Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing ...efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation - multi-modal treatment approaches and exploitation of biologically integrated targets - which aim to remodel the TME against PDAC.
High efficiency and flexible inverted organic solar cells have been fabricated using solution-processed silver nanowire/zinc oxide composite transparent electrodes. The transparent electrodes showed ...a low sheet resistance of -13 ff）.sq-1 and high transmittance of -93% as well as superior mechanical flexibility. Power conversion efficiencies of -7.57% and -7.21% were achieved for devices fabricated on glass and plastic substrate, respectively. Moreover, the flexible devices did not show any degradation in their performance even after being folded with a radius of-480 μm.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, ...pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.
During the coronavirus disease (COVID-19) pandemic, social distancing was effective in controlling disease spread across South Korea. The impact of national social distancing on the spread of common ...respiratory virus infections has rarely been investigated. We evaluated the weekly proportion of negative respiratory virus polymerase chain reaction (PCR) test results and weekly positive rates of each respiratory virus during the social distancing period (10th-41st weeks of 2020) and the corresponding period in different years, utilizing the national respiratory virus surveillance dataset reported by the Korean Center for Disease Control and Prevention. The proportions of negative respiratory virus PCR test results increased up to 87.8% and 86.1% during level 3 and level 2 of the social distancing period, respectively. The higher the level of social distancing, the higher the proportion of negative respiratory virus PCR test results. During the social distancing period, the mean weekly positive rates for parainfluenza virus, influenza virus, human coronavirus, and human metapneumovirus were significantly lower than those during the same period in 2015-2019 (0.1% vs. 9.3%, P <0.001; 0.1% vs. 7.2%, P <0.001; 0.4% vs. 2.3%, P <0.001; and 0.2% vs. 5.3%, P <0.001, respectively). The mean positive rate for rhinovirus/enterovirus during level 3 social distancing was lower than that in the same period in 2015-2019 (8.5% vs. 19.0%, P <0.001), but the rate during level 1 social distancing was higher than that in the same period in 2015-2019 (38.3% vs. 19.4%, P <0.001). The national application of social distancing reduced the spread of common respiratory virus infections during the COVID-19 pandemic.
Background
Inactivation of
TP53
, a tumor suppressor gene, is associated with the development of several malignancies, including gastric cancer (GC). The present study aimed to evaluate the ...correlation between the overexpression of p53 and survival in different Lauren-type GCs.
Methods
From May 2003 to December 2019, 3608 GC patients treated endoscopically or surgically at the Seoul National University Bundang Hospital were enrolled for the study. Immunohistochemical staining for p53 was performed on all endoscopic and surgical gastric specimens. Clinicopathologic characteristics with Lauren classification, survival rate, and cancer recurrence were analyzed according to p53 overexpression.
Results
Among 3608 GC patients, p53 overexpression was seen in 1334 patients (37%). p53 overexpression was associated with lower depth of invasion (
P
= 0.026) and Early gastric cancer (
P
= 0.044) in intestinal-type GC, and with advanced TNM stage (
P
< 0.001) and Advanced gastric cancer (
P
< 0.001) in diffuse-type GC. The overall survival (OS) and GC-specific survival (GCSS) were significantly lower in p53 overexpression positive patients. This significance was more pronounced and enhanced in the diffuse-type GC and was absent in the intestinal-type GC. In multivariate analyses, p53 overexpression was associated with poor OS in both subtypes of GC and cancer recurrence in diffuse-type GC. (OS in intestinal-type: adjusted hazard ratio aHR = 1.423,
P
= 0.022; OS in diffuse-type: aHR = 1.401
P
= 0.035; cancer recurrence in diffuse-type: aHR = 1.502,
P
= 0.039).
Conclusion
p53 overexpression was associated with poor prognosis in GC, especially in diffuse-type. In addition, p53 overexpression was associated with early stage disease in intestinal-type GC and with advanced stage disease in diffuse-type GC.
Whereas the conventional anti-dihalogenation of alkenes is a valuable synthetic tool with highly predictable stereospecificity, the restricted reaction mechanism makes it challenging to alter the ...diastereochemical course into the complementary syn-dihalogenation process. Only a few notable achievements were made recently by inverting one of the stereocenters after anti-addition using a carefully designed reagent system. Here, we report a conceptually distinctive strategy for the simultaneous double electrophilic activation of the two alkene carbons from the same side. Then, the resulting vicinal leaving groups can be displaced iteratively by nucleophilic halides to complete the syn-dihalogenation. For this purpose, thianthrenium dication is employed, and all possible combinations of chlorine and bromine are added onto internal alkenes successfully, particularly resulting in the syn-dibromination and the regiodivergent syn-bromochlorination.
Background The association between epicardial fat and coronary artery disease has not been evaluated. The objective of the present study was to evaluate the relationship of echocardiographic ...epicardial fat to the presence and severity of coronary artery disease in a clinical setting. Methods and Results Two hundred and three consecutive patients who underwent echocardiography and diagnostic coronary angiography were studied. The epicardial fat thickness on the free wall of the right ventricle was measured at end-diastole from the parasternal long-axis views of 3 cardiac cycles. Coronary angiograms were analyzed for the extent and severity of coronary artery disease using Gensini's score. The patients were divided into 2 groups according to the fourth quartile of epicardial fat thickness (Group I <7.6 mm; Group II ≥7.6 mm). There were no significant differences in the baseline characteristics except for waist circumference (p=0.023). Significant correlations were demonstrated between epicardial fat thickness and age (r=0.332, p<0.001), C-reactive protein (r=0.182, p=0.009), body mass index (r=0.142, p=0.044) and waist circumference (r=0.229, p=0.001). The patients with a higher epicardial fat thickness were associated with a high Gensini's score (p=0.014). Multivariate analysis showed that age (odds ratio (OR) 5.29, p=0.003), epicardial fat thickness (OR 10.53, p=0.004), diabetes (OR 8.06, p=0.006) and smoking (OR 14.65, p=0.015) were independent factors affecting significant coronary artery stenosis. Conclusions Epicardial fat thickness was significantly correlated with the severity of coronary artery disease in patients with known coronary artery disease. (Circ J 2007; 71: 536 - 539)
Objectives
White matter hyperintensities (WMHs) are implicated in the etiology of dementia. The underlying pathology of WMHs involves myelin and axonal loss due to chronic ischemia. We investigated ...myelin loss in WMHs and normal-appearing white matter (NAWM) in patients with various degrees of cognitive impairment using quantitative synthetic magnetic resonance imaging (MRI).
Methods
We studied 99 consecutive patients with cognitive complaints who underwent 3 T brain MRI between July 2016 and August 2017. Myelin partial volume maps were generated with synthetic MRI. Region-of-interest–based analysis was performed on these maps to compare the myelin partial volumes of NAWM and periventricular and deep WMHs. The effects of myelin partial volume of NAWMs on clinical cognitive function were evaluated using multivariate linear regression analysis.
Results
WMHs were present in 30.3% of patients. Myelin partial volume in NAWM was lower in patients with WMHs than in those without (37.5 ± 2.7% vs. 39.9 ± 2.4%,
p
< 0.001). In patients with WMHs, myelin partial volume was highest in NAWMs (median interquartile range, 37.2% 35.5–39.0%), followed by deep WMHs (7.2% 3.2–10.5%) and periventricular WMHs (2.1% 1.1–3.9%,
p
< 0.001). After adjusting for sex and education years, myelin partial volume in NAWMs was associated with the Clinical Dementia Rating Scale Sum of Box (
β
= -0.189 95% CI, -0.380 to -0.012,
p
= 0.031).
Conclusion
Myelin loss occurs in both NAWM and WMHs of cognitively impaired patients. Synthetic MRI-based myelin quantification may be a useful imaging marker of cognitive dysfunction in patients with cognitive complaints.
Key Points
•
Quantitative synthetic MRI allows simultaneous acquisition of conventional MRI and myelin quantification without additional scanning time.
•
Normal-appearing and hyperintense white matter demonstrate myelin loss in cognitively impaired patients.
•
This myelin loss partially explains cognitive dysfunction in patients with cognitive complaints.
The main focus of the paper is to propose a smart recommender system based on the methods of hybrid learning for personal well-being services, called a smart recommender system of hybrid learning ...(SRHL). The essential health factor is considered to be personal lifestyle, with the help of a critical examination of various disciplines. Integrating the recommender system effectively contributes to the prevention of disease, and it also leads to a reduction in treatment cost, which contributes to an improvement in the quality of life. At the same time, there exist various challenges within the recommender system, mainly cold start and scalability. To effectively address the inefficiencies, we propose combined hybrid methods in regard to machine learning. The primary aim of this learning method is to integrate the most effective and efficient learning algorithms to examine how combined hybrid filtering can help to improve the cold star problem efficiently in the provision of personalized well-being in regard to health food service. These methods include: (1) switching among content-based and collaborative filtering; (2) identifying the user context with the integration of dynamic filtering; and (3) learning the profiles with the help of processing and screening of reflecting feedback loops. The experimental results were evaluated by using three absolute error measures, providing comparable results with other studies relative to machine learning domains. The effects of using the hybrid learning method are gathered with the help of the experimental results. Our experiments also show that the hybrid method improves accuracy by 14.61% of the average error predicted in the recommender systems in comparison to the collaborative methods, which mainly focus on the computation of similar entities.
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