Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

Published in final edited form as: Sci Transl Med. 2017 May 10; 9(389). https://doi.org/10.1126/scitranslmed.aal2668.Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates

Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus

Cohesin is a chromatin-associated protein complex that mediates sister chromatid cohesion by connecting replicated DNA molecules. Cohesin also has important roles in gene regulation, but the mechanistic basis of this function is poorly understood. In mammalian genomes, cohesin co-localizes with CCCTC binding factor (CTCF), a zinc finger protein implicated in multiple gene regulatory events. At the imprinted IGF2-H19 locus, CTCF plays an important role in organizing allele-specific higher-order chromatin conformation and functions as an enhancer blocking transcriptional insulator. Here we have used chromosome conformation capture (3C) assays and RNAi-mediated depletion of cohesin to address whether cohesin affects higher order chromatin conformation at the IGF2-H19 locus in human cells. Our data show that cohesin has a critical role in maintaining CTCF-mediated chromatin conformation at the locus and that disruption of this conformation coincides with changes in IGF2 expression. We show that the cohesin-dependent, higher-order chromatin conformation of the locus exists in both G1 and G2 phases of the cell cycle and is therefore independent of cohesin's function in sister chromatid cohesion. We propose that cohesin can mediate interactions between DNA molecules in cis to insulate genes through the formation of chromatin loops, analogous to the cohesin mediated interaction with sister chromatids in trans to establish cohesion

Replacing Fishmeal with Soybean and Acetes Meal: Effects on Growth Parameters and Survival Rates of Litopenaeus vannamei (Boone, 1931)

Aquatic foods are increasingly recognized for their crucial role in nutrition and food security, not just as a source of protein. Replacement of fish meal with cheaper ingredients of animal origin in shrimp feed is necessary because of the rising cost and uncertain availability of fish meal. Diets should be prepared with locally available ingredients to make formulation easier and lower the cost of production. The current study evaluates the feed utilization and growth performance of L. vannamei post larvae fed with soybean meal and Acetes meal-based practical diets. A 60-day trial of substituting dietary fishmeal with a mixture of soybean meal and Acetes meal was conducted to assess its impact on the growth performance, survival rate and digestive enzyme activities of Litopenaeus vannamei. Six iso-nitrogenous experimental diets were formulated for this study, each maintaining around 36 % protein level. The control diet (T1) did not include soybean or Acetes meals. The treatment diets contained 1:1 ratio mixtures of soybean meal and Acetes meal replacing fishmeal at 20% (T2), 40% (T3), 60% (T4), 80% (T5), and 100% (T6) levels. These diets were fed to L. vannamei four times daily, depending on their body weight. The data on growth, feed conversion ratio (FCR), survival rate, specific growth rate (SGR) and protein efficiency ratio (PER) of L. vannamei were evaluated. The highest weight gain and SGR were observed in treatment T5 compared to other treatments. The higher PER and lowest FCR were recorded in treatment T5. The present investigation revealed that 80% fishmeal replacement with 1:1 soybean meal and Acetes meal significantly improves the weight gain, survival rate, SGR, FCR and PER of L. vannamei juveniles. The study concluded that soybean and Acetes meal can effectively serve as substitutes for fishmeal, promoting the growth and health of shrimp while reducing dependence on traditional fishmeal. This strategy supports environmental sustainability and enhances cost efficiency in shrimp farming

Rebuilding the health care system in Afghanistan: an overview of primary care and emergency services

Developing nations have many challenges to the growth of emergency medical systems. This development in Afghanistan is also complicated by many factors that plague post-conflict countries including an unstable political system, poor economy, poor baseline health indices, and ongoing violence. Progress has been made in Afghanistan with the implementation of the Basic Package of Health Service (BPHS) by the Ministry of Public Health in an effort to provide healthcare that would have the most cost-effective impact on common health problems. Trauma and trauma-related disability were both identified as priorities under the BPHS, and efforts have begun to address these problems. Most of the emergency care delivered in Afghanistan is provided by the military sector and non-governmental organizations. Security, lack of infrastructure, economic hardship, difficult access to healthcare facilities, poor healthcare facility conditions, and lack of trained healthcare providers, especially women, are all problems that need to be addressed. The long-term goal of quality healthcare for all Afghan citizens will only be met by a combination of specific goal-oriented projects, foreign aid, domestic responsibility, and time

CTCF binds to sites in the major histocompatibility complex that are rapidly reconfigured in response to interferon-gamma

Activation of the major histocompatibility complex (MHC) by interferon-gamma (IFN−γ) is a fundamental step in the adaptive immune response to pathogens. Here, we show that reorganization of chromatin loop domains in the MHC is evident within the first 30 min of IFN−γ treatment of fibroblasts, and that further dynamic alterations occur up to 6 h. These very rapid changes occur at genomic sites which are occupied by CTCF and are close to IFN−γ-inducible MHC genes. Early responses to IFN−γ are thus initiated independently of CIITA, the master regulator of MHC class II genes and prepare the MHC for subsequent induction of transcription

The FUN30 Chromatin Remodeler, Fft3, Protects Centromeric and Subtelomeric Domains from Euchromatin Formation

The chromosomes of eukaryotes are organized into structurally and functionally discrete domains. This implies the presence of insulator elements that separate adjacent domains, allowing them to maintain different chromatin structures. We show that the Fun30 chromatin remodeler, Fft3, is essential for maintaining a proper chromatin structure at centromeres and subtelomeres. Fft3 is localized to insulator elements and inhibits euchromatin assembly in silent chromatin domains. In its absence, euchromatic histone modifications and histone variants invade centromeres and subtelomeres, causing a mis-regulation of gene expression and severe chromosome segregation defects. Our data strongly suggest that Fft3 controls the identity of chromatin domains by protecting these regions from euchromatin assembly

Differential nuclear scaffold/matrix attachment marks expressed genes†

It is well established that nuclear architecture plays a key role in poising regions of the genome for transcription. This may be achieved using scaffold/matrix attachment regions (S/MARs) that establish loop domains. However, the relationship between changes in the physical structure of the genome as mediated by attachment to the nuclear scaffold/matrix and gene expression is not clearly understood. To define the role of S/MARs in organizing our genome and to resolve the often contradictory loci-specific studies, we have surveyed the S/MARs in HeLa S3 cells on human chromosomes 14–18 by array comparative genomic hybridization. Comparison of LIS (lithium 3,5-diiodosalicylate) extraction to identify SARs and 2 m NaCl extraction to identify MARs revealed that approximately one-half of the sites were in common. The results presented in this study suggest that SARs 5′ of a gene are associated with transcript presence whereas MARs contained within a gene are associated with silenced genes. The varied functions of the S/MARs as revealed by the different extraction methods highlights their unique functional contribution

Schimke immunoosseous dysplasia: defining skeletal features

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations