Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study.

Asunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.

Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Experiments were carried out using primary mouse peritoneal macrophages and the murine macrophage cell line RAW264.7, to elucidate the mechanisms by which HDAC2 modulates endotoxin-induced inflammation. RESULTS: Results revealed that PAI-1, TNF, and MIP-2 expression were inhibited by theophylline, an HDAC2 enhancer, in a RAW macrophage cell line, following LPS-induced inflammation. Thus, HDAC2 plays an important role in immune defense by regulating the expression of inflammatory genes via the c-Jun/PAI-1 pathway. During LPS-induced inflammation, overexpression of HDAC2 was found to inhibit PAI-1, TNF, and MIP-2 expression. Following LPS stimulation, HDAC2 knockdown increased nuclear translocation and DNA binding of c-Jun to the PAI-1 gene promoter, thereby activating PAI-1 gene transcription. Furthermore, inhibition of PAI-1 by TM5275 alone or in combination with theophylline notably suppressed TNF and MIP-2 expression. CONCLUSION: HDAC2 can attenuate lipopolysaccharide-induced inflammation by regulating c-Jun and PAI-1 expression in macrophages.

Achiral polyamine-induced chiral zinc gallophosphates with fused double helix-like strands exhibiting blue to green photoluminescence.

This study found non-chiral polyamines to be effective in inducing chiral frameworks. Four zinc gallophosphates with a chiral UCSB-7 topology were generated from the use of four different linear-chain polyamines as templates. In the structure, helical inorganic strands and templates appeared to fuse into a double helix-like arrangement. Notably, they are the first chiral frameworks to display optical analogues and intriguing photoluminescence properties.

From Bola-Surfactant Templated Bimetal Phosphites to the Design of Crystalline Inorganic Mesoporous Frameworks.

Reproducing inorganic modules in situ for pore augmentation of pure inorganic frameworks is challenging but can be a key to rational synthesis. After the first success of using monoamines of varied lengths as a template in producing a set of building blocks that led to a series of growing channels up to a 72-membered ring (72R), research continued into those building blocks to seek any new topologies from them. In this study, another type of template is reported that can control the same building blocks to repeatedly form in situ. By using long linear-chain bola-type surfactants, two new bimetal phosphites, a monoclinic phase exhibiting remarkable quasi-channels of 1.15 nm and an orthorhombic phase with 28R channels of 1.06 nm have been created. By taking them as the first members, two series of novel topologies can be devised, each having a general formula to predict the size and channel wall compositions.

Evaluation of performance of human immunodeficiency virus antigen/antibody combination assays in Taiwan.

BACKGROUND: The fourth-generation human immunodeficiency virus (HIV) combination assay, which can simultaneously detect the presence of anti-HIV antibody and HIV antigen, has been shown to shorten the window period in HIV diagnosis compared with the third-generation HIV antibody immunoassay. This study was aimed to determine the performance of HIV combination assays in Taiwan, where the HIV-1 seroprevalence is 0.007% and HIV-2 infection has never been reported. METHODS: Performance of three fourth-generation HIV Ag/Ab combination assays (Dia.Pro, Wantai, and Bio-Rad) and one third-generation HIV Ab immunoassay (AxSYM HIV 1/2 gO) was assessed. RESULTS: A total of 152 specimens, including 86 confirmed HIV-seropositive and 66 HIV-seronegative samples, were used in the study. The sensitivity of four assays varied from 98.8% to 100%, and specificity varied from 98.5% to 100%. Performance of the 75 equivocal samples, the HIV status of which was confirmed later, in terms of negative prediction varied from 81.8% to 87.5%. The Bio-Rad and Dia.Pro assays exhibited higher sensitivity for the detection of p24 antigen among the three fourth-generation HIV combination assays. CONCLUSION: The three fourth-generation HIV Ag/Ab combination assays exhibited better sensitivity, specificity, and negative prediction than the third-generation HIV Ab immunoassay.

Correction: A highly flexible inorganic framework with amphiphilic amine assemblies as templates.

Correction for 'A highly flexible inorganic framework with amphiphilic amine assemblies as templates' by Hui-Lin Huang et al., Dalton Trans., 2017, DOI: 10.1039/c6dt04165e.

A highly flexible inorganic framework with amphiphilic amine assemblies as templates.

A zinc phosphite-phosphate framework, (HA)2[Zn3(HPO3)4-x(HPO4)x] (1; A = cha, coa, iba, pa, and ha; x = 0.3-1) with nanometer-scale channels was prepared. The framework exhibited an extraordinarily high flexibility, 13% expansion at ambient pressure and 27% contraction under a high pressure of over 2.3 GPa without undergoing any phase transformation. The volume changes in the compression-decompression process are reversible. Such unusual adaptability is rare in pure inorganic networks. The molecular volumes of templates range from 165 Å3 to 228 Å3, which allows to vary channel aperture increasingly from 13.02 to 15.34 Å. Remarkably, three types of organic amine template assemblies, captured in inorganic frameworks, were identified in this study. Presented herein is the first example that demonstrates a successfully controlled template assembly that helps to obtain a flexible inorganic framework with nanosized pores in a systematic manner.

A Crystalline Mesolamellar Gallium Phosphate with Zwitterionic-type Templates Exhibiting Green Afterglow Property.

We synthesized a unique layer structure of gallium phosphates containing zwitterionic-type templates under mild hydrothermal reactions. The zwitterionic-type templates, formed of long-alkyl-chain diamine cations and biphenyldicarboxylate anions, resided upright between adjacent layers, propping the interlayer distance up to 2.2 nm. For the first time, the mesoscale interlayer templates were sufficiently well-ordered to afford elucidation to the atomic-level. The mesolamellar (HDADD)2(BPDC)0.5[Ga3(OH)2(HPO4)4] (1; DADD = 1,12-diaminododecane, BPDC = 4,4'-biphenyldicarboxylate) was composed of inorganic layers built up exclusively with a unique type of heptameric unit which featured an unprecedented trimeric cluster of [Ga3(OH)2O12]. Unexpectedly, compound 1 possessed an unusual green afterglow. To interpret the interesting photoluminescence (PL) property, three other low-dimensional structures related to 1 were prepared as well. The data from PL and electron paramagnetic resonance indicated that the afterglow was mainly attributed to lattice defects and the orientations of BPDC.

Effects of Different Blood Glucose Levels on Critically Ill Patients in an Intensive Care Unit.

AIMS: We explore the infection incidence and possible prognostic outcome relevance for patients with different blood glucose levels in an intensive care unit (ICU). METHODS: A total of 98 cases were enrolled and divided into three groups based on average fasting blood glucose levels (group A: ≤ 6.1 mmol/l; group B: 6.1-10 mmol/l; group C: ≥ 10 mmol/l). RESULTS: There were no statistical differences in the time to ICU admission, the indwelling durations of gastric tubes, urinary or deep vein catheters, tracheal intubations and tracheotomies, or the length of ventilator use (all p > 0.05). No evident difference in the multiple organ dysfunction syndrome rate was found between the three groups (p = 0.226). The infection and mortality rates between the groups showed significant differences (all p < 0.05). Furthermore, the difference of respiratory system infections was statistically significant among the three groups (p = 0.008), yet no such statistical difference was observed among groups regarding nonrespiratory system infections (p = 0.227). CONCLUSIONS: Critically ill patients with a high blood glucose level were positively correlated with a relatively high APACHE II score and more serious degree of disease, as well as a higher incidence of respiratory infection during their ICU stay than those with lower blood glucose levels (<10 mmol/l).

Nanoribbon-structured organo zinc phosphite polymorphs with white-light photoluminescence.

The first neutral organo zinc phosphites composed of 2.8 nm-wide ribbons were obtained in pure phases and exhibit near-white-light photoluminescence (PL). By using the "mesitylene strategy", interesting polymorphism in the system of NTHU-14 was discovered. The S-shaped ribbons are arranged into R and L arrays, resulting in RLR and RRR stacking for two polymorphs. π-π interactions exist within each array and hydrogen bonding between adjacent arrays. Besides a common ligand-based emission band at 410 nm, the PL curves of polymorphs 14-α and 14-ß are distinctly different: 14-α gave a defect-based emission at 565 nm, whereas 14-ß primarily shows a π-excimer-based emission at 535 nm. Electron paramagnetic resonance (EPR) data disclosed that radical species exist in the reaction and that the two phases were growing from different environments. Based on these results, the origin of the 565 nm band can be ascribed to lattice defects, and one possible cause of 14-ß not showing noticeable yellow emission is identified.

Chiral framework with 20-ring channels exhibiting metal-activator-free photoluminescence.

The use of biomass-derived sucrose has unprecedentedly induced the first chiral zinc phosphite structure with 20R channels along with a series of acentric frameworks, unveiling a facile synthesis of chiral nanoporous frameworks. The 20R-channel structures are metal-activator free but display blue-to-white photoluminescence under long UV excitation.

Study of insulin resistance in cybrid cells harboring diabetes-susceptible and diabetes-protective mitochondrial haplogroups.

AIM: This study aims to elucidate the independent role of mitochondria in the pathogenesis of insulin resistance (IR). METHODS: Cybrids derived from 143B osteosarcoma cell line and harboring the same nuclear DNA but different mitochondrial haplogroups were studied. Cybrid B4 (the major diabetes-susceptible haplogroup in Chinese population), cybrid D4 (the major diabetes-resistant haplogroup in Chinese population) and cybrid N9 (the diabetes-resistant haplogroup in Japanese population) were cultured in a medium containing 25 mM glucose and stimulated with 0 µM, 0.1 µM, and 1.0 µM insulin. We compared the insulin activation of PI3K-Akt (glucose uptake) and ERK-MAPK (pro-inflammation) signaling pathways, intracellular and mitochondrial oxidative stress (DCF and MitoSOX Red), and their responses to the antioxidant N-acetylcysteine (NAC). RESULTS: Upon insulin treatment, the translocation of cytoplasmic GLUT1/GLUT4 to the cell membrane in cybrid D4 and N9 cells increased significantly, whereas the changes in B4 cells were not or less significant. On the contrary, the ratio of insulin-induced JNK and P38 to Akt phosphorylation was significantly greater in cybrid B4 cells than in cybrid D4 and N9 cells. The levels of DCF and MitoSOX Red, which are indicative of the oxidative stress, were significantly higher in the B4 cells in basal conditions and after insulin treatment. Following treatment with the antioxidant NAC, cybrid B4 cells showed significantly reduced insulin-induced phosphorylation of P38 and increased GLUT1/GLUT4 translocation to the cell membrane, suggesting that NAC may divert insulin signaling from pro-inflammation to glucose uptake. CONCLUSIONS: Mitochondria play an independent role in the pathogenesis of IR, possibly through altered production of intracellular ROS.

Crystalline inorganic frameworks with 56-ring, 64-ring, and 72-ring channels.

The development of zeolite-like structures with extra-large pores (>12-membered rings, 12R) has been sporadic and is currently at 30R. In general, templating via molecules leads to crystalline frameworks, whereas the use of organized assemblies that permit much larger pores produces noncrystalline frameworks. Synthetic methods that generate crystallinity from both discrete templates and organized assemblies represent a viable design strategy for developing crystalline porous inorganic frameworks spanning the micro and meso regimes. We show that by integrating templating mechanisms for both zeolites and mesoporous silica in a single system, the channel size for gallium zincophosphites can be systematically tuned from 24R and 28R to 40R, 48R, 56R, 64R, and 72R. Although the materials have low thermal stability and retain their templating agents, single-activator doping of Mn(2+) can create white-light photoluminescence.

Slow immunological progression in HIV-1 CRF07_BC-infected injecting drug users.

Human immunodeficiency virus type 1 (HIV-1) circulating recombinant form (CRF) 07_BC has caused serious HIV-1 epidemics among injecting drug users (IDUs) in East Asia. Little is known about the characteristics of the virus and its impact on disease progression among the infected individuals. In this study, we compared immunological progression between 423 IDUs infected with CRF07_BC and 194 men who have sex with men (MSM) with primary subtype B infection, and a representative full-length CRF07_BC molecular clone, pCRF07_BC, was constructed to characterize the virus. We found that IDUs infected with CRF07_BC had significantly slower immunological progression in the Cox proportional hazards model (hazard ratio: 0.30; 95% confidence interval: 0.13-0.69; P=0.004). The constructed recombinant CRF07_BC viruses had a reduced processing of the Gag/Gag-Pol polyproteins, a decreased incorporation of Vpr in the virus particle, tethering of virus particles on the plasma membrane and decreased virus growth kinetics. These phenotypes are related to the unique 7-amino acid deletion in the p6 of CRF07_BC, since complementation of the 7-amino acid in pCRF07_BC could improve the defective phenotypes. In summary, compared with MSM infected with HIV-1 subtype B, IDUs infected with CRF07_BC had slower immunological progression, which is likely correlated with interference of virus particle maturation by the 7-amino acid deletion in p6.

Translational repression of cyclin D3 by a stable G-quadruplex in its 5' UTR: implications for cell cycle regulation.

cyclin D3 (CCND3) is one of the three D-type cyclins that regulate the G1/S phase transition of the cell cycle. Expression of CCND3 is observed in nearly all proliferating cells; however, the presence of high levels of CCND3 has been linked to a poor prognosis for several types of cancer. Therefore, further mechanistic studies on the regulation of CCND3 expression are urgently needed to provide therapeutic implications. In this study, we report that a conserved RNA G-quadruplex-forming sequence (hereafter CRQ), located in the 5' UTR of mammalian CCND3 mRNA, is able to fold into an extremely stable, intramolecular, parallel G-quadruplex in vitro. The CRQ G-quadruplex dramatically reduces the activity of a reporter gene in human cell lines, but it has little impact on its mRNA level, indicating a translational repression. Moreover, the CRQ sequence in its natural context inhibits translation of CCND3. Disruption of the G-quadruplex structure by G/U-mutation or deletion results in an elevated expression of CCND3 and an increased phosphorylation of Rb, a downstream target of CCND3, which promotes progression of cells through the G1 phase. Our results add to the growing understanding of the regulation of CCND3 expression and provide a potential therapeutic target for cancer treatment.

Triggering Fbw7-mediated proteasomal degradation of c-Myc by oridonin induces cell growth inhibition and apoptosis.

The transcription factor c-Myc is important in cell fate decisions and is frequently overexpressed in cancer cells, making it an attractive therapeutic target. Natural compounds are among the current strategies aimed at targeting c-Myc, but their modes of action still need to be characterized. To explore the mechanisms underlying the anticancer activity of a natural diterpenoid, oridonin, we conducted miRNA expression profiling and statistical analyses that strongly suggested that c-Myc was a potential molecular target of oridonin. Furthermore, experimental data showed that oridonin significantly reduced c-Myc protein levels in vitro and in vivo and that this reduction was mediated by the ubiquitin-proteasome system. Fbw7, a component of the ubiquitin-proteasome system and an E3 ubiquitin ligase of c-Myc, was upregulated rapidly in K562 cells and other leukemia and lymphoma cells, resulting in the rapid turnover of c-Myc. In cell lines harboring mutations in the WD domain of Fbw7, the degradation of c-Myc induced by oridonin was attenuated during short-term treatment. GSK-3, an Fbw7 priming kinase, was also activated by oridonin, along with an increase in T58-phosphorylated c-Myc. Furthermore, the knockdown of Fbw7 or the forced expression of stable c-Myc resulted in reduced sensitization to oridonin-induced apoptosis. Our observations help to clarify the anticancer mechanisms of oridonin and shed light on the application of this natural compound as an Fbw7-c-Myc pathway targeting agent in cancer treatment.

Intrinsic optical properties and divergent doping effects of manganese(II) on luminescence for tin(II) phosphite grown from a deep-eutectic solvent.

This is the first study on the ionothermal synthesis, intrinsic photoluminescence (PL), and dopant effects for tin(II) phosphite, a stereochemically active 5s(2) lone-pair-electron-containing compound, the fundamental properties of which have rarely been explored before. In a new deep-eutectic solvent, single-phased products of SnHPO(3) (1) and Sn(1-x)Mn(x)HPO(3) (2) have been achieved in high yield. The crystalline powder of 1 is nonenantiomorphic, with an intense second-harmonic generation comparable to that of potassium dihydrogen phosphate. Under UV excitation, it unexpectedly emits white PL, an important intrinsic property never discovered in tin(II) oxysalts. Electron paramagnetic resonance hyperfine splitting characteristic of manganese has been detected on 2 and a three-pulse electron-spin-echo envelope modulation technique implemented to locate its corresponding location in the inorganic host. On the basis of temperature-dependent PL and lifetime measurements, the incorporated Mn(2+) uncommonly acts as a sensitizer in enhancing white emission until extremely low temperatures, in which it would resume its normal role as an activator to give out characteristic orange light.

Predicting and analyzing DNA-binding domains using a systematic approach to identifying a set of informative physicochemical and biochemical properties.

BACKGROUND: Existing methods of predicting DNA-binding proteins used valuable features of physicochemical properties to design support vector machine (SVM) based classifiers. Generally, selection of physicochemical properties and determination of their corresponding feature vectors rely mainly on known properties of binding mechanism and experience of designers. However, there exists a troublesome problem for designers that some different physicochemical properties have similar vectors of representing 20 amino acids and some closely related physicochemical properties have dissimilar vectors. RESULTS: This study proposes a systematic approach (named Auto-IDPCPs) to automatically identify a set of physicochemical and biochemical properties in the AAindex database to design SVM-based classifiers for predicting and analyzing DNA-binding domains/proteins. Auto-IDPCPs consists of 1) clustering 531 amino acid indices in AAindex into 20 clusters using a fuzzy c-means algorithm, 2) utilizing an efficient genetic algorithm based optimization method IBCGA to select an informative feature set of size m to represent sequences, and 3) analyzing the selected features to identify related physicochemical properties which may affect the binding mechanism of DNA-binding domains/proteins. The proposed Auto-IDPCPs identified m = 22 features of properties belonging to five clusters for predicting DNA-binding domains with a five-fold cross-validation accuracy of 87.12%, which is promising compared with the accuracy of 86.62% of the existing method PSSM-400. For predicting DNA-binding sequences, the accuracy of 75.50% was obtained using m = 28 features, where PSSM-400 has an accuracy of 74.22%. Auto-IDPCPs and PSSM-400 have accuracies of 80.73% and 82.81%, respectively, applied to an independent test data set of DNA-binding domains. Some typical physicochemical properties discovered are hydrophobicity, secondary structure, charge, solvent accessibility, polarity, flexibility, normalized Van Der Waals volume, pK (pK-C, pK-N, pK-COOH and pK-a(RCOOH)), etc. CONCLUSIONS: The proposed approach Auto-IDPCPs would help designers to investigate informative physicochemical and biochemical properties by considering both prediction accuracy and analysis of binding mechanism simultaneously. The approach Auto-IDPCPs can be also applicable to predict and analyze other protein functions from sequences.

An extraordinary boron-mediated 16R-channel-containing trivalent vanadium phosphite with unique solid state redox properties.

For the first time, an open-framework oxysalt of trivalent vanadium is demonstrated, prepared from a single tetravalent vanadium source under acidic hydrothermal conditions. The borate-incorporated structure features intersecting 2D 16R channels and unusual solid-state redox properties confirmed by K-edge XANES, EPR spectral data and magnetic susceptibility measurements.

High glucose down-regulates miR-29a to increase collagen IV production in HK-2 cells.

Deposition of collagen IV in proximal tubule cells (PTCs) plays an important role during diabetic nephropathy, but the mechanism underlying excessive production of collagen IV remains poorly understood. In this study, we examined the miRNA profile of HK-2 cells and found that high glucose/TGF-beta1 induced significant down-regulation of miR-29a. We then showed that miR-29a negatively regulated collagen IV by directly targeting the 3'UTRs of col4a1 and col4a2. These results suggest that miR-29a acts as a repressor to fine-tune collagen expression and that the reduction of miR-29a caused by high glucose may increase the risk of excess collagen deposition in PTCs.