ABSTRACT
OBJECTIVE: To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature. METHODS: Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed. RESULTS: Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001). CONCLUSION: Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.
Subject(s)
Dwarfism , Human Growth Hormone , Adult , Humans , Child , Genotype , Phenotype , Heterozygote , Homozygote , Patients , AggrecansABSTRACT
A small library of 120 compounds was established with seventy new alkylated derivatives of the natural product terphenyllin, together with 45 previous reported derivatives and four natural p-terphenyl analogs. The 70 new derivatives were semi-synthesized and evaluated for cytotoxic activities against four cancer cell lines. Interestingly, 2',4''-diethoxyterphenyllin, 2',4,4''-triisopropoxyterphenyllin, and 2',4''-bis(cyclopentyloxy)terphenyllin showed potent activities with IC50 values in a range from 0.13 to 5.51â µM, which were similar to those of the positive control, adriamycin. The preliminary structure-activity relationships indicated that the introduction of alkyl substituents including ethyl, allyl, propargyl, isopropyl, bromopropyl, isopentenyl, cyclopropylmethyl, and cyclopentylmethyl are important for improving the cytotoxicity.
Subject(s)
Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Small Molecule Libraries/chemistry , Terphenyl Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aspergillus/chemistry , Aspergillus/isolation & purification , Biological Products/chemical synthesis , Biological Products/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship , Terphenyl Compounds/chemical synthesis , Terphenyl Compounds/chemistryABSTRACT
With random block experimental design, the soil microbial biomass carbon, soil temperature, soil moisture, and litterfall input in secondary oak forest and Pinus taeda plantation were measured in successive two years at the Xiashu Experimental Forest of Nanjing Forestry University. The results showed that in the two stands, soil microbial biomass carbon had an obvious seasonal fluctuation, being lower in plant vigorous growth season but higher during plant dormancy. The microbial biomass carbon in 0-10 cm soil layer ranged from 267.8 mg x kg(-1) to 459.8 mg x kg(-1) in P. taeda plantation and from 278.6 mg x kg(-1) to 467.8 mg x kg(-1) in secondary oak forest. Soil microbial biomass carbon had a significant negative correlation with soil temperature, but no significant correlations with soil moisture and litterfall input. It was suggested that the seasonal fluctuation of soil microbial biomass carbon in test stands could be more related to the availability of soil carbon and other nutrients, competition of plant roots for soil nutrients, and plant growth rhythm.
