Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia.

Approximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5' splice site due to the IVS20 + 6 T > C mutation. Knockdown experiments reveal that exon 20 inclusion is suppressed in the absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20. We show that RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation. Consistently, exon 20 splicing is bidirectionally manipulated by targeting cellular CLK activity with RECTAS versus CLK inhibitors. The therapeutic potential of RECTAS is validated in multiple FD disease models. Our study indicates that small synthetic molecules affecting phosphorylation state of SRSFs is available as a new therapeutic modality for mechanism-oriented precision medicine of splicing diseases

Application of the CDK9 inhibitor FIT-039 for the treatment of KSHV-associated malignancy

Abstract Chronic infection with Kaposi’s sarcoma-associated herpes virus (KSHV) in B lymphocytes causes primary effusion lymphoma (PEL), the most aggressive form of KSHV-related cancer, which is resistant to conventional chemotherapy. In this study, we report that the BCBL-1 KSHV+ PEL cell line does not harbor oncogenic mutations responsible for its aggressive malignancy. Assuming that KSHV viral oncogenes play crucial roles in PEL proliferation, we examined the effect of cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on KSHV viral gene expression and KSHV+ PEL proliferation. We found that FIT-039 treatment impaired the proliferation of KSHV+ PEL cells and the expression of KSHV viral genes in vitro. The effects of FIT-039 treatment on PEL cells were further evaluated in the PEL xenograft model that retains a more physiological environment for the growth of PEL growth and KSHV propagation, and we confirmed that FIT-039 administration drastically inhibited PEL growth in vivo. Our current study indicates that FIT-039 is a potential new anticancer drug targeting KSHV for PEL patients

Application of the CDK9 inhibitor FIT-039 for the treatment of KSHV-associated malignancy

Chronic infection with Kaposi’s sarcoma-associated herpes virus (KSHV) in B lymphocytes causes primary effusion lymphoma (PEL), the most aggressive form of KSHV-related cancer, which is resistant to conventional chemotherapy. In this study, we report that the BCBL-1 KSHV⁺ PEL cell line does not harbor oncogenic mutations responsible for its aggressive malignancy. Assuming that KSHV viral oncogenes play crucial roles in PEL proliferation, we examined the effect of cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on KSHV viral gene expression and KSHV⁺ PEL proliferation. We found that FIT-039 treatment impaired the proliferation of KSHV⁺ PEL cells and the expression of KSHV viral genes in vitro. The effects of FIT-039 treatment on PEL cells were further evaluated in the PEL xenograft model that retains a more physiological environment for the growth of PEL growth and KSHV propagation, and we confirmed that FIT-039 administration drastically inhibited PEL growth in vivo. Our current study indicates that FIT-039 is a potential new anticancer drug targeting KSHV for PEL patients

双生児を育てる母親の生活実態の検討

本研究では,双生児を出産してから現在に至るまでの母親の生活の実態を明らかにし,双生児を育てる母親の育児支援に対するニーズを明らかにすべく,双生児を育てる母親38組にアンケート調査を実施した。その結果は,(1)双生児の育児は日常生活で身体的な面での負担も大きい一方,ストレスにより,精神的な面に関しても負担が重なっていく,(2)育児情報が氾濫しているにも関わらず,双生児の子育てに関する情報・支援は少ない,(3)双生児の母親は夫以外に父母の援助も受けられ,睡眠に関する問題点は少ない,(4)友達づくりで得られた友達は育児に影響を与え,その役割は大きい,(5)日常生活上,多くの家庭において,双生児の育児に対する経済的な負担が大きい,であった。In order to reveal the actual conditions of mothers after giving birth to twins and find what support in rearing twins they need, we conducted a questionnaire survey on 38 mothers who are raising twins. This survey shows the following facts. 1. In addition to the considerable physical burden, raising twins imposes a stress-related mental burden on them. 2. Despite an abundance of information about child-rearing, little information and support as to raising twins is given. 3. In addition to assistance from husbands, their parents\u27 often provide assistance in rearing children. 4. They tend to experience difficulty in sleeping. 5. Their friends often have an influence on their raising children and play a large part in it. 6. Raising twins puts a great strain on family finances in many families