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Payne EM Virgilio M Narla A Sun H Levine M Paw BH Berliner N Look AT Ebert BL Khanna-Gupta A 《Blood》2012,120(11):2214-2224
Haploinsufficiency of ribosomal proteins (RPs) has been proposed to be the common basis for the anemia observed in Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome with loss of chromosome 5q [del(5q) MDS]. We have modeled DBA and del(5q) MDS in zebrafish using antisense morpholinos to rps19 and rps14, respectively, and have demonstrated that, as in humans, haploinsufficient levels of these proteins lead to a profound anemia. To address the hypothesis that RP loss results in impaired mRNA translation, we treated Rps19 and Rps14-deficient embryos with the amino acid L-leucine, a known activator of mRNA translation. This resulted in a striking improvement of the anemia associated with RP loss. We confirmed our findings in primary human CD34(+) cells, after shRNA knockdown of RPS19 and RPS14. Furthermore, we showed that loss of Rps19 or Rps14 activates the mTOR pathway, and this is accentuated by L-leucine in both Rps19 and Rps14 morphants. This effect could be abrogated by rapamycin suggesting that mTOR signaling may be responsible for the improvement in anemia associated with L-leucine. Our studies support the rationale for ongoing clinical trials of L-leucine as a therapeutic agent for DBA, and potentially for patients with del(5q) MDS. 相似文献
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Carla Sustek D'Angelo Ilana Kohl Monica Castro Varela Cláudia Irene Emílio de Castro Chong Ae Kim Débora Romeo Bertola Charles Marques Lourenço Ana Beatriz Alvarez Perez Celia Priszkulnik Koiffmann 《American journal of medical genetics. Part A》2013,161(3):479-486
Obesity is a major threat to public health worldwide, and there is now mounting evidence favoring a role for the central nervous system (CNS) in weight control. A causal relationship has been recognized in both monogenic (e.g., BDNF, TRKB, and SIM1 deficiencies) and syndromic forms of obesity [e.g., Prader–Willi syndrome (PWS)]. Syndromic obesity arising from chromosomal abnormalities, that typically also affect learning and development, are often associated with congenital malformations and behavioral characteristics. We report on nine unrelated patients with a diagnosis of learning disability and/or developmental delay (DD) in addition to obesity that were found to have copy number variants (CNVs) by single nucleotide polymorphism array‐based analysis. Each patient also had a distinct and complex phenotype, and most had hypotonia and other neuroendocrine issues, such as hyperphagia and hypogonadism. Molecular and clinical characterization of these patients enabled us to determine with confidence that the CNVs we observed were pathogenic or likely to be pathogenic. Overall, the CNVs reported here encompassed a candidate gene or region (e.g., SIM1) that has been reported in patients associating obesity and DD and/or intellectual disability (ID) and novel candidate genes and regions. © 2013 Wiley Periodicals, Inc. 相似文献
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Cazzola M Calzetta L Bettoncelli G Cricelli C Romeo F Matera MG Rogliani P 《Respiratory medicine》2012,106(2):249-256
We conducted a large population-based retrospective cross-sectional study for determining the extent of clinically recognized chronic obstructive pulmonary disease (COPD) and asthma, and the prevalence of associated cardiovascular diseases (CVDs), using information obtained from the Health Search Database (HSD) owned by the Italian College of General Practitioners (SIMG). Our study provides further evidence that patients with the diagnosis of COPD are at increased association with the diagnosis of most CVDs. It also documents that age clusters between 35 and 54 years are those at highest association of simultaneous presence of the diagnosis of CVD and that of COPD, with a progressive significant reduction in older age clusters. Moreover, it shows that the diagnosis of asthma is modestly associated with the diagnosis of different CV morbidities. 相似文献
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Martini R Andreozzi GM Tiengo C Azzena B Mazzoleni F 《Clinical hemorheology and microcirculation》2012,51(2):149-157
A 46 years old male with a post traumatic loss of tissue localized on the anterior surface of the right thigh and knee due to a road accident, was treated with different surgical reconstructive techniques. Combined use of autologous skin graft and acellular dermal substitute Integra? allowed the satisfactory recovery of the patient who was discharged after 82 days from the trauma. To analyse the characteristics and the quality of the healing tissues we performed a videocapillaroscopy study to assess the microcirculatory pattern of the autologous skin grafted on the dermal substitute in comparison with the autologous skin grafted on granulation tissue. The videocapillaroscopy was performed in the zone skin grafted directly on granulation tissue, Zone 1 (Z1); on the region of the lesion in the knee, treated with dermal substitute and autologous skin graft, Zone 2 (Z2), and on the undamaged controlateral knee skin. Zone 3 (Z3). The results showed that the capillary density was similar between Z2 and Z3, while in Z1, the zone skin grafted on the granulation tissue without Integra? the capillary density was significatively reduced. These preliminary observations within the clinical data may be an useful contribute to better understand the tissue healing process. 相似文献
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