Long-term safety of infants from mothers with chronic hepatitis B treated with tenofovir disoproxil in China.

OBJECTIVE: The physical and neuromental development of infants remains uncertain after fetal exposure to tenofovir disoproxil fumarate (TDF) for the prevention of mother-to-child transmission of HBV. We aimed to investigate the safety of TDF therapy during the third trimester of pregnancy. DESIGN: Infants from a previous randomised controlled trial were recruited for our long-term follow-up (LTFU) study. Mothers with chronic hepatitis B were randomised to receive TDF therapy or no treatment during the third trimester. Infants' physical growth or malformation, bone mineral density (BMD) and neurodevelopment, as assessed using Bayley-III assessment, were examined at 192 weeks of age. RESULTS: Of 180 eligible infants, 176/180 (98%) were enrolled and 145/176 (82%) completed the LTFU (control group: 75; TDF-treated group: 70). In the TDF-treated group, the mean duration of fetal exposure to TDF was 8.57±0.53 weeks. Congenital malformation rates were similar between the two groups at week 192. The mean body weight of boys in the control and TDF-treated groups was significantly higher (19.84±3.46 kg vs. 18.47±2.34 kg; p=0.03) and within the normal range (18.48±2.35 kg vs. 17.80±2.50 kg; p=0.07), respectively, when compared with the national standard. Other prespecified outcomes (head circumference, height, BMD, and cognitive, motor, social-emotional, and adaptive behaviour measurements) were all comparable between the groups. CONCLUSION: Infants with fetal exposure to TDF had normal physical growth, BMD and neurodevelopment at week 192. Our findings provide evidence on the long-term safety of infants after fetal exposure to maternal TDF therapy for preventing hepatitis B transmission. TRIAL REGISTRATION NUMBER: NCT01488526.

Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load.

BACKGROUND: Few data are available regarding the use of tenofovir disoproxil fumarate (TDF) during pregnancy for the prevention of mother-to-child transmission of hepatitis B virus (HBV). METHODS: In this trial, we included 200 mothers who were positive for hepatitis B e antigen (HBeAg) and who had an HBV DNA level higher than 200,000 IU per milliliter. Participants were randomly assigned, in a 1:1 ratio, to receive usual care without antiviral therapy or to receive TDF (at an oral dose of 300 mg per day) from 30 to 32 weeks of gestation until postpartum week 4; the participants were followed until postpartum week 28. All the infants received immunoprophylaxis. The primary outcomes were the rates of mother-to-child transmission and birth defects. The secondary outcomes were the safety of TDF, the percentage of mothers with an HBV DNA level of less than 200,000 IU per milliliter at delivery, and loss or seroconversion of HBeAg or hepatitis B surface antigen at postpartum week 28. RESULTS: At delivery, 68% of the mothers in the TDF group (66 of 97 women), as compared with 2% in the control group (2 of 100), had an HBV DNA level of less than 200,000 IU per milliliter (P<0.001). At postpartum week 28, the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group, both in the intention-to-treat analysis (with transmission of virus to 5% of the infants [5 of 97] vs. 18% [18 of 100], P=0.007) and the per-protocol analysis (with transmission of virus to 0 vs. 7% [6 of 88], P=0.01). The maternal and infant safety profiles were similar in the TDF group and the control group, including birth-defect rates (2% [2 of 95 infants] and 1% [1 of 88], respectively; P=1.00), although more mothers in the TDF group had an increase in the creatine kinase level. After the discontinuation of TDF, alanine aminotransferase elevations above the normal range occurred more frequently in mothers in the TDF group than in those in the control group (45% [44 of 97 women] vs. 30% [30 of 100], P=0.03). The maternal HBV serologic outcomes did not differ significantly between the groups. CONCLUSIONS: In a cohort of HBeAg-positive mothers with an HBV DNA level of more than 200,000 IU per milliliter during the third trimester, the rate of mother-to-child transmission was lower among those who received TDF therapy than among those who received usual care without antiviral therapy. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01488526.).

4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[2-(2-methyl-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[1,2-a]pyrimidin-3-yl)eth-yl]piperidinium nitrate.

In the risperidone cation of the title compound, C(23)H(28)FN(4)O(2) (+)·NO(3) (-), the piperidine ring adopts a chair conformation and the tetra-hydro-pyridine ring is disordered over two orientations in a 0.620 (11):0.380 (11) ratio. N-H⋯O, C-H⋯O and C-H⋯F hydrogen bonds are present in the crystal structure.

µ(3)-Oxido-hexa-µ(2)-pivalato-tris[(methanol-κO)cobalt(III)] chloride.

The crystal structure of the title compound, [Co(3)(C(5)H(9)O(2))(6)O(CH(4)O)(3)]Cl, consists of trinuclear Co(III) complex cations and chloride anions. The Co(III) cation has site symmetry m, and is coordinated by four oxygen atoms from four bridging pivalate groups, one central O anion and a methanol oxygen atom, forming a distorted octa-hedral geometry. The coordinated methanol mol-ecule is located on a crystallographic special position, the C and O atoms being located on the mirror plane. The central O anion lies in the crystallographic position, and acts as a µ(3)-O bridge, linking three equivalent Co(III) cations and generating the oxo-centered trinuclear Co(III) complex. The chloride anion, which acts as the counter-ion, is located on crystallographic position. O-H⋯Cl hydrogen bonding between the Cl anion and hydroxyl group of the coordinated methanol mol-ecule links the mol-ecules into a supra-molecular network.

Bis[2-meth-oxy-6-(3-pyridylmethyl-imino-meth-yl)phenolato-κN,O]copper(II).

In the title complex, [Cu(C(14)H(13)N(2)O(2))(2)], the Cu(II) ion is located on a crystallographic inversion center. The complex thus adopts a square-planar trans-[CuN(2)O(2)] coordination geometry, with the Cu(II) ion coordinated by two 2-meth-oxy-6-(3-pyridylmethyl-imino-meth-yl)phenolate (Schiff base) ligands. The aryl and pyridyl rings in the Schiff base are almost perpendicular to each other, with a dihedral angle of 87.61 (6)° between the planes of the two six-membered rings. The pyridyl ring was refined using a disorder model with approximately 70% occupancy for the major component.

Aqua-[4-chloro-2-(2-pyridylmethyl-imino-meth-yl)phenolato]copper(II) nitrate monohydrate.

In the title mononuclear complex, [Cu(C(13)H(10)ClN(2)O)(H(2)O)]-NO(3)·H(2)O, the Cu(II) atom is four-coordinated by two N atoms and one O atom of the tridentate Schiff base ligand and one O atom from the coordinated water mol-ecule in a slightly distorted square-planar configuration. The nitrate ion inter-acts with the copper center [Cu1⋯O3 = 2.579 (4) Å]. In the crystal, the cations, anions and water mol-ecules are linked by O-H⋯O and O-H⋯N hydrogen bonds.

Aqua-bis(2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-olato)nickel(II).

In the crystal structure of the mononuclear title complex, [Ni(C(10)H(9)N(2)O(2))(2)(H(2)O)], the Ni(II) ion is five-coordinated in a distorted square-pyramidal geometry by two N atoms and two O atoms from 2,3-dimethyl-4-oxopyrido[1,2-a]pyrimidin-9-olate ligands and one O atom from a water mol-ecule. O-H⋯O hydrogen bonds between the coordinated water mol-ecule and the ligand connect adjacent mol-ecules, forming a ribbon parallel to the b axis.

Bis{µ-2-[1-(2-Pyridylmethyl-imino)eth-yl]phenolato}bis-[azido-copper(II)].

The title compound, [Cu(2)(C(14)H(13)N(2)O)(2)(N(3))(2)], was synthesized by the reaction of Cu(NO(3))(2)·3H(2)O with the Schiff base 2-[1-(2-pyridylmethyl-imino)eth-yl]phenol (HL) in methanol-water solution, adding NaN(3) as the bridging ligand. The asymmetric unit contains one half-mol-ecule, the other half being generated by the inversion center. Each Cu(II) atom shows a slightly distorted trigonal-pyramidal geometry formed by two N atoms and one O atom from one Schiff base ligand, by another O atom of a second Schiff base ligand and by an azide N atom. The crystal structure is stabilized by intermolecular C-H⋯N hydrogen bonds.

Di-µ-chlorido-bis-[aqua-(2,2'-bipyridine-κN,N')chloridocobalt(II)].

The title complex, [Co(2)Cl(4)(C(10)H(8)N(2))(2)(H(2)O)(2)], is composed of two Co(II) atoms, each hexa-coordinated by three Cl atoms, one 2,2'-bipyridine (bpy) ligand and one water mol-ecule in a distorted octa-hedral geometry. Neighboring Co(II) atoms are linked together by two Cl bridges, forming a dinuclear Co(II) complex with inversion symmetry. There are inter-molecular O-H⋯Cl hydrogen bonds and inter-molecular π-π stacking inter-actions between adjacent bpy ligands [centroid-centroid distance = 3.617 (2) Å] in the structure.

Aqua-(1,10-phenanthroline-κN,N')bis-(trimethyl-acetato)-κO,O';κO-cobalt(II).

In the title compound, [Co(C(5)H(9)O(2))(2)(C(12)H(8)N(2))(H(2)O)], the Co(II) atom is coordinated in a distorted octahedral environment by three carboxyl O atoms of two trimethyl-acetate ligands, one aqua O atom and two N atoms from 1,10-phen-anthroline. The crystal structure is stabilized by O-H⋯O hydrogen bonds and π-π stacking inter-actions [inter-planar distance between inter-digitating 1,10-phenanthroline ligands = 3.378 (2) Å].

Aqua-bis(2-methyl-4-oxopyrido[1,2-a]pyrimidin-9-olato)zinc(II) monohydrate.

The crystal structure of the title compound, [Zn(C(9)H(7)N(2)O(2))(2)(H(2)O)]·H(2)O, involves discrete mononuclear complex mol-ecules. The special positions on the rotation twofold axis are occupied by Zn(II) and O atoms of the coordinated and uncoordinated water mol-ecules. The coordination around the Zn(II) atom can be described as transitional from trigonal-bipyramidal to square-pyramidal. The two chelating 2-methyl-4-oxopyrido[1,2-a]pyrimidin-9-olate ligands and the coordin-ated water mol-ecule form the Zn coordination. O-H⋯O hydrogen bonds between the coordinated water mol-ecule and the ligand and between the uncoordinated water mol-ecule and the ligand dominate the crystal packing.

pH-sensitive prodrug conjugated polydopamine for NIR-triggered synergistic chemo-photothermal therapy.

Combination of chemotherapy with photothermal therapy (PTT) demonstrate highly desirable for efficient medical treatment of tumor. At present works, camptothecin (CPT)-containing polymeric prodrug (PCPT) were fabricated by polymerization of a pH-sensitive camptothecin (CPT) prodrug monomer and MPC using reversible addition-fragmentation transfer (RAFT) strategy. The pH-sensitive polymeric prodrug was tethered onto surface of polydopamine (PDA) nanoparticles by amidation chemistry for combination of chemotherapy with photothermal therapy. Specifically, the active CPT quickly released from the multifunctional nanoparticles in acidic microenvironment ascribe to the cleavage of bifunctional silyl ether linkage. Meanwhile, the PDA could convert the near infrared (NIR) light energy into heat with high efficiency, which makes the resulted nanoparticles an effective platform for photothermal therapy. In vitro analysis confirmed that the PDA@PCPT nanoparticles could be efficiently uptaked by HeLa cells and deliver CPT into the nuclei of cancer cells. The cell viability assays indicated an evident in vitro cytotoxicity to HeLa cancer cells under 808 nm light irradiation. Significant tumor regression was also observed in the tumor-bearing mice model with the combinational therapy provided from the PDA@PCPT nanoparticles. The PDA@PCPT multifunctional system which was achieved by a facile route should be a potential candidate in the anti-cancer field due to the synergistic therapeutic effect, which is superior to any single approach.

Hepatitis B virus X protein mediates yes-associated protein 1 upregulation in hepatocellular carcinoma.

Hepatitis B virus (HBV) X protein (HBx) is implicated in the development of hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP) is an important proto-oncogene, which is a downstream effector molecule in the Hippo signaling pathway. The aim of the present study was to investigate the association between HBx expression in HCC samples and YAP expression in the Hippo pathway. A total of 20 pathologically confirmed HCC samples, 20 corresponding adjacent non-tumor liver tissues and 5 normal liver tissue samples were collected. The expression of HBx and YAP in the tissues was analyzed by quantitative reverse transcription-polymerase chain reaction and western blot analysis. The intensity and location of YAP expression were analyzed by immunohistochemistry. YAP mRNA and protein expression levels in HCC samples infected with HBV were significantly higher than those of normal liver tissues. Furthermore, YAP expression was positively correlated with HBx expression in HBV-positive HCC samples. Immunohistochemical staining revealed that YAP was predominantly expressed in the nuclei in HBV-positive HCC tissues. YAP expression was significantly decreased in the normal liver tissue and corresponding adjacent liver tissue when compared with the HCC tissues and by contrast to HCC tissues, YAP was predominantly located in the cytoplasm. In conclusion, these results indicate that the YAP gene is a key driver of HBx-induced liver cancer. Therefore, YAP may present a novel target in the treatment of HBV-associated HCC.

Influenza virus H1N1 induced apoptosis of mouse astrocytes and the effect on protein expression.

OBJECTIVE: To investigate the effects of influenza A virus H1N1 infection on the proliferation and apoptosis of mouse astrocytes cells and its protein expression. METHODS: After mouse astrocytes was infected with purified influenza A virus H1N1 in vitro, viral integration and replication status of the cells were detected by RT-PCR assay, cell proliferation and apoptosis was determined by MTT method and flow cytometry, respectively. Associated protein expression was detected by Western blotting. RESULTS: Agarose gel electrophoresis showed H1N1 virus can infect astrocytes and can be copied. MTT staining showed H1N1 virus infection can inhibit the proliferation of mouse astrocytes, which makes cell viability decreased significantly. Flow cytometry showed that the proportion of Annein V staining positive vascular endothelial cells in the influenza A virus group was significantly higher than that in the control group. Western blot analysis showed after 24 h and 32 h of infection, there were cells caspase-3 protein and the expression of its active form (lysed caspase-3 protein) increased. The proportion of Bax/Bcl-2 also increased. CONCLUSIONS: Influenza A virus can infect human vascular endothelial cells and proliferation and it can induce apoptosis of endothelial cells.

Graphene oxide-coumarin derivative conjugate as activatable nanoprobe for intracellular imaging with one- or two-photon excitation.

An interesting activatable fluorescent imaging probe based on a graphene oxide-coumarin derivative conjugate with high sensitivity in cancer cell visualization was proposed. The nanoprobe has a fluorescence off-on response for intracellular imaging via covalently linking coumarin derivatives to graphene oxide (GO) through disulfide bonds. The obtained nanoprobe shows no or weak fluorescence (OFF) most likely due to the fluorescence resonance energy transfer from the coumarin moiety to GO. It becomes activated (ON) inside the cells by glutathione initiated dissociation, showing remarkably enhanced fluorescence. More significantly, the present activatable nanoprobe can be efficiently taken up by cells. Two-photon induced fluorescence imaging of the proposed nanoprobe was also clearly observed by utilizing femtosecond pulse laser excitation, and affords a powerful alternative candidate for near-infrared (NIR) fluorescence imaging of tumors. Similar fluorescence was visualized in a tumor-bearing mouse model using this probe. These results demonstrate the potential of using this activatable nanoprobe for the detection of cancer.

Folate-conjugated ß-cyclodextrin from click chemistry strategy and for tumor-targeted drug delivery.

To enhance site-specific intracellular delivery against the folate receptor, a drug carrier was designed and synthesized by bioconjugation of folic acid (FA) to ß-cyclodextrins (ß-CD) through a poly(ethylene glycol) (PEG) spacer from "click chemistry" strategy. The resulted conjugates were confirmed by (1)H NMR and IR spectroscopy. Host-guest interactions between hydrophobic drug and ß-CD are capable of entrapping a hydrophobic drug, like 5-Fluorouracil, to form drug-ß-CD-PEG-FA nanoparticles (NPs) in aqueous solution. The morphology and size of ß-CD-PEG-FA NPs were measured by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The targeting ability of the ß-CD-PEG-FA NPs was investigated against two kinds of cell lines (HeLa and A549), which have different amounts of folate receptors on their surface. Confocal image analysis revealed that ß-CD-PEG-FA conjugate-assembled nanoparticles exhibited a greater extent of cellular uptake against HeLa cells than A549 cells. This suggests folate-receptor-mediated endocytosis can affect the cellular uptake efficiency of drug-loaded ß-CD-PEG-FA NPs. The ß-CD-PEG-FA conjugates that are presented may be promising active tumor-targeting carrier candidates via folate mediation.

A blue-emitting organic compound 9-hydroxyl-3-hydroxyethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one: Synthesis, crystal structure and luminescent properties.

A blue-emitting organic compound, 9-hydroxyl-3-hydroxyethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (I), was synthesized by the reaction of 2-amino-3-hydroxylpridine with 2-acetylbutyrolactone. The crystal of the title compound in larger size was reported for the first time through the slow evaporation method. The whole molecule in the crystal is non-planar, but the two conjugated rings are almost co-planar (with an average dihedral angle of only about 1.621degrees). The hydroxyl group is in trans position to the pyrido[1,2-a]pyrimidin heterocyclic moiety. The molecules are linked by the N-HO, O-HO and C-HO hydrogen bonds into two-dimensional sheets. Additionally, the pi-pi interactions (average distance 3.3680 A) interconnect the sheets stabilizing the crystal structure. At room temperature, the compound exhibits an intense blue emission at 432 nm upon 323 nm excitation in the solid state. The simple EL device with the configuration of ITO/I + PMMA/Ag was fabricated, where the compound (I) was used as a main emitting material. The EL device fabricated had a maximum brightness of 289 cd m-2. The thermal stability of the compound was also investigated by thermogravimetric analysis (TGA).