Poisoning is a leading cause of admission to medical emergency departments and intensive care units. Supramolecular detoxification, which involves injecting supramolecular receptors that bind with ...toxins to suppress their biological activity, is an emerging strategy for poisoning treatment; it has few requirements and a broad application scope. However, it is still a formidable challenge to design supramolecular therapeutic materials as an antidote to macromolecular toxins, because the large size, flexible conformation, and presence of multiple and diverse binding sites of biomacromolecules hinder their recognition. Herein, a supramolecular antidote to macromolecular toxins is developed through the coassembly of macrocyclic amphiphiles, relying on heteromultivalent recognition between the coassembled components and toxic macromolecules. The coassembly of amphiphilic cyclodextrin and calixarene strongly and selectively captures melittin, a toxin studied herein; this imparts various therapeutic effects such as inhibiting the interactions of melittin with cell membranes, alleviating melittin cytotoxicity and hemolytic toxicity, reducing the mortality rate of melittin‐poisoned mice, and mitigating damage to major organs. The use of the proposed antidote overcomes the limitation of supramolecular detoxification applicability to only small‐molecular toxins. The antidote can also detoxify other macromolecular toxins as long as selective and strong binding is achieved because of the coassembling tunability.
Supramolecular detoxification is an emerging strategy for treating poisoning; however, developing supramolecular therapeutic materials as an antidote to macromolecular toxins is challenging. To overcome this challenge, a heteromultivalent coassembling material (CCA‐CD) comprising macrocyclic amphiphiles is developed. The CCA‐CD binds with melittin strongly and selectively, and significantly alleviates its toxicity, serving as a novel supramolecular antidote used for melittin poisoning treatment.
Cancer stem cells (CSCs) are cancer‐initiating cells that are not only a source of tumorigenesis but also the cause of tumour progression, metastasis and therapy resistance. EBV‐associated gastric ...cancer (EBVaGC) is a distinct subtype of gastric cancer with unique clinicopathological and molecular features. However, whether CSCs exist in EBVaGC, and the tumorigenic mechanism of EBV, remains unclear. Here, NOD/SCID mice were injected subcutaneously with the EBVaGC cell line SNU719 and treated with 5‐fluorouracil weekly. Successive generations of xenografts yielded a highly malignant EBVaGC cell line, SNU‐4th, which displays properties of CSCs and mainly consists of CD44+CD24− cells. In SNU‐4th cells, an EBV‐encoded circRNA, ebv‐circLMP2A, expression increased and plays crucial roles in inducing and maintaining stemness phenotypes through targeting miR‐3908/TRIM59/p53 axis. Additionally, high expression of ebv‐circLMP2A is significantly associated with metastasis and poor prognosis in patients with EBVaGC. These findings not only provide evidence for the existence of CSCs in EBVaGC and elucidate the pathogenic mechanism of ebv‐circLMP2A in EBVaGC, but also provide a promising therapeutic target for EBVaGC.
Synopsis
The circRNA LMP2A produced by the Epstein‐Barr virus induces stemness of EBV‐associated gastric cancer cells by attenuating the tumor suppressive effect of the miR‐3908/TRIM59/p53 axis, thereby promoting metastasis and tumor progression.
Cells with properties of cancer stem cells were isolated form EBV‐associated gastric cancer (EBVaGC).
The levels of an EBV‐encoded circRNA (ebv‐circLMP2A) are significantly increased in EBVaGC.
ebv‐circLMP2A has crucial roles in inducing and maintaining cancer stemness in EBVaGC.
High expression of ebv‐circLMP2A is significantly associated with metastasis and poor prognosis in EBVaGC patients.
The circRNA LMP2A produced by the Epstein‐Barr virus induces stemness of EBV‐associated gastric cancer cells by attenuating the tumor suppressive effect of the miR‐3908/TRIM59/p53 axis, thereby promoting metastasis and tumor progression.
Proper placement of suture anchors is an important step in Bankart repair as improper placement can lead to failure. Concern surrounding suture anchor placement inspired the use navigation systems in ...shoulder arthroscopy. We aimed to demonstrate the technological advantage of using the O-arm (Medtronic Navigation, Denver, CO, USA) image guidance system to provide real-time images during portal and anchor placements in shoulder arthroscopy. Consecutive patients (from July to October 2014) who were admitted for arthroscopic capsulolabral repair surgeries were included. Ten patients were randomly enrolled in the navigation group and 10 in the traditional group. The glenoid was divided into four zones, and the penetration rates in each zone were compared between the two groups. In zone III, the most inferior region of the glenoid, the penetration rate was 40.9% in the traditional group and 15.7% in the navigation group (P = 0.077), demonstrating a trend toward improved accuracy of anchor placement with the aid of the navigation system; however, this was not statistically significant. Average surgical time in the navigation and traditional groups was 177.6±40.2 and 117.7±17.6 mins, respectively. American Shoulder and Elbow Surgeons Shoulder Scores showed no difference before and 6 months after surgery. This pilot study showed a trend toward decreased penetration rate in O-arm-navigated capsulolabral repair surgeries and decreased risks of implant misplacement; however, possibly due to the small sample size, the difference was not statistically significant. Further large-scale studies are needed to confirm the possible benefit of the navigation system. Even with the use of navigation systems, there were still some penetrations in zone III of the glenoid. This penetration may be attributed to the micro-motion of the acromioclavicular joint. Although the navigation group showed a significant increase in surgical time, with improvements in instrument design, O-arm-navigated arthroscopy will gain popularity in clinical practice.
Oncogene‐derived metabolic reprogramming is important for anabolic growth of cancer cells, which is now considered to be not simply rely on glycolysis. Pentose phosphate pathway and tricarboxylic ...acid cycle also play pivotal roles in helping cancer cells to meet their anabolic and energy demands. The present work focused on gankyrin, a relatively specific oncogene in hepatocellular carcinoma (HCC), and its impact on glycolysis and mitochondrial homeostasis. Metabolomics, RNA‐seq analysis, and subsequent conjoint analysis illustrated that gankyrin regulated the pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and mitochondrial function and homeostasis, which play pivotal roles in tumor development. Mechanistically, gankyrin was found to modulate HCC metabolic reprogramming via TIGAR. Gankyrin positively regulated the transcription of TIGAR through Nrf2, which bound to the antioxidant response elements (AREs) in the promoter of TIGAR. Interestingly, TIGAR feedback regulated the transcription of Nrf2 and subsequently gankyrin by promoting nuclear importation of PGC1α. The loop between gankyrin, Nrf2, and TIGAR accelerated glucose metabolism toward the PPP and TCA cycle, which provided vital building blocks, such as NADPH, ATP, and ribose of tumor and further facilitated the progression of HCC.
Gankyrin positively regulated the transcription of TIGAR through Nrf2, which bound to the antioxidant response elements (AREs) in the promoter of TIGAR. Interestingly, TIGAR feedback regulated the transcription of Nrf2 and subsequently gankyrin by promoting nuclear importation of PGC1a. The loop between gankyrin, Nrf2, and TIGAR accelerated glucose metabolism toward the pentose phosphate pathway (PPP) and tricarboxylic acid (TCA) cycle, which provided vital building blocks, such as NADPH, ATP, and ribose of tumor and further facilitated tumorigenesis of hepatocellular carcinoma (HCC).
Background
The aberrant expression of long noncoding RNAs (lncRNAs) is found in various types of cancers and also showed its association with the occurrence and development of gastric cancer (GC). We ...found lncRNA COL1A1-014 was frequently upregulated in GC.
Methods
This study investigated COL1A1-014 for its biological function at both cellular and animal levels, using MTT, flow cytometry, colony formation and transwell assays. The expression levels of COL1A1-014 and other genes were detected by RT-PCR and western blot. Luciferase reporter assay was used to detect the potential binding of miR-1273h-5p to COL1A1-014 and CXCL12.
Results
We found that COL1A1-014 was frequently upregulated in GC tissues as well as cells. COL1A1-014 increased cell proliferation, colony forming efficiency, migration ability, invasion ability, and weight and volume of grafted tumors, while reduced cell apoptosis. Overexpression of COL1A1-014 increased the mRNA expression of chemokine (CXCmotif) ligand (CXCL12) and high levels of CXCL12 and CXCR4 proteins in GC cells. The levels of miR-1273h-5p showed an inverse correlation with COL1A1-014 and CXCL12 in GC cells transfected with miR-1273h-5p. The mRNAs of wild-type COL1A1-014 and CXCL12 showed reduction in HEK293 cells transfected with miR-1273h-5p. This suggested that COL1A1-014 functions as an efficient miR-1273h-5p sponge and as a competing endogenous RNA (ceRNA) to regulate CXCL12. The proliferative activity of COL1A1-014 on GC cells was blocked by CXCL12-CXCR4 axis inhibitor AMD-3100.
Conclusions
These findings demonstrated that COL1A1-014 play an important regulatory role in GC development by functioning as a ceRNA in regulating the CXCL12/CXCR4 axis via sponging miR-1273h-5p.
Free-standing graphene oxide (GO) thin films have been assembled by a pressurized ultrafiltration method. The GO films exhibit a layered microstructure with high structural stability and ...hydrophilicity, as analyzed by XPS, FESEM, XRD, positron annihilation spectroscopy (PAS), etc. The effects of ultrafiltration pressure and feed composition on the film׳s microstructure and pervaporation performance for dehydration of ethanol were investigated and correlated with XRD and PAS observations. Experimental results suggest that the interlaminar spacing is determined by both packing density of GO nanosheets and water content in the feed solution. The packing density is sensitively affected by the ultrafiltration pressure applied during film formation. By tuning the ultrafiltration pressure, a high separation performance with water permeability of 13,800Barrer (1 Barrer=3.348×10−19 kmol m m−2 s−1 Pa−1) and water/ethanol selectivity of 227 is achieved for dehydration of an 85wt% ethanol aqueous solution at 24°C. Additionally, the total permeability varied from 50 to 113,000Barrer by increasing the water content in the feed from 0 to 100wt%. As a result, the ideal water/ethanol selectivity calculated from single-component feed tests is about 2260 which is much higher than the selectivity obtained from binary-component feed tests. This discrepancy is probably attributed to the effect of intermolecular hydrogen bonding between water molecules and the functional groups on GO nanosheets that enlarges the interlaminar spacing and allows more ethanol transport through the GO film. The interactions among the GO nanosheets and the feed components enable the film to effectively dehydrate ethanol via pervaporation.
Display omitted
•A facile ultrafiltration method is developed to assemble the GO films.•The films exhibit a well-packed microstructure with high structural stability.•The interlaminar spacing is sensitive to both ultrafiltration pressure and feed composition.•The GO films show particularly high water permeability as well as outstanding selectivity.
A
bstract
We present two alternative proofs for the cancellation mechanism in the U(1) symmetric pseudo-Nambu-Goldstone-Boson Dark Matter (pNGB DM) model. They help us to have a better understanding ...of the mechanism from multi-angle, and inspire us to propose some interesting generalizations. In the first proof, we revisit the non-linear representation method and rephrase the argument with the interaction eigenstates. In this picture, the phase mode (DM) can only have a trilinear interaction with a derivative-squared acting on the radial mode when the DM is on-shell. Thus, the DM-quark scattering generated by a mass mixing between the radial mode and the Higgs boson vanishes in the limit of zero-momentum transfer. Using the same method, we can easily generalize the model to an SO(N) model with general soft-breaking structures. In particular, we study the soft-breaking cubic terms and identify those terms which preserve the cancellation mechanism for the DM candidate. In our discussion of the second method, we find that the cancellation relies on the special structure of mass terms and interactions of the mediators. This condition can be straightforwardly generalized to the vector-portal models. We provide two examples of the vector-portal case where the first one is an SU(2)
L
× U(1)
Y
× U(1)
X
model and the second one is an SU(2)
L
× U(1)
Y
× U(1)
B−L
× U(1)
X
model. In the first model the vector mediators are the
Z
μ
boson and a new U(1)
X
gauge boson
X
ν
, while in the second model the mediators are the U(1)
B−L
and U(1)
X
gauge bosons. The cancellation mechanism works in both models when there are no generic kinetic mixing terms for the gauge bosons. Once the generic kinetic mixing terms are included, the first model requires a fine-tuning of the mixing parameter to avoid the stringent direct detection bound, while the second model can naturally circumvent it.
Cancer‐associated fibroblasts (CAFs), as the activated fibroblasts in the tumor stroma, are important modifiers of tumour progression. In the present study, we observed that azoxymethane and dextran ...sodium sulfate treatments induced increasingly severe colorectal mucosal inflammation and the intratumoural accumulation of CAFs. Fibroblast growth factor (FGF)‐1 and FGF‐3 were detected in infiltrating cells, and FGFR4, the specific receptor for FGF‐1 and FGF‐3, was detected in colon cancer tissues. The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)‐7 and mitogen‐activated protein kinase kinase (Mek)/extracellular signal‐regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation. Moreover, we separated CAFs, pericarcinoma fibroblasts (PFs), and normal fibroblasts (NFs) from human colon tissue specimens to characterize the function of CAFs. We observed that CAFs secrete more FGF‐1/‐3 than NFs and PFs and promote cancer cell growth and angiogenesis through the activation of FGFR4, which is followed by the activation of Mek/Erk and the modulation of MMP‐7 expression. The administration of FGF‐1/‐3‐neutralizing antibodies or the treatment of cells with FGFR4 siRNA or the FGFR4 inhibitor PD173074 markedly suppressed colon cancer cell proliferation and neovascularization. These observations suggest a crucial role for CAFs and FGF signaling in the initiation and progression of colorectal cancer. The inhibition of the FGF signaling pathway may be a useful strategy for the treatment of colon cancer.
We used the well‐established murine model of colitis‐associated cancer based on the use of azoxymethane (AOM) and dextran sodium sulphate (DSS) and separated CAFs, pericarcinoma fibroblasts (PFs), and normal fibroblasts (NFs) from human colon tissue specimens to characterise the function of CAFs in colon carcinogenesis.Our data suggested that crucial role for CAFs and FGF signalling in the initiation and progression of colorectal cancer. Inhibition of the FGF signalling pathway may be a useful strategy for the treatment of colon cancer.
This paper presents a new configuration of a linear control system that provides a superior disturbance-rejection performance. The concept of equivalent input disturbance (EID) is used to estimate ...the influence of an exogenous disturbance on the system. Compared with the Luenberger observer, an extra integrating term from a proportional-integral observer (PIO) helps to introduce a relaxing variable to the system design. This increases the flexibility of system design and enables the robustness of the system. Moreover, the integrating term improves the estimation precision of the system state. Taking advantages of these merits, the combination of an EID estimator and a PIO is used to produce an EID. Then, a new control law, which incorporates the EID estimate, is designed to ensure good control performance. A stability condition of the closed-loop control system is derived in terms of linear matrix inequalities (LMIs). Further, the gains of the state-feedback controller and PIO are designed based on the LMIs. Comparisons with related methods demonstrate the validity of the developed method.
PDF
