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1.
J Lipid Res ; 65(3): 100514, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38309418

RESUMO

Human genetic evidence suggests a protective role of loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) for liver fibrotic diseases. Although there is limited preclinical experimental data on Hsd17b13 antisense oligonucleotide (ASO) or siRNA in a fibrosis model, several ASO and siRNA approaches are being tested clinically as potential therapies for nonalcoholic steatohepatitis (NASH). The aim of this study was to assess the therapeutic potential of Hsd17b13 ASO in a preclinical advanced NASH-like hepatic fibrosis in vivo model. In vitro testing on primary hepatocytes demonstrated that Hsd17b13 ASO exhibited strong efficacy and specificity for knockdown of the Hsd17b13 gene. In choline-deficient, L-amino acid-defined, HFD (CDAHFD)-induced steatotic and fibrotic mice, therapeutic administration of Hsd17b13 ASO resulted in a significant and dose-dependent reduction of hepatic Hsd17b13 gene expression. The CDAHFD group exhibited considerably elevated liver enzyme levels, hepatic steatosis score, hepatic fibrosis, and increased fibrotic and inflammatory gene expression, indicating an advanced NASH-like hepatic fibrosis phenotype. Although Hsd17b13 ASO therapy significantly affected hepatic steatosis, it had no effect on hepatic fibrosis. Our findings demonstrate, for the first time, that Hsd17b13 ASO effectively suppressed Hsd17b13 gene expression both in vitro and in vivo, and had a modulatory effect on hepatic steatosis in mice, but did not affect fibrosis in the CDAHFD mouse model of NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Modelos Animais de Doenças , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/metabolismo
2.
Mol Ther Nucleic Acids ; 29: 625-642, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36090761

RESUMO

Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic-acid (LNA)-modified antisense oligonucleotides (ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3' UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well tolerated and produced a robust, long-lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post injection and corresponded with tau protein reduction in the cerebrospinal fluid (CSF). Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.

3.
Nucleic Acid Ther ; 32(3): 151-162, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35166597

RESUMO

Antisense oligonucleotides are a relatively new therapeutic modality and safety evaluation is still a developing area of research. We have observed that some oligonucleotides can produce acute, nonhybridization dependent, neurobehavioral side effects after intracerebroventricular (ICV) dosing in mice. In this study, we use a combination of in vitro, in vivo, and bioinformatics approaches to identify a sequence design algorithm, which can reduce the number of acutely toxic molecules synthesized and tested in mice. We find a cellular assay measuring spontaneous calcium oscillations in neuronal cells can predict the behavioral side effects after ICV dosing, and may provide a mechanistic explanation for these observations. We identify sequence features that are overrepresented or underrepresented among oligonucleotides causing these reductions in calcium oscillations. A weighted linear combination of the five most informative sequence features predicts the outcome of ICV dosing with >80% accuracy. From this, we develop a bioinformatics tool that allows oligonucleotide designs with acceptable acute neurotoxic potential to be identified, thereby reducing the number of toxic molecules entering drug discovery pipelines. The informative sequence features we identified also suggest areas in which to focus future medicinal chemistry efforts.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Oligonucleotídeos Antissenso , Animais , Encéfalo , Camundongos , Oligonucleotídeos Antissenso/farmacologia
4.
Science ; 373(6560): 1265-1270, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516793

RESUMO

The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food and Drug Administration approvals for therapeutic oligonucleotides, by far most of which contain modified phosphate linkages. These unnatural linkages have desirable biological and physical properties but are often accessed with difficulty using phosphoramidite chemistry. We report a flexible and efficient [P(V)]­based platform that can install a wide variety of phosphate linkages at will into oligonucleotides. This approach uses readily accessible reagents and can install not only stereodefined or racemic thiophosphates but any combination of (S, R or rac)­PS with native phosphodiester (PO2) and phosphorodithioate (PS2) linkages into DNA and other modified nucleotide polymers. This platform easily accesses this diversity under a standardized coupling protocol with sustainably prepared, stable P(V) reagents.


Assuntos
Oligonucleotídeos/síntese química
5.
Bioorg Med Chem Lett ; 31: 127624, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33096162

RESUMO

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP Ki = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (FPO = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP Ki = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat FPO = 17%).


Assuntos
Azepinas/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Indazóis/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Azepinas/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/química , Relação Dose-Resposta a Droga , Humanos , Indazóis/química , Estrutura Molecular , Relação Estrutura-Atividade
6.
J Cutan Pathol ; 46(4): 243-250, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30588645

RESUMO

BACKGROUND: Atypical spiradenoma and spiradenocarcinoma present a diagnostic challenge. We aim to assess the significance of certain histologic features, which may facilitate diagnosis of these tumors. METHODS: A natural language search for cases of "atypical spiradenoma" and "spiradenocarcinoma" diagnosed between 2009 and 2018 was performed. Original slides were retrieved and a subset of cases (n = 5) were stained for Ki-67, p53, carcinoembryonic antigen (CEA), and S100. All cases (n = 7) were assessed for overall architecture, atypical mitotic figures, abnormal cytology, necrosis, ductal proliferation, dilated vessels, and loss of dual cell population. RESULTS: All our cases showed an abrupt transition from benign to malignant morphology, nuclear atypia, atypical mitotic figures, and a monomorphic loss of the dual cell population (7/7; 100%). The majority also had dilated vessels (6/7; 85.7%), and ductal dilation or proliferation (5/7; 71.4%). Fewer cases showed tumor encapsulation (3/7; 43%), massive necrosis (3/7; 43%), and focal cellular necrosis (1/7; 14%). All cases showed a relatively increased Ki-67 proliferation index at the transitional interface (5/5; 100%). Almost all cases stained positively for p53 (4/5; 80%). Malignant areas of tumor or at the transitional interface showed more intense S100 staining (3/5; 60%). All cases were negative for CEA. CONCLUSION: Histologic features that strongly favor atypical spiradenoma or spiradenocarcinoma include abrupt transition to malignant foci, atypical mitotic figures, and monomorphic loss of the dual cell population. Ki-67, p53, and S100 may help delineate areas of atypical or malignant transformation in spiradenomas.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenoma de Glândula Sudorípara/diagnóstico , Adenoma de Glândula Sudorípara/patologia , Neoplasias das Glândulas Sudoríparas/diagnóstico , Neoplasias das Glândulas Sudoríparas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Humanos , Pessoa de Meia-Idade
7.
Science ; 361(6408): 1234-1238, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30072577

RESUMO

Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]-based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.


Assuntos
Nucleotídeos/química , Oligonucleotídeos Fosforotioatos/síntese química , Terapia Genética , Isomerismo , Oligonucleotídeos Fosforotioatos/química , Oligonucleotídeos Fosforotioatos/uso terapêutico , Enxofre/química
8.
Am J Dermatopathol ; 37(7): 563-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26091514

RESUMO

The authors report 2 cases of measles demonstrating novel skin pathology that may be useful in establishing early diagnosis. Syncytial epithelial giant cells, which are characteristic of measles, were found to be present in the dermis, indicating that these cells are not specific to the lymphoid tissue and epithelia of which they are classically attributed to. The cells were not prominent, and required step sectioning to observe. These results were confirmed by electron microscopy, which showed virus capsid particles within the endoplasmic reticulum, secretory vesicles, and cytoplasm of multinucleated cells. One of the cases also demonstrated an unusual mixed infiltrate of eosinophils and fibrin thrombi, which has not been previously described. Both patients in this report recovered with supportive therapy.


Assuntos
Derme/patologia , Células Gigantes/ultraestrutura , Sarampo/patologia , Dermatopatias Virais/patologia , Capsídeo/ultraestrutura , Derme/ultraestrutura , Feminino , Humanos , Masculino , Vírus do Sarampo , Pessoa de Meia-Idade , Adulto Jovem
9.
Genes Cancer ; 5(1-2): 22-30, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24955215

RESUMO

Mirk kinase is a gene upregulated and sometimes amplified in pancreatic cancers and in ovarian cancers, but expressed at very low levels in most normal diploid cells except for skeletal muscle. The muscle cell function of Mirk kinase selected for by cancer cells is unknown. It is now shown that Mirk protein is expressed at low levels and is largely nuclear in cycling skeletal muscle C2C12 myoblasts, but is translocated to the cytoplasm and upregulated when myoblasts initiate differentiation, as shown by immunofluorescence staining and by cell fractionation. Either Mirk depletion or Mirk kinase inhibition increased ROS levels in cycling C2C12 myoblasts. However, Mirk protein is localized in the cytoplasm of mature muscle fibers, specifically in the fast twitch fibers of human skeletal muscle where toxic ROS levels are generated by muscle contraction. C2C12 myoblasts at high density in differentiation media fuse to form differentiated postmitotic myotubes that can contract. A Mirk kinase inhibitor induced a dose-dependent increase in ROS in this model for fast twitch fibers of human skeletal muscle. Efficient Mirk depletion in SU86.86 pancreatic cancer cells by an inducible shRNA decreased expression of eight antioxidant genes. Thus both cancer cells and differentiated myotubes utilize Mirk kinase to relieve oxidative stress.

10.
Dermatol Online J ; 19(7): 18958, 2013 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-24010504

RESUMO

Acquired Perforating Dermatosis (APD) is a perforating disease characterized by transepidermal elimination of dermal material [1,2]. This disease usually develops in adulthood. APD has been reported to occur in association with various diseases, but is most commonly associated with dialysis-dependent chronic renal failure (CRF) or diabetes mellitus (DM) [1,2,3,4]. Morton et al found that APD occurs in up to 10% of patients undergoing hemodialysis [5]. Additionally, Saray et al found that sixteen of twenty-two cases with APD were associated with CRF [3].


Assuntos
Dermoscopia , Foliculite/patologia , Hiperpigmentação/patologia , Ceratose/patologia , Idoso , Feminino , Foliculite/complicações , Foliculite/tratamento farmacológico , Humanos , Hiperpigmentação/complicações , Hiperpigmentação/tratamento farmacológico , Ceratose/complicações , Ceratose/tratamento farmacológico , Prurido/etiologia
11.
Bioorg Med Chem Lett ; 23(11): 3157-61, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23632269

RESUMO

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow.


Assuntos
Amidas/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indazóis/química , Quinolonas/química , Administração Intranasal , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Células CACO-2 , Callithrix , Vasos Coronários/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Face/irrigação sanguínea , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Coelhos , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia
12.
Int J Dermatol ; 52(2): 172-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22417052

RESUMO

BACKGROUND: While serological studies are the primary tool used to confirm the diagnosis of secondary syphilis, skin biopsies are often performed to control for potential false positives and negatives. Immunohistochemistry using anti-T. pallidum specific antibodies has proven to have a very high sensitivity and specificity for identification of spirochetes in biopsy specimens, but can occasionally fail to identify organisms in clinically and serologically confirmed cases. METHODS: We report two cases of apparently negative biopsy specimens in which rare organisms were subsequently identified by detailed study of multiple additional sections. RESULTS: Our experience suggests that the sensitivity of immunohistochemistry for syphilitic spirochetes may be improved by repeat immunostaining.


Assuntos
Imuno-Histoquímica/normas , Sorodiagnóstico da Sífilis/normas , Sífilis/diagnóstico , Treponema pallidum/isolamento & purificação , Adulto , Anticorpos Antibacterianos/imunologia , Biópsia , Reações Falso-Negativas , Humanos , Imuno-Histoquímica/métodos , Masculino , Sensibilidade e Especificidade , Sífilis/patologia , Sorodiagnóstico da Sífilis/métodos , Treponema pallidum/imunologia
14.
J Clin Aesthet Dermatol ; 5(4): 25-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22708004

RESUMO

OBJECTIVE: To determine the prognostic significance of follicular extension in actinic keratosis. DESIGN: Retrospective, case-controlled study. SETTING: Mount Sinai Dermatopathology Services. PATIENTS/PARTICIPANTS: Out of a randomly selected pool of 1,000 biopsies, 104 cases of actinic keratosis with follicular extension and 104 cases of actinic keratosis without follicular extension were chosen for the study (56.7% male; mean [SD] age, 67.5 [11.8] years; age range, 28-93). MAIN OUTCOME MEASURES: Presence of follicular extension and location of the actinic keratosis. Age and gender of the patient. Number of previously diagnosed squamous cell carcinomas, basal cell carcinomas, and melanomas per patient. RESULTS: Patients with follicular extension of actinic keratosis were 1.8 times more likely to have a previous history of invasive carcinoma than patients without follicular extension. Patients with follicular extension were 11 times more likely to have a previous history of invasive melanoma than patients with actinic keratoses without follicular extension. Patients with follicular extension were more likely to be male, had an older average age, and more often presented with lesions on their leg when compared to patients with actinic keratoses lacking follicular extension. CONCLUSION: Patients presenting with actinic keratoses with follicular extension were more likely to have increased risk factors for skin cancer. These findings have implications for identifying patient factors predictive of progression of actinic keratosis to invasive carcinoma, providing potentially valuable patient screening guidelines.

15.
J Clin Aesthet Dermatol ; 5(4): 40-3, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22708008

RESUMO

A 46-year-old man presented with a two-week history of fatigue, fevers, and multiple nonhealing ulcers on his abdomen and back. He also had several dermatomal plaques clinically consistent with multifocal herpes zoster. Biopsy revealed large atypical myeloid cells dissecting through the dermis as well as marked papillary edema reminiscent of Sweet's syndrome. Blood work revealed an elevated white count (35-10(9) cells/L) with 11 percent blasts. Fluorescence in situ hybridization demonstrated a t(15;17) rearrangement diagnostic of M3 acute nonlymphocytic leukemia/acute promyelocytic leukemia. Chemotherapy was initiated, but the patient became septic and expired within two weeks. Acute promyelocytic leukemia cutis is exceedingly rare with only 24 previously reported cases, all of which occurred following treatment with all-trans retinoic acid, which is thought to induce the dermal tropism. The authors believe this is the first reported case of acute promyelocytic leukemia initially presenting with cutaneous involvement. The case is also notable for the Sweet's-like features of the infiltrate.

16.
J Cutan Pathol ; 39(6): 644-50, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22616604

RESUMO

Histiocytic/dendritic cell sarcomas are rare tumors, a few of which have been reported in association with B-cell lymphoma/leukemia. Isolated reports have documented identical immunoglobulin gene rearrangements suggesting a common clonal origin for both the sarcoma and the B-cell neoplasm from individual patients. We report a case of a 75-year-old male with hairy cell leukemia who subsequently developed Langerhans cell sarcoma 1 year after his primary diagnosis of leukemia. The bone marrow biopsy containing hairy cell leukemia and skin biopsies of Langerhans cell sarcoma were evaluated by routine histology, immunohistochemistry, flow cytometric immunophenotyping and PCR-based gene rearrangement studies of the immunoglobulin heavy chain and kappa genes. The hairy cell leukemia showed characteristic morphologic, immunohistochemical and flow cytometric features. The Langerhans cell sarcoma showed pleomorphic cytology, a high mitotic rate and characteristic immunohistochemical staining for Langerin, S100 and CD1a. There was no evidence of B-cell differentiation or a background B-cell infiltrate based on the absence of immunoreactivity with antibodies to multiple B-cell markers. Identical immunoglobulin gene rearrangements were identified in both the hairy cell leukemia and Langerhans cell sarcoma specimens. Despite the phenotypic dissimilarity of the two neoplasms, identical immunoglobulin gene rearrangements indicate a common origin.


Assuntos
Linfócitos B , Sarcoma de Células de Langerhans , Leucemia de Células Pilosas , Segunda Neoplasia Primária , Neoplasias Cutâneas , Hipermutação Somática de Imunoglobulina/genética , Idoso , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Medula Óssea , Diferenciação Celular/genética , Humanos , Imuno-Histoquímica , Sarcoma de Células de Langerhans/genética , Sarcoma de Células de Langerhans/metabolismo , Sarcoma de Células de Langerhans/patologia , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/metabolismo , Leucemia de Células Pilosas/patologia , Masculino , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Tempo
17.
ACS Med Chem Lett ; 3(4): 337-41, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900474

RESUMO

Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification of potent and orally bioavailable compounds has been challenging. Herein, we describe the conceptualization, synthesis, and preclinical characterization of a potent, orally active CGRP receptor antagonist 5 (BMS-846372). Compound 5 has good oral bioavailability in rat, dog, and cynomolgus monkeys and overall attractive preclinical properties including strong (>50% inhibition) exposure-dependent in vivo efficacy in a marmoset migraine model.

18.
Pediatr Dermatol ; 29(2): 220-2, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22044342

RESUMO

Melanonychia is a black, tan, or brown streak within the nail plate subsequent to activation of melanocytes in the nail matrix. We present a case of a Haitian girl who presented with transverse melanonychia involving all 10 fingernails in the setting of hyperthyroidism and acute liver injury. Melanonychia has been described only one time in the literature in the setting of hyperthyroidism though this patient also underwent radium treatment which could have led to nail changes.


Assuntos
Doença de Graves/diagnóstico , Hepatite/diagnóstico , Doenças da Unha/diagnóstico , Transtornos da Pigmentação/diagnóstico , Adolescente , Biópsia , Feminino , Doença de Graves/complicações , Doença de Graves/cirurgia , Hepatite/complicações , Humanos , Doenças da Unha/etiologia , Transtornos da Pigmentação/etiologia , Tireoidectomia
19.
J Clin Aesthet Dermatol ; 4(12): 37-42, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22191007

RESUMO

Multiple cutaneous and uterine leiomyomatosis, also known as Reed's syndrome, is an autosomal dominant genetic condition. Affected individuals have an increased predisposition to develop benign smooth muscle tumors (leiomyomas) in the skin and uterus. Affected females frequently develop uterine leiomyomas (fibroids) that are larger and more numerous and emerge earlier than those in the general population. Subsets of these patients are at risk for renal cell cancer and have been determined to have mutations in the fumarate hydratase gene. In individuals or families without renal cell cancer, the syndrome may be referred to as multiple cutaneous leiomyomatosis or multiple cutaneous and uterine leiomyomatosis. The term hereditary leiomyomatosis and renal cell cancer refers to families with an increased prevalence of smooth muscle tumors and renal cell cancer as a result of the fumarate hydratase genetic defect. In this article, the authors introduce a case of a young woman who presented with multiple, intermittently painful, cutaneous leiomyomas and a history of large uterine fibroids previously causing anemia and requiring surgical intervention. Further investigation revealed a family history of mutations in the fumarate hydratase gene. The patient is currently being monitored by the National Institutes of Health.

20.
Int J Dermatol ; 50(12): 1560-3, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22098007

RESUMO

BACKGROUND: Surgical excision of severely dysplastic nevi and thin cutaneous melanomas (<1 mm in depth) remains the most effective treatment to date. However, sometimes a severely dysplastic nevus may be upstaged to a melanoma in situ, or a melanoma in situ may be upgraded to an invasive melanoma once the completely excised specimen is reviewed microscopically. This then requires a re-excision around the entire scar at follow-up as the dermatological surgeon can be perplexed as to where the precise locations of the pigmented lesion and the tissue cones are, thereby generating a longer scar. OBJECTIVE: We want to introduce a simple, cost-effective and easy-to-implement approach that permits the dermatological surgeon to distinguish from a linear scar the site of the original pigmented lesion and the lengths of the tissue cones. Therefore, if a re-excision is necessary, instead of surgical removal around the entire scar, only a focal directed excision of the pigmented lesion is necessary and this will result in a shorter scar; this will be useful for cosmetically sensitive areas on the face. A case is included to illustrate our objective. RESULTS AND DISCUSSION: Using our surgical method on a patient's left cheek pigmented lesion originally diagnosed as melanoma in situ with a subsequent revised diagnosis of invasive melanoma generated a shorter scar and a favorable cosmetic outcome.


Assuntos
Cicatriz/patologia , Conização/métodos , Melanoma/patologia , Melanoma/cirurgia , Nevo Pigmentado/patologia , Nevo Pigmentado/cirurgia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Conização/economia , Análise Custo-Benefício , Humanos , Masculino , Pessoa de Meia-Idade , Reoperação
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