Understanding FABP7 binding to fatty acid micelles and membranes.

Fatty acid-binding proteins (FABPs) are chaperones that facilitate the transport of long-chain fatty acids within the cell and can provide cargo-dependent localization to specific cellular compartments. Understanding the nature of this transport is important because lipid signaling functions are associated with metabolic pathways impacting disease pathologies including cancer, autism, and schizophrenia. FABPs often associate with cell membranes to acquire and deliver their bound cargo as part of transport. We focus on brain FABP (FABP7), which demonstrates localization to the cytoplasm and nucleus, influencing transcription and fatty acid metabolism. We use a combined biophysical-computational approach to elucidate the interaction between FABP7 and model membranes. Specifically, we use multiple experiments to demonstrate that FABP7 can bind oleic acid and docosahexaenoic acid micelles. Data from NMR and multiscale molecular dynamics simulations reveal that the interaction with micelles is through FABP7's portal region residues. Simulations suggest that binding to membranes occurs through the same residues as micelles. Simulations also capture binding events where fatty acids dissociate from the membrane and enter FABP7's binding pocket. Overall, our data shed light on the interactions between FABP7 and OA or DHA micelles and provide insight into the transport of long-chain fatty acids.

Clinical features and predictive biomarkers for bladder cancer in patients with type 2 diabetes presenting with haematuria.

AIMS: To identify clinical features and protein biomarkers associated with bladder cancer (BC) in individuals with type 2 diabetes mellitus presenting with haematuria. MATERIALS AND METHODS: Data collected from the Haematuria Biomarker (HaBio) study was used in this analysis. A matched sub-cohort of patients with type 2 diabetes and patients without diabetes was created based on age, sex, and BC diagnosis, using approximately a 1:2 fixed ratio. Randox Biochip Array Technology and ELISA were applied for measurement of 66 candidate serum and urine protein biomarkers. Hazard ratios and 95% confidence intervals were estimated by chi-squared and Wilcoxon rank sum test for clinical features and candidate protein biomarkers. Diagnostic protein biomarker models were identified using Lasso-based binominal regression analysis. RESULTS: There was no difference in BC grade, stage, and severity between individuals with type 2 diabetes and matched controls. Incidence of chronic kidney disease (CKD) was significantly higher in patients with type 2 diabetes (p = 0.008), and CKD was significantly associated with BC in patients with type 2 diabetes (p = 0.032). A biomarker model, incorporating two serum (monocyte chemoattractant protein 1 and vascular endothelial growth factor) and three urine (interleukin 6, cytokeratin 18, and cytokeratin 8) proteins, predicted incidence of BC with an Area Under the Curve (AUC) of 0.84 in individuals with type 2 diabetes. In people without diabetes, the AUC was 0.66. CONCLUSIONS: We demonstrate the potential clinical utility of a biomarker panel, which includes proteins related to BC pathogenesis and type 2 diabetes, for monitoring risk of BC in patients with type 2 diabetes. Earlier urology referral of patients with type 2 diabetes will improve outcomes for these patients. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN25823942.

Healing the Hearts of Bereaved Parents: Impact of Legacy Artwork on Grief in Pediatric Oncology.

CONTEXT: Approximately 12% of children with cancer will not survive, representing a devastating loss for parents. Strategies to improve parental coping and grief have been understudied. Although legacy-making is frequently offered as standard care to children with terminal illness and their families, these interventions have received little empirical attention. OBJECTIVES: This study qualitatively explores the legacy-making and grief experiences of bereaved parents who participated in legacy artwork with their child before his or her death from cancer. METHODS: Twelve bereaved parents and 12 healthcare providers participated in individual semistructured interviews guided by the Dual Process Model of Grief and Continuing Bonds theory. Qualitative data were analyzed via conventional content analysis. RESULTS: Five themes emerged. Legacy artwork allows for family bonding and opens communication regarding the child's impending death; provides opportunities for parents to engage in life review and meaning-making; is often displayed in the parents' home after the child's death, and parents take comfort in using these projects to continue their bond with their deceased child; can ameliorate parents' grief after their child's death; and may reduce healthcare providers' compassion fatigue and provide them an outlet for coping with their patients' deaths. CONCLUSION: Participating in legacy artwork may result in self-reported positive outcomes for bereaved parents before and after their child's death, including family bonding, enhanced communication, meaning-making, and improvements in grief. As a result of these benefits, children's hospitals may consider offering legacy artwork for children with cancer and their families.

Modulating cellular cytotoxicity and phototoxicity of fluorescent organic salts through counterion pairing.

Light-activated theranostics offer promising opportunities for disease diagnosis, image-guided surgery, and site-specific personalized therapy. However, current fluorescent dyes are limited by low brightness, high cytotoxicity, poor tissue penetration, and unwanted side effects. To overcome these limitations, we demonstrate a platform for optoelectronic tuning, which allows independent control of the optical properties from the electronic properties of fluorescent organic salts. This is achieved through cation-anion pairing of organic salts that can modulate the frontier molecular orbital without impacting the bandgap. Optoelectronic tuning enables decoupled control over the cytotoxicity and phototoxicity of fluorescent organic salts by selective generation of mitochondrial reactive oxygen species that control cell viability. We show that through counterion pairing, organic salt nanoparticles can be tuned to be either nontoxic for enhanced imaging, or phototoxic for improved photodynamic therapy.

Research and policy priorities for addressing prenatal exposure to opioids in Alaska.

The current opioid crisis in Alaska and the USA will negatively affect the health and wellbeing of future generations. The increasing number of infants born with neonatal opioid withdrawal syndrome (NOWS) has had a profound impact on families, health care providers and the child welfare system. This manuscript summarises the main themes of a Symposium held in Anchorage, Alaska with health care providers, researchers, elders and public health officials that focused on identifying emerging challenges, trends and potential solutions to address the increasing number of infants and children affected by maternal opioid use. Five areas of importance for research and policy development that would direct improvement in the care of infants with NOWS in Alaska are outlined with the goal of supporting a research agenda on opioid misuse and child health across the circumpolar north. Abbreviations: NOWS - neonatal opioid withdrawal syndrome; NAS - neonatal abstinence syndrome; MAT - medication-assisted treatment; NICU - neonatal intensive care unit; OATs - opioid agonist treatments; OCS - office of children's services; ANTHC - Alaska Native Tribal Health Consortium; OUD - opioid use disorder; SBIRT - screening, brief intervention and referral to treatment; ISPCTN - IDeA States Pediatric Clinical Trials Network; NIH - National Institutes of Health; ANMC - Alaska Native Medical Center; DHSS - Department of Health and Social Services; AAPP - All Alaska Pediatric Partnership.

Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats.

Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with "second hits." The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12 months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12 months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12 months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1α levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12 months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12-month-old rats and it is females who are at particular risk of developing long-term hypertension following growth restriction.

The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers.

Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in ∼30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by ∼80% compared with the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity, but coexpression of the two proteins in cells profoundly inhibits the WT enzyme by disrupting its ability to homotetramerize. AML cells with the R882H mutation have severely reduced de novo methyltransferase activity and focal hypomethylation at specific CpGs throughout AML cell genomes.

Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.

A unique service in UK delivering Plastibell circumcision: review of 9-year results.

Muslim infants undergo circumcision for religious reasons and Bradford has a high Muslim population. The National Health Service in UK does not provide religious circumcision, so in 1996 a nurse-delivered circumcision service led by consultant urologists was set up at a no-profit and cost-only basis. Plastibell circumcision was offered to all infants between 6 and 14 weeks old and performed under local anaesthesia. Information leaflets and videotapes about the procedure were available to parents prior to the procedure. A three monthly audit of the service was undertaken. Between July 1996 and June 2005 (9 years) 1,129 circumcisions were performed. The common complications were problems with the ring (3.6%) and bleeding (3%). Overall, there was 96% satisfaction rate among the service users. The Plastibell technique for circumcision is a simple method and can be safely performed by trained nurses with acceptable complication rates.