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PURPOSE The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Lung cancer is one of the most threatening diseases to human life and health because of its mortality. How to choose more efficient drugs and the appropriate timing of treatment for patients with advanced lung cancer is still a problem. As the urine proteome can sensitively reflect the pathological or physiological changes of the body, it has the potential to reflect the dynamic changes of the body after drug treatment. To investigate the changes in the urine proteome of patients with advanced lung cancer after different drug treatments, urine samples were collected and analyzed at different time points. The changes in the urine proteome from the pretreatment state were different in each patient, although some of them were treated with the same drugs. The changes in the biological processes reflected by the differential urinary proteins were consistent with the changes in the clinical manifestations of the patients. This study demonstrates that the pathophysiological changes of patients with advanced lung cancer can be reflected by changes in urinary protein after different drug treatments. In addition, the changes in urinary proteins can reflect the different biological processes in patients after the same drug treatment, and the patients’ clinical condition assessment results are consistent with these changes. These findings may provide additional information for clinical treatment.

Glioblastoma (GBM) is the most lethal primary brain tumor in adults and harbors a subpopulation of glioma stem cells (GSCs). Enhancer of Zeste Homolog 2 (EZH2), a histone lysine methyltransferase, deeply involves in the stemness maintenance of GSC. However, the precise mechanism and therapeutic potential remain elusive. We postulated that the interactome of EZH2 in GSC is unique. Therefore, we performed proteomic and transcriptomic research to unveil the oncogenic mechanism of EZH2. Immunoprecipitation and mass spectrometry were used to identify proteins that co-precipitate with EZH2. We show that EZH2 binds to heterochromatin protein 1 binding protein 3 (HP1BP3) in GSCs and impairs the methylation of H3K9. Overexpression of HP1BP3 enhances the proliferation, self-renewal and temozolomide (TMZ) resistance of GBM cells. Furthermore, EZH2 and HP1BP3 co-activate WNT7B expression thereby increasing TMZ resistance and stemness of GBM cells. Importantly, inhibition of WNT7B autocrine via LGK974 effectively reverses the TMZ resistance. Our work clarifies a new oncogenic mechanism of EZH2 by which it interacts with HP1BP3 and epigenetically activates WNT7B thereby promoting TMZ resistance in GSCs. Our results provide a rationale for targeting WNT/β-catenin pathway as a promising strategy to overcome TMZ resistance in GSCs.

This study evaluated the role of miRNA-1592 (miR-1592) carried by exosomes that originated from bone marrow mesenchymal stem cell (BMSC) in glioma. BMSCs were cultured and identified, followed by being co-cultured with glioma cells to measure cell invasion, metastasis, and apoptosis by transwell assay and flow cytometry, cell proliferation by MTT, PI3K/AKT signal protein expression by western blot. BMSC-originated exosomes with different concentrations were used as a treatment strategy for established tumor models. The tumor volume was measured and tumor tissues were harvested for immunohistochemistry and immunoblot analysis. After co-culture with BMSC-originated exosomes, glioma cells showed an up-regulated transcription of miR-1592, along with inhibited phosphorylation and activation of PI3K/AKT signal pathway. Moreover, glioma cells exhibited reduced migration and invasiveness In Vitro, which was accompanied by diminished levels of proteins involved in cellular invasiveness. Simultaneously, co-culture with BMSC-originated exosomes can restrain glioma cell proliferation via facilitating cell apoptosis In Vivo and In Vitro. In conclusion, exosome-encapsulated microRNA-1592 from BMSCs can suppress the In Vivo and In Vitro development of glioma through interfering with PI3K/AKT signaling pathway.

Energy availability and the selection of suitable energy sources have substantial implications on both economic and environmental sustainability, and it is because the environmental protection cost is directly linked to overall energy inclusion in the economy. Thus, the importance of clean energy has been noticed in the literature regardless of the economic structure. The purpose of the study is to discover the effects of financial deepening (FD), urbanization (UR), and institutional quality (IQ) on China’s energy consumption. Annual time series date for 1985 to 2019 utilized for documenting the coefficients of explanatory variables by implementing both linear and nonlinear Autoregressive Distributed Lagged (ARDL) and the Fourier-TY causality test. In terms of the test statistics for combined and Maki cointegration, the study revealed that a long-run association prevails in the empirical nexus. Moreover, the symmetric and asymmetric framework established long-run associations. Referring to the coefficients of financial deepening, UR, and governmental effectiveness, the study found a statistically significant and favorable impression of REC. While financial deepening and governmental effectiveness unveiled negatively influenced NREC and fossil energy consumption. The asymmetric linkage between explained and explanatory variables was confirmed through the execution of a standard weld test with a null symmetry. The asymmetry coefficients of FD, UR, and IQ were positive and statistically significant at the 1% level in both the long and short runs. The directional causality revealed feedback hypothesis holds in understanding the causal relationship between explanatory factors and RE usage. The policy recommendations for the future were generated from the research findings.

As rare ginsenosides, 20(R, S)-ginsenoside Rh1 [20(R, S)-Rh1] are isomers and have been reported to exhibit multiple biological effects. However, the application of 20(R, S)-Rh1 is still limited due to their poor solubilities and low bioavailabilities. Here, the complexation mechanism between 20(R, S)-Rh1 and serum albumin (SA) was explored by a combination of multi-spectroscopy and in silico investigations. Results of spectra experiments showed that 20(R, S)-Rh1 could form complexes with bovine serum albumin (BSA) and quench its intrinsic fluorescence. In addition, the influence of BSA on the anti-cancer activity of 20(R, S)-Rh1 was also evaluated in A549 cells. The result of the MTT assay indicated that anti-cancer activity of 20(R, S)-Rh1 was enhanced when combined with BSA. The results of molecular docking and dynamics simulation demonstrated that the subtle structural differences of 20(R, S)-Rh1 at the 20-carbon atom may be responsible for their different binding capacities and binding stabilities with human serum albumin. The cytotoxicity assay for 20(R, S)-Rh1 alone and their complexes with BSA demonstrated the enhancement effect of BSA for inhibition of cell proliferation. In conclusion, this work provided insight into the complexation mechanism between 20(R, S)-Rh1 and SA. PRACTICAL APPLICATION: The complexation mechanism between 20(R, S)-ginsenoside Rh1 [20(R, S)-Rh1] and serum albumin (SA) was explored by a combination of multi-spectroscopy and in silico investigations in this work. The cytotoxicity assay for 20(R, S)-Rh1 alone and their complexes with bovine serum albumin (BSA) demonstrates the enhancement effect of BSA for inhibition of cell proliferation. Hence, this work provided insight into the complexation mechanism between 20(R, S)-Rh1 and SA.

Mutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous lethality of Gjb2 mutations in mice, there are currently no perfect mouse models carrying Gjb2 mutations derived from patients for mimicking human hereditary deafness and for unveiling the pathogenesis of the disease. Here, we successfully constructed heterozygous Gjb2+/35delG and Gjb2+/235delC mutant mice through advanced androgenic haploid embryonic stem cell (AG-haESC)-mediated semi-cloning technology, and these mice showed normal hearing at postnatal day (P)28. A homozygous mutant mouse model, Gjb235delG/35delG, was then generated using enhanced tetraploid embryo complementation, demonstrating that GJB2 plays an indispensable role in mouse placenta development. These mice exhibited profound hearing loss similar to human patients at P14, i.e., soon after the onset of hearing. Mechanistic analyses showed that Gjb2 35delG disrupts the formation of intercellular gap junction channels and impairs mechanoelectrical transduction of the cochlea rather than affecting the survival and function of hair cells. Collectively, our study provides ideal mouse models for understanding the pathogenic mechanism of DFNB1A-related hereditary deafness and opens up a new avenue for investigating the treatment of this disease.

Purpose Approximately 1/3 of brain tumors are gliomas. Previous glioma-related studies have reported increased expression of periostin (POSTN) in these cancerous tissues, but the role and mechanism of POSTN in glioma development remain unclear. Methods Nanoscale liquid chromatography coupled with tandem mass spectrometry (nano LC–MS/MS) and RNA sequencing were used to identify differential protein and mRNA expression in clinical glioma samples. Quantitative real-time PCR (qRT–PCR) was used to measure the expression of POSTN in tissues and cells. The effects of POSTN on glioma cell migration and invasion were examined using wound healing, Transwell, and three-dimensional spheroid assays in vitro and a nude mouse xenograft model in vivo. The effects of POSTN on the stability, endocytosis, and degradation of EGFR were examined by immunoblotting and immunofluorescence staining. Truncation mutation analysis was performed to investigate direct interactions between POSTN and EGFR. Immunohistochemical staining was carried out to confirm the clinical significance of POSTN. Results Overexpression of POSTN induced epithelial-to-mesenchymal transition (EMT) in glioma cells in vivo and in vitro. Mechanistically, POSTN downregulation inhibited EGFR signaling by promoting EGFR endocytosis and degradation. In addition, POSTN was found to bind to EGFR and RIN1, inhibiting EGFR endocytosis and degradation and thus activating the PI3K-Akt signaling pathway. Conclusion These findings indicate the mechanism by which the POSTN/EGFR/RIN1 axis inhibits EGFR endocytosis and degradation, resulting in glioma cell EMT through the PI3K-AKT signaling pathway. Targeting POSTN/EGFR/RIN1 interactions may guarantee beneficial outcomes of glioma treatment.

The MnO2-based aqueous Zn cell can meet the requirements of safety, flexibility, and low cost for portable/wearable electronics; however, its low intrinsic conductivity, weak kinetics, and poor high-loading capacity restrict its practical performance. In this study, the synergistic architecture of MoS2-loaded, oxygen-defect-rich MnO2-x nanocrystals with a carbon coating (M-PM2-x-H2 aerogel) was prepared. As corevealed by various characterizations, this synergistic design not only improves the electronic/ionic conductivity but also motivates the conversion kinetics of the surficial electrochemical reaction. As a result, the M-PM2-x-H2 cathode delivers a much improved capacity of 567 mA h·g-1 at 0.1 A·g-1 and shows a high capacity retention of 176% after 150 cycles at 0.5 A·g-1. More impressively, the high areal loading (3.97 mg·cm-1) of the M-PM2-x-H2 electrode also displays a high capacity of 367 mA h·g-1 at 0.1 A·g-1. In addition, the derived all-solid-state cell exhibits excellent flexibility and safety under the conditions of weight loading, cutting, and bending.

Background Profound heterogeneity in prognosis has been observed in colorectal cancer (CRC) patients with intermediate levels of disease (stage II–III), advocating the identification of valuable biomarkers that could improve the prognostic stratification. This study aims to develop a deep learning-based pipeline for fully automatic quantification of immune infiltration within the stroma region on immunohistochemical (IHC) whole-slide images (WSIs) and further analyze its prognostic value in CRC. Methods Patients from two independent cohorts were divided into three groups: the development group (N = 200), the internal (N = 134), and the external validation group (N = 90). We trained a convolutional neural network for tissue classification of CD3 and CD8 stained WSIs. A scoring system, named stroma-immune score, was established by quantifying the density of CD3+ and CD8+ T-cells infiltration in the stroma region. Results Patients with higher stroma-immune scores had much longer survival. In the development group, 5-year survival rates of the low and high scores were 55.7% and 80.8% (hazard ratio [HR] for high vs. low 0.39, 95% confidence interval [CI] 0.24–0.63, P Conclusions We proposed a stroma-immune score via a deep learning-based pipeline to quantify CD3+ and CD8+ T-cells densities within the stroma region on WSIs of CRC and further predict survival.

Background Thyroid dysfunction is a common adverse event after immune checkpoint inhibitor (ICI) therapy. The clinical manifestations of thyroid immune-related adverse events (irAEs) are variable and the underlying mechanism is unclear. Purpose To identify the clinical and biochemical characteristics of Chinese patients with ICI-related thyroid dysfunction. Methods We retrospectively reviewed patients with carcinoma who received ICI therapy and underwent evaluation of thyroid function during hospitalization at Peking Union Medical College Hospital between January 1, 2017 and December 31, 2020. Clinical and biochemical features were analyzed in patients who developed ICI-related thyroid dysfunction. Survival analyses were performed to determine the effect of thyroid autoantibodies on thyroid abnormalities and the impact of thyroid irAEs on clinical outcomes. Results The cohort included 270 patients with a median follow-up of 17.7 months; 120 (44%) of these patients developed thyroid dysfunction on immunotherapy. The most common thyroid irAE was overt hypothyroidism (with/without transient hyperthyroidism), which occurred in 38% of patients (n = 45), followed by subclinical thyrotoxicosis (n = 42), subclinical hypothyroidism (n = 27), and isolated overt thyrotoxicosis (n = 6). The median time to onset was 49 days (interquartile range 23, 93) for thyrotoxicosis and 98 days (interquartile range 51, 172) for hypothyroidism. In patients treated with PD-1 inhibitors, hypothyroidism was strongly associated with younger age (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.29–0.67; P

Correction for ‘Novel anilino quinazoline-based EGFR tyrosine kinase inhibitors for treatment of non-small cell lung cancer’ by Lili Yang et al., Biomater. Sci., 2021, 9, 443–455. DOI: 10.1039/D0BM00293C.

Imbuing artificial sensory system with intelligence of the biological counterpart is limited by challenges in emulating perceptual learning ability at the device level. In biological systems, stimuli from the surrounding environment are detected, transmitted, and processed by receptor, afferent nerve, and brain, respectively. This process allows the living creatures to identify the potential hazards and improve their adaptability in various environments. Here, inspired by the biological olfaction system, a gas sensory system with perceptual learning is developed. As a proof-of-concept, H2S gas with various concentrations is used as the stimulation and the stimuli will be converted to pulse-like physiological signals in the designed system, which consists of a gas sensor, a flexible oscillator, and a memristor-type artificial synapse. Furthermore, the learning ability is implemented using a supervised learning method based on k-nearest neighbors (KNN) algorithm. The recognition accuracy can be enhanced by repeating training, illustrating a great potential to be used as the neuromorphic sensory system with a learning ability for the applications in robotics.

This article mainly analyzes the clinical effects of magnetic resonance diagnosis in knee meniscus injury. Patients with knee meniscus injury were taken as the research object. All patients used magnetic resonance examination and surgery and arthroscopy examination, and surgery and arthroscopy examination as the control parameters. The analysis used magnetic resonance diagnosis results and the classification of meniscus injury diagnosed by magnetic resonance and surgery and arthroscopy. The results showed that the sensitivity, specificity, and accuracy of conventional MR1 sequence diagnosis of medial meniscus injury were 86.3%, 95.6%, and 92.4%, respectively. The sensitivity, specificity and accuracy of conventional MRI in diagnosing lateral meniscus injury of the knee joint were 91.3%, 94.5%, and 92.5% respectively. The sensitivity of MRI to medial and lateral meniscus injury was (χ2 = 0.07, P > 0.77), There were no significant differences in specificity χ2 = 0.01, P > 0.77) and accuracy χ2 = 0.01, P > 0.77). The knee meniscus injury has a greater impact on patients. The diagnostic effect of magnetic resonance imaging is better and the diagnostic accuracy is higher. It can help clinical judgment and treatment. The effect is obvious and worthy of clinical promotion.

Jingzhaotoxin-I, -III, -IV, -XIII, and −35 (JZTX-I, -III, -IV, -XIII, and −35), gating modifier toxins isolated from the venom of the Chinese tarantula Chilobrachys Jingzhao, were reported to act on cardiac sodium channels and Kv channels. JZTX-I and JZTX-XIII inhibited the hERG channel with the IC50 value of 626.9 nM and 612.6 nM, respectively. JZTX-III, -IV, and −35 share high sequence similarity with JZTX-I and JZTX–XIII, but they showed much lower affinity on the hERG channel compared with JZTX-I and JZTX-XIII. The inhibitory potency of the above five toxins on the hERG channel was not in accordance with their affinity on the Nav1.5 and Kv2.1 channels, indicating that the bioactive surfaces of the five toxins interacting with hERG, Nav1.5 and Kv2.1 are at least in part different. Structure-function analysis of the gating modifier toxins suggested that the functional bioactive surface binding to the hERG channel consists of a conserved hydrophobic patch, surrounding acidic residues (Glu10 in JZTX-XIII, Glu11 in JZTX-I), and basic residues which may be different from residues binding to the Kv2.1 channel.

Objective The Immunoscore method has proved fruitful for predicting prognosis in patients with colon cancer. However, there is still room for improvement in this scoring method to achieve further advances in its clinical translation. This study aimed to develop and validate a modified Immunoscore (IS-mod) system for predicting overall survival (OS) in patients with stage I-III colon cancer. Methods The IS-mod was proposed by counting CD3+ and CD8+ immune cells in regions of the tumor core and its invasive margin by drawing two lines of interest. A discovery cohort (N=212) and validation cohort (N=103) from two centers were used to evaluate the prognostic value of the IS-mod. Results In the discovery cohort, 5-year survival rates were 88.6% in the high IS-mod group and 60.7% in the low IS-mod group. Multivariate analysis confirmed that the IS-mod was an independent prognostic factor for OS [adjusted hazard ratio (HR)=0.36, 95% confidence interval (95% CI): 0.20-0.63]. With less annotation and computation cost, the IS-mod achieved performance comparable to that of the Immunoscore-like (IS-like) system (C-index, 0.676 vs. 0.661, P=0.231). The 2-category IS-mod using 47.5% as the threshold had a better prognostic value than that using a fixed threshold of 25% (C-index, 0.653 vs. 0.573, P=0.004). Similar results were confirmed in the validation cohort. Conclusions Our method simplifies the annotation and accelerates the calculation of Immunoscore method, thus making it easier for clinical implementation. The IS-mod achieved comparable prognostic performance when compared to the IS-like system in both cohorts. Besides, we further found that even with a small reference set (N≥120), the IS-mod still demonstrated a stable prognostic value. This finding may inspire other institutions to develop a local reference set of an IS-mod system for more accurate risk stratification of colon cancer.

Recent studies have reported the crucial role of stanniocalcin-2 (STC2) in hepatocellular carcinoma; however, its role in head and neck squamous cell carcinoma (HNSCC) remains elusive. In this study, microRNA-206 (miR-206) was predicted to target STC2 gene. The study herein aimed to elucidate the effect of miR-206 on HNSCC by targeting STC2. STC2 was highly expressed in HNSCC tissues and cells. By targeting STC2, miR-206 decreased mRNA and protein expression of STC2. Importantly, our study showed that miR-206 blocked the Akt signaling pathway by inhibiting STC2. Intriguingly, our data from in vitro and in vivo experiments suggested that miR-206 overexpression led to decreased cell proliferation and increased cell apoptosis and autophagy, as well as suppressed tumor growth; whereas, STC2 silencing reversed the effects of miR-206 inhibitor on those biological behaviors. In this study, we investigated the antioncogenic effect of miR-206 on HNSCC by targeting STC2, and highlighted miR-206/STC2 aixs as potential therapeutic targets for HNSCC.

Purpose We aimed to develop a nomogram for predicting the prognosis of patients with distal cholangiocarcinoma (DCC) and to compare its performance with that of the American Joint Committee on Cancer (AJCC) TNM system. Patients and Methods To develop a nomogram, we collected the clinical data of 147 patients diagnosed with DCC who underwent pancreatoduodenectomy. Predictive accuracy and discriminative ability were determined using a concordance index and a calibration curve. Predictive performance was compared with that of a current staging systems for DCC. Results Multivariate analysis revealed that jaundice, alcohol consumption, high fibrinogen, poorly differentiated tumor cells, positive lymph nodes, and positive margins were significantly associated with overall survival. These variables were incorporated into the nomogram. The concordance index of the nomogram for predicting overall survival was 0.737 (P

The memristor has been regarded as a promising candidate for constructing a neuromorphic computing platform that is capable of confronting the bottleneck of the traditional von Neumann architecture. Here, inspired by the working mechanism of the G-protein-linked receptor of biological cells, a novel double-layer memristive device with reduced graphene oxide (rGO) nanosheets covered by chitosan (an ionic conductive polymer) as the channel material is constructed. The protons in chitosan and the functional groups in rGO nanosheets imitate the functions of the ligands and receptors of biological cells, respectively. Smooth changes in the response current depending on the historical applied voltages are observed, offering a promising pathway toward biorealistic synaptic emulation. The memristive behavior is mainly a result of the interaction between protons provided by chitosan and the defects and functional groups in the rGO nanosheets. The channel current is due to the hopping of protons through functional groups and is limited by the traps in the rGO nanosheets. The transition from short-term to long-term potentiation is achieved, and learning-forgetting behaviors of the memristor mimicking those of the human brain are demonstrated. Overall, the bioinspired memristor-type artificial synaptic device shows great potential in neuromorphic networks.

Rationale and Objectives To evaluate the noninvasive predictive performance of deep learning features based on staging CT for sentinel lymph node (SLN) metastasis of breast cancer. Materials and Methods A total of 348 breast cancer patients were enrolled in this study, with their SLN metastases pathologically confirmed. All patients received contrast-enhanced CT preoperative examinations and CT images were segmented and analyzed to extract deep features. After the feature selection, deep learning signature was built with the selected key features. The performance of the deep learning signatures was assessed with respect to discrimination, calibration, and clinical usefulness in the primary cohort (184 patients from January 2016 to March 2017) and then validated in the independent validation cohort (164 patients from April 2017 to December 2018). Results Ten deep learning features were automatically selected in the primary cohort to establish the deep learning signature of SLN metastasis. The deep learning signature shows favorable discriminative ability with an area under curve of 0.801 (95% confidence interval: 0.736–0.867) in primary cohort and 0.817 (95% confidence interval: 0.751–0.884) in validation cohort. To further distinguish the number of metastatic SLNs (1–2 or more than two metastatic SLN), another deep learning signature was constructed and also showed moderate performance (area under curve 0.770). Conclusion We developed the deep learning signatures for preoperative prediction of SLN metastasis status and numbers (1–2 or more than two metastatic SLN) in patients with breast cancer. The deep learning signature may potentially provide a noninvasive approach to assist clinicians in predicting SLN metastasis in patients with breast cancer.

Manufacture of large-scale patterned nanomaterials via top-down techniques, such as printing and slurry coating, have been used for fabrication of miniaturized gas sensors. However, the reproducibility and uniformity of the sensors in wafer-scale fabrication are still a challenge. In this work, a “top-down” and “bottom-up” combined strategy was proposed to manufacture wafer-scaled miniaturized gas sensors with high-throughput by in-situ growth of Ni(OH)2 nanowalls at specific locations. First, the micro-hotplate based sensor chips were fabricated on a two-inch (2”) silicon wafer by micro-electro-mechanical-system (MEMS) fabrication techniques (“top-down” strategy). Then a template-guided controllable de-wetting method was used to assemble a porous thermoplastic elastomer (TPE) thin film with uniform micro-sized holes (relative standard deviation (RSD) of the size of micro-holes 300), which serves as the patterned mask for in-situ growing Ni(OH)2 nanowalls at the micro-hole areas (“bottom-up” strategy). The obtained gas microsensors based on this strategy showed great reproducibility of electric properties (RSD

Objective Electroconvulsive therapy (ECT) is an effective option for treatment-resistant bipolar disorder (trBD). However, the mechanisms of its effect are unknown. Oxidative stress is thought to be involved in the underpinnings of BD. Our study is the first, to our knowledge, to report the association between notable oxidative stress parameters (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT], and malondialdehyde [MDA]) levels and ECT response in trBD patients. Methods A total 28 trBD patients and 49 controls were recruited. Six-week ECT and naturalistic follow-up were conducted. SOD, GSH-Px, CAT, and MDA levels were measured by enzyme-linked immunosorbent assay, and the 17-item Hamilton Depression Rating Scale and Young Mania Rating Scale were administered at baseline and the end of the 6th week. MANCOVA, ANCOVA, 2 × 2 ANCOVA, and a multiple regression model were conducted. Results SOD levels were lower in both trBD mania and depression (P = .001; P = .001), while GSH-Px (P = .01; P = .001) and MDA (P = .001; P = .001) were higher in both trBD mania and depression compared with controls. CAT levels were positively associated with 17-item Hamilton Depression Rating Scale scores in trBD depression (radjusted = 0.83, P = .005). MDA levels in trBD decreased after 6 weeks of ECT (P = .001). Interestingly, MDA levels decreased in responders (P = .001) but not in nonresponders (P > .05). Conclusions Our study indicates that decreased SOD could be a trait rather than a state in trBD. Oxidative stress levels are associated with illness severity and ECT response. This suggests that the mechanism of oxidative stress plays a crucial role in the pathophysiology of trBD.

Jiayi Li, 1,* Qiao Chen, 1,* Bao Jin, 1 Yue Shi, 1 Xiangan Wu, 1 Haifeng Xu, 1 Yongchang Zheng, 1 Yingyi Wang, 2 Shunda Du, 1 Xin Lu, 1 Yilei Mao, 1 Xinting Sang 1 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People’s Republic of China; 2Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shunda DuDepartment of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai-Fu-Yuan, Wang-Fu-Jing, Beijing 100730, People’s Republic of ChinaTel +86-139 1183 2900Fax +86-10-69156043Email dushd@pumch.cnPurpose: The aims of our study were to investigate the prognostic impact of the rate of preoperative serum carbohydrate antigen 19-9/bilirubin (CA19-9/BR) on patients with extrahepatic bile duct cancer.Patients and Methods: We collected clinical data from 89 patients who underwent surgery for extrahepatic cholangiocarcinoma (ECC) at Peking Union Medical College Hospital between January 2012 and December 2017. The Kaplan–Meier analysis for univariate analysis and the Cox proportional hazards models for multivariate analysis were used to determine possible independent prognostic factors.Results: CA19-9/BR was classified as elevated compared with normal based on the upper serum normal values of CA19-9 (37 U/mL) and bilirubin (1.5 mg/dL), which gives a cut-off at 25 U/mL/mg/dL. Univariate analysis showed that the overall survival of patients with a high CA19-9/BR ratio was significantly worse compared with patients with a low CA19-9/BR ratio (Hazard Ratio [HR] 2.149; 95% Confidence Interval [95% CI] 1.027– 4.495; P=0.042). Multivariate analysis revealed that a high CA19-9/BR ratio (HR 3.250; 95% CI 1.165– 9.067; P=0.024), low differentiation (HR 3.551; 95% CI 1.231– 10.244; P=0.019), and positive margin (HR 2.555; 95% CI 1.111– 5.875; P=0.027) remained independent prognostic factors after adjusting for age at diagnosis, maximal diameters, and other possible factors.Conclusion: The preoperative CA19-9/BR ratio is a good prognostic factor in predicting survival in ECC patients and closer follow-up is recommended in patients with a higher CA19-9/BR ratio before surgery.Keywords: prognosis, preoperative bilirubin-adjusted carbohydrate antigen 19-9, extrahepatic cholangiocarcinoma

Jiayi Li,1,2,&ast; Qiao Chen,1,3,&ast; Lei Guo,4,&ast; Ji Li,5 Bao Jin,1 Xiangan Wu,1 Yue Shi,1 Haifeng Xu,1 Yongchang Zheng,1 Yingyi Wang,6 Shunda Du,1 Zhili Li,4 Xin Lu,1 Xinting Sang,1 Yilei Mao1 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 2Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 3Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 4Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, People’s Republic of China; 5Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 6Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shunda Du; Zhili Li, Email dushd@pumch.cn; lizhili@ibms.pumc.edu.cnPurpose: To quantitatively analyze lipid molecules in tumors and adjacent tissues of intrahepatic cholangiocarcinoma (ICC), to establish diagnostic model and to examine lipid changes with clinical classification.Patients and Methods: We measured the quantity of 202 lipid molecules in 100 tumor observation points and 100 adjacent observation points of patients who were diagnosed with ICC. Principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were handles, along with Student’s t-test to identify specific metabolites. Prediction accuracy was validated in the validation set. Another logistic regression model was also established on the training set and validated on the validation set.Results: Distinct separation was obtained from PCA and OPLS-DA model. Ten differentiating metabolites were identified using PCA, OPLA-DA and Lasso regression: [m/z 722.5130], [m/z 863.5655], [m/z 436.2834], [m/z 474.2626], [m/z 661.4813], [m/z 750.5443], [m/z 571.2889], [m/z 836.5420], [m/z 772.5862] and [m/z 478.2939]. Using logical regression, a diagnostic equation: y = 3.4&ast;[m/z 436.2834] - 3.773&ast;[m/z 474.2626] + 3.82&ast;[m/z 661.4813] - 4.394&ast;[m/z 863.5655] + 10.165 based on four metabolites successfully differentiated cancerous areas from adjacent normal areas. The AUROC of the model reached 0.993 (95% CI: 0.985– 0.999) in the validation group. Compared with the adjacent non-tumor area, three characteristic metabolites FA (22:4), PA (P-18:0/0:0) and Glucosylceramide (d18:1/12:0) showed an increasing trend from stage I to stage II, while seven other metabolites LPA(16:0), PE(34:2), PE(36:4), PE(38:3), PE(40:6), PE(40:5) and LPE(16:0) showed a decreasing trend from stage I to stage II.Conclusion: We successfully identified lipid molecules in differentiating tumor tissue and adjacent tissue of ICC, established a discrimination logistic model which could be used as a classifier to classify tumor and non-tumor regions based on analysis in tumor margins and provided information for biomarker changes in ICC, and proposed to related lipid changes with clinical classification.Keywords: intrahepatic cholangiocarcinoma, in situ lipids profiles, metabolomics, mass spectrometry, classification and diagnostic model

Background: Lepidic adenocarcinoma (LPA) is an infrequent subtype of invasive pulmonary adenocarcinoma (ADC). However, the clinicopathological features and prognostic factors of LPA have not been elucidated.Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database of 4087 LPA patients were retrospectively analyzed and compared with non-LPA pulmonary ADC to explore the clinicopathological and prognosis features of LPA. Univariate and multivariate Cox proportional hazard models were performed to identify independent survival predictors for further nomogram development. The nomograms were validated by using the concordance index, receiver operating characteristic curves, and calibration plots, as well as decision curve analysis, in both the training and validation cohorts.Results: Compared with non-LPA pulmonary ADC patients, those with LPA exhibited unique clinicopathological features, including more elderly and female patients, smaller tumor size, less pleural invasion, and lower histological grade and stage. Multivariate analyses showed that age, sex, marital status, primary tumor size, pleural invasion, histological grade, stage, primary tumor surgery, and chemotherapy were independently associated with overall survival (OS) and cancer-specific survival (CSS) in patients with LPA, while race was the only independent prognostic factor for OS, not for CSS. The nomograms showed good accuracy compared with the actual observed results and demonstrated improved prognostic capacity compared with TNM stage.Conclusions: Patients with LPA are more likely to be older and female. Smaller tumor size, lower histological grade and stage are the clinicopathological features of LPA, which may indicate a good prognosis. The constructed nomograms accurately predict the long-term survival of LPA patients.

The development of high-performance, portable and miniaturized gas sensors has aroused increasing interest in the fields of environmental monitoring, security, medical diagnosis, and agriculture. Among different detection tools, metal oxide semiconductor (MOS)-based chemiresistive gas sensors are the most popular choice in commercial applications and have the advantages of high stability, low cost, and high sensitivity. One of the most important ways to further enhance the sensor performance is to construct MOS-based nanoscale heterojunctions (heteronanostructural MOSs) from MOS nanomaterials. However, the sensing mechanism of heteronanostructural MOS-based sensors is different from that of single MOS-based gas sensors in that it is fairly complex. The performance of the sensors is influenced by various parameters, including the physical and chemical properties of the sensing materials (e.g., grain size, density of defects, and oxygen vacancies of materials), working temperatures, and device structures. This review introduces several concepts in the design of high-performance gas sensors by analyzing the sensing mechanism of heteronanostructural MOS-based sensors. In addition, the influence of the geometric device structure determined by the interconnection between the sensing materials and the working electrodes is discussed. To systematically investigate the sensing behavior of the sensor, the general sensing mechanism of three typical types of geometric device structures based on different heteronanostructural materials are introduced and discussed in this review. This review will provide guidelines for readers studying the sensing mechanism of gas sensors and designing high-performance gas sensors in the future.

Food contamination and poisoning caused by bacteria will endanger human health, and the development of natural antibacterial agents is a pressing issue. We prepared ALA-Car complex and demonstrated its formation by multi-spectroscopy techniques and localized surface plasmon resonance experiments. Computer simulations have shown that van der Waals forces dominate the interaction between ALA and Car. The minimum inhibitory concentration (MIC) of Car toward Gram-negative Escherichia coli was decreased from 336 μg/mL to 224 μg/mL after binding to ALA. It had little effect on the MIC of Gram-positive Staphylococcus aureus (224 μg/mL), but further proved Car had a weaker antibacterial activity than the ALA-Car complex by the spread plate method. Overall, this work demonstrated that the ALA-Car complex had significantly higher antibacterial activities than Car, further advancing the development of natural antibacterial agents.

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Yongqiang Yang, Xiaole Li, Pengcheng Zhou, Xiaoyu Deng, Yingyi Wang, Qianqian Dang, Yingjuan Zheng, Daoke Yang Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Yingjuan Zheng; Daoke YangDepartment of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, Henan Province, People’s Republic of ChinaTel +86-15738872856; +86-15903650068Email zdyfyzlyy@163.com; 15903650068@163.comPurpose: To analyze the effects of radiotherapy and its timing on the survival and safety of patients with newly diagnosed distant metastatic NPC in non-high-incidence areas.Patients and Methods: We retrospectively analyzed 94 newly diagnosed NPC patients with distant metastatic admitted to our hospital from January 2011 to June 2018. They were divided into three groups: no radiotherapy group received chemotherapy alone, early radiotherapy group was combined with radiotherapy during 1 to 3 cycles of chemotherapy, and late radiotherapy group was combined with radiotherapy after 4– 6 cycles of chemotherapy were effective. The efficacy and side effects of the three groups were compared, and the prognostic factors were analyzed.Results: The 6-month, 1-year and 2-year PFS were 53.6%, 14.3% and 3.6% in no radiotherapy group, 71.0%, 38.7% and 19.4% in early radiotherapy group, 88.6%, 48.6% and 22.9% in late radiotherapy group; the radiotherapy groups were better than the no radiotherapy group, and the difference was statistically significant (P < 0.017). The 1-year, 2-year and 3-year OS were 75.0%, 32.1% and 0 in no radiotherapy group, 77.4%, 54.8% and 12.9% in early radiotherapy group, 85.7%, 71.4% and 31.4% in late radiotherapy group; the radiotherapy groups were better than the no radiotherapy group, and the differences were statistically significant (P < 0.017). There was no significant difference in OS and PFS between the two radiotherapy groups. Univariate and multivariate analysis showed that HBV (P = 0.031), number of metastases (P = 0.002), liver metastases (P = 0.038), radiotherapy (P < 0.001) and treatment response (P = 0.011) were related to OS. There was no significant difference in the incidence of adverse events (P > 0.017).Conclusion: Early and late combined radiotherapy had similar clinical efficacy and both prolonged PFS and OS for patients with newly diagnosed distant metastatic NPC in non-high-risk areas. If chemotherapy response is expected to be poor, radiotherapy can be received early.Keywords: radiotherapy, nasopharyngeal carcinoma, metastasis, non-high-incidence area, prognosis

Heterostructured metal oxides with large specific surface area are crucial for constructing gas sensors with high performance. However, using slurry-coating and screen-printing methods to fabricate...

Background Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are two key protein-bound uremic toxins that accumulate in patients with end-stage renal disease. IS and pCS cannot be efficiently removed by conventional hemodialysis because they are highly bound to proteins. One promising means to optimize the removal of protein-bound uremic toxins involves using binding competitors to liberate uremic toxins from protein-binding partners. Purpose In this study, we try to identify potential binding competitors that can enhance the dialysis removal of IS and pCS in natural compounds of phytomedicine. Methods We employed microdialysis to evaluate whether Danhong injection (DHI) and its salvianolic acids can increase the free fractions of IS and pCS and thus improve their dialysis efficiency in vitro. Furthermore, we confirmed the positive effects of DHI and salvianolic acids in vivo on chronic kidney disease model rats in which IS and pCS had heavily accumulated. Results DHI significantly increased the dialysis efficiency of IS and pCS by 99.13% and 142.00% in vitro (10-fold dilution), respectively, and by 135.61% and 272.13% in vivo (4.16 ml/kg). Salvianolic acids including lithospermic acid (LA), salvianolic acid A (SaA), tanshinol (DSS), caffeic acid (CA), salvianolic acid B (SaB), protocatechuic aldehyde (PA) and rosmarinic acid (RA) significantly enhanced the dialysis removal of IS and pCS in a concentration-dependent manner. LA, the best competitor of the tested salvianolic acids, increased dialysis efficiency levels of IS and pCS by 197.23% and 198.31% in vitro (400 μM), respectively, and by 119.55% and 127.56% in vivo (24.69 mg/kg). Conclusion The removal of protein-bound uremic toxins IS and pCS using DHI or salvianolic acids as protein-bound competitors is superior to previously reported strategies and drugs and may contribute to clinical hemodialysis therapeutic practice.

e23519 Background: Both undifferentiated sarcoma of soft tissue and undifferentiated carcinomas can arise in multiple tissue and are with an aggressive clinical course. While undifferentiated sarcomas that remain a diagnosis of exclusion and show extreme genomic complexity, less is known about undifferentiated carcinoma. Methods: Sixty-two patients diagnosed as undifferentiated sarcoma (n = 36, 10 bone/limbs, 9 abdomen, 9 pelvis, and 8 chest/intrathoracic) or carcinoma (n = 26, excluding undifferentiated carcinoma of nasopharynx and thyroid, 15 chest/intrathoracic, 8 abdomen, and 3 pelvis) were recruited in the study. Mutational analysis was performed by next-generation sequencing of 1021 tumor related genes, which enabled analysis of TMB and MSI as well. PD-L1 expression data was available in 24 patients. Results: Fifty-eight patients (93.5%, 58/62) had at least 1 mutation identified and 542 SNV, 115 CNV and 5 fusions were identified in total in the 62 patients. The top 5 mutant genes were TP53 (56.5%, 35/62), TERT (11.3 %, 7/62), SMARCA4 (9.7%, 6/62), LRP1B (9.7%, 6/62), and MLL2 (9.7%, 6/62). Interestingly, mutation in TP53 was more common in undifferentiated carcinoma (73.08%, 19/26) than sarcoma (44.44%, 16/36, p = 0.0377). Two ERBB2 CNV and 1 KIF5B-RET fusion were identified in 2 gastric carcinoma and 1 lung large cell carcinoma. However, no carcinoma but 2 sarcoma (1 polymorphic undifferentiated sarcoma in the limb and 1 undifferentiated small round cell sarcoma in the lung) showed MSI-H, with TMB as high as 22.08 and 65.28 respectively, while the median TMB was 3.84 mutations/Mb. Among the 24 patients with PD-L1 data, 16 were > 1%, and 5 were > 50%, with no significant difference between undifferentiated carcinoma and sarcoma. Conclusions: In spite of the genome complexity in undifferentiated sarcoma of soft tissue and carcinoma, there was limited actionable mutations in these two aggressive tumors. However, immunotherapy should be considered since over half of these patients were PD-L1 positive and nearly a quarter of them had high PD-L1 expression.

Temozolomide was recognized as the first-line therapy for glioblastoma to prolong the survival of patients noticeably, while recent clinical studies found that some patients were not sensitive to temozolomide treatment. The possible mechanisms seemed to be methylguanine-DNA-methyltransferase (MGMT), mismatch repair, PARP, etc. And the abnormal expression of MGMT might be the most direct factor. In this study, we provide evidence that Fstl1 plays a vital role in temozolomide resistance by sequentially regulating DIP2A protein distribution, H3K9 acetylation (H3K9Ac), and MGMT transcription. As a multifunctional protein widely distributed in cells, DIP2A cooperates with the HDAC2–DMAP1 complex to enhance H3K9Ac deacetylation, prevent MGMT transcription, and increase temozolomide sensitivity. Fstl1, a glycoprotein highly expressed in glioblastoma, competitively binds DIP2A to block DIP2A nuclear translocation, so as to hinder DIP2A from binding the HDAC2–DMAP1 complex. The overexpression of Fstl1 promoted the expression of MGMT in association with increased promoter H3K9Ac. Upregulation of Fstl1 enhanced temozolomide resistance, whereas Fstl1 silencing obviously sensitized GBM cells to temozolomide both in vivo and in vitro. Moreover, DIP2A depletion abolished the effects of Fstl1 on MGMT expression and temozolomide resistance. These findings highlight an important role of Fstl1 in the regulation of temozolomide resistance by modulation of DIP2A/MGMT signaling.

It is of great value to use bioinformatics methods to screen the core differentially expressed genes (DEGs) at different times after mouse skin and skeletal muscle wound, and to explore the relationship between them and the wound age. To this end, we downloaded the gene expression profiles of GSE140517 and GSE23006 from the NCBI-GEO gene database, used GEO2R online tools and Venn diagrams to screen out DEGs at different times and common-DEGs. The Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) channel analysis were carried out through the DAVID website respectively. Use STRING tool to build a Protein-protein Interaction (PPI) network, and use Cytoscape software to screen out core DEGs. The results showed that 13, 53, 43 and 13 core DEGs were screened out in the 6 h, 12 h, 24 h and common-DEGs group after wound. There were 7 core DEGs (Cxcl2, Cxcl3, Il1b, Ptgs2, Cxcl1, Timp1, Ccl3) in both the different time point and the common DEGs group. Meanwhile, there are 1 core DEGs (Ccl4) specifically expressed in the 6 h, 29 specifically expressed core DEGs (Isg20, Rtp4, Fcgr1, Ifi44, Trim30a, etc.) in the 12 h, and 18 specifically expressed core DEGs (Ccr7, Myd88, Igsf6, Ccr2, Gpsm3, etc.) in the 24 h, there are 6 core DEGs (Ccl4, Ccl7, Saa3, Cxcl5, Ccl2, Lcn2) specifically expressed in the common-DEGs group. The results of GO and KEGG analysis showed that the deterioration and exudation of the inflammatory response were the main cause at 6 h after wound. In addition to inflammation at 12 h and 24 h, the systemic immune response against viral and bacterial infections also gradually increased. In summary, the core DEGs selected in this study have combined characteristics, consistent with the healing function at the corresponding time point, and they are also has specificity and correlation with wound age. Therefore, by detecting the changes in the expression of co-expressed core DEGs at different times after wound, as well as detecting specific expressed DEGs at a specific time point or a specific period of time, it is very promising to provide help for the wound age estimation. However, limited by the GSE140517 gene expression profile in the database, only the difference in gene expression at different times within 24 h after wound was explored, and the research on the late wound age still needs to be further in-depth.

Background Treatment for non-small cell lung cancer (NSCLC) has greatly improved in recent years. However, noninvasive early screening for carcinogenesis and progression unclear. The aim of this study was to explore the predictive value of peripheral blood immune cells in untreated NSCLC patients. Methods We retrospectively enrolled 305 untreated NSCLC patients and 132 healthy participants from February 2016 to August 2019 in Peking Union Medical College Hospital. Immune cell levels were determined by flow cytometry and routine blood tests. Results NSCLC patients had lower levels of T lymphocytes, NK cells, CD8+ T cells, naïve CD4+/CD4+, naïve CD4+ T cells and higher levels of CD4+ T cells, memory CD4+/CD4+ T cells, memory CD4+ T cells, CD4+CD28+/CD4+ T cells, CD4+CD28+ T cells, CD8+CD28+/CD8+ T cells, CD8+HLA-DR+/CD8+ T cells, CD8+HLA-DR+ T cells T cells, CD8+CD38+/CD8+ T cells, CD8+CD38+ T cells and CD4+/CD8+ T cells than those in controls. The percentages of specific lymphocyte subtypes were significantly different in cancer patients versus healthy individuals. For instance, cancer patients had lower levels of B cells, CD4+ T cells, naïve CD4+/CD4+ T cells, naïve CD4+ T cells, CD4+CD28+ T cells, CD8+CD28+ T cells and higher levels of NK cells, white blood cells (WBC), monocytes, neutrophils, eosinophils, basophils, monocytes to lymphocyte ratio (MLR), neutrophils to lymphocyte ratio (NLR), eosinophil to lymphocyte ratio (ELR), basophil to lymphocyte ratio (BLR), and blood platelet to lymphocyte ratio (PLR). Conclusions Abnormal T cell levels can be used as an independent predictive biomarker for noninvasive early screening in NSCLC occurrence and progression.

This study reported a novel humidity-insensitive nitrogen dioxide (NO2) gas sensor based on tin dioxide (SnO2)/reduced graphene oxide (rGO) composites through the sol-gel method. The sensor demonstrated ppb-level NO2 detection in p-type sensing behaviors (13.6% response to 750 ppb). Because of the synergistic effect on SnO2/rGO p-n heterojunction, the sensing performance was greatly enhanced compared to that of bare rGO. The limit of detection of sensors was as low as 6.7 ppb under dry air. Moreover, benefited from the formed superhydrophobic structure of the SnO2/rGO composites (contact angle: 149.0°), the humidity showed a negligible influence on the dynamic response (Sg) of the sensor to different concentration of NO2 when increasing the relative humidity (RH) from 0 to 70% at 116°C. The relative conductivity of the sensor to 83% relative humidity was 0.11%. In addition, the response ratio (Sg/SRH) between 750 ppb NO2 and 83% RH was 649.0, indicating the negligible impaction of high-level ambient humidity on the sensor. The as-fabricated humidity-insensitive gas sensor can promise NO2 detection in real-world applications such as safety alarm, chemical engineering, and so on.

Background Lepidic adenocarcinoma (LPA) is an infrequent subtype of invasive pulmonary adenocarcinoma (ADC). However, the clinicopathological features and prognostic factors of LPA have not been elucidated. We undertook a retrospective population-based analysis to examine the clinicopathological features of LPA, and construct nomograms predicting long-term survival of LPA patients. Methods Data from the Surveillance, Epidemiology, and End Results (SEER) database of 4087 LPA patients diagnosed between 2005 and 2014 were retrospectively analyzed and compared with non-LPA pulmonary ADC to explore the clinicopathological and prognosis features of LPA. All patients included in our study were histologically confirmed. Those with multiple primary tumors in their lifetime, unknown survival data, unknown tumor-node-metastasis (TNM) stage, and unknown information including age, race, and marital status were excluded. Univariate and multivariate Cox proportional hazard models were performed to identify independent survival predictors for further nomogram development. The nomograms were internally and externally validated for concordance index and calibration plots as well as decision curve analysis. Results Compared with non-LPA pulmonary ADC patients, those with LPA exhibited unique clinicopathological features, including more elderly and female patients, smaller tumor size, lesser pleural invasion, lower histological grade and stage. Multivariate analyses showed that age, sex, marital status, primary tumor size, pleural invasion, histological grade, stage, primary tumor surgery, and chemotherapy were independently associated with overall survival (OS) and cancer-specific survival (CSS) in patients with LPA, while race was the only independent prognostic factor for OS, not for CSS. The nomograms showed good accuracy comparing with actual observed results and demonstrated improved prognostic capacity than TNM stage. Conclusions Patients with LPA are more common in older age and female. The smaller tumor size, lower histological grade and stage are the clinicopathological features of LPA which may indicate a good prognosis. The constructed nomograms accurately predict the long-term survival of LPA patients.