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OBJECTIVE: Inhibition of the MAPK pathway by MEK inhibitors (MEKi) is currently a therapeutic standard in several cancer types, including ovarian low-grade serous carcinoma (LGSC). A common MAPK pathway alteration in tubo-ovarian high-grade serous carcinoma (HGSC) is the genomic inactivation of neurofibromin 1 (NF1). The primary objectives of our study were to survey the prevalence of NF1 inactivation in the principal ovarian carcinoma histotype as well as to evaluate its associations with clinico-pathological parameters and key biomarkers including BRCA1/2 status in HGSC. METHODS: A recently commercialized NF1 antibody (clone NFC) was orthogonally validated on an automated immunohistochemistry (IHC) platform and IHC was performed on tissue microarrays containing 2140 ovarian carcinoma cases. Expression was interpreted as loss/inactivated (complete or subclonal) versus normal/retained. RESULTS: Loss of NF1 expression was detected in 250/1429 (17.4%) HGSC including 11% with subclonal loss. Survival of NF1-inactivated HGSC patients was intermediate between favorable BRCA1/2 mutated HGSC and unfavorable CCNE1 high-level amplified HGSC. NF1 inactivation was mutually exclusive with CCNE1 high-level amplifications, co-occurred with RB1 loss and occurred at similar frequencies in BRCA1/2 mutated versus wild-type HGSC. NF1 loss was found in 21/286 (7.3%) endometrioid carcinomas with a favorable prognostic association (p = 0.048), and in 4/64 (5.9%) LGSC, mutually exclusive with other driver events. CONCLUSIONS: NF1 inactivation occurs in a significant subset of BRCA1/2 wild-type HGSC and a subset of LGSC. While the functional effects of NF1 inactivation need to be further characterized, this signifies a potential therapeutic opportunity to explore targeting NF1 inactivation in these tumors.
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Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1 , Neurofibromina 1/genética , Inmunohistoquímica , Proteína BRCA2 , Neoplasias Ováricas/patología , Carcinoma Endometrioide/patología , Cistadenocarcinoma Seroso/patología , Carcinoma Epitelial de OvarioRESUMEN
In order to clarify the differences in the effects of vegetation restoration strategies on soil carbon sequestration and aggregate stability under different water-eroded environments, we collected experimental data from 91 papers and evaluated the response of soil organic carbon (SOC) stock and aggregate stability to vegetation restoration based on Meta-analysis. The results showed the following:â compared with cropland or bare land, forestland/grassland restoration was beneficial to increase SOC stock and improve aggregate stability, but the dominant functions of the two were different. The effect of forestland restoration on carbon sequestration was stronger than that of grassland reforestation, and the effect of grassland restoration on aggregate stability was stronger than that of forestland restoration. â¡ Multi-factor Meta-analysis showed that the factors that significantly affected SOC were restoration year, soil clay content, vegetation coverage, mean annual precipitation (MAP), mean annual temperature (MAT), and soil depth. The positive effect of vegetation restoration on SOC stock increased with the increase in vegetation coverage rate. Grassland restoration had a more significant effect on SOC stock when soil clay content was 20%-32%, it was more likely to promote the carbon sequestration effect of grassland when MAP>800 mm or MAT<15â, and there was no significant change in SOC stock under different restoration years. However, the effect of forestland restoration on SOC stock was more significant when soil clay content was>32%. Climate conditions had no limited effect on SOC stock in forestland, and there was a positive effect between SOC stock under forestland restoration and restoration years. ⢠Vegetation restoration had stronger significant positive effects on mean weight diameter (MWD) and mean geometric diameter (GMD) when the clay content was 20%-32%, and MWD and GMD increased with the increase in vegetation coverage. â£SOC stock growth could explain 25% and 24% of the variation in the effect value of MWD and GMD, respectively. These results indicated that the formation of SOC was the result of multiple factors, and soil aggregate stability was limited only by vegetation coverage and soil clay content. The increase in SOC stock could promote the improvement of water stability MWD and GMD. These results can clarify the carbon sequestration effect of different vegetation restoration measures in water-eroded environments and provide theoretical reference for the restoration and reconstruction of degraded ecosystems.
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Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. The standard treatment achieves a median overall survival for GBM patients of only 15 months. Hence, novel therapies based on an increased understanding of the mechanistic underpinnings of GBM are desperately needed. In this study, we show that elevated expression of 28S rRNA (cytosine-C(5))-methyltransferase NSUN5, which methylates cytosine 3782 of 28S rRNA in GBM cells, is strongly associated with the poor survival of GBM patients. Moreover, we demonstrate that overexpression of NSUN5 increases protein synthesis in GBM cells. NSUN5 knockdown decreased protein synthesis, cell proliferation, sphere formation, migration, and resistance to temozolomide in GBM cell lines. NSUN5 knockdown also decreased the number and size of GBM neurospheres in vitro. As a corollary, mice harboring U251 tumors wherein NSUN5 was knocked down survived longer than mice harboring control tumors. Taken together, our results suggest that NSUN5 plays a protumorigenic role in GBM by enabling the enhanced protein synthesis requisite for tumor progression. Accordingly, NSUN5 may be a hitherto unappreciated target for the treatment of GBM.
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Neoplasias Encefálicas , Glioblastoma , Animales , Ratones , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Glioblastoma/patología , Metiltransferasas/genética , Metiltransferasas/metabolismo , ARN , ARN Ribosómico 28S , Temozolomida/farmacología , Temozolomida/uso terapéutico , HumanosRESUMEN
Lipids exert many essential physiological functions, such as serving as a structural component of biological membranes, storing energy, and regulating cell signal transduction. Dysregulation of lipid metabolism can lead to dyslipidemia related to various human diseases, such as obesity, diabetes, and cardiovascular disease. Therefore, lipid metabolism is strictly regulated through multiple mechanisms at different levels, including the extracellular matrix. Membrane-type I matrix metalloproteinase (MT1-MMP), a zinc-dependent endopeptidase, proteolytically cleaves extracellular matrix components, and non-matrix proteins, thereby regulating many physiological and pathophysiological processes. Emerging evidence supports the vital role of MT1-MMP in lipid metabolism. For example, MT1-MMP mediates ectodomain shedding of low-density lipoprotein receptor and increases plasma low-density lipoprotein cholesterol levels and the development of atherosclerosis. It also increases the vulnerability of atherosclerotic plaque by promoting collagen cleavage. Furthermore, it can cleave the extracellular matrix of adipocytes, affecting adipogenesis and the development of obesity. Therefore, the activity of MT1-MMP is strictly regulated by multiple mechanisms, such as autocatalytic cleavage, endocytosis and exocytosis, and post-translational modifications. Here, we summarize the latest advances in MT1-MMP, mainly focusing on its role in lipid metabolism, the molecular mechanisms regulating the function and expression of MT1-MMP, and their pharmacotherapeutic implications.
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Aterosclerosis/metabolismo , Metabolismo de los Lípidos , Metaloproteinasa 14 de la Matriz/metabolismo , Obesidad/metabolismo , Transducción de Señal , Adipocitos/metabolismo , Animales , Membrana Celular/metabolismo , Matriz Extracelular/metabolismo , Humanos , Macrófagos/metabolismo , Músculo Liso Vascular/metabolismo , Receptores de LDL/metabolismoRESUMEN
Myocardin (MYOCD) plays an important role in cardiovascular disease. However, its underlying impact on atherosclerosis remains to be elucidated. ATP binding cassette transporter A1 (ABCA1), a key membrane-associated lipid transporter which maintains intracellular lipid homeostasis, has a protective function in atherosclerosis progress. The purpose of this study was to investigate whether and how the effect of MYOCD on atherosclerosis is associated with ABCA1 in vascular smooth muscle cells (VSMCs). We found both MYOCD and ABCA1 expression were dramatically decreased in atherosclerotic patient aortas compared to control. MYOCD knockdown inhibited ABCA1 expression in human aortic vascular smooth muscle cells (HAVSMCs), leading to reduced cholesterol efflux and increased intracellular cholesterol contents. MYOCD overexpression exerted the opposite effect. Mechanistically, MYOCD regulates ABCA1 expression in an SRF-dependent manner. Consistently, apolipoprotein E-deficient mice treated with MYOCD shRNA developed more plaques in the aortic sinus, which is associated with reduced ABCA1 expression, increased cholesterol retention in the aorta, and decreased high-density lipoprotein cholesterol levels in the plasma. Our data suggest that MYOCD deficiency exacerbates atherosclerosis by downregulating ABCA1 dependent cholesterol efflux from VSMCs, thereby providing a novel strategy for the therapeutic treatment of atherosclerotic cardiovascular disease.