RESUMO
Ovarian aging is the main cause of infertility and telomere attrition is common to both aging and fertility disorders. Senescence-Accelerated Mouse Prone 8 (SAMP8) model has shortened lifespan and premature infertility, reflecting signs of reproductive senescence described in middle-aged women. Thus, our objective was to study SAMP8 female fertility and the telomere pathway at the point of reproductive senescence. The lifespan of SAMP8 and control mice was monitored. Telomere length (TL) was measured by in situ hybridization in blood and ovary. Telomerase activity (TA) was analyzed by telomere-repeat amplification protocol, and telomerase expression, by real-time quantitative PCR in ovaries from 7-month-old SAMP8 and controls. Ovarian follicles at different stages of maturation were evaluated by immunohistochemistry. Reproductive outcomes were analyzed after ovarian stimulation. Unpaired t-test or Mann-Whitney test were used to calculate p-values, depending on the variable distribution. Long-rank test was used to compare survival curves and Fisher's exact test was used in contingency tables. Median lifespan of SAMP8 females was reduced compared to SAMP8 males (p = 0.0138) and control females (p < 0.0001). In blood, 7-month-old SAMP8 females presented lower mean TL compared to age-matched controls (p = 0.041). Accordingly, the accumulation of short telomeres was higher in 7-month-old SAMP8 females (p = 0.0202). Ovarian TA was lower in 7-month-old SAMP8 females compared to controls. Similarly, telomerase expression was lower in the ovaries of 7-month-old SAMP8 females (p = 0.04). Globally, mean TL in ovaries and granulosa cells (GCs) were similar. However, the percentage of long telomeres in ovaries (p = 0.004) and GCs (p = 0.004) from 7-month-old SAMP8 females was lower compared to controls. In early-antral and antral follicles, mean TL of SAMP8 GCs was lower than in age-matched controls (p = 0.0156 for early-antral and p = 0.0037 for antral follicles). Middle-aged SAMP8 showed similar numbers of follicles than controls, although recovered oocytes after ovarian stimulation were lower (p = 0.0068). Fertilization rate in oocytes from SAMP8 was not impaired, but SAMP8 mice produced significantly more morphologically abnormal embryos than controls (27.03% in SAMP8 vs. 1.22% in controls; p < 0.001). Our findings suggest telomere dysfunction in SAMP8 females, at the time of reproductive senescence.
Assuntos
Infertilidade , Telomerase , Masculino , Feminino , Camundongos , Animais , Telomerase/genética , Telomerase/metabolismo , Envelhecimento/genética , Fertilidade/fisiologia , Telômero/metabolismoRESUMO
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Hereditary factors play a role in the development of PDAC in 3% to 5% of all patients. Surveillance of high-risk groups, may facilitate detection of PDAC at an early stage. The aim of this study was to assess whether surveillance aids detection of early-stage PDAC or precursor lesions (PRLs) and improves the prognosis. PATIENTS AND METHODS: Screening outcomes were collected from three European centers that conduct prospective screening in high-risk groups including families with clustering of PDAC (familial pancreatic cancer [FPC]) or families with a gene defect that predisposes to PDAC. The surveillance program consisted of annual magnetic resonance imaging, magnetic resonance cholangiopancreatography, and/or endoscopic ultrasound. RESULTS: Four hundred eleven asymptomatic individuals participated in the surveillance programs, including 178 CDKN2A mutation carriers, 214 individuals with FPC, and 19 BRCA1/2 or PALB2 mutation carriers. PDAC was detected in 13 (7.3%) of 178 CDKN2A mutation carriers. The resection rate was 75%, and the 5-year survival rate was 24%. Two CDKN2A mutation carriers (1%) underwent surgical resection for low-risk PRL. Two individuals (0.9%) in the FPC cohort had a pancreatic tumor, including one advanced PDAC and one early grade 2 neuroendocrine tumor. Thirteen individuals with FPC (6.1%) underwent surgical resection for a suspected PRL, but only four (1.9%) had high-risk lesions (ie, high-grade intraductal papillary mucinous neoplasms or grade 3 pancreatic intraepithelial neoplasms). One BRCA2 mutation carrier was found to have PDAC, and another BRCA2 mutation carrier and a PALB2 mutation carrier underwent surgery and were found to have low-risk PRL. No serious complications occurred as consequence of the program. CONCLUSION: Surveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident.
Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Detecção Precoce de Câncer , Seguimentos , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Pancreatic cancer remains one of the most difficult cancers to treat with the poorest prognosis. The key to improving survival rates in this disease is early detection and monitoring of disseminated and residual disease. However, this is hindered due to lack reliable diagnostic and predictive markers which mean that the majority of patients succumb to their condition within a few months. METHODS: We present a pilot study of the detection circulating free DNA (cfDNA) combined with tumor specific mutation detection by digital PCR as a novel minimally invasive biomarker in pancreatic ductal adenocarcinoma (PDAC). This was compared to the detection of CTC by the CellSearch® system and a novel CTC enrichment strategy based on CD45 positive cell depletion. The aim of the study was to assess tumor specific DNA detection in plasma and CTC detection as prognostic markers in PDAC. RESULTS: We detected KRAS mutant cfDNA in 26% of patients of all stages and this correlated strongly with Overall Survival (OS), 60 days (95% CI: 19-317) for KRAS mutation positive vs 772 days for KRAS mutation negative (95% CI: 416-1127). Although, the presence of CTC detected by the CellSearch® system did correlate significantly with OS, 88 days (95% CI: 27-206) CTC positive vs 393 days CTC negative (95% CI: 284-501), CTC were detected in only 20% of patients, the majority of which had metastatic disease, whereas KRAS mutant cfDNA was detected in patients with both resectable and advanced disease. CONCLUSIONS: Tumor specific cfDNA detection and CTC detection are promising markers for the management of patients with PDAC, although there is a need to validate these results in a larger patient cohort and optimize the detection of CTC in PDAC by applying the appropriate markers for their detection.
Assuntos
Biomarcadores Tumorais/sangue , DNA/sangue , Mutação/fisiologia , Células Neoplásicas Circulantes/metabolismo , Neoplasias Pancreáticas/sangue , Proteínas Proto-Oncogênicas p21(ras)/sangue , Idoso , Biomarcadores Tumorais/genética , Estudos de Coortes , DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Projetos Piloto , Proteínas Proto-Oncogênicas p21(ras)/genética , Taxa de Sobrevida/tendências , Neoplasias PancreáticasRESUMO
The contribution of chronic skin inflammation to the development of squamous cell carcinoma (SCC) is poorly understood. While the mitogen-activated protein kinase p38α regulates inflammatory responses and tumour development, little is known about the role of p38γ and p38δ in these processes. Here we show that combined p38γ and p38δ (p38γ/δ) deletion blocked skin tumour development in a chemically induced carcinogenesis model. p38γ/δ deletion reduced TPA-induced epidermal hyperproliferation and inflammation; it inhibited expression of proinflammatory cytokines and chemokines in keratinocytes in vitro and in whole skin in vivo, resulting in decreased neutrophil recruitment to skin. Our data indicate that p38γ/δ in keratinocytes promote carcinogenesis by enabling formation of a proinflammatory microenvironment that fosters epidermal hyperproliferation and tumourigenesis. These findings provide genetic evidence that p38γ and p38δ have essential roles in skin tumour development, and suggest that targeting inflammation through p38γ/δ offers a therapeutic strategy for SCC treatment and prevention.
Assuntos
Carcinogênese/metabolismo , Dermatite/enzimologia , Proteína Quinase 12 Ativada por Mitógeno/deficiência , Proteína Quinase 13 Ativada por Mitógeno/deficiência , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/enzimologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Células HEK293 , Xenoenxertos , Humanos , Camundongos Knockout , Camundongos Nus , Proteína Quinase 12 Ativada por Mitógeno/genética , Proteína Quinase 13 Ativada por Mitógeno/genética , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/enzimologiaRESUMO
p38 MAPK signaling has been implicated in the regulation of processes leading to cancer development and progression. Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association remains largely unknown. The related p38αMAPK (MAPK14) proteins p38γ (MAPK12) and p38δ (MAPK13) were recently shown to modulate the immune response, although their role in tumorigenesis remains controversial and their function in inflammation-associated cancer has not been studied. We analyzed the role of p38γ and p38δ in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model in wild-type (WT), p38γ-, p38δ-, and p38γ/δ-deficient (p38γ/δ(-/-)) mice. We found that p38γ/δ deficiency significantly decreased tumor formation, in parallel with a decrease in proinflammatory cytokine and chemokine production. Analysis of leukocyte populations in p38γ/δ(-/-) mouse colon showed less macrophage and neutrophil recruitment than in WT mice. Furthermore, WT chimeric mice with transplanted p38γ/δ(-/-) bone marrow had less tumors than WT mice transplanted with WT bone marrow, whereas tumor number was significantly increased in p38γ/δ(-/-) chimeric mice with WT bone marrow compared with p38γ/δ(-/-) mice transplanted with p38γ/δ(-/-) bone marrow. Together, our results establish that p38γ and p38δ are central to colitis-associated colon cancer formation through regulation of hematopoietic cell response to injury, and validate p38γ and p38δ as potential targets for cancer therapy.
Assuntos
Colite/genética , Neoplasias do Colo/genética , Proteína Quinase 12 Ativada por Mitógeno/genética , Proteína Quinase 13 Ativada por Mitógeno/genética , Animais , Carcinogênese/genética , Carcinogênese/imunologia , Transformação Celular Neoplásica/genética , Colite/complicações , Colite/patologia , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Imunidade Inata/genética , Inflamação/genética , Inflamação/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Proteína Quinase 12 Ativada por Mitógeno/metabolismo , Proteína Quinase 13 Ativada por Mitógeno/metabolismoRESUMO
BACKGROUND: The glandular odontogenic cyst is a rare jawbone cyst that is considered to be an independent entity, although its histopathological characteristics may lead to an incorrect diagnosis as a low-grade mucoepidermoid carcinoma. The treatment of glandular odontogenic cysts is controversial. CASE REPORT: We present two high-risk cases treated with conservative approaches, one by enucleation and curettage and the other by marsupialisation. This report also presents a review of the clinical and pathological aspects of glandular odontogenic cysts, and considers their development. No evidence of disease was observed after 3 years of follow-up in the two cases presented. CONCLUSIONS: When possible, treatment plans for these lesions should be customised for each case, taking into account the data available in the literature and patient preferences. For high-risk cases, that are treated with conservative approaches, such as the two cases presented here, strict and regular controls and rigorous radiological follow-up evaluations are mandatory.