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A patient with intrahepatic breast cancer metastasis underwent both 18F-FDG and 68Ga-FAPI PET/CT. However, the lesions are only 68Ga-FAPI avid. Our case illustrates that 68Ga-FAPI PET/CT can be more sensitive in detecting intrahepatic metastasis of breast cancer in some cases.

Automatic extraction of road from multisource remote sensing data has always been a challenging task. Factors such as shadow occlusion and multisource data alignment errors prevent current deep learning-based road extraction methods from acquiring road features with high complementarity, redundancy, and crossover. Unlike previous works that capture contexts by multiscale feature fusion, we propose a dual attention dilated-LinkNet (DAD-LinkNet) to adaptively integrate local road features with their global dependencies by joint using satellite image and floating vehicle trajectory data. First, a joint least-squares feature matching-based floating vehicle trajectory correction model is used to correct the floating vehicle trajectory; then a convolutional network model DAD-LinkNet based on a dual-attention mechanism is proposed, and road features are extracted from the channel domain and spatial domain of the target image in turn by constructing a dual-attention module in the dilated convolutional layer and adopting a cascade connection; a weighted hyperparameter loss function is used as the loss function of the model; finally, the road extraction is completed based on the proposed DAD-LinkNet model. Experiments on three datasets show that the proposed DAD-LinkNet model outperforms the state-of-the-art methods in terms of accuracy and connectivity.

Alzheimer’s disease (AD) is a central neurodegenerative disease generally among the elderly; it accounts for approximately 50–75%of total cases of dementia patients and poses a serious threat to physical and mental health. Currently available treatments for AD mainly relieves its symptoms, and effective therapy is urgently needed. Deposition of amyloid-β protein in the brain is an early and invariant neuropathological feature of AD. Currently the main efforts in developing anti-AD drugs focus on anti-amyloidogenic therapeutics that prevent amyloid-β production or aggregation and decrease the occurrence of neurotoxic events. The results of an increasing number of studies suggest that natural extracts and phytochemicals have a positive impact on brain aging. Flavonoids belong to the broad group of polyphenols and recent data indicate a favorable effect of flavonoids on brain aging. In this review, we collect relevant discoveries from 1999 to 2021, discuss 75 flavonoids that effectively influence AD pathogenesis, and summarize their functional mechanisms in detail. The data we have reviewed show that, these flavonoids belong to various subclasses, including flavone, flavanone, biflavone, etc. Our results provide a reference for further study of the effects of flavonoids on AD and the progress of anti-AD therapy.

Cigarette smoke (CS) exposure results in lung damage and inflammation through mitochondrial dysfunction. Mitochondria quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase by its interaction with PINK1/Parkin during mitophagy. However, the exact mechanism that operates this interaction of mitophagy machinery in Miro1 degradation and CS-induced mitochondrial dysfunction that results in lung inflammation remains unclear. We hypothesized that mitochondrial Miro1 plays an important role in regulating mitophagy machinery and resulting lung inflammation by CS in mouse lung. We showed a role of Miro1 in CS-induced mitochondrial dysfunction and quality control mechanisms. The Rhot1Fl/Fl (WT) and lung epithelial cell-specific Rhot1 KO were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). The cellular infiltration, cytokines, and lung histopathology were studied for the inflammatory response in the lungs. Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils associated with inflammatory mediators and Miro1 associated mitochondrial quality control proteins Parkin and OPA1. Chronic exposure showed an increase infiltration of total inflammatory cells and neutrophils versus air controls. Histopathological changes, such as pulmonary macrophages and neutrophils were increased in CS exposed mice. The epithelial Miro1 ablation led to augmentation of inflammatory cell infiltration with alteration in the levels of pro-inflammatory cytokines and histopathological changes. Thus, CS induces disruption of mitochondrial quality control mechanisms, and Rhot1/Miro1 mediates the process of CS-induced mitochondrial dysfunction ensuing lung inflammatory responses.

Mitochondrial quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase during mitophagy. The exact mechanism that operates the interaction of Miro1 with mitophagy machinery and their role in cigarette smoke (CS)-induced mitochondrial dysfunction that often results in lung inflammation is unclear. We hypothesized that Miro1 plays an important role in regulating mitophagy machinery and the resulting lung inflammation by CS exposure to mice. The lung epithelial Rhot1fl/fl (WT) and Rhot1CreCC10 mice were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils that are associated with inflammatory mediators. Chronic exposure showed increased infiltration of neutrophils versus air controls. The effects of acute and chronic CS exposure were augmented in the Rhot1CreCC10 group, indicating that epithelial Miro1 ablation led to the augmentation of inflammatory cell infiltration with alteration in the inflammatory mediators. Thus, Rhot1/Miro1 plays an important role in regulating CS-induced lung inflammatory responses with implications in mitochondrial quality control.

We report a case of organizing pneumonia, which revealed intense uptake on both 18F-FDG and 68Ga-FAPI (fibroblast activation protein inhibitor) PET/CT. Our findings indicate that organizing pneumonia should be taken into consideration when diagnosing a cancer-like pulmonary mass with intense 68Ga-FAPI uptake.

Cigarette smoke (CS) is the main etiological factor in the pathogenesis of emphysema/chronic obstructive pulmonary disease (COPD), which is associated with abnormal epithelial-mesenchymal transition (EMT). Previously, we have shown an association among circadian rhythms, CS-induced lung inflammation, and nuclear heme receptor α (REV-ERBα), acting as an antiinflammatory target in both pulmonary epithelial cells and fibroblasts. We hypothesized that molecular clock REV-ERBα plays an important role in CS-induced circadian dysfunction and EMT alteration. C57BL/6J WT and REV-ERBα heterozygous (Het) and -KO mice were exposed to CS for 30 days (subchronic) and 4 months (chronic), and WT mice were exposed to CS for 10 days with or without REV-ERBα agonist (SR9009) administration. Subchronic/chronic CS exposure caused circadian disruption and dysregulated EMT in the lungs of WT and REV-ERBα-KO mice; both circadian and EMT dysregulation were exaggerated in the REV-ERBα-KO condition. REV-ERBα agonist, SR9009 treatment reduced acute CS-induced inflammatory response and abnormal EMT in the lungs. Moreover, REV-ERBα agonist (GSK4112) inhibited TGF-β/CS-induced fibroblast differentiation in human fetal lung fibroblast 1 (HFL-1). Thus, CS-induced circadian gene alterations and EMT activation are mediated through a Rev-erbα-dependent mechanism, which suggests activation of REV-ERBα as a novel therapeutic approach for smoking-induced chronic inflammatory lung diseases.

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis and propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function and others are regulated by tumor suppressor P53, which plays a pivotal role in leukemogenesis. Opposing P53-mediated activities is the mouse double minute 2 homolog (MDM2), which promotes P53 degradation. Because the TP53 mutation rate is low, and MDM2 frequently overexpressed, in patients with leukemia, targeting the MDM2-P53 axis to restore P53 function has emerged as an attractive AML treatment strategy. APG-115 is a potent MDM2 inhibitor under clinical development for patients with solid tumors. In cellular cultures and animal models of AML, we demonstrate that APG-115 exerted substantial antileukemic activity, as either a single agent or when combined with standard-of-care (SOC) hypomethylating agents azacitidine (AZA) and decitabine (DAC), or the DNA-damaging agent cytarabine (Ara-C). By activating the P53/P21 pathway, APG-115 exhibited potent antiproliferative and apoptogenic activities, and induced cell cycle arrest, in TP53 wild-type AML lines. In vivo, APG-115 significantly reduced tumor burden and prolonged survival. Combinations of APG-115 with SOC treatments elicited synergistic antileukemic activity. To explain these effects, we propose that APG-115 and SOC agents augment AML cell killing by complementarily activating the P53/P21 pathway and upregulating DNA damage. These findings and the emerging mechanism of action afford a sound scientific rationale to evaluate APG-115 (with or without SOC therapies) in patients with AML.

Metabolites are essential intermediate products in metabolism, and metabolism dysregulation indicates different types of diseases. Previous studies have shown that cigarette smoke dysregulated metabolites, however, limited information is available with electronic cigarette (e-cig) vaping. We hypothesized that e-cig vaping and cigarette smoking alters systemic metabolites, and we propose to understand the specific metabolic signature between e-cig users and cigarette smokers. Plasma from non-smoker controls, cigarette smokers, and e-cig users was collected, and metabolites were identified by UPLC–MS (ultra-performance liquid chromatography mass spectrometer). Nicotine degradation was activated by e-cig vaping and cigarette smoking with increased concentrations of cotinine, cotinine N-oxide, (S)-nicotine, and (R)-6-hydroxynicotine. Additionally, we found significantly decreased concentrations in metabolites associated with tricarboxylic acid (TCA) cycle pathways in e-cig users versus cigarette smokers, such as d-glucose, (2R,3S)-2,3-dimethylmalate, (R)-2-hydroxyglutarate, O-phosphoethanolamine, malathion, d-threo-isocitrate, malic acid, and 4-acetamidobutanoic acid. Cigarette smoking significant upregulated sphingolipid metabolites, such as D-sphingosine, ceramide, N-(octadecanoyl)-sphing-4-enine, N-(9Z-octadecenoyl)-sphing-4-enine, and N-[(13Z)-docosenoyl]-sphingosine, versus e-cig vaping. Overall, e-cig vaping dysregulated TCA cycle-related metabolites while cigarette smoking altered sphingolipid metabolites. Both e-cig and cigarette smoke increased nicotinic metabolites. Therefore, specific metabolic signatures altered by e-cig vaping and cigarette smoking could serve as potential systemic biomarkers for early pathogenesis of cardiopulmonary diseases.

BackgroundWaterpipe tobacco (WPT) smoking is associated with deleterious effects on cardio-pulmonary systems which may have adverse repercussions in pathophysiology and progression of chronic lung and cardiovascular diseases. We compared the biomarkers of systemic inflammation, lipid mediators, injury/repair and oxidative stress between groups of non-smokers (NS), exclusive WPT smokers (WPS), exclusive cigarette smokers (CS) and dual WPS and CS (DS).MethodsTwo cohorts were recruited. Cohort I consisted of WPS (n=12), CS (n=26), DS (n=10) and NS (n=25). Cohort II consisted of WPS (n=33) and NS (n=24). Plasma and urine samples were collected and analysed for various systemic biomarkers.ResultsCompared with NS, plasma levels of inflammatory mediators (interleukin (IL)-6, IL-8, IL1β and tumor necrosis factor-α) were significantly higher in WPS and CS, and were further augmented in DS. Endothelial biomarkers (intracellular adhesion molecule-1, prostaglandin E-2 and metalloproteinase-9) were significantly higher in CS. Most notably, pro-resolving lipid mediator (resolvin E1) and biomarkers of immunity, tissue injury, and repair were significantly lower in WPS and CS. Urinary levels of 8-isoprostane were significantly higher in all smoking groups in cohort I, while 8-isoprostane, myeloperoxidase, receptor for advanced glycation end products (RAGE), En-RAGE and matrix metalloproteinase-9 were significantly higher in all smoking groups in cohort II.ConclusionsBiomarkers of inflammation, oxidative stress, immunity, tissue injury and repair were elevated in WPS and CS groups. Furthermore, concurrent use of WPT and cigarettes is more harmful than cigarette or WPT smoking alone. These data may help inform the public and policy-makers about the dangers of WPT smoking and dual use of tobacco products.

Nicotine inhalation via electronic cigarettes (e‐cigs) is an emerging concern. However, little is known about the acute toxicity in the lungs following inhalation of nicotine‐containing e‐cig aerosols. We hypothesized that acute exposure to aerosolized nicotine causes lung toxicity by eliciting inflammatory and dysregulated repair responses. Adult C57BL/6J mice were exposed 2 hours daily for 3 days to e‐cig aerosols containing propylene glycol (PG) with or without nicotine. Acute exposure to nicotine‐containing e‐cig aerosols induced inflammatory cell influx (neutrophils and CD8a+ T lymphocytes), and release of pro‐inflammatory cytokines in bronchoalveolar lavage fluid in a sex‐dependent manner. Inhalation of e‐cig aerosol containing PG alone significantly augmented the lung levels of various homeostasis/repair mediators (PPARγ, ADRP, ACTA2, CTNNB1, LEF1, β‐catenin, E‐cadherin, and MMP2) in a sex‐dependent manner when compared to air controls. These findings were accompanied by an increase in protein abundance and altered gene expression of lipogenic markers (PPARγ, ADRP) and myogenic markers (fibronectin, α‐smooth muscle actin and β‐catenin), suggesting a dysregulated repair response in mouse lungs. Furthermore, exposure to nicotine‐containing e‐cig aerosols or PG alone differentially affected the release of pro‐inflammatory cytokines in healthy and COPD human 3D EpiAirway tissues. Overall, acute exposure to nicotine‐containing e‐cig aerosols was sufficient to elicit a pro‐inflammatory response and altered mRNA and protein levels of myogenic, lipogenic, and extracellular matrix markers in mouse lung in a sex‐dependent manner. Thus, acute exposure to inhaled nicotine via e‐cig leads to dysregulated repair and inflammatory responses, which may lead to airway remodeling in the lungs.

To investigate the cardioprotective effect of Danqi Tablet (DQT, 丹七片) on ischemic heart model rats and the regulative effect on energy metabolism through peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Rat ischemic heart model was induced by ligation of left anterior descending coronary artery. Totally 40 Sprague-Dawley rats were randomly divided into sham group, model group, DQT group (1.5 mg/kg daily) and trimetazidine (TMZ) group (6.3 mg/kg daily) according to a random number table, 10 rats in each group. Twenty-eight days after continuous administration, cardiac function was assessed by echocardiography and the structures of myocardial cells were observed by hematoxylin-eosin staining. The level of adenosine triphosphate (ATP) in myocardial cells was measured by ATP assay kit. Expressions level of key transcriptional regulators, including PGC-1α, Sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and downstream targets of PGC-1α, such as mitofusin 1 (MFN1), mitofusin 2 (MFN2) and superoxide dismutase 2 (SOD2) were measured by Western blot. Expression level of PGC-1α was examined by immunohistochemical staining. The rat ischemic heart model was successfully induced and the heart function in model group was compromised. Compared with the model group, DQT exerted cardioprotective effects, up-regulated the ATP production in myocardial cells and inhibited the infiltration of inflammatory cells in the margin area of infarction of the myocardial tissues (P

Background Pegylated interferon (PEG-IFN) alfa-2b is recommended for chronic hepatitis B (CHB). We aimed to investigate the sustainability of off-treatment responses among Chinese HBeAg-positive CHB patients treated with PEG-IFN alfa-2b from a randomized trial. Methods Eligible Chinese patients (n = 322) were followed up by one visit after a median of 6 years (LTFU) following their participation in a randomized trial evaluating the efficacy of three PEG-IFN alfa-2b dosing regimens (1.0 or 1.5 μg/kg/wk. 24 weeks or 1.5 μg/kg/wk. 48 weeks). Primary endpoints at the LTFU were sustained SR and CR (SR/CR at the end of original study [EOS] and at the LTFU). SR was defined as HBeAg loss and seroconversion to anti-HBe and CR as HBeAg loss and seroconversion to anti-HBe and HBV-DNA

Metabolites are essential intermediate products in metabolism, and metabolism dysregulation indicates different types of diseases. Previous studies have shown that cigarette smoke dysregulated metabolites; however, limited information is available with electronic cigarette (E-cig) vaping. We hypothesized that E-cig vaping and cigarette smoking altered systemic metabolites, and we propose to understand the specific metabolic signature between E-cig users and cigarette smokers. Plasma from non-smoker controls, cigarette smokers, and e-cig users were collected, and metabolites were identified by UPLC–MS (Ultraperformance liquid chromatography-mass spectrometer). Nicotine degradation was activated by e-cig vaping and cigarette smoking with increased concentrations of cotinine, cotinine N-oxide, (S)-nicotine, and (R)-6-hydroxynicotine. Additionly, we found significant decreased concentrations in metabolites associated with tricarboxylic acid (TCA) cycle pathways in e-cig users verses cigarette smokers, such as: D-glucose, (2R,3S)-2,3-dimethylmalate, (R)-2-hydroxyglutarate, O-phosphoethanolamine, malathion, D-threo-isocitrate, malic acid, and 4-acetamidobutanoic acid. Cigarette smoking significant up-regulated sphingolipid metabolites, such as D-sphingosine, ceramide, N-(octadecanoyl)-sphing-4-enine, N-(9Z-octadecenoyl)-sphing-4-enine, and N-[(13Z)-docosenoyl]sphingosine, verses e-cig vaping. Overall, e-cig vaping dysregulated TCA cycle realted metabolites while cigarette smoking altered sphingolipid metabolites. Both e-cig and cigarette smoke increased nicotinic metabolites. Therefore, specific metabolic signature altered by e-cig vaping and cigarette smoking could serve as potential systemic biomarkers for early cardiopulmonary diseases.

68Ga-labeled quinoline-based fibroblast activation protein inhibitors (68Ga-FAPIs) has been used in the evaluation of a variety of malignancies. We report the case of a patient with rib plasmacytoma, which showed elevated 68Ga-FAPI activity. This case indicated fibroblast activation protein overexpression and some degree of fibrosis in the plasmacytoma lesion. Therefore, 68Ga-FAPI can be a potential tracer in the evaluation of plasmacytoma.

Langerhans cell histiocytosis (LCH) is a rare proliferative histiocytic disorder. It mainly occurs in the pediatric population, whereas it is rarely reported in adults. Herein, we reported a case of a patient with isolated rib LCH, which showed elevated 18F-FDG uptake. Our case showed that 18F-FDG PET/CT can be a potential tool in the evaluation of LCH.

Background The pathological cardiac functions of ankyrin repeat domain 1 (ANKRD1) in left ventricle can directly aggravate cardiac hypertrophy (CH) and fibrosis through the activation of extracellular signal-regulated kinase (ERK)/ transcription factor GATA binding protein 4 (GATA4) pathway, and subsequently contribute to heart failure (HF). Baoyuan Decoction (BYD), which is a famous classic Chinese medicinal formulation, has shown impressive cardioprotective effects clinically and experimentally. However, the knowledge is still limited in its underlying mechanisms against HF. Purpose To explore whether BYD plays a protective role against HF by attenuating CH via the ANKRD1-ERK/GATA4 pathway. Methods In vivo, HF rat models were prepared using left anterior descending coronary artery (LADCA) ligation. Rats in the BYD group were administered a dosage of 2.57 g/kg of BYD for 28 days, while in the positive control group rats were given 4.67 mg/kg of Fosinopril. In vitro, a hypertrophic model was constructed by stimulating H9C2 cells with 1 uM Ang II. An ANKRD1-overexpressing cell model was established through transient transfection of ANKRD1 plasmid into H9C2 cells. Subsequently, BYD intervention was performed on the cell models to further elucidate its effects and underlying mechanism. Results In vivo results showed that BYD significantly improved cardiac function and inhibited pathological hypertrophy and fibrosis in a rat model of HF post-acute myocardial infarction (AMI). Noticeably, label-free proteomic analysis demonstrated that BYD could reverse the CH-related biological turbulences, mainly through ANKRD1-ERK/GATA4 pathway. Further in vitro results validated that the hypertrophy was attenuated by BYD through suppression of AT1R, ANKRD1, Calpain1, p-ERK1/2 and p-GATA4. The results of in vitro model indicated that BYD could reverse the outcome of transfected over-expression of ANKRD1, including down-regulated expressions of ANKRD1, p-ERK1/2 and p-GATA4. Conclusion BYD ameliorates CH and improves HF through the ANKRD1-ERK/GATA4 pathway, providing a novel therapeutic option for the treatment of HF.

Global Positioning System (GPS) stations installed in and around the epicenter of the Lushan earthquake (Mw 6.7), which occurred almost 5 years after the 2008 Wenchuan earthquake, recorded preseismic deformation corresponding to the Lushan earthquake within the southern Longmenshan thrust belt. A half-space dislocation model is used to simulate the theoretical values of the postseismic displacements caused by the 2008 Wenchuan earthquake, and after transforming the reference frame and filtering the GPS displacement time series, the theoretical and observed GPS values are compared to identify the geodetic anomaly preceding the Lushan earthquake. The abnormal extent of this geodetic anomaly decreases with increasing epicentral distance for each GPS site. This geodetic signal reflects preslip along a locked section of the 2013 seismogenic fault, which caused the accumulation of elastic strain energy until the faulting strength was overcome, thereby generating the Lushan earthquake. Hence, this anomaly might be used as an observable and identifiable precursor to forecast an impending earthquake within a period of less than two and half years before its occurrence.

In this paper, we present a deep hybrid model to detect abnormal flights. Deep hybrid models for anomaly detection use deep neural networks mainly autoencoder as feature extractors, the features learned within the hidden representations of autoencoder are then input to cluster algorithm to detect abnormal flights. The model can detect flight anomalies and associated risks without requiring predefined criteria or domain knowledge. In this paper, 2018 annual flight data of Daocheng Yading airport was taken as the experimental data which contains 981 flights. Our model performed well and 91 abnormal flights were detected.

The abnormal inflammatory responses due to the lung tissue damage and ineffective repair/resolution in response to the inhaled toxicants result in the pathological changes associated with chronic respiratory diseases. Investigation of such pathophysiological mechanisms provides the opportunity to develop the molecular phenotype-specific diagnostic assays and could help in designing the personalized medicine-based therapeutic approaches against these prevalent diseases. As the central hubs of cell metabolism and energetics, mitochondria integrate cellular responses and interorganellar signaling pathways to maintain cellular and extracellular redox status and the cellular senescence that dictate the lung tissue responses. Specifically, as observed in chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, the mitochondria-endoplasmic reticulum (ER) crosstalk is disrupted by the inhaled toxicants such as the combustible and emerging electronic nicotine-delivery system (ENDS) tobacco products. Thus, the recent research efforts have focused on understanding how the mitochondria-ER dysfunctions and oxidative stress responses can be targeted to improve inflammatory and cellular dysfunctions associated with these pathologic illnesses that are exacerbated by viral infections. The present review assesses the importance of these redox signaling and cellular senescence pathways that describe the role of mitochondria and ER on the development and function of lung epithelial responses, highlighting the cause and effect associations that reflect the disease pathogenesis and possible intervention strategies.

In this work, we aim to propose a reliable automatic highway on-ramp smart vehicle merging protocol that tolerates arbitrary wireless packet losses, and guarantees the widely adopted safety rule of Constant Time Headway (CTH) [1] . This is different from the existing literature, which assumes reliable communications infrastructure (e.g. [2] ) or focuses on safety rules other than the CTH (e.g. [3] ).

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has conducted to understand the mechanism of toxicological and pulmonary effects of e-cigs. We hypothesized that sub-chronic exposure of e-cigs induced inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChR α7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial-cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lungs were collected for determination of inflammatory responses and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased the lung influx of macrophages and T-lymphocytes, and the levels of pro-inflammatory cytokines, while nAChR α7 knockdown blocked the inflammatory responses. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8, and MMP9, in both sex mice were altered at both protein and gene levels when WT mice were exposed to PG alone in a sex-dependent manner. Moreover, MMP12 increased significantly in male mice exposed to PG with or without nicotine in a nAChR α7 dependent manner. Additionally, the abundance of ECM proteins, such as collagen and fibronectin, was significantly altered after sub-chronic e-cig exposure with or without nicotine in a sex-dependent manner, but nAChR α7 independent manner. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChR α7 in a sex-dependent manner.

Introduction FLT3-ITD mutations occur in approximately 25% of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Despite initial efficacy, short duration of response and high relapse rates limit clinical use of selective FLT3 inhibitors. Combination approaches with other targeted therapies may achieve better clinical outcomes. Materials and methods Anti-leukemic activity of multikinase inhibitor olverembatinib (HQP1351), alone or in combination with BCL-2 inhibitor lisaftoclax (APG-2575), was evaluated in FLT3-ITD mutant AML cell lines in vitro and in vivo. A patient-derived FLT3-ITD mutant AML xenograft model was also used to assess the anti-leukemic activity of this combination. Results HQP1351 potently induced apoptosis and inhibited FLT3 signaling in FLT3-ITD mutant AML cell lines MV-4-11 and MOLM-13. HQP1351 monotherapy also significantly suppressed growth of FLT3-ITD mutant AML xenograft tumors and prolonged survival of tumor-bearing mice. HQP1351 and APG-2575 synergistically induced apoptosis in FLT3-ITD mutant AML cells and suppressed growth of MV-4–11 xenograft tumors. Combination therapy improved survival of tumor bearing-mice in a systemic MOLM-13 model and showed synergistic anti-leukemic effects in a patient-derived FLT3-ITD mutant AML xenograft model. Mechanistically, HQP1351 downregulated expression of myeloid-cell leukemia 1 (MCL-1) by suppressing FLT3-STAT5 (signal transducer and activator of transcription 5) signaling and thus enhanced APG-2575-induced apoptosis in FLT3-ITD mutant AML cells. Conclusions FLT3 inhibition by HQP1351 downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 to potentiate cellular apoptosis in FLT3-ITD mutant AML. Our findings provide a scientific rationale for further clinical investigation of HQP1351 combined with APG-2575 in patients with FLT3-ITD mutant AML.

Macrophages play a pivotal role in myocardial remodeling (MR) process which could eventually lead to heart failure. Splenic monocytes could be mobilized and recruited under inflammatory conditions and differentiated into different types of macrophages in heart tissues. Inflammatory M1 macrophages could aggravate tissue damage whereas M2 macrophages could promote angiogenesis and tissue repair process. Unbalanced ratio of M1/M2 macrophages may eventually lead to adverse remodeling. Therefore, regulating differentiation and activities of macrophages are potential strategies for the management of myocardial remodeling. Qishen Granule (QSG) is an effective Chinese medicine for treating heart failure. Our previous studies demonstrated that QSG could inhibit myocardial fibrosis through regulating secretion of cytokines and activation of macrophages. However, the detailed effects of QSG on had not been elucidated yet. In this study, we aimed to explore the effect of QSG on the release of splenic monocytes, the recruitment of monocytes into heart tissues and the differentiation of macrophages under ischemic conditions. Our results showed that QSG could suppress the release of monocytes from the spleen and recruitment of monocytes to heart tissues via inhibiting splenic angiotensin (Ang) II/AT1-cardiac monocyte chemotactic protein (MCP)-1/CC chemokine receptor 2 (CCR2) pathway. The anti-fibrotic effect of QSG was exerted by inhibiting M1 macrophage-activated transforming growth factor (TGF)-β1/Smad3 pathway. Meanwhile, QSG could promote angiogenesis by promoting differentiation of M1 macrophages into M2 macrophages. Our results suggest that compounds of Chinese medicine have synergistic effects on cardiac and splenic organs through regulating differentiation of monocytes/macrophages in inhibiting myocardial remodeling.

The paper takes 996 IPO companies in China from 2012 to 2016 as samples and investigates the effect on IPO pricing efficiency under the “Direct Investment + Sponsor” Mode. The research shows that there is no significant difference between companies that intend to IPO under the “Direct Investment + Sponsor” mode and companies that intend to IPO under the non-“Direct Investment + Sponsor” mode in the discount of new stocks and one-year returns. The result shows that the firewall mechanism between the direct investment department and the investment banking department of Chinese securities traders is in good condition, verifies the rationality of not abolishing “Direct Investment + Sponsor” mode in Guidelines for Direct Investment Business of Securities Companies introduced by China Securities Regulatory Commission in July 2011 and powerfully refutes the market’s long-lasting query that China Securities Regulatory Commission retains “Direct Investment + Sponsor” mode. Meanwhile, it provides evidence for the existence compliance of “Direct Investment + Sponsor” mode with financial innovation made by securities traders on the occasion of introducing new policies such as Management Standards for Private Equity Subsidiaries of Securities Companies and Management Standard for Alternative Investment Subsidiaries of Securities Companies.

Solitary non-Hodgkin lymphoma of the trachea is extremely rare. Herein, we reported a case of solitary laryngotracheal lymphoma in a 55-year-old man. He complained of cough, tachypnea, and dyspnea. 18F-FDG PET/CT showed a hypermetabolic lesion in the subglottic larynx and upper cervical trachea. The subsequent histology and immunohistochemistry of the laryngotracheal lesion tissue confirmed the diagnosis of non-Hodgkin lymphoma (mucosa-associated lymphatic tissue lymphoma).

The AML treatment landscape has improved dramatically in the past decade, with improved objective response rates and overall survival after treatment with newly approved targeted therapies. BCL-2 inhibition combined with a hypomethylating agent or low-dose cytosine arabinoside (Ara-C) is also effective in previously untreated elderly patients who are not candidates for standard induction therapy. However, the effect of BCL-2 inhibition is commonly weakened when tumor cells upregulate antiapoptotic protein MCL-1 to escape apoptosis. Thus, combination therapy is introduced to suppress MCL-1 levels. HHT (omacetaxine mepesuccinate) has been widely used in Chinese patients with AML for 30 years. As an inhibitor of protein synthesis, HHT decreases MCL-1. This study investigated the effect of combining clinical stage BCL-2 selective inhibitor APG-2575 with HHT in AML and MDS cells, as well as murine xenograft tumor models. In AML (MV-4-11, OCI-AML-3) and MDS (SKM-1) cell lines, single-agent HHT exerted stronger antiproliferative and apoptogenic activities compared to APG-2575 (as assessed by Cell Titer Glo assay or flow cytometry). When combined, these treatments synergistically inhibited cellular proliferation and induced apoptosis. In a mouse xenograft tumor model derived from MV-4-11 cells, APG-2575 demonstrated limited antitumor activity, with a T/C (Treated/Control tumor volume %) value of 63% whereas HHT showed stronger activity, with T/C equal to 30%. Most importantly, these antitumor effects were potentiated when APG-2575 and HHT were combined, yielding a T/C value of 3% and partial regression in all treated tumors. Mechanistically, BCL-2 inhibition with APG-2575 decreased BCL-2:BIM complexes and but increased MCL-1:BIM complexes, as liberated BIM was re-sequestered by MCL-1. On the other hand, concomitant treatment with HHT abolished induction of MCL-1:BIM complexes. Besides BIM complexes, MCL-1:PUMA and MCL-1:BAK pairings also decreased after exposure to HHT. The decrease in MCL-1 complex coincided with its downregulation at protein levels. Thus, under such an MCL-1-supressed condition facilitated by HHT treatment, the freed proapoptotic proteins (BIM, PUMA, BAK) more potently manifested apoptotic signals triggered by APG-2575. In summary, APG-2575 synergizes with HHT to potentiate antitumor activity in preclinical models of AML/MDS. HHT suppresses MCL-1 protein, preventing or abolishing formation of MCL-1:BIM, MCL-1:PUMA, and MCL-1:BAK complexes, and hence allowing prodeath proteins to fully engage in tumor cell apoptosis induction. Our results provide scientific rationale for clinical development of APG-2575 plus HHT in patients with AML/MDS. Citation Format: Douglas D. Fang, Qiuqiong Tang, Yanhui Kong, Tao Rong, Qixin Wang, Jing Deng, Dajun Yang, Yifan Zhai. BCL-2 inhibitor APG-2575 and homoharringtonine (HHT) synergistically induces apoptosis and inhibits tumor growth in preclinical models of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 981.

Ovarian cancer is one of the deadliest malignancies in women, and up to 70% of patients with epithelial ovarian cancer have FAK overexpression, amplification, or activation. FAK plays an important role in cellular migration, growth factor signaling, cell cycle progression, cellular survival and chemoresistance. This biomarker is also significantly associated with higher tumor stage, metastasis, and shorter overall survival in patients with ovarian cancer. Inhibition of FAK is therefore emerging as a promising treatment target. APG-2449 is a clinical stage FAK/ALK/ROS1 multi-kinase inhibitor. In this study we investigated antitumor activity of APG-2449 combined with standard-of-care chemotherapeutics in ovarian cancer in the preclinical setting. In a mouse xenograft tumor model derived from ovarian cancer cell line OVCAR-3, which was resistant to platinum-based therapies, APG-2449 combined with paclitaxel, and paclitaxel plus carboplatin, synergistically enhanced antitumor activity, whereas the chemotherapeutics showed no activity. Synergistic antitumor activity was also observed in multiple patient-derived xenograft (PDX) models derived from women with chemoinsensitive ovarian cancer, which also frequently expresses high levels of FAK. By comparing gene expression profiles of PDX tumors obtained from responders and nonresponders to the combined therapy, we identified CD44 (a marker for cancer stem cells) as a potentially predictive biomarker. Western blot analysis confirmed higher protein levels of CD44 in pretreated tumors of responders. Interestingly, downregulation of CD44 levels was observed in combination-treated tumors, suggesting that these combinations reduced cancer stem cell populations in ovarian cancer. Accordingly, in ovarian cancer cells exposed to APG-2449 alone or combined with paclitaxel, numbers of cells positive for CD44 or aldehyde dehydrogenase 1 (ALDH1; another marker for cancer stem cells) decreased in a dose-dependent manner. In summary, our data suggest that FAK inhibition by APG-2449 sensitizes ovarian tumors to chemotherapeutics in preclinical tumor models of ovarian cancer. The synergistic antitumor activity was mediated by downregulation of CD44+ or ALDH1+ cancer stem cell populations. These findings encourage clinical development of APG-2449 in combination with chemotherapies for treatment of ovarian cancer. Citation Format: Ran Tao, Douglas D. Fang, Yuanbao Li, Kaixiang Zhang, Chunhua Xu, Xu Fang, Qixin Wang, Dajun Yang, Yifan Zhai. Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 968.

A weighted directed flight network in the Belt and Road Initiative(BRI) region was constructed in this paper, which takes the airports as nodes and the connection relations between airports as edges. Based on the complex network, the structural characteristics of the BRI flight network are statistically analyzed. At the same time, the Markov clustering algorithm was used to explore the clustering characteristics of national airports. The research results showed that: l The average degree of nodes in the flight network is 13.36, which means there are more than 13 airports directly connected with the one in average; The average distance among the BRI flight network is about 3.2, which means any two airports can be reached within more than 3 transfers in the regions of BRI; 2 The degree distribution of the nodes in the flight network presented a power-law distribution, BRI flight network is a kind of typical scale-free network which means vast majority of airports have a very small number of direct connections with other airports while the few remaining airports possess most direct links; 3 In this paper, we got 12 clusters in which the number of airports is more than 10 based on Markov clustering, airports in the Belt and Road Initiative show the characteristic of spatial clustering, that is, airports near to each other in space gather together. This paper aims to provide support for the development and decision-making of the Belt and Road Initiative aviation industry.

Control-CPS software fault localization (SFL, aka bug localization) is of critical importance as bugs may cause major failures, even injuries/deaths. To locate the bugs in control-CPSs, SFL tools often demand many labeled ("correct"/"incorrect") source code execution traces as inputs. To label the correctness of these traces, we must judge the corresponding control-CPS physical trajectories' correctness. However, unlike discrete outputs, the boundaries between correct and incorrect physical trajectories are often vague. The mechanism (aka oracle) to judge the physical trajectories' correctness thus becomes a major challenge. So far, the ad hoc practice of ``human oracles'' is still widely used, whose qualities heavily depend on the human experts' expertise and availability. This paper proposes an oracle based on the well adopted autoregressive system identification (AR-SI). With proven success for controlling black-box physical systems, AR-SI is adapted by us to identify the buggy control-CPS as a black-box. We use this identification result as an oracle to judge the control-CPS's behaviors, and propose a methodology to prepare traces for control-CPS debugging. Comprehensive evaluations on classic control-CPSs with injected real-life and artificial bugs show that our proposed approach significantly outperforms the human oracle approach in SFL accuracy (recall) and latency, and in oracle false positive/negative rates. Our approach also helps discover a new real-life bug in a consumer-grade control-CPS.

Background Programmed death-1 (PD-1) immune checkpoint blockade has achieved clinical successes in cancer therapy. However, the response rate of anti-PD-1 agents remains low. Additionally, a subpopulation of patients developed hyperprogressive disease upon PD-1 blockade therapy. Combination therapy with targeted agents may improve immunotherapy. Recent studies show that p53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization, and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may augment antitumor immunity elicited by anti-PD-1 therapy. Method Using APG-115 that is a MDM2 antagonist in clinical development as a pharmacological p53 activator, we investigated the role of p53 in immune modulation and combination therapy with PD-1 blockade. Results In vitro treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21, and a decrease in immunosuppressive M2 macrophage population through downregulation of c-Myc and c-Maf. Increased proinflammatory M1 macrophage polarization was observed in the spleen from mice treated with APG-115. Additionally, APG-115 has co-stimulatory activity in T cells and increases PD-L1 expression in tumor cells. In vivo, APG-115 plus anti-PD-1 combination therapy resulted in enhanced antitumor activity in Trp53 wt , Trp53 mut , and Trp53-deficient (Trp53 −/− ) syngeneic tumor models. Importantly, such enhanced activity was abolished in a syngeneic tumor model established in Trp53 knockout mice. Despite differential changes in tumor-infiltrating leukocytes (TILs), including the increases in infiltrated cytotoxic CD8+ T cells in Trp53 wt tumors and M1 macrophages in Trp53 mut tumors, a decrease in the proportion of M2 macrophages consistently occurred in both Trp53 wt and Trp53 mut tumors upon combination treatment. Conclusion Our results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53 mut tumors.

Non-destructive measurement of hand vein is challenging but has potentialities in many applications. Because the hand veins are under skin, the 3D annotations of hand veins are hard to obtain, and the captured images also have much noise from the skins. The traditional binocular vision methods and supervised neural networks are hard to implement in such situation. In this paper, We propose a end-to-end self-supervised binocular network (SBMNet) to compute disparities by matching pixels between the left and right images without annotations. The Region Strategy and Perceptual Loss are adopted in the training phase to improve the accuracy and the robustness to the noise. We set up the hand vein measurement system and collect simulated and real hand vein data for evaluation. SBMNet has made a successful attempt on non-destructive hand vein measurement and also has impressive results on the public KITTI dataset.

Networked robotics are a typical cyber–physical system (CPS). This paper presents the cyber physical interaction model to perform formation control and tracking in the presence of other robots and static obstacles. It discusses how such a model can be effectively utilized to deal with kinodynamic and operation range constraints. The cyber system is also responsible for feasible trajectory generation based upon regional path segments and to ensure that all the robots maneuver through obstacles in a safe manner. The introduction of virtual robot restructures the formation control problem into a tracking control problem between virtual reference robot and follower robots. A novel obstacle avoidance approach is proposed based upon the scaling of whole (partial) formation corresponding to centralized (distributed) framework. The involved CPS has network structure preserving properties that are key to effective distributed decision making. The novel formation control, obstacle avoidance, and trajectory tracking approaches facilitate networked robots to be effectively controlled through the cyber system. We also discuss efficient and optimal implementation of the proposed trajectory generator using computer-aided design for CPSs. Evaluation of the proposed approach is provided that demonstrate the formation control, trajectory tracking, and obstacle avoidance for multirobots using the proposed scheme.

Multimedia streaming applications with stringent QoS requirements in 60 GHz mmWave wireless personal area networks (WPANs) demand high rate and low latency data transfer as well as little service disruption. In this paper, we consider the problem of robust relay placement in 60 GHz WPANs with directional antenna. Relays forward traffic from transmitter devices to receiver devices facilitating i ) the primary communication path for non-line-of-sight (NLOS) transceiver pairs, and ii ) secondary (backup) communication path for line-of-sight (LOS) or NLOS transceiver pairs. By incorporating a classic directional antenna model and characterizing the link contention, we formulate the robust minimum relay placement problem and the robust maximum utility relay placement problem with the objective to minimize the number of relays deployed and maximize the network utility, respectively. Efficient algorithms are developed to solve both problems and have been shown to incur less service disruption in presence of moving subjects that may block the LOS paths in the environment.

This paper mainly addresses formation control problem of non-holonomic systems in an optimized manner. Instead of using linearization to solve this problem approximately, we designed control laws with guaranteed global convergence by leveraging nonlinear transformations. Under this nonlinear transformation, consensus of non-holonomic robots can be converted into a stabilization problem, to which optimal treatment applies. This concept is then extended to the formation control and tracking problem for a team of robots following leader-follower strategy. A trajectory generator prescribes the feasible motion of virtual reference robot, a decentralized control law is used for each robot to track the reference while maintaining the formation. The asymptotic convergence of follower robots to the position and orientation of the reference robot is ensured using the Lyapunov function which is also generated using chained form differential equations. In order to witness the efficacy of the scheme, simulations results are presented for Unicycle and Car-like robots.

NAND flash memory is widely used in both hard real-time and soft real-time systems because of its unique properties, such as non-volatility, low power consumption, and fast access time. However, due to the variable garbage collection latency, the response time becomes unpredictable when multiple I/O requests are issued from the file system to flash media. In NAND flash memory storage systems, flash translation layer (FTL) is a typical software module to handle the I/O requests and manage NAND flash memory. Most of existing FTL schemes focus on improving average response time but worst-case response time remains an open problem. This paper proposes a real-time flash translation layer (RFTL) scheme to evenly distribute garbage collection time-cost, so as to guarantee a near optimum worst-case response time. This is achieved by using a new hybrid-level address mapping approach, which can provide guaranteed physical space to serve requests in any time period. Moreover, we propose a distributed garbage collection policy that enables RFTL to reclaim the space and serve the requests simultaneously. We conduct a set of experiments on a real hardware platform. Both the proposed scheme and other representative FTL schemes have been implemented in the hardware evaluation board. Experimental results show that our scheme improves worst-case response time by 41.51 percent and average response time by 88.85 percent.

HQP1351 is a novel, orally bioavailable multi-kinase inhibitor targeting BCR-ABL, KIT, and FLT3. Currently, HQP1351 is in phase II clinical trials in relapsed and refractory chronic myeloid leukemia (CML) patients by targeting BCR-ABL. Besides, HQP1351 inhibits both wild-type and mutant FLT3 in kinase binding assay. APG-115 is another clinical stage, small molecule MDM2 antagonist. In the present study, we explored the antitumor effect of the combination of HQP1351 and APG-115, and the molecular mechanism in FLT3-ITD and TP53 wild-type acute myeloid leukemia (AML) in the preclinical setting. First, the effect of HQP1351 as single agent on cell viability in FLT3-ITD mutant and TP53 wild-type human AML cell lines, including MV-4-11 and MOLM-13. Second, antitumor activity of the combination was investigated in systemic and subcutaneous xenograft models in NOD/SCID mice derived from these cells. The results showed that HQP1351 alone exhibited potent antiproliferative activity in both cell lines in vitro, with nanomolar IC50 values. The activity was enhanced in the combination treatment with APG-115. In vivo, HQP1351 single agent demonstrated significant antitumor activity evidenced by a markedly reduction of tumor burden (i.e., CD45+ human tumor cells) in systemic MOLM-13 xenograft model. Treatment with HQP1351 at 3, 10 and 30 mg/kg significantly prolonged mice survival with median survival of 20.5 days, 26.0 days and 35 days, respectively, compared with 18 days in the control group. In subcutaneous MV-4-11 xenograft model, treatment with HQP1351 or APG-115 single agents achieved T/C values of 28.6% and 59.6%, respectively. The combination achieved synergistic antitumor activity with a T/C value of 13.4%. The benefit of the combination was also demonstrated in systemic MOLM-13 xenograft model. Mechanistically, the combined treatment synergistically downregulated p-FLT3, p-ERK, p-STAT5 and anti-apoptotic protein MCL-1, and thus enhanced antitumor effect. Taken together, our data provide scientific rationale for clinical development of the combination of HQP1351 and APG-115 in FLT3-ITD mutant and TP53 wild-type AML patients. Citation Format: Douglas D. Fang, Qiuqiong Tang, Qixin Wang, Na Li, Xu Fang, Jiaxing Gu, Yanhui Kong, Tao Rong, Guangfeng Wang, Dajun Yang, Yifan Zhai. Synergy of tyrosine kinase inhibitor HQP1351 and MDM2-P53 antagonist, APG-115, in preclinical models of FLT3 mutant and TP53 wild-type acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4217.

Aim: Heart failure (HF) post-acute myocardial infarction (AMI) contributes to increasing mortality and morbidity worldwide. Baoyuan decoction (BYD) is a well-known traditional Chinese medicine formula that exhibits myocardial protection clinically. The aim of this study was to identify the effects of BYD on oxidative stress-induced apoptosis in HF post-AMI and characterize the underlying mechanism. Methods and Results: In our study, we constructed left anterior descending (LAD)-induced AMI rat models and a macrophage-conditioned media (CM)-induced H9C2 injury model. In vivo, BYD could protect cardiac functions, decrease inflammatory cell infiltration and inhibit oxidative stress-induced apoptosis. In vitro, BYD inhibited cellular apoptosis and regulated the expressions of key apoptotic molecules, including reducing the expression of B cell lymphoma-2 (Bcl-2) associated X protein (Bax) and cleaved caspase-3 and -9. Interestingly, the P38 mitogen-activated protein kinase (MAPK)-αB-crystallin (CRYAB) signaling pathway was activated by BYD treatment, and the P38 MAPK inhibitor SB203580 could reverse the protective effects of BYD. Conclusion: This study identified that BYD protected against oxidative stress-induced myocardial apoptosis via the P38 MAPK-CRYAB pathway. CRYAB may become a novel therapeutic target for AMI.

Localization is one of the fundamental tasks of Autonomous unmanned Vehicles (AuV) navigation systems [1]. In open space, Global Position System (GPS) can serve the localization need well. However, GPS is not always available in underwater environments due to high electromagnetic (EM) attenuation [2]. As a result, acoustic localization is more practical in the long range underwater context. Meanwhile, due to the wide availability of simple microphones and onboard clocks, Time of Arrival (ToA) based acoustic underwater localization algorithms is prevailing. Hence we shall focus on ToA based underwater acoustic localization.

Cyber-Physical Systems (CPS) integrate discrete-time computing and continuous-time physical-world entities, which are often wirelessly interlinked. The use of wireless safety-critical CPS requires safety guarantees despite communication faults. This paper focuses on one important set of such safety rules: Proper-Temporal-Embedding (PTE), where distributed CPS entities must enter/leave risky states according to properly nested temporal pattern and certain duration spacing. Our solution introduces hybrid automata to formally describe and analyze CPS design patterns. We propose a novel leasing based design pattern, along with closed-form configuration constraints, to guarantee PTE safety rules under arbitrary wireless communication faults. We propose a formal procedure to transform the design pattern hybrid automata into specific wireless CPS designs. This procedure can effectively isolate physical world parameters from affecting the PTE safety of the resultant specific designs. We conduct two wireless CPS case studies, one on medicine and the other on control, to show that the resulted system is safe against communication failures. We also compare our approach with a polling based approach. Both approaches support PTE under arbitrary communication failures. The polling approach performs better under severely adverse wireless medium conditions; while ours performs better under benign or moderately adverse wireless medium conditions.

A wireless electrocardiogram case study suggests that current CDMA2000 cellular technology has considerable potential in medical telemetry. Modifications to the network protocol stack ensure the highest data integrity and lowest service delay.

The charging power supply for batteries may be variable under many circumstances, e.g., when using solar panels or air-driven generators as the energy source. The mismatch between the voltages of the power supply and the battery may cause significant charging inefficiency. In this paper, we use reconfigurable batteries to solve this voltage mismatch problem. We develop algorithms to dynamically decide the battery connections, to both minimize the voltage mismatch and maintain SOC balancing among difference batteries. We build a hardware prototype to implement and validate our method and use simulation experiments to empirically evaluate its performance.

Aims Upregulation of heme oxygenase (HO)-1 plays an important role in vascular protection. Valsartan attenuates neointimal hyperplasia in animal studies. The objective of this study was to examine the role of HO-1 and angiotensin II type 1 (AT 1 ) receptor in the action of valsartan on neointimal hyperplasia in balloon-injured rat aortic arteries. Main methods Thirty-six male Wistar rats were randomly divided into the following three groups with twelve rats in each group: control group, surgery (model) group, and valsartan group. Aortic balloon injury was performed to elicit endothelial denudation with a 2F balloon catheter. On days 14 and 28 after injury, blood was harvested to measure bilirubin levels. Aortic arteries were harvested for morphometry analysis, to determine angiotensin II (Ang II) level, and to analyze mRNA or protein expression. Key findings Compared with the control group, proliferation and intimal thickening of vascular smooth muscle cells (VSMCs) were obvious in the surgery group rats on days 14 and 28 after injury. Valsartan significantly reduced the proliferation and intimal thickening. Additionally, pretreatment with valsartan significantly reduced Ang II levels, AT 1 receptor, and p38 mitogen-activated protein kinase (MAPK) expression. Valsartan increased HO-1 protein and mRNA expression, as well as increased serum bilirubin levels compared with the surgery group. Significance Valsartan treatment decreased neointimal hyperplasia in balloon-injured rats. The mechanism of action might be linked to the upregulation of HO-1, downregulation of AT 1 receptor and inhibition of p38MAPK signal pathway.

The aim of the study was to evaluate the clinical efficacy of hydrogen sulfide (H2S) treatment on the endothelin-induced cardiac hypertrophy. Sixty-four adult male rats, weighing from 180 to 200 g, were randomly divided into four groups: ten in normal group, ten in sham group, 44 in model group established by inducing the myocardial hypertrophy with endothelin. The myocardial hypertrophy model rats were randomly divided into two groups: 22 in the simple myocardial hypertrophy model group and 22 in the H2S treatment group. Rats in normal group were given 2 ml pure water by gavage per day, those in the sham group and simple cardiac hypertrophy model group were given 2 ml of saline by gavage per day, and rats in the pure cardiac hypertrophy with H2S treatment were given intraperitoneal injections of 2 ml NaHS saline per day for a period of 4 weeks. Left ventricular mass index, myocyte hypertrophy, volume fraction of myocardial interstitial collagen, myocardial hydroxyproline content and other indicators of cardiac hypertrophy were observed after 4 weeks. (1) There were significant differences on the ventricular mass between the treatment group and the cardiac hypertrophy group: The left ventricular mass decreased 21.4 % and the left ventricular mass index decreased 5.97 % (P < 0.05; (2) the smallest cardiomyocytes diameter and cardiomyocytes cross-sectional area decreased 12.5 and 10.8 %, respectively (P < 0.05) in the treatment group compared to the cardiac hypertrophy group; (3) the volume fraction of myocardial interstitial collagen and the myocardial hydroxyproline content decreased 22.3 and 31.3 % in treatment group compared with the cardiac hypertrophy group, respectively (P < 0.05). H2S had a good clinical efficacy in reducing left ventricular mass fraction and myocardial collagen levels, improving myocardial hypertrophy and decrease myocardial fibrosis. It is worthy for further clinical studies.

Wireless side monitoring employing distributed sniffers has been shown to complement wired side monitoring using Simple Network Management Protocol (SNMP) and base station logs, since it reveals detailed PHY and MAC behaviors, as well as timing information. Due to hardware limitations, wireless sniffers typically can only collect information on one channel at a time. Distributed algorithms are desirable to determine the optimal channel allocation of sniffer nodes to maximize the information collected. In this paper, we propose Gibbs sampler based algorithms for robust distributed monitoring of multi-channel wireless networks. Among several variants of the base Gibbs sampling approach, we find that most algorithms suffer from high sensitivity to parameter selection. In contrast, Gibbs sampling using a thermodynamic schedule is self-tuned and can adapt to different network configurations. Simulation studies show that the proposed algorithms can achieve faster convergence rate and have higher chance of reaching global optima than traditional Gibbs sampler algorithm.

ZigBee and other wireless technologies operating in the (2.4GHz) ISM band are being applied in Wireless Personal Area Networks (WPAN) for many medical applications. However, these low duty cycle, low power, and low data rate medical WPANs suffer from WiFi co-channel interferences. WiFi interference can lead to longer latency and higher packet losses in WPANs, which can be particularly harmful to safety-critical applications with stringent temporal requirements, such as ElectroCardioGraphy (ECG). This paper exploits the Clear Channel Assessment (CCA) mechanism in WiFi devices and proposes a novel policing framework, WiCop, that can effectively control the temporal white-spaces between WiFi transmissions. Such temporal white-spaces can be utilized for delivering low duty cycle WPAN traffic. We have implemented and validated WiCop on SORA, a software-defined radio platform. Experimental results show that with the assistance of the proposed WiCop policing schemes, the packet reception rate of a ZigBee-based WPAN can increase by up to 116% in the presence of a heavy WiFi interferer. A case study on the medical application of WPAN ECG monitoring demonstrates that WiCop can bound ECG signal distortion within 2% even under heavy WiFi interference. An analytical framework is devised to model the CCA behavior of WiFi interferers and the performance of WPANs under WiFi interference with or without WiCop protection. The analytical results are corroborated by experiments.

Blockade of the checkpoint inhibitor programmed death 1 (PD-1) has gained big success in cancer therapy. However, the response rate of anti-PD1 agents remains low. Molecularly targeted agents offer selectivity and high tumor response rates, but patients develop resistance to these drugs inevitably. Combinations of targeted agents and immunotherapy provide new opportunities to improve cancer treatments. Recent studies found that p53 activation in the myeloid linage suppressed alternative (M2) macrophage polarization and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may further augment antitumor immunity elicited by anti-PD-1 therapy. APG-115 is an orally active, selective, small molecule inhibitor of the MDM2-p53 protein-protein interaction. APG-115 acts as an antitumor agent by activating the p53 tumor suppressor in p53 wild-type tumors. However, its role in regulating immune responses remained unknown. In this study, we investigated the role of APG-115 in immune modulation both in vitro and in vivo. Enhanced antitumor activity was first demonstrated in p53 wild-type MH-22A, p53 mutant MC38, and p53 knockout (p53-/-) MH-22A syngeneic tumor models after the combination treatment of APG-115 and anti-PD-1 antibody. Despite differential changes in tumor-infiltrating leukocytes, including an increase in cytotoxic CD8+ T cells in the p53 wild-type tumors and an increase in proinflammatory M1 macrophages in the p53 mutant tumors, the combination treatment consistently reduced immunosuppressive M2 macrophages in the tumor microenvironment regardless of p53 status of tumor cells. In addition, in vitro, the treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21 gene expression, as well as a decrease in M2 macrophages population and reduction of c-MYC and M2-related gene expression. Moreover, enhanced M1 macrophage polarization in the spleen was also observed in naïve mice treated with APG-115. Furthermore, APG-115 increased production of multiple proinflammatory cytokines, including IFN-γ, TNF-α, IL-2 and IL-6, in stimulated T cells. Collectively, for the first time, our findings suggest that p53 activation by a pharmacological MDM2 inhibitor enables reversal of immunosuppressive tumor microenvironment and enhance antitumor immunity independently of p53 status of tumors. Specifically, in complementary to PD-1 blockade that predominantly activates cytotoxic CD8+ T cell populations, APG-115 primarily targets tumor-associated macrophages. Collectively, our data provide a rationale for applying the combination of APG-115 plus PD-1 blockade to a broader patient population with p53 mutant tumors. Accordingly, a clinical trial of APG-115 in combination with pembrolizumab in metastatic melanoma patients regardless of p53 status has been initiated in the USA. Citation Format: Douglas D. Fang, Qiuqiong Tang, Yanhui Kong, Qixin Wang, Jiaxing Gu, Xu Fang, Peng Zou, Tao Rong, Jingwen Wang, Dajun Yang, Yifan Zhai. Activation of p53 in the tumor microenvironment by MDM2 inhibitor APG-115 synergizes with PD-1 blockade independently of p53 status of tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3192.