Combination of betulinic acid and EGFR-TKIs exerts synergistic anti-tumor effects against wild-type EGFR NSCLC by inducing autophagy-related cell death via EGFR signaling pathway.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. METHODS: We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. RESULTS: Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. CONCLUSIONS: BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.

Diminished expression of GLS in CD4+ T cells serves as a prognostic indicator associated with cuproptosis in septic patients.

OBJECTIVES: Sepsis is defined as a life-threatening disease associated with a dysfunctional host immune response. Stratified identification of critically ill patients might significantly improve the survival rate. The present study sought to probe molecular markers associated with cuproptosis in septic patients to aid in stratification and improve prognosis. METHODS: We studied expression of cuproptosis-related genes (CRGs) using peripheral blood samples from septic patients. Further classification was made by examining levels of expression of these potential CRGs in patients. Coexpression networks were constructed using the weighted gene coexpression network analysis (WGCNA) method to identify crucial prognostic CRGs. Additionally, we utilized immune cell infiltration analysis to further examine the immune status of septic patients with different subtypes and its association with the CRGs. ScRNA-seq data were also analysed to verify expression of key CRGs among specific immune cells. Finally, immunoblotting, flow cytometry, immunofluorescence, and CFSE analysis were used to investigate possible regulatory mechanisms. RESULTS: We classified septic patients based on CRG expression levels and found significant differences in prognosis and gene expression patterns. Three key CRGs that may influence the prognosis of septic patients were identified. A decrease in GLS expression was subsequently verified in Jurkat cells, accompanied by a reduction in O-GlcNAc levels, and chelation of copper by TTM could not rescue the reduction in GLS and O-GLcNAc levels. Moreover, immoderate chelation of copper was detrimental to mitochondrial function, cell viability and cell proliferation as well as the immune status of the host. CONCLUSION: We have identified novel molecular markers associated with cuproptosis, which could potentially function as diagnostic indicators for septic patients. The reversible nature of the observed alterations in FDX1 and LIAS was demonstrated through copper chelation, while the correlation between copper and the observed changes in GLS requires further investigation.

Lnc-Clic5 as a sponge for miR-212-5p to inhibit cow barn PM2.5-induced apoptosis in rat alveolar macrophages.

Particulate matter 2.5 (PM2.5) is a highly hazardous airborne particulate matter that poses a significant risk to humans and animals. Urban airborne particulate matter contributes to the increased incidence and mortality of respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), in humans. However, the specific mechanism by which PM2.5 affects animals in barn environments is yet to be elucidated. In this study, we investigated the effect of exposure to cow barn PM2.5 on rat alveolar macrophages (NR8383) and found that it induced apoptosis via the miR-212-5p/RASSF1 pathway. We found that lnc-Clic5 expression was downregulated in NR8383 cells exposed to cow barn PM2.5. Lnc-Clic5 plays a competitive endogenous RNA (ceRNA) regulatory role by sponging miR-212-5p to attenuate the regulation of RASSF1. Moreover, lnc-Clic5 overexpression inhibited NR8383 apoptosis by targeting the miR-212-5p/RASSF1 pathway. Co-treatment with miR-212-5p and lnc-Clic5 in the presence of cow barn PM2.5 revealed that lnc-Clic5 reversed NR8383 cell apoptosis induced by PM2.5 when miR-212-5p was overexpressed. These findings contribute to the study of ncRNAs and ceRNAs regulating PM2.5-induced apoptosis in animal farms, provide therapeutic targets for lung macrophage apoptosis, and may be useful for further evaluating the toxicological effects of PM2.5 in farmhouses on the respiratory systems of humans and animals.

Improving photochemical indicators for attributing ozone sensitivities in source apportionment analysis.

Comprehensive Air Quality Model with extensions (CAMx)-Decoupled Direct Method (DDM) simulations of first-order ozone (O3) sensitivity to nitrogen oxides (NOx) and volatile organic compounds (VOCs) emissions were performed and combined with modelled [Formula: see text] ratios to obtain a range of thresholds for determining O3-sensitivity regimes for different areas of China. Utilising the new threshold ranges for photochemical indicators, the method for determining O3 formation in the Ozone Source Apportionment Technology (OSAT) module within CAMx was improved by a dynamically varied threshold of [Formula: see text] ratio. The O3 concentration contributions in the newly added transition regime were apportioned to NOx and VOCs emissions in proportion to the relationship between the [Formula: see text] ratio and first-order O3 sensitivity. The source contributions of O3 concentrations from different emission sectors from June to September 2019 were compared using the original and improved CAMx-OSAT. The results showed that the O3 concentration contributions changed significantly in the NOx-limited regime, with a maximum decrease of 21.89%, while the contributions increased by up to 7.57% in the VOC-limited regime, and were within 15 µg/m3 in the transition regime. The modified OSAT module enabled a more sophisticated attribution of O3 to precursor emissions and may have far-reaching implications for informing O3 pollution control policy.

Construction of dose prediction model and identification of sensitive genes for space radiation based on single-sample networks under spaceflight conditions.

PURPOSE: To identify sensitive genes for space radiation, we integrated the transcriptomic samples of spaceflight mice from GeneLab and predicted the radiation doses absorbed by individuals in space. METHODS AND MATERIALS: A single-sample network (SSN) for each individual sample was constructed. Then, using machine learning and genetic algorithms, we built the regression models to predict the absorbed dose equivalent based on the topological structure of SSNs. Moreover, we analyzed the SSNs from each tissue and compared the similarities and differences among them. RESULTS: Our model exhibited excellent performance with the following metrics: R2=0.980, MSE=6.74e-04, and the Pearson correlation coefficient of 0.990 (p value <.0001) between predicted and actual values. We identified 20 key genes, the majority of which had been proven to be associated with radiation. However, we uniquely established them as space radiation sensitive genes for the first time. Through further analysis of the SSNs, we discovered that the different tissues exhibited distinct mechanisms in response to space stressors. CONCLUSIONS: The topology structures of SSNs effectively predicted radiation doses under spaceflight conditions, and the SSNs revealed the gene regulatory patterns within the organisms under space stressors.

H3K27ac-activated LncRNA NUTM2A-AS1 Facilitates the Progression of Colorectal Cancer Cells via MicroRNA-126-5p/FAM3C Axis.

OBJECTIVE: Long non-coding RNAs (lncRNAs) are of great importance in the process of colorectal cancer (CRC) tumorigenesis and progression. However, the functions and underlying molecular mechanisms of the majority of lncRNAs in CRC still lack clarity. METHODS: A Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect lncRNA NUTM2A-AS1 expression in CRC cell lines. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to examine the biological functions of lncRNA NUTM2A-AS1 in the proliferation and apoptosis of CRC cells. RT-qPCR and western blot were implemented for the detection of cell proliferation-, apoptosis-related proteins, and FAM3C. Bioinformatics analysis and dual- luciferase reporter assays were utilized to identify the mutual regulatory mechanism of ceRNAs. RESULTS: lncRNA NUTM2A-AS1 notably elevated in CRC cell lines and the silencing of NUTM2A- AS1 declined proliferation and facilitated apoptosis. Mechanistically, NUTM2A-AS1 was transcriptionally activated by histone H3 on lysine 27 acetylation (H3K27ac) enriched at its promoter region, and NUTM2A-AS1 acted as a sponge for miR-126-5p, leading to the upregulation of FAM3C expression in CRC cell lines. CONCLUSION: Our research proposed NUTM2A-AS1 as an oncogenic lncRNA that facilitates CRC malignancy by upregulating FAM3C expression, which might provide new insight and a promising therapeutic target for the diagnosis and treatment of CRC.

Setting goals for agricultural nitrogen emission reduction to ensure safe air and groundwater quality: A case study of Quzhou, the North China Plain.

Setting nitrogen (N) emission targets for agricultural systems is crucial to prevent to air and groundwater pollution, yet such targets are rarely defined at the county level. In this study, we employed a forecasting-and-back casting approach to establish human health-based nitrogen targets for air and groundwater quality in Quzhou county, located in the North China Plain. By adopting the World Health Organization (WHO) phase I standard for PM2.5 concentration (35 µg m-3) and a standard of 11.3 mg NO3--N L-1 for nitrate in drinking water, we found that ammonia (NH3) emissions from the entire county must be reduced by at least 3.2 kilotons year-1 in 2050 to meet the WHO's PM2.5 phase I standard. Additionally, controlling other pollutants such as sulfur dioxide (SO2) and nitrogen oxides (NOx) is necessary, with required reductions ranging from 16% to 64% during 2017-2050. Furthermore, to meet the groundwater quality standard, nitrate nitrogen (NO3--N) leaching to groundwater should not exceed 0.8 kilotons year-1 by 2050. Achieving this target would require a 50% reduction in NH3 emissions and a 21% reduction in NO3--N leaching from agriculture in Quzhou in 2050 compared to their respective levels in 2017 (5.0 and 2.1 kilotons, respectively). Our developed method and the resulting N emission targets can support the development of environmentally-friendly agriculture by facilitating the design of control strategies to minimize agricultural N losses.

Oxyhaemoglobin saturation NIR-IIb imaging for assessing cancer metabolism and predicting the response to immunotherapy.

In vivo quantitative assessment of oxyhaemoglobin saturation (sO2) status in tumour-associated vessels could provide insights into cancer metabolism and behaviour. Here we develop a non-invasive in vivo sO2 imaging technique to visualize the sO2 levels of healthy and tumour tissue based on photoluminescence bioimaging in the near-infrared IIb (NIR-IIb; 1,500-1,700 nm) window. Real-time dynamic sO2 imaging with a high frame rate (33 Hz) reveals the cerebral arteries and veins through intact mouse scalp/skull, and this imaging is consistent with the haemodynamic analysis results. Utilizing our non-invasive sO2 imaging, the tumour-associated-vessel sO2 levels of various cancer models are evaluated. A positive correlation between the tumour-associated-vessel sO2 levels and the basal oxygen consumption rate of corresponding cancer cells at the early stages of tumorigenesis suggests that cancer cells modulate the tumour metabolic microenvironment. We also find that a positive therapeutic response to the checkpoint blockade cancer immunotherapy could lead to a dramatic decrease of the tumour-associated-vessel sO2 levels. Two-plex dynamic NIR-IIb imaging can be used to simultaneously observe tumour-vessel sO2 and PD-L1, allowing a more accurate prediction of immunotherapy response.

Expression characteristics of peripheral lymphocyte programmed death 1 and FoxP3+ Tregs in gastric cancer during surgery and chemotherapy.

BACKGROUND: Programmed death 1 (PD-1) and CD4+CD25+FoxP3+ expression in peripheral blood T-cells has been previously reported in various types of cancer. However, the specific variation tendency during surgery and chemotherapy, as well as their relationship in gastric cancer patients, still remain unclear. Understanding this aspect may provide some novel insights for future studies on tumor recurrence and tumor immune escape, and also serve as a reference for determining the optimal timing and dose of clinical anti-PD-1 antibodies. AIM: To observe and analyze the expression characteristics of peripheral lymphocyte PD-1 and FoxP3+ regulatory T cells (FoxP3+ Tregs) before and after surgery or chemotherapy in gastric cancer patients. METHODS: Twenty-nine stomach cancer patients undergoing chemotherapy after a D2 gastrectomy provided 10 mL peripheral blood samples at each phase of the perioperative period and during chemotherapy. This study also included 29 age-matched healthy donors as a control group. PD-1 expression was detected on lymphocytes, including CD4+CD8+CD45RO+, CD4+CD45RO+, and CD8+CD45RO+ lymphocytes as well as regulatory T cells. RESULTS: We observed a significant increase of PD-1 expression on immune subsets and a larger number of FoxP3+ Tregs in gastric cancer patients (P < 0.05). Following D2 gastrectomy, peripheral lymphocytes PD-1 expression and the number of FoxP3+ Tregs notably decrease (P < 0.05). However, during postoperative chemotherapy, we only observed a decrease in PD-1 expression on lymphocytes in the CD8+CD45RO+ and CD8+CD45RO+ populations. Additionally, linear correlation analysis indicated a positive correlation between PD-1 expression and the number of CD4+CD45RO+FoxP3high activated Tregs (aTregs) on the total peripheral lymphocytes (r = 0.5622, P < 0.0001). CONCLUSION: The observed alterations in PD-1 expression and the activation of regulatory T cells during gastric cancer treatment may offer novel insights for future investigations into tumor immune evasion and the clinical application of anti-PD-1 antibodies in gastric cancer.

High expression of miR-22-3p in chicken hierarchical follicles promotes granulosa cell proliferation, steroidogenesis, and lipid metabolism via PTEN/PI3K/Akt/mTOR signaling pathway.

MicroRNAs (miRNAs) are a class of RNA macromolecules that play regulatory roles in follicle development by inhibiting protein translation through binding to the 3'UTR of its target genes. Granulosa cell (GC) proliferation, steroidogenesis, and lipid metabolism have indispensable effect during folliculogenesis. In this study, we found that miR-22-3p was highly expressed in the hierarchical follicles of the chickens, which indicated that it may be involved in follicle development. The results obtained suggested that miR-22-3p promoted proliferation, hormone secretion (progesterone and estrogen), and the content of lipid droplets (LDs) in the chicken primary GC. The results from the bioinformatics analysis, luciferase reporter assay, qRT-PCR, and Western blotting, confirmed that PTEN was directly targeted to miR-22-3p. Subsequently, it was revealed that PTEN inhibited proliferation, hormone secretion, and the content of LDs in GC. Therefore, this study showed that miR-22-3p could activate PI3K/Akt/mTOR pathway via targeting PTEN. Taken together, the findings from this study indicated that miR-22-3p was highly expressed in the hierarchical follicles of chickens, which promotes GC proliferation, steroidogenesis, and lipid metabolism by repressing PTEN to activate PI3K/AKT/mTOR pathway.

Anti-Aging of the Nervous System and Related Neurodegenerative Diseases With Chinese Herbal Medicine.

Human beings have always pursued a prolonged lifespan, while the aging of the nervous system is associated with a large variety of diseases. Pathological aging of the nervous system results in a series of neurodegenerative diseases and can cause disability and death in the elderly. Therefore, there is an urgent need for the prevention and treatment of nervous system aging. Chinese herbal medicines have a long history, featuring rich and safe ingredients, and have great potential for the development of anti-aging treatment. We searched the publications on PubMed with key words "anti-aging of the nervous system" and "Chinese herbal medicine" in recent 10 years, and found sixteen Chinese herbal medicines. Then by comparing their popularity of use as well as active components based on the research articles, five common Chinese herbal medicines namely Ginseng Radix, Lycii Fructus, Astragali Radix, Coptidis Rhizoma and Ginkgo Folium, were confirmed to be the most related to anti-nervous system aging and neural degenerative diseases. At the same time, the active ingredients, research models, action mechanisms and curative effects of these five common Chinese herbal medicines were reviewed. From the five common Chinese herbal medicines reviewed in this paper, many encouraging effects of Chinese herbal medicines on treating nervous system aging and related diseases were revealed and more potent herbs would be explored with the help of the proposed possible mechanisms.

Blockade of adenosine A2A receptors reverses early spatial memory defects in the APP/PS1 mouse model of Alzheimer's disease by promoting synaptic plasticity of adult-born granule cells.

BACKGROUND: The over-activation of adenosine A2A receptors (A2AR) is closely implicated in cognitive impairments of Alzheimer's disease (AD). Growing evidence shows that A2AR blockade possesses neuroprotective effects on AD. Spatial navigation impairment is an early manifestation of cognitive deficits in AD. However, whether A2AR blockade can prevent early impairments in spatial cognitive function and the underlying mechanism is still unclear. METHODS: A transgenic APP/PS1 mouse model of AD amyloidosis was used in this study. Behavioral tests were conducted to observe the protective effects of A2AR blockade on early spatial memory deficits in 4-month old APP/PS1 mice. To investigate the underlying synaptic mechanism of the protective effects of A2AR blockade, we further examined long-term potentiation (LTP) and network excitation/inhibition balance of dentate gyrus (DG) region, which is relevant to unique synaptic functions of immature adult-born granule cells (abGCs). Subsequently, the protective effects of A2AR blockade on dendritic morphology and synaptic plasticity of 6-week-old abGCs was investigated using retrovirus infection and electrophysiological recordings. The molecular mechanisms underlying neuroprotective properties of A2AR blockade on the synaptic plasticity of abGCs were further explored using molecular biology methods. RESULTS: APP/PS1 mice displayed DG-dependent spatial memory deficits at an early stage. Additionally, impaired LTP and an imbalance in network excitation/inhibition were observed in the DG region of APP/PS1 mice, indicating synaptic structural and functional abnormalities of abGCs. A2AR was found to be upregulated in the hippocampus of the APP/PS1 mouse model of AD. Treatment with the selective A2AR antagonist SCH58261 for three weeks significantly ameliorated spatial memory deficits in APP/PS1 mice and markedly restored LTP and network excitation/inhibition balance in the DG region. Moreover, SCH58261 treatment restored dendritic morphology complexity and enhanced synaptic plasticity of abGCs in APP/PS1 mice. Furthermore, SCH58261 treatment alleviated the impairment of synaptic plasticity in abGCs. It achieved this by remodeling the subunit composition of NMDA receptors and increasing the proportion of NR2B receptors in abGCs of APP/PS1 mice. CONCLUSIONS: Blockade of A2AR improves early spatial memory deficits in APP/PS1 mice, possibly by reversing synaptic defects of abGCs. This finding suggests that A2AR blockade could be a potential therapy for AD.

Multidisciplinary discussion and management of synchronous colorectal liver metastases: A single center study in China.

BACKGROUND: The multidisciplinary team (MDT) has been carried out in many large hospitals now. However, given the costs of time and money and with little strong evidence of MDT effectiveness being reported, critiques of MDTs persist. AIM: To evaluate the effects of MDTs on patients with synchronous colorectal liver metastases and share our opinion on management of synchronous colorectal liver metastases. METHODS: In this study we collected clinical data of patients with synchronous colorectal liver metastases from February 2014 to February 2017 in the Chinese People's Liberation Army General Hospital and subsequently divided them into an MDT+ group and an MDT- group. In total, 93 patients in MDT+ group and 169 patients in MDT- group were included totally. RESULTS: Statistical increases in the rate of chest computed tomography examination (P = 0.001), abdomen magnetic resonance imaging examination (P = 0.000), and preoperative image staging (P = 0.0000) were observed in patients in MDT+ group. Additionally, the proportion of patients receiving chemotherapy (P = 0.019) and curative resection (P = 0.042) was also higher in MDT+ group. Multivariable analysis showed that the population of patients assessed by MDT meetings had higher 1-year [hazard ratio (HR) = 0.608, 95% confidence interval (CI): 0.398-0.931, P = 0.022] and 5-year (HR = 0.694, 95%CI: 0.515-0.937, P = 0.017) overall survival. CONCLUSION: These results proved that MDT management did bring patients with synchronous colorectal liver metastases more opportunities for comprehensive examination and treatment, resulting in better outcomes.

Whole-genome sequencing revealed genetic diversity, structure and patterns of selection in Guizhou indigenous chickens.

BACKGROUND: The eight phenotypically distinguishable indigenous chicken breeds in Guizhou province of China are great resources for high-quality development of the poultry industry in China. However, their full value and potential have yet to be understood in depth. To illustrate the genetic diversity, the relationship and population structure, and the genetic variation patterns shaped by selection in Guizhou indigenous chickens, we performed a genome-wide analysis of 240 chickens from 8 phenotypically and geographically representative Guizhou chicken breeds and 60 chickens from 2 commercial chicken breeds (one broiler and one layer), together with 10 red jungle fowls (RJF) genomes available from previous studies. RESULTS: The results obtained in this present study showed that Guizhou chicken breed populations harbored higher genetic diversity as compared to commercial chicken breeds, however unequal polymorphisms were present within Guizhou indigenous chicken breeds. The results from the population structure analysis markedly reflected the breeding history and the geographical distribution of Guizhou indigenous chickens, whereas, some breeds with complex genetic structure were ungrouped into one cluster. In addition, we confirmed mutual introgression within Guizhou indigenous chicken breeds and from commercial chicken breeds. Furthermore, selective sweep analysis revealed candidate genes which were associated with specific and common phenotypic characteristics evolved rapidly after domestication of Guizhou local chicken breeds and economic traits such as egg production performance, growth performance, and body size. CONCLUSION: Taken together, the results obtained from the comprehensive analysis of the genetic diversity, genetic relationships and population structures in this study showed that Guizhou indigenous chicken breeds harbor great potential for commercial utilization, however effective conservation measures are currently needed. Additionally, the present study drew a genome-wide selection signature draft for eight Guizhou indigenous chicken breeds and two commercial breeds, as well as established a resource that can be exploited in chicken breeding programs to manipulate the genes associated with desired phenotypes. Therefore, this study will provide an essential genetic basis for further research, conservation, and breeding of Guizhou indigenous chickens.

Interaction analysis of high-risk pathological features on adjuvant chemotherapy survival benefit in stage II colon cancer patients: a multi-center, retrospective study.

BACKGROUND: We aimed to analyze the benefit of adjuvant chemotherapy in high-risk stage II colon cancer patients and the impact of high-risk factors on the prognostic effect of adjuvant chemotherapy. METHODS: This study is a multi-center, retrospective study, A total of 931 patients with stage II colon cancer who underwent curative surgery in 8 tertiary hospitals in China between 2016 and 2017 were enrolled in the study. Cox proportional hazard model was used to assess the risk factors of disease-free survival (DFS) and overall survival (OS) and to test the multiplicative interaction of pathological factors and adjuvant chemotherapy (ACT). The additive interaction was presented using the relative excess risk due to interaction (RERI). The Subpopulation Treatment Effect Pattern Plot (STEPP) was utilized to assess the interaction of continuous variables on the ACT effect. RESULTS: A total of 931 stage II colon cancer patients were enrolled in this study, the median age was 63 years old (interquartile range: 54-72 years) and 565 (60.7%) patients were male. Younger patients (median age, 58 years vs 65 years; P < 0.001) and patients with the following high-risk features, such as T4 tumors (30.8% vs 7.8%; P < 0.001), grade 3 lesions (36.0% vs 22.7%; P < 0.001), lymphovascular invasion (22.1% vs 6.8%; P < 0.001) and perineural invasion (19.4% vs 13.6%; P = 0.031) were more likely to receive ACT. Patients with perineural invasion showed a worse OS and marginally worse DFS (hazardous ratio [HR] 2.166, 95% confidence interval [CI] 1.282-3.660, P = 0.004; HR 1.583, 95% CI 0.985-2.545, P = 0.058, respectively). Computing the interaction on a multiplicative and additive scale revealed that there was a significant interaction between PNI and ACT in terms of DFS (HR for multiplicative interaction 0.196, p = 0.038; RERI, -1.996; 95%CI, -3.600 to -0.392) and OS (HR for multiplicative interaction 0.112, p = 0.042; RERI, -2.842; 95%CI, -4.959 to -0.725). CONCLUSIONS: Perineural invasion had prognostic value, and it could also influence the effect of ACT after curative surgery. However, other high-risk features showed no implication of efficacy for ACT in our study. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov, NCT03794193 (04/01/2019).

Causal relationships between delirium and Alzheimer's disease: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Previous observational studies have reported that delirium has an association with an increased risk of Alzheimer's disease (AD), and that patients with AD have a higher risk of developing delirium. However, due to the limitations of observational study, it is challenging to confirm whether delirium has a causal effect on AD or reverse causation exists. METHODS: A bidirectional two-sample Mendelian randomization (MR) was performed to investigate the relationship between delirium and AD. Summary statistics from genome-wide association studies of delirium and AD phenotypes were utilized. Inverse-variance weighted (IVW) method was used as the main analysis approach, and additional analyses were performed using MR Egger, weighted median, simple mode and weighted mode to ensure result accuracy. Heterogeneity and horizontal pleiotropy were assessed using Cochran's Q statistics and MR Egger intercept, separately. RESULTS: The MR analyses showed that genetically predicted delirium was not associated with AD (IVW: odds ratio [OR] 0.98, 95% CI 0.91-1.05, P = 0.544; MR Egger: OR 0.98, 95% CI 0.83-1.15, P = 0.780; weighted median: OR 0.96, 95% CI 0.88-1.05, P = 0.323; simple mode: OR 0.91, 95% CI 0.80-1.04, P = 0.212; weighted mode: OR 0.93, 95% CI 0.83-1.05, P = 0.277). However, in the reverse direction, AD was associated with delirium (IVW: OR 1.32, 95% CI 1.13-1.54, P = 3.91E-04; MR Egger: OR 1.42, 95% CI 1.02-1.98, P = 5.60E-02; Weighted median: OR 1.39, 95% CI 1.18-1.63, P = 8.22E-05; Simple mode: OR 1.41, 95% CI 1.10-1.80, P = 1.41E-02; Weighted mode: OR 1.39, 95% CI 1.16-1.67, P = 3.23E-03). CONCLUSION: Based on the results of our MR study, there is no bidirectional causality between delirium and AD, delirium is not associated with an increased risk of AD, while genetically predicted AD is a potential causal risk factor for delirium.

High-Linearity Flexible Pressure Sensor Based on the Gaussian-Curve-Shaped Microstructure for Human Physiological Signal Monitoring.

Flexible pressure sensors with high-performance show broad application prospects in health monitoring, wearable electronic devices, intelligent robot sensing, and other fields. Although flexible pressure sensors have made significant progress in sensitivity and detection range, most of them still exhibit strong nonlinearity, which leads to significant troubles in signal acquisition and thus limits their popularity in practical applications. It remains a serious challenge for the flexible pressure sensor to achieve high linearity while maintaining high sensitivity. Herein, a doped sensing membrane with a uniformly distributed Gaussian-curve-shaped micropattern array was developed using the micro-electromechanical systems (MEMS) process, and a flexible sensor structure with the doped film as the core was designed and constructed. The prototype sensor has a high sensitivity of 1.77 kPa-1 and a linearity of 0.99 in the full detection range of 20 Pa to 30 kPa. In addition, its excellent performance also includes fast response/recovery times (∼25/50 ms) and long-term endurance (>10,000 cycles at 15 kPa). The prototype sensor has been successfully demonstrated in human pulse monitoring, speech recognition, and gesture recognition. The 2 × 6 sensor array can detect the spatial pressure distribution. Thus, such a microstructure shape design will open a new way to fabricate a high-linearity pressure sensor for potential applications in health monitoring, human-machine interaction, etc.

Quantitative phase imaging of living red blood cells combining digital holographic microscopy and deep learning.

Digital holographic microscopy as a non-contacting, non-invasive, and highly accurate measurement technology, is becoming a valuable method for quantitatively investigating cells and tissues. Reconstruction of phases from a digital hologram is a key step in quantitative phase imaging for biological and biomedical research. This study proposes a two-stage deep convolutional neural network named VY-Net, to realize the effective and robust phase reconstruction of living red blood cells. The VY-Net can obtain the phase information of an object directly from a single-shot off-axis digital hologram. We also propose two new indices to evaluate the reconstructed phases. In experiments, the mean of the structural similarity index of reconstructed phases can reach 0.9309, and the mean of the accuracy of reconstructions of reconstructed phases is as high as 91.54%. An unseen phase map of a living human white blood cell is successfully reconstructed by the trained VY-Net, demonstrating its strong generality.