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BACKGROUND: Immunosuppressed (IS) patients, particularly solid organ transplant recipients and those on immunosuppressive therapy, face a higher incidence and recurrence of nonmelanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Mohs micrographic surgery (MMS) is the preferred treatment for high-risk NMSC due to its high cure rate and margin examination capabilities. However, IS patients may experience more complications, such as surgical site infections, and a greater risk of recurrence, making their outcomes a subject of interest. OBJECTIVES: This study aimed to compare IS and immunocompetent (IC) patients undergoing MMS for NMSC in terms of baseline characteristics, intra- and post-surgical complications, and postoperative recurrence rates. METHODS: The study utilized data from the REGESMOHS registry, a 7-year prospective cohort study in Spain. It included 5226 patients, categorizing them into IC (5069) and IS (157) groups. IS patients included solid organ transplant recipients, those on immunosuppressive treatments, individuals with haematological tumours and HIV-positive patients. Patient data, tumour characteristics, surgical details and outcomes were collected and analysed. RESULTS: IS patients demonstrated a higher proportion of SCC, multiple synchronous tumours and tumours invading deeper structures. Complex closures, unfinished MMS and more surgical sections were observed in the IS group. Although intra-operative morbidity was higher among IS patients, this difference became non-significant when adjusted for other variables such as year of surgery, antiplatelet/anticoagulant treatment or type of closure. Importantly, IS patients had a substantially higher recurrence rate (IRR 2.79) compared to IC patients. CONCLUSIONS: This study suggests that IS patients may be at a higher risk of development of AE such as bleeding or tumour necrosis and are at a higher risk of tumour recurrence. Close follow-up and consideration of the specific characteristics of NMSC in IS patients are crucial. Further research with extended follow-up is needed to better understand the long-term outcomes for this patient group.
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BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an invasive skin tumor traditionally associated with very high recurrence rates when treated with conventional surgery (CS). OBJECTIVE: To calculate the minimum margin that would have been required to achieve complete tumor clearance with hypothetical CS. To analyze DFSP characteristics and Mohs micrographic surgery (MMS) effectiveness in treatment of this tumor. MATERIALS AND METHODS: Minimum margin was calculated by measuring the largest distance from the visible edge of the tumor to the edge of the surgical defect. Tumor variables (age, sex, size, time since onset, and location) were correlated with surgical variables (number of stages and minimum margin). RESULTS: We studied 222 cases of DFSP treated with MMS. A mean of 1.47 MMS stages and a mean minimum margin of 1.23 cm were required to achieve tumor clearance. Tumors on the head and neck required significantly more stages and a significantly wider margin. Tumor size was positively correlated with time to diagnosis, age, and number of MMS stages. CONCLUSION: Tumors located on the head and neck have greater subclinical extension. Tumor size was also a predictor of surgical difficulty, but time to diagnosis was not.
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Dermatofibrossarcoma/cirurgia , Neoplasias de Cabeça e Pescoço/cirurgia , Cirurgia de Mohs/métodos , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Cutâneas/cirurgia , Adolescente , Adulto , Dermatofibrossarcoma/diagnóstico , Dermatofibrossarcoma/patologia , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estudos Longitudinais , Masculino , Margens de Excisão , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Small series of ultrasound findings in dermatofibrosarcoma protuberans (DFSP) have been published, but the usefulness of this technique as a preoperative planning tool for tumor resection has not been studied. MATERIALS AND METHODS: We retrospectively reviewed patients with DFSP at our hospital that underwent ultrasound examination. Depth of invasion was evaluated by ultrasound and histopathology. Accuracy of ultrasound for assessing depth of tumor invasion was estimated. RESULTS: Thirty histopathologically confirmed DFSPs were studied. Classic finger-like projections were observed in 73.3% of cases. A posterior hyperechoic area extending deep into the subcutaneous tissue correlated with the honeycomb DFSP pattern and was observed in 53.3% of patients. Concordance between ultrasound and histopathologic depth measurements was excellent. Lateral tumor extension and Doppler activity were not evaluated in our series. CONCLUSION: Ultrasound showed excellent prediction of depth of invasion. Further studies are required to define the usefulness of ultrasound for determining lateral tumor extension.
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Dermatofibrossarcoma , Neoplasias Cutâneas , Dermatofibrossarcoma/diagnóstico por imagem , Humanos , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico por imagem , Tela Subcutânea , UltrassonografiaRESUMO
Sambucus nigra flowers (elderflower) have been widely used in traditional medicine for the relief of early symptoms of common cold. Its chemical composition mainly consists of polyphenolic compounds such as flavonoids, hydroxycinnamic acids, and triterpenes. Although the antioxidant properties of polyphenols are well known, the aim of this study is to assess the antioxidant and protective potentials of Sambucus nigra flowers in the human neuroblastoma (SH-SY5Y) cell line using different in vitro approaches. The antioxidant capacity is first evaluated by the oxygen radical absorbance capacity (ORAC) and the free radical scavenging activity (DPPH) methods. Cell viability is assessed by the crystal violet method; furthermore, the intracellular ROS formation (DCFH-DA method) is determined, together with the effect on the cell antioxidant defenses: reduced glutathione (GSH) and antioxidant enzyme activities (GPx, GR). On the other hand, mTORC1 hyperactivation and autophagy blockage have been associated with an increase in the formation of protein aggregates, this promoting the transference and expansion of neurodegenerative diseases. Then, the ability of Sambucus nigra flowers in the regulation of mTORC1 signaling activity and the reduction in oxidative stress through the activation of autophagy/mitophagy flux is also examined. In this regard, search for different molecules with a potential inhibitory effect on mTORC1 activation could have multiple positive effects either in the molecular pathogenic events and/or in the progression of several diseases including neurodegenerative ones.
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Técnicas de Cultura de Células , Degeneração Neural/tratamento farmacológico , Sambucus nigra/química , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Flores/química , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Degeneração Neural/patologia , Picratos/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Identification schemes are interactive cryptographic protocols typically involving two parties, a prover, who wants to provide evidence of their identity and a verifier, who checks the provided evidence and decides whether or not it comes from the intended prover. Given the growing interest in quantum computation, it is indeed desirable to have explicit designs for achieving user identification through quantum resources. In this paper, we comment on a recent proposal for quantum identity authentication from Zawadzki. We discuss the applicability of the theoretical impossibility results from Lo, Colbeck and Buhrman et al. and formally prove that the protocol must necessarily be insecure. Moreover, to better illustrate our insecurity claim, we present an attack on Zawadzki's protocol and show that by using a simple strategy an adversary may indeed obtain relevant information on the shared identification secret. Specifically, through the use of the principal of conclusive exclusion on quantum measurements, our attack geometrically reduces the key space resulting in the claimed logarithmic security being reduced effectively by a factor of two after only three verification attempts.
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BACKGROUND: The plaque variant of trichoblastoma has been described as a solitary tumor with diffuse infiltration of the lower dermis and hypodermis, with poorly defined borders. Herein, we report a new variant of multiple centrofacial trichoblastoma. OBJECT: To describe clinical and pathological features of a new multiple kind of plaque variant of centrofacial trichoblastoma. METHODS: Case series of patients with a multiple-plaque variant of centrofacial trichoblastoma treated in our department between 2005 and 2017. We identified eight patients with the centrofacial plaque variant of trichoblastoma treated in our department from 2005 to 2017. RESULTS: The final study sample comprised 13 trichoblastomas from four patients. All patients also developed at least one basal cell carcinoma. Mohs surgery was the method of treatment in the majority of the cases of trichoblastoma and in all the cases of basal cell carcinoma. We needed between 2 and 6 stages to obtain free margins in our cases of facial plaque trichoblastomas treated by Mohs surgery. CONCLUSION: To the best of our knowledge, a multiple-plaque variant of trichoblastoma has not been described in the literature. We suggest a genetic origin of this variant of trichoblastoma and describe its remarkable infiltrative nature, with poorly defined surgical margins.
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Doenças do Cabelo/patologia , Folículo Piloso/patologia , Neoplasias Cutâneas/patologia , Idoso , Face/patologia , Feminino , Doenças do Cabelo/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Cirurgia de Mohs , Neoplasias Cutâneas/cirurgiaRESUMO
Cutaneous angiosarcoma (AS) is an uncommon, aggressive sarcoma whose incidence is rising because of the increasing use of radiation therapy, especially in breast cancer. The few studies on the relevance of prognostic factors, such as MYC status in cutaneous AS, have reported inconclusive findings, with some authors reporting MYC amplification only in postirradiation and lymphedema-associated AS and others reporting evidence of MYC amplification in idiopathic AS. We analyzed 17 cases of cutaneous AS (6 idiopathic AS, 10 postirradiation AS, and 1 lymphedema-associated AS) treated at our institute between 2000 and 2015. Follow-up data were available in all cases. We compared the presence/absence of MYC amplification by fluorescence in situ hybridization (FISH) and immunohistochemical (IHC) MYC overexpression in the different AS subtypes. We also investigated potential associations between MYC amplification and prognosis. MYC amplification was observed by FISH in 6 of 14 informative cases. The positive cases were all secondary AS (5 postirradiation AS and 1 lymphedema-associated AS). IHC detected MYC overexpression in 8 of 15 informative cases (7 secondary AS and 1 idiopathic AS). In conclusion, MYC amplification and MYC overexpression were detected almost exclusively in secondary AS. No associations were found between MYC amplification/overexpression and prognosis. We found MYC amplification or overexpression in a similar proportion of the patients who died and who were still alive at the end of the study. In the group of 9 patients who died, MYC was detected by FISH in 4 cases and by IHC in 5. The corresponding figures in the group of 6 patients still alive were 2 by FISH and 3 by IHC.
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Hemangiossarcoma/genética , Neoplasias Induzidas por Radiação/genética , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Amplificação de Genes , Hemangiossarcoma/mortalidade , Hemangiossarcoma/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologiaRESUMO
There is a growing evidence of the role of protein acetylation in different processes controlling metabolism. Sirtuins (histone deacetylases nicotinamide adenine dinucleotide-dependent) activate autophagy playing a protective role in cell homeostasis. This study analyzes tuberous sclerosis complex (TSC2) lysine acetylation, in the regulation of mTORC1 signaling activation, autophagy and cell proliferation. Nicotinamide 5mM (a concentration commonly used to inhibit SIRT1), increased TSC2 acetylation in its N-terminal domain, and concomitantly with an augment in its ubiquitination protein status, leading to mTORC1 activation and cell proliferation. In contrast, resveratrol (RESV), an activator of sirtuins deacetylation activity, avoided TSC2 acetylation, inhibiting mTORC1 signaling and promoting autophagy. Moreover, TSC2 in its deacetylated state was prevented from ubiquitination. Using MEF Sirt1 +/+ and Sirt1 -/- cells or a SIRT1 inhibitor (EX527) in MIN6 cells, TSC2 was hyperacetylated and neither NAM nor RESV were capable to modulate mTORC1 signaling. Then, silencing Tsc2 in MIN6 or in MEF Tsc2-/- cells, the effects of SIRT1 modulation by NAM or RESV on mTORC1 signaling were abolished. We also observed that two TSC2 lysine mutants in its N-terminal domain, derived from TSC patients, differentially modulate mTORC1 signaling. TSC2 K599M variant presented a lower mTORC1 activity. However, with K106Q mutant, there was an activation of mTORC1 signaling at the basal state as well as in response to NAM. This study provides, for the first time, a relationship between TSC2 lysine acetylation status and its stability, representing a novel mechanism for regulating mTORC1 pathway.
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Autofagia , Complexos Multiproteicos/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Acetilação , Animais , Autofagia/efeitos dos fármacos , Carbazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Células HEK293 , Inibidores de Histona Desacetilases/farmacologia , Humanos , Lisina , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/genética , Niacinamida/farmacologia , Domínios Proteicos , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Interferência de RNA , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Estilbenos/farmacologia , Serina-Treonina Quinases TOR/genética , Fatores de Tempo , Transfecção , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) typically affects the dermis and subcutaneous tissue. The subcutaneous variant is rare. OBJECTIVE: We sought to characterize the subcutaneous DFSP (SC-DFSP) variant and compare it with cutaneous DFSP (C-DFSP). METHODS: This work was a retrospective study of DFSP treated in our institution. RESULTS: Of 124 cases of DFSP, 18 were SC-DFSP (14.5%). Except for the deep location, the pathologic and genetic features were indistinguishable from the C-DFSP variant. Histologically, of 18 SC-DFSP cases, 13 were classic DFSP, 3 fibrosarcomatous DFSP (FS-DFSP), 1 Bednar tumor, and 1 giant-cell fibroblastoma. All tumors expressed CD34 and the COL1A1-PDGFB fusion transcripts. In our series, higher proportions of SC-DFSP tumors (61%) than C-DFSP tumors (8.5%) were located on the head (P < .001). Of the 20 DFSP tumors on the head (16.1%), 11 were SC-DFSP and 9 were C-DFSP. In addition, half the SC-DFSP tumors affected muscle or periosteum, compared with a quarter of the C-DFSP tumors (P = .009). SC-DFSP needed a higher number of Mohs stages than did C-DFSP (P = .009). Median follow-up time was 63 months, and 2 FS-DFSP tumors recurred (1 SC-DFSP, 1 C-DFSP). LIMITATIONS: Limitations include the retrospective aspect of the study. CONCLUSIONS: Most DFSP tumors involving the head were subcutaneous and required more complex surgery. Dermatologists should be aware of this atypical presentation, especially in lesions involving the head.
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Dermatofibrossarcoma/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Cutâneas/patologia , Tela Subcutânea , Adolescente , Adulto , Dermatofibrossarcoma/classificação , Feminino , Neoplasias de Cabeça e Pescoço/classificação , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/classificação , Adulto JovemRESUMO
Breast implant-associated anaplastic large cell lymphoma (ALCL) is a newly described clinical and pathologic entity that typically presents as seroma in the fibrous scar around the implant. Less frequently, it presents as a solid peri-implant mass, and there have been no reports to date of cutaneous lesions as the presenting manifestation. We report the case of a 56-year-old woman with a history of bilateral breast reconstruction following breast cancer of the right breast who consulted with several papules on the right breast suggestive of metastasis. Histopathology showed a proliferation of large epithelioid lymphocytes with highly pleomorphic cells and nuclei. The neoplastic cells were CD15 and CD30 positive and ALK-1 negative. The epithelial markers were all negative except for epithelial membrane antigen (EMA), which was weakly positive. Molecular analysis showed monoclonal T-cell receptor γ gene rearrangement, confirming a diagnosis of breast implant-associated ALCL. The non-specific morphology of the skin lesions, the epithelioid nature of the neoplastic cells and the expression of EMA can lead to an erroneous diagnosis of skin metastases from a poorly differentiated adenocarcinoma of the breast. We recommend immunohistochemical staining for CD30 and ALK-1 for patients with breast implants who develop anaplastic lesions.
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BACKGROUND: Treatment of oral erosive lichen planus is considered a therapeutic challenge. Various systemic and topical agents aimed at controlling the symptoms, rather than curing the lesions, have been used with varying results. OBJECTIVE: To evaluate the response to treatment with antimalarial drugs in patients with oral erosive lichen planus. METHODS: Eight patients diagnosed with oral erosive lichen planus were treated with antimalarial agents. The first clinical evaluation was made after a month of treatment and then every 2-3 months. Baseline ophthalmologic examinations were performed, and laboratory values were monitored before and during treatment. RESULTS: All studied patients who had previously been resistant to other treatments responded favorably. Pain relief and reduced erythema and erosions were observed after of a mean of 2.4 months. CONCLUSION: Antimalarials may be useful for the treatment of oral erosive lichen planus. They are easily administered and affordable, with few adverse effects.
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Antimaláricos/uso terapêutico , Líquen Plano Bucal/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: While there are questionnaires for evaluating the effects of skin cancer on patient quality of life, there are no specific questionnaires available in Spanish for evaluating quality of life in patients with actinic keratosis. The aim of this study was to translate and culturally adapt the Actinic Keratosis Quality of Life (AKQoL) questionnaire into Spanish. PATIENTS AND METHODS: The original questionnaire was translated into Spanish following the guidelines for the cross-cultural adaptation of self-report measures. Several measures of general reliability and validity were calculated, including Cronbach α for internal consistency and the Spearman rank-order correlation coefficient and a Bland-Altman plot for test-retest reliability. To test concurrent validity, we used the Pearson correlation coefficient to measure the correlation between AKQoL and Skindex-29 scores. RESULTS: The final version of the questionnaire was administered to 621 patients with actinic keratosis, who scored a mean (SD) of 5.25 (4.73) points (total possible score, 0-25). The Cronbach α reliability coefficient analysis was 0.84. The correlation between the mean (SD) score on the Skindex-29 (1.87 [4.07]) and on the AKQoL (1.97 [2.98] was 0.344 (P=.002, Spearman's rho), with a proportion of shared variance of 11.8%. CONCLUSIONS: The translation, cross-cultural adaptation, and validation of the original AKQoL produced a reliable, easily understandable questionnaire for evaluating the impact of actinic keratosis on the quality of life of patients in our setting.
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Autoavaliação Diagnóstica , Ceratose Actínica/diagnóstico , Qualidade de Vida , Idoso , Feminino , Humanos , Idioma , Masculino , Pessoa de Meia-Idade , TraduçõesRESUMO
Atypical Spitz tumor with loss of BAP1 or Wiesner nevus is a peculiar variant of intradermal spitzoid melanocytic neoplasm composed of epithelioid melanocytes with a sheet-like growth pattern, abundant infiltrating lymphocytes and rare or absent mitotic activity. This subset of atypical spitzoid tumors is characterized by the BRAF(V600E) mutation and loss of BAP1 expression. Recognition of these lesions is important because they can be a marker for a hereditary BAP1-associated cancer syndrome. We present an unusual case of sporadic Wiesner nevus that had typical histopathologic features and a BAP1 but not a BRAF mutation. The biological significance of Wiesner nevus is controversial, and little is known about prognosis, particularly in atypical cases like this one.
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Nevo de Células Epitelioides e Fusiformes/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Supressoras de Tumor/deficiência , Ubiquitina Tiolesterase/deficiência , Adulto , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Mutação , Nevo de Células Epitelioides e Fusiformes/genética , Nevo de Células Epitelioides e Fusiformes/metabolismo , Nevo de Células Epitelioides e Fusiformes/patologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismoRESUMO
Melanoma is potentially curable if diagnosed at its earliest stages and treated properly. The best approaches for reducing deaths due to melanoma are primary and secondary prevention. The objective of this study is to evaluate patient awareness of the risk factors for developing melanoma and attitudes toward its prevention. Also, this study aims to assess observance of recommended preventive measures and to identify possible factors associated with a low adoption of these measures. This cross-sectional study based on an online questionnaire included 185 consecutively enrolled subjects at risk of developing melanoma monitored in a pigmented lesion unit in Valencia (Spain). Level of knowledge, attitude, and observance of preventive measures were evaluated. Statistical analysis was carried out using contingency tables, chi-squared test, and Spearman correlation. Out of those who reported practicing skin self-examination, only 24.1 % performed it in the optimal way. A better attitude was observed in low-risk patients (r = -0.28, p < 0.01). Being female (p < 0.01), aged 18-35 (p = 0.02), fair-haired (p = 0.02), having skin phototype I-II (p < 0.01), and a suitable attitude (p = 0.05) and knowledge (p < 0.01) were related to a better use of sunscreens and avoidance of sun exposure. Knowledge was inversely associated with age (p = 0.01). Despite the high level of knowledge and positive attitude, inadequate practice of compliance with recommended primary and secondary preventive measures was observed in our risk population.
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Conscientização , Conhecimentos, Atitudes e Prática em Saúde , Melanoma/prevenção & controle , Neoplasias Cutâneas/prevenção & controle , Adolescente , Adulto , Fatores Etários , Estudos Transversais , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Cooperação do Paciente , Fatores de Risco , Autoexame , Fatores Sexuais , Neoplasias Cutâneas/diagnóstico , Fatores Socioeconômicos , Espanha , Banho de Sol , Protetores Solares/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: It has been reported that increased expression of UCP-2 in the vasculature may prevent the development of atherosclerosis in patients with increased production of reactive oxygen species, as in the diabetes, obesity or hypertension. Thus, a greater understanding in the modulation of UCP-2 could improve the atherosclerotic process. However, the effect of TNF-α or insulin modulating UCP-2 in the vascular wall is completely unknown. In this context, we propose to study new molecular mechanisms that help to explain whether the moderate hyperinsulinemia or lowering TNF-α levels might have a protective role against vascular damage mediated by UCP-2 expression levels. METHODS: We analyzed the effect of insulin or oleic acid in presence or not of TNF-α on UCP-2 expression in murine endothelial and vascular smooth muscle cells. At this step, we wondered if some mechanisms studied in vitro could be of any relevance in vivo. We used the following experimental models: ApoE-/- mice under Western type diet for 2, 6, 12 or 18 weeks, BATIRKO mice under high-fat diet for 16 weeks and 52-week-old BATIRKO mice with o without anti-TNF-α antibody pre-treatment. RESULTS: Firstly, we found that TNF-α pre-treatment reduced UCP-2 expression induced by insulin in vascular cells. Secondly, we observed a progressive reduction of UCP-2 levels together with an increase of lipid depots and lesion area in aorta from ApoE-/- mice. In vivo, we also observed that moderate hyperinsulinemic obese BATIRKO mice have lower TNF-α and ROS levels and increased UCP-2 expression levels within the aorta, lower lipid accumulation, vascular dysfunction and macrovascular damage. We also observed that the anti-TNF-α antibody pre-treatment impaired the loss of UCP-2 expression within the aorta and relieved vascular damage observed in 52-week-old BATIRKO mice. Finally, we observed that the pretreatment with iNOS inhibitor prevented UCP-2 reduction induced by TNF-α in vascular cells. Moreover, iNOS levels are augmented in aorta from mice with lower UCP-2 levels and higher TNF-α levels. CONCLUSIONS: Our data suggest that moderate hyperinsulinemia in response to insulin resistance or lowering of TNF-α levels within the aorta attenuates vascular damage, this protective effect being mediated by UCP-2 expression levels through iNOS.
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Insulina/farmacologia , Canais Iônicos/antagonistas & inibidores , Canais Iônicos/biossíntese , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/biossíntese , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Células Cultivadas , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Proteína Desacopladora 2RESUMO
BACKGROUND: BRAF mutations are frequent in melanoma but their prognostic significance remains unclear. OBJECTIVE: We sought to further evaluate the prognostic value of BRAF mutations in localized cutaneous melanoma. METHODS: We undertook an observational retrospective study of 147 patients with localized invasive (stages I and II) cutaneous melanomas to determine the prognostic value of BRAF mutation status. RESULTS: After a median follow-up of 48 months, patients with localized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype (hazard ratio 2.2, 95% confidence interval 1.1-4.3) even after adjustment for Breslow thickness, tumor ulceration, location, age, sex, and tumor mitotic rate. LIMITATIONS: The retrospective design and the small number of events are limitations. CONCLUSIONS: Our findings suggest that reappraisal of clinical treatment approaches for patients with localized melanoma harboring tumors with BRAF mutation might be warranted.
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Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Melanoma/patologia , Mutação , Invasividade Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Cutâneas/patologiaRESUMO
Autophagy is a highly regulated homoeostatic process involved in the lysosomal degradation of damaged cell organelles and proteins. This process is considered an important pro-survival mechanism under diverse stress conditions. A diabetic milieu is known to hamper osteoblast viability and function. In the present study, we explored the putative protective role of autophagy in osteoblastic cells exposed to an HG (high glucose) medium. HG was found to increase protein oxidation and triggered autophagy by a mechanism dependent on reactive oxygen species overproduction in osteoblastic MC3T3-E1 cells. MC3T3-E1 cell survival was impaired by HG and worsened by chemical or genetic inhibition of autophagy. These findings were mimicked by H2O2-induced oxidative stress in these cells. Autophagy impairment led to both defective mitochondrial morphology and decreased bioenergetic machinery and inhibited further osteoblast differentiation in MC3T3-E1 cells upon exposure to HG. These novel findings indicate that autophagy is an essential mechanism to maintain osteoblast viability and function in an HG environment.
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Autofagia , Glucose/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Sobrevivência Celular , Peróxido de Hidrogênio/metabolismo , Camundongos , Oxirredução , Estresse Oxidativo/fisiologiaRESUMO
Extracellular vesicles represent a group of structures with the capacity to communicate with different cells and organs. This complex network of interactions can regulate multiple physiological processes in the organism. Very importantly, these processes can be altered during the appearance of different diseases including cancer, metabolic diseases, etc. In addition, these extracellular vesicles can transport different cargoes, altering the initiation of the disease, driving the progression, or even accelerating the pathogenesis. Then, we have explored the implication of these structures in different alterations such as pancreatic cancer, and in different metabolic alterations such as diabetes and its complications and non-alcoholic fatty liver disease. Finally, we have explored in more detail the communication between the liver and the pancreas. In summary, extracellular vesicles represent a very efficient system for the communication among different tissues and permit an efficient system as biomarkers of the disease, as well as being involved in the extracellular-vesicle-mediated transport of molecules, serving as a potential therapy for different diseases.