Co-development of autoimmune hepatitis and Sj?gren's syndrome triggered by the administration of herbal medicines

Autoimmune hepatitis (AIH) has been reported in association with Sjögren''s syndrome (SS). Drug-induced AIH has been rarely reported. A rare case of the co-development of AIH and SS in a 53-year-old woman after the consumption of herbal medicines is described. After admission, the patient complained of dryness in her mouth, and she was subsequently diagnosed with SS, which had not been detected previously. The patient''s bilirubin and aminotransferase levels initially decreased following conservative management; however, they later began to progressively increase. A diagnosis of AIH was made based on the scoring system proposed by the International Autoimmune Hepatitis Group. The patient was administered a combination of prednisolone and azathioprine, and the results of follow-up liver-function tests were found to be within the normal range. This is an unusual case of AIH and SS triggered simultaneously by the administration of herbal medicines.     

Reverse shape selectivity of hexane isomer in ligand inserted MOF-74

Separation of linear, mono-branched, and di-branched isomers is critically important in the petrochemical industry. In this computational study, we demonstrate that the ligand inserted Mg-MOF-74 structure leads to a reverse selectivity effect (i.e. phenomenon that preferentially allows larger species molecules to permeate in a gas mixture) of hexane isomers in the resulting material. Molecular dynamics simulations suggest that strong confinement of the di-branched hydrocarbons in the small pores lead to reverse selectivity. Over a magnitude difference in diffusivity between linear alkanes and their di-branched isomers was observed, clearly showing the steric effects imposed by the pore structure.

The ligand inserted Mg-MOF-74 structure leads to a reverse selectivity effect (i.e. phenomenon that preferentially allows larger species molecules to permeate in a gas mixture) of hexane isomers in the resulting material.

In the petrochemical industry, separation of the hexane isomers is an important process that removes impurities for fuel purification and the isolation of mixtures for applied further reaction.^1,2 The sieving of n-hexane and its branched isomers is particularly interesting research because of the varying octane numbers in the isomers affecting the gasoline production,^3–5 and as such, it is imperative to facilitate separation of these isomers. Unfortunately, this separation is particularly challenging due to the similar polarizabilities and chemical inertness of the molecules, leading one to resort to highly energy expensive distillation processes.^1,6The presently used methods such as molecular sieving using zeolites and the conventional distillation processes still include mixtures of the isomers that lowers the overall octane number^7,8 compared to the pure di-branched molecule composition. To discover the adsorbent materials that can completely separate the isomers into their individual components, many researchers have investigated adsorbent materials with an appropriate pore size and shape.^9–12 Recently, metal–organic frameworks (MOFs) have attracted great deal of attention from the researchers due to their potential applications in gas separations,^13–20 CO₂ capture,^21,22 catalysis,^23–26 water harvesting^27–29 and several other applications.^30–32 MOFs are crystalline microporous materials composed of inorganic metal nodes and organic linkers^33–35 and via combining various metal clusters and organic linkers, MOFs can be tuned specifically to ideal shapes and pore chemical environment for targeted gas separations.^36–38 This tunability allows one to potentially design MOFs that are ideal for hexane isomers. Bárcia et al.³⁹ firstly used MOFs called Zn(BDC)(DABCO)_0.5 (MOF-1) to separate hexane isomers, although this MOF showed low adsorption capacities. Also, Herm et al.¹² synthesized a MOF named Fe₂(BDP)₃ (BDP²⁻ = 1,4-benzenedipyrazolate), which contain triangular pore channels that can discriminate hexane isomers better than the commercial standard. More recently, Lv et al.⁴⁰ demonstrated that [Fe₃(μ3-O)(COO)₆] and 2,2-bis(4-carboxyphenyl)-hexafluoropropane (6FDCA) have strong capability to separate n-hexane from its branched isomers on the basis of a kinetically controlled molecular sieve separation.Overall, conventional wisdom dictates that one would seek to design materials whose pore limiting diameter can separate the molecules of interest within the mixture. With that being said, there have been few observances where the ordering based on kinetic diameters is reversed (in what is called reverse selectivity).⁴¹ Previous study by Bárcia et al.⁴² used the concept of “length entropy” to describe the adsorption and separation behavior in UiO-66(Zr). They showed that UiO-66(Zr) preferentially adsorb branched alkanes over their linear isomer, in what they called “reverse selectivity”. Moreover, Pan et al.⁴³ described the unusual reverse selective separation of n-butane from normal hydrocarbons above C₄ in a fluorinated MOF with 1D channels. Additionally, reverse selectivity has also been mentioned in recent works with IRMOF-8 (ref. 44) and UiO-66@SiO₂ (ref. 45) with regards to linear and iso-alkane separation.In our previous computational work, we designed the ligand inserted MOF frameworks using the ligand insertion strategy. Using computational analysis, these structures showed increase in the working capacity of CO₂ under humid flue gas conditions,²² utility as a catalyst for enhanced ethane oxidation²⁵ and potential usage in water harvesting material.²⁹ In the current work, the dpt ligand inserted Mg-MOF-74 structures with 1-D channel was used to examine the reverse selectivity of hexane isomer and separation properties by considering mixtures of n-hexane and its branched isomers (2,2-dimethylbutane, 2,3-dimethylbutane, 2-methylpentane and 3-methylpentane). In the context of the hexane isomer separation, the inserted ligand finely tuned the shape and the size of the pores within the MOF such that branched isomer can reverse selectively pass through the MOF channel.Optimization of the MOFs and the hexane isomer binding energy calculations were conducted using the first-principles calculations through the density functional theory (DFT) as implemented by the plane-wave pseudopotential approach in Quantum Espresso.⁴⁶ The second version of a van der Waals dispersion-corrected density functional (vdW-DF2)⁴⁷ was used to describe the dispersion interactions. Ultrasoft pseudopotentials were used for GGA and vdW-DF2 calculations. A 2 × 2 × 2 k-point mesh was used for the Brillouin zone sampling in the reciprocal space. The kinetic energy and charge density planewave cutoff were set to 30 Ry and 240 Ry, respectively.All molecular dynamics simulations were carried out using the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) program.⁴⁸ In the simulations, the MOF structures are set to be fixed with the dpt ligand and the hexane isomers considered to be flexible, incorporating all intramolecular motions such as bond vibrations, bond angle bending, and torsional motions. All non-bonded interactions between the atoms were calculated using the Lennard-Jones (LJ) potential. Adsorbate–adsorbate and adsorbate–MOF interactions were truncated at 14 Å and at 12.8 Å with analytical tail-corrections applied for interactions beyond this cutoff distance, respectively. The LJ parameters for the atoms of the MOF were taken from the UFF⁴⁹ and The TraPPE force field were employed to model the inter- and intramolecular interactions of the hexane isomers as previous studies reported that these models accurately model the adsorption and diffusion properties of alkanes⁵⁰ and nHEX⁵¹ in the MOFs. Initially, all systems were equilibrated for 2 ns in an NVT ensemble, and afterwards, another 10 ns of simulation was performed in the NVT ensemble during which the equilibrated phase space trajectories were stored at every 10 ps. These trajectories were then used to analyze the diffusion behavior of the hexane isomers with the diffusion coefficients calculated from the mean square displacements (MSD) of the molecules using the Einstein''s relation.The ligand insertion strategy within the MOF-74 structure can be used to reconfigure the pore space to enhance the separation performance. To demonstrate this, a size-matching regulated ligand (2,4-di(4-pyridinyl)-1,3,5-triazine (dpt)) was inserted as shown in Fig. 1(a).Open in a separate windowFig. 1Illustration of pore space partitioned Mg-MOF-74 using ligands 2,4-di(4-pyridinyl)-1,3,5-triazine. (a) Viewed along z axis and (b) side view of the channels showing the cylindrical channel.The insertion of 2,4-di(4-pyridinyl)-1,3,5-triazine (dpt) ligands into the hexagonal channels of Mg-MOF-74 was demonstrated in our previous theoretical study on catalyst for ethane oxidation.²⁵ In the previous work, the computed DFT binding energy of the dpt ligand was −198.3 kJ mol⁻¹ in the Mg-MOF-74 structures, providing evidence that the ligands would stay intact and not wash away, post synthesis. The dpt ligands were inserted such that the distance between the two dpt ligands is 8.3 Å along the channel direction in the z-axis (Fig. 1(b)). In the alkane separations, configurational and length entropy effects may act in a completely different manner. These effects plays a bigger role for separating linear and branched alkanes in materials such as AFI⁵² and MOF-74 that have cylindrical channels. Hence, it is important to consider both the maximum diameter (i.e. molecular length)⁵³ of the molecules as well as kinetic diameter. As can be seen from 53,54

Alteration of the E-cadherin/β-Catenin Complex Predicts Poor Response to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) Treatment

Background

Epidermal growth factor receptor (EGFR) mutation alone may be insufficient to predict clinical outcomes in the response to EGFR-tyrosine kinase inhibitor (TKI) therapy. The secondary mutation T790 M and MET amplification are mechanisms of acquired resistance to EGFR-TKI in approximately 50 % of patients, but the remaining mechanisms are unknown.

Methods

Eight metastatic lesions and specimens from 41 non-small cell lung carcinoma (NSCLC) patients harbouring activating EGFR mutations who underwent surgical resection and EGFR-TKI therapy were available. Immunohistochemistry was used to evaluate E-cadherin, β-catenin, and PTEN. Chromogenic in situ hybridisation and silver-enhanced in situ hybridisation were used to evaluate EGFR and MET amplification.

Results

Patients with E-cadherin/β-catenin alteration showed a poor objective response rate (ORR) (p = 0.005) and shorter overall survival (p = 0.059). Additionally, β-catenin alteration was associated with a poor ORR (p = 0.012). Of the metastatic tumours, three cases (37.5 %) showed the acquisition of altered E-cadherin/β-catenin and PTEN loss and two cases (25 %) demonstrated MET/EGFR amplification.

Conclusions

Altered E-cadherin/β-catenin expression in NSCLC harbouring EGFR mutations was associated with a poor response to EGFR-TKI. During metastatic progression, changes in E-cadherin/β-catenin were found. These results may suggest that E-cadherin/β-catenin alteration is related to poor TKI response and resistance.

     

Anti‐inflammatory effect of platelet‐rich plasma on nucleus pulposus cells with response of TNF‐α and IL‐1

The purpose of this study was to investigate the anti‐inflammatory effect of platelet‐rich plasma (PRP) with collagen matrix on human nucleus pulposus (NP) cell in response to pro‐inflammatory cytokines such as tumor necrosis factor‐alpha (TNF‐α) and interleukin‐1 (IL‐1). NP cells from human disks were cultured in a monolayer and maintained in the collagen matrix prior to the addition of recombinant human IL‐1 and TNF‐α. After applying IL‐1 and TNF‐α, PRP prepared by using a commercially available platelet concentration system was added. The response was investigated using real‐time PCR for mRNA expression of type II collagen, aggrecan, matrix metalloproteinase‐3 (MMP‐3), and cyclooxygenase‐2 (COX‐2). The combination of IL‐1β and TNF‐α led to decrease of matrix synthesis gene expression such as collagen type II and aggrecan and increase of the degradation gene expression of COX‐2 and MMP‐3, compared to the control. Consecutive PRP exposure significantly recovered the down‐regulated gene expression of collagen type II and aggrecan and significantly reduced the increased MMP‐3 and COX‐2 gene expression, compared to that of control groups with pro‐inflammatory cytokines. The administration of PRP with collagen matrix markedly suppressed cytokine‐induced pro‐inflammatory degrading enzymes and mediators in the NP cell. It also rescued gene expression concerning matrix synthesis, thereby stabilizing NP cell differentiation. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:551–556, 2014.     

The effect of psychosocial factors on outcomes of cochlear implantation

Conclusion: Psychosocial factors should be considered during cochlear implantation (CI). There were differences in psychosocial characteristics according to the etiology of deafness. The outcomes may be affected by psychosocial variables such as the severity of mental distress and social problems as well as duration of deafness. Objective: To evaluate the psychosocial characteristics of deaf people undergoing CI and to determine which psychosocial factors affect performance after CI. Methods: A total of 289 subjects who underwent CI were enrolled. The participants were classified into prelingually deaf (pre-LD) and postlingually deaf groups (post-LD), including progressive and sudden deafness subgroups. The Minnesota Multiphasic Personality Inventory (MMPI) was administered before CI to measure psychosocial and emotional problems. To measure CI outcomes, speech perception ability was assessed by the open-set Korean version of the Central Institute of Deafness (K-CID) test and categories of auditory performance (CAP) scores before and after CI. Results: Approximately 45% of subjects experienced psychological problems before undergoing CI. Subjects in the Pre-LD group had more psychosocial distress and were more likely to be oversensitive in interpersonal situations, while those in the post-LD group were more depressed. Deafness duration and psychosocial factors significantly predicted hearing ability after CI. Deafness duration directly and indirectly affected the outcome of CI. That is, duration of deafness caused psychosocial problems, which may have resulted in negative effects on outcomes of CI.     

Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens

Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that C_peak, C_trough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies.