OpenPBTA: The Open Pediatric Brain Tumor Atlas.

Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas and TP53 loss as a significant marker for poor overall survival in ependymomas and H3 K28-mutant diffuse midline gliomas. Already being actively applied to other pediatric cancers and PNOC molecular tumor board decision-making, OpenPBTA is an invaluable resource to the pediatric oncology community.

Durian Shell-Mediated Simple Green Synthesis of Nanocopper against Plant Pathogenic Fungi.

The synthesis of fungicides in eco-friendly and cost-effective ways is significantly essential for agriculture. Plant pathogenic fungi cause many ecological and economic issues worldwide, which must be treated with effective fungicides. Here, this study proposes the biosynthesis of fungicides, which combines copper and Cu2O nanoparticles (Cu/Cu2O) synthesized using durian shell (DS) extract as a reducing agent in aqueous media. Sugar and polyphenol compounds contained in DS, as the main phytochemicals acting in the reduction procedure, were extracted under different temperatures and duration conditions to obtain the highest yields. We confirmed the extraction process performed at 70 °C for 60 min to be the most effective in extracting sugar (6.1 g/L) and polyphenols (22.7 mg/L). We determined the suitable conditions for Cu/Cu2O synthesis using a DS extract as a reducing agent for a synthesis time of 90 min, a volume ratio of DR extract/Cu2+ of 15:35, an initial pH solution of 10, a synthesis temperature of 70 °C, and a CuSO4 concentration of 10 mM. The characterization results of as-prepared Cu/Cu2O NP showed a highly crystalline structure of Cu2O and Cu with sizes estimated in the range of 40-25 nm and 25-30 nm, respectively. Through in vitro experiments, the antifungal efficacy of Cu/Cu2O against Corynespora cassiicola and Neoscytalidium dimidiatum was investigated by the inhibition zone. The green-synthesized Cu/Cu2O nanocomposites, which are potential antifungals against plant pathogens, exhibited excellent antifungal efficacy against both Corynespora cassiicola (MIC = 0.25 g/L, the diameter of the inhibition zone was 22.00 ± 0.52 mm) and Neoscytalidium dimidiatum (MIC = 0.0625 g/L, the diameter of the inhibition zone was 18.00 ± 0.58 mm). Cu/Cu2O nanocomosites prepared in this study could be a valuable suggestion for the control of plant pathogenic fungi affecting crop species globally.

Green Orange Peel-Mediated Bioinspired Synthesis of Nanoselenium and Its Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus.

In this study, green orange peel (GOP) was feasibly evidenced in preparing selenium nanoparticles (SeNPs). Acting as reducing agents, polyphenolic compounds were extracted from GOP at the optimal extraction conditions (at 70 °C for 1.5 h, mass ratio of dried orange peel/distilled water of 5/100). The formation of SeNPs was observed at the wavelength range of 250-300 nm by ultraviolet-visible spectroscopy (UV-vis), and their highest yield could be reached at the following conditions: volume ratio of extract/selenious acid solution (V Ext/V Se) of 40/10, synthesis duration of 4 h, selenious acid concentration (C Se) of 80 mM, and reaction temperature of 120 °C. The highly crystalline structure of SeNPs in the hexagonal phase was characterized by powder X-ray diffraction (XRD) with a lattice parameter of 4.3 Å; meanwhile, their spheres with an average crystal size of 18.3 nm were estimated by high-resolution transmission electron microscope (HR-TEM). The rationale of bioreducing agents extracted from green orange peel for the formation of SeNPs was also recognized by Fourier-transform infrared spectroscopy (FT-IR). The antibacterial investigation of the SeNP sample was assessed against antibiotic-resistant bacteria, typically methicillin-resistant Staphylococcus aureus (MRSA), by executing the zone of inhibition and the minimum inhibitory concentration (MIC) tests. The SeNP sample demonstrated excellent antibacterial activity with an average diameter of inhibition zones of 20.0 ± 0.7 mm and an MIC of 4.94 µg/L. A comparison of the physicochemical properties of SeNPs synthesized from GOP extract by the hydrothermal method with SeNP products from other green reducing agents and other methods as well as its antibacterial activity compared with other nanoparticles and some antibiotics was conducted to highlight the superiority of GOP-mediated green-synthesized SeNPs.

A novel biosensing system for rapid and sensitive detection of heavy metal toxicity in water.

Toxicity biosensors have recently gained significant attention due to their potential use in online monitoring. However, the effects of toxicants and the influence of dose, exposure time, and type and concentration of respiration substrate (RS) on the performance of a bioreactor are species-specific. Although these factors need to be investigated case-by-case as they can lead either to damage or self-repair of the affected microorganisms, they have seldom been considered in previous studies. Therefore, this work examined, for the first time, the effects of resting time and RS concentration on the performance of the biosensing system for toxicity of Cr6+ in water. In addition, it is also the first time that a novel non-contact fluid delivery system was applied to a toxicity biosensing system to prevent unstable responses. By choosing the best RS concentration and balancing the resting and exposure times, the proposed procedure exhibits promising results in terms of minimum detectable concentration (MDC), limit of detection (LOD), detection range, linearity, sensitivity, reproducibility and accuracy. The recovery time was only a few hours and the coefficients of variation of inhibition and recovery were only 12% and 9.6%, respectively, during six times reuse over one month of storage.

Simple approach for the rapid estimation of BOD5 in food processing wastewater.

A simple approach was developed for the rapid and accurate estimation of 5-day biochemical oxygen demand (BOD5) in food processing wastewater. Immobilization of the natural microbial consortium that was collected from an aerobic compartment of a food processing wastewater treatment plant was simply performed by adhesion using a low-cost porous carrier. Pseudomonas aeruginosa, Bacillus cereus, and Streptomyces, whose salt-tolerance and ability to break down organic compounds have been widely reported, were found to be predominant. These microorganisms may cause an enhancement of the bioreactor response in the presence of sodium chloride. Consequently, a modified glucose-glutamic acid (GGA) calibration standard was proposed in which an appropriate amount of NaCl was added; this solution was found to be more effective in terms of accuracy and practicality than both conventional GGA and the synthetic wastewater recipe from the Organisation for Economic Cooperation and Development (OECD). The calibrated self-built packed-bed bioreactor exhibited good precision of 3% or less in predicting BOD5 in influent, which is similar to the performance of the most common commercial biochemical oxygen demand (BOD) bioreactors. There was a statistical agreement between the results obtained from this rapid BOD biosensor and the conventional methods, even when testing treated wastewater samples.

Evaluating the response of the PIPER scalable human body model across child restraining seats in simulated frontal crashes.

OBJECTIVE: Booster seats ensure appropriate belt fit for children that a traditional vehicle seat belt cannot offer to small occupants. In this study, the responses of the PIPER 6-year-old human body model are compared to the traditional Q6 anthropomorphic test dummy (ATD). METHODS: Eight frontal impact finite element simulations were run using 4 different child restraining systems on the FMVSS 213 test bench. Kinematics and kinetics were extracted and compared between the 2 child models. RESULTS: The PIPER 6-year-old showed variation by 11.2 ± 14.1% (head resultant acceleration, G), 20.4 ± 50.3% (chest resultant acceleration, G), 272.9 ± 188.4% (chest displacement, mm), 24.8 ± 17.5% (maximum head excursion, mm), -31.5 ± 5.1% (neck force, Fz, N), -73.8 ± 2.8% (neck moment, My, N.m), and -60.4 ± 7.2% (Nij) compared to the Q6. However, the kinematics of both models were nearly similar. CONCLUSIONS: The PIPER model has a flexible neck and shows higher chest displacement compared to the Q6. We hypothesize that this is due to the inherent anatomical and mechanical differences between the human body model and the ATD model. More research is needed to explore these differences systematically.

Encapsulating darunavir nanocrystals within Eudragit L100 using coaxial electrospraying.

Electrospraying is renowned for its simplicity and versatility, and which can effectively produce particles with well-controlled size, size distribution, particle shape, morphology and microstructure at the nano/microscale. In this study, coaxial electrospraying was used to investigate its feasibility for preparing nanoparticles made up of nanocrystals encapsulated within a polymer shell. Firstly, aqueous nanosuspensions of darunavir were prepared by wet media milling. Then the nanosuspension and solutions of an enteric polymer, Eudragit L100, were used as the inner/core liquid and outer/shell liquid in a coaxial electrospraying setup, respectively. As long as a sufficiently high voltage was applied, a stable Taylor cone-jet mode was obtained to produce very fine core-shell structure nanoparticles with high darunavir encapsulation efficiency of approximately 90%. The influence of the starting nanosuspension and the flow rates on the characteristics of the final electrosprayed particles was also evaluated. Using an optimized nanosuspension with reasonable size, size distribution and flow rates, the enteric coating layer reduced the percentage of DRV release in acidic medium in the in vitro dissolution test to ca. 20%. This study indicates that coaxial electrospraying is a potential and unique technique for encapsulating drug nanocrystals within a polymeric shell.

Pharmaceutical Applications of Electrospraying.

The electrohydrodynamic atomization technique, or simply called electrospraying, has been extensively studied for biomedical as well as for pharmaceutical applications over the past years. The simplicity, flexibility, and efficiency of producing particles at the microscale or nanoscale, with tailored size, shape, morphology, and microstructure, make electrospraying to become one of the most promising and well-practiced approaches to be applied in many biomedical and pharmaceutical fields, from improving the bioavailability of poorly aqueous soluble drugs, preparing targeted drug delivery systems, and controllable drug release systems to delivering sensitive therapeutic agents such as protein-based drugs or even living cells. Nevertheless, some issues still remain with respect to low throughput as well as the complex interplay between a great number of processing and formulation factors. A comprehensive understanding of these fundamental aspects is essential for the successful application of electrospraying for the production of particulate formulations with desired properties.

One-step production of darunavir solid dispersion nanoparticles coated with enteric polymers using electrospraying.

OBJECTIVES: The aim of this work was to investigate the feasibility of producing darunavir (DRV) solid dispersion nanoparticles coated with an enteric polymer in one single step using electrospraying. METHODS: The core-shell nanoparticles were made using coaxial electrospraying. A solution of DRV with hydroxypropyl methylcellulose in a mixture of organic solvents formed the core, while the shell was produced from an enteric polymer (Eudragit L100) dissolved in an organic solvent. The final particles were evaluated in terms of morphology, physical state, encapsulation efficiency and in-vitro dissolution. KEY FINDINGS: Nanoparticles of encapsulated DRV solid dispersions within Eudragit L100 were successfully prepared with high encapsulation efficiency (90%). The enteric coating layer reduced the percentage of DRV release in acidic medium in the in-vitro dissolution test to less than 20%. CONCLUSIONS: This study showed the potential of coaxial electrospraying for encapsulating solid dispersions within core-shell structured nanoparticles.

Breast cancer aromatase expression evaluated by the novel antibody 677: correlations to intra-tumor estrogen levels and hormone receptor status.

Breast cancer tissue estrogen levels on an average exceed plasma as well as benign breast tissue levels. To evaluate the contribution of intra-tumor aromatization to individual tumor estrogen levels (estradiol, E2; estrone, E1; estrone sulfate, E1S), breast cancer tissue sections obtained during mastectomy in 28 postmenopausal breast cancer patients were stained for aromatase protein expression using the aromatase antibody 677. The findings were correlated to intra-tumor estrogen levels determined with a highly sensitive HPLC-RIA. Staining with 677 alone (irrespective of the hormone receptor status) revealed no difference in tumor E2 levels comparing 677+ versus 677- tumors, although a non-significant trend towards higher tumor E1 and E1S levels was observed in 677+ breast cancers. In contrast, tumor levels of E(2) were significantly higher in ER+ tumors compared to ER- tumors (P<0.001) and to benign breast tissue from the same breast (P<0.001). Analysing the additional effect of positive staining with the aromatase antibody 677 on tumor estrogen levels in the subgroup of ER+ tumors, revealed significantly higher tumor levels of E2 (mean level of 544.7 versus 197.1 fmol/g tissue) as well as a non-significant trend concerning tumor E1 (mean level of 296.9 versus 102.1 fmol/g tissue). The mean tumor tissue E1S level was observed somewhat lower in ER+677+ (103.5 fmol/g) versus ER+677- tumors (190.1 fmol/g). In the subgroup of ER+PgR+ tumors, tissue levels of E2 were also found to be significantly higher among 677+ compared to 677- tumors: 873.2 fmol/g (95% CI 395.9-1925.6) versus 217.9 fmol/g (95% CI 88.8-534.9) (P=0.015). In conclusion, our results indicate a moderate effect of aromatase enzyme expression evaluated by IHC using the antibody 677 on intra-tumor estrogen levels among ER+ breast cancers. A substantial interindividual variation in the ratios between the individual estrogen fractions suggests additional effects, like alterations in other enzymes to be involved in the intra-tumor estrogen homeostasis.

Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels.

PURPOSE: To evaluate the influence of the third-generation aromatase inhibitor letrozole (Femara) on breast cancer tissue levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S) in postmenopausal women undergoing primary treatment for locally advanced estrogen receptor/progesterone receptor-positive breast cancers. EXPERIMENTAL DESIGN: Breast cancer tissue samples were collected before and following 4 months of neoadjuvant therapy with letrozole (2.5 mg o.d.), and tissue estrogen levels measured using a highly sensitive RIA after high-pressure liquid chromatography purification. RESULTS: Letrozole suppressed pretreatment tumor levels of E(2), E(1), and E(1)S by 97.6%, 90.7%, and 90.1%, respectively. These data reveal that letrozole suppresses tissue estrogen levels significantly below what has previously been recorded with anastrozole (89.0%, 83.4%, and 72.9% suppression, respectively) using the same methods. To confirm the differential effect of letrozole and anastrozole on each plasma estrogen fraction, we re-analyzed plasma samples obtained from a previous intrapatient cross-over study comparing letrozole and anastrozole using an improved RIA (detection limits of 0.67, 1.14, and 0.55 pmol/L for E(2), E(1), and E(1)S, respectively). Letrozole consistently suppressed each plasma estrogen fraction below the levels recorded for anastrozole: E(2) (average suppression by 95.2% versus 92.8%; P = 0.018), E(1) (98.8% suppression versus 96.3%; P = 0.003), and E(1)S (98.9% suppression versus 95.3%; P = 0.003). CONCLUSION: Our data reveals that letrozole (2.5 mg o.d.) is more effective compared with anastrozole (1.0 mg o.d.) with respect to tissue as well as plasma estrogen suppression in patients with postmenopausal breast cancer.

An optimised, highly sensitive radioimmunoassay for the simultaneous measurement of estrone, estradiol and estrone sulfate in the ultra-low range in human plasma samples.

Following the introduction of potent aromatase inhibitors for the treatment of breast cancer patients, highly sensitive methods have become mandatory to evaluate the influence of these drugs on plasma estrogen levels. Commercially available kits for estrogen measurements are not suitable for these kinds of evaluations due to their detection limits that are close to baseline estrogen levels in postmenopausal women. We describe here an optimised radioimmunoassay suitable for the simultaneous measurement of plasma estrone (E1), estradiol (E2) and estrone sulfate (E1S) levels in the ultra-low range. Following incubation with [3H]-labelled estrogens as internal standards, crude estrogen fractions were separated by ether extraction. The E1S fraction was hydrolysed with sulfatase followed by eluation on a Sephadex column. Free estrogens (E1, E2) were separated by chromatography (LH-20). Estrone and E1S (following hydrolysis) were converted into E2, and each estrogen fraction was measured by the same highly sensitive and specific radioimmunoassay using estradiol-6-(O-carboxymethyl)-oximino-2-(2-[125 I]-iodo-histamine) as ligand. Although several purification steps were involved, the internal recovery values for tritiated estrogens were found to be 88%, 90%, and 49% for E1, E2 and E1S, respectively. The intra-assay coefficient of variation was <5% for all recovery measurements. The detection limits were calculated following repeated blank measurements and found to be 1.14 pmol/L for E1, 0.67 pmol/L for E2, and 0.55 pmol/L for E1S, respectively. The intra-assay coefficient of variation (CV) was found to be 3.4% for E1, 5.1% for E2 and 6.1% for E1S, while the inter-assay CV was 13.6%, 7.6% and 7.5% for E1, E2, and E1S, respectively. Considering normal plasma levels for E2 (15 pmol/L), E1 (80 pmol/L) and E1S (400 pmol/L) in postmenopausal women, the method allows theoretically to detect suppression of plasma E2, E1 and E1S levels by 95.5%, 98.6% and 99.9% when starting from average, normal postmenopausal levels. Thus, the method presented here is to our knowledge the currently most sensitive assay available for plasma estrogen measurements in the ultra-low range and, as such, a reliable tool for a proper evaluation of potent aromatase inhibitors and other potential drugs influencing on plasma estrogen levels.

Periodic knolls and valleys: coexistence of solid and liquid states in granular suspensions.

We report the spontaneous emergence of a doubly periodic train of sedimented knolls in a dense suspension. These solidified knolls rise out of, and coexist alongside, a sea of freely flowing liquid in a slowly rotating horizontal bottle. We apply a variable viscosity model that permits simultaneous analysis of fluidlike and solidlike behaviors that are ubiquitous in a variety of sedimenting flows. The model generates qualitative agreement with experiments, and produces new insights into mechanisms by which sedimented structures form.

A homogeneity study using NIR spectroscopy: tracking magnesium stearate in Bohle bin-blender.

A method was developed for studying mixing of cohesive pharmaceutical mixtures. A combination of accurate sampling and NIR spectroscopic analysis was developed as a suitable method to determine homogenization of magnesium stearate as a function of blending variables. A typical pharmaceutical blend containing a ratio 35:64:1 lactose, avicel, and magnesium stearate was used as a model system. The method accounted for variability of the concentration of magnesium stearate as well as variability of the excipients. Levels of magnesium stearate as low as 0.05% could be resolved by the method, and showed a predicting confidence interval above 98%.