Novel insights into histone lysine methyltransferases in cancer therapy:From epigenetic regulation to selective drugs / 药物分析学报

The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and im-mune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.

Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+synthesis by reprogramming H3K79 methylation in uveal melanoma / 药物分析学报

Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1 L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1 L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accel-erator by enhancing nicotinamide adenine dinucleotide(NAD+)synthesis.Therapeutically,DOT1L inhi-bition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.

Ethical Problems and Discussion on the Protection of Clinical Research Rights and Interests of the Elderly / 中国医学伦理学

With the aggravation of aging population in China, clinical research on the elderly is increasing. How to protect the health and rights of the elderly as vulnerable groups in clinical research and reduce their risks is an urgent problem to be solved in the research of geratology. This paper analyzed the main problems including the inclusion of age limits, the performance of the informed consent, the scheme design of multiple drugs and the professionalism of review in geriatric clinical research, and proposed corresponding countermeasures to protect the rights and interests of the elderly, in order to improve the quality of geriatric clinical research and protect the rights and interests of elderly subjects.

Classification and treatment of orbital venous malformations: an updated review / 医学前沿

Orbital venous malformation (OVM) is a congenital vascular disease. As a common type of vascular malformation in the orbit, OVM may result in vision deterioration and cosmetic defect. Classification of orbital vascular malformations, especially OVMs, is carried out on the basis of different categories, such as angiogenesis, hemodynamics, and locations. Management of OVM is complicated and challenging. Treatment approaches include sclerotherapy, laser therapy, embolization, surgical resection, and radiotherapy. A satisfactory outcome can be achieved only by selecting the appropriate treatment according to lesion characteristics and following the sequential multi-method treatment strategy. This article summarizes the current classification and treatment advances in OVM.