Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy (DEE) and severe neurodevelopmental disorders (NDDs). Exome sequencing and family-based rare variant analyses on a cohort with NDD identified two siblings with DEE and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar DEE phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and cerebrospinal fluid of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for DEE and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis

High inorganic phosphate intake promotes tumorigenesis at early stages in a mouse model of lung cancer

© 2015 Lee et al. Inorganic phosphate (Pi) is required by all living organisms for the development of organs such as bone, muscle, brain, and lungs, regulating the expression of several critical genes as well as signal transduction. However, little is known about the effects of prolonged dietary Pi consumption on lung cancer progression. This study investigated the effects of a highphosphate diet (HPD) in a mouse model of adenocarcinoma. K-rasLA1 mice were fed a normal diet (0.3% Pi) or an HPD (1% Pi) for 1, 2, or 4 months. Mice were then sacrificed and subjected to inductively coupled plasma mass/optical emission spectrometry and laser ablation inductively coupled plasma mass-spectrometry analyses, western blot analysis, histopathological, immunohistochemical, and immunocytochemical analyses to evaluate tumor formation and progression (including cell proliferation, angiogenesis, and apoptosis), changes in ion levels and metabolism, autophagy, epithelial-to-mesenchymal transition, and protein translation in the lungs. An HPD accelerated tumorigenesis, as evidenced by increased adenoma and adenocarcinoma rates as well as tumor size. However, after 4 months of the HPD, cell proliferation was arrested, and marked increases in liver and lung ion levels and in energy production via the tricarboxylic acid cycle in the liver were observed, which were accompanied by increased autophagy and decreased angiogenesis and apoptosis. These results indicate that an HPD initially promotes but later inhibits lung cancer progression because of metabolic adaptation leading to tumor cell quiescence. Moreover, the results suggest that carefully regulated Pi consumption are effective in lung cancer prevention

Hereditary hemochromatosis variant associations with incident non-liver malignancies: 11-year follow-up in UK Biobank

This is the author accepted manuscript.Data Availability: Data are available on application to the UK Biobank (https://www.ukbiobank.ac.uk/enable-yourresearch/register).Background: In European ancestry populations, iron overload disorder Hereditary Hemochromatosis (HH) is predominantly caused by HFE p.C282Y and p.H63D mutations. Male p.C282Y homozygotes have markedly increased hepatic malignancy incidence but risks for other cancers in male and female homozygotes are unclear. Methods: 451,143 UK Biobank European ancestry participants (aged 40-70 years; 54.3% female) were followed (mean 11.6 years) via hospital admissions and national cancer registries. We estimated risks of any incident cancer (other than non-melanoma and liver cancer) and common incident cancers (bladder, blood [with sub-analyses of leukemia and lymphoma], bone, brain, breast, colorectal, kidney, lung, melanoma, oesophageal, ovarian, pancreatic, prostate and stomach) in those with p.C282Y and p.H63D genotypes, compared to participants without HFE mutations. Results: Male p.C282Y homozygotes (n=2,890, 12.1% with baseline diagnosed HH) had increased incidence of prostate cancer (6.8% versus 5.4% without mutations, HR=1.32, 95% CI=1.07-1.63, p=0.01, Bonferroni adjusted p-value=0.17) during follow-up. In lifetable estimates from ages 40-75 years, 14.4% of male p.C282Y homozygotes are projected to develop prostate cancer (versus 10.7% without mutations, excess 3.8%, 95% CI = 1.3-6.8). No increases in risks were found for other studied cancers in male or female p.C282Y homozygotes, or in any other p.C282Y/p.H63D genotype groups of either sex. Conclusions: In a large community sample of male p.C282Y homozygotes, there is suggestive evidence of increased prostate cancer incidence, with no evidence of excess of other studied (non-liver) cancers. Impact: Replication of results in other large community genotyped cohorts are needed to confirm if clinical monitoring for prostate cancer is necessary in p.C282Y homozygous males.Medical Research Council (MRC)National Institute for Health Research (NIHR)University of ExeterNational Cancer InstituteNational Institute on AgingTravelers Chair in Geriatrics and Gerontolog

Differential cytotoxic and radiosensitizing effects of silver nanoparticles on triple-negative breast cancer and non-triple-negative breast cells

Jessica Swanner,1 Jade Mims,2 David L Carroll,3,4 Steven A Akman,5 Cristina M Furdui,2 Suzy V Torti,6 Ravi N Singh1,7 1Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, NC, USA; 2Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA; 3Center for Nanoscale and Molecular Materials, Wake Forest University, Winston-Salem, NC, USA; 4Department of Physics, Wake Forest University, Winston-Salem, NC, USA; 5Roper St Francis Cancer Care, Charleston, SC, USA; 6Department of Molecular Biology and Biophysics, University of Connecticut Health Center, CT, USA; 7Comprehensive Cancer Center of Wake Forest School of Medicine, Winston-Salem, NC, USA Abstract: Identification of differential sensitivity of cancer cells as compared to normal cells has the potential to reveal a therapeutic window for the use of silver nanoparticles (AgNPs) as a therapeutic agent for cancer therapy. Exposure to AgNPs is known to cause dose-dependent toxicities, including induction of oxidative stress and DNA damage, which can lead to cell death. Triple-negative breast cancer (TNBC) subtypes are more vulnerable to agents that cause oxidative stress and DNA damage than are other breast cancer subtypes. We hypothesized that TNBC may be susceptible to AgNP cytotoxicity, a potential vulnerability that could be exploited for the development of new therapeutic agents. We show that AgNPs are highly cytotoxic toward TNBC cells at doses that have little effect on nontumorigenic breast cells or cells derived from liver, kidney, and monocyte lineages. AgNPs induced more DNA and oxidative damage in TNBC cells than in other breast cells. In vitro and in vivo studies showed that AgNPs reduce TNBC growth and improve radiation therapy. These studies show that unmodified AgNPs act as a self-therapeutic agent with a combination of selective cytotoxicity and radiation dose-enhancement effects in TNBC at doses that are nontoxic to noncancerous breast and other cells. Keywords: DNA damage, radiation sensitizer, glutathione, redo