Development of Hybrid Electrospun Nanofibers: Improving Effects of Cellulose Nanofibers (CNFs) on Electrospinnability of Gelatin.

Cellulose nanofibers (CNFs) were used to improve the electrospinnability of the gelatin protein in a water/ethanol/acetic acid (3:2:3, v/v) solution. The effects of different concentrations of CNFs (0.5-4%) on the important physical properties of the gelatin solution (15%), including rheology, conductivity, and surface tension, were investigated. The apparent viscosity and shear-thinning behavior were increased by increasing the CNF concentration from 0 to 4% at a low shear rate (<10 s-1). CNFs also increased the electrical conductivity and surface tension of the gelatin solution. Scanning electron microscopy (SEM) images revealed uniformly ordered structures with good continuity without fracture or bead formation in all hybrid nanofibers. They also showed that the average diameters of fibers decreased from 216 nm in the pure gelatin nanofibers to 175.39 nm in the hybrid gelatin/CNF (4%) ones. Differential scanning calorimetry (DSC) results showed that CNFs increased Tg, and X-ray diffraction (XRD) analysis showed that the electrospinning process caused the formation of more amorphous structures in the gelatin/CNF hybrid nanofibers. The tensile test indicated that by adding 2% CNFs, the ultimate tensile strength (UTS) and strain at break (SB) of nanofiber mats increased from 4.26 to 10.5 MPa and 3.3% to 6.25%, respectively. The current study indicated that incorporating CNFs at the optimal concentration into a gelatin solution can improve the resulting hybrid nanofibers' morphology, average diameter, and mechanical properties.

Effect of corticosteroids on ischemia-reperfusion injury of deep inferior epigastric perforator flap after re-exploration for anastomosis thrombosis: A prospective randomized trial.

Patients undergoing breast reconstruction with the deep inferior epigastric perforator (DIEP) flap are at risk of arterial and venous thrombosis, necessitating flap salvage surgery. However, this carries the risk of ischemia-reperfusion injury (IRI) and potential significant partial or complete flap loss. The objective of this study was to evaluate the potential benefit of corticosteroids in reducing IRI related complications in DIEP flaps that are returned to the operation theater for attempted salvage after venous or arterial failure. A double-blinded prospective randomized study was conducted between January 2012 and January 2023 on patients scheduled for secondary unilateral breast reconstruction using the DIEP flap technique. Patients were included if they developed post-operative venous or arterial flap thrombosis and experienced DIEP flap IRI following operative take-back and anastomosis revision. The treatment group (TG) received a 5-day course of corticosteroids, while the control group (CG) did not receive any specific treatment. Forty-six patients were enrolled in the study. In the CG, two cases of total flap loss and eight cases of partial flap necrosis were observed, while the TG had only 1 case of partial flap necrosis (p < 0.05). The complete resolution of clinical signs of IRI occurred within 13 ± 2.1 days for the TG and 21 ± 3.5 days for the CG (p = 0.00001). The TG had a significantly shorter hospital stay (11.13 ± 0.38 days) compared with the CG (15.47 ± 1.27 days; p < 0.0001). Targeted corticosteroid therapy following a salvage procedure for vascular thrombosis in DIEP flaps has shown promise as an effective treatment for subsequent IRI. This approach may be considered as a viable option for managing IRI in free flaps. However, further studies involving a larger number of patients are required to substantiate our hypothesis.

The Gelatin-Coated Nanostructured Lipid Carrier (NLC) Containing Salvia officinalis Extract: Optimization by Combined D-Optimal Design and Its Application to Improve the Quality Parameters of Beef Burger.

The current study aims to synthesize the gelatin-coated nanostructured lipid carrier (NLC) to encapsulate sage extract and use this nanoparticle to increase the quality parameters of beef burger samples. NLCs were prepared by formulation of gelatin (as surfactant and coating biopolymer), tallow oil (as solid lipid), rosemary essential oil (as liquid lipid), sage extract (as active material or encapsulant), polyglycerol ester and Tween 80 (as low-molecular emulsifier) through the high-shear homogenization-sonication method. The effects of gelatin concentrations and the solid/liquid ratio on the particle size, polydispersity index (PDI), and encapsulation efficiency (EE%) of sage extract-loaded NLCs were quantitatively investigated and optimized using a combined D-optimal design. Design expert software suggested the optimum formulation with a gelatin concentration of 0.1 g/g suspension and solid/liquid lipid ratio of 60/40 with a particle size of 100.4 nm, PDI of 0.36, and EE% 80%. The morphology, interactions, thermal properties, and crystallinity of obtained NLC formulations were investigated by TEM, FTIR, DSC, and XRD techniques. The optimum sage extract-loaded/gelatin-coated NLC showed significantly higher antioxidant activity than free extract after 30 days of storage. It also indicated a higher inhibitory effect against E. coli and P. aeruginosa than free form in MIC and MBC tests. The optimum sage extract-loaded/gelatin-coated NLC, more than free extract, increased the oxidation stability of the treated beef burger samples during 90 days of storage at 4 and -18 °C (verified by thiobarbituric acid and peroxide values tests). Incorporation of the optimum NLC to beef burgers also effectively decreased total counts of mesophilic bacteria, psychotropic bacteria, S. aureus, coliform, E. coli, molds, and yeasts of treated beef burger samples during 0, 3, and 7 days of storage in comparison to the control sample. These results suggested that the obtained sage extract-loaded NLC can be an effective preservative to extend the shelf life of beef burgers.

New Healthy Low-Sugar and Carotenoid-Enriched/High-Antioxidant Beverage: Study of Optimization and Physicochemical Properties.

Lutein is a prominent biologically active carotenoid pigment with a polyene skeleton that has great benefits for human health. The study examined the synergistic effects of potentially functional components, including lutein carotenoid (LC), Mentha × Piperita extract (MPE), and Citrus × aurantifolia essential oil (CAEO), all three as bioactive components and antioxidants (AOs), on the physicochemical characteristics of a new low-sugar and carotenoid-enriched high-antioxidant beverage. Sucralose was utilized as a non-nutritive sweetener. Polynomial equations obtained by combined design methodology (CDM) were fitted to the experimental data of total phenolic and flavonoid contents (TPC and TFC, respectively) and antioxidant potential of the beverages using multiple regression analysis with R2 (determination coefficient) values of 0.87, 0.89, and 0.97, respectively. Estimated response values for the TPC, TFC, and antioxidant potential (determined as 2, 2-diphenyl-1-picrylhydrazyl radical (DPPH•) scavenging activity) of the optimum beverage formulation were 41.90 mg gallic acid equivalent (GAE) per L-1, 27.51 mg quercetin equivalent (QE) per L-1, and 34.06%, respectively, with a desirability value of 0.74. The potentially functional components had a synergistic effect on the antioxidant potential. This healthy beverage can have the potential to enhance health benefits and may have therapeutic potential for diabetic patients.

Physico-Mechanical Optimization and Antimicrobial Properties of the Bionanocomposite Films Containing Gallic Acid and Zinc Oxide Nanoparticles.

The mechanical and physical properties of the bionanocomposite films based on κ-carrageenan (KC)-gelatin (Ge) containing zinc oxide nanoparticles (ZnONPs) and gallic acid (GA) were optimized using the response surface method, and the optimum amounts of 11.19 wt% GA and 1.20 wt% ZnONPs were obtained. The results of XRD, SEM, and FT-IR tests showed the uniform distribution of the ZnONPs and GA in the film microstructure, and suitable interactions between biopolymers and these additives, which led to increasing the structural cohesion of the biopolymer matrix and improving the physical and mechanical properties of the KC-Ge-based bionanocomposite. In the films containing gallic acid and ZnONPs, an antimicrobial effect was not observed against E. coli; however, the GA-loaded and optimum films show an antimicrobial effect against S. aureus. The optimum film showed a higher inhibition effect against S. aureus compared to the ampicillin- and gentamicin-loaded discs.

Development of a Novel Low-Calorie Lime Juice-Based Prebiotic Beverage Using a Combined Design Optimization Methodology.

A novel lime-juice based low-calorie functional beverage was developed by using D-optimal combined design optimization. For the preparation of the beverage, the following functional ingredients were used: lime juice, lime peel essential oil (LEO) as a flavoring agent and bioactive component, sucralose as a low-calorie sweetener, an inulin/polydextrose (I/P) mixture as prebiotic fibers, pectin as a thickening agent and soluble dietary fiber, lutein as a carotenoid colorant and antioxidant, and peppermint extract (ME) as a flavoring agent and bioactive component. A combined design consisting of one mixture factor (LEO/ME ratio), one numeric factor (lutein concentration), and one categoric factor (presence or absence of prebiotics) was used for optimizing the functional beverage based on the sensory quality. Regression models were adequately fitted to the data of sensory acceptance with a determination coefficient >90%. The sample containing a mixture of prebiotics, 2:3 (v/v) ratio of LEO: ME, and 3 mg/100 mL lutein was selected as the best formulation among the six optimal beverages which was suggested by Design-Expert software. This final optimum sample showed the highest total phenolic (44.22 mg gallic acid equivalents/L) and flavonoid (25.49 mg quercetin equivalents/L) contents, and its antioxidant activity (as 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) scavenging) was 38.30%. The newly designed beverage has the potential to promote health benefits and in therapeutic applications.

Cauliflower by-products as functional ingredient in bakery foods: Fortification of pizza with glucosinolates, carotenoids and phytosterols.

Industrial cauliflower by-products still represent a no-value food waste, even though they are rich in bioactive compounds. With the aim of valorizing them, optimized special flours rich in glucobrassicin, lutein, ß-carotene, and ß-sitosterol obtained from leaves, orange and violet stalks were used at 10 and 30% w/w in the formulation of functional leavened bakery. For the first time, the effect of bioactive compounds enrichment in pizza products as well as the rheological properties were evaluated. As results, pizza making process affected the recovery of the bioactive compounds. The recovery of glucobrassicin and carotenoids in pizza depended on the aerial part of cauliflower. Pizza with violet stalks was the richest in glucobrassicin, providing 8.4 mg per portion (200 g). Pizza with leaves showed the highest carotenoid content with a 90% of recovery rate while pizza with orange stalks provided up to 5.8% of the phytosterols health claim requirement. All 10% enriched pizzas revealed viscoelastic and springiness properties similar to the control, contrary to 30% fortification level. Therefore, the use of 10% special flour in pizza should meet both technological industrial processing and consumer acceptance. Orange stalks are the most promising ingredients for high levels of fortification in pizzas.

Application of mixture design methodology for development of high antioxidant fruity functional beverage.

Three red color fruit juice (pomegranate (PJ), barberry (BJ), and grape juice (GJ)) and three plant extracts (cardamom essential oil (CE), ginger extract (GE), and hibiscus solution (HS)) were used for the development of different functional beverages. Organoleptic analysis was done to detect the most acceptable fruit juice blend. The physicochemical properties of the samples including total phenols, 1,1-diphenyl-2-picrylhydrazyl (DPPH) inhibition percent, anthocyanin, flavonoid, and vitamin C content of optimum fruit juice blend (60% PJ/20% BJ/20% GJ) were 121.57 µg gallic acid equivalent (GAE)/ml, 80.28%, 4.03 mg/L, 64.87 mg/100 ml, and 51.10 mg/100 ml, respectively. To determine the optimum level of extracts and essential oil (GE, CE, and HS) in fruit juice blends, the mixture design method was used and 14 runs (formulations) were obtained. In all formulations, samples containing HS had the highest content of antioxidant and active components and the statistical analysis indicated that the sample containing 0.5 CE/0.5 GE/1 HS (ml/100 ml) had the optimum content of antioxidant components. Thus, the results of this study introduce a functional drink possessing high polyphenols, antioxidants, anthocyanin, and vitamin C content.

Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder.

Telomere biology disorders (TBDs) are a spectrum of multisystem inherited disorders characterized by bone marrow failure, resulting from mutations in the genes encoding telomerase or other proteins involved in maintaining telomere length and integrity. Pathogenicity of variants in these genes can be hard to evaluate, because TBD mutations show highly variable penetrance and genetic anticipation related to inheritance of shorter telomeres with each generation. Thus, detailed functional analysis of newly identified variants is often essential. Herein, we describe a patient with compound heterozygous variants in the TERT gene, which encodes the catalytic subunit of telomerase, hTERT. This patient had the extremely severe Hoyeraal-Hreidarsson form of TBD, although his heterozygous parents were clinically unaffected. Molecular dynamic modeling and detailed biochemical analyses demonstrate that one allele (L557P) affects association of hTERT with its cognate RNA component hTR, whereas the other (K1050E) affects the binding of telomerase to its DNA substrate and enzyme processivity. Unexpectedly, the data demonstrate a functional interaction between the proteins encoded by the two alleles, with wild-type hTERT rescuing the effect of K1050E on processivity, whereas L557P hTERT does not. These data contribute to the mechanistic understanding of telomerase, indicating that RNA binding in one hTERT molecule affects the processivity of telomere addition by the other molecule. This work emphasizes the importance of functional characterization of TERT variants to reach a definitive molecular diagnosis for patients with TBD, and, in particular, it illustrates the importance of analyzing the effects of compound heterozygous variants in combination, to reveal interallelic effects.

Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28-4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Polysaccharide extracted from Althaea officinalis L. root: New studies of structural, rheological and antioxidant properties.

A water-soluble acidic polysaccharide (AOP-2) from Althaea officinalis L. root was isolated by water extraction and purified by ion exchange chromatography (Cellulose DEAE-52) and gel filtration (Sephadex G-200). The structure characteristics of AOP-2 was determined by gel permeation chromatography (GPC), high performance liquid chromatography (HPLC), fourier transform infrared (FT-IR), nuclear magnetic resonance (NMR) spectrum and gas chromatography-mass spectrometry (GC_MS). The results indicated that the AOP-2 was an acidic hetropolysaccharide with the molecular weight of 639.27 kDa. The AOP-2 composed of 51% galacturonic acid, 32.56% rhamnose, 12.73% glucose and 3.71% galactose. It could be found that the main backbone chain of AOP-2 consisted of →3)-α-D-GalpA-(1→, →3)-α-D-Rhap-(1→ and→3,4)-ß-D-Galp-(1→ with branches of →4)-α-D-Rhap-(1→, →4)-α-D-Glcp-(1→ and α-D-Rhap-(1 â†’ . Thermal analysis revealed that the AOP-2 had high thermal stability and according to the results obtained from XRD analysis, it had a semi-crystalline structure. The results of Steady-shear flow and dynamical viscoelasticity showed that AOP-2 solutions exhibited shear-thinning behavior with high viscosity and a weak gel-like behavior at concentrations above 1% in linear viscoelastic region. In addition, it showed relatively high antioxidant property.

γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival.

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4+ or CD8+ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (>20% DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2- γδ T cells. In the context of γδ T-cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T-cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti-PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T-cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions.See related Spotlight on p. 600.

A novel cause of DKC1-related bone marrow failure: Partial deletion of the 3' untranslated region.

Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting in the bone marrow failure that is characteristic of these disorders. While an increasing number of genes are being linked to TBDs, the causative mutation remains unidentified in 30-40% of patients with DC. There is therefore a need for whole genome sequencing (WGS) in these families to identify novel genes, or mutations in regulatory regions of known disease-causing genes. Here we describe a family in which a partial deletion of the 3' untranslated region (3' UTR) of DKC1, encoding the protein dyskerin, was identified by WGS, despite being missed by whole exome sequencing. The deletion segregated with disease across the family and resulted in reduced levels of DKC1 mRNA in the proband. We demonstrate that the DKC1 3' UTR contains two polyadenylation signals, both of which were removed by this deletion, likely causing mRNA instability. Consistent with the major function of dyskerin in stabilization of the RNA subunit of telomerase, hTR, the level of hTR was also reduced in the proband, providing a molecular basis for his very short telomeres. This study demonstrates that the terminal region of the 3' UTR of the DKC1 gene is essential for gene function and illustrates the importance of analyzing regulatory regions of the genome for molecular diagnosis of inherited disease.

The effect of Macro and Nano-emulsions of cinnamon essential oil on the properties of edible active films.

The effect of Nano-emulsion (NE) and Macro-emulsion (ME) of cinnamon essential oil (CEO) on the properties of carboxymethyl cellulose (CMC)-based films was investigated. MEs (diameters of 242-362 nm) and NEs (diameters of 59-80 nm) of CEO were produced through Ultra-Turrax and Ultrasonication, respectively. The scanning electron microscopy (SEM) and atomic force microscopy (AFM) images showed different morphologies in the films containing ME and NE, also a denser and more uniform microstructure was observed in the NE films in comparison with the ME ones. The higher stability of NE in the CMC matrix, increased the thickness of the resulted films. The water vapor permeability (WVP) was increased from 2.59 × 10-9 g/ms Pa in the control film to 4.43 × 10-9 g/m s Pa in the ME film, and decreased to 1.80 × 10-9 g/ms Pa in the NE film. Adding CEO led to more flexible films with enhanced strain at break (SAB) from 53.56% in the control film to 80% and 94.77% in the ME and NE films, respectively. The antifungal indices against A. niger and M. racemous were 14.16% and 20.82% in the ME films, and were improved to 18.81% and 25% in the NE ones.

The emulsifying and foaming properties of Amuniacum gum (Dorema ammoniacum) in comparison with gum Arabic.

In this study, the emulsifying and foaming properties of a novel exudate gum from Dorema ammoniacum (AMG) were assessed in comparison with the well-known gum Arabic from Acacia tree (GAC). The sunflower oil-based emulsion (10% v/v) containing various concentrations (5%-15% w/v) of AMG and GAC was prepared. At all concentrations, AMG showed higher surface and interface activity than GAC. Increasing in AMG and GAC concentrations caused to increase and decrease in Z average, respectively. Overall, the GAC-stabilized emulsion showed lower Z average and PDI value than the AMG-stabilized emulsion during storage time. The sample containing AMG showed higher emulsion capacity and lower emulsion stability in comparison with the one containing GAC at all concentrations. The storage stability decreased and increased with increasing in AMG and GAC concentrations, respectively. After two-week storage, the emulsions containing 10 and 15% AMG showed higher phase separation than those containing GAC; however, this was opposite about sample containing 5% AMG. At thermal, centrifuge, and freezing conditions, the emulsion containing 5% AMG indicated significantly higher stability than GAC samples; however, at higher concentration, opposite effect could be observed. The foaming capacity of the samples containing AMG increased from 81% to 93% by increasing gum concentration from 5% to 15%. The solutions containing AMG showed higher foam capacity than control samples (without gum) and those containing GAC at all concentrations. Increasing in AMG and GAC concentrations slightly improved foam stability, and the highest value (92%) belonged to 15% AMG solution.

Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children.

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. METHODS: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. RESULTS: No SNPs reached genome-wide significance (p < 5 × 10-8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10-6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10-7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10-7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. CONCLUSION: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.

Observation of inverse Compton emission from a long γ-ray burst.

Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1-6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7-9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10-6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.

Propofol-based palliative sedation in terminally ill children with solid tumors: A case series.

RATIONALE: The palliative sedation therapy is defined as the intentional reduction of the alert state, using pharmacological tools. Propofol is a short-acting general anesthetic agent, widely used for induction and maintenance of general anesthesia and rarely employed in palliative care. PATIENT CONCERNS AND DIAGNOSES: This case series describes 5 pediatric oncology inpatients affected by relapsed/refractory solid tumors received palliative sedation using propofol alone or in combination with opioids and benzodiazepines. INTERVENTIONS AND OUTCOMES: Five terminally ill children affected by solid tumors received propofol-based palliative sedation. All patients were previously treated with opioids and some of them reduced the consumption of these drugs after propofol starting. In all cases the progressive increase of the level of sedation until the death has been the only effective measure of control of refractory symptoms related todisease progression and psychological suffering. LESSONS: We evaluated the quality of propofol-based palliative sedation in a series of pediatric oncology patients with solid tumors at the end of their life. We concluded that propofol represents an effective and tolerable adjuvant drug for the management of intractable suffering and a practicable strategy for palliative sedation in pediatric oncology patients at the end of their life.

Morphology and dynamics of tumor cell colonies propagating in epidermal growth factor supplemented media.

The epidermal growth factor (EGF) plays a key role in physiological and pathological processes. This work reports on the influence of EGF concentration (c EGF) on the modulation of individual cell phenotype and cell colony kinetics with the aim of perturbing the colony front roughness fluctuations. For this purpose, HeLa cell colonies that remain confluent along the whole expansion process with initial quasi-radial geometry and different initial cell populations, as well as colonies with initial quasi-linear geometry and large cell population, are employed. Cell size and morphology as well as its adhesive characteristics depend on c EGF. Quasi-radial colonies (QRC) expansion kinetics in EGF-containing medium exhibits a complex behavior. Namely, at the first stages of growth, the average QRC radius evolution can be described by a t 1/2 diffusion term coupled with exponential growth kinetics up to a critical time, and afterwards a growth regime approaching constant velocity. The extension of each regime depends on c EGF and colony history. In the presence of EGF, the initial expansion of quasi-linear colonies (QLCs) also exhibits morphological changes at both the cell and the colony levels. In these cases, the cell density at the colony border region becomes smaller than in the absence of EGF and consequently, the extension of the effective rim where cell duplication and motility contribute to the colony expansion increases. QLC front displacement velocity increases with c EGF up to a maximum value in the 2-10 ng ml-1 range. Individual cell velocity is increased by EGF, and an enhancement in both the persistence and the ballistic characteristics of cell trajectories can be distinguished. For an intermediate c EGF, collective cell displacements contribute to the roughening of the colony contours. This global dynamics becomes compatible with the standard Kardar-Parisi-Zhang growth model, although a faster colony roughness saturation in EGF-containing medium than in the control medium is observed.