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9065 Background: The presence of Tertiary Lymphoid Structures (TLS) in multiple cancer types has been recognized as a potential predictive biomarker for response to immune-checkpoint blockade. However, there is no standardized method to quantify their presence. In this context, Artificial Intelligence (AI)-based assessment of histology images may well contribute to improve reproducibility, accuracy and speed of TLS quantification. Methods: We developed an automated workflow for quantification of TLS on digitized H&E slides through A) pixel-level classification of tissue using supervised artificial neural networks model, B) object-level cell classification of candidate TLS regions, C) merging the two approaches for curation and validation of TLS versus non-TLS regions. 433 advanced stage non-small cell lung cancer (NSCLC) patients treated with first or subsequent line of anti-PD-(L)1 single agent at DFCI were included in this study. Results: TLS were detected in 37% (n = 161) of the patients H&E slides, with the highest score of 4.7 TLS per mm2 (interquartile range: Q1 = 0, Q2 = 0, Q3 = 0.03 TLS/mm2). TLS density (per mm2) was significantly higher in surgically resected (n = 246; TLSPOS= 49%) compared to bioptic samples (n = 187; TLSPOS= 21%). No association was observed between TLS and tumor mutational burden (TMB) or PD-L1 protein expression as continuous variables. Among clinically actionable mutations, EGFR (all subtypes) mutated patients (n = 38) had a significantly lower number of TLS compared to patients without EGFR mutations. Patients with ≥ 0.01 TLS/mm2 had a significantly higher objective response rate (32% vs 22%, p = 0.03), a significantly longer median progression-free survival (PFS, 4.8 vs 2.7 months, HR: 0.73, 95% CI: 0.59-0.90, p = 0.004), and a significantly improved median overall survival (OS, 16.5 vs 12.5 months, HR: 0.72, 95% CI: 0.57-0.92, p = 0.008). In multivariable analysis, after adjusting for PD-L1 (≥ vs < 50%), TMB (≥ vs < 10 mu/Mb), sex, age, ECOG score, smoking and line of treatment, TLS/mm2 (≥ vs < 0.01) levels were found to be an independent positive predictive factor for both PFS (HR:0.69, 95% CI: 0.54-0.88, p = 0.003) and OS (HR: 0.70, 95% CI: 0.52-0.93, p = 0.01). Conclusions: These findings suggest that TLS status is an independent predictor of immunotherapy effectiveness in NSCLC, with predictive value similar to that of PD-L1 expression and TMB. This novel AI system has potential for automated identification and quantification of the TLS on digital histopathological slides, and could be utilized in a standard pathology workflow with relative ease. These findings are currently being validated in other solid tumors and cohorts.

Objective Colorectal cancer is one of the most prevalent types of cancer worldwide. Right-sided and left-sided colorectal cancer (RCC and LCC) patients respond differently to treatment. We aimed to identify the different mutational profile between RCC and LCC and provided evidence for future precision therapy. Methods A total of 630 Chinese colorectal cancer patients, including 467 (74.1%) LCC and 163 (25.9%) RCC, were enrolled in this cohort. Both formalin-fixed paraffin-embedded tumor tissues and matching blood samples were collected and deep sequenced targeting 450 cancer genes for genomic alteration analysis. Tumor mutational burden was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher’s exact test. Results The most common mutated genes were TP53 (77.0%), APC (71.7%), KRAS (50.0%), SMAD4 (19.8%), PIK3CA (18.3%), FBXW7 (17.5%), TCF7L2 (12.5%), SOX9 (11.3%), LRP1B (10.8%), ARID1A (10.3%) and FAT4 (10.3%). The mutation frequencies of TP53 and APC in LCC were significantly higher than that of RCC, while the mutation frequency of PIK3CA was lower than that of RCC. Six gene fusions were specifically detected in RCC patients. Colorectal cancer sites were associated with gender (P = 4.15 × 10−5) and tumor differentiation (P = 0.059). In LCC, the gender-associated genes were FAT4, EP300, FAT1, LRP1, ARID1B, AR, FYN and TAF1, while in RCC, they were ARID1A, SMARCA4, LRP1 and GRIN2A. The mutations of 18 genes were associated with tumor differentiation (8 for LCC and 10 for RCC). High tumor mutational burden was more common in RCC. Our results implied more potential targeted drug therapy opportunities for RCC. Conclusion We describe the different molecular characteristics of LCC and RCC. Our result supported a better prognosis of RCC than LCC in Chinese colorectal cancer patients.

Lipopolysaccharide (LPS)-induced inflammatory microenvironment can enhance the dental follicle cells (DFCs) proliferation, differentiation, and adhesion abilities beneficial to periodontal regeneration, which possibly attributes the success to exosomes according to recent studies. This study aimed to investigate the therapeutic efficacy and underlying mechanisms of LPS-preconditioned DFC-derived small extracellular vesicles (sEVs), which enriched exosomes for periodontal regeneration in an inflammatory microenvironment. LPS preconditioning could significantly increase the secretion of sEVs derived from DFCs. Both LPS-preconditioned dental follicle cell-derived sEV (L-D-sEV) and DFC-derived sEV (D-sEV) promoted the proliferation of periodontal ligament cells from periodontitis (p-PDLCs) with a dose-dependent and saturable manner and also enhanced the migration and differentiation of p-PDLCs. Furthermore, L-D-sEV showed a modest benefit than D-sEV to promote p-PDLCs differentiation. In vivo, an L-D-sEV-loaded hydrogel applied in the treatment of periodontitis was beneficial to repair lost alveolar bone in the early stage of treatment and to maintain the level of alveolar bone in the late stage of treatment in experimental periodontitis rats, which could partly decrease the expression of the RANKL/OPG ratio. In conclusion, L-D-sEV was beneficial to p-PDLCs forming an integrity periodontal tissue. The biological injectable L-D-sEV-loaded hydrogel could be used as a treatment method for experimental periodontitis in rats, promoting periodontal tissue regeneration and providing a new alternative cell therapy method for periodontal tissue regeneration.

Technological advances in the semiconductor industry and the increasing demand and development of wearable medical systems have enabled the development of dedicated chips for complex electroencephalogram (EEG) signal processing with smart functions and artificial intelligence‐based detections/classifications. Around 10 million transistors are integrated into a 1 mm2 silicon wafer surface in the dedicated chip, making wearable EEG systems a powerful dedicated processor instead of a wireless raw data transceiver. The reduction of amplifiers and analog‐digital converters on the silicon surface makes it possible to place the analog front‐end circuits within a tiny packaged chip; therefore, enabling high‐count EEG acquisition channels. This article introduces and reviews the state‐of‐the‐art dedicated chip designs for EEG processing, particularly for wearable systems. Furthermore, the analog circuits and digital platforms are included, and the technical details of circuit topology and logic architecture are presented in detail.

Background: Next generation sequencing (NGS) and the according target-based precision therapy has shown promising efficacy in many tumors. Here we report the genomic characteristics of Chinese breast cancer to support the development of more precise treatment strategy. Methods: Formalin fixed, paraffin embedded (FFPE) tumor samples and matched peripheral blood samples of 220 Chinese cancer patients including 218 females and 2 males were collected for NGS-based 450-genes panel assay. Pathological subtypes included 104 HR+/HER2-, 30 HR-/HER2+, 44 HR+/HER2+ and 42 triple negative breast cancers (TNBC). Assessed genomic alterations included single base substitution, short and long insertions/deletion, copy number variation, gene fusion and rearrangement. MSK breast cancer data was obtained from cBioPortal for comparing the difference between Chinese and Western patients. Results: The top mutated genes were TP53 (88.1%), PIK3CA (26.2%) and PTEN (21.4%) in TNBC; ERBB2 (86.7%), TP53 (86.7%), CDK12 (80.0%) and PIK3CA (23.3%) in HR-/HER2+ patients; ERBB2 (75%), TP53 (61.4%), CDK12 (54.5%) and PIK3CA (45.5%) in HR+/HER2+ patients. In HR+/HER2- patients, the most frequently mutated genes was PIK3CA (49.0%), followed by TP53 (30.8%) and GATA3 (27.9%), whereas the frequency of PIK3CA and GATA3 mutation were lower (41.6% and 19%, respectively) in Western patients. Although Alpelisib was approved by FDA in PIK3CA mutated HR+/HER2- patients, we observed PIK3CA mutation frequency had no difference among four subtypes. In this cohort, patients with PIK3CA mutation were significantly elder than patient without PIK3CA mutation (50 vs 47 years old, p=0.006). The hotspot mutations of PIK3CA (E542X, E545X and H1047X) accounted for 79.8% of PIK3CA mutations (71/89). Gene fusion/rearrangement was observed in 26% patients, in which 4 patients had gene fusions. Gene variations in homologous recombination pathway were found in 27.7% of patients. Among the 11.4% of patients with BRCA1/2 mutations, 11 patients harbored germline mutations and 19 patients had somatic mutations. Rearrangement accounted for 35% in somatic BRCA1/2 mutations. In the patients with germline BRCA1/2 mutation, 6 were HR+/HER2- patients who have been approved to use Olaparib. Based on the usage of CDK4/6 inhibitor in HR+/HER2- patients, this 450-genes panel enabled us to find that 41.3% HR+/HER2- patients had genes variations are related to CDK4/6 inhibitor resistance (CCND1, 18.3%; FGFR1 17.3%; NF1, 7.7%; MDM2, 6.7%; ESR1, 6.7% and RB1, 1.9%). The median TMB was 4.3 Muts/Mb in the whole cohort and patients with KMT2C mutations had significantly higher TMB (5.5 vs 3.8 Muts/Mb, p=0.004). In addition, Chinese breast cancer patients had a significantly higher frequency of KMT2C mutations compared to western patients (11.4% vs 1.4%, p Citation Format: Ning Liao, Guochun Zhang, Bo Chen, Yulei Wang, Kai Li, Chongyang Ren, Hsiaopei Mok, Li Cao, Lingzhu Wen, Minghan Jia, Cheukfai Li, Liping Guo, Guangnan Wei, Jiali Lin, Jiangguo Lai, Honglin Guo, Wenjing Wang, Shiyue Zhang, Zhijian Song, Jian Wang, Hui Chen, Jinwei Hu, Weifeng Wang, Weiwei Shi, Kai Wang. Comprehensive genomic analysis of Chinese breast cancer and clinical application [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-07-03.

In this paper, we propose a novel deep CNN-based framework to improve object detection performance. First, we introduce the Class Aware Region Proposal Network (CARPN) to produce high quality region proposals by using a new strategy for anchor generation, and by training the network with both bounding boxes and category labels of the objects. Instead of learning a binary object/non-object classifier for generating region proposals, we assign the class label to each anchor, and train the region proposal network with a multi-class loss. Second, we introduce the Focused Attention (FA) objective to encourage the network to learn features mainly from objects of interest while suppressing those features from the background region. As a result, false positive proposals caused by strong background features can be reduced to a large extent. Comprehensive experimental evaluations reveal that the proposed CARPN & FA framework remarkably outperforms the baseline Faster R-CNN method up to 4.1% mAP with a shallower network and 2.8% mAP with a deeper network, and achieves a better mAP than most of the latest state-of-the-art methods.

This paper focuses on the Multi-Target Multi-Camera Tracking task (MTMCT), which aims at tracking multiple targets within a multi-camera network. As the trajectory of each target is inherently split into multiple sub-trajectories (namely local tracklets) in a multi-camera network, a major challenge of MTMCT is how to accurately match the local tracklets generated within each camera across different cameras and generate a complete global trajectory for each target, i.e. , the cross-camera tracklet matching problem. We solve the cross-camera tracklet matching problem by TRACklet-to-Target Assignment (TRACTA), and propose the Restricted Non-negative Matrix Factorization (RNMF) algorithm to compute the optimal assignment solution that meets a set of constraints, which should be in force in practice. TRACTA can correct the tracking errors caused by occlusions and missed detections in local tracklets, and produce a complete global trajectory for each target across all the cameras. Moreover, we also develop an analytical way of estimating the total number of targets in the camera network, which plays an important role to compute the tracklet-to-target assignment. Experimental evaluations and ablation studies on four MTMCT benchmark datasets show the superiority of the proposed TRACTA method.

Flexible solid-state supercapacitors have been considered one of the non-substitutable power supply devices for flexible and even wearable electronics. However, the highly capacitive behavior of carbon-based solid-state capacitors is restricted by the incompatible characteristics of the highly accessible surface area, efficient ion transport paths and superior electrical conductivity in carbonaceous electrodes. Herein, we propose a facile, effective strategy for the preparation of N/O dual-doped microporous carbon nanosheets (NMCNSs) with a 3D microstructure to solve the mutual competitiveness of necessary features for highly capacitive carbons. This strategy is a simple, template-free one-step heat-treatment process of organic salts, which combines the self-activation by the in situ formed activating agent to generate developed microporosity and the synergistic effect of gas blowing to hinder the aggregation of carbon sheets. The resulting NMCNSs exhibit an interconnected nonaggregated sheet-like morphology, a high surface area of 1900.5 m2 g−1 with an exceptionally large microporosity of 93%, and multiscale micropore systems with ultramicropores of 0.45–0.80 nm and supermicropores of 0.85–1.58 nm. The assembled NMCNS-based symmetric aqueous supercapacitors present a remarkable capacitive performance in KOH and Na2SO4 electrolytes. Meanwhile, we compare their electrochemical capacitive behaviors in various electrolytes and summarize a valuable reference for the potential application of NMCNS electrodes in different system supercapacitors. The constructed flexible NMCNS-based solid-state capacitors exhibit an excellent capacitive performance including high energy density, superb rate capability and outstanding long-term cycle stability. More importantly, the devices also possess an exceptional mechanical and thermal robustness, which can normally work under consecutive high bending cycles and at various ambient temperatures of 0–50 °C.

In this paper we deal with a system of partial differential equations describing a steady motion of an incompressible magnetohydrodynamic fluid, where the extra stress tensor is induced by a potential with $p$-structure ($p=2$ corresponds to the Newtonian case). By using a fixed point argument in an appropriate functional setting, we proved the existence and uniqueness of strong solutions for the problem in a smooth domain $\Omega\subset\mathbb{R}^{n}$ $(n=2,3)$ under the conditions that the external force is small in a suitable norm.

Digital instruments are widely used in industrial control, traffic, equipment displays and other fields because of the intuitive characteristic of their test data. Aiming at the character recognition scene of digital display Vernier caliper, this paper creatively proposes an intelligent instrument recognition system based on multi-step convolution neural network (CNN). Firstly, the image smples are collected from the Vernier caliper test site, and their resolution and size are normalized. Then the CNN model was established to train the image smples and extract the features. The digital display region in the image smples were extracted according to the image features, and the numbers in the Vernier caliper were cut out. Finally, using the MINIST datas set of Vernier caliper is established, and the CNN model is used to recognize it. The test results show that the overall recognition rate of the proposed CNN model is more than 95%, and has good robustness and generalization ability.

A bit-level object storage system is a foundational building block of long-term digital preservation (LTDP). To achieve the purposes of LTDP, the system must be able to: preserve the authenticity and integrity of the original digital objects; scale up with dramatically increasing demands for preservation storage; mitigate the impact of hardware obsolescence and software ephemerality; replicate digital objects among distributed data centers at different geographical locations; and to constantly audit and automatically recover from compromised states. A realistic and daunting challenge to satisfy these requirements is not only to overcome technological difficulties but also to maintain economic sustainability by implementing and continuously operating such systems in a cost-effective way. In this paper, we present OpenStack Swift, an open-source, mature and widely accepted cloud platform, as a practical and proven solution with a case study at the University of Alberta Library. We emphasize the implementation, application, cost analysis and maintenance of the system, with the purpose of contributing to the community with an exceedingly robust, highly scalable, self-healing and comparatively cost-effective bit-level object storage system for long-term digital preservation.

BACKGROUND Salt substitutes with reduced sodium levels and increased potassium levels have been shown to lower blood pressure, but their effects on cardiovascular and safety outcomes are uncertain. METHODS We conducted an open-label, cluster-randomized trial involving persons from 600 villages in rural China. The participants had a history of stroke or were 60 years of age or older and had high blood pressure. The villages were randomly assigned in a 1:1 ratio to the intervention group, in which the participants used a salt substitute (75% sodium chloride and 25% potassium chloride by mass), or to the control group, in which the participants continued to use regular salt (100% sodium chloride). The primary outcome was stroke, the secondary outcomes were major adverse cardiovascular events and death from any cause, and the safety outcome was clinical hyperkalemia. RESULTS A total of 20,995 persons were enrolled in the trial. The mean age of the participants was 65.4 years, and 49.5% were female, 72.6% had a history of stroke, and 88.4% a history of hypertension. The mean duration of follow-up was 4.74 years. The rate of stroke was lower with the salt substitute than with regular salt (29.14 events vs. 33.65 events per 1000 person-years; rate ratio, 0.86; 95% confidence interval [CI], 0.77 to 0.96; P=0.006), as were the rates of major cardiovascular events (49.09 events vs. 56.29 events per 1000 person-years; rate ratio, 0.87; 95% CI, 0.80 to 0.94; P

An iodine-catalyzed coupling of β-hydroxyketones with aromatic amines to yield β-aminoketones and benzo[h]quinolones had been developed. Noble metallic catalysts, oxidants, α, β-unsaturated ketone intermediates and aza-Michael addition were not involved in this coupling reaction which made it unique when compared to other reactions reported in literature. Inexpensive iodine catalyst, easy accessible raw materials, mild reaction conditions, good functional group tolerance and excellent selectivity made this coupling reaction be a practical method. This reaction can also be scaled up.

Background Lung adenocarcinoma in young adults is a rare entity with the oncogenic genetic alterations associated being poorly understood. In the present study, the effect of genetic alterations in lung adenocarcinoma patients diagnosed in young patients is reported. Methods Twenty young lung adenocarcinoma patients (age years: median: 33.5, range: 24‐36) were enrolled in the current study and 24 patients who were at common age of the disease onset (age years: median: 61.5, range: 52‐79) were selected for comparison. Paraffin sections of lung adenocarcinoma were analyzed using the whole‐exome sequencing platform. Results Similar number of somatic mutations per tumor were found in the young patients and their older counterparts. Although no age‐related differences were detected in the numbers of lung adenocarcinoma patients harboring well‐known gene variants, mutations in FRG1 and KMT2C were associated with a younger age especially after correcting for tobacco smoking and sex (FRG1: P = 0.027, KMT2C: P = 0.046). Five genetic variants showed higher alteration frequencies in young patients compared to the unclassified East Asian population, suggesting these mutations as disease‐related hereditary germline variants. Conclusions These results suggest different characteristics of lung adenocarcinoma between the young and the patients at common age of onset. Young patients with lung adenocarcinoma have a distinctly unique prevalence of oncogenic genetic alterations.

As major precursors of disinfection by-products (DBPs), soluble microbial products (SMPs) generated by sewage discharge can adversely affect drinking water quality. It is essential to understand the adsorption behaviours of SMPs onto sediments and the effect of DBPs formation. In this study, the adsorption ability of sediments was evaluated by adsorption isotherms with respect to temperature and salinity. Adsorption behaviours were investigated using X-ray photoelectron spectroscopy, electron microscopy analysis, and excitation emission matrix fluorescence analysis. Chlorination was also employed to explore the influence of sediment adsorption on drinking water quality. The results indicated that the maximum adsorption potential of sediments to SMPs was 1.60 mg/g, which involved exothermic processes. SMPs adsorption declined with increasing temperature and salinity, and fulvic acid and protein in SMPs were more readily adsorbed on sediments than was humic acid. Correlation analysis results indicated that adsorption behaviours of sediments to SMPs could significantly reduce the generation potential of DBPs (r = 0.882-0.938, p 0.01). In addition, the decrease of C-DBPs was considerably greater than that of N-DBPs. These research findings are of importance to assessments of the fate and transport of SMPs in water-sediment systems, as well as the effect of following DBPs formation in the drinking water supply.

Background: Several metabolic steps are mediated by distinct proteins or isoenzymes that catalyze the same reaction, providing redundancy of metabolic functions. Metabolic states are frequently altered in cancer to support survival and proliferation in hypoxic and otherwise hostile microenvironments, and metabolic re-wiring often involve loss of isoenzyme diversity. We hypothesize that targeting enzymes that have lost isoenzyme diversity in cancer, but not in normal cells, provides an opportunity to selectively target cancers. In this study, we assessed mRNA expression of all known human isoenzyme families in breast cancer and normal breast tissue and identified isoenzymes with loss of diversity within each breast cancer subtype. Methods: We obtained RNAseq data from cancer and patient-matched normal breast tissues from the TCGA (N=66 HR+, N=24 HER2+, and N=15 TNBC tumors). We retrieved annotated human isoenzyme families from the ENZYME nomenclature database. We compared expression in cancer and matched normal samples from the same patient to identify isoenzymes that had i) same or increased expression of the target isoenzyme in cancer vs normal and ii) reduced expression of the complementary isoenzymes in cancer. We developed five scores that capture various elements of these characteristics and prioritized candidates as targets based on clustering and their combined ranking based on the five scores. We validated overexpression of the candidate isoenzymes relative to other isoforms in breast cancer microarray data from ArrayExpress (E-GEOD-76250: 33 TNBC, and E-GEOD-70951: 30 TNBC, 108 HR+, 10 HER2+). Results: We identified 321 enzymes in the TCGA discovery cohort that correspond to 829 unique isoenzymes. Overall, 636, 483 and 429 isoenzymes were differentially expressed in HR+, HER2+ and TNBC cancers, respectively, compared to corresponding normal samples. Of these, 308 isoenzymes were differentially expressed relative to normal in all 3 subtypes. In all, 112 and 92, and 84 were selected as candidate isoenzyme therapeutic targets in HR+, HER2+ and TNBC, respectively. 23 isoenzymes prioritized in clustering step were further validated. Finally, 6 isoenzymes were validated in HR+ (ALDOA, GUSB, GYG1, MIF, P3H1, PCK2), 10 in HER2+ (ALDH1L2, ALDOA, GLYATL2, GUSB, GYG1, GYS1, MIF, P3H1, PCK2, PTGS1) and 12 in TNBC (ADSS, ALAS1, ALDH1L2, ALDOA, ART3, GLYATL2, GUSB, GYS1, HS3ST1, MIF, PCK2, SOAT1), as potential targets for breast cancer treatment. Of these, 5 potential isoenzyme targets (ALDH1L2, GUSB, GLYATL2, MIF, PCK2), which were mostly hydrolases and transferases, were further selected for ongoing experimental validation in the laboratory. Decreased expression of the complementary isoforms of these 5 targets were primarily due to DNA methylation of the genes in cancer. Conclusions: We found that loss of isoenzyme diversity is a broad phenomenon in breast cancers that may be explored therapeutically. We identified several instances of “isoenzyme addiction” in which cancers depend exclusively on a single isoenzyme while downregulating via methylation the complementary isoenzymes, providing cancer-specific targeting opportunities. We are currently validating several of these targets in cell line models. Citation Format: Marczyk M, Gunasekharan V, Wali VB, Shi W, Patwardhan G, Qing T, Pusztai L, Hatzis C. Targeting loss of isoenzyme diversity as a novel therapeutic strategy in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-06.

Glucocorticoid receptor (GR) is involved in the transcriptional regulation of genes that are important for various biological functions, including tumor growth and metastatic progression. However, the cellular and biological effects of GR remain poorly understood. Here, we investigated the role of GR and its underlying mechanism in mediating breast cancer cell survival and metastasis. We observed that the GR levels were increased in drug-resistant breast cancer cells and in metastatic breast cancer samples. GR promoted tumor cell invasion and lung metastasis in vivo. The GR expression levels were negatively correlated with the survival rates of breast cancer patients. Both ectopic expression and knockdown of GR revealed that GR is a strong inducer of epithelial-to-mesenchymal transition (EMT), which is consistent with its effects on cell survival and metastasis. GR suppressed the expression of insulin receptor substrate 1 (IRS-1) by acting as an IRS-1 transcriptional repressor. In addition, GR has an opposite effect on the expression levels of IRS-2, indicating that GR is able to differentially regulate the IRS-1 and IRS-2 expression. The cellular and biological effects elicited by GR were consistent with the reduced levels of IRS-1 observed in cancer cells, and GR-mediated IRS-1 suppression activated the ERK2 MAP kinase pathway, which is required for GR-mediated EMT. Taken together, our results indicate that GR–IRS-1 signaling axis plays an essential role in regulating the survival, invasion, and metastasis of breast cancer cells.

Poplar catkins are an environmental pollutant because they can trigger sneezing, shortness of breath, skin allergy and even cause forest fire. It is very attractive to discover ways for reducing the threats of poplar catkins to the environment and human health and even to convert poplar catkins into useful materials. Herein we report on a facile and cost-efficient strategy for the synthesis of hierarchical porous carbon microtubes using poplar catkins as the carbon source. The synthesis involves pre-carbonization and subsequent ZnCl2 activation. The resultant materials not only inherit the natural tubular morphology of poplar catkins, but also develop a hierarchical porous structure, with nitrogen from the biomass being self-doped in the resultant carbon skeleton. The hierarchical porosity, especially the microporosity with the pore size from 0.5 to 1 nm, surface structure, tube wall thickness and nitrogen content can be readily controlled by adjusting the activation temperature and the ZnCl2-to-precursor mass ratio. The produced materials exhibit an excellent CO2 capture capacity. The optimal sample activated at 800 °C with a ZnCl2-to-precursor mass ratio of 4:1 shows an extraordinarily high CO2 adsorption capacity of 6.22 and 4.05 mmol g−1 at 273 and 298 K, respectively, at 1 bar of CO2. Furthermore, the material also displays an excellent recyclability and CO2/N2 selectivity. Our approach not only relieves the environmental pollution of poplar catkins but also leads to the production of a high-performance CO2 adsorbent, which is promising for industrial CO2 capture and separation. It therefore demonstrates an example of trash-to-treasure transformation.

Crab shells derived from discarded seafood bio-waste, are a naturally abundant and sustainable resource, but their difficult solubility limits their processing and applications, resulting in severe environmental pollution. It is very attractive to discover approaches for reducing the threats of crab shells to the environment and even to convert crab shells into useful materials. Herein, we attempted to convert crab shells into three-dimensional (3D) honeycomb-like graphitized hierarchically porous carbons (GHPCs) by a convenient one-step carbonization process simultaneously combining catalytic graphitization and chemical activation routes. The removal of abundant inorganics from crab shells resulted in a unique honeycomb-like structure, and meanwhile a high doping concentration of N element was inherited in the framework of GHPCs. Furthermore, the simultaneous activation/graphitization treatment developed interconnected hierarchical porosity with a large accessible surface area and highly graphitized skeleton. Benefiting from these unique structural characteristics, GHPCs exhibited a remarkable capacitive performance as supercapacitor electrodes. The GHPC electrode delivered a high gravimetric capacitance of 367.4 F g−1 at 1 A g−1 in 6 M KOH electrolyte. More importantly, the electrode showed satisfactory rate capability where an extremely high current density of 100 A g−1 for charge–discharge operation was available in both KOH and Na2SO4 electrolytes. Furthermore, the assembled symmetric flexible all-solid-state capacitor exhibited a high energy density of 11.1 W h kg−1 and a power density of 100.5 W kg−1, as well as a good cycling stability of 90.8% capacitance retention after 10 000 cycles in a PVA/KOH gel electrolyte. Our approach not only relieved the environmental pollution caused by crab shells but also achieved the production of a high-performance supercapacitor electrode, which was promising for industrial energy conversion and storage. It therefore demonstrated an example of trash-to-treasure transformation.

Considering the characteristics of abundant narrow micropores of

Organically modified silica (ORMOSIL) nanoparticles (NPs) are widely used in biomedicine. However, their cell uptake process has not yet been characterised in detail. Here, we investigated the mechanism underlying endocytosis and subcellular localisation of ORMOSIL NPs. Exposure to ORMOSIL NPs induced a decrease in cell viability and increase in lactate dehydrogenase release in a dose-dependent manner in A549 cells. Once internalised, ORMOSIL NPs were translocated from early endosomes to the lysosomes, where they accumulated. Furthermore, deficiency of autophagosomal/lysosomal fusion failed to block lysosomal localisation of ORMOSIL NPs, suggesting that autophagy was not involved in the final lysosomal accumulation of ORMOSIL NPs. Meanwhile, an inhibitor of caveolae-mediated endocytosis, rather than inhibitors of phagocytosis or clathrin-mediated endocytosis, succeeded in blocking ORMOSIL NP cell uptake, indicating the involvement of caveolae-mediated endocytosis. Together, these results provide a new understanding of the toxicity, and suggest better biomedical applications, of ORMOSIL NPs.

We focus on the causes of fluctuations in wintertime PM10 in nine regional core cities of China using two machine learning models, Random Forest (RF) and Recurrent Neural Network (RNN). RF and RNN both show high performance in predicting hourly PM10 using only gaseous air pollutants (SO2, NO2 and CO) as inputs, showing the predominance of the secondary inorganic aerosol and implying the existence of thermodynamic equilibrium between gaseous air pollutants and PM10. Also, we find the following results. The correlation of gaseous air pollutants and PM10 were more relevant than that of meteorological conditions and PM10. CO was the predominant factor for PM10 in the Beijing-Tianjin-Hebei Plain and the Yangtze River Delta while SO2 and NO2 were also important features for PM10 in the Pearl River Delta and Sichuan Basin. The spatial heterogeneity and temporal homogeneity of PM10 in China are revealed. The long-range transported PM10 was substantiated to be insignificant, except in the sandstorms. The severity of PM10 was attributable to the lopsided shift of thermodynamic equilibrium and the phenology of indigenous flora.

The superior ultramicroporosity and enriched surface CO2-philic sites are simultaneously required features for high-efficiency carbon-based CO2 adsorbents. Unfortunately, these characteristics are usually incompatible and difficult to integrate into one porous carbon material. Herein, we report a new copper ions (Cu2+)-assisted dynamic porogen to construct hierarchically microporous carbon nanosheets in a large scale with high heterogeneity for solving such issue. Cu2+ can be equably dispersed in precursor by coordination interactions of COO-Cu and Cu-N, which can anchor more N/O-containing species in final product. The reduced cuprous ions (Cu+) in pyrolysis process functions as a dynamic porogen to tailor uniform ultramicropores. Importantly, copper salt extracted in this synthetic procedure allows cyclic utilization, realizing a green and low-cost process. The obtained carbon sheets possess a graphene-like morphology, a high surface area and a high-proportioned multiscale microporosity, especially a high-density ultramicropores of 0.4–0.7 nm and supermicroproes of 0.8–1.5 nm. The maximized synergistic effect of morphology, high density of multi-sized ultramicroporosity and surface high heterogeneity endow the resultant microporous carbon nanosheets with the remarkable CO2 capture property, including a high uptake, a moderate adsorption heat, a good selectivity and superior recyclability.

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Over 60-year clinical use of vancomycin led to the emergence of vancomycin-resistant bacteria and threatened our health. To combat vancomycin-resistant strains, numerous vancomycin analogues were developed, such as Telavancin, Oritavancin and Dalbavancin. Extra structures embedded on C-terminus has been proved to be an effective strategy to promote antibacterial activity of vancomycin against vancomycin-resistant strains. Here, we reported a facile strategy, inspired by native chemical ligation, for vancomycin C-terminus functionalization and derivatization. The introduction of C-terminal hydrazide on vancomycin not only provided us an accessible method for C-terminus functionalization through carbonyl azide and thioester, also acted as an efficient site for vancomycin structure modifications. Based on hydrazide-vancomycin, we effectively conjugated cysteine and cysteine containing peptides onto vancomycin C-terminus, and two fluorescent FITC-vancomycin were prepared through Cys-Maleimide conjugation. Meanwhile, we introduced lipophilic structures onto vancomycin C-terminus via the hydrazide moiety. The obtained vancomycin derivatives were evaluated against both Gram-positive and negative bacteria strains.

At present, the economics and social developments show the characteristics of diversification, and the focus of social enterprise management is driven by the allocation of human resources. Human resource allocation is a way of appropriate allocation and reasonable placement of human resources. It means that, under the guidance of science, human resources can maintain the best combination with other resources at any time. Nevertheless, the irregularities in management teams and the balanced differences of talent quality have a great effect on the balanced development of an enterprise. Based on this, this paper studies the establishment of a recurrent neural network (RNN) model to realize the allocation of human resources and the balanced development of enterprise management. Firstly, a deep learning model, based on the recurrent neural network, is established. Then, the human resources data is analyzed to calculate the matching degree between the human resources and posts. Finally, personnel scheduling is carried out according to the matching degree score between the human resources and posts, to obtain the optimal balanced allocation result of the human resources. Experimental results show that our method can bring significant improvements to personnel position matching and effectively enhance the efficiency of human resource allocation based on the cloud environment.

e17561 Background: HRD test from Myriad Inc. was approved by FDA as a biomarker for niraparib in ovarian cancer. Its threshold (as 42) was initially established by capturing 95% of tumors with BRCA1/2 mutation and BRCA1 promoter methylation in the training cohort. Here, we explored the stochasticity of such threshold, when the test noises themselves were concerned. Methods: We simulated HRD scores from figure 1 of Telli et al., 2016 by assigning the median from each histogram bin to the associated samples. The threshold was calculated, as described in the original paper, and the standard error (SE) and confidence interval (CI) for such threshold were estimated from bootstrapping the cohort. Furthermore, the entire cohort was down-sampled to determine the effect of sample size on the threshold. Results: The threshold of 42.5 was calculated from our simulated dataset, close to the original one, with SE of 1.62 and 95% CI of 40.75 - 47.5 for the bootstrap. As expected, SE steadily increased to 2.21, 2.84, 2.97 when the sample sizes decreased to 250, 230, and 210 respectively. When the dataset was further down-sampled to include only 200 BRCA deficient samples, SE increased to 3.76, and drastically, CI ranged between 36.5 and 51.2. Conclusions: We have showed there exists manifest stochasticity in the original threshold of 42 for the Myriad HRD test, which is likely close to platform noise in magnitude. The minimum size of BRCA deficient patients to obtain a stable threshold is 200, as shown in our study.

Water is essential for life. However, water scarcity is becoming one of the most severe issues worldwide in terms of its potential impacts. There are diverse forms of water on earth and water harvesting from them is quite feasible to access more fresh water for drinking, sanitation and irrigation. In this review, we summarize the recent technologies of various water harvesters, based on different forms of water resources, aiming to improve the water harvesting systems. We mainly address three points: forming principles of different water circumstance, working mechanism of typical water harvesters, and the challenges and future research orientations. This systemic review on recent technologies in water harvesting provides insight into the sustainable water resources, water supply, and water collecting systems for the future.

In this study, two Cr(VI)-reducing functional bacterial strains (TJ-1 and TJ-5) were successfully isolated and screened from the chromium-contaminated soil from a real site. The 16S rRNA gene sequences were analysed, which showed high similarity (99%) with Stenotrophomonas maltophilia (TJ-1) and Brucella intermedius (TJ-5) species. The optimum growth for the two bacteria to reduce Cr(VI) were achieved at pH 7.0 and initial inoculation amount of 5%. The two strains were applied to real contaminated soil samples and showed better Cr removal when external carbon sources were added. Using sawdust as a solid-phase carbon source supplement, both TJ-1 and TJ-5 showed higher remediation efficiency (99.77% and 93.86%) than using glucose as the carbon source (68.56% and 70.87%). Results of the stability of soil Cr(VI) bioremediation revealed that the water-soluble Cr(VI) content of bioremediated sample remained unchanged, indicating that Cr(VI) is not easily released after death of the strains. Solid-phase carbon source supplements may help the cells to attach and grow into biofilms, creating a better growth condition which improved the remediation efficiency. Column experiments showed that the total remediation efficiencies by the two strains were 34.23% and 20.63%, respectively, within a short time period (76 h). Therefore, the two strains showed great bioremediation potentials for chromium-contaminated sites and can be used in future application of in-situ bioremediation.

Antimicrobial resistance poses an increasingly serious global health threat. Hence, new antimicrobials with low propensity toward inducing resistance in bacteria are being developed to combat this threat. In this work, a series of imidazolium tetramers have been synthesized by modulating the linkers between imidazoliums or the length of the end groups within the structures of oligomers in order to optimize the activity, selectivity, and biocompatibility of the compounds. These new materials possess high biocompatibility, Gram selectivity, and high efficacy against the selected bacterium as well as clinically isolated methicillin-resistant Staphylococcus aureus species without inducing drug resistance. Therefore, we believe that these compounds can potentially be used to mitigate resistance as highly effective disinfectants in healthcare products or as antimicrobial therapies specifically for Gram-positive bacterial infections.

Vagus nerve stimulation, an emerging technology for the treatment of many neurological diseases, is considered an alternative to medical treatment and surgical treatment. This paper introduces the circuit implementation of the SVM (Support Vector Machine) module in the neural signal monitoring chip classifier. The support vector machine module includes an exponential function operation unit and a scaling unit. The exponential function operation circuit is designed based on the coordinate rotation digital calculation method (CORDIC). In order to reduce the amount of computation, some of unimportant or redundant features are removed from the complete feature set by selecting the patient’s EEG (electroencephalogram) signal path. In addition, the decision function is transformed to optimize the transmission path of the data. Finally, the indicators for evaluating this system are given by the simulation results.

In arid yet foggy regions, fog harvesting is emerging as a promising approach to combat water scarcity. The mesh netting used by current fog harvesters suffers from inefficient drainage, which severely constrains the water collection efficiency. Recently, it was demonstrated that fog harps can significantly enhance water harvesting as the vertical wire array does not obstruct the drainage pathway. However, fabrication limitations resulted in a very low shade coefficient of 18% for the initial fog harp prototype and the field testing was geographically confined to light fog conditions. Here, we use wire-electrical discharge machining (wire-EDM) to machine ultrafine comb arrays; winding the harp wire along a comb-embedded reinforced frame enabled a shade coefficient of 50%. To field test under heavy fog conditions, we placed the harvesters on a closed-circuit test road and inundated them with fog produced by an array of overlying fog towers. On average, the fog harps collected about three times more water than the mesh netting. During fog harvesting, the harp wires were observed to tangle together due to the surface tension of water. We developed a rational model to predict the extent of the tangling problem for any given fog harp design. By designing next-generation fog harps to be anti-tangling, we expect that even larger performance multipliers will be possible compared to the current mesh harvesters.

Background A therapeutic strategy involving combined treatment with lenvatinib plus pembrolizumab (LEP) has demonstrated a relatively high antitumor response in several solid tumors; however, the efficacy and safety of LEP in patients with refractory bile tract carcinoma (BTC) remains unknown. Methods This is a single-arm study for a preliminary assessment of the efficacy and tolerability of LEP in patients who experienced progression from prior systemic treatments. Pre-treatment tumor tissues were collected to retrospectively evaluate the expression status of PDL1. Results Thirty-two patients received second-line and above treatment with LEP. Overall, the objective response rate (ORR) was 25%, the disease control rate (DCR) was 78.1%, and the clinical benefit rate (CBR) was 40.5%. The median progression-free survival (PFS) was 4.9 months (95% CI: 4.7-5.2 months), and the median overall survival (OS) was 11.0 months (95% CI: 9.6-12.3 months). For tolerability, no grade 5 serious adverse events (AEs) were reported. All patients had any-grade AEs, and 59.3% of the patients experienced grade 3 AEs, while only 1 patient experienced a grade 4 AE of stomach bleeding. Fatigue was the most common AE, followed by hypertension and elevated aminotransferase levels. Retrospective analysis for PDL1 expression revealed that PDL1 positive tumor cells were associated with improved clinical benefits and survival outcomes. Conclusions LEP is a promising alternative as a non-first-line therapeutic regimen for patients with refractory BTC. Furthermore, well-designed prospective clinical trials with a control arm are still needed to obtain more evidences to confirm the efficacy and safety of this particular regimen as well as the role of PDL1 expression.

Background: Triple negative breast cancer (TNBC) features poor prognosis which partialy attributed to the high metastasis rate. However, there is no effective target for systemic TNBC therapy due to the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors (ER, PR, HER-2) up to date. In the present study, we evaluated the role of sphingosine kinase 2 (SphK2) and its catalysate sphingosine-1-phosphate (S1P) in TNBC metastasis, and the antitumor activity of SphK2 specific inhibitor ABC294640 in TNBC metastasis. Methods: The function of SphK2 and S1P in migration of TNBC cells was evaluated by Transwell migration and wound healing assays. The molecular mechanisms of SphK2/S1P mediating TNBC metastasis were investigated using cell line establishment, western blot, histological examination and immunohistochemistry assays. The antitumor activity of ABC294640 was examined in TNBC lung metastasis model in vivo. Results: SphK2 regulated TNBC cells migration through the generation of S1P. Targeting SphK2 with ABC294640 inhibited TNBC lung metastasis in vivo . p21-activated kinase 1 (PAK1), p-Lin-11/Isl-1/Mec-3 kinase 1 (LIMK1) and Cofilin1 was the downstream signaling cascade of SphK2/S1P. Inhibition of PAK1 suppressed SphK2/S1P induced TNBC cells migration. Concusion: SphK2/S1P promotes TNBC metastasis through the activation of the PAK1/LIMK1/Cofilin1 signaling pathway. ABC294640 potently inhibits TNBC metastasis in vivo which could be developed as a novel agent for the clinical treatment of TNBC.

Introduction: Urinary tract infections (UTIs) have been proven to be the most encountered bacterial infection in humans. We hope to establish a prediction model for significant bacteriuria by comprehensively analyzing the relevant parameters of age, gender, and urine automatic analysis data. Methods: A retrospective study was performed at Tai’an Central Hospital. All samples included in the study were tested for urine culture and urine automatic analysis. Data analysis was conducted with the SPSS. Results: The binary logistic regression module is used to establish the forecast formula, which gender, age, leukocyte count, bacterial count, leukocyte esterase, and nitrite were included. Receiver operating characteristic (ROC) curves showed that the area under ROC curve (AUC) of the prediction model was 0.878, bigger than the AUCs of the other 6 independent variables. The sensitivity and specificity of prediction model were 61.68 and 95.98%, respectively. The positive and the negative predictive values of the predictive model are 87.13 and 85.02%, respectively. Conclusions: The prediction formula obtained in our study can achieve good prediction effect for significant bacteriuria, which can effectively avoid the treatment delay or antibiotic abuse caused by the subjective judgment of doctors.

Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) have been identified as predictors of treatment response in a variety of cancers. We conducted a retrospective analysis to investigate the usefulness of NLR, PLR and SII at baseline and at 6 weeks post-treatment as predictors of response to anti-PD-1/PD-L1 antibody treatment in small cell lung cancer (SCLC). Data of 41 SCLC patients receiving immunotherapy as second- or later-line treatment were analyzed. The overall median progression-free survival (PFS) was 5.1 months (95% CI 3.2–6.2). The median PFS was significantly longer in patients with NLR

Antimony (Sb) is a potentially toxic chemical element abundantly found in the environment. We previously reported that Sb promoted neuronal deathvia reactive oxygen species-dependent autophagy. Here, we assessed the role of cyclic adenosine monophosphate response element-binding protein (CREB) in Sb-induced neuronal damage. We found that Sb treatment induced CREB phosphorylation and neuronal apoptosis both in vitro and in vivo. Interestingly, inhibition of CREB's transcriptional activity with 666-15 dramatically enhanced apoptosis in PC12 cells by downregulating B-cell lymphoma 2 (Bcl-2). Additionally, Sb activated ERK, JNK, and p38 signaling ; however, only JNK promoted CREB phosphorylation. In conclusion, our findings suggest that CREB phosphorylation by JNK attenuates Sb-induced neuronal apoptosis via Bcl-2 upregulation. These data suggest that JNK-dependent CREB activation prevents neurons from Sb-induced apoptosis and guides the development of novel strategies to prevent Sb-induced neurotoxicity.

RhoA is a member of the RHO family GTPases and is associated with essential functions in gastric cancer. In this study, we identified a gastric cancer biomarker, termed the "regulation of RhoA activity panel" (RRAP). Patients with gastric cancer from The Cancer Genome Atlas database were divided into training (N=160) and validation (N=155) cohorts. A cohort of 109 Chinese gastric cancer patients was utilized as an independent validation. Patients with mutated RRAP showed significantly better overall survival than patients with wild type RRAP. We also analyzed the association between RRAP and the migration capacity, immune-related signatures, and the tumor microenvironment. RRAP-mutant tumors had a significantly lower degree of lymph node metastasis and lower activities of migration-related pathways. These tumors also showed significantly increased immune cell infiltration and cytotoxic activity. Furthermore, two independent patient cohorts who received immune checkpoint blockade therapy were assessed for RRAP mutant status. As expected, for both immunotherapy cohorts, higher response rates to immune checkpoint blockade therapy were observed in patients with RRAP-mutant tumors than in patients with wild type RRAP tumors. Overall, this study indicates that the RRAP gene set is a potential biomarker for gastric cancer prognosis and therapeutic selection.

The transpiration cycle in trees is powered by a negative water potential generated within the leaves, which pumps water up a dense array of xylem conduits. Synthetic trees can mimic this transpiration cycle, but have been confined to pumping water across a single microcapillary or microfluidic channels. Here, we fabricated tall synthetic trees where water ascends up an array of large diameter conduits, to enable transpiration at the same macroscopic scale as natural trees. An array of 19 tubes of millimetric diameter were embedded inside of a nanoporous ceramic disk on one end, while their free end was submerged in a water reservoir. After saturating the synthetic tree by boiling it underwater, water can flow continuously up the tubes even when the ceramic disk was elevated over 3 m above the reservoir. A theory is developed to reveal two distinct modes of transpiration: an evaporation-limited regime and a flow-limited regime.