Deep learning for digital pathology is hindered by the extremely high spatial resolution of whole-slide images (WSIs). Most studies have employed patch-based methods, which often require detailed ...annotation of image patches. This typically involves laborious free-hand contouring on WSIs. To alleviate the burden of such contouring and obtain benefits from scaling up training with numerous WSIs, we develop a method for training neural networks on entire WSIs using only slide-level diagnoses. Our method leverages the unified memory mechanism to overcome the memory constraint of compute accelerators. Experiments conducted on a data set of 9662 lung cancer WSIs reveal that the proposed method achieves areas under the receiver operating characteristic curve of 0.9594 and 0.9414 for adenocarcinoma and squamous cell carcinoma classification on the testing set, respectively. Furthermore, the method demonstrates higher classification performance than multiple-instance learning as well as strong localization results for small lesions through class activation mapping.
Apoptosis and fibrosis play a vital role in myocardial infarction (MI) induced tissue injury. Although microRNAs have been the focus of many studies on cardiac apoptosis and fibrosis in MI, the ...detailed effects of miR‐26a is needed to further understood. The present study demonstrated that miR‐26a was downregulated in ST‐elevation MI (STEMI) patients and oxygen‐glucose deprivation (OGD)‐treated H9c2 cells. Downregulation of miR‐26a was closely correlated with the increased expression of creatine kinase, creatine kinase‐MB and troponin I in STEMI patients. Further analysis identified that ataxia–telangiectasia mutated (ATM) was a target gene for miR‐26a based on a bioinformatics analysis. miR‐26a overexpression effectively reduced ATM expression, apoptosis, and apoptosis‐related proteins in OGD‐treated H9c2 cells. In a mouse model of MI, the expression of miR‐26a was significantly decreased in the infarct zone of the heart, whereas apoptosis and ATM expression were increased. miR‐26a overexpression effectively reduced ATM expression and cardiac apoptosis at Day 1 after MI. Furthermore, we demonstrated that overexpression of miR‐26a improved cardiac function and reduced cardiac fibrosis by the reduced expression of collagen type I and connective tissue growth factor (CTGF) in mice at Day 14 after MI. Overexpression of miR‐26a or ATM knockdown decreased collagen I and CTGF expression in cultured OGD‐treated cardiomyocytes. Taken together, these data demonstrate a prominent role for miR‐26a in linking ATM expression to ischemia‐induced apoptosis and fibrosis, key features of MI progression. miR‐26a reduced MI development by affecting ATM expression and could be targeted in the treatment of MI.
Our study demonstrated that ataxia–telangiectasia mutated (ATM) is the target for miR‐26a. miR‐26a attenuated cardiac apoptosis and fibrosis by targeting ATM both in vitro and in vivo. Additionally, miR‐26a regulated the expression of collagen type I and connective tissue growth factor (CTGF). We elucidated the role and function of miR‐26a in cardiac apoptosis and fibrosis, suggesting that miR‐26a may lead to a new therapeutic intervention in heart disease.
Nasopharyngeal carcinoma Chen, Yu-Pei; Chan, Anthony T C; Le, Quynh-Thu ...
The Lancet (British edition),
07/2019, Letnik:
394, Številka:
10192
Journal Article
Recenzirano
Nasopharyngeal carcinoma is characterised by distinct geographical distribution and is particularly prevalent in east and southeast Asia. Epidemiological trends in the past decade have shown that its ...incidence has declined gradually but progressively, and mortality has been reduced substantially. These findings probably reflect lifestyle and environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening, advancements in imaging techniques, and individualised comprehensive chemoradiotherapy strategies. In particular, plasma Epstein-Barr virus (EBV) DNA has been used for population screening, prognostication, predicting treatment response for therapeutic adaptation, and disease surveillance. Moreover, the widespread application of intensity-modulated radiotherapy and optimisation of chemotherapy strategies (induction, concurrent, adjuvant) have contributed to improved survival with reduced toxicities. Among the existing developments in novel therapeutics, immune checkpoint therapies have achieved breakthroughs for treating recurrent or metastatic disease and represent a promising future direction in nasopharyngeal carcinoma.
Curcumin, a constituent of the turmeric plant, has antitumor, anti‐inflammatory, and antioxidative effects, but its effects on wound healing are unclear. We created back wounds in 72 mice and treated ...them with or without topical curcumin (0.2 mg/mL) in Pluronic F127 gel (20%) daily for 3, 5, 7, 9, and 12 days. Healing in wounds was evaluated from gross appearance, microscopically by haematoxylin and eosin staining, by immunohistochemistry for tumour necrosis factor alpha and alpha smooth muscle actin, and by polymerase chain reaction amplification of mRNA expression levels. Treatment caused fast wound closure with well‐formed granulation tissue dominated by collagen deposition and regenerating epithelium. Curcumin increased the levels of tumour necrosis factor alpha mRNA and protein in the early phase of healing, which then decreased significantly. However, these levels remained high in controls. Levels of collagen were significantly higher in curcumin‐treated wounds. Immunohistochemical staining for alpha smooth muscle actin was increased in curcumin‐treated mice on days 7 and 12. Curcumin treatment significantly suppressed matrix metallopeptidase‐9 and stimulated alpha smooth muscle levels in tumour necrosis factor alpha‐treated fibroblasts via nuclear factor kappa B signalling. Thus, topical curcumin accelerated wound healing in mice by regulating the levels of various cytokines.
Abstract Background Epidemiological studies have shown that ambient air pollution is closely associated with increased respiratory inflammation and decreased lung function. Particulate matters (PMs) ...are major components of air pollution that damages lung cells. However, the mechanisms remain to be elucidated. This study examines the effects of PMs on intercellular adhesion molecule-1 (ICAM-1) expression and the related mechanisms in vitro and in vivo. Result The cytotoxicity, reactive oxygen species (ROS) generation, and monocyte adherence to A549 cells were more severely affected by treatment with O-PMs (organic solvent-extractable fraction of SRM1649b) than with W-PMs (water-soluble fraction of SRM1649b). We observed a significant increase in ICAM-1 expression by O-PMs, but not W-PMs. O-PMs also induced the phosphorylation of AKT, p65, and STAT3. Pretreating A549 cells with N-acetyl cysteine (NAC), an antioxidant, attenuated O-PMs-induced ROS generation, the phosphorylation of the mentioned kinases, and the expression of ICAM-1. Furthermore, an AKT inhibitor (LY294002), NF-κB inhibitor (BAY11–7082), and STAT3 inhibitor (Stattic) significantly down-regulated O-PMs-induced ICAM-1 expression as well as the adhesion of U937 cells to epithelial cells. Interleukin-6 (IL-6) was the most significantly changed cytokine in O-PMs-treated A549 cells according to the analysis of the cytokine antibody array. The IL-6 receptor inhibitor tocilizumab (TCZ) and small interfering RNA for IL-6 significantly reduced ICAM-1 secretion and expression as well as the reduction of the AKT, p65, and STAT3 phosphorylation in O-PMs-treated A549 cells. In addition, the intratracheal instillation of PMs significantly increased the levels of the ICAM-1 and IL-6 in lung tissues and plasma in WT mice, but not in IL-6 knockout mice. Pre-administration of NAC attenuated those PMs-induced adverse effects in WT mice. Furthermore, patients with chronic obstructive pulmonary disease (COPD) had higher plasma levels of ICAM-1 and IL-6 compared to healthy subjects. Conclusion These results suggest that PMs increase ICAM-1 expression in pulmonary epithelial cells in vitro and in vivo through the IL-6/AKT/STAT3/NF-κB signaling pathway.
Summary
Dysregulation of plasma lipids is associated with age‐related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low‐density lipoprotein (LDL), ...induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5‐treated but not L1‐treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high‐fat diet, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N‐acetyl‐cysteine (free‐radical scavenger) or caffeine (ATM blocker), as well as in lectin‐like oxidized LDL receptor‐1 (LOX‐1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free‐radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5‐induced endothelial senescence. In conclusion, L5 may promote mitochondrial free‐radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5‐induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.
This is the first meta-analysis to compare the treatment effects and safety of administering donepezil alone versus a combination of memantine and donepezil to treat patients with moderate to severe ...Alzheimer Disease, particularly regarding cognitive functions, behavioral and psychological symptoms in dementia (BPSD), and global functions.
PubMed, Medline, Embase, PsycINFO, and Cochrane databases were used to search for English and non-English articles for inclusion in the meta-analysis to evaluate the effect size and incidence of adverse drug reactions of different treatments.
Compared with patients who received donepezil alone, those who received donepezil in combination with memantine exhibited limited improvements in cognitive functions (g = 0.378, p < .001), BPSD (g = -0.878, p < .001) and global functions (g = -0.585, p = .004). Gradual titration of memantine plus a fixed dose and gradual titration of donepezil as well as a fixed dose and gradual titration of memantine resulted in limited improvements in cognitive functions(g = 0.371, p = .005), BPSD(g = -0.913, p = .001), and global functions(g = -0.371, p = .001).
Both in the 24th week and at the final evaluation point, the combination of donepezil and memantine led to greater improvement in cognitive functions, BPSD, and global functions than did donepezil alone in patients with moderate to severe Alzheimer Disease.
We investigated whether microRNA expression profiles can predict clinical outcome of NSCLC patients. Using real-time RT-PCR, we obtained microRNA expressions in 112 NSCLC patients, which were divided ...into the training and testing sets. Using Cox regression and risk-score analysis, we identified a five-microRNA signature for the prediction of treatment outcome of NSCLC in the training set. This microRNA signature was validated by the testing set and an independent cohort. Patients with high-risk scores in their microRNA signatures had poor overall and disease-free survivals compared to the low-risk-score patients. This microRNA signature is an independent predictor of the cancer relapse and survival of NSCLC patients.
Near‐infrared organic light‐emitting diodes (NIR OLEDs) enable many unique applications ranging from night‐vision displays and photodynamic therapies. However, the development of efficient NIR OLEDs ...with a low efficiency roll‐off is still challenging. Here, a series of new heteroleptic Pt(II) complexes (1–4) flanked by both pyridyl pyrimidinate and functional azolate chelates are synthesized. The reduced ππ* energy gap of the pyridyl pyrimidinate chelate, and strong intermolecular interaction and high crystallinity in vacuum‐deposited thin films engender strong intermolecular charge transfer transition including metal–metal‐to‐ligand charge transfer; thereby, exhibiting efficient photoluminescence within 776–832 nm and short radiative lifetimes of 0.52–0.79 µs. Consequently, nondoped NIR‐emitting OLEDs based on these Pt(II) complexes are fabricated, to which Pt(II) complexes 2 and 4 give record high maximum external quantum efficiency of 10.61% at 794 nm and 9.58% at 803 nm, respectively. Moreover, low efficiency roll‐off is also observed, among which the device efficiencies of 2 and 4 are at least four times higher than that of the best NIR‐emitting OLEDs recorded at current density of 100 mA cm−2.
Nondoped near‐infrared organic light‐emitting diodes based on pyrimidinate‐pyrazolate Pt(II) metal complexes 2 and 4 are fabricated, yielding a record high maximum external quantum efficiency of 10.61% at 794 nm and 9.58% at 803 nm, respectively.
Carbodicarbene (CDC), unique carbenic entities bearing two lone pairs of electrons are well‐known for their strong Lewis basicity. We demonstrate herein, upon introducing a weak Brønsted acid benzyl ...alcohol (BnOH) as a co‐modulator, CDC is remolded into a Frustrated Lewis Pair (FLP)‐like reactivity. DFT calculation and experimental evidence show BnOH loosely interacting with the binding pocket of CDC via H‐bonding and π‐π stacking. Four distinct reactions in nature were deployed to demonstrate the viability of proof‐of‐concept as synergistic FLP/Modulator (CDC/BnOH), demonstrating enhanced catalytic reactivity in cyclotrimerization of isocyanate, polymerization process for L‐lactide (LA), methyl methacrylate (MMA) and dehydrosilylation of alcohols. Importantly, the catalytic reactivity of carbodicarbene is uniquely distinct from conventional NHC which relies on only single chemical feature of nucleophilicity. This finding also provides a new spin in diversifying FLP reactivity with co‐modulator or co‐catalyst.
In the presence of co‐modulator alcohol, the putative strong σ donor, CDC is reshaped into frustrated Lewis pair‐like reactivity. The unique synergistic FLP behavior of CDC; unachievable by its counterpart NHCs, is shown to have beneficial and complementary effects on isocyanate cyclotrimerization, LA polymerization, MMA polymerization and dehydrosilylation of alcohols.
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