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BioRxiv : the Preprint Server For... Jun 2024About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor...
About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor growth. Despite progress in development of small molecules for treatment of mutant KRAS cancers, there is a need for a pan-RAS inhibitor that is effective against all RAS isoforms and variants and that avoids drug resistance. We have previously shown that the naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is a potent RAS degrader that can be re-engineered as a biologic therapy to induce regression of colorectal, breast, and pancreatic tumors. Here, we have developed a strategy for in vivo expression of this RAS degrader via mRNA delivery using a synthetic nonviral gene delivery platform composed of the poly(ethylene glycol)--poly(propylene sulfide) (PEG--PPS) block copolymer conjugated to a dendritic cationic peptide (PPDP2). Using this strategy, PPDP2 is shown to deliver mRNA to both human and mouse pancreatic cells resulting in RRSP gene expression, activity, and loss of cell proliferation. Further, pancreatic tumors are reduced with residual tumors lacking detectable RAS and phosphorylated ERK. These data support that mRNA-loaded synthetic nanocarrier delivery of a RAS degrader can interrupt the RAS signaling system within pancreatic cancer cells while avoiding side effects during therapy.
PubMed: 38948803
DOI: 10.1101/2024.06.11.598439 -
ACS Applied Materials & Interfaces Jun 2024Membranous nephropathy (MN) is a common immune-mediated glomerular disease that requires the development of safe and highly effective therapies. Celastrol (CLT) has...
Membranous nephropathy (MN) is a common immune-mediated glomerular disease that requires the development of safe and highly effective therapies. Celastrol (CLT) has shown promise as a therapeutic molecule candidate, but its clinical use is currently limited due to off-target toxicity. Given that excess levels of reactive oxygen species (ROS) contributing to podocyte damage is a key driver of MN progression to end-stage renal disease, we rationally designed ROS-responsive cationic polymeric nanoparticles (PPS-CPNs) with a well-defined particle size and surface charge by employing poly(propylene sulfide)-polyethylene glycol (PPS-PEG) and poly(propylene sulfide)-polyethylenimine (PPS-PEI) to selectively deliver CLT to the damaged glomerulus for MN therapy. Experimental results show that PPS-CPNs successfully crossed the fenestrated endothelium, accumulated in the glomerular basement membrane (GBM), and were internalized by podocytes where rapid drug release was triggered by the overproduction of ROS, thereby outperforming nonresponsive CLT nanotherapy to alleviate subepithelial immune deposits, podocyte foot process effacement, and GBM expansion in a rat MN model. Moreover, the ROS-responsive CLT nanotherapy was associated with significantly lower toxicity to major organs than free CLT. These results suggest that encapsulating CLT into PPS-CPNs can improve efficacy and reduce toxicity as a promising treatment option for MN.
PubMed: 38940537
DOI: 10.1021/acsami.4c04345 -
Micromachines Jun 2024This study developed a novel dielectric wetting microfluidic operation platform combining parallel-plate and coplanar-plate regions with a curved surface structure as...
This study developed a novel dielectric wetting microfluidic operation platform combining parallel-plate and coplanar-plate regions with a curved surface structure as the connection structure. With the new electrowetting on dielectric (EWOD) platform, "droplet pull-out" has been successfully achieved and viewed as an essential new operation for microfluidics with the dielectric wetting technique. The EWOD system is divided into a PDMS substrate top plate and an indium tin oxide (ITO) glass substrate as a bottom layer on this chip. In the parallel-plate region, the droplets can be generated and transported through the square parallel electrodes; in the single-plate area, the droplets can be pulled out from the parallel structure, transported and mixed through the common grounded coplanar electrodes. In dielectric wetting performance testing, coplanar electrodes can apply a maximum driving force of 31.22 µN to DI water and 13.38 µN to propylene carbonate (PC). This driving force is sufficient to detach the sample from the top cover and pull the sub-droplet from the parallel plate structure for DI water, PC and polyethylene glycol diacrylate (PEGDA) buffer. The novel EWOD system also possesses the advantage of precise volume control for liquid samples; the volume error of the generated droplet can be controlled within 0.1% to 2%.
PubMed: 38930767
DOI: 10.3390/mi15060797 -
Materials (Basel, Switzerland) Jun 2024Studying multiple properties of a material concurrently is essential for obtaining a comprehensive understanding of its behavior and performance. However, this approach...
Studying multiple properties of a material concurrently is essential for obtaining a comprehensive understanding of its behavior and performance. However, this approach presents certain challenges. For instance, simultaneous examination of various properties often necessitates extensive experimental resources, thereby increasing the overall cost and time required for research. Furthermore, the pursuit of desirable properties for one application may conflict with those needed for another, leading to trade-off scenarios. In this study, we focused on investigating adhesive joint strength and elastic modulus, both crucial properties directly impacting adhesive behavior. To determine elastic modulus, we employed a non-destructive indentation method for converting hardness measurements. Additionally, we introduced a specimen apparatus preparation method to ensure the fabrication of smooth surfaces and homogeneous polymeric specimens, free from voids and bubbles. Our experiments utilized a commercially available bisphenol A-based epoxy resin in combination with a Poly(propylene glycol) curing agent. We generated an initial dataset comprising experimental results from 32 conditions, which served as input for training a machine learning model. Subsequently, we used this model to predict outcomes for a total of 256 conditions. To address the high deviation in prediction results, we implemented active learning approaches, achieving a 50% reduction in deviation while maintaining model accuracy. Through our analysis, we observed a trade-off boundary (Pareto frontier line) between adhesive joint strength and elastic modulus. Leveraging Bayesian optimization, we successfully identified experimental conditions that surpassed this boundary, yielding an adhesive joint strength of 25.2 MPa and an elastic modulus of 182.5 MPa.
PubMed: 38930235
DOI: 10.3390/ma17122866 -
Chemistry & Biodiversity Jun 2024This research aims to create an emulsion formulation utilizing lignin as a carrier and citronella oil for its application as a herbicide. The formulation composition...
This research aims to create an emulsion formulation utilizing lignin as a carrier and citronella oil for its application as a herbicide. The formulation composition includes lignin solution 55-62%v/v, Tween 80 25%w/v, propylene glycol 10%w/v, and citronella oil 3-10%w/v. The preparation steps involve preparing the oil phase by mixing tween 80 surfactant, propylene glycol, and citronella oil; preparing the aqueous phase by mixing lignin into distilled water at pH 12 with stirring; mixing the oil phase and the water phase accompanied by stirring at 5000-10000 rpm for 1-5 minutes until a stable solution is formed as a natural herbicide. The application outcomes revealed that the formulation successfully eliminated specific weeds within two to three days at the maximum concentration of 10%, leaving no detectable herbicide residue after 7 and 15 days of treatment. The result demonstrates how green technology has the capacity to replace herbicides derived from chemicals, especially in the agricultural sector.
PubMed: 38927001
DOI: 10.1002/cbdv.202400861 -
Dermatitis : Contact, Atopic,... Jun 2024Recent evidence shows similar rates of allergic contact dermatitis (ACD) among children and adults despite children accounting for less than 10% of patch testing...
Recent evidence shows similar rates of allergic contact dermatitis (ACD) among children and adults despite children accounting for less than 10% of patch testing subjects. With a need for in-depth analyses of pediatric ACD, we herein characterize a pediatric cohort at a large North American patch testing center. A retrospective chart review was conducted for 135 patients ages 1-17 years who underwent patch testing from July 2020 from August 2023. Data were stratified by age 1-5, 6-11, and 12-17 years. Significance-Prevalence Index Numbers (SPIN) were calculated. A total of 86% were sensitized, 40% had a relevant reaction, and positivity rates were equal between males and females. Top allergens by SPIN differed with age, but overall were linalool hydroperoxides (SPIN = 11.01), propylene glycol (10.30), limonene hydroperoxides (10.27), fragrance mix I (5.62), and lanolin (4.90). In total, 14% of the top allergens were not represented on the North American Contact Dermatitis Group standard series. Of those tested to personal products, 45% had positive reactions and 72% of which were relevant. Emulsifiers and fragrances were the most relevant allergen categories, with the impact of emulsifiers not previously reported. ACD may affect males and females equally in this population. Supplemental allergens and personal products tested "as-is" contribute to conclusive pediatric patch testing.
PubMed: 38913333
DOI: 10.1089/derm.2024.0005 -
Dental Materials : Official Publication... Jun 2024The permeability of triamcinolone acetonide (TA), from bilayer mucoadhesive buccal films, through a biomimetic membrane, Permeapad™, was investigated employing Franz...
OBJECTIVES
The permeability of triamcinolone acetonide (TA), from bilayer mucoadhesive buccal films, through a biomimetic membrane, Permeapad™, was investigated employing Franz diffusion cell. The delivery systems composition and ethyl cellulose (EC) backing layer, on drug permeability, were assessed.
METHODS
Three TA-loaded films were tested; hydroxypropyl methylcellulose (HPMC K4M; bilayer [F1] and monolayer), HPMC K4M/Polyvinylpyrrolidone (PVP): 90/10 [F2], and HPMC K15M film [F3]. All films contained propylene glycol (PG-plasticiser). TA solution alone was used as a control. TA permeability via a Permeapad™ barrier, simulating buccal mucosa, was assessed over 8 h using a Franz diffusion cell. TA permeated into the receptor compartment, released in the donor compartment, and located on/within the Permeapad™ barrier were analysed using UV-spectrophotometer.
RESULTS
45.7 % drug retention within the Permeapad™ barrier was delivered from F1 (highest). F1, F2, and F3 significantly improved the TA's permeability through Permeapad™, compared to TA solution alone (e.g., 8.5 % TA-solution, 21.5 %-F1), attributed to the synergy effect of HPMC and propylene glycol acting as penetration enhancers. F1 displayed a significant increase in drug permeability (receptor compartment; 21.5 %) compared to F3 (17.0 %). PVP significantly enhanced drug permeability (27.5 %). Impermeable EC backing layer controlled unidirectional drug release and reduced drug loss into the donor compartment (e.g., ∼28 % for monolayer film to ∼10 % for bilayer film, F1).
SIGNIFICANCE
The mucoadhesive films demonstrated improved TA permeability via Permeapad™. The findings suggest that these bilayer mucoadhesive films, particularly F1, hold promise for the effective topical treatment of oral mucosa disorders, such as recurrent aphthous stomatitis and oral lichen planus.
PubMed: 38902145
DOI: 10.1016/j.dental.2024.06.016 -
Materials (Basel, Switzerland) Jun 2024The application of polyesters as food contact materials is an alternative to epoxy resin coatings, which can be a source of endocrine migrants. By using high-pressure...
The application of polyesters as food contact materials is an alternative to epoxy resin coatings, which can be a source of endocrine migrants. By using high-pressure liquid chromatography/electrospray ionization-mass spectrometry (HPLC/ESI-MS) with cone voltage-induced fragmentation in-source, a number of polyester-derived migrants were detected in the extracts of inner coatings of metallic cans. The polyester-derived migrants were detected in each inner coating of fish product-containing cans (5/5) and in one inner coating of meat product-containing can (1/5). They were not detected in the inner coatings of vegetable/fruit product-containing cans (10 samples). The respective detected parent and product ions enabled differentiation between cyclic and linear compounds, as well as unambiguous identification of diol and diacid units. Most of the detected compounds, cyclic and linear, were composed of neopentyl glycol as diol and two diacid comonomers, namely isophthalic acid and hexahydrophthalic acid. The other detected oligoesters were composed of neopentyl glycol or propylene glycol and adipic acid/isophthalic acid as comonomers. The compounds containing propylene glycol as diol were found to be exclusively linear cooligoesters. On the basis of abundances of [M+Na] ions, the relative contents of cyclic and linear oligoesters were evaluated.
PubMed: 38894033
DOI: 10.3390/ma17112771 -
Dermatitis : Contact, Atopic,... Jun 2024Topical minoxidil is generally well tolerated, yet there have been a few reports of allergic contact dermatitis (ACD) confirmed through patch testing. This systematic... (Review)
Review
Topical minoxidil is generally well tolerated, yet there have been a few reports of allergic contact dermatitis (ACD) confirmed through patch testing. This systematic review and individual participant data meta-analysis sought to elucidate the primary allergens in patients exhibiting ACD in response to topical minoxidil formulations and to ascertain the appropriate testing concentrations and vehicles of minoxidil itself. A comprehensive search was conducted across the PubMed, Scopus, and Embase databases utilizing the keywords "minoxidil" and "contact dermatitis," or "contact allergy," or "contact eczema." Studies documenting ACD in patients using topical minoxidil confirmed by patch testing were deemed eligible. Our analysis included 46 studies encompassing 99 patients with patch-test-confirmed ACD to minoxidil-based topical treatments. The majority of these patients (93.9%) were exposed to minoxidil without additional active components. Minoxidil itself was identified as the primary allergen in 74.7% of the patients, with propylene glycol being the next most common allergen at 17.1%. Other allergens identified included estradiol, butylene glycol, methylchloroisothiazolinone/methylisothiazolinone, canrenone, and latanoprost. The most effective concentration was found to be 2% minoxidil in propylene glycol, which yielded a 100% positivity rate. The findings indicate that minoxidil is the predominant allergen in ACD reactions to its topical formulations, followed by propylene glycol. For the accurate diagnosis of ACD related to minoxidil, patch testing with 2% minoxidil in propylene glycol is recommended, as are separate tests for propylene glycol and other potential allergenic ingredients.
PubMed: 38885151
DOI: 10.1089/derm.2024.0092 -
Pediatrics Jul 2024We assessed awareness and perceptions of, information sources about, and engagement in modifying electronic nicotine delivery systems (ENDS) among adolescents and young...
OBJECTIVES
We assessed awareness and perceptions of, information sources about, and engagement in modifying electronic nicotine delivery systems (ENDS) among adolescents and young adults (AYAs).
METHODS
AYAs (N = 1018) endorsing past-month ENDS use completed a survey on awareness and use of the following modifications: (1) refilling rechargeable cartridges/pods or (2) disposable pods, (3) rewicking or (4) recharging disposable pods, (5) modifying nicotine e-liquids (eg, changing propylene glycol/vegetable glycerin, nicotine), (6) combining nicotine and cannabis for simultaneous vaping, and (7) putting cannabis in ENDS designed for nicotine vaping. Logistic regression assessed how sources of information (eg, friends, social media, nonsocial media Web sites, vape shops) about and perceptions of ENDS modifications associated with ENDS modifications.
RESULTS
Refilling (69.0% heard, 40.1% tried) and recharging the battery (66.4% heard, 35.8% tried) of disposable pods were most common. Friends (64.4%) and social media (46.7%) were the most common sources of information. Notable significant associations between information sources and modifications were: 1. nonsocial media Web sites and vape shops with rewicking and recharging disposable devices and modifying nicotine e-liquid; 2. nonsocial media Web sites with refilling rechargeable cartridges/pods and disposable pods; and 3. social media with recharging disposable devices and mixing nicotine and cannabis liquids. Perceptions of reduced harm and "coolness" were associated with various modifications.
DISCUSSION
AYAs are aware of and modify ENDS for purposes unintended by manufacturers. ENDS policies should consider unintended ENDS use to safeguard public health. Prevention efforts should communicate about the potential harms of ENDS modifications.
Topics: Humans; Adolescent; Electronic Nicotine Delivery Systems; Young Adult; Male; Female; Vaping; Nicotine
PubMed: 38881359
DOI: 10.1542/peds.2023-063984