Search

Medical practitioners generally rely on multimodal brain images, for example based on the information from the axial, coronal, and sagittal views, to inform brain tumor diagnosis. Hence, to further utilize the 3D information embedded in such datasets, this paper proposes a multi-view dynamic fusion framework (hereafter, referred to as MVFusFra) to improve the performance of brain tumor segmentation. The proposed framework consists of the following three key building blocks. First, a multi-view deep neural network architecture, which represents multi learning networks for segmenting the brain tumor from different views and each deep neural network corresponds to multi-modal brain images from one single view. Second, the dynamic decision fusion method, which is mainly used to fuse segmentation results from multi-views into an integrated method. Then, two different fusion methods (i.e., voting and weighted averaging) are used to evaluate the fusing process. Third, the multi-view fusion loss (comprising segmentation loss, transition loss, and decision loss) is proposed to facilitate the training process of multi-view learning networks, so as to ensure consistency in appearance and space, for both fusing segmentation results and the training of the learning network. We evaluate the performance of MVFusFra on the BRATS 2015 and BRATS 2018 datasets. Findings from the evaluations suggest that fusion results from multi-views achieve better performance than segmentation results from the single view, and also implying effectiveness of the proposed multi-view fusion loss. A comparative summary also shows that MVFusFra achieves better segmentation performance, in terms of efficiency, in comparison to other competing approaches.

With the development of the cloud computing market, cloud computing providers are offering to their users the flexibility to choose the desired capacity of both processing and data transfer (bandwidth) to use during the execution of their applications. The selected processing capacity can be shared among the number of virtual machines (VMs) that are capable of completing the user’s application within optimal time. During the execution of the users’ application, each task is scheduled on the VM that is capable of minimizing its execution time. However, the tasks are interdependent which means that the execution delay of a parent task will lead to the delay of its dependent tasks. The Bandwidth can be used to reduce the waiting time and avoid this delay of the dependent task. The execution time of the user’s application depends on some factors such as tasks’ priority, application’s structure, size, and the number of the VM selected to share the selected processing capacity. Determining the number of VM to share the users’ selected capacities under users’ specified quality of services remains a big challenge. Determining the number of VM to share the users selected processing capacity has been studied in our previous paper, where makespan idle-time was given the same weight. In this paper, we extended our previous work by adding the bandwidth capacity to the user’s selection and use CRITIC a multi-criteria decision-making technique to determine the weight of each criterion. The evaluation results show that the proposed heuristic can work well under different parameter settings.

Mite-borne diseases, such as scrub typhus and hemorrhagic fever with renal syndrome, present an increasing global public health concern. Most of the mite-borne diseases are caused by the blood-sucking mites. To present a comprehensive understanding of the distributions and diversity of blood-sucking mites in China, we derived information from peer-reviewed journal articles, thesis publications and books related to mites in both Chinese and English between 1978 and 2020. Geographic information of blood-sucking mites’ occurrence and mite species were extracted and georeferenced at the county level. Standard operating procedures were applied to remove duplicates and ensure accuracy of the data. This dataset contains 6,443 records of mite species occurrences at the county level in China. This geographical dataset provides an overview of the species diversity and wide distributions of blood-sucking mites, and can potentially be used in distribution prediction of mite species and risk assessment of mite-borne diseases in China., Measurement(s) Distribution Technology Type(s) digital curation • Geographic Information System Factor Type(s) genus • species • province • city • county • GPS Sample Characteristic - Organism mite • Acari Sample Characteristic - Location China Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.14459055

A reliable 235U enrichment uniformity detection system based on a compact D-D neutron generator is developed to detect the 235U enrichment uniformity of different fuel elements in the same nuclear fuel rod. The high-yield compact D-D neutron generator provides 2.45 MeV D-D neutrons, decelerated by a moderator to thermal neutrons or epithermal neutrons, thereby inducing 235U fission to produce highly excited state fission fragments that undergo de-excitation via γ-ray emission. The system detects the 235U enrichment uniformity of a nuclear fuel rod by measuring γ-rays and establishing a relationship between the γ-ray count rate and 235U enrichment in nuclear fuel. The proposed system yields a confidence probability of 99.99% for a relative 235U enrichment deviation of 10% and a neutron yield of 5 × 108 n/s, and the detection accuracy increases with increasing neutron yield. Furthermore, the developed system can satisfy quality control requirements for nuclear fuel production to promote the safe development of nuclear power.

Here, evodiamine (EVO) and the photosensitizer indocyanine green (ICG) were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma (OSCC). EVO, as an active component extracted from traditional Chinese medicine, not only functioned as an antitumor chemotherapeutic agent but was also capable of 68Ga-chelation, thus working as a contrast agent for positron emission tomography/computed tomography (PET/CT) imaging. Moreover, EVO could exhibit peroxidase-like catalytic activity, converting endogenous tumor H2O2 into cytotoxic reactive oxygen species (ROS), enabling Chemo catalytic therapy beyond the well-known chemotherapy effect of EVO. As proven by in vitro and in vivo experiments, guided by optical imaging and PET/CT imaging, we show that the theragnostic liposomes have a significant inhibiting effect on in situ tongue tumor through photodynamic therapy combined with chemodynamic chemotherapy., Graphical abstract Image 1, Highlights • Proposing water-soluble nanoliposomes to solve the problem of drug insoluble in water. • Evodiamine is found to have HRP mimic catalase activity. • EI@lipo displays photodynamic/chemodynamic/chemo therapy abilities. • Ei@Lipo significantly inhibits tongue tumor through in situ.

Lili Wu,1 Guiyu Lei,1 Ying Liu,2 Zheng Wei,1 Yue Yin,1 Yanru Li,3 Guyan Wang1 1Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Operating Room, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Key Laboratory of Otolaryngology, Head and Neck Surgery (Ministry of Education of China), Beijing, People’s Republic of ChinaCorrespondence: Guyan WangDepartment of Anesthesiology, Beijng Tongren Hospital, Capital Medical University, Beijing, People’s Republic of ChinaTel +8613910985139Email guyanwang2006@163.comPurpose: Current data on the occurrence of EFBs in relation to different time periods are scant. The purpose of this study was to compare the occurrence, type and location of EFBs in people who presented at our center on weekdays, weekends and holidays.Patients and Methods: A retrospective analysis of patients (n=1353) received rigid esophagoscopy for foreign body extraction under general anesthesia from January 2018 to 2020 December.Results: The occurrence of EFB ingestion was significantly higher (p< 0.05) on holidays (2.75/day) than on weekdays (0.91/day) and weekends (1.46/day). Patients were much older on holidays, with a mean age of 58.18 ± 17.34 years, than patients on weekdays (54.71 ± 16.71 years) and weekends (55.05 ± 17.36 years).Conclusion: Our findings demonstrate that EFB ingestion is most likely to occur on weekends and holidays, and elderly patients should be advised to chewing slowly and eating non-nuclear jujube, especially during holidays, to minimize their risk.Keywords: esophageal foreign body, weekday, weekend, holiday

BackgroundSeasonal influenza imposes a significant clinical and economic burden, yet vaccine coverage remains low in China due to possible influenza vaccine hesitancy (IVH) and practical issues. We sought to investigate IVH and its determinants among children’s guardians and the elderly for better understanding of the situation and for future intervention.MethodsIVH scales for the guardians and elderly were designed. We then performed two cross-sectional studies to identify the profiles and determinants of IVH using stratified cluster random sampling in an eastern China province in 2019.ResultsOf the 1,564 guardians and 522 elders, 43.2% (95% confidence interval: 40.4–46.0%) of guardians and 33.5% of elders (95% confidence interval: 29.5–37.6%) had IVH, whereas 31.3% of the guardians and 5.5% of the elderly had Influenza vaccine demand. The scales were well structured (KMO: 0.736 and 0.682; Cronbach’s α: 0.638 and 0.611). ‘From rural area’ (Odds ratio: 1.36), ‘don’t know government recommendation for flu vaccination’ (1.39), ‘don’t know flu vaccine is vaccinated annually’ (1.93), ‘family members (0.22), friends and neighbors had positive attitude toward flu vaccine’(0.58) were related factors of the guardians’ IVH. ‘Aged 70–79 years’ (0.46), ‘had flu before’ (0.35) and ‘once had been vaccinated’ (0.42) were related to the elderly’s IVH.ConclusionPoor awareness of influenza and vaccination, relatives’ negative/positive attitude, lack of government recommendations, anxiety about vaccine quality, and practical issues such as short supply are related to IVH in China. Precision education aiming hesitancy in wider groups are anticipated to increase vaccine confidence and coverage in influenza-vulnerable groups.

To quickly isolate suspected cases to control the epidemics, this study proposes a body temperature monitoring system with a thermography based on the Internet of Things (IoT) architecture. The collected data are transmitted to a back-end platform via wireless communication. Using the analyzed data, the platform provides services, such as instant alerts for any anomalies, infectious disease outbreak prediction, and risk level assessment for a given area, and it will be a great help to epidemic prevention. The mean absolute percentage error and root mean square error of the proposed monitoring system under an extensive series of experiments are 0.04% and 0.0204°C, respectively. It shows that the body temperature measured by the thermal imaging sensor in the system can accurately represent the actual body temperature after specific calibrations that take the environmental temperature into account. It can also be expanded to a decision supporting system to help schools or government agencies to make proper decisions to stop the spread of infectious diseases.

Background: Data on the efficacy and safety of balloon pulmonary angioplasty (BPA) in Taiwanese patients with chronic thromboembolic pulmonary hypertension (CTEPH) are lacking. In this study, we evaluated the effects of BPA on clinical parameters including hemodynamics, echocardiography and functional status in patients with inoperable CTEPH in Taiwan. Methods: We retrospectively collected the clinical data of inoperable CTEPH patients who underwent ≥3 BPA sessions. Pulmonary hemodynamic parameters of right heart catheterization, echocardiography, 6-min walk distance and World Health Organization (WHO) functional class were collected and analyzed before and after BPA treatment. Results: A total of 59 BPA sessions were performed in 13 inoperable CTEPH patients. No periprocedural deaths or major complications requiring tracheal intubation with mechanical ventilation occurred. WHO functional class significantly improved in all 13 patients (P

AIM: To determine the etiologies, treatment modalities and visual outcomes of vitreous hemorrhage (VH; range from birth to 18y). METHODS: A total of 262 eyes from 210 patients between January 2010 and September 2016 were included. All children underwent an appropriate ocular and systemic examination. Data collected included demographics, clinical manifestations, details of the ocular and systemic examination, management details, final fundus anatomy and visual acuity (VA). RESULTS: The most common etiologies were non-traumatic VH (64.89%), most of which were due to retinopathy of prematurity (ROP; 37.10%); while traffic accidents, including 16 (21.00%) eyes, was the most common ocular traumas. Surgery, performed in 143 (54.58%) eyes, was the most common management modality. The initial mean baseline visual acuity was 2.77±0.21 logarithm of the minimal angle of resolution (logMAR) in children and adolescent with traumatic VH, which was significantly improved to 2.15±1.31 logMAR (P

Secondary fracture healing is a complex multi‐stage process in which the mechanical environment plays a key role. The use of an appropriate mechanical stimulation such as strain is conducive to tissue formation between fracture ends, thus aiding the healing process. However, if the strain is too large or too small, the biological behavior of the cells involved in bone healing will be affected, resulting in non‐union or delayed healing. In this review, we summarize the current state of knowledge regarding the effect of strain on cells that play a role in the fracture‐healing process. Overall, the related literature suggests that selection of an adequate strain promotes fracture healing through the stimulation of angiogenesis and osteogenesis, along with inhibition of osteoclast differentiation and bone resorption. However, standardized methods for the application of mechanical stimulation are lacking, and a unified consensus on the mechanism by which strain promotes cell differentiation has not yet been reached. These issues, therefore, deserve further investigation., This article summarizes the state of knowledge regarding the effect of strain on cells involved in the fracture‐healing process.

For patients with angiitis‐induced critical limb ischemia (AICLI), cell transplantation, such as purified CD34+ cells (PCCs) and peripheral blood mononuclear cells (PBMNCs), is gradually being used as a promising treatment. This was the first randomized single‐blinded noninferiority trial (number: {"type":"clinical-trial","attrs":{"text":"NCT 02089828","term_id":"NCT02089828"}}NCT 02089828) specifically designed to evaluate the therapeutic efficacies of the transplantation of PCCs vs those of PBMNCs for the treatment of AICLI. We aimed to compare the mid‐term safety and efficacy between the two groups and determine their respective advantages. From April 2014 to September 2019, 50 patients with AICLI were equally allocated to the two groups, except for 1 lost patient, 1 amputee, and 1 patient who died of heart disease. The other 47 patients completed the 36‐month follow‐up. The endpoints were as follows: major amputation‐free survival and total amputation‐free survival at 6 months, which were 96.0% and 84.0% in the PBMNCs group and 96.0% and 72.0% in the PCCs group, respectively. These rates remained stable at 12, 24, and 36 months. The PCCs group had a significant higher probability of rest pain relief than the PBMNCs group, whereas earlier significant improvements in the Rutherford classification were observed in the PBMNCs group. Accordingly, PCCs would be preferred for patients with significant pain, whereas PBMNCs may be a good option for patients with two or more critically ischemic limbs. Concerning cost‐effectiveness, PCCs are not more cost‐effective than PBMNCs. These outcomes require verification from long‐term trials involving larger numbers of patients.

Primary aldosteronism is the most common secondary endocrine form of hypertension and causes many cardiovascular injuries. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma. However, their impacts on left ventricular remodeling precluding the interference of age, sex, and blood pressure are still uncertain. We enrolled 184 aldosterone-producing adenoma patients who received adrenalectomy. Clinical, biochemical, and echocardiographic data were analyzed preoperatively and 1 year postoperatively. KCNJ5 gene sequencing of aldosterone-producing adenoma was performed. After propensity score matching for age, sex, body mass index, blood pressure, hypertension duration, and number of hypertensive medications, there were 60 patients in each group with and without KCNJ5 mutations. The mutation carriers had higher left ventricular mass index (LVMI) and inappropriately excessive LVMI (ieLVMI) and lower e′ than the noncarriers. After adrenalectomy, the mutation carriers had greater decreases in LVMI and ieLVMI than the noncarriers. In addition, only mutation carriers had a significant decrease in E/e′ after surgery. In multivariate analysis, baseline LVMI correlated with KCNJ5 mutations, the number of hypertensive medications, and systolic blood pressure. Baseline ieLVMI correlated with KCNJ5 mutations and the number of hypertensive medications. The regression of both LVMI and ieLVMI after surgery was mainly correlated with KCNJ5 mutations and changes in systolic blood pressure. Aldosterone-producing adenoma patients with KCNJ5 mutations had higher LVMI and ieLVMI and a greater regression of LVMI and ieLVMI after adrenalectomy than those without mutations. The patients with KCNJ5 mutations also benefited from adrenalectomy with regard to left ventricular diastolic function, whereas noncarriers did not.

Primary aldosteronism (PA) is a common cause of secondary hypertension and is associated with worse cardiovascular outcomes. The elevated aldosterone in PA leads to left ventricular (LV) remodeling and dysfunction. In recent decades, clinical studies have demonstrated worse LV remodeling including increased LV mass and cardiac fibrosis in patients with PA compared to patients with essential hypertension. Several mechanisms may explain the process of aldosterone-induced LV remodeling, including directly profibrotic and hypertrophic effects of aldosterone on myocardium, increased reactive oxygen species and profibrotic molecules, dysregulation of extracellular matrix metabolism, endothelium dysfunction and circulatory macrophages activation. LV remodeling causes LV diastolic and systolic dysfunction, which may consequently lead to clinical complications such as heart failure, atrial fibrillation, ischemic heart disease, and other vascular events. Adequate treatment with adrenalectomy or medical therapy can improve LV remodeling and dysfunction in PA patients. In this review, we discuss the mechanisms of aldosterone-induced LV remodeling and provide an up-to-date review of clinical research about LV remodeling-related heart structural changes, cardiac dysfunction, and their clinical impacts on patients with PA.

Atomically thin molybdenum disulfide (MoS2) is a promising semiconductor material for integrated flexible electronics due to its excellent mechanical, optical and electronic properties. However, the fabrication of large-scale MoS2-based flexible integrated circuits with high device density and performance remains a challenge. Here, we report the fabrication of transparent MoS2-based transistors and logic circuits on flexible substrates using four-inch wafer-scale MoS2 monolayers. Our approach uses a modified chemical vapour deposition process to grow wafer-scale monolayers with large grain sizes and gold/titanium/gold electrodes to create a contact resistance as low as 2.9 kΩ μm−1. The field-effect transistors are fabricated with a high device density (1,518 transistors per cm2) and yield (97%), and exhibit high on/off ratios (1010), current densities (~35 μA μm−1), mobilities (~55 cm2 V−1 s−1) and flexibility. We also use the approach to create various flexible integrated logic circuits: inverters, NOR gates, NAND gates, AND gates, static random access memories and five-stage ring oscillators. Wafer-scale monolayers of MoS2 can be used to create flexible transistors and circuits that exhibit on/off ratios of 1010, current densities of ~35 μA μm−1 and mobilities of ~55 cm2 V−1 s−1.

Two-dimensional molybdenum disulfide (MoS2) is an emergent semiconductor with great potential in next-generation scaled-up electronics, but the production of high-quality monolayer MoS2 wafers still remains a challenge. Here, we report an epitaxy route toward 4 in. monolayer MoS2 wafers with highly oriented and large domains on sapphire. Benefiting from a multisource design for our chemical vapor deposition setup and the optimization of the growth process, we successfully realized material uniformity across the entire 4 in. wafer and greater than 100 μm domain size on average. These monolayers exhibit the best electronic quality ever reported, as evidenced from our spectroscopic and transport characterizations. Our work moves a step closer to practical applications of monolayer MoS2.

Cerebral edema is a pathological hallmark of various central nervous system (CNS) insults, including traumatic brain injury (TBI) and excitotoxic injury such as stroke. Due to the rigidity of the skull, edema-induced increase of intracranial fluid significantly complicates severe CNS injuries by raising intracranial pressure and compromising perfusion. Mortality due to cerebral edema is high. With mortality rates up to 80% in severe cases of stroke, it is the leading cause of death within the first week. Similarly, cerebral edema is devastating for patients of TBI, accounting for up to 50% mortality. Currently, the available treatments for cerebral edema include hypothermia, osmotherapy, and surgery. However, these treatments only address the symptoms and often elicit adverse side effects, potentially in part due to non-specificity. There is an urgent need to identify effective pharmacological treatments for cerebral edema. Currently, ion channels represent the third-largest target class for drug development, but their roles in cerebral edema remain ill-defined. The present review aims to provide an overview of the proposed roles of ion channels and transporters (including aquaporins, SUR1-TRPM4, chloride channels, glucose transporters, and proton-sensitive channels) in mediating cerebral edema in acute ischemic stroke and TBI. We also focus on the pharmacological inhibitors for each target and potential therapeutic strategies that may be further pursued for the treatment of cerebral edema.

The CsI detectors of the High Energy X-ray Telescope of the Hard X-ray Modulation Telescope (HXMT/CsI) can be used for gamma-ray all sky monitoring and searching for the electromagnetic counterpart of gravitational wave source. The instrumental responses are mainly obtained by Monte Carlo simulation with the Geant4 tool and the mass model of both the satellite and all the payloads, which is updated and tested with the Crab pulse emission in various incident directions. Both the Energy-Channel relationship and the energy resolution are calibrated in two working modes (Normal-Gain mode & Low-Gain Mode) with the different detection energy ranges. The simulative spectral analyses show that HXMT/CsI can constrain the spectral parameters much better in the high energy band than that in the low energy band. The joint spectral analyses are performed to ten bright GRBs observed simultaneously with HXMT/CsI and other instruments (Fermi/GBM, Swift/BAT, Konus-Wind), and the results show that the GRB flux given by HXMT/CsI is systematically higher by 7.0 ± 8.8 % than those given by the other instruments. The HXMT/CsI-Fermi/GBM joint fittings also show that the high energy spectral parameter can be constrained much better as the HXMT/CsI data are used in the joint fittings.

Purpose To clarify the role of different cytokines and selenite in the defective necroptotic pathway of chronic lymphocytic leukemia (CLL). Patients and methods We randomly collected the peripheral blood samples of 11 untreated CLL patients and 10 healthy volunteers, and then separated B lymphocytes from peripheral blood. Then, real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA) and Western Blot were performed to detect the expression of different cytokines, including CXC-motif chemokine ligand 1 (CXCL-1). Finally, we used flow cytometry to analyze the percentage of surviving cells to figure out whether CLL cells or normal B lymphocytes underwent necroptosis. Results 1) The high expression of CXCL-1 was seen in CLL cells compared with normal B lymphocytes (p = 0.0001, adjusted p =0.0012); 2) The downregulation of CXCL-1 was shown in normal B lymphocytes after induction by TNF-α and z-VAD; 3) CLL cells could restore necroptosis induced by TNF-α and z-VAD after knockdown of CXCL-1; 4) The transcriptional and translational expression of LEF-1 were downregulated after the knockdown of CXCL-1 in CLL cells; 5. 3.2μM selenite could help CLL cells restore necroptosis (p = 0.0102) and inhibit the transcriptional and translational expression of CXCL-1. Conclusion CXCL-1 played an important role in the defective necroptosis of CLL cells and regulated the expression of LEF-1. Selenite could inhibit the expression of CXCL-1 and help CLL cells restore necroptosis together with TNF-α and z-VAD. Selenite might be the potential medication of CLL in the future.

Growing evidence indicates that the development and progression of multiple complex diseases are influenced by microRNA (miRNA). Identifying more miRNAs as biomarkers for clinical diagnosis, treatment and prognosis is vital to promote the development of bioinformatics and medicine. Considering that the traditional biological experimental methods are generally time-consuming and expensive, high-efficient computational methods are encouraged to uncover potential disease-related miRNAs. In this paper, FCGCNMDA is presented to predict latent miRNA-disease associations by utilizing fully connected graph convolutional networks. Specially, our method first constructs a fully connected graph in which edge weights represent correlation coefficient between any two pairs of miRNA-disease pair, and then feeds this fully connected graph along with miRNA-disease pairs feature matrix into a two-layer graph convolutional networks (GCN) for training. At last, we utilize the trained network to predict the scores for unknown miRNA-disease pairs. As a result, FCGCNMDA achieves AUC value of [Formula: see text] and AUPRC value of [Formula: see text] in HMDD v2.0 based on five-fold cross validation. Moreover, case studies on Lymphoma, Breast Neoplasms and Prostate Neoplasms shown that 98%, 98%, 98% of the top 50 selected miRNAs were validated by recent experimental evidence. From above results, we can deduce that FCGCNMDA can be regarded as reliable method for potential miRNA-disease associations prediction.

Three high energy particle monitors (HPMs) employed onboard the Hard X-ray Modulation Telescope Insight-HXMT) can detect the charged particles from South Atlantic Anomaly (SAA) and hence provide the alert trigger for switch-on/off of the main detectors. Here a typical design of HPM with high stability and reliability is adopted by taking a plastic scintillator coupled with a small photomultiplier tube (PMT). The window threshold of HPM is designed as 1 MeV and 20 MeV for the incident electron and proton, respectively. Before the launch of Insight-HXMT, we performed in details the ground calibration of HPM. The measured energy response and its dependence on temperature are taken as essential input of Geant4 simulation for estimating the HPM count rate given with an incident particle energy spectrum. This serves as a guidance for choosing a reasonable working range of the PMT high voltage once the real SAA count rate is measured by HPM in orbit. So far the three HPMs have been working in orbit for more than two years. Apart from providing reliable alert trigger, the HPMs data are used as well to map the SAA region., Comment: 7 pages,15 figures

Primary aldosteronism (PA) is the most common cause of secondary hypertension. Increasing evidence has demonstrated an increased cardiovascular risk in patients with PA compared to those with essential hypertension (EH), including atrial fibrillation (AF), the most prevalent arrhythmia among adults that is associated with an elevated risk of subsequent cerebro-cardiovascular adverse events. The mechanisms of increased prevalence of AF in PA patients are complex. Excessive aldosterone production is regarded to be a key component in the pathogenesis of AF, in addition to arterial hypertension and electrolyte imbalance. In addition, several translational and clinical studies have reported that structural remodeling with atrial fibrosis and electrical remodeling with arrhythmogenicity induced by an excess of aldosterone also play major roles in AF genesis. Clinical studies from several registries and meta-analysis have reported an increased prevalence and risk of AF in PA patients compared to EH patients. Recent trials have further demonstrated a reduction in the risk of new-onset atrial fibrillation (NOAF) after adrenalectomy, while the results of medical treatment with mineralocorticoid receptor antagonists (MRAs) have been inconsistent. This review outlines the current evidence of the relationship between PA and AF, and highlights recent progress in the management of PA with regards to the development of AF.

The effects of super-Gaussian chirped laser pulse and inhomogeneity of plasma on space distribution and amplitude of wakefield are studied. The different super-Gaussian chirped laser pulse envelopes are used to strike the uniform and various inhomogeneous plasmas. The results show that compared with the unchirped laser pulse, the chirped laser pulse can enhance the wakefield generation, make the bubbles’ structure deformative seriously, reduce the numbers of bubbles in the same longitudinal distance, and enlarge the size of the wakefield bubbles. Besides, the stronger wakefield is generated in inhomogeneous plasma compared with a uniform one. Moreover, the characteristics of the wakefield can be controlled efficiently by the super-Gaussian pulse index. That is, the amplitude and spatial structure of the plasma wakefield can be modulated by the super-Gaussian chirped laser pulse and the inhomogeneity of the plasma.

PURPOSE Treatments that improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) have shown no benefits for those with heart failure with preserved ejection fraction (HFpEF). Our study aimed to investigate the effect of inhaled iloprost on myocardial performance during exercise in HFpEF. METHODS The study participants were enrolled from the ILO-HOPE trial (NCT03620526), a prospective randomized, double-blind, placebo-controlled study that was designed to investigate the effects of iloprost on cardiovascular hemodynamics during exercise in patients with HFpEF. Subjects were randomized 1:1 to inhalation of iloprost or placebo for 5 min. Two-dimensional transthoracic echocardiography with high temporal resolution was implemented to measure left ventricular (LV) longitudinal strain, LV diastolic function, and RV function both at rest and during supine exercise at 20-W workload. RESULTS LV global longitudinal strain (GLS) in response to exercise increased more in the iloprost group (LV GLS, -24.96 ± 1.20 vs -20.75 ± 3.00, P < 0.001). Iloprost also resulted in greater increment of LV GLS during exercise (ΔLV GLS, +6.02 ± 1.39 vs +3.44 ± 0.80, P < 0.001). Moreover, iloprost use was associated with enhancement of LV diastolic function, RV systolic function, and relief of pulmonary hypertension during exercise. CONCLUSIONS In patients with HFpEF, inhaled iloprost favorably improved myocardial performance during exercise by increasing LV GLS reserve, decreasing LV diastolic filling load, and reducing stress-induced pulmonary hypertension and thereby improving RV systolic function. Larger studies are needed to validate the result and long-term benefits of iloprost in patients with HFpEF.

Purpose Chemotherapy in head and neck squamous cell carcinoma (HNSCC) has many systemic side effects, as well as hypoxia-induced chemoresistance. To reduce side effects and enhance chemosensitivity are urgently needed. Methods We synthesized a drug delivery system (named CECMa NPs) based on cisplatin (CDDP) and metformin (chemotherapeutic sensitizer), of which chlorin e6 (Ce6) and polyethylene glycol diamine (PEG) were synthesized as the shell, an anti-LDLR antibody (which can target to hypoxic tumor cells) was modified on the surface to achieve tumor targeting. Results The NPs possessed a great synergistic effect of chemotherapy and phototherapy. After laser stimulation, both CDDP and metformin can be released in situ to achieve anti-tumor effects. Meanwhile, PDT and PTT triggered by a laser have anticancer effects. Furthermore, compared with free cisplatin, CECMa exhibits less systemic toxicity with laser irradiation in the xenograft mouse tumor model. Conclusion CECMa effectively destroyed the tumors via hypoxia targeting multimodal therapy both in vitro and in vivo, thereby providing a novel strategy for targeting head and neck squamous cell carcinoma.

Skeletal muscle is one of the major tissues in the body and is important for performing daily physical activity. Previous studies suggest that vascular dysfunction contributes to reduced skeletal muscle mass. However, the association between vascular dysfunction and muscle mass, muscle strength and muscle flexibility are less established. Therefore, the focus of this review was to investigate the association between arterial stiffness (AS) which is a marker of vascular function, and muscle indices among healthy and those with cardiovascular risk factors. Three databases were used to search for relevant studies. These keywords were used: “arterial stiffness” OR “vascular stiffness” OR “aortic stiffness” OR “pulse wave velocity” OR “carotid femoral pulse wave velocity” OR “pulse wave analysis” AND “muscle” OR “skeletal” OR “flexibility” OR “range of motion” OR “articular” OR “arthrometry” OR “strength” OR “hand strength” OR “pinch strength” OR “mass” OR “lean” OR “body composition.” The criteria were; (1) original, full-text articles, (2) articles written in English language, (3) human studies involving healthy adults and/or adults with cardiovascular disease (CVD) or CVD risk factors (4) articles that reported the relationship between AS (measured as carotid-femoral pulse wave velocity or brachial-ankle pulse wave velocity) and muscle indices (measured as muscle mass, muscle flexibility and muscle strength) after adjusting for relevant confounders. The search identified 2295 articles published between 1971 and June 2021. Only 17 articles fulfilled the criteria. Two studies showed an inverse association between AS and muscle strength in healthy subjects, whereas in subjects with CVD risk factors, five out of seven studies found an inverse correlation between the two parameters. Eleven studies showed an inverse association between AS and muscle mass in subjects with CVD and CVD risk factors. The association between AS and muscle flexibility was not studied in any of the articles reviewed. In conclusion, there is an inverse correlation between muscle indices and AS in healthy adults and those with CVD or CVD risk factors. However, most of the studies were cross-sectional studies, hence the need for future prospective studies to address this issue.

Due to the increase in computing power, it is possible to improve the feature extraction and data fitting capabilities of DNN networks by increasing their depth and model complexity. However, the big data and complex models greatly increase the training overhead of DNN, so accelerating their training process becomes a key task. The Tianhe-3 peak speed is designed to target E-class, and the huge computing power provides a potential opportunity for DNN training. We implement and extend LeNet, AlexNet, VGG, and ResNet model training for a single MT-2000+ and FT-2000+ compute nodes, as well as extended multi-node clusters, and propose an improved gradient synchronization process for Dynamic Allreduce communication optimization strategy for the gradient synchronization process base on the ARM architecture features of the Tianhe-3 prototype, providing experimental data and theoretical basis for further enhancing and improving the performance of the Tianhe-3 prototype in large-scale distributed training of neural networks.

Alcohol metabolism causes hepatocytes to release damage-associated molecular patterns (DAMPs). This includes mitochondrial DNA (mtDNA), which is generated and released from damaged hepatocytes and contributes to liver injury by producing proinflammatory cytokines. STING is a pattern recognition receptor of DAMPs known to control the induction of innate immunity in various pathological processes. However, the expression profile and functions of STING in the Gao binge ethanol model remain poorly understood. We demonstrated that STING is upregulated in the Gao binge ethanol model. STING functions as an mtDNA sensor in the Kupffer cells of the liver and induces STING-signaling pathway-dependent inflammation and further aggravates hepatocyte apoptosis in the Gao binge ethanol model. This study provides novel insights into predicting disease progression and developing targeted therapies for alcoholic liver injury.

Background: Epithelial ovarian cancer (EOC) is a disease with high morbidity and mortality worldwide, which is seriously harmful to female health. LncRNA has an important relationship with the occurrence and development of tumors. Hence, the investigation of the underlying mechanism between LncRNA and EOC is of great importance.Results: In this study, we found that LINC01503 was highly expressed in EOC with a poor prognosis based on microarray datasets GSE119056 and GSE135886 obtained from Gene Expression Omnibus (GEO) database, and this result was verified by RT-qPCR. The database lncBase Predicted v.2 and starBase v2.0 were used to predict the targeted relationship of lncRNA-miRNA-mRNA, then the ceRNA network was established by Cytoscape software. Following, the expression and overall survival (OS) analysis of key lncRNAs were analyzed by GEPIA and Kaplan-Meier plotter database. Gene Ontology (GO) functional enrichment analysis was performed by DAVID database and enriched two cancer related biological processes (BP) that response to endoplasmic reticulum stress and IRE1-mediated unfolded protein. Moreover, we verified that LINC01503 was an oncogene regulated by C-terminal binding protein 1 (CTBP1) to promote cell proliferation, migration and inhibited cell apoptosis in ovarian cancer. Conclusion: In conclusion, these results identified LINC01503 as a potential gene for EOC diagnosis and prognosis.

Primary aldosteronism (PA) is associated with higher arterial stiffness compared to essential hypertension (EH). However, few studies have compared different pulse wave velocity (PWV) parameters to detect aldosterone-induced arterial stiffness. In this study, we aimed to compare the sensitivity in detecting aldosterone-induced arterial stiffness between brachial-ankle PWV (baPWV) and heart-ankle PWV (haPWV). We prospectively enrolled 1006 PA patients and 983 EH patients. Detailed medical history, basic biochemistry data and two PWV measurements (baPWV and haPWV) were collected in both groups. We performed analysis on the original cohort and two propensity score matching (PSM) models (model 1 adjusted for age and sex, model 2 adjusted for age, sex, systolic and diastolic blood pressure). The DeLong test was used to compare areas under receiver operating characteristic curves (AUCs) between baPWV and haPWV to predict PA. In all models, the PA patients had significantly higher baPWV compared to the EH patients. The AUC of haPWV was greater than that of baPWV. In conclusion, haPWV seems to be a better PWV parameter than baPWV in detecting aldosterone-induced arterial stiffness.

Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.

Introduction Ultrasound sonography provides a quick method for determining which nodule to sample for fine needle aspiration biopsy in thyroid nodules. On the other hand, the computed tomography examination is not restricted by echo attenuation and distinguishes between benign and malignant nodules. Objective To compare computed tomography examinations against ultrasound/fine needle aspiration biopsy in the differential diagnosis of thyroid nodules. Methods Data regarding computed tomography examinations, sonographic finding following fine needle aspiration biopsy, and tumor histology of 953 nodules from 698 patients who underwent thyroidectomy were collected and analyzed. The beneficial score for detection of the malignant tumor for each adopted modality was evaluated. Results Ultrasound images did not show a well-circumscribed solid mass in 89 nodules, and ultimately did not detect nodules in fine needle aspiration biopsies (false positive non-malignant nodules). Ultrasound images showed parenchymatous disease (false positive malignant nodules) in several nodules. Computed tomography examinations demonstrated higher difficulty in detection of malignant nodules of 1.0-2.0 cm size than ultrasound examination following fine needle aspiration biopsies; compared to tumor histological data, computed tomography examinations had a sensitivity of 0.879. Conclusion Computed tomography examinations are a more reliable method for differential diagnosis of thyroid nodules than ultrasound examinations followed by fine needle aspiration biopsy. Level of Evidence III. Resumo Introdução A ultrassonografia é um método rápido para determinar de qual nódulo se deve coletar uma amostra para biópsia por aspiração com agulha fina. Por outro lado, o exame de tomografia computadorizada não é restringido pela atenuação do eco e distingue entre nódulos benignos e malignos. Objetivo Comparar exames tomográficos versus biópsia por ultrassonografia/aspiração por agulha fina no diagnóstico diferencial de nódulos tireoidianos. Método Dados sobre exames tomográficos, achados ultrassonográficos após biópsia por aspiração com agulha fina e histologia tumoral de 953 nódulos de 698 pacientes submetidos à tireoidectomia foram coletados e analisados. O escore de benefício para detecção do tumor maligno para cada modalidade adotada foi avaliado. Resultados As imagens de ultrassom não mostraram uma lesão sólida bem circunscrita em 89 nódulos; e na análise final não foram detectados nódulos nas biópsias por aspiração com agulha fina (nódulos não malignos falsos positivos). As imagens ultrassonográficas mostraram doença parenquimatosa (nódulos malignos falsos positivos) em vários nódulos. Os exames de tomografia computadorizada apresentaram grandes dificuldades na detecção de nódulos malignos de 1,0-2,0 cm de tamanho em comparação com o exame de ultrassonografia após biópsias por aspiração com agulha fina; comparados aos dados histológicos do tumor, os exames de tomografia computadorizada apresentaram sensibilidade de 0,879. Conclusão Os exames de tomografia computadorizada são um método mais confiável para o diagnóstico diferencial de nódulos tireoidianos do que os exames de ultrassonografia, seguidos por biópsia por aspiração com agulha fina.

Simple Summary Primary aldosteronism (PA) is the most common form of secondary hypertension and induces various cardiovascular injuries. Aldosterone-producing adenoma (APA) is one of the major forms of PA. The occurrence of APA is closely correlated with somatic mutations, including KCNJ5. We described here the impact of KCNJ5 somatic mutations on arterial stiffness excluding the influence of age, sex, and blood pressure status. We found KCNJ5 mutation carriers had similar arterial stiffness before surgery, but greater improvement of arterial stiffness after adrenalectomy compared with non-carriers. Hence, APA patients with KCNJ5 mutations had a greater improvement in arterial stiffness after adrenalectomy than those without mutations. Abstract Primary aldosteronism is the most common form of secondary hypertension and induces various cardiovascular injuries. In aldosterone-producing adenoma (APA), the impact of KCNJ5 somatic mutations on arterial stiffness excluding the influence of confounding factors is uncertain. We enrolled 213 APA patients who were scheduled to undergo adrenalectomy. KCNJ5 gene sequencing of APA was performed. After propensity score matching (PSM) for age, sex, body mass index, blood pressure, number of hypertensive medications, and hypertension duration, there were 66 patients in each group with and without KCNJ5 mutations. The mutation carriers had a higher aldosterone level and lower log transformed brachial–ankle pulse wave velocity (baPWV) than the non-carriers before PSM, but no difference in log baPWV after PSM. One year after adrenalectomy, the mutation carriers had greater decreases in log plasma aldosterone concentration, log aldosterone–renin activity ratio, and log baPWV than the non-carriers after PSM. Only the mutation carriers had a significant decrease in log baPWV after surgery both before and after PSM. KCNJ5 mutations were not correlated with baseline baPWV after PSM but were significantly correlated with ∆baPWV after surgery both before and after PSM. Conclusively, APA patients with KCNJ5 mutations had a greater regression in arterial stiffness after adrenalectomy than those without mutations.

Considering the level of the existing acoustic Doppler wave and current measurement instrument, This paper designs a new acoustic Doppler wave and current measurement instrument, the new instrument adopts modular design, which combines the various modules to form an acoustic Doppler wave current measurement instrument, it can shorten the production cycle, improve production efficiency, and reduce design and production costs. Comparing the newly designed acoustic Doppler wave and current measurement instrument with Nortek instrument, the results show that the newly designed acoustic Doppler wave and current measurement instrument is highly consistent with Nortek instrument, the new designed instrument has good accuracy, stability and reliability.

Due to the exhaustion of fossil fuels and environmental degradation, biodiesel has attracted much attention as a new energy source. Currently, microwave reactors are used extensively for producing biodiesel. However, nonuniform heating of producing biodiesel in microwave reactors is a major problem. In order to solve the problem, a microwave reactor with an interlayer which can obviously improve the uniformity of microwave heating was designed. In this work, the heating efficiency and heating uniformity of the reactor were discussed from two aspects of waveguide position and interlayer thickness by means of multi-physical coupling calculation. According to the calculation results, the optimization model of a microwave reactor with an interlayer was obtained. Then, based on the above optimization model of a microwave reactor with an interlayer, a stirrer that can improve the heat transfer of the fluid material was introduced. The Maxwell equation, heat transfer equation, and flow equation were coupled by the multi-physical field simulation method to explore the influence of different factors of the stirrer on power consumption and heating uniformity. Through response surface analysis, it was found that the primary and secondary order of stirring factors affecting microwave heating uniformity was stirring speed > impeller diameter > bottom clearance, and there was an interaction between different factors. From the two aspects of stirring power consumption and heating uniformity, the best stirring effect was obtained.

Background: Worldwide medication error is a common problem and inappropriate use of medicinal drugs is a major issue of drug resistance. Self-medication is a main contributor to human pathogen resistance to certain antibiotics. This research aims to investigate the prevalence, perception and predictors of self-medication among students in a Malaysian University. Methods: A total number of 317 students were included in this study. This cross-sectional study was conducted from Feb-May 2018. A convenience sample was taken from medical and non-medical university students. The association between the independents factors and the prevalence of self-medication was analysed using binary logistic regression. Data was analysed using SPSS version 23. Results: Among the respondents, 39.1% of them had recently practiced self-medication. The most common reason for self-medication was due to convenience (50%) and the most common source of the medication is directly from pharmacies (46.4%). Commonly used medicines were analgesics (44.4%), cough and cold remedies (31.0%) and antibiotics (9.9%). The majority of students (46.0%) experienced sleepiness after self-medication. Overall, the participants scored a mean 8 out of 10 questions for knowledge assessments on self-medication. In the assessment of the participants’ attitude towards self-medications, the participants agreed with 4 of 5 statements that are against self-medication. The probability of self-medication was higher among medical students compare to non medical students (OR=2.039, P=0.025). In addition, students who are suffering from long term illness are at more risk of self medication (OR=5.190, P= 0.004). Conclusion: Selfmedication poses significant risk of toxicity upon misuse and proper selfmedication should be taught to all people through educational programs and better drug dispensing systems. Key words: Self-medication, Over the counter, Medical and non-medical.

High energy X-ray telescope (HE) is one of the three instruments of Insight-HXMT (Hard X-ray Modulation Telescope) payload. The HE detector (HED) array is composed of 18 actively NaI(Tl)/CsI(Na) phoswich scintillators with a total geometric area of ∼ 5100 cm 2 and cover the energy range 20∼250 keV. In this paper we describe the on-ground detector-level calibration campaigns and present the principal instrument properties of HEDs.

The strong physical effects of ultrasound can change the state of water in food. In order to study the effect of ultrasound on the microwave drying of apple slices, an ultrasonic online-assisted mi...

This paper presents the results of an experimental study on the lateral loading behavior of glulam frame-midply hybrid lateral systems. Such systems are composed of glulam post-and-beam frames and infill midply shear walls. Reversed cyclic tests of six full-scale glulam frame-midply hybrid systems and two bare post-and-beam frames were conducted. The initial lateral stiffness, lateral load-carrying capacity, ductility and hysteresis characteristics of the hybrid systems were investigated. The load sharing mechanism between the outer frame and the infill midply subsystems was evaluated. Test results show that the installation of the infill midply shear walls can bring great improvements in the lateral resistance and the energy dissipation to the bare post-and-beam frames. The outer post-and-beam frames are basically in elastic range and can effectively restrain the infill midply shear walls from suffering further severe damages. For this reason, the post-peak lateral resistances of the hybrid systems can keep no less than 70% of their own load-carrying capacities within 4.41% drift ratio, and there is no need to install hold-down connectors in the infill midply shear walls. The load-carrying capacity of frame-midply hybrid lateral system is at least 1.5 times that of comparable frame infilled with standard wood-frame shear wall.

Primary aldosteronism (PA) is hemodynamically independently associated with arterial wall stiffness as assessed by pulse wave velocity (PWV) compared with essential hypertension. Arterial wave reflection parameters derived from pulse wave analysis, such as forward and backward wave amplitudes (Pf and Pb), are promising vascular markers to predict cardiovascular outcomes in addition to PWV. These vascular parameters have never been studied in patients with PA before. In study part A, we prospectively enrolled 67 patients with PA and 132 patients with essential hypertension. In study part B, another 54 patients with PA were enrolled. Heart-carotid PWV was measured, and carotid pressure waveforms were recorded to calculate Pf, Pb, and augmentation index at baseline (part A and B) and 6 months after treatment (part B). The results showed that the patients with PA had significantly higher Pf ( P =0.001), Pb ( P =0.01), and PWV ( P =0.021) than the patients with essential hypertension. In univariate correlation analysis, both log Pf and Pb were significantly correlated with age, office blood pressure, serum potassium level, log PWV, and the presence of PA. However, only Pb was significantly correlated with log plasma renin activity and log aldosterone to renin ratio. In multivariate analysis, log Pf was significantly correlated with the presence of PA ( P =0.001), male sex, age, and mean arterial blood pressure. Pb was significantly correlated with the presence of PA ( P =0.031), age, and mean arterial pressure. Six months after treatment, Pf and Pb decreased significantly. In conclusion, the patients with PA had significantly increased wave reflections compared with the patients with essential hypertension. Our results provide clinical evidence of aldosterone-related extensive vascular dysfunction of the arterial system.

Emerging evidences show that microRNA (miRNA) plays an important role in many human complex diseases. However, considering the inherent time-consuming and expensive of traditional in vitro experiments, more and more attention has been paid to the development of efficient and feasible computational methods to predict the potential associations between miRNA and disease. In this work, we present a machine learning-based model called MLMDA for predicting the association of miRNAs and diseases. More specifically, we first use the k-mer sparse matrix to extract miRNA sequence information, and combine it with miRNA functional similarity, disease semantic similarity and Gaussian interaction profile kernel similarity information. Then, more representative features are extracted from them through deep auto-encoder neural network (AE). Finally, the random forest classifier is used to effectively predict potential miRNA–disease associations. The experimental results show that the MLMDA model achieves promising performance under fivefold cross validations with AUC values of 0.9172, which is higher than the methods using different classifiers or different feature combination methods mentioned in this paper. In addition, to further evaluate the prediction performance of MLMDA model, case studies are carried out with three Human complex diseases including Lymphoma, Lung Neoplasm, and Esophageal Neoplasms. As a result, 39, 37 and 36 out of the top 40 predicted miRNAs are confirmed by other miRNA–disease association databases. These prominent experimental results suggest that the MLMDA model could serve as a useful tool guiding the future experimental validation for those promising miRNA biomarker candidates. The source code and datasets explored in this work are available at http://220.171.34.3:81/ .

Since Xi Jinping placed poverty alleviation on the main agenda of the Chinese Communist Party (CCP), various means have been adopted to promote a more rational distribution of income in difficult-t...

As a new type of high-precision gear transmission mechanism, the transmission accuracy of the 2K-V reducer will be greatly affected by vibration. With the RV110E reducer as the research object, a three-dimensional model of the needle wheel is established. Using the finite element analysis software, the natural frequency and mode shape of the needle wheel are calculated, when it’s under the output condition, then compared with the calculated gear meshing frequency. It is found when the needle wheel is used as an output, the vibration frequency is within the gear meshing frequency range, which is easy to cause resonance, thereby affects the transmission precision of the whole machine. The part of the outer shell of the needle wheel and the oil seal of the skeleton is the weakest and prone to deformation. By adding 6 reinforcing ribs between the needle wheel flange and the outer casing, increasing the flange outer diameter at the same time, the natural frequency can be increased, the deformation concentrated region can be transferred to the outer casing and the reinforcing rib. The connected parts avoid resonance and increase the service life of the needle wheel.

Head and neck squamous cell carcinoma (HNSCC), a major histologic subtype of head and neck cancer, presents great mortality and morbidity worldwide. The aim of this study is to discover new potential biomarkers closely correlated with HNSCC progression. In this study, weighted gene co-expression network analysis was applied to construct a co-expression network, and the brown module was identified as the most correlated with HNSCC progression. Hub gene identification combined with survival analyses determined RHCG as a candidate biomarker for cancer progression and prognosis prediction. Further experimental results proved that RHCG was aberrantly downregulated in HNSCC tissues and cell lines. Moreover, decreased RHCG expression was shown to be associated with advanced stage and dismal prognosis in HNSCC patients. Functional assays revealed that RHCG could inhibit cell viability, clonogenicity, cell migration in vitro and suppress tumor formation in vivo. Further bioinformatics study demonstrated that DNA promoter hypermethylation of RHCG could lead to its downregulation and serve as potential prognostic maker in HNSCC. Our study reveals that RHCG acts as a tumor suppressor gene that plays a crucial role in inhibiting tumorigenicity and metastasis in HNSCC, which will shed light on the potential diagnostic and therapeutic strategies for HNSCC.

Tumor-associated macrophages (TAMs) play an important role in drug resistance in many tumors, including head and neck squamous cell carcinoma (HNSCC). However, how TAMs interact with HNSCC cells to induce drug resistance, especially under hypoxic conditions, is unclear. In this study, we investigated the mechanism of TAM-induced gefitinib resistance in HNSCC cells and sought for novel therapeutic strategies. The effects of hypoxia-treated HNSCC cells on the migration and polarization of macrophages were analyzed. Recombinant cytokine proteins and neutralizing antibodies were used as controls. In addition, we assessed the cytotoxic effects of gefitinib on HNSCC cells treated with M2-type macrophage conditioned medium, and carried out a cytokine antibody array analysis, thereby revealing the key factor CCL15. The relationship between serum CCL15 expression levels and prognosis in HNSCC patients was analyzed. In addition, we performed bioinformatic analyses to pursue the mechanisms of CCL15-induced gefitinib resistance. Finally, metformin was used to evaluate the sensitizing effects of gefitinib treatment on HNSCC cells in vitro and in vivo. We found that HNSCC cells recruited macrophages by secreting VEGF and polarized the macrophages to the M2 phenotype through IL-6. Conversely, we found that M2-type TAMs promoted HNSCC cell resistance to gefitinib through paracrine CCL15 signaling. The serum CCL15 levels in HNSCC patients showed a significant correlation with patient prognosis. Furthermore, we found that M2-type TAMs could suppress the sensitivity of HNSCC cells to gefitinib through the CCL15-CCR1-NF-κB pathway. In addition, we found that metformin not only inhibited CCL15 expression in M2-type TAMs enhanced by hypoxia, but also suppressed CCR1 surface expression in HNSCC cells. Encouragingly, we found that metformin sensitized HNSCC cells to gefitinib treatment in vitro and in vivo. Based on our data we conclude that we have identified a novel interaction between M2-type TAMs and HNSCC cells that contributes to gefitinib resistance. We also found that metformin inhibited the cross-talk between macrophages and tumor cells, thereby eliciting therapeutic effects both in vitro and in vivo.