Tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), both related to persistent β-catenin activation, remain formidable challenges for chronic myeloid leukemia (CML). We ...observed overexpression of β-catenin in BC-CML stem/progenitor cells, particularly in granulocyte-macrophage progenitors, and highest among a novel CD34
CD38
CD123
Tim-3
subset as determined by CyTOF analysis. Co-culture with mesenchymal stromal cells (MSCs) induced the expression of β-catenin and its target CD44 in CML cells. A novel Wnt/β-catenin signaling modulator, C82, and nilotinib synergistically killed KBM5
and TKI-resistant primary BC-CML cells with or without BCR-ABL kinase mutations even under leukemia/MSC co-culture conditions. Silencing of β-catenin by short interfering RNA restored sensitivity of primary BCR-ABL
BC-CML cells to nilotinib. Combining the C82 pro-drug, PRI-724, with nilotinib significantly prolonged the survival of NOD/SCID/IL2Rγ null mice injected with primary BCR-ABL
BC-CML cells. The combined treatment selectively targeted CML progenitors and inhibited CD44, c-Myc, survivin, p-CRKL and p-STAT5 expression. In addition, pretreating primary BC-CML cells with C82, or the combination, but not with nilotinib alone, significantly impaired their engraftment potential in NOD/SCID/IL2Rγ-null-3/GM/SF mice and significantly prolonged survival. Our data suggest potential benefit of concomitant β-catenin and Bcr-Abl inhibition to prevent or overcome Bcr-Abl kinase-dependent or -independent TKI resistance in BC-CML.
Organic Rankine Cycle (ORC) could be used to recover low-grade waste heat. When a vehicle is running, the engine exhaust gas states have a wide range of variance. Defining the operational conditions ...of the ORC that achieve the maximum utilization of waste heat is important. In this paper the performance of different working fluids operating in specific regions was analyzed using a thermodynamic model built in Matlab together with REFPROP. Nine different pure organic working fluids were selected according to their physical and chemical properties. The results were compared in the regions when net power outputs were fixed at 10
kW. Safety levels and environmental impacts were also evaluated. The outcomes indicate that R11, R141b, R113 and R123 manifest slightly higher thermodynamic performances than the others; however, R245fa and R245ca are the most environment-friendly working fluids for engine waste heat-recovery applications. The optimal control principle of ORC under the transient process is discussed based on the analytical results.
► R11, R141b, R113 and R123 manifest the best thermodynamic performances. ► R245fa and R245ca are the most environment-friendly working fluids for the engine waste heat-recovery application. ► The condensing temperature has more important effect than the evaporating pressure to the performance of ORC. ► The optimal control principle of ORC under the transient process was defined according to the calculation results for the vehicle engine waste heat-recovery application. ► ORC thermodynamic model was built in Matlab together with REFPROP.
Essential oils have been found to exert antibacterial, antifungal, spasmolytic, and antiplasmodial activity and therapeutic effect in cancer treatment. In this study, the antibacterial activities of ...four main essential oils' components (thymol (Thy), eugenol (Eug), berberine (Ber), and cinnamaldehyde (Cin)) were evaluated against two food‐borne pathogens, Listeria monocytogenes and Salmonella Typhimurium, either alone or in combination with streptomycin. Checkerboard assay demonstrated that Thy and Cin elicited a synergistic effect with streptomycin against L. monocytogenes, while a synergy existed between Cin or Eug and streptomycin against Salm. Typhimurium. Further experiments showed that this synergy was sufficient to eradicate biofilms formed by these two bacteria. Thus, our data highlighted that the combinations of specific components from essential oils and streptomycin were useful for the treatment of food‐borne pathogens, which might help prevent the spread of antibiotic resistance through improving antibiotic effectiveness. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has shown the synergistic effect of four components of essential oil (thymol, eugenol, berberine and cinnamaldehyde) combined with streptomycin on planktonic and biofilm‐associated food‐borne pathogens Listeria monocytogenes and Salmonella Typhimurium. These findings indicate that combination of specific components of essential oils with streptomycin may provide alternative methods to overcome the problem of food‐borne bacteria both in suspension and in biofilm.
An independent self-assembling heterobimetallic Ni(II)–Eu(III) salamo-like coordination polymer,
∞
1
Ni(L)Eu(NO
3
)
3
(4,4′-bipy), is synthesized by the one-pot reaction of a symmetrical salamo-like ...hexadentate ligand (H
2
L = 6,6′-dimethoxy-2,2′-1,2-ethylenedioxybis(nitrilomethylidyne)diphenol), Ni(OAc)
2·
4H
2
O, Eu(NO
3
)
3·
6H
2
O, and 4,4′-bipy. The coordination polymer is obtained by the reaction in the 1:1:1:1 ratio and characterized by elemental analyses, IR and UV-Vis absorption spectra, and single crystal X-ray diffraction. The newly synthesized polymer is constructed from heterobimetallic Ni(II)(L)Eu(III) units connected by the 4,4′-bipy exodentate ligand bearing N donor atoms. Meanwhile, the hydrogen bonding, π⋯π stacking and C–H⋯π interactions play an important role in the structure of the coordination polymer. In terms of the antibacterial activity, the polymer dissolved in DMF has a good antibacterial effect on
Staphylococcus aureus.
Background:
Revision hip arthroscopy is increasingly common and often addresses acetabular labrum pathology. There is a lack of consensus on indications or outcomes of revision labral repair versus ...reconstruction.
Purpose:
To report clinical outcomes of labral reconstruction during revision hip arthroscopy at minimum 2-year follow-up as compared with pair-matched labral repair during revision hip arthroscopy (control group) and to suggest a decision-making algorithm for labral treatment in revision hip arthroscopy.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
Patients who underwent revision hip arthroscopy with labral reconstruction were matched 1:2 with patients who underwent revision arthroscopic labral repair. Patients were matched according to age, sex, and body mass index. Outcome scores, including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score, Hip Outcome Score–Sport-Specific Subscale, and a visual analog scale for pain, were collected preoperatively and at minimum 2-year follow-up. At latest follow-up, patient satisfaction on a 0-10 scale and the abbreviated International Hip Outcome Tool (iHOT-12) were collected. Complications, subsequent arthroscopies, and conversion to total hip arthroplasty were collected as well.
Results:
A total of 15 revision labral reconstructions were pair matched to 30 revision labral repairs. The reconstructions had fewer isolated Seldes type I detachments (P = .008) and lower postoperative lateral center-edge angle, but there were otherwise no significant differences in demographics, radiographics, intraoperative findings, or procedures. Both groups demonstrated significant improvements in all outcomes and visual analog scale at minimum 2-year follow-up. The revision repairs trended toward better preoperative scores: mHHS (mean ± SD: 59.3 ± 16.5 vs 54.2 ± 16.0), Non-Arthritic Hip Score (61.0 ± 16.7 vs 51.2 ± 17.6), Hip Outcome Score–Sport-Specific Subscale (39.6 ± 25.1 vs 30.5 ± 22.1), and visual analog scale (5.8 ± 1.8 vs 6.2 ± 2.2). At follow-up, the revision repair group had significantly higher mHHS (84.1 ± 14.8 vs 72.0 ± 18.3, P = .043) and iHOT-12 (72.2 ± 23.3 vs 49.0 ± 27.6, P = .023) scores than the reconstruction group. The magnitudes of pre- to postoperative improvement between the groups were comparable. The groups also had comparable rates of complications: 1 case of numbness in each group (P > .999), subsequent arthroscopies (repair: n = 2, 6.5%; revision: n = 3, 20%; P = .150), and conversion to total hip arthroplasty (1 patient in each group, P > .999).
Conclusion:
Labral reconstruction safely and effectively treats irreparable labra in revision hip arthroscopy. However, labral repair is another treatment option for reparable labra, yielding similar magnitude of improvement. A proposed algorithm may assist in surgical decision making to achieve optimal outcomes based on the condition and history of each patient’s acetabular labrum.
Reverse cholesterol transport (RCT) is a pathway by which accumulated cholesterol is transported from the vessel wall to the liver for excretion, thus preventing atherosclerosis. Major constituents ...of RCT include acceptors such as high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I), and enzymes such as lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), hepatic lipase (HL) and cholesterol ester transfer protein (CETP). A critical part of RCT is cholesterol efflux, in which accumulated cholesterol is removed from macrophages in the subintima of the vessel wall by ATP-binding membrane cassette transporter A1 (ABCA1) or by other mechanisms, including passive diffusion, scavenger receptor B1 (SR-B1), caveolins and sterol 27-hydroxylase, and collected by HDL and apoA-I. Esterified cholesterol in the HDL is then delivered to the liver for excretion. In patients with mutated ABCA1 genes, RCT and cholesterol efflux are impaired and atherosclerosis is increased. In studies with transgenic mice, disruption of ABCA1 genes can induce atherosclerosis. Levels of HDL are inversely correlated with incidences of cardiovascular disease. Supplementation with HDL or apoA-I can reverse atherosclerosis by accelerating RCT and cholesterol efflux. On the other hand, pro-inflammatory factors such as interferon-gamma (IFN-γ), endotoxin, tumour necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), can be atherogenic by impairing RCT and cholesterol efflux, according to in vitro studies. RCT and cholesterol efflux play a major role in anti-atherogenesis, and modification of these processes may provide new therapeutic approaches to cardiovascular disease. Further research on new modifying factors for RCT and cholesterol efflux is warranted.
Some plants of Buddleja genus possessed antimicrobial activity. In this study, the antibacterial activities of nine compounds from Buddleja albiflora were evaluated against Listeria monocytogenes, ...Staphyloccocus aureus, Escherichia coli and Pseudomonas aeruginosa, either alone or in combination with Erythromycin (Ery), Gentamicin (Gen) and Ampicillin (Amp). Checkerboard assay demonstrated that Kumatakenin elicited synergistic effects with all three antibiotics, and chrysin displayed synergistic effect with Ery against L. monocytogenes. Further experiments showed that the synergy effect was sufficient to eradicate biofilms formed by L. monocytogenes. Thus, our data highlighted that the combinations of secondary metabolites from B. albiflora and specific antibiotics were useful for the treatment of pathogens, which might help prevent the spread of antibiotic resistance through improving antibiotic effectiveness.
Significance and Impact of the Study
This study measured the antibacterial activity of the metabolites from Buddleja albiflora and the synergistic interactions with antibiotics against Listeria monocytogenes on planktonic cells as well as on biofilms. The results of this study provide valuable evidence that Kumatakenin/antibiotic combination can be considered as a promising antimicrobial agent for the treatment of pathogens, which subsequently help prevent the spread of antibiotic resistance through improving antibiotic effectiveness.
Significance and Impact of the Study: This study measured the antibacterial activity of the metabolites from Buddleja albiflora and the synergistic interactions with antibiotics against Listeria monocytogenes on planktonic cells as well as on biofilms. The results of this study provide valuable evidence that Kumatakenin/antibiotic combination can be considered as a promising antimicrobial agent for the treatment of pathogens, which subsequently help prevent the spread of antibiotic resistance through improving antibiotic effectiveness.
Background
Angiogenesis is a critical biological process essential for solid cancer growth and metastasis. It has been shown that microRNAs (miRNAs) play a vital role in a variety of biological ...processes in cancers. However, whether miR-130b is involved in prostate cancer angiogenesis remains ill-defined.
Methods
We performed the miRNA microarray to analyze miRNA expression in human prostate cancer specimens. In vitro gain-of-function assays and loss-of-function assays were conducted to explore the potential functions of miR-130b in human prostate cancer cells. Correlation analysis and dual-luciferase reporter assay were performed to validate whether tumor necrosis factor-α (TNF-α) was a direct target of miR-130b. The Matrigel plug and tumor vascular imaging assays were performed to confirm the anti-angiogenic activity of miR-130b in nude mice.
Results
We found that miR-130b was one of the miRNAs being most significantly downregulated. Subsequently, we found that miR-130b expression was markedly downregulated in human prostate cancer cell lines. Down-regulation of miR-130b in prostate cancer cells significantly promoted the proliferation, invasion and tubule formation of human umbilical vein endothelial cells (HUVECs), while ectopic expression of miR-130b blocked prostate cancer angiogenesis in vitro and in vivo. Mechanistic analyses indicated that tumor necrosis factor-α (TNF-α) was regulated by miR-130b directly. MiR-130b attenuated nuclear factor-κB (NF-κB) signaling and its downstream gene vascular endothelial growth factor-A (VEGFA) by directly inhibiting TNF-α expression. Additionally, subsequent investigations identified that the ectopic level of VEGFA markedly abrogated the anti-angiogenic effect induced by miR-130b. Interestingly, VEGFA could in turn decrease the expression of miR-130b, thus forming a negative feedback loop that drives the angiogenesis of prostate cancer.
Conclusion
These findings show that miR-130b/TNF-α/NF-κB/VEGFA feedback loop is significantly correlated with angiogenesis in prostate cancer and miR-130b could be regarded as potential therapeutic target for prostate cancer anti-angiogenesis treatment.
Abstract
Realizing applicably appreciated spintronic functionalities basing on the coupling between charge and spin degrees of freedom is still a challenge. For example, the anisotropic ...magnetoresistance (AMR) effect can be utilized to read out the information stored in magnetic structures. However, the application of AMR in antiferromagnet-based spintronics is usually hindered by the small AMR value. Here, we discover a colossal AMR with its value reaching 1.84 × 10
6
% at 2 K, which stems from the field-induced metal-to-insulator transition (MIT), in a nearly Dirac material EuMnSb
2
. Density functional theory calculations identify a Dirac-like band around the
Y
point that depends strongly on the spin–orbit coupling and dominates the electrical transport. The indirect band gap at the Fermi level evolves with magnetic structure of Eu
2+
moments, consequently giving rise to the field-induced MIT and the colossal AMR. Our results suggest that the antiferromagnetic topological materials can serve as a fertile ground for spintronics applications.
•Polyelectrolyte complexes of chitosan and alginate were the matrix of buccal foams.•GO made clotrimazole-loaded foams mechanically stronger and increased the rate of drug release.•The ionization ...degree of clotrimazole and its interactions with excipients were affected by the pH of the medium.
Polyelectrolyte complexes (PECs) have been used as the matrix of solid foams for drug delivery. This study aimed at investigating the effect of graphene oxide (GO) and the composition of excipients in chitosan/alginate-based buccal foams on the clotrimazole release and antifungal activities. The investigation has been focused on the interactions of the drug with excipients in the foams, and the changes of ionization degree upon exposure to various media are discussed. The solid foams were prepared by mixing the excipients and clotrimazole via probe sonication, followed by a freeze-drying method. The pH values of the formulations were measured during the foam preparation process to estimate the ionization degree of clotrimazole and the other excipients. The foam matrix was the PECs between the cationic chitosan and anionic alginate. The mechanical strength of clotrimazole-loaded foams was lower than that of drug-free foams due to the positively charged clotrimazole interacting with the anionic alginate and interfering the PECs between chitosan and alginate. Addition of GO in the clotrimazole-loaded matrix made the foams mechanically stronger and contributed to a faster release of clotrimazole from the buccal foams by disrupting the electrostatic interactions between alginate and clotrimazole. However, addition of 1 wt% GO in the formulations didn't affect the antifungal activity of clotrimazole-loaded foams significantly. A lower amount GO in the formulation may be required for enhancing the antifungal effect, which should be further investigated in future.
Display omitted
PDF
