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Survivors of childhood cancer treated with anthracycline chemotherapy or chest radiation are at an increased risk of developing congestive heart failure. In this population, congestive heart failure is well recognised as a progressive disorder, with a variable period of asymptomatic cardiomyopathy that precedes signs and symptoms. As a result, several clinical practice guidelines have been developed independently to help with detection and treatment of asymptomatic cardiomyopathy. These guidelines differ with regards to definitions of at-risk populations, surveillance modality and frequency, and recommendations for interventions. Differences between these guidelines could hinder the effective implementation of these recommendations. We report on the results of an international collaboration to harmonise existing cardiomyopathy surveillance recommendations using an evidence-based approach that relied on standardised definitions for outcomes of interest and transparent presentation of the quality of the evidence. The resultant recommendations were graded according to the quality of the evidence and the potential benefit gained from early detection and intervention.

Stimulation of resting CD4+ T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabolic programs to support subset specification, survival, and function. Here, we describe that the orphan nuclear receptor estrogen-related receptor-α (ERRα) regulates metabolic pathways critical for Teff. Resting CD4+ T cells expressed low levels of ERRα protein that increased on activation. ERRα deficiency reduced activated T-cell numbers in vivo and cytokine production in vitro but did not seem to modulate immunity through inhibition of activating signals or viability. Rather, ERRα broadly affected metabolic gene expression and glucose metabolism essential for Teff. In particular, up-regulation of Glut1 protein, glucose uptake, and mitochondrial processes were suppressed in activated ERRα–/– T cells and T cells treated with two chemically independent ERRα inhibitors or by shRNAi. Acute ERRα inhibition also blocked T-cell growth and proliferation. This defect appeared as a result of inadequate glucose metabolism, because provision of lipids, but not increased glucose uptake or pyruvate, rescued ATP levels and cell division. Additionally, we have shown that Treg requires lipid oxidation, whereas Teff uses glucose metabolism, and lipid addition selectively restored Treg—but not Teff—generation after acute ERRα inhibition. Furthermore, in vivo inhibition of ERRα reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERRα is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity.

The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early dry age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that AhR activity and protein levels in human retinal pigment epithelial (RPE) cells, cells vulnerable in AMD, decrease with age. This finding is significant given that age is the most established risk factor for development of AMD. Moreover, AhR ⁻/⁻ mice exhibit decreased visual function and develop dry AMD-like pathology, including disrupted RPE cell tight junctions, accumulation of RPE cell lipofuscin, basal laminar and linear-like deposit material, Bruch’s membrane thickening, and progressive RPE and choroidal atrophy. High-serum low-density lipoprotein levels were also observed in AhR ⁻/⁻ mice. In its oxidized form, this lipoprotein can stimulate increased secretion of extracellular matrix molecules commonly found in deposits from RPE cells, in an AhR-dependent manner. This study demonstrates the importance of cellular clearance via the AhR signaling pathway in dry AMD pathogenesis, implicating AhR as a potential target, and the mouse model as a useful platform for validating future therapies.

Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were given radiation to fields that include breast tissue (ie, chest radiation) have an increased risk of breast cancer. Clinical practice guidelines are essential to ensure that these individuals receive optimum care and to reduce the detrimental consequences of cancer treatment; however, surveillance recommendations vary among the existing long-term follow-up guidelines. We applied evidence-based methods to develop international, harmonised recommendations for breast cancer surveillance among female survivors of CAYA cancer who were given chest radiation before age 30 years. The recommendations were formulated by an international, multidisciplinary panel and are graded according to the strength of the underlying evidence.

Rational design of enzymes is a stringent test of our understanding of protein chemistry and has numerous potential applications. Here, we present and experimentally validate the computational design of enzyme activity in proteins of known structure. We have predicted mutations that introduce triose phosphate isomerase activity into ribosebinding protein, a receptor that normally lacks enzyme activity. The resulting designs contain 18 to 22 mutations, exhibit$10^5- to 10^6-fold$rate enhancements over the uncatalyzed reaction, and are biologically active, in that they support the growth of Escherichia coli under gluconeogenic conditions. The inherent generality of the design method suggests that many enzymes can be designed by this approach.

The formation of complexes between proteins and ligands is fundamental to biological processes at the molecular level. Manipulation of molecular recognition between ligands and proteins is therefore important for basic biological studies 1 and has many biotechnological applications, including the construction of enzymes 2 , 3 , 4 , biosensors 5 , 6 , genetic circuits 7 , signal transduction pathways 8 and chiral separations 9 . The systematic manipulation of binding sites remains a major challenge. Computational design offers enormous generality for engineering protein structure and function 10 . Here we present a structure-based computational method that can drastically redesign protein ligand-binding specificities. This method was used to construct soluble receptors that bind trinitrotoluene, l -lactate or serotonin with high selectivity and affinity. These engineered receptors can function as biosensors for their new ligands; we also incorporated them into synthetic bacterial signal transduction pathways, regulating gene expression in response to extracellular trinitrotoluene or l -lactate. The use of various ligands and proteins shows that a high degree of control over biomolecular recognition has been established computationally. The biological and biosensing activities of the designed receptors illustrate potential applications of computational design.

Long-term survivors of childhood, adolescent and young adult (AYA) malignancies with past exposure to potentially cardiotoxic treatments are at risk of peripartum cardiac dysfunction. Incidence and risk factors for peripartum cardiac dysfunction and maternal cardiac outcomes in this population were investigated. Eligible long-term survivors were aged <30 years at cancer diagnosis, with ≥1 pregnancy occurring ≥5 years after diagnosis. “Peripartum” cardiac events were defined as occurring within pregnancy or ≤5months after delivery. Cardiac events were classified “symptomatic” or “subclinical”. “Peripartum cardiomyopathy” (PPCM) was defined as symptomatic dysfunction without prior cardiac dysfunction. Of 64 eligible women, 5 (7.8%) had peripartum cardiac events: 3 symptomatic, 2 subclinical. Of 110 live births, 2 (1.8%, 95% CI 0.2–6.4) were defined as PPCM: Significantly greater than the published general population incidence of 1:3000 (p < 0.001), representing a 55-fold (95% CI 6.6–192.0) increased risk. Risk factor analyses were hypothesis-generating, revealing younger age at cancer diagnosis and higher anthracycline dose. Postpartum, cardiac function of 4 women (80%) failed to return to baseline. In conclusion, peripartum cardiac dysfunction is an uncommon but potentially serious complication in long-term survivors of paediatric and AYA malignancies previously treated with cardiotoxic therapies. Peripartum cardiac assessment is strongly recommended for at-risk patients.

Background Women treated with chest irradiation for childhood, adolescent, and young adulthood (CAYA) malignancies, in particular Hodgkin’s lymphoma, have an increased risk of developing second cancers of the breast (SCB). However, there are few uniform guidelines regarding surveillance and prevention for this high-risk group. Methods A systematic search using PUBMED and OVID MEDLINE was performed. Publications listed under the terms “breast neoplasm”, “neoplasm, radiation-induced”, “therapeutic radiation-induced breast cancer”, “screening”, “surveillance”, “prevention”, and “prophylaxis” between January 1992 and January 2015 were assessed. Results A total of 138 publications were reviewed. Factors associated with increased SCB risk include young age at irradiation, prolong duration since irradiation (peak relative risk 13.87 at 15–19 years postradiation), and increased radiation dose and field. Early menopause reduces SCB risk. Annual screening mammography and breast MRI is recommended from age 25 or 8 years posttreatment for women treated with ≥20 Gy chest radiation before age 30 years. Compared with sporadic primary breast cancers (PBC), SCB more often are bilateral (6–34 %), managed with mastectomy (56–100 %), hormone receptor-negative (27–49 %), and high-grade (35 %). Women with SCB have a similar breast cancer event-free survival and breast cancer-specific survival compared to women with PBC. However, their overall survival is worse due to comorbid conditions. There is paucity of information regarding secondary prevention of SCB. Conclusions Survivors of CAYA malignancy are at risk of many late effects, including iatrogenic breast cancer from chest irradiation. They are best managed in a multidisciplinary late-effects setting where tailored risk management can be provided.

Placental nutrient transport capacity influences fetal growth and development; however, it is affected by environmental factors, which are poorly understood. The objective of this study was to understand the impact of the ovine placentome morphological subtype, tissue type, and maternal parenteral supplementation of arginine mono-hydrochloride (Arg) on nutrient transport capacity using a gene expression approach. Placentomal tissues of types A, B, and C morphologic placentome subtypes were derived from 20 twin-bearing ewes, which were infused thrice daily with Arg (n = 9) or saline (Ctrl, n = 11) from 100 to 140 days of gestation. Samples were collected at day 140 of gestation. Expression of 31 genes involved in placental nutrient transport and function was investigated. Differential expression of specific amino acid transporter genes was found in the subtypes, suggesting a potential adaptive response to increase the transport capacity. Placentomal tissues differed in gene expression, highlighting differential transport capacity. Supplementation with Arg was associated with differential expressions of genes involved in amino acid transport and angiogenesis, suggesting a greater nutrient transport capacity. Collectively, these results indicate that the morphological subtype, tissue type, and maternal Arg supplementation can influence placental gene expression, which may be an adaptive response to alter the transport capacity to support fetal growth in sheep.

The thermodynamics and kinetics of the interaction of dihydrofolate reductase (DHFR) with methotrexate have been studied by using fluorescence, stopped-flow, and single-molecule methods. DHFR was modified to permit the covalent addition of a fluorescent molecule, Alexa 488, and a biotin at the N terminus of the molecule. The fluorescent molecule was placed on a protein loop that closes over methotrexate when binding occurs, thus causing a quenching of the fluorescence. The biotin was used to attach the enzyme in an active form to a glass surface for single-molecule studies. The equilibrium dissociation constant for the binding of methotrexate to the enzyme is 9.5 nM. The stopped-flow studies revealed that methotrexate binds to two different conformations of the enzyme, and the association and dissociation rate constants were determined. The single-molecule investigation revealed a conformational change in the enzyme-methotrexate complex that was not observed in the stopped-flow studies. The ensemble averaged rate constants for this conformation change in both directions is about 2-4 s-1and is attributed to the opening and closing of the enzyme loop over the bound methotrexate. Thus the mechanism of methotrexate binding to DHFR involves multiple steps and protein conformational changes.