Two isoleucyl tRNAs that decode synonymous codons divergently regulate breast cancer metastatic growth by controlling translation of proliferation-regulating genes.

The human genome contains 61 codons encoding 20 amino acids. Synonymous codons representing a given amino acid are decoded by a set of transfer RNAs (tRNAs) called isoacceptors. We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons become modulated in opposing directions during breast cancer progression.

A pro-metastatic tRNA fragment drives Nucleolin oligomerization and stabilization of its bound metabolic mRNAs.

Stress-induced cleavage of transfer RNAs (tRNAs) into tRNA-derived fragments (tRFs) occurs across organisms from yeast to humans; yet, its mechanistic underpinnings and pathological consequences remain poorly defined. Small RNA profiling revealed increased abundance of a cysteine tRNA fragment (5'-tRF) during breast cancer metastatic progression. 5'-tRF was required for efficient breast cancer metastatic lung colonization and cancer cell survival.

Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics.

Tumourigenesis and cancer progression require enhanced global protein translation. Such enhanced translation is caused by oncogenic and tumour-suppressive events that drive the synthesis and activity of translational machinery. Here we report the surprising observation that leucyl-tRNA synthetase (LARS) becomes repressed during mammary cell transformation and in human breast cancer.

A stress-induced tyrosine-tRNA depletion response mediates codon-based translational repression and growth suppression.

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine-tRNA fragments in human cells-causing significant depletion of the precursor tRNA.

Dietary thiamine influences l-asparaginase sensitivity in a subset of leukemia cells.

Tumor environment influences anticancer therapy response but which extracellular nutrients affect drug sensitivity is largely unknown. Using functional genomics, we determine modifiers of l-asparaginase (ASNase) response and identify thiamine pyrophosphate kinase 1 as a metabolic dependency under ASNase treatment. While thiamine is generally not limiting for cell proliferation, a DNA-barcode competition assay identifies leukemia cell lines that grow suboptimally under low thiamine and are characterized by low expression of solute carrier family 19 member 2 (SLC19A2), a thiamine transporter.

ZBTB1 Regulates Asparagine Synthesis and Leukemia Cell Response to L-Asparaginase.

Activating transcription factor 4 (ATF4) is a master transcriptional regulator of the integrated stress response (ISR) that enables cell survival under nutrient stress. The mechanisms by which ATF4 couples metabolic stresses to specific transcriptional outputs remain unknown. Using functional genomics, we identified transcription factors that regulate the responses to distinct amino acid deprivation conditions.

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2.

Calcium signaling and transcription: elongation, DoGs, and eRNAs.

The calcium ion (Ca) is a key intracellular signaling molecule with far-reaching effects on many cellular processes. One of the most important such Ca regulated processes is transcription. A body of literature describes the effect of Ca signaling on transcription initiation as occurring mainly through activation of gene-specific transcription factors by Ca-induced signaling cascades.

Widespread Inducible Transcription Downstream of Human Genes.

Pervasive transcription of the human genome generates RNAs whose mode of formation and functions are largely uncharacterized. Here, we combine RNA-seq with detailed mechanistic studies to describe a transcript type derived from protein-coding genes. The resulting RNAs, which we call DoGs for downstream of gene containing transcripts, possess long non-coding regions (often >45 kb) and remain chromatin bound.

Potentially inappropriate medications among elderly Brazilian outpatients.

CONTEXT AND OBJECTIVES In Brazil, few studies have investigated the prevalence of potentially inappropriate medications (PIMs) among elderly outpatients. This study aimed to determine the prevalence of PIMs prescribed for elderly outpatients, identify the PIMs most commonly involved, and investigate whether age, sex and number of medications are related to prescription of such medications. DESIGN AND SETTING Observational descriptive study developed in the Geriatrics Service of the Central Institute of Hospital das Clínicas (HC), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.

Adverse drug reactions in an elderly hospitalised population: inappropriate prescription is a leading cause.

Objective: Adverse drug reactions (ADRs) represent a major public health problem in the aged. In order to better evaluate this problem in Brazil, this study was designed to assess the prevalence of ADRs in an elderly hospitalised population, identify the most common ADRs and the principal medications involved, evaluate the appropriateness of use of these drugs in elderly people and determine the risk factors implicated in the appearance of such ADRs.

Methods: The study population was comprised of 186 elderly patients (> or =60 years of age) admitted to the internal medicine service of a teaching hospital.