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[Image: see text] A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs, including the skin, joints and kidneys. Though SLE typically cycles through periods of flares and remission, patients often eventually succumb to end-stage kidney or cardiovascular damage1. SLE is characterized by the presence of autoantibodies that form immune complexes resulting in kidney deposition that significantly contribute to lupus nephritis pathogenesis. Phosphatidylinositol 3-kinases (PI3Ks) are divided into three classes (Class I, II, and III) according to their structure, regulation and substrate specificity. The Class I PI3K delta isoform (PI3Kδ) has been implicated in autoimmune diseases associated with aberrant B cell and antibody responses. INCB050465 is an oral small molecule PI3Kδ selective inhibitor currently being evaluated in clinical trials for the inflammatory indications Sjogren’s syndrome and autoimmune hemolytic anaemia (NCT03627065 & NCT03538041). Objectives: To quantify the efficacious potential of INCB050465, a selective PI3Kδ inhibitor, in a preclinical model of systemic lupus erythematosus with kidney pathology. Methods: The MRL/lpr mouse model spontaneously develops multiple inflammatory phenotypes that mimic human SLE pathologies, including kidney damage resulting in proteinuria, cutaneous skin lesions and anti-double stranded DNA (anti-dsDNA) antibodies. Kidney sections were stained with hematoxylin and eosin (H&E) and assigned a composite score based on glomerulus, crescents, protein casts, interstitial inflammation and vasculitis by a rater unaware of the treatment groups2. Flow cytometry was performed on splenocytes to characterize B cell and T cell subsets. Anti-dsDNA antibodies were determined by commercial ELISA. Results: In vitro enzymatic selectivity screening revealed INCB050465 potently inhibited the PI3Kδ kinase enzyme (IC50 = 1.1 ± 0.5 nM), with ∼20,000-fold selectivity for the other PI3K family member enzymes. Proteinuria identified spontaneous kidney damage in 85%+ of vehicle treated mice by 21 weeks of age, and kidney histology revealed gross tissue enlargement associated with structural abnormalities. In contrast, therapeutic INCB050465 treatment (0.3 – 3.0 mg/kg, b.i.d.) dose-dependently reduced the incidence of proteinuria (p Conclusion: INCB050465, a selective PI3Kδ inhibitor, was highly efficacious against immune-mediated mechanisms associated with lupus nephritis, but not cutaneous lupus disease manifestations in this preclinical model. Treatment-induced preservation of kidney tissue integrity corresponded to specific B cell subset modulation and autoantibody reduction. Selective PI3Kδ inhibitor treatment did not induce lymphocyte depletion. Reference: [1] Grande, et al. Experimental models of lupus nephritis. Contrib Nephrol. 2011; 169:183-97. [2] Chan, et al. The roles of B cells in MRL/lpr murine lupus. Ann N Y Acad Sci. 1997Apr5;815:75-87. Disclosure of Interests: Brittany Fay Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Monika Scuron Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Niu Shin Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Yan-ou Yang Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Eddy Yue Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Andrew Combs Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Eduardo Huarte Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Melissa Parker Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Paul Smith Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation.

Additional file 2. Demographics questionnaire

The quaternary amine Aliquat 336 (A336·Cl) was dissolved in toluene and thoroughly mixed with aqueous solutions containing LiCl or HCl. After mixing, the organic phase was separated from the aqueous phase and analysed using NMR and acid–base titration. The different proton species HCl, H2O and H3O+ present in the aqueous phase are normally not distinguishable using NMR due to fast exchange conditions (on the NMR time scale) and therefore they give rise to mainly one single peak in the proton spectrum. The chemical shift of this single ‘composite’ peak is affected by the relative distribution of the various proton species present in the aqueous solution and is made use of in this work. For instance, ratio of molecular hydrochloric acid (HCl) and dissociated acid (H3O+-Cl−) was found to be between 0.966 and 1.005 in a concentrated (37 wt%) HCl solution, assuming a HCl chemical shift of 0.5 ppm. Moreover, by applying 7Li NMR, the number ratio between Li+ and A336 in the organic phase was found to increase from 0.12 to 5.4 as the LiCl concentration increased from 0.2 to 5 mol/kg in the aqueous phase, before extraction. In addition, the average chemical shift of the –N-C H 3 protons in A336 was found to increase linearly with the concentration of Li+ and introduces a simple and fast technique to determine the concentration of Li+ in the organic phase. Not surprisingly, the NMR data suggest that most cations in the organic phase are located in spatial proximity to the –N-CH3 group. Finally, the relative number of Cl− ions in the organic phase, after extraction, was estimated from the NMR data by imposing electrical neutrality, on the solution.

The spin–spin relaxation rate distribution of water in a porcine longissimus dorsi muscle was derived from an inverse integral transformation of the proton CPMG (Carr–Purcell–Meiboom–Gill) NMR (nuclear magnetic resonance) signal at each hour during a 49 h drip period. This “continuous (C)” relaxation rate distribution was found to be excellently represented by an empirical peak function, characterized by three parameters: a peak width, an average relaxation rate, and a skewness parameter, which enable the distribution to be quantitatively defined. In addition, the same CPMG response was fitted to a sum of three single-exponential decay functions, denoted a “discrete (D)” relaxation rate model. The analysis shows that when the fraction of the slow relaxation component $$f_{2}^{\text{C}}$$ from the continuous model is close to 5 %, which is a rather typical value, the mean relaxation rate $$\bar{R}_{22}^{\text{D}}$$ from the discrete model becomes larger than the corresponding relaxation rate $$\bar{R}_{22}^{\text{C}}$$ from the continuous model by nearly 25 % and $$f_{2}^{\text{D}}$$ becomes larger than $$f_{2}^{\text{C}}$$ by more than 75 %. Likewise, when $$f_{2}^{\text{C}}$$ approaches 2.5 %, $$\bar{R}_{22}^{\text{D}}$$ becomes larger than $$\bar{R}_{22}^{\text{C}}$$ by more than 75 % and $$f_{2}^{\text{D}}$$ becomes larger than $$f_{2}^{\text{C}}$$ by more than a factor of 3 which are supported by model simulations. The relative quality and goodness of the two different relaxation rate models are discussed. Finally, the number of transients needed to obtain a preset error in relaxation rate and/or mole fraction was determined by model simulation.

The potential of using NMR as a reference method for WHC measurement in porcine longissimus dorsi was investigated. The accuracy of NMR when measuring small water changes was assessed in a model system and in muscles. Visible/near infrared (Vis/NIR) and X-ray were used as potential online spectroscopic methods to assess WHC on 40 muscles. Drip loss and spin–spin relaxation were also measured. Calibration models were built using partial least squares regression (PLSR) with Vis/NIR or X-ray spectra as input and NMR or drip loss values as output. The slowest spin–spin relaxation time (T 22 ) showed higher correlation with both Vis/NIR ( R CV 2 = 0.66) and X-ray spectra ( R CV 2 = 0.76) than EZ-DripLoss values, demonstrating NMR has potential as a reference method for WHC measurement. NMR was more robust against variation along the length of the muscle when compared to the EZ-DripLoss method.

One of the bottlenecks to efficient phosphorus (P) recycling is limited understanding of the relationships between inorganic P species in waste products and their P fertilisation effects. In this study, we characterised inorganic P species in seven waste products (two biomass ashes, meat bone meal, fish sludge, catering waste and two food waste-based digestate products) and two manure products (dairy and chicken manure) by: (1) Sequential chemical fractionation, (2) X-ray powder diffraction and (3) solid-state 31P MAS-NMR spectroscopy. We then used the characterisation data to explain the results of a bioassay studying the fertilisation effects of waste and manure products after application to a nutrient-deficient model soil that was limed to two pH levels (approximately pH 5.5 and 6.9 at pH level 1 and 2), with ryegrass (Lolium multiflorum) as the experimental crop. The P in waste products was mainly present as a complex mixture of inorganic P species, predominantly Ca phosphates with differing solubility. Fertilisation effects were largely explained by sequential fractionation data, with a positive relationship between apparent P use efficiency and the H2O-soluble inorganic P fraction at pH level 1 (R2 = 0.52) and a negative relationship between apparent P use efficiency and the HCl-soluble inorganic P fraction at pH level 2 (R2 = 0.66). X-ray powder diffraction and solid-state 31P MAS-NMR spectroscopy confirmed the sequential fractionation data, but provided little additional information.

Introduction of hydrophilic components, particularly amines and zwitterions, onto a degradable polymer platform, while maintaining precise control over the polymer composition, has been a challenge. Recognizing the importance of these hydrophilic residues in multiple aspects of the nanobiomedicine field, herein, a straightforward synthetic route to access well-defined amphiphilic and hydrophilic degradable block copolymers from diethanolamine-derived functional eight-membered N-substituted aliphatic cyclic carbonates is reported. By this route, tertiary amine, secondary amine, and zwitterion residues can be incorporated across the polymer backbone. Demonstration of pH-responsiveness of these hydrophilic residues and their utility in the development of drug-delivery vehicles, catered for the specific requirements of respective model drugs (doxorubicin and diclofenac sodium salt) are shown. As hydrophilic components in degradable polymers play crucial roles in the biological interactions, these materials offers opportunities to expand the scope and applicability of aliphatic cyclic carbonates. Our approach to these functional polycarbonates will expand the range of biocompatible and biodegradable synthetic materials available for nanobiomedicine, including drug and gene delivery, antimicrobials, and hydrophilic polymers as poly(ethylene glycol) (PEG) alternatives.

The ability of NMR to predict purge from vacuum-packed pork that was stored for 9 days was investigated. T2 relaxation was measured at 24 h post mortem (p.m.) and again after 9 days of chilled storage. NMR measurements from day 1 p.m. were limited in predicting day-9 purge (|r| = 0.37–0.52). The root mean square error of linear regression (RMSD) for measuring day-9 purge using the relaxation time of intra-myofibrillar water (T21) measured on day 1 p.m. (r = −0.46) was 1.31% (range: 1.15–7.69% purge), corresponding to ±2.62% (2 × RMSD) prediction error of purge with 95% probability. This indicated that for purge production rate, the distribution and mobility of water in meat on day 1 p.m. may be of little relevance. Further tests were conducted to explain this poor predictability, by taking NMR measurements of water mobility and distribution made on the same meat sample (taken at 96 h p.m.) every day, during a 9-day storage period. By analyzing the T21 and T22 domains every day, it was revealed that during the first 5-day of storage, water (86%) moved from intra-myofibrillar space to extra-myofibrillar space. However, this movement did not result in detectable drip. A major liquid loss followed between days 6 and 7 and ceased day 8. This complexity of the water movement between domains during storage may explain the poor predictability of day-9 purge using NMR measurements from day 1.

The crystal structure and magnetic properties of a penta-coordinate iron(III) complex of pyridoxal-4-methylthiosemicarbazone, [Fe(H(2)mthpy)Cl-2](CH3C6H4SO3), are reported. The synthesised ligand and the metal complex were characterised by spectroscopic methods (H-1 NMR, IR, and mass spectroscopy), elemental analysis, and single crystal X-ray diffraction. The complex crystallises as dark brown microcrystals. The crystal data determined at 100(l) K revealed a triclinic system, space group P (1) over bar (Z = 2). The ONSCl2, geometry around the iron(III) atom is intermediate between trigonal bipyramidal and square pyramidal (tau = 0.40). The temperature dependence of the magnetic susceptibility (5-300 K) is consistent with a high spin Fe(III) ion (S = 5/2) exhibiting zero-field splitting. Interpretation of these data yielded: D = 0.34(1) cm(-1) and g = 2.078(3). (c) 2007 Elsevier B.V. All rights reserved.

The focus of this report concerns the preparation nanocomposites from poly(propylene carbonate) (PPC) and multiwall carbon nanotubes (MWNTs). A solvent route using tetrahydrofuran, ethoxylated non- ionic surfactants combined with sonication was found to be successful in deagglomerating and dispersing the nanotubes. Transmission electron microscopy revealed highly disentangled and dispersed nanotubes and was supported by the qualitative stability evaluations. The morphology and molecular mobility of the prepared nanocomposites (0.5, 3.0 and 5.0 wt% of nanotubes) were characterized by rheology, microscopy, low-field solid-state nuclear magnetic resonance, and electrical conductivity. The networking of nanotubes was highest with a stearyl alcohol ethoxylate surfactant, and was found to improve with the sonication time. Nanotube percolation was established, both rheologically and electrically, from a filler content of approximately 0.5 wt%. A higher tendency toward particle agglomeration was observed at higher MWNT loadings. Only minor changes in the glass transition temperature were measured presumably due to the presence of solvent and surfactant residues. The thermal stability was marginally improved by increasing the loading and dispersion of the nanotubes, and appeared to be modified by solvent and surfactant residues.

The properties of composites prepared by melt compounding from graphite nanoplatelets (GNP) and pyromellitic anhydride modified poly(propylene carbonate) (PPC) were investigated. GNPs of different morphologies and acid residue levels were selected. Acid residues in GNP grades were detrimental for PPC in terms of thermal stability, stiffness and conservation of the molecular weight. The exfoliation of graphite nanoparticles was challenging, and morphologies of combined tactoids with thicknesses both on the micro and nano scales were observed. The filler contributed to the thermal stability, and the mechanical reinforcement was observed from approximately 6 wt% GNP and accompanied by an increase in the glass transition temperature. For a specific GNP grade, at a 15 wt% filler content, the glass transition temperature increased by 10 degrees C and the storage modulus measured at 20 and 30 degrees C increased correspondingly by a factor of ca. 3 and 30, respectively. Solid state NMR spin-spin relaxation time T-2 measurements (Carr-Purcell-Meiboom-Gill pulse sequence) revealed three significantly different components. Using PLS, empirical models were established which enable the prediction of some viscoelastic parameters as a function of filler parameters and the average T-2.

A compressed exponential function (CEF) is shown to be represented by a distribution of Gaussian functions. The properties and characteristics of the distribution are detailed and discussed, and are illustrated with reference to the change in the NMR spectroscopy proton Hahn echo relaxation response that takes place in a composite material (prepared by melt compounding a mixture of graphite nanoparticles and pyromellitic anhydride modified polypropylene carbonate (PPC)) during aging at 90 °C. The results show that both the width and the average value of the spin-spin relaxation rate distribution decrease during aging, suggesting that the molecular motion becomes less constrained and less heterogeneous.

We present an alternative polymer modification of poly (propylene carbonate) (PPC). A conventional practice for PPC melt processing is the melt – modification with maleic anhydride (MAH) – a di-carboxylic anhydride –. In our work, PPC is melt-modified with pyromellitic di-anhydride (PDAH) – a tetra-carboxylic dianhydride –. Using MAH modified PPC as reference, the polymer degradation and the thermal and viscoelastic properties of the materials are studied. Both anhydrides after their melt compounding have similar efficiency in the conservation of the molecular weight. Strikingly, the use of PDAH is advantageous over MAH considering the improvement of the thermal stability, the decrease of the complex melt viscosity and higher storage modulus (stiffness) of the modified PPC. It is speculated that the changes in the material performance arise from the occurrence of long chain branching and non-covalent interactions from the PDAH modifier.

A spectral analysis procedure for single-pulse 1 H-MAS spectra acquired at 20 kHz MAS-rate is presented and thoroughly discussed and demonstrates that all relevant functional groups can be identified and quantified. In particular, the present technique finds special application in the analysis of oxidation products formed during ageing of cross-linked polymers, which are generally difficult or impossible to study by solution state NMR, since these polymers are mostly insoluble. The main objective and advantages of applying 1 H-MAS solid-state NMR compared to liquid state 13 C NMR are related to; 1) a much shorter experimental sampling time, on the order of a few minutes, 2) the bypass of sample preparation, as compared to traditional high-resolution liquid state 13 C NMR which requires a high temperature (130 °C) preparation period of days, or even weeks and 3) the technique is non-destructive. Finally, the present technique gives a much easier access to quantitative information compared to solid-state 13 C-CPMAS NMR.

A matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)-based method has been developed for rapid differentiation between Panax ginseng and Panax quinquefolius, two herbal medicines with similar chemical and physical properties but different therapeutic effects. This method required only a small quantity of samples, and the herbal medicines were analyzed by MALDI-MS either after a brief extraction step, or directly on the powder form or small pieces of raw samples. The acquired MALDI-MS spectra showed different patterns of ginsenosides and small chemical molecules between P. ginseng and P. quinquefolius, thus allowing unambiguous differentiation between the two Panax species based on the specific ions, intensity ratios of characteristic ions or principal component analysis. The approach could also be used to differentiate red ginseng or P. quinquefolius adulterated with P. ginseng from pure P. ginseng and pure Panax quinquefolium. The intensity ratios of characteristic ions in the MALDI-MS spectra showed high reproducibility and enabled quantitative determination of ginsenosides in the herbal samples and percentage of P. quinquefolius in the adulterated binary mixture. The method is simple, rapid, robust, and can be extended for analysis of other herbal medicines.

Ageing of cross-linked polyethylene (XLPE) insulation used in high voltage cable was monitored using low-field solid-state 1 H NMR. The effect of thermal ageing at different temperatures on the phase composition and molecular mobility was studied by 1 H NMR relaxation time experiments. The onset and progress of oxidation is observed to be very different for XLPE aged at different temperatures. Crystalline fraction dropped monotonically after the onset of oxidation for sample aged above melting point while it remained constant after a small initial drop for the sample aged near the melting point. Thermal oxidation caused a drastic change in molecular dynamics of the amorphous region as indicated by the change in correlation time. Thermal oxidation is confined to the amorphous region in the case of sample aged close to the melting point. The change in phase composition and relaxation time suggest that chain scission was predominant during the early stages of oxidation and later dominated by crosslinking. The presence of antioxidant prolonged the onset of oxidation depending on the ageing temperature.

To critically evaluate the use of endoscopic nasopharyngectomy in the treatment of recurrent nasopharyngeal carcinoma (NPC) through a case series, systematic literature review, and pooled analysis.A case series of 18 patients combined with systematic literature review and pooled analysis of PubMed, Web of Science, and Scopus search, identifying 576 papers. After excluding 307 papers as search engine duplicates, only 16 of the remaining papers had adequate patient data to be included.Our case series of 18 patients had a 2-year disease-free survival (DFS) and overall survival (OS) of 90.0% and 100%, respectively. The pooled analysis of 300 patients that had an endoscopic resection of recurrent NPC showed recurrence-free survival and overall survival were 85.8% and 82.9%, respectively. Most, 56.1%, were recurrent T1 lesions. Resection margins were negative in 90.2% of patients. Local recurrence occurred in 20.1% of patients. Major complications occurred in 13.6% of patients. The mean hospital stay was 5.8 days, the mean operating time was 228.3 minutes, and the mean operative blood loss was 163 mL.Endoscopic resection of recurrent NPC occurs with low surgical morbidity. However, further long-term evaluation with longer follow-up data is needed to evaluate if the survival data is comparable or better than open approaches.