson's Melanotic Freckle/diagnosis , Hutchinson's Melanotic Freckle/epidemiology , Male , Retrospective Studies , Sex Factors , Skin Neoplasms/diagnosis , Skin Neoplasms/epidemiology
4.
Eur J Cancer Prev ; 23(5): 458-63, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25068806

ABSTRACT

Patients with a high total nevus count (TNC) merit a total-body examination, but a simple strategy to identify these high-risk individuals is essentially missing. The aim of this study was to investigate the correlation between the number of melanocytic nevi on both arms and the TNC, and to evaluate patient variables that may have an effect on this association. In this multicenter, cross-sectional study, 2175 patients were examined and the mean number of arm nevi in relation to TNC was calculated. A mean value of fewer than 10 arm nevi was found in patients with TNC lower than 51 and a mean value of greater than 19 arm nevi was scored in patients with TNC greater than 50. These values remained unchanged after adjustment for various patient variables. In relation to TNC greater than 50, the presence of 20 or more arm nevi had specificity and negative predictive values of 95.2 and 89.6%, respectively. The sensitivity was 65.5% in patients younger than 50 years of age and 37.5% in the older age group. The number of arm nevi was significantly higher in individuals with a history of melanoma and in those with a melanoma detected during the study period. The presence of 20 or more nevi on the arms is an independent predictor of a high TNC and risk of melanoma. This sign thus represents a simple and rapid screening tool for either the primary care physician or the dermatologist to help identify high-risk patients.


Subject(s)
Arm/pathology , Melanoma/etiology , Nevus, Pigmented/complications , Skin Neoplasms/complications , Cohort Studies , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Male , Melanoma/pathology , Middle Aged , Neoplasm Staging , Nevus, Pigmented/pathology , Prognosis , Risk Factors , Skin Neoplasms/pathology
6.
Dermatol Clin ; 31(4): 549-64, vii-viii, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24075544

ABSTRACT

As the population continues to age, clinicians and dermatologists are increasingly faced with geriatric patients presenting with a range of dermatologic manifestations, including benign and malignant skin tumors. Knowledge of epidemiologic and morphologic features, including dermoscopy of common and benign melanocytic and nonmelanocytic skin tumors, provides the basis for a better understanding and management of problematic skin tumors in this age group. This article provides an overview of common and problematic skin lesions in elderly patients and addresses epidemiologic, clinical, and dermoscopic clues that aid the differential diagnosis and management of challenging skin lesions.


Subject(s)
Carcinoma, Squamous Cell/diagnosis , Facial Dermatoses/diagnosis , Melanoma/diagnosis , Nevus, Pigmented/diagnosis , Skin Neoplasms/diagnosis , Aged , Dermoscopy , Diagnosis, Differential , Female , Humans , Male , Middle Aged
8.
Stem Cells Dev ; 21(17): 3091-103, 2012 Nov 20.
Article in English | MEDLINE | ID: mdl-22512762

ABSTRACT

The specific molecular determinants that govern progenitor expansion and final compartment size in the myogenic lineage, either during gestation or during regenerative myogenesis, remain largely obscure. Recently, we retrieved d-asb11 from a zebrafish screen designed to identify gene products that are downregulated during embryogenesis upon terminal differentiation and identified it as a potential regulator of compartment size in the ectodermal lineage. A role in mesodermal derivatives remained, however, unexplored. Here we report pan-vertebrate expression of Asb11 in muscle compartments, where it highly specifically localizes to the Pax7(+) muscle satellite cell compartment. Forced expression of d-asb11 impaired terminal differentiation and caused enhanced proliferation in the myogenic progenitor compartment both in in vivo and in vitro model systems. Conversely, introduction of a germline hypomorphic mutation in the zebrafish d-asb11 gene produced premature differentiation of the muscle progenitors and delayed regenerative responses in adult injured muscle. Thus, the expression of d-asb11 is necessary for muscle progenitor expansion, whereas its downregulation marks the onset of terminal differentiation. Hence, we provide evidence that d-asb11 is a principal regulator of embryonic as well as adult regenerative myogenesis.


Subject(s)
Gene Expression Regulation, Developmental , Muscle Development , Regeneration , Suppressor of Cytokine Signaling Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/metabolism , Alleles , Animals , Blastomeres/cytology , Blastomeres/metabolism , Cell Count , Cell Differentiation , Cell Proliferation , Cells, Cultured , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/metabolism , Germ-Line Mutation , Immunohistochemistry , Mice , Models, Animal , Muscle, Skeletal/cytology , Muscle, Skeletal/injuries , Muscle, Skeletal/metabolism , PAX7 Transcription Factor/genetics , PAX7 Transcription Factor/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Satellite Cells, Skeletal Muscle/cytology , Satellite Cells, Skeletal Muscle/metabolism , Suppressor of Cytokine Signaling Proteins/genetics , Transfection , Zebrafish/embryology , Zebrafish/genetics , Zebrafish Proteins/genetics
10.
Dev Biol ; 355(2): 286-301, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21565180

ABSTRACT

Nucleostemin (NS), a member of a family of nucleolar GTP-binding proteins, is highly expressed in proliferating cells such as stem and cancer cells and is involved in the control of cell cycle progression. Both depletion and overexpression of NS result in stabilization of the tumor suppressor p53 protein in vitro. Although it has been previously suggested that NS has p53-independent functions, these to date remain unknown. Here, we report two zebrafish mutants recovered from forward and reverse genetic screens that carry loss of function mutations in two members of this nucleolar protein family, Guanine nucleotide binding-protein-like 2 (Gnl2) and Gnl3/NS. We demonstrate that these proteins are required for correct timing of cell cycle exit and subsequent neural differentiation in the brain and retina. Concomitantly, we observe aberrant expression of the cell cycle regulators cyclinD1 and p57kip2. Our models demonstrate that the loss of Gnl2 or NS induces p53 stabilization and p53-mediated apoptosis. However, the retinal differentiation defects are independent of p53 activation. Furthermore, this work demonstrates that Gnl2 and NS have both non-cell autonomously and cell-autonomous function in correct timing of cell cycle exit and neural differentiation. Finally, the data suggest that Gnl2 and NS affect cell cycle exit of neural progenitors by regulating the expression of cell cycle regulators independently of p53.


Subject(s)
Cell Cycle/physiology , GTP-Binding Proteins/metabolism , Gene Expression Regulation/physiology , Neurogenesis/physiology , Nuclear Proteins/metabolism , Retina/embryology , Zebrafish/embryology , Animals , Blotting, Western , Bromodeoxyuridine , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p57/metabolism , GTP-Binding Proteins/genetics , Immunohistochemistry , In Situ Hybridization , Microarray Analysis , Microscopy, Fluorescence , Mutation/genetics , Nuclear Proteins/genetics , Oligonucleotides/genetics , Plasmids/genetics
12.
Hum Mol Genet ; 20(8): 1574-84, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21273289

ABSTRACT

Pontocerebellar hypoplasia (PCH) represents a group (PCH1-6) of neurodegenerative autosomal recessive disorders characterized by hypoplasia and/or atrophy of the cerebellum, hypoplasia of the ventral pons, progressive microcephaly and variable neocortical atrophy. The majority of PCH2 and PCH4 cases are caused by mutations in the TSEN54 gene; one of the four subunits comprising the tRNA-splicing endonuclease (TSEN) complex. We hypothesized that TSEN54 mutations act through a loss of function mechanism. At 8 weeks of gestation, human TSEN54 is expressed ubiquitously in the brain, yet strong expression is seen within the telencephalon and metencephalon. Comparable expression patterns for tsen54 are observed in zebrafish embryos. Morpholino (MO) knockdown of tsen54 in zebrafish embryos results in loss of structural definition in the brain. This phenotype was partially rescued by co-injecting the MO with human TSEN54 mRNA. A developmental patterning defect was not associated with tsen54 knockdown; however, an increase in cell death within the brain was observed, thus bearing resemblance to PCH pathophysiology. Additionally, N-methyl-N-nitrosourea mutant zebrafish homozygous for a tsen54 premature stop-codon mutation die within 9 days post-fertilization. To determine whether a common disease pathway exists between TSEN54 and other PCH-related genes, we also monitored the effects of mitochondrial arginyl-tRNA synthetase (rars2; PCH1 and PCH6) knockdown in zebrafish. Comparable brain phenotypes were observed following the inhibition of both genes. These data strongly support the hypothesis that TSEN54 mutations cause PCH through a loss of function mechanism. Also we suggest that a common disease pathway may exist between TSEN54- and RARS2-related PCH, which may involve a tRNA processing-related mechanism.


Subject(s)
Endoribonucleases/genetics , Gene Silencing , Olivopontocerebellar Atrophies/genetics , Zebrafish Proteins/genetics , Zebrafish/embryology , Zebrafish/growth & development , Animals , Arginine-tRNA Ligase/genetics , Base Sequence , Body Patterning/genetics , Brain/abnormalities , Brain/embryology , Brain/metabolism , Cell Death/genetics , Endoribonucleases/metabolism , Fibroblast Growth Factors/genetics , Humans , In Situ Hybridization , Larva/growth & development , Otx Transcription Factors/genetics , Phenotype , Transcription, Genetic , Zebrafish/genetics , Zebrafish Proteins/metabolism
13.
PLoS One ; 5(11): e14023, 2010 Nov 19.
Article in English | MEDLINE | ID: mdl-21124961

ABSTRACT

ECS (Elongin BC-Cul2/Cul5-SOCS-box protein) ubiquitin ligases recruit substrates to E2 ubiquitin-conjugating enzymes through a SOCS-box protein substrate receptor, an Elongin BC adaptor and a cullin (Cul2 or Cul5) scaffold which interacts with the RING protein. In vitro studies have shown that the conserved amino acid sequence of the cullin box in SOCS-box proteins is required for complex formation and function. However, the in vivo importance of cullin boxes has not been addressed. To explore the biological functions of the cullin box domain of ankyrin repeat and SOCS-box containing protein 11 (d-Asb11), a key mediator of canonical Delta-Notch signaling, we isolated a zebrafish mutant lacking the Cul5 box (Asb11(Cul)). We found that homozygous zebrafish mutants for this allele were defective in Notch signaling as indicated by the impaired expression of Notch target genes. Importantly, asb11(Cul) fish were not capable to degrade the Notch ligand DeltaA during embryogenesis, a process essential for the initiation of Notch signaling during neurogenesis. Accordingly, proper cell fate specification within the neurogenic regions of the zebrafish embryo was impaired. In addition, Asb11(Cul) mRNA was defective in the ability to transactivate a her4::gfp reporter DNA when injected in embryos. Thus, our study reporting the generation and the characterization of a metazoan organism mutant in the conserved cullin binding domain of the SOCS-box demonstrates a hitherto unrecognized importance of the SOCS-box domain for the function of this class of cullin-RING ubiquitin ligases and establishes that the d-Asb11 cullin box is required for both canonical Notch signaling and proper neurogenesis.


Subject(s)
Neurons/metabolism , Receptors, Notch/metabolism , Signal Transduction , Suppressor of Cytokine Signaling Proteins/physiology , Zebrafish Proteins/physiology , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Binding Sites/genetics , Cell Proliferation , Cullin Proteins/metabolism , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/embryology , Embryo, Nonmammalian/metabolism , Gene Expression Regulation, Developmental , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Immunoblotting , In Situ Hybridization , Intracellular Signaling Peptides and Proteins , Membrane Proteins/genetics , Membrane Proteins/metabolism , Microscopy, Confocal , Mutation , Neurons/cytology , Receptors, Notch/genetics , Reverse Transcriptase Polymerase Chain Reaction , Suppressor of Cytokine Signaling Proteins/genetics , Suppressor of Cytokine Signaling Proteins/metabolism , Zebrafish/embryology , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
15.
Dermatology ; 221(1): 51-4, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20375489

ABSTRACT

BACKGROUND: The clinical variability of cutaneous sarcoidosis (CS) often makes its correct diagnosis challenging. Although traditionally employed for the diagnosis of skin tumors, during the past years dermoscopy also gained increasing interest as an aid in the clinical diagnosis of inflammatory and infectious skin manifestations in general dermatology. OBJECTIVE: Our purpose was to evaluate the usefulness of dermoscopy in the differential diagnosis of CS. METHODS: This was a retrospective analysis of 7 clinical and dermoscopic images of CS that were collected at dermatology clinics in France and Italy between 2005 and 2009. RESULTS: Retrospective dermoscopic evaluation revealed small grouped, translucent orange globular structures associated with linear vessels of variable diameter in all 7 cases. In 5 cases, additional central scar-like areas were seen. CONCLUSION: Lesions showing dermoscopically translucent yellow to orange globular-like or structureless areas associated with linear vessels should raise the suspicion of a granulomatous skin disease, including CS.


Subject(s)
Dermoscopy , Sarcoidosis/diagnosis , Skin Diseases/diagnosis , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective Studies
16.
PLoS One ; 4(6): e5880, 2009 Jun 11.
Article in English | MEDLINE | ID: mdl-19517013

ABSTRACT

Deviation from proper muscle development or homeostasis results in various myopathic conditions. Employing genetic as well as chemical intervention, we provide evidence that a tight regulation of Wnt/beta-catenin signaling is essential for muscle fiber growth and maintenance. In zebrafish embryos, gain-of-Wnt/beta-catenin function results in unscheduled muscle progenitor proliferation, leading to slow and fast muscle hypertrophy accompanied by fast muscle degeneration. The effects of Wnt/beta-catenin signaling on fast muscle hypertrophy were rescued by misexpression of Myostatin or p21(CIP/WAF), establishing an in vivo regulation of myofibrillogenesis by Wnt/beta-catenin signaling and Myostatin. Epistatic analyses suggest a possible genetic interaction between Wnt/beta-catenin and Myostatin in regulation of slow and fast twitch muscle myofibrillogenesis.


Subject(s)
Gene Expression Regulation, Developmental , Gene Expression Regulation , Muscle Fibers, Fast-Twitch/pathology , Muscle Fibers, Slow-Twitch/pathology , Muscles/embryology , Myostatin/metabolism , Wnt Proteins/metabolism , Zebrafish/embryology , beta Catenin/metabolism , Animals , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Epistasis, Genetic , Hypertrophy , Signal Transduction
17.
Dev Biol ; 331(2): 101-12, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19397905

ABSTRACT

The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway, which is vital for induction and patterning of the early vertebrate brain. However, its role in later brain development is less clear. Here, we examined the mechanisms underlying effects of an Apc1 zygotic-effect mutation on late brain development in zebrafish. Apc1 is required for maintenance of established brain subdivisions and control of local organizers such as the isthmic organizer (IsO). Caudal expansion of Fgf8 from IsO into the cerebellum is accompanied by hyperproliferation and abnormal cerebellar morphogenesis. Loss of apc1 results in reduced proliferation and apoptosis in the dorsal midbrain. Mosaic analysis shows that Apc is required cell-autonomously for maintenance of dorsal midbrain cell fate. The tectal phenotype occurs independently of Fgf8-mediated IsO function and is predominantly caused by stabilization of beta-catenin and subsequent hyperactivation of Wnt/beta-catenin signalling, which is mainly mediated through LEF1 activity. Chemical activation of the Wnt/beta-catenin in wild-type embryos during late brain maintenance stages phenocopies the IsO and tectal phenotypes of the apc mutants. These data demonstrate that Apc1-mediated restriction of Wnt/beta-catenin signalling is required for maintenance of local organizers and tectal integrity.


Subject(s)
Brain/embryology , Organizers, Embryonic/physiology , Tumor Suppressor Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/embryology , Animals , Body Patterning/physiology , Brain/abnormalities , Brain/metabolism , Embryo, Nonmammalian/metabolism , Fibroblast Growth Factors/metabolism , Mesencephalon/abnormalities , Mesencephalon/embryology , Mesencephalon/metabolism , Mutation , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics , Wnt Proteins/physiology , Zebrafish/metabolism , Zebrafish Proteins/genetics , beta Catenin/genetics , beta Catenin/metabolism
18.
Zebrafish ; 6(1): 41-7, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19292673

ABSTRACT

The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway. We examined the effects of an Apc1 loss-of-function mutation on retino-tectal axon pathfinding in zebrafish. In apc mutants, the retina is disorganized and optic nerves portray pathfinding defects at the optic chiasm and do not project properly to the tectum. Wild-type cells, transplanted into mutant retinae, acquire retinal ganglion cell fate and project axons that cross at the mispositioned optic chiasm and extend to the contralateral tectum, suggesting a function of apc1 in axon pathfinding. These defects are caused mainly by stabilization of beta-catenin. These data demonstrate that Apc1 function is required for correct patterning of the retina and proper retinal ganglion axon projections.


Subject(s)
Retina/embryology , Signal Transduction , Tectum Mesencephali/embryology , Tumor Suppressor Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/embryology , beta Catenin/metabolism , Animals , Axons , Embryo, Nonmammalian , Mutation , Optic Nerve , Retina/cytology , Retina/metabolism , Retinal Ganglion Cells/metabolism , Tectum Mesencephali/cytology , Tectum Mesencephali/metabolism , Tumor Suppressor Proteins/genetics , Zebrafish Proteins/genetics
19.
Ageing Res Rev ; 8(2): 71-82, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19101658

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by amyloid-beta (Abeta) plaques and hyperphosphorylated tau accumulation. AD occurs sporadically (SAD), or is caused by hereditary missense mutations in the amyloid precursor protein (APP) or presenilin-1 and -2 (PSEN1 and PSEN2) genes, leading to early-onset familial AD (FAD). Accumulating evidence points towards a role for altered Wnt/beta-catenin-dependent signaling in the etiology of both forms of AD. Presenilins are involved in modulating beta-catenin stability; therefore FAD-linked PSEN-mediated effects can deregulate the Wnt pathway. Genetic variations in the low-density lipoprotein receptor-related protein 6 and apolipoprotein E in AD have been associated with reduced Wnt signaling. In addition, tau phosphorylation is mediated by glycogen synthase kinase-3 (GSK-3), a key antagonist of the Wnt pathway. In this review, we discuss Wnt/beta-catenin signaling in both SAD and FAD, and recapitulate which of its aberrant functions may be critical for (F)AD pathogenesis. We discuss the intriguing possibility that Abeta toxicity may downregulate the Wnt/beta-catenin pathway, thereby upregulating GSK-3 and consequent tau hyperphosphorylation, linking Abeta and tangle pathology. The currently available evidence implies that disruption of tightly regulated Wnt signaling may constitute a key pathological event in AD. In this context, drug targets aimed at rescuing Wnt signaling may prove to be a constructive therapeutic strategy for AD.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Signal Transduction , Wnt Proteins/metabolism , beta Catenin/metabolism , Aging/metabolism , Alzheimer Disease/drug therapy , Down-Regulation , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/metabolism , Humans , Phosphorylation , Up-Regulation , tau Proteins/metabolism
20.
Nat Cell Biol ; 10(10): 1190-8, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18776899

ABSTRACT

In canonical Delta-Notch signalling, expression of Delta activates Notch in neighbouring cells, leading to downregulation of Delta in these cells. This process of lateral inhibition results in selection of either Delta-signalling cells or Notch-signalling cells. Here we show that d-Asb11 is an important mediator of this lateral inhibition. In zebrafish embryos, morpholino oligonucleotide (MO)-mediated knockdown of d-Asb11 caused repression of specific Delta-Notch elements and their transcriptional targets, whereas these were induced when d-Asb11 was misexpressed. d-Asb11 also activated legitimate Notch reporters cell-non-autonomously in vitro and in vivo when co-expressed with a Notch reporter. However, it repressed Notch reporters when expressed in Delta-expressing cells. Consistent with these results, d-Asb11 was able to specifically ubiquitylate and degrade DeltaA both in vitro and in vivo. We conclude that d-Asb11 is a component in the regulation of Delta-Notch signalling, important in fine-tuning the lateral inhibition gradients between DeltaA and Notch through a cell non-autonomous mechanism.


Subject(s)
Membrane Proteins/metabolism , Receptors, Notch/metabolism , Signal Transduction , Suppressor of Cytokine Signaling Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/metabolism , Animals , Embryo, Nonmammalian/metabolism , Feedback, Physiological , Genes, Reporter , HeLa Cells , Humans , Intracellular Signaling Peptides and Proteins , Protein Binding , Transcriptional Activation/genetics , Zebrafish/embryology
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