Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma.

Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.

Multiomic atlas with functional stratification and developmental dynamics of zebrafish cis-regulatory elements.

Zebrafish, a popular organism for studying embryonic development and for modeling human diseases, has so far lacked a systematic functional annotation program akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created a central repository to store and process zebrafish developmental functional genomic data. Our data coordination center ( https://danio-code.zfin.org ) combines a total of 1,802 sets of unpublished and re-analyzed published genomic data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements throughout development, including classes with distinct features dependent on their activity in time and space. We delineated the distinct distance topology and chromatin features between regulatory elements active during zygotic genome activation and those active during organogenesis. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predicted functional relationships between them beyond sequence similarity, thus extending the utility of zebrafish developmental genomics to mammals.

Identifying speech, language and communication needs among children and young people in residential care.

BACKGROUND: There are claims that elevated levels of speech, language and communication needs (SLCN) exist among looked-after children and young people, and that their needs remain largely undetected and unmet. Scarce empirical evidence exists to support these assertions. AIMS: To investigate whether elevated levels of communication impairment exist among children and young people in residential care; to begin to explore the nature of any communication impairment indicated, including social and pragmatic difficulties; to consider the extent to which communication impairment may be undetected and unmet; and to consider the suitability of the Children's Communication Checklist 2 (CCC-2) as a screening tool in this context. METHODS & PROCEDURES: In four local authority areas in Scotland residential care workers completed the CCC-2 on children and young people well known to them, and provided information about previous concerns and/or referrals regarding communication. OUTCOMES & RESULTS: Results are presented for 30 children and young people ranging in age from 11;01 to 17;01 years (133-205 months, mean = 172.57, SD = 19.97 months). CCC-2 scores indicated impairment in 19 out of 30 cases. In eight of those 19 cases profiles were suggestive of autistic spectrum disorder (ASD), while for the remaining eleven cases impairment was indicated in other aspects of speech, language or communication. The general trend was towards greater severity of impairment in both ASD and non-ASD profiles. Information regarding previous concerns and/or referrals was available for ten of the 19 cases whose profiles indicated impairment: in nine out of these ten cases there had been no concerns, and in the final case no referrals had been made despite concerns. CONCLUSIONS & IMPLICATIONS: This study indicates the presence of high levels of SLCN among individuals in residential care, much of it severe and pervasive in nature, and in large part unsuspected. The CCC-2 has the potential for use as a screening tool for this population. There is a compelling case for speech and language therapy services to address issues of awareness and access with regard to this population. This preliminary research supports the need for further investigation on a larger and wider scale.