Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance,and is associated with worse prognosis in triple-negative breast cancer

Background Glutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and particularly triple-receptor negative breast cancer (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. Despite intense research on the role of the intracellular Gln pathway, few reports have focussed on Gln transporters in breast cancer and TNBC.Methods The role and localisation of the Gln transporter SLC38A2/SNAT2 in response to Gln deprivation or pharmacological stresses was examined in a panel of breast cancer cell lines. Subsequently, the effect of SLC38A2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SLC38A2 in a cohort of breast cancer was determined by immunohistochemistry.Results SLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SLC38A2. SLC38A2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of Gln-sensitive cell lines. High expression of SLC38A2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p = 0.004), particularly in TNBC (p = 0.02).Conclusions These results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines.Subject terms: Breast cancer, Cancer metabolism     

Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.     

Les manifestations des infections liées au cathéter chez les patients en nutrition parentérale à domicile

ObjectiveManifestations of catheter-related infections (CRI) can be various; we studied the symptoms leading to the diagnosis.MethodsDuring 14 months, we have identified clinical and laboratory manifestations and germs responsible. The results are expressed either as a percentage or median and comparisons with Fisher's exact test.ResultsForty-nine patients out of 192 presented 60 episodes of CRI. For 75%, fever and/or chills during the infusion led to a rapid diagnosis. For 25% of cases, the ILC has been evocated after receiving a biological balance disturbed (16.7%) or found during hospitalization for another reason (8.3%). In 73.3% of cases, a history of fever and/or chills was then found, without alerting the patient. Other symptoms, which were sometimes the warning signs were headache (45%), myalgia (40%), gastrointestinal symptoms (33.3%) and hypotension (20%). Laboratory abnormalities were elevated CRP (86.4%), decreased lymphocytes (59.6%), a change in platelets (43.3%) or leukocytes (40%), renal impairment (45%) and liver (37.5%). Gram-negative bacilli were more often responsible for typical forms as gram-positive cocci were isolated in 86.7% of rough forms (P < 0.000).ConclusionsA CRI can manifest by other clinical signs as fever and/or chills. Biological monitoring can sometimes detect crude forms. Educating patients is crucial to learn the early diagnosis of ILC in home parenteral nutrition.     

Emotional security theory: An application to sibling bereavement

Abstract

There is a need for guiding theory to understand the experiences and outcomes of bereaved siblings, particularly from a family systems framework. The present study investigated the relevance of emotional security theory in a sample of 72 young adults who experienced sibling bereavement. We investigated (1) whether perceptions of prolonged parental grief predicted key aspects of emotional security (disengagement, preoccupation, and security), and (2) whether emotional security mediated a relation between perceptions of prolonged parental grief and young adult emotional functioning. Results supported the potential utility of emotional security theory as a theoretical framework for understanding sibling bereavement.     

The clinical utility of the continuous performance test and objective measures of activity for diagnosing and monitoring ADHD in children: a systematic review

Attention-deficit hyperactivity disorder (ADHD) is typically diagnosed using clinical observation and subjective informant reports. Once children commence ADHD medication, robust monitoring is required to detect partial or non-responses. The extent to which neuropsychological continuous performance tests (CPTs) and objective measures of activity can clinically aid the assessment and titration process in ADHD is not fully understood. This review describes the current evidence base for the use of CPTs and objectively measured activity to support the diagnostic procedure and medication management for children with ADHD. Four databases (PsycINFO, Medline, Allied and Complementary Medicine (AMED), and PsycARTICLES) were systematically searched to understand the current evidence base for (1) the use of CPTs to aid clinical assessment of ADHD; (2) the use of CPTs to aid medication management; and (3) the clinical utility of objective measures of activity in ADHD. Sixty relevant articles were identified. The search revealed six commercially available CPTs that had been reported on for their clinical use. There were mixed findings with regard to the use of CPTs to assess and manage medication, with contrasting evidence on their ability to support clinical decision-making. There was a strong evidence base for the use of objective measures of activity to aid ADHD/non-ADHD group differentiation, which appears sensitive to medication effects and would also benefit from further research on their clinical utility. The findings suggest that combining CPTs and an objective measure of activity may be particularly useful as a clinical tool and worthy of further pursuit.     

Slime mold uses an externalized spatial “memory” to navigate in complex environments

Spatial memory enhances an organism’s navigational ability. Memory typically resides within the brain, but what if an organism has no brain? We show that the brainless slime mold Physarum polycephalum constructs a form of spatial memory by avoiding areas it has previously explored. This mechanism allows the slime mold to solve the U-shaped trap problem—a classic test of autonomous navigational ability commonly used in robotics—requiring the slime mold to reach a chemoattractive goal behind a U-shaped barrier. Drawn into the trap, the organism must rely on other methods than gradient-following to escape and reach the goal. Our data show that spatial memory enhances the organism’s ability to navigate in complex environments. We provide a unique demonstration of a spatial memory system in a nonneuronal organism, supporting the theory that an externalized spatial memory may be the functional precursor to the internal memory of higher organisms.