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10.
JAMA Dermatol ; 158(4): 447-448, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35171240
13.
J Am Acad Dermatol ; 77(4): 728-734, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28666611

ABSTRACT

BACKGROUND: Xanthelasma palpebrarum is the most common cutaneous xanthoma characterized by soft, yellow papules or plaques that arise on the periorbital skin. As these lesions can be cosmetically disfiguring, many patients seek medical help to remove these lesions. OBJECTIVE: To determine the effectiveness and minimum number of treatment sessions with a 1064-nm, Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser for the treatment of xanthelasma. METHODS: A retrospective review of patients with xanthelasma consecutively treated with Q-switched Nd:YAG laser was conducted. Forty-six patients with 103 lesions were identified from January 2012 through August 2015. Photographs taken of patients immediately before treatment and 4-8 weeks after treatment were independently evaluated by 2 dermatologists. RESULTS: After a single treatment session, 93.2% of lesions had some degree of clearance. All lesions had excellent-to-complete clearance after at least 4 treatment sessions. Patients usually required 4 treatment sessions for optimal results. LIMITATIONS: This was a retrospective study. Treatment parameters varied, follow-up periods were not uniform, and response was not assessed with a validated scale. CONCLUSION: The Q-switched Nd:YAG laser is effective and well tolerated in the treatment of xanthelasma in our study population.


Subject(s)
Eyelid Diseases/radiotherapy , Lasers, Solid-State/therapeutic use , Low-Level Light Therapy/methods , Xanthomatosis/radiotherapy , Adult , Aged , Female , Humans , Laser Therapy/adverse effects , Laser Therapy/methods , Lasers, Solid-State/adverse effects , Low-Level Light Therapy/adverse effects , Male , Middle Aged , Photography , Retrospective Studies
14.
PLoS Biol ; 15(3): e2001192, 2017 03.
Article in English | MEDLINE | ID: mdl-28267757

ABSTRACT

Student creation of educational materials has the capacity both to enhance learning and to decrease costs. Three successive honors-style classes of undergraduate students in a cancer genetics class worked with a new software system, CuboCube, to create an e-textbook. CuboCube is an open-source learning materials creation system designed to facilitate e-textbook development, with an ultimate goal of improving the social learning experience for students. Equipped with crowdsourcing capabilities, CuboCube provides intuitive tools for nontechnical and technical authors alike to create content together in a structured manner. The process of e-textbook development revealed both strengths and challenges of the approach, which can inform future efforts. Both the CuboCube platform and the Cancer Genetics E-textbook are freely available to the community.


Subject(s)
Access to Information , Neoplasms/genetics , Social Learning , Software , Students , Textbooks as Topic
16.
Dermatitis ; 25(2): 77-82, 2014.
Article in English | MEDLINE | ID: mdl-24603520

ABSTRACT

BACKGROUND: Preservatives are indispensable agents used to prevent bacterial and fungal contamination of cosmetics, personal care products, domestic preparations, and industrial products. OBJECTIVE: We evaluated patch-test data at the National Skin Centre, Singapore, from 2006 to 2011 to identify the trends in preservative contact allergies. METHODS: All patients with suspected contact dermatitis were patch tested to 4 preservatives within the modified European standard series. Patients were also tested with 7 preservatives from our special series if clinically indicated. RESULTS: Three thousand one hundred seventy-seven patients were tested to preservatives in the standard series. Sensitization frequencies were all greater than 1%: parabens (2.58%), methylchloroisothiazolinone/methylisothiazolinone (1.75%), quaternium 15 (1.43%), and methyldibromoglutaronitrile (1.2%). There was no change in trends in sensitization frequencies from 2006 to 2011, with no increase in sensitization frequency to methylchloroisothiazolinone/methylisothiazolinone. The sensitization frequencies for methyldibromoglutaronitrile/phenoxyethanol and diazolidinylurea were 2.03% and 1.37%, respectively, and remained less than 1% for bronopol, imidazolidinyl urea, and 2-phenoxyethanol. A rate of 0% was seen for 1,3-dimethylol-5,5-dimethyl hydantoin and formaldehyde; 9.4% of positive patch-test results became positive only at day 7. CONCLUSIONS: Preservatives are common causes of allergic contact dermatitis. This should be considered when introducing new preservatives into the market. Day 7 readings are important to detect late reactions.


Subject(s)
Dermatitis, Allergic Contact/epidemiology , Dermatitis, Allergic Contact/etiology , Patch Tests , Preservatives, Pharmaceutical/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Cosmetics/adverse effects , Dermatitis, Allergic Contact/diagnosis , Ethylene Glycols/adverse effects , Facial Dermatoses/epidemiology , Female , Formaldehyde/adverse effects , Hand Dermatoses/epidemiology , Humans , Hydantoins/adverse effects , Male , Methenamine/adverse effects , Methenamine/analogs & derivatives , Middle Aged , Neck , Nitriles/adverse effects , Parabens/adverse effects , Prevalence , Propylene Glycols/adverse effects , Retrospective Studies , Singapore/epidemiology , Thiazoles/adverse effects , Time Factors , Urea/adverse effects , Urea/analogs & derivatives , Young Adult
17.
Lancet Oncol ; 15(3): 323-32, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24508103

ABSTRACT

BACKGROUND: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. METHODS: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. FINDINGS: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. INTERPRETATION: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. FUNDING: F Hoffmann-La Roche-Genentech.


Subject(s)
Indoles/therapeutic use , Melanoma/drug therapy , Mutation , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Sulfonamides/therapeutic use , Adult , Aged , Dacarbazine/therapeutic use , Disease-Free Survival , Female , Follow-Up Studies , Humans , Indoles/adverse effects , Male , Melanoma/genetics , Melanoma/mortality , Middle Aged , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/adverse effects , Vemurafenib
18.
Mol Cell Biol ; 34(3): 348-61, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24248601

ABSTRACT

The integrin-activated Src-focal adhesion kinase (FAK) kinase complex phosphorylates PTPα at Tyr789, initiating PTPα-mediated signaling that promotes cell migration. Recruitment of the BCAR3-Cas complex by PTPα-phospho-Tyr789 at focal adhesions is one mechanism of PTPα signaling. The adaptor protein Grb2 is also recruited by PTPα-phospho-Tyr789, although the role of the PTPα-Grb2 complex in integrin signaling is unknown. We show that silencing Grb2 expression in fibroblasts abolishes PTPα-Tyr789 phosphorylation and that this is due to two unexpected actions of Grb2. First, Grb2 promotes integrin-induced autophosphorylation of FAK-Tyr397. This is impaired in Grb2-depleted cells and prohibits FAK activation and formation of the Src-FAK complex. Grb2-depleted cells contain less paxillin, and paxillin overexpression rescues FAK-Tyr397 phosphorylation, suggesting that the FAK-activating action of Grb2 involves paxillin. A second distinct role for Grb2 in PTPα-Tyr789 phosphorylation involves Grb2-mediated coupling of Src-FAK and PTPα. This requires two phosphosites, FAK-Tyr925 and PTPα-Tyr789, for Grb2-Src homology 2 (SH2) binding. We propose that a Grb2 dimer links FAK and PTPα, and this positions active Src-FAK in proximity with other, perhaps integrin-clustered, molecules of PTPα to enable maximal PTPα-Tyr789 phosphorylation. These findings identify Grb2 as a new FAK activator and reveal its essential role in coordinating PTPα tyrosine phosphorylation to enable downstream integrin signaling and migration.


Subject(s)
Fibroblasts/metabolism , Focal Adhesion Kinase 1/metabolism , GRB2 Adaptor Protein/metabolism , Receptor-Like Protein Tyrosine Phosphatases, Class 4/metabolism , src Homology Domains , Animals , Cells, Cultured , Embryo, Mammalian/cytology , Fibroblasts/cytology , Focal Adhesion Kinase 1/genetics , GRB2 Adaptor Protein/genetics , Immunoblotting , Integrins/metabolism , Mice , Mice, Knockout , Paxillin/genetics , Paxillin/metabolism , Phosphorylation , Protein Binding , RNA Interference , Receptor-Like Protein Tyrosine Phosphatases, Class 4/genetics , Signal Transduction , Tyrosine/genetics , Tyrosine/metabolism
19.
Mol Cell Biol ; 32(18): 3776-89, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22801373

ABSTRACT

Integrin-mediated focal adhesions connect the extracellular matrix and cytoskeleton to regulate cell responses, such as migration. Protein tyrosine phosphatase α (PTPα) regulates integrin signaling, focal adhesion formation, and migration, but its roles in these events are incompletely understood. The integrin-proximal action of PTPα activates Src family kinases, and subsequent phosphorylation of PTPα at Tyr789 acts in an unknown manner to promote migration. PTPα-null cells were used in reconstitution assays to distinguish PTPα-Tyr789-dependent signaling events. This showed that PTPα-Tyr789 regulates the localization of PTPα and the scaffolding protein Cas to adhesion sites where Cas interacts with and is phosphorylated by Src to initiate Cas signaling. Linking these events, we identify BCAR3 as a molecular connector of PTPα and Cas, with phospho-Tyr789 PTPα serving as the first defined cellular ligand for the BCAR3 SH2 domain that recruits BCAR3-Cas to adhesions. Our findings reveal a novel role of PTPα in integrin-induced adhesion assembly that enables Src-mediated activation of the pivotal function of Cas in migration.


Subject(s)
Crk-Associated Substrate Protein/metabolism , Focal Adhesions/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Receptor-Like Protein Tyrosine Phosphatases, Class 4/metabolism , Adaptor Proteins, Signal Transducing , Animals , Cell Line , Cell Movement , Cytoskeleton/metabolism , Extracellular Matrix/metabolism , Integrins/metabolism , Mice , Phosphorylation , Signal Transduction , src-Family Kinases/metabolism
20.
N Biotechnol ; 29(6): 682-8, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22391147

ABSTRACT

Oncology drug development is a long and costly process associated with a success rate of 5-10%. The parallel development of companion diagnostic tests that will identify patients most likely to receive benefit has the potential to increase the success rate for oncology drugs and decrease development time and associated costs. Metastatic melanoma is a challenging disease that has been associated with poor survival. Identification of a mutated BRAF kinase gene in many cases of melanoma provided a promising therapeutic target. Here we describe the successful co-development of vemurafenib, a first-in-class selective inhibitor of oncogenic BRAF kinase, and its companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. Key success factors in the development process included early identification of the BRAF V600E biomarker, early development of the diagnostic test, and early and close collaboration between the pharmaceutical and diagnostic development teams. This focused and integrated process resulted in the first personalized medicine for the treatment of metastatic melanoma less than five years after the Investigational New Drug Application, a remarkably short time.


Subject(s)
Molecular Diagnostic Techniques/methods , Molecular Targeted Therapy/methods , Neoplasms/diagnosis , Neoplasms/therapy , Humans , Indoles/pharmacology , Mutant Proteins/antagonists & inhibitors , Mutant Proteins/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Sulfonamides/pharmacology , Vemurafenib
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