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William B. Dobyns Ghayda M. Mirzaa 《American journal of medical genetics. Part C, Seminars in medical genetics》2019,181(4):582-590
Megalencephaly (MEG) is a developmental abnormality of brain growth characterized by early onset, often progressive, brain overgrowth. Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K‐AKT‐MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype–phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and/or autism spectrum disorder; moderately activating variants (that are typically high‐level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low‐level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K‐AKT–MTOR pathway inhibitors. 相似文献
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Maureen Handoko Lisa T. Emrick Jill A. Rosenfeld Xia Wang Alyssa A. Tran Alicia Turner John W. Belmont Undiagnosed Diseases Network Brendan H. Lee Carlos A. Bacino Hsiao‐Tuan Chao 《American journal of medical genetics. Part A》2019,179(3):475-479
Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling result in brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri‐color of the Blaschko‐linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C > T (p.Thr1977Ile) MTOR variant. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings. We report a fourth case of a 3‐year‐old female presenting with megalencephaly, obstructive hydrocephalus due to cerebral aqueductal stenosis, asymmetric polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism. Oligonucleotide and SNP chromosomal microarray (CMA), karyotype, and trio whole exome sequencing (WES) in the peripheral blood, as well as a targeted gene variant panel from fibroblasts derived from hyperpigmented and non‐hyperpigmented skin did not detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes. Unlike the previously reported cases, the de novo c.5930C > T (p.Thr1977Ile) MTOR variant was detected at 32% mosaicism in our patient only after WES was performed on fibroblast‐derived DNA from the hyperpigmented skin. This case demonstrates the tissue variability in mosaic expression of the recurrent p.Thr1977Ile MTOR variant, emphasizes the need for skin biopsies in the genetic evaluation of patients with skin pigmentary mosaicism, and expands the clinical phenotype associated with this pathogenic MTOR variant. 相似文献
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《Annales d'endocrinologie》2018,79(5):591-595
The present final consensus statement of the French Society of Endocrinology lays out the assessments that are to be systematically performed before and during anticancer treatment by immunotherapy, tyrosine kinase inhibitors or mTOR inhibitors, even without onset of any endocrinopathy. It also discusses the CTCAE adverse event grading system in oncology and the difficulty of implementing it for endocrine side-effects of these anticancer treatments. Notably, this is why certain treatment steps applied in other side-effects (e.g., high-dose corticosteroids, contraindications to immunotherapy, etc.) need to be discussed before implementation for endocrine side-effects. 相似文献
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《Annales d'endocrinologie》2018,79(5):535-538
Over the last 10 years, cancer treatment has progressed, with increasing use of tyrosine kinase inhibitors, mTOR inhibitors and, most recently, immunotherapy. These molecules, however, also incur side-effects, including endocrine toxicity. As their indications are constantly increasing, due to proven efficacy, it is important for endocrinologists to know how to monitor and manage such toxicity. The French Society of Endocrinology therefore drew up a consensus statement on these points. The present introductory text summarizes the main data on these molecules’ action mechanisms and the epidemiology of the main endocrine side-effects. It will be followed up by sections on organ toxicity and a summary section on patients’ overall survival. 相似文献
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Although the progress of aging research relies heavily on a theoretical framework, today there is no consensus on many critical questions in aging biology. I hypothesize that a systematic analysis of the intersection of different evolutionary mechanisms of aging with diverse resource allocation strategies in different organisms may reconcile aging hypotheses. The application of disposable soma, mutation accumulation, antagonistic pleiotropy, and life-history theory is considered across organisms with asexual reproduction, organisms with sexual reproduction and indeterminate growth in different conditions of extrinsic mortality, and organisms with determinate growth, with endotherms/homeotherms as a subgroup. This review demonstrates that different aging mechanisms are complementary to each other, and in organisms with different resource allocation strategies they form aging modalities ranging from immortality to suicidal programs. It also revamps the role of growth arrest in aging. Growth arrest evolved in many different groups of organisms as a result of resource reallocation from growth to reproduction (e.g., semelparous animals, holometabolic insects), or from growth to nutrient storage (endotherms/homeotherms). Growth arrest in different animal lineages has similar molecular mechanisms and similar consequences for longevity due to the conflict between growth-promoting and growth-suppressing programs and suppression of regenerative capacity. 相似文献
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Ethnopharmacological relevance
Tripterygium wilfordii Hook. f. (Tripterygium wilfordii), also known as Huangteng and gelsemium elegan, is a traditional Chinese medicine that has been marketed in China as Tripterygium wilfordii glycoside tablets. Triptolide (TP), an active component in Tripterygium wilfordii extracts, has been used to treat various diseases, including lupus, cancer, rheumatoid arthritis and nephritic syndrome. This review summarizes recent developments in the research on the pharmacodynamics, pharmacokinetics, pharmacy and toxicology of TP, with a focus on its novel mechanism of reducing toxicity. This review provides insight for future studies on traditional Chinese medicine, a field that is both historically and currently important.Materials and methods
We included studies published primarily within the last five years that were available in online academic databases (e.g., PubMed, Google Scholar, CNKI, SciFinder and Web of Science).Results
TP has a long history of use in China because it displays multiple pharmacological activities, including anti-rheumatism, anti-inflammatory, anti-tumor and neuroprotective properties. It has been widely used for the treatment of various diseases, such as rheumatoid arthritis, nephritic syndrome, lupus, Behcet?s disease and central nervous system diseases. Recently, numerous breakthroughs have been made in our understanding of the pharmacological efficacy of TP. Although TP has been marketed as a traditional Chinese medicine, its multi-organ toxicity prevents it from being widely used in clinical practice.Conclusions
Triptolide, a biologically active natural product extracted from the root of Tripterygium wilfordii, has shown promising pharmacological effects, particularly as an anti-tumor agent. Currently, in anti-cancer research, more effort should be devoted to investigating effective anti-tumor targets and confirming the anti-tumor spectrum and clinical indications of novel anti-tumor pro-drugs. To apply TP appropriately, with high efficacy and low toxicity, the safety and non-toxic dose range for specific target organs and diseases should be determined, the altered pathways and mechanisms of exposure need to be clarified, and an early warning system for toxicity needs to be established. With further in-depth study of the efficacy and toxicity of TP, we believe that TP will become a promising multi-use drug with improved clinical efficacy and safety in the future. 相似文献9.
目的探讨胃肠胰神经内分泌肿瘤中Akt/mTOR信号通路的作用及意义。方法选取60例胃肠胰神经内分泌肿瘤作为实验研究对象,同时纳入胃肠胰腺炎症患者30例作为对照组,ELISA法检测入组患者血液中Akt、mTOR水平,免疫组织化学法检测组织中Akt、mTOR的表达,分析AKt、mTOR表达水平与胃肠胰神经内分泌肿瘤临床病理特征的关系。结果实验组血清AKt、mTOR水平较对照组升高,差异有统计学意义(P<0.05);实验组瘤组织中AKt、mTOR阳性率均较瘤旁组织、对照组升高,差异有统计学意义(P<0.05);AKt、mTOR表达水平与胃肠胰神经内分泌肿瘤的分化程度、肿瘤大小、肿瘤数目、远处转移、患者生存时间有关(P<0.05)。结论在胃肠胰神经内分泌肿瘤患者的血清及组织中均存在AKt、mTOR的高度表达,表达水平与胃肠胰神经内分泌肿瘤的分化程度、肿瘤大小、肿瘤数目、远处转移、患者生存时间有关。 相似文献
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Smith–Kingsmore syndrome: A third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism
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