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71.
72.
Se-Jin Lee Adam Lehar Yewei Liu Chi Hai Ly Quynh-Mai Pham Michael Michaud Renata Rydzik Daniel W. Youngstrom Michael M. Shen Vesa Kaartinen Emily L. Germain-Lee Thomas A. Rando 《Proceedings of the National Academy of Sciences of the United States of America》2020,117(49):30907
Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit skeletal muscle growth (for review, see ref. 1). Mice lacking MSTN exhibit dramatic increases in muscle mass throughout the body, with individual muscles growing to about twice the normal size (2). MSTN appears to play two distinct roles in regulating muscle size, one to regulate the number of muscle fibers that are formed during development and a second to regulate the growth of those fibers postnatally. The sequence of MSTN has been highly conserved through evolution, with the mature MSTN peptide being identical in species as divergent as humans and turkeys (3). The function of MSTN has also been conserved, and targeted or naturally occurring mutations in MSTN have been shown to cause increased muscling in numerous species, including cattle (3–5), sheep (6), dogs (7), rabbits (8), rats (9), swine (10), goats (11), and humans (12). Numerous pharmaceutical and biotechnology companies have developed biologic agents capable of blocking MSTN activity, and these have been tested in clinical trials for a wide range of indications, including Duchenne and facioscapulohumeral muscular dystrophy, inclusion body myositis, muscle atrophy following falls and hip fracture surgery, age-related sarcopenia, Charcot–Marie–Tooth disease, and cachexia due to chronic obstructive pulmonary disease, end-stage kidney disease, and cancer.The finding that certain inhibitors of MSTN signaling can increase muscle mass even in Mstn−/− mice revealed that the function of MSTN as a negative regulator of muscle mass is partially redundant with at least one other TGF-β family member (13, 14), and subsequent studies have identified activin A as one of these cooperating ligands (15, 16). MSTN and activin A share many key regulatory and signaling components. For example, the activities of both MSTN and activin A can be modulated extracellularly by naturally occurring inhibitory binding proteins, including follistatin (17, 18) and the follistatin-related protein, FSTL-3 or FLRG (19, 20). Moreover, MSTN and activin A also appear to share receptor components. Based on in vitro studies, MSTN is capable of binding initially to the activin type II receptors, ACVR2 and ACVR2B (also called ActRIIA and ActRIIB) (18) followed by engagement of the type I receptors, ALK4 and ALK5 (21). In previous studies, we presented genetic evidence supporting a role for both ACVR2 and ACVR2B in mediating MSTN signaling and regulating muscle mass in vivo. Specifically, we showed that mice expressing a truncated, dominant-negative form of ACVR2B in skeletal muscle (18) or carrying deletion mutations in Acvr2 and/or Acvr2b (13) have significantly increased muscle mass. One limitation of the latter study, however, was that we could not examine the consequence of complete loss of both receptors using the deletion alleles, as double homozygous mutants die early during embryogenesis (22). Moreover, the roles that the two type I receptors, ALK4 and ALK5, play in regulating MSTN and activin A signaling in muscle in vivo have not yet been documented using genetic approaches. Here, we present the results of studies in which we used floxed alleles for each of the type II and type I receptor genes in order to target these receptors alone and in combination in muscle fibers. We show that these receptors are functionally redundant and that signaling through each of these receptors contributes to the overall control of muscle mass. 相似文献
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Emmi Helle Aldo Córdova-Palomera Tiina Ojala Priyanka Saha Praneetha Potiny Stefan Gustafsson Erik Ingelsson Michael Bamshad Deborah Nickerson Jessica X. Chong University of Washington Center for Mendelian Genomics Euan Ashley James R. Priest 《Genetic epidemiology》2019,43(2):215-226
Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes. 相似文献
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Mahwash Kassi Venkateshwar Polsani Robert C. Schutt Solomon Wong Faisal Nabi Michael J. Reardon Dipan J. Shah 《The Journal of thoracic and cardiovascular surgery》2019,157(5):1912-1922.e2
Background
The purpose of this analysis is to describe the differences in cardiac magnetic resonance characteristics between benign and malignant tumors, which would be helpful for surgical planning.Methods
This was a prospective cohort study of 130 patients who underwent cardiac magnetic resonance imaging for evaluation of a suspected cardiac mass. After excluding thrombi and tumors without definitive diagnosis, 66 tumors were evaluated for morphologic features and tissue composition.Results
Of the 66 patients, 39 (59.0%) had malignant tumors and 27 (41.0%) had benign tumors. Patients with malignant tumors were younger when compared with those with benign tumors (age 51 years [42.8-60.0] vs 65 years [60.0-71.0] median). Malignant tumors more often demonstrated tumor invasion (69% vs 0% P < .001) and were more often associated with pericardial effusion (41% vs 7.4% P = .004). Presence of first-pass perfusion (100% vs 33% P < .001) and late gadolinium enhancement (100% vs 59.2%, P < .001) were significantly higher in malignant tumors. In logistic regression modeling, tumor invasion (P < .001) and first-pass perfusion (P < .001) were independently associated with malignancy. Furthermore, using classification and regression tree analysis, we developed a decision tree algorithm to help differentiate benign from malignant tumors (diagnostic accuracy ~90%). The algorithm-weighted cost of misclassifying a malignant tumor as benign was twice that of classifying a benign tumor as malignant.Conclusions
Our study demonstrates that cardiac magnetic resonance imaging is a useful noninvasive method for differentiating malignant from benign cardiac tumors. Tumor size, invasion, and first-pass perfusion were useful imaging characteristics in differentiating benign from malignant tumors. 相似文献78.
Der Freie Zahnarzt - Rechtstipp. Für angebliche Behandlungs- und Aufklärungsfehler bleiben die Zivilgerichte auch bei Kostenerstattung zuständig. Eine kuriose, wiewohl wichtige... 相似文献
79.
80.
Oral Everolimus for Treatment of a Giant Left Ventricular Rhabdomyoma in a Neonate—Rapid Tumor Regression Documented by Real Time 3D Echocardiography
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Robert Wagner M.D. Ph.D. Frank Thomas Riede M.D. Hiroshi Seki M.D. Frauke Hornemann M.D. Steffen Syrbe M.D. Ingo Daehnert M.D. Ph.D. Michael Weidenbach M.D. Ph.D. 《Echocardiography (Mount Kisco, N.Y.)》2015,32(12):1876-1879
The presented case reports on successful treatment with everolimus in a neonate with left ventricular giant rhabdomyoma. The authors used a different dosage regime compared to literature and documented rapid tumor regression by 3D echocardiography. 相似文献