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Graphene is a 2D material with promising commercial applications due to its physicochemical properties. Producing high-quality graphene economically and at large scales is currently of great interest and demand. Here, the potential of producing high-quality graphene at a large scale via water-phase exfoliation methods is investigated. By altering exfoliation parameters, the production yield of graphene and flake size are evaluated. Pretreatment of the precursor graphite powder using acidic solutions of H 2 SO 4 at different concentrations is found to increase further the yield and structural quality of the exfoliated graphene flakes. These findings are confirmed through various spectroscopy and surface characterization techniques. Controlling flake size, thickness, and yield are demonstrated via optimization of the sonication process, centrifuge time, and H 2 SO 4 pretreatment., (© 2023. The Author(s).)

The irradiation of ( Z )-2-phenyl-4-aryliden-5(4 H )-thiazolones 2 with blue light (465 nm) in CH 2 Cl 2 solution promotes [2 + 2]-photocycloaddition of the exocyclic C═C bonds and the formation of the dispirocyclobutanes 3 . This reaction takes place with high stereoselectivity, given that the ε-isomer (1,3 head-to-tail syn coupling) is formed in more than 90% yield in most of the cases. However, irradiation of 5(4 H )-thiazolones 2 with blue light (456 nm) in dry MeOH in the presence of BF 3 ·OEt 2 leads to the monospirocyclobutanes 4 with full stereoselectivity, also affording the ε-isomer. A ring-opening reaction of only one of the thiazolone rings appears to have taken place in 4 upon methanolysis, leading to the corresponding ester and thioamide groups. The treatment of free 4-aryliden-5(4 H )-thiazolones 2 with a base in alcohol (NaOR/ROH) also produces a ring-opening reaction of the heterocycle by methanolysis, although, under these reaction conditions, further intramolecular S-attack at the exocyclic C(H)═C bond and cyclization is observed, forming the dihydrothiazoles 5 or 6 as mixtures of cis ( RS / SR )- and trans ( RR / SS )-isomers with high diastereomeric excess. trans -( RR/SS )-Dihydrothiazoles 6 can be isolated as pure diastereoisomers by column chromatography. Surprisingly, dihydrothiazoles 5 can also be obtained by the treatment of 4-aryliden-5(4 H )-thiazolones 2 with BF 3 ·OEt 2 in methanol in the absence of a base.

The goal of the work reported here was to amplify the fluorescent properties of 4-aryliden-5(4 H )-oxazolones by suppression of the hula-twist non-radiative deactivation pathway. This aim was achieved by simultaneous bonding of a Pd center to the N atom of the heterocycle and the ortho carbon of the arylidene ring. Two different 4-(( Z )-arylidene)-2-(( E )-styryl)-5(4 H )-oxazolones, the structures of which are closely related to the chromophore of the Kaede protein and substituted at the 2- and 4-positions of the arylidene ring ( 1a OMe; 1b F), were used as starting materials. Oxazolones 1a and 1b were reacted with Pd(OAc) 2 to give the corresponding dinuclear orthometalated palladium derivates 2a and 2b by regioselective C-H activation of the ortho -position of the arylidene ring. Reaction of 2a ( 2b ) with LiCl promoted the metathesis of the bridging carboxylate by chloride ligands to afford dinuclear 3a ( 3b ). Mononuclear complexes containing the orthopalladated oxazolone and a variety of ancillary ligands (acetylacetonate ( 4a , 4b ), hydroxyquinolinate ( 5a ), aminoquinoline ( 6a ), bipyridine ( 7a ), phenanthroline ( 8a )) were prepared from 3a or 3b through metathesis of anionic ligands or substitution of neutral weakly bonded ligands. All species were fully characterized and the X-ray determination of the molecular structure of 7a was carried out. This structure has strongly distorted ligands due to intramolecular interactions. Fluorescence measurements showed an increase in the quantum yield (QY) by up to one order of magnitude on comparing the free oxazolone (QY < 1%) with the palladated oxazolone (QY = 12% for 6a ). This fact shows that the coordination of the oxazolone to the palladium efficiently suppresses the hula-twist deactivation pathway.

Purpose: To evaluate the efficacy and safety of SYL1001, a short interfering (si) RNA targeting the transient receptor potential cation channel subfamily V member 1 (TRPV1), for the treatment of dry eye disease (DED)., Methods: This study combines a phase I and two phase II clinical trials to test different doses of SYL1001 in a total of 156 healthy subjects and patients with DED. After 10 days of treatment, the primary efficacy endpoints were the effect on (1) the scoring in the Visual Analogue Scale (VAS) and Ocular Surface Disease Index (OSDI) questionnaires, and (2) ocular tolerance evaluated by corneal fluorescein staining and conjunctival hyperemia. Secondary endpoints included the assessment of systemic and local tolerance., Results: Topical administration of SYL1001 1.125% once daily produced a significant decrease in VAS scores compared with placebo from day 4 until the end of treatment (change from baseline at day 10: -1.73 ± 0.32 vs. -0.91 ± 0.34; P = 0.013). For all treatments, OSDI scores were significantly reduced compared to their respective baseline values (P < 0.01), although no significant changes were detected between groups. Conjunctival hyperemia (quantified as normal or abnormal) significantly improved after instillation of SYL1001 1.125% compared with placebo (50% vs. 20%; P < 0.05). Excellent tolerability was reported, with no differences in the rates of occurrence of adverse events between groups., Conclusion: These trials achieved their primary endpoints of identifying the most effective dose of SYL1001 (1.125%). SYL1001 showed a large safety margin and may provide novel therapeutic opportunity for the relief of dry eye. (ClinicalTrials.gov numbers, NCT01438281, NCT01776658, and NCT02455999.).

The objective of this study was to evaluate ocular tolerance, safety, and effect on intraocular pressure (IOP) of a topically administered small interfering RNA; SYL040012, on healthy volunteers. The study was an open-label, controlled, single-center study comprised of two intervals that enrolled 30 healthy subjects having IOP below 21 mmHg. SYL040012 was administered to one eye as a single dose to six subjects during interval 1. During interval 2 two different doses of SYL040012 were administered to one eye on a daily basis to two separate groups of 12 subjects each, over a period of 7 days. The contralateral eye was evaluated but not administered and served as control for the tolerance study. SYL040012 was well tolerated locally. No local or systemic adverse events related to the product developed in response to any of the doses studied. SYL040012 was not detected in plasma at any time point. Administration of SYL040012 over a period of 7 days reduced IOP values in 15 out of 24 healthy subjects regardless of the dose used. IOP decrease was statistically significant in response to one of the doses tested and responsiveness to SYL040012 seemed to be greater in individuals with higher baseline IOP.

Introduction: The superfamily of transient receptor potential (TRP) cation channels is involved in nociception. Members of this family, such as the vanilloid receptor type 1 (TRPV1) channel, are activated by a wide range of stimuli including heat (⟩43°C), low pH (⟨6.5), hypoxia, and hypertonicity. Here we report TRPV1 expression in rabbit and human eyes., Material and Methods: We analyzed the expression of TRPV1 mRNA by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and protein by immunohistochemistry in eyes of New Zealand White rabbits and humans., Results: In rabbit and human eyes, TRPV1 protein was present in all layers of the corneal epithelium, but only in the basal layer of the conjunctiva. It was also in the ciliary and lens epithelia of both species as well as in the secretory cells of the rabbit lacrimal gland. The retinal pigment epithelium was positive for this protein in both species. TRPV1 was also present in rabbit Müller cells, where it had a similar pattern of expression to vimentin intermediate filaments. Analysis by qRT-PCR showed that TRPV1 mRNA was found in all of the structures where the protein was present. The highest level was in the lens and the lowest in the retina., Conclusion: TRPV1 is expressed in cells that are particularly active in Ca²⁺ exchange as well as in cells with significant water transport activity. Because TRPV1 is a Ca²⁺ channel, it probably functions in the regulation of both water and Ca²⁺ movements in ocular tissues.

The tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) specifically homes to tumors by binding to fibrin and fibrin-associated clotted plasma proteins in tumor vessels. Previous results show that CREKA-coated superparamagnetic iron oxide particles can cause additional clotting in tumor vessels, which creates more binding sites for the peptide. We have used this self-amplifying homing system to develop theranostic nanoparticles that simultaneously serve as an imaging agent and inhibit tumor growth by obstructing tumor circulation through blood clotting. The CREKA nanoparticles were combined with nanoparticles coated with another tumor-homing peptide, CRKDKC, and nanoparticles with an elongated shape (nanoworms) were used for improved binding efficacy. The efficacy of the CREKA peptide was then increased by replacing some residues with nonproteinogenic counterparts, which increased the stability of the peptide in the circulation. Treatment of mice bearing orthotopic human prostate cancer tumors with the targeted nanoworms caused extensive clotting in tumor vessels, whereas no clotting was observed in the vessels of normal tissues. Optical and magnetic resonance imaging confirmed tumor-specific targeting of the nanoworms, and ultrasound imaging showed reduced blood flow in tumor vessels. Treatment of mice with prostate cancer with multiple doses of the nanoworms induced tumor necrosis and a highly significant reduction in tumor growth.

LKB1, a tumor-suppressor gene that codifies for a serine/threonine kinase, is mutated in the germ-line of patients affected with the Peutz-Jeghers syndrome (PJS), which have an increased incidence of several cancers including gastrointestinal, pancreatic and lung carcinomas. Regarding tumors arising in non-PJS patients, we recently observed that at least one-third of lung adenocarcinomas (LADs) harbor somatic LKB1 gene mutations, supporting a role for LKB1 in the origin of some sporadic tumors. To characterize the pattern of LKB1 mutations in LADs further, we first screened for LKB1 gene alterations (gene mutations, promoter hypermethylation and homozygous deletions) in 19 LADs and, in agreement with our previous data, five of them (26%) were shown to harbor mutations, all of which gave rise to a truncated protein. Recent reports demonstrate that LKB1 is able to suppress cell growth, but little is known about the specific mechanism by which it functions. To further our understanding of LKB1 function, we analysed global expression in lung primary tumors using cDNA microarrays to identify LKB1-specific variations in gene expression. In all, 34 transcripts, 24 of which corresponded to known genes, differed significantly between tumors with and without LKB1 gene alterations. Among the most remarkable findings was deregulation of transcripts involved in signal transduction (e.g. FRAP1/mTOR, ARAF1 and ROCK2), cytoskeleton (e.g. MPP1), transcription factors (e.g. MEIS2, ATF5), metabolism of AMP (AMPD3 and APRT) and ubiquitinization (e.g. USP16 and UBE2L3). Real-time quantitative RT-PCR on 15 tumors confirmed the upregulation of the homeobox MEIS2 and of the AMP-metabolism AMPD3 transcripts in LKB1-mutant tumors. In addition, immunohistochemistry in 10 of the lung tumors showed the absence of phosphorylated FRAP1/mTOR protein in LKB1-mutant tumors, indicating that LKB1 mutations do not lead to FRAP1/mTOR protein kinase activation. In conclusion, our results reveal that several important factors contribute to LKB1-mediated carcinogenesis in LADs, confirming previous observations and identifying new putative pathways that should help to elucidate the biological role of LKB1.

Germ-line mutations in LKB1 gene cause the Peutz-Jeghers syndrome (PJS), a genetic disease with increased risk of malignancies. Recently, LKB1-inactivating mutations have been identified in one-third of sporadic lung adenocarcinomas, indicating that LKB1 gene inactivation is critical in tumors other than those of the PJS syndrome. However, the in vivo substrates of LKB1 and its role in cancer development have not been completely elucidated. Here we show that overexpression of wild-type LKB1 protein in A549 lung adenocarcinomas cells leads to cell-growth suppression. To examine changes in gene expression profiles subsequent to exogenous wild-type LKB1 in A549 cells, we used cDNA microarrays. We detected deregulation of 100 genes involved in cell proliferation, apoptosis, and cell adhesion. Strikingly, modification of the expression of well-known p53-responsive genes such as GADD45, TOP2A, and p21 suggests that growth suppression in A549 cells overexpressing LKB1 may be mediated by p53. In addition, PTEN up-regulation indicates that LKB1 could be involved in the PTEN/phosphatidylinositol-3'-kinase(PI3K)/AKT molecular pathway. Thus, our results give some insights into the understanding of how LKB1 inactivation contributes to lung carcinogenesis.