The Anaphase Promoting Complex (APC, also called APC/C) regulates cell cycle progression by forming two closely related, but functionally distinct E3 ubiquitin ligase sub-complexes, APCCdc20 and APCCdh1, respectively. Emerging evidence has begun to reveal that Cdc20 and Cdh1 have opposing functions in tumorigenesis. Specifically, Cdh1 functions largely as a tumor suppressor, whereas Cdc20 exhibits an oncogenic function, suggesting that Cdc20 could be a promising therapeutic target for combating human cancer. However, the exact underlying molecular mechanisms accounting for their differences in tumorigenesis remain largely unknown. Therefore, in this review, we summarize the downstream substrates of Cdc20 and the critical functions of Cdc20 in cell cycle progression, apoptosis, ciliary disassembly and brain development. Moreover, we briefly describe the upstream regulators of Cdc20 and the oncogenic role of Cdc20 in a variety of human malignancies. Furthermore, we summarize multiple pharmacological Cdc20 inhibitors including TAME and Apcin, and their potential clinical benefits. Taken together, development of specific Cdc20 inhibitors could be a novel strategy for the treatment of human cancers with elevated Cdc20 expression.
One-electron oxidation of the 1,2,4-diazaphospholide anion [3,5-R2dp](-) by BiCl3 generated several remarkable paddlewheel dibismuthanes [L2(Bi-Bi)L2] (L = η(1),η(1)-3,5-R2dp, R = tBu, iPr, or Ph) with very short Bi-Bi single bond lengths (2.7964(4)-2.8873(3) Å).
Background
Treatment non-adherence is a serious challenge to effective tuberculosis (TB) control in Tibet. In this study we will pilot and evaluate the effectiveness of using new electronic monitors (e-monitors) and a smartphone app to improve treatment adherence among new pulmonary TB patients in Tibet.
Methods
We will use a multicentre, parallel-group, individually randomised controlled, superiority trial with blinded outcome evaluation and unblinded treatment. We will randomise new pulmonary TB outpatients (aged ≥ 15 years old and free from communication impairment) from Shigatse, Tibet to either the intervention or control arm in a 1:1 ratio at the time of their diagnosis. All patients will be treated according to the World Health Organisation standard 6-month TB treatment regimen and the China National TB programme guidelines. Intervention arm patients will be given their medication via e-monitors that have automatic voice reminders, and record medication adherence data and share it with health staff via Cloud connection. Intervention patients will also be encouraged to receive smartphone-based video-observed treatment if their adherence is problematic. Control arm patients will receive their medication in e-monitors that will collect medication adherence history, but will have their reminder function deactivated and are not linked to the app. The primary outcome is the rate of poor adherence, measured monthly during treatment as a binary indicator where poor adherence means missing ≥ 20% of doses in a month. We will conduct a qualitative process evaluation to explore operational questions regarding acceptability, cultural appropriateness and burden of technology use, as well as a cost-effectiveness analysis and an analysis of the long-term effects of the intervention on TB control.
Discussion
Our study is one of the first trials to evaluate the use of e-monitors and smartphone apps for customised treatment support in low- and middle-income countries (LMICs). All intervention activities are designed to be embedded into routine TB care with strong local ownership. Through the trial we intend to understand the feasibility of our intervention, its effectiveness, its cost-effectiveness and its long-term impacts to inform future scale-up in remote areas of China and other LMICs.
Trial registration
Current Controlled Trials, ID:
ISRCTN52132803
. Registered on 9 November 2018.
Electronic supplementary material
The online version of this article (10.1186/s13063-019-3364-x) contains supplementary material, which is available to authorized users.
Treatment
of cardiovascular diseases suffers from the lack of transplantable
small-diameter blood vessel (SDBV) grafts that can prohibit/eliminate
thrombosis. Although expanded poly(tetrafluoroethylene) (ePTFE) has
the potential to be used for SDBV grafts, recurrence of thrombus remains
the biggest challenge. In this study, a reactive oxygen species (ROS)-responsive
antithrombogenic drug synthesis and a bulk coating process were employed
to fabricate functional ePTFE grafts capable of prohibiting/eliminating
blood clots. The synthesized drug that would release antiplatelet
ethyl salicylate (ESA), in responding to ROS, was dissolved in a polycaprolactone
(PCL) solution, followed by a bulk coating of the as-fabricated ePTFE
grafts with the PCL/drug solution. Nuclear magnetic resonance (NMR)
spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, scanning
electron microscopy (SEM), and atomic force microscopy (AFM) were
employed to investigate and confirm the synthesis and presence of
the ROS-responsive drug in the ePTFE grafts. The ESA release functions
were demonstrated via the drug-release profile and dynamic anticoagulation
tests. The biocompatibility of the ROS-responsive ePTFE grafts was
demonstrated via lactate dehydrogenase (LDH) cytotoxicity assays,
live and dead cell assays, cell morphology, and cell–graft
interactions. The ROS-responsive, antithrombogenic ePTFE grafts provide
a feasible way for maintaining long-term patency, potentially solving
a critical challenge in SDBV applications.
Azacalix[3]pyridine[3]pyrimidine was synthesized efficiently by means of a [3+3] fragment coupling approach. Adopting a preorganized symmetric 1,3,5-alternate conformation, the macrocycle formed complexes with fullerenes through the multiple intramolecular π/π and CH/π interactions.
Synthesis, structure, and fullerene-binding property of azacalix[6]aromatics were systematically studied. By means of [3 + 3] and [2 + 2 + 2] fragment coupling protocols, a number of azacalix[6]aromatics containing different combinations of benzene, pyridine, and pyrimidine rings and various substituents on the bridging nitrogen atoms were synthesized conveniently in moderate to good yields. The resulting macrocycles adopt in the solid state symmetric and heavily distorted 1,3,5-alternate conformations depending on the aromatic building units, whereas, in solution, they exist as a mixture of conformers that undergo rapid interchanges relative to the NMR time scale. All macrocycles were able to form 1:1 complexes with C60 and C70 in toluene with the association constants up to 7.28 × 10(4) M(-1). In the crystalline state, azacalix[6]aromatics form complexes with C60 and C70 with 2:1, 1:1, and 1:2 stoichiometric ratios between host and guest. Azacalix[6]aromatics interact with fullerene by forming mainly the sandwich structure in which C60 or C70 is sandwiched by two macrocycles. X-ray molecular structures revealed that multiple π-π and CH-π interactions between concave azacalix[6]aromatics and convex fullerenes C60 and C70 contribute a joint driving force to the formation of host-guest complexes.
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