Abstract
Background
The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to ...evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine.
Methods
A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18–45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission.
Results
In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months.
Conclusions
The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18–associated high-grade genital lesions and persistent infection in women.
An efficient and direct ruthenium-catalyzed regioselective hydroxymethylation of (hetero)arenes via C–H activation with paraformaldehyde as a hydroxymethylating reagent is described. The ...corresponding products can be obtained in good to excellent yield. A number of aryl aldehydes can also be used in place of paraformaldehyde giving the desired alcohol products with similarly good results.
E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we ...characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPlus, Lancaster, CA, USA). Furthermore, tissue distribution and the human PK profiles of different administration dosages and forms were predicted. The 0.002 L/h of CL and 0.005 L of V
in mice were calculated and optimized from observed PK data. The plasma exposure of E0703 was availably predicted by the CL using the simple allometry (SA) method. The plasma concentration-time profiles of other dosages (20 and 40 mg) and two oral administrations (30 mg) were well-fitted to the observed values. In addition, the PK profile of target organs for E0703 exhibited a higher peak concentration (C
) and AUC than plasma. The developed E0703-PBPK model, which is precisely applicable to multiple species, benefits from further clinical development to predict PK in humans.
In present work, spectrum of the
S
-wave fully-heavy tetraquark states
Q
Q
Q
¯
Q
¯
(
Q
=
c
,
b
), i.e.,
c
c
c
¯
c
¯
,
b
b
b
¯
b
¯
,
c
c
b
¯
b
¯
/
b
b
c
¯
c
¯
,
b
c
c
¯
c
¯
/
c
c
b
¯
c
¯
,
b
b
c
¯
b
¯
.../
c
b
b
¯
b
¯
, and
b
c
b
¯
c
¯
are systematically investigated within a nonrelativistic constituent quark model, in which the instanton-induced and one-gluon-exchange interactions are taken into account as the residual spin-dependent hyperfine interaction. Our results show that the states with
c
c
c
¯
c
¯
and
b
b
b
¯
b
¯
components could be located around 6500 MeV and 19,200 MeV, respectively. Based on our calculations, the new
X
(6900) state observed by LHCb may be not a ground
c
c
c
¯
c
¯
tetraquark state, while it could be an orbitally or radially excited state of
c
c
c
¯
c
¯
system. On the other hand, the recently reported
X
(6600) state by CMS and ATLAS can be explained as a ground
c
c
c
¯
c
¯
tetraquark state with spin-parity
J
PC
=
0
+
+
.
Ni-based transition metal oxides are promising oxygen-evolution reaction (OER) catalysts due to their abundance and high activity. Identification and manipulation of the chemical properties of the ...real active phase on the catalyst surface is crucial to improve the reaction kinetics and efficiency of the OER. Herein, we used electrochemical-scanning tunnelling microscopy (EC-STM) to directly observe structural dynamics during the OER on LaNiO3 (LNO) epitaxial thin films. Based on comparison of dynamic topographical changes in different compositions of LNO surface termination, we propose that reconstruction of surface morphology originated from transition of Ni species on LNO surface termination during the OER. Furthermore, we showed that the change in surface topography of LNO was induced by Ni(OH)2/NiOOH redox transformation by quantifying STM images. Our findings demonstrate that in situ characterization for visualization and quantification of thin films is very important for revealing the dynamic nature of the interface of catalysts under electrochemical conditions. This strategy is crucial for in-depth understanding of the intrinsic catalytic mechanism of the OER and rational design of high-efficiency electrocatalysts.
The Myoviridae cyanophage A-1(L) specifically infects the model cyanobacteria Anabaena sp. PCC 7120. Following our recent report on the capsid structure of A-1(L), here we present the high-resolution ...cryo-EM structure of its intact tail machine including the neck, tail and attached fibers. Besides the dodecameric portal, the neck contains a canonical hexamer connected to a unique pentadecamer that anchors five extended bead-chain-like neck fibers. The 1045-Å-long contractile tail is composed of a helical bundle of tape measure proteins surrounded by a layer of tube proteins and a layer of sheath proteins, ended with a five-component baseplate. The six long and six short tail fibers are folded back pairwise, each with one end anchoring to the baseplate and the distal end pointing to the capsid. Structural analysis combined with biochemical assays further enable us to identify the dual hydrolytic activities of the baseplate hub, in addition to two host receptor binding domains in the tail fibers. Moreover, the structure of the intact A-1(L) also helps us to reannotate its genome. These findings will facilitate the application of A-1(L) as a chassis cyanophage in synthetic biology.
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•A 3D cationic covalent organic framework (TFAM-BDNP) was synthesized via Zincke reaction.•TFAM-BDNP exhibits high adsorption capacity and extremely fast exchange kinetic for ...ReO4−.•TFAM-BDNP demonstrates remarkable selectivity for ReO4−.•TFAM-BDNP has outstanding removal efficiency of ReO4− from simulated Hanford flow sample.
Due to the long half-life and high environmental mobility, the selective and efficient capture of TcO4− from nuclear effluents is very important, but it is still very challenging. Herein, we design and synthesize a novel three-dimensional (3D) cationic covalent organic framework (TFAM-BDNP) via Zincke reaction for selective capture of TcO4−/ReO4−. TFAM-BDNP exhibits high adsorption capacity (998 mg g−1) and extremely fast exchange kinetic (60 s) for ReO4− (the non-radioactive alternative to TcO4−), attributing to the open 3D hydrophobic channels, abundant active sites, and high chemical stability. More importantly, TFAM-BDNP shows good adsorption performance for ReO4− in the presence of significant excess competing anions with a wide pH value range of 2 to 12. Under complex simulated Hanford flow sample, TFAM-BDNP has outstanding removal efficiency of ReO4−. The adsorption mechanism of ReO4− is mainly caused by anion exchange process. This study provides a novel adsorbent for efficient capture of TcO4−/ReO4− in complex environmental systems and exploits an effective strategy for broadening the types of 3D COFs.
The decline of fossil fuels is fostering research on carbon–neutral fuels such as nuclear energy, yet uranium supply is limited by actual techniques of uranium extraction from seawater. In ...particular, biofouling by marine bacteria and adsorbent instability are major drawbacks. Here we synthesized a novel amidoxime-functionalized antibacterial covalent organic framework that displays high stability and inhibits more than 90% the growth of marine bacteria, thus resulting in an enhanced uranium recovery capacity of 6.64 mg/g. Meanwhile, due to its exceptional fluorescence properties, the adsorbent can also be applied to highly sensitive on-site and real-time monitoring of UO
2
2+
.
Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili ...peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA.
Cardiomyocyte apoptosis is initiated by various cellular insults and accumulated cardiomyocyte apoptosis leads to the pathogenesis of heart failure. Excessive reactive oxygen species (ROS) provoke ...apoptotic cascades. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme that converts cellular ROS into harmless products. In this study, we demonstrate that MnSOD is down-regulated upon hydrogen peroxide treatment or ischemia/reperfusion (I/R) injury. Enhanced expression of MnSOD attenuates cardiomyocyte apoptosis and myocardial infarction induced by I/R injury. Further, we show that miR-23a directly regulates the expression of MnSOD. miR-23a regulates cardiomyocyte apoptosis by suppressing the expression of MnSOD. Our study reveals a novel model regulating cardiomyocyte apoptosis which is composed of miR-23a and MnSOD. Our study provides a new method to tackling apoptosis related cardiac diseases.
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