Green-light photocleavable meso-methyl BODIPY building blocks for macromolecular chemistry

We report the design of easily accessible, photocleavable meso-methyl BODIPY monomers suitably functionalised for incorporation into macromolecules. Firstly a BODIPY-diol as a novel AA-type bifunctional monomer is reported. Secondly, from the same common BODIPY precursor, a clickable, azide functionalised AB-type hetero-bifunctional monomer was prepared. Photochemical studies of model compounds confirmed the ability of these compounds to undergo photocleavage in green light (lambda > 500 nm). Their usefulness for photoclippable macromolecular systems is then demonstrated: firstly by incorporating the diols into polyurethane hydrogels shown to undergo photocleavage and hence dissolution under visible light irradiation and secondly, the preparation of water-soluble macromolecular photocages able to photorelease small molecules. Thus the results presented herein describe a proof-of-principle for BODIPY-based photoresponsive materials, for example, for use as degradable polymers, sacrificial materials for lithography or for the delivery of caged pharmaceuticals

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

Liquid Extraction Surface Analysis (LESA) of Hydrophobic TLC Plates Coupled to Chip-Based Nanoelectrospray High-resolution Mass Spectrometry

Direct identification and structural characterization of analyte spots on TLC plates have always been of great interest and the development of interfaces that allow TLC to be combined with MS is making steady progress. The recently introduced liquid extraction surface analysis (LESA) approach has the potential to hyphenate TLC with MS. A mixture of lipid standards was separated on HPTLC RP-18 glass plates using chloroform:methanol :acetonitrile 2:1:1 (v:v:v) as mobile phase. After visualization with primuline dye (0.02% in acetone:water 8:2 (v:v)), LESA was performed, followed by a chip-based nanoflow infusion in combination with FTICRMS. The optimized extraction solvent composition was methanol:chloroform:water:formic acid 52:24:24:0.2 (v:v:v:v). A nanoelectrospray voltage of 1.6 kV and a gas pressure of 0.2 psi were applied in all experiments. All phospholipids were extracted successfully and detected unambiguously using the optimized TLC-LESA-FTICRMS procedure. Sampling the tricaprylin spot gave the most intense signals and also tricaprin was detected. Three other triacylglycerols of higher molecular mass have logP values between 15.5 and 21.6, which are the highest among all investigated compounds and are not detected from their corresponding spots, due to the fact that the solubility of very apolar lipids is not high enough in the extraction solvent. It was demonstrated that TLC can be elegantly combined with mass spectrometry based on the LESA approach. In general, apart from the analysis of lipids, TLC-LESA-MS has a high potential for medium-polar compounds separated on reversed-phase TLC plates, but limitations are present when very apolar compounds have to be extracted

Analysis of polycyclic aromatic hydrocarbons migrating from polystyrene/divinylbenzene-based food contact materials

Single-use utensils made from polystyrene (PS), coming into contact with food or beverages during consumption or storage were analyzed with respect to the presence of polycyclic aromatic hydrocarbons (PAHs). Using the developed sample preparation procedure and high-performance liquid chromatography with fluorescence detection allowed the analysis of 14 PS-based items, thereby detecting several PAHs. Additionally the potential migration of PAHs from the PS material into a food simulant (95% ethanol) was investigated experimentally. After 24 h of contact between the PS and the ethanol several PAHs were detected in the food simulant at concentrations in the ng cm3 range.(VLID)358779

The plant hopper Issus coleoptratus can detoxify phloem sap saponins including the degradation of the terpene core

Issus coleoptratus is a small plant hopper which mainly feeds on the phloem sap from ivy. Although all parts of ivy are poisonous as the plant contains saponins, especially hederasaponins, I. coleoptratus can cope with the poison. In contrast to other animals like the stick insect Carausius morosus which accumulates saponins in its body, I. coleoptratus can degrade and disintegrate not only the saponins but even the genines, i.e. the triterpene core of the substances. This is perhaps made possible by a specialised midgut and/or the salivary glands. When the glands and the gut are dissected and added to saponins in solution, the saponins, including the genines, are degraded ex vivo

Uptake and metabolism of the antidepressants sertraline, clomipramine, and trazodone in a garden cress (Lepidium sativum) model

Environmental contamination with pharmaceuticals has received growing attention in recent years. Several studies describe the presence of traces of drugs in water bodies and soils and their impacts on nontarget organisms including plants. Due to these facts investigations of the uptake and metabolism of pharmaceuticals in organisms is an emerging research area. The present study demonstrates the analysis of three selected antidepressants (sertraline, clomipramine, and trazodone) as well as metabolites and transformation products in a cress model (Lepidium sativum). Cress was treated with tap water containing 10 mg/L of the parent drugs. Employing an analytical approach based on high performance liquid chromatography coupled with quadrupole time of flight or Orbitrap mass spectrometry in MS and MS modes, in total 14 substances were identified in the cress extracts. All three parent drugs were taken up by the cress and translocated from the roots to the leaves in specific patterns. In addition to this, eleven metabolite species were identified. They were generated by hydroxylation, demethylation, conjugation with amino acids, or combinations of these mechanisms. Finally, the inclusion of control cultures in the experimental setup allowed for a differentiation of “true” metabolites generated by the cress and transformation products generated by plantindependent mechanisms.I3046(VLID)344843

Plasma Metabolomic Profiling Reveals Four Possibly Disrupted Mechanisms in Systemic Sclerosis

Systemic sclerosis (SSc) is a rare systemic autoimmune disorder marked by high morbidity and increased risk of mortality. Our study aimed to analyze metabolomic profiles of plasma from SSc patients by using targeted and untargeted metabolomics approaches. Furthermore, we aimed to detect biochemical mechanisms relevant to the pathophysiology of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry technology. The investigation of plasma samples from SSc patients (n = 52) compared to a control group (n = 48) allowed us to identify four different dysfunctional metabolic mechanisms, which can be assigned to the kynurenine pathway, the urea cycle, lipid metabolism, and the gut microbiome. These significantly altered metabolic pathways are associated with inflammation, vascular damage, fibrosis, and gut dysbiosis and might be relevant for the pathophysiology of SSc. Further studies are needed to explore the role of these metabolomic networks as possible therapeutic targets of SSc

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Insulin Mimetic Properties of Extracts Prepared from Bellis perennis

Diabetes mellitus (DM) and consequential cardiovascular diseases lead to millions of deaths worldwide each year; 90% of all people suffering from DM are classified as Type 2 DM (T2DM) patients. T2DM is linked to insulin resistance and a loss of insulin sensitivity. It leads to a reduced uptake of glucose mediated by glucose transporter 4 (GLUT4) in muscle and adipose tissue, and finally hyperglycemia. Using a fluorescence microscopy-based screening assay we searched for herbal extracts that induce GLUT4 translocation in the absence of insulin, and confirmed their activity in chick embryos. We found that extracts prepared from Bellis perennis (common daisy) are efficient inducers of GLUT4 translocation in the applied in vitro cell system. In addition, these extracts also led to reduced blood glucose levels in chicken embryos (in ovo), confirming their activity in a living organism. Using high-performance liquid chromtaography (HPLC) analysis, we identified and quantified numerous polyphenolic compounds including apigenin glycosides, quercitrin and chlorogenic acid, which potentially contribute to the induction of GLUT4 translocation. In conclusion, Bellis perennis extracts reduce blood glucose levels and are therefore suitable candidates for application in food supplements for the prevention and accompanying therapy of T2DM

Investigation of photochemical reactions of saccharides during direct ultraviolet absorbance detection in capillary electrophoresis

Direct UV detection of saccharides in capillary electrophoresis is possible due to a base-catalyzed con-version into UV absorbing substances initiated by the light of the UV detector lamp. In the present studythe compounds formed during this reaction were investigated with capillary electrophoresis using anadditional UV lamp for online irradiation at a certain distance before the detector resulting in a separa-tion of the conversion products. It was found that for all investigated saccharides (glucose, ribose andsucrose) the major portion of the UV absorption in direct UV detection resulted from one and the samesubstance. By CE–UV, CE–MS as well as HPLC–MS measurements this substance was demonstrated tobe malondialdehyde, present as its conjugate base malonenolate under alkaline conditions. Additionalexperiments revealed that the conversion reaction is highly sensitive to the residence time under theUV light as malondialdehyde can further degrade into non-UV absorbing products. NMR measurementsshowed that under alkaline conditions this degradation proceeds slowly even without UV irradiation