Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy ...before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients' quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients' quality of life.
Asymptomatic carotid stenosis of ≥70% increases the incidence of microembolism and/or chronic hypoperfusion, which may consequently impair neurocognition and brain connections. We sought controlled ...evidence for any cognitive benefit of aggressive medical therapy and combined carotid revascularization.
Patients with asymptomatic, unilateral, ≧70% stenosis of the extracranial ICA chose either aggressive medical therapy alone or in combination with carotid artery stent placement in this nonrandomized controlled study. They were examined with a battery of neuropsychological tests, structural MR imaging, DTI, and resting-state fMRI before and 3 months after treatment.
Forty patients were included with 15 in the medical group and 25 in the stent-placement group. Among them, 13 and 21 in the respective groups completed neuroimaging follow-up. The baseline characteristics and the changes in cognitive performance during 3 months showed no differences between treatment groups. Nevertheless, compared with the medical group, the stent-placement group showed subjective dizziness alleviation (
= .045) and a small increase in fractional anisotropy at the splenium of the corpus callosum and the posterior periventricular white matter ipsilateral to carotid artery stent placement. Moreover, only the stent-placement group showed interval improvement in immediate memory and visuospatial performance, which was accompanied by an increase of functional connectivity at the insular cortex of the dorsal attention network and the medial prefrontal cortex of the default mode network.
Both aggressive medical therapy alone and combined carotid revascularization in ≧70% asymptomatic carotid stenosis similarly preserved cognition during 3-month follow-up, though the latter had the potential for dizziness alleviation and cognitive and connectivity enhancement.
Whether four direct oral anticoagulants (DOACs) are superior to warfarin in Asian patients with nonvalvular atrial fibrillation (NVAF) remains unclear.
This nationwide retrospective cohort study was ...based on data from Taiwan’s National Health Insurance Research Database from June 1, 2012, to December 31, 2017, covering patients with NVAF taking edoxaban (n = 4,577), apixaban (n = 9,952), rivaroxaban (n = 33,022), dabigatran (n = 22,371), and warfarin (n = 19,761). Propensity score weighting was used to balance covariates across study groups. Patients were followed up until occurrence of study outcomes or end date of study.
Edoxaban, apixaban, and rivaroxaban were associated with a lower risk of ischemic stroke/systemic embolism than warfarin. All DOACs had a lower risk of major bleeding than warfarin. Apixaban was associated with a lower risk of major bleeding than rivaroxaban and dabigatran, whereas the risk of major bleeding was comparable between edoxaban and apixaban. The reduced risks of thromboembolism/major bleeding for the four DOACs persisted in high-risk subgroups, including those with chronic kidney disease, elderly patients (age ≥ 75 years), secondary stroke prevention, or CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65-74 years, and female sex) ≥ 4. A total of 2,924 (64%), 6,359 (64%), 31,108 (94%), and 19,821 (89%) patients received low-dose edoxaban (15-30 mg/d), apixaban (2.5 mg bid), rivaroxaban (10-15 mg/d), and dabigatran (110 mg bid), respectively. The effectiveness/safety outcomes with the four low-dose DOACs compared with warfarin were consistent with the main analysis.
In the largest real-world practice study among Asian patients with NVAF, four DOACs were associated with a comparable or lower risk of thromboembolism, and a lower risk of bleeding than warfarin. There was consistency even among high-risk subgroups and whether standard-or low-dose regimens were compared.
Macrophages play an important role in regulating the tumor microenvironment (TME). Here we show that classical (M1) macrophage polarization reduced expression of LSD1, nuclear REST corepressor 1 ...(CoREST), and the zinc finger protein SNAIL. The LSD1 inhibitor phenelzine targeted both the flavin adenine dinucleotide (FAD) and CoREST binding domains of LSD1, unlike the LSD1 inhibitor GSK2879552, which only targeted the FAD domain. Phenelzine treatment reduced nuclear demethylase activity and increased transcription and expression of M1-like signatures both
and in a murine triple-negative breast cancer model. Overall, the LSD1 inhibitors phenelzine and GSK2879552 are useful tools for dissecting the contribution of LSD1 demethylase activity and the nuclear LSD1-CoREST complex to switching macrophage polarization programs. These findings suggest that inhibitors must have dual FAD and CoREST targeting abilities to successfully initiate or prime macrophages toward an anti-tumor M1-like phenotype in triple-negative breast cancer.
Porous tin-based films are electrodeposited on copper foils from a choline chloride/ethylene glycol based electrolyte containing SnCl2·2H2O without any complexing agent or additive. Increasing the ...deposition time and voltage produces thicker films. The initially deposited Sn grains are relatively uniform with an average size of 200–300 nm and a kind of self-assembly distribution constructing an open and bicontinuous porous network. The architecture of these films possesses a double-layer structure, i.e. SnO2 (superficial layer)/Sn–Cu alloy (bottom layer), which is revealed by X-ray diffractometer and X-ray photoelectron spectroscopy. The electrochemical performance of the porous tin-based films as anode for lithium-ion batteries is measured. Although the capacity fades gradually with repeated cycling, a reversible capacity of 300-350 mAh g−1 is maintained for more than 50 cycles, which suggests that the in situ formed Sn--Cu alloy could provide an interlocking interface between active materials and current collector. Therefore, the tin's shedding from the current collector can be restrained. Moreover, the inactive materials, such as the oxide in the superficial layer and the Cu in the bottom layer, could also act as buffers to relieve the induced volume expansion of Sn during the repeated lithiathion/delithiation process, thus giving the good cycle performances.
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► Porous tin-based film with double-layer structure, i.e. SnO2/Sn–Cu. ► Tin-based film electrodeposited from Ethaline based electrolyte. ► Self-assembly distribution constructing an open and bicontinuous porous Sn network. ► Double-layer tin-based film delivering a satisfactory Li ion storage capacity.
The Askaryan Radio Array (ARA) is an ultra-high energy (>1017eV) cosmic neutrino detector in phased construction near the south pole. ARA searches for radio Cherenkov emission from particle cascades ...induced by neutrino interactions in the ice using radio frequency antennas (∼150-800MHz) deployed at a design depth of 200m in the Antarctic ice. A prototype ARA Testbed station was deployed at ∼30m depth in the 2010–2011 season and the first three full ARA stations were deployed in the 2011–2012 and 2012–2013 seasons. We present the first neutrino search with ARA using data taken in 2011 and 2012 with the ARA Testbed and the resulting constraints on the neutrino flux from 1017-1021eV.
Fatty liver hemorrhage syndrome (FLHS) is the leading cause of noninfectious mortality in caged layers worldwide. Osteocalcin (OCN) is a protein secreted by osteoblasts, and its undercarboxylated ...form (ucOCN) acts as a multifunctional hormone that protects laying hens from FLHS. Lipophagy is a form of selective autophagy that breaks down lipid droplets (LDs) through lysosomes, and defective lipophagy is associated with FLHS. The aim of this study was to investigate the effects of ucOCN on the lipophagy of chicken embryonic hepatocytes and associated the function of the adiponectin (ADPN) signaling pathway. In this study, chicken embryonic hepatocytes were divided into 5 groups: control (CONT), fat emulsion (FE, 10% FE, v/v), FE with ucOCN at 1 ng/mL (FE-LOCN), 3 ng/mL (FE-MOCN), and 9 ng/mL (FE-HOCN). In addition, 4 μM AdipoRon, an adiponectin receptor agonist, was used to investigate the function of ADPN. The results showed that compared with CONT group, FE promoted the levels of phosphorylation of mammalian target of rapamycin (p-mTOR) (P < 0.05) and decreased the mRNA expression of ADNP receptors (AdipoR1 and AdipoR2). Compared with FE group, 3 and 9 ng/mL ucOCN inhibited the levels of autophagy adaptor p62 and p-mTOR (P < 0.05), increased the ratios of LC3-II/LC3-I (P < 0.05) and phosphorylated adenosine 5′-monophosphate-activated protein kinase (p-AMPK)/AMPK (P < 0.05), as well as the levels of peroxisome proliferator-activated receptor α (PPAR-α) and ADPN (P < 0.05). In addition, ucOCN at the tested concentrations increased the colocalization of LC3 and LDs in fatty hepatocytes. Administrated 4 μM AdipoRon activated AdipoR1 and AidpoR2 mRNA expression (P < 0.05), decreased the concentrations of triglyceride (P < 0.05), without effects on cell viability (P > 0.05). AdipoRon also increased the LC3-II/LC3-I ratio (P < 0.05) and the levels of p-AMPK/AMPK and PPAR-α (P < 0.05). In conclusion, the results reveal that ucOCN regulates lipid metabolism by activating lipophagy via the ADPN-AMPK/PPARα-mTOR signaling pathway in chicken embryonic hepatocytes. The results may provide new insights for controlling FLHS in laying hens.
Molecular motions are essential natures of matter and play important roles in their structures and properties. However, owing to the diversity and complexity of structures and behaviors, the study of ...motion–structure–property relationships remains a challenge, especially at all levels of structural hierarchy from molecules to macro-objects. Herein, luminogens showing aggregation-induced emission (AIE), namely, 9-(pyrimidin-2-yl)-carbazole (PyCz) and 9-(5-R-pyrimidin-2-yl)-carbazole R = Cl (ClPyCz), Br (BrPyCz), and CN (CyPyCz), were designed and synthesized, to decipher the dependence of materials’ structures and properties on molecular motions at the molecule and aggregate levels. Experimental and theoretical analysis demonstrated that the active intramolecular motions in the excited state of all molecules at the single-molecule level endowed them with more twisted structural conformations and weak emission. However, owing to the restriction of intramolecular motions in the nano/macroaggregate state, all the molecules assumed less twisted conformations with bright emission. Unexpectedly, intermolecular motions could be activated in the macrocrystals of ClPyCz, BrPyCz, and CyPyCz through the introduction of external perturbations, and synergic strong and weak intermolecular interactions allowed their crystals to undergo reversible deformation, which effectively solved the problem of the brittleness of organic crystals, while endowing them with excellent elastic performance. Thus, the present study provided insights on the motion–structure–property relationship at each level of structural hierarchy and offered a paradigm to rationally design multifunctional AIE-based materials.
The ability to modulate reaction rates like controlling speeds by the transmission of vehicles is highly desirable and challenging. Herein, a regio- and stereoselective photodimerization with four ...tunable and visible rates were realized at the molecular level via the synergy of host–guest chemistry and AIE technology: (i) normal rate without adding macrocycles (ν1), (ii) greatly accelerated rate by the formation of 2:2 complex between γ-cyclodextrin (γ-CD) and an AIE luminogen (AIEgen) (ν2), (iii) deactivated reaction by 1:1 binding of β-cyclodextrin (β-CD) with the AIEgen (ν3), and (iv) completely inhibited photoreaction in the β-CD-based hydrogel (ν4). The restriction of intramolecular motions of AIEgen activates the fluorescence of the transmission with the rate of ν2 > ν1 > ν3 > ν4 ≈ 0 and enhances the fluorescent contrast before and after photoirradiation, which not only provides in situ trackability to the microscopic process, but also endows intuitive mechanistic insights. The synergy of AIE and host–guest chemistry can also amplify the signal of the reversible reaction and visualize “tiny” ring-opening product. Microscopic mechanism was further applied to the construction of a porous hydrogel-based microreactor which exhibited enhanced microscopic visualization and excellent recyclability. The present approach demonstrated a powerful platform for the understanding, monitoring and controlling reaction kinetics. Meanwhile, the porous hydrogel reactor based on precise molecular design serves as a new inspiration for heterogeneous catalysis.
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