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Peptide drugs that target protein-protein interactions have attracted mounting research efforts towards clinical developments over the past decades. Increasing reports have indicated that expression of Musashi 1 (MSI1) is tightly correlated to high grade of cancers as well as enrichment of cancer stem cells. Treatment failure in malignant tumors glioblastoma multiform (GBM) had also been correlated to CSC-regulating properties of MSI1. It is thus imperative to develop new therapeutics that could effectively improve current regimens used in clinics. MSI1 and AGO2 are two emerging oncogenic molecules that both contribute to GBM tumorigenesis through mRNA regulation of targets involved in apoptosis and cell cycle. In this study, we designed peptide arrays covering the C-terminus of MSI1 and identified two peptides (Pep#11 and Pep#26) that could specifically interfere with the binding with AGO2. Our Biacore analyses ascertained binding between the identified peptides and AGO2. Recombinant reporter system Gaussian luciferase and fluorescent bioconjugate techniques were employed to determine biological functions and pharmacokinetic characteristics of these two peptides. Our data suggested that Pep#11 and Pep#26 could function as decoy peptides by mimicking the interaction function of MSI1 with its binding partner AGO2 in vitro and in vivo. Further experiments using GMB animal models corroborated the ability of Pep#11 and Pep#26 in disrupting MSI1/AGO2 interaction and consequently anti-tumorigenicity and prolonged survival rates. These striking therapeutic efficacies orchestrated by the synthetic peptides were attributed to the decoy function to C-terminal MSI1, especially in malignant brain tumors and glioblastoma.

Background: Multidisciplinary management strategies are standard in esophageal cancer. Based on a multidisciplinary tumor board (MTB) database in a high-volume center, we aimed to evaluate real-world treatment patterns and patient outcomes in patients with esophageal cancer. In addition, we determined the impact of MTB discussions on patient prognosis., Methods: Patients diagnosed with esophageal cancer between 2010 and 2019 were retrospectively reviewed. The pattern of treatment modalities and overall survival (OS) of patients with limited, locally advanced, and advanced/metastatic disease were reported., Results: Data from 1132 patients, including 247 patients with limited esophageal cancer, 606 patients with locally advanced esophageal cancer, and 279 patients with advanced/metastatic esophageal cancer were included. Upfront surgery was the most common (56.3%) treatment modality for patients with limited esophageal cancer, while treatment for locally advanced esophageal cancer included upfront surgery (19.1%), neoadjuvant chemoradiotherapy (44.9%), and definitive chemoradiotherapy (36.0%); however, 27.9% of patients undergoing neoadjuvant chemoradiotherapy did not receive planned esophagectomy. Definitive chemoradiotherapy was mainly used for patients with locally advanced and advanced/metastatic disease, but had an incompletion rate of 22.0% and 33.7%, respectively. Regarding survival, the 5-year OS rates were 56.4%, 26.3%, and 5.1% in patients with limited, locally advanced, and advanced/metastatic disease, respectively. Additionally, patients whose clinical management was discussed in the MTB had a significantly better 5-year OS rate than the other patients (27.3% vs. 20.5%, p < 0.001)., Conclusions: We report the real-world data of treatment patterns and patient outcomes in patients with esophageal cancer with respect to multidisciplinary management, and demonstrate the positive impact of MTB discussions on patient prognosis., (© 2021. Society of Surgical Oncology.)

Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular noncoding RNA, hsa&#95;circ&#95;0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo . RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo . TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR-MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC. SIGNIFICANCE: The circRNA C190 is identified as a mediator of multiple pro-oncogenic signaling pathways in lung cancer and can be targeted to suppress tumor progression., (©2021 American Association for Cancer Research.)

This pioneering study was to assess the acute and sub-acute toxicity of the ethanolic extract of the aerial parts of Crassocephalum rabens (Asteraceae) in rats. C. rabens is a common vegetable and herb for treating inflammation-related syndromes in Taiwan. Pharmacological studies have unveiled that the extracts of C. rabens have potential to become hepatoprotective, anti-inflammatory, or anti-cancer agents. The toxicological effects of the aerial parts of C. rabens in rodents are still elusive. For the acute toxicity study, rats were administrated with a single dose of 5,000 mg/kg body weight (BW) and observed for 14 days in accordance with the Organization for Economic Cooperation and Development (OECD) guideline No. 420. For the sub-acute toxicity study, animals were orally treated with daily doses of 0, 416.7, 833.3, and 1,666.7 mg/kg BW for 28 days based on the OECD guideline No. 407. The toxicity of the repeated dose was observed with anthropometric, hematological, and biochemical parameters as well as histology. The mortality and critical pathological and biochemical abnormalities were not observed in the acute and/or sub-acute toxicity studies. The oral median lethal dose (LD 50 ) of the extract was greater than 5000 mg/kg BW. The no-observed-adverse-effect-level (NOAEL) in male and female rats was greater than 1,666.7 mg/kg BW. As such, the extract of the aerial parts of C. rabens is considered a non-toxic substance., Competing Interests: The authors report no declarations of interest., (© 2021 The Authors.)

Signaling networks are at the heart of almost all biological processes. Most of these networks contain large number of components, and often either the connections between these components are not known or the rate equations that govern the dynamics of soluble signaling components are not quantified. This uncertainty in network topology and parameters can make it challenging to formulate detailed mathematical models. Boolean networks, in which all components are either on or off, have emerged as viable alternatives to detailed mathematical models that contain rate constants and other parameters. Therefore, open-source platforms of Boolean models for community use are desirable. Here, we present Boolink, a freely available graphical user interface that allows users to easily construct and analyze existing Boolean networks. Boolink can be applied to any Boolean network. We demonstrate its application using a previously published network for abscisic acid (ABA)-driven stomatal closure in Arabidopsis spp. (Arabidopsis thaliana). We also show how Boolink can be used to generate testable predictions by extending the network to include CO2 regulation of stomatal movements. Predictions of the model were experimentally tested, and the model was iteratively modified based on experiments showing that ABA effectively closes Arabidopsis stomata at near-zero CO2 concentrations (1.5-ppm CO2). Thus, Boolink enables public generation and the use of existing Boolean models, including the prior developed ABA signaling model with added CO2 signaling components., (© American Society of Plant Biologists 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Stomatal pores close rapidly in response to low-air-humidity-induced leaf-to-air vapor pressure difference (VPD) increases, thereby reducing excessive water loss. The hydroactive signal-transduction mechanisms mediating high VPD-induced stomatal closure remain largely unknown. The kinetics of stomatal high-VPD responses were investigated by using time-resolved gas-exchange analyses of higher-order mutants in guard-cell signal-transduction branches. We show that the slow-type anion channel SLAC1 plays a relatively more substantial role than the rapid-type anion channel ALMT12/QUAC1 in stomatal VPD signaling. VPD-induced stomatal closure is not affected in mpk12 / mpk4GC double mutants that completely disrupt stomatal CO 2 signaling, indicating that VPD signaling is independent of the early CO 2 signal-transduction pathway. Calcium imaging shows that osmotic stress causes cytoplasmic Ca 2+ transients in guard cells. Nevertheless, osca1-2 / 1.3 / 2.2 / 2.3 / 3.1 Ca 2+ -permeable channel quintuple, osca1.3 / 1.7 -channel double, cngc5 / 6 -channel double, cngc20 -channel single, cngc19 / 20crispr -channel double, glr3.2 / 3.3 -channel double, cpk- kinase quintuple, cbl1 / 4 / 5 / 8 / 9 quintuple, and cbl2 / 3rf double mutants showed wild-type-like stomatal VPD responses. A B3-family Raf-like mitogen-activated protein (MAP)-kinase kinase kinase, M3Kδ5/RAF6, activates the OST1/SnRK2.6 kinase in plant cells. Interestingly, B3 Raf-kinase m3kδ5 and m3kδ1 / δ5 / δ6 / δ7 ( raf3 / 6 / 5 / 4 ) quadruple mutants, but not a 14-gene raf-kinase mutant including osmotic stress-linked B4-family Raf-kinases, exhibited slowed high-VPD responses, suggesting that B3-family Raf-kinases play an important role in stomatal VPD signaling. Moreover, high VPD-induced stomatal closure was impaired in receptor-like pseudokinase GUARD CELL HYDROGEN PEROXIDE-RESISTANT1 (GHR1) mutant alleles. Notably, the classical transient "wrong-way" VPD response was absent in ghr1 mutant alleles. These findings reveal genes and signaling mechanisms in the elusive high VPD-induced stomatal closing response pathway., Competing Interests: The authors declare no competing interest.

Background/aims: In a recent study, attenuation imaging (ATI) with ultrasound was used as a new approach for detecting liver steatosis. However, although there are many studies on ATI and controlled attenuation parameter (CAP) that prove their practicability, there are few studies comparing these two methods. As such, this study compared CAP and ATI for the detection and evaluation of liver steatosis., Methods: A prospective analysis of 28 chronic liver disease patients who underwent liver biopsy, FibroScan® imaging, and ATI with ultrasound was conducted. The presence and degree of steatosis, as measured with the FibroScan® device and ATI, were compared with the pathological results obtained using liver biopsy., Results: The areas under the receiver operating characteristic curve (AUROC) of ATI and CAP for differentiating between normal and hepatic steatosis were 0.97 (95% confidence interval [CI] 0.83-1.00) and 0.96 (95% CI 0.81-0.99), respectively. ATI has a higher AUROC than CAP does in liver steatosis, at 0.99 (95% CI, 0.86-1.00) versus 0.91 (95% CI, 0.74-0.98) in grade ≥ 2 and 0.97 (95% CI, 0.82-1.00) versus 0.88 (95% CI, 0.70-0.97) in grade = 3, respectively., Conclusion: The ATI and CAP results showed good consistency and accuracy for the steatosis grading when compared with the liver biopsy results. Moreover, ATI is even better than CAP in patients with moderate or severe steatosis. Therefore, ATI represents a non-invasive and novel diagnostic tool with which to support the diagnosis of liver steatosis in clinical practice., Competing Interests: The authors have declared that no competing interests exist.

Lung cancer is the leading cause of cancer-related mortality worldwide, and its tumorigenesis involves the accumulation of genetic and epigenetic events in the respiratory epithelium. Epigenetic modifications, such as DNA methylation, RNA modification, and histone modifications, have been widely reported to play an important role in lung cancer development and in other pulmonary diseases. Whereas the functionality of DNA and chromatin modifications referred to as epigenetics is widely characterized, various modifications of RNA nucleotides have recently come into prominence as functionally important. N6-methyladosine (m6A) is the most prevalent internal modification in mRNAs, and its machinery of writers, erasers, and readers is well-characterized. However, several other nucleotide modifications of mRNAs and various noncoding RNAs have also been shown to play an important role in the regulation of biological processes and pathology. Such epitranscriptomic modifications play an important role in regulating various aspects of RNA metabolism, including transcription, translation, splicing, and stability. The dysregulation of epitranscriptomic machinery has been implicated in the pathological processes associated with carcinogenesis including uncontrolled cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In recent years, with the advancement of RNA sequencing technology, high-resolution maps of different modifications in various tissues, organs, or disease models are being constantly reported at a dramatic speed. This facilitates further understanding of the relationship between disease development and epitranscriptomics, shedding light on new therapeutic possibilities. In this review, we summarize the basic information on RNA modifications, including m6A, m1A, m5C, m7G, pseudouridine, and A-to-I editing. We then demonstrate their relation to different kinds of lung diseases, especially lung cancer. By comparing the different roles RNA modifications play in the development processes of different diseases, this review may provide some new insights and offer a better understanding of RNA epigenetics and its involvement in pulmonary diseases.

Objective: Nonintubated anesthesia, electromagnetic navigation (EMN)-guided preoperative localization, and uniportal video-assisted thoracic surgery (VATS) are recent innovations in minimally invasive thoracic surgery. This study aimed to explore the feasibility of applying nonintubated anesthesia in a "one-stage" localization and resection workflow., Methods: Patients who underwent EMN-guided preoperative percutaneous localization with indocyanine green (ICG) and uniportal VATS were included. Perioperative data were compared between patients receiving nonintubated anesthesia and those receiving general anesthesia with endotracheal intubation., Results: Forty-six patients with a total of 50 nodules were included in the study. Overall, finger palpation could be avoided in 94% of the nodules, whereas fluorescent green signals with a clear border on the pleural surface were noted in 91.3% (21 of 23) of nodules in the nonintubated group and 88.9% (24 of 27) of nodules in the intubated group. Intraoperatively, the nonintubated group had a lower median pH (7.33 [interquartile range (IQR), 7.28-7.40] vs 7.41 [IQR, 7.38-7.44]; P  = .003), higher median arterial CO 2 (45.5 [IQR, 41.1-58.7] mm Hg vs 38.4 [IQR, 35.3-40.6] mm Hg; P  < .001), and lower arterial oxygen (322 [IQR, 211-433] mm Hg vs 426 [IQR, 355-471] mm Hg; P  = .005) levels compared with the intubated group. The nonintubated group also had a shorter median registration time (2.0 [IQR, 1.0-3.0] minutes vs 3.0 [IQR, 2.0-8.0] minutes; P  = .008) and total time in the operating room (150 [IQR, 130-175] minutes vs 170 [IQR, 135-203] minutes; P  = .035), whereas no between-group differences were seen in localization and operative time. The duration of chest drainage, postoperative complications, pathologic diagnosis, and margins were similar in the 2 groups., Conclusions: Nonintubated "one-stage" EMN-guided percutaneous ICG localization and uniportal VATS can be an option for selected patients undergoing treatment for small peripheral nodules., (© 2021 The Author(s).)

Objectives: Successful antiviral treatment in patients with hepatitis C can lead to reduced liver stiffness. In this study, we attempted to compare 2-dimensional (2D) shear wave elastography (SWE), shear wave dispersion (SWD), and attenuation imaging (ATI) with transient elastography (TE) and the controlled attenuation parameter (CAP) in patients under direct-acting antiviral (DAA) therapy., Methods: Patients with chronic hepatitis C infection undergoing DAA therapy from January 2017 to June 2020 were retrospectively examined. The results of 2D SWE, SWD, ATI, TE, and CAP were recorded before and 12 weeks after the completion of DAA therapy., Results: A total of 122 patients with a median age of 61 years were investigated; among them, 121 (99.2%) achieved a sustained virologic response at 12 weeks after DAA therapy. Fibrosis 4, the aspartate aminotransferase-to-platelet ratio index, 2D SWE, and TE were reduced after DAA therapy. The CAP was increased; however, SWD and ATI showed no statistically significant changes after DAA therapy. Two-dimensional SWE and TE were strongly correlated (r = 0.885-0.897; P < .001). Albumin and the baseline liver stiffness measurement were independent factors of liver stiffness measurement changes after DAA therapy., Conclusions: Direct-acting antiviral therapy can significantly decrease liver stiffness (using both 2D SWE and TE) but not SWD and ATI values in patients with hepatitis C. An increased CAP is also observed after DAA therapy., (© 2020 American Institute of Ultrasound in Medicine.)

Abstract: The incidence rates of type 2 diabetes mellitus (T2DM) and colorectal polyps have been increasing over the last decades. However, direct associations between T2DM and colorectal polyps have not been extensively reported. We will explore the relationship between T2DM and colorectal polyps.In the retrospective study, we classified DM and NonDM groups (control) from 993,516 people in Taiwan nationwide population insurance database from the period of 2000 to 2013. We collected data on income and comorbidities through the international classification of diseases, ninth revision-clinical modification (ICD-9-CM) codes.The T2DM group had a higher incidence rate of colorectal polyps (31.97%, 95% confidence interval [CI] = 30.97-33.28) than the control group (25.9%, 95% CI = 25.1-26.72), and the crude incidence ratio was 1.235 (95% CI = 1.174-1.300). In 13 years of follow-up (2000-2013), T2DM was linked to a significantly higher cumulative probability of colorectal polyps (log-rank test: P = .0001).Patients with T2DM had a 1.23-fold higher risk of new colorectal polyps than control patients in 13 years of follow-up. We explain the T2DM increases incidence for colorectal polyps in long term follow-up., Competing Interests: The authors have no conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Hepatitis C virus (HCV) is one of the major causes of chronic liver disease, cirrhosis, and liver cancer. Most of the infected people have no clinical symptoms. The current strategy for HCV elimination includes test and treatment. In this study, we aimed to evaluate the campaign for retrieving patients who were lost to follow-up, for subsequent re-evaluation., Methods: From January 2020 to October 2020, patients who had prior tests for positive anti-HCV antibody in 2010-2018 in our hospital were enrolled for our patient callback campaign. Patients who had unknown HCV RNA status or no documented successful antiviral therapy history were selected for anti-HCV therapy re-evaluation. To facilitate patient referral in the hospital, we developed an electronic reminding system and called the candidate patients via telephone during the study period., Results: Through the hospital electronic system, 3783 patients with positive anti-HCV antibody documentation were identified. Among them, 1446 (38.22%) had tested negative for HCV RNA or had anti-HCV therapy, thereby excluded. Of the 2337 eligible patients, 1472 (62.99%) were successfully contacted and called back during the study period for subsequent HCV RNA testing and therapy. We found that 42.19% of the patients had positive HCV RNA and 88% received subsequent anti-HCV therapy., Conclusions: A significant number of patients with positive HCV serology were lost for HCV confirmatory test or therapy in the hospital. Therefore, this targeted HCV callback approach in the hospital is feasible and effective in achieving microelimination.

The prognostic role of histological patterns of dominant tumor (DT) and second dominant tumor (sDT) in synchronous multiple adenocarcinoma (SMADC) of lung remains unclear. SMADC patients diagnosed between 2003 and 2015 were retrospectively reviewed. DT and sDT were defined as two maximum diameters of consolidation among multiple tumors. Histological pattern was determined using IASLC/ATS/ERS classification system. DTs were divided into low- (lepidic), intermediate- (acinar, papillary) and high-grade (micropapillary, solid) subtypes, and sDTs into non-invasive predominant (lepidic) and invasive predominant (acinar, papillary, micropapillary, solid) subtypes. During mean 74-month follow-up among 149 nodal-negative patients having SMADC resected, recurrence was noted in 44 (29.5%), with significantly higher percentage in high-grade DT (p < 0.001). Five-year overall (OS) and disease-free (DFS) survivals in low-, intermediate- and high-grade DT were 96.9%, 94.3%, 63.3% (p < 0.001) and 100%, 87.2%, 30.0%, respectively (p < 0.001). Cox-regression multivariate analysis demonstrated high-grade DT as a significant predictor for DFS (Hazard ratio [HR] 5.324; 95% CI 2.570-11.462, p < 0.001) and OS (HR 3.287; 95% CI 1.323-8.168, p = 0.010). Analyzing DT and sDT together, we found no significant differences in DFS, either in intermediate- or high-grade DT plus invasive or non-invasive sDT. DT was histologically an independent risk factor of DFS and OS in completely resected nodal-negative SMADCs.

Objectives: The present study aimed to clarify the association between preoperative biopsy and surgical outcomes in clinical stage I non-small-cell lung cancer (NSCLC) with different proportions of ground-glass opacity (GGO)., Methods: Data on patients who underwent pulmonary resection for NSCLC from 2006 to 2016 were drawn from a prospective registered database and analysed retrospectively. Patient characteristics collected included tumour size, location and staging, surgical approach, consolidation-tumour ratio, histopathology and the presence or absence of preoperative biopsy to identify the independent prognostic factors of disease-free survival (DFS) and cancer-specific survival. A 1:1 propensity score matching was conducted between the preoperative biopsy and reference groups based on their baseline characteristics measured before the decision for preoperative biopsy., Results: A total of 1427 patients were collected to achieve an overall 5-year DFS as 84.5% (median follow-up: 67.3 months), stratified to be 99.5% in the GGO-dominant group (n = 430) and 78.2% in the solid-dominant group (n = 997). Only 2 patients (0.5%) in the GGO-dominant group experienced tumour recurrence. For solid-dominant tumours matched with propensity scores (279 in preoperative biopsy vs 279 in reference group), the independent predictors of DFS included preoperative biopsy, sublobar resection, pathological staging and angiolymphatic invasion. Preoperative biopsy was a predictor of cancer-specific survival in univariable analysis but was not in multivariable analysis. Significant differences were also found between matched groups in those with late-delay surgery, but not in patients receiving preoperative biopsy with early-delay surgery (≤21 days)., Conclusion: Preoperative biopsy may worsen surgical outcomes in patients with clinical stage I, solid-dominant NSCLC., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Preoperative positron emission tomography/computed tomography (PET/CT) is recommended as a guideline for staging of lung cancer. However, for patients with pulmonary ground-glass opacity (GGO) nodules who are supposed to have a relatively low risk of incidence of lymphatic metastasis, it remains uncertain whether PET/CT is more effective than consolidation-to-tumor ratio (CTR) in the prediction of regional lymphatic metastasis., Methods: The data on patients who underwent surgery for lung cancer from 2011 to 2016 were collected retrospectively, which included CTR, results of PET/CT, and pathological characteristics. The patients who had undergone preoperative PET/CT were identified to find the risk factors for lymphatic metastasis. A receiver operating characteristic (ROC) curve and multiple logistic regression was utilized to clarify the predictive value of CTR and main tumor maximal standardized uptake value (SUVmax)., Results: Among 217 patients who had PET/CT before lobectomy, chest computed tomography revealed that 75 patients had CTR greater than 62%. The patients with lymphatic metastasis were shown to have higher CTR and higher main tumor SUVmax. Multiple logistic regression showed that younger age (<60 years), higher main tumor SUVmax on PET/CT, and greater CTR were independent predictive factors for lymphatic metastasis. The area under the ROC curve was comparable, 0.817 for CTR, and 0.816 for main tumor SUVmax., Conclusions: The present study revealed that CTR was not inferior to main tumor SUVmax considering the predictive power for lymphatic metastasis preoperatively in lung cancer patients with a GGO component. PET/CT might not be necessary preoperatively in selected patients., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Pathologic complete lymph node regression (LNR), where the lymph nodes show evidence of neoadjuvant treatment effect but have no viable residual tumor cells, is sometimes observed following neoadjuvant treatments and has been shown to be prognostic; conflicting results exist in the current literature., Methods: Patients who received neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for squamous carcinoma (ESCC) were retrospectively reviewed and classified according to their LNR score; 0: N(-) with no evidence of tumor involvement or regression; 1: N(-) with evidence of complete regression; 2: N(+) with < 50% viable tumor; and 3: N(+) with > 50% viable tumor., Results: In total, 136 patients, comprising 73, 25, 16, and 22 patients with LNR scores of 0, 1, 2, or 3, respectively, were included. Pathologic complete LNR (LNR 1) was significantly associated with lower risks of lymphovascular invasion (0%, p < 0.001) and perineural invasion (4%, p = 0.038), and a higher rate of pathologic complete response in the primary tumor (76%, p < 0.001). The 5-year overall survival rates were 42.1%, 52.8%, and 8.0% in patients with an LNR score of 0, 1, and 2/3, respectively (p < 0.001). There was no significant difference between patients with LNR scores of 0 and 1 in overall survival (p = 0.454), disease-free survival (p = 0.501), and cumulative incidence of recurrences (hazard ratio 0.84, 95% confidence interval 0.432-1.623, p = 0.601)., Conclusions: Pathologic complete LNR could be an indicator of nCRT sensitivity and can be regarded as a good prognostic factor in patients with ESCC. In the survival curve analysis that included patients with lymph node regression (LNR) scores of 0 (blue), 1 (red), and 2/3 (green), we found that patients with pathologic complete LNR (LNR 1), which suggests prior positive nodal involvement, had similar outcomes as those without evidence of prior tumor involvement in lymph node (LNR0).

In recent years, ultrasound attenuation imaging (ATI) has emerged as a new method to detect liver steatosis. However, thus far, no studies have confirmed the clinical utility of this technology. Using a retrospective database analysis of 28 patients with chronic liver disease who underwent ultrasound liver biopsy and ATI, we compared the presence and degree of steatosis measured by ATI with the results obtained through liver biopsy. The area under the receiver operating characteristic curve (AUROC) of the ATI for differentiating between normal and hepatic steatosis was 0.97 (95% confidence interval: 0.83-1.00). The AUROC of the ATI was 0.99 (95% confidence interval: 0.86-1.00) in grade ≥2 liver steatosis and 0.97 (95% confidence interval: 0.82-1.00) in grade 3. ATI showed good consistency and accuracy for the steatosis grading of liver biopsy. Therefore, ATI represents a novel diagnostic measurement to support the diagnosis of liver steatosis in non-invasive clinical practice.

Background: The presence of lymphovascular invasion (LVI) and perineural invasion (PNI) are of great prognostic importance in esophageal squamous cell carcinoma. Currently, positron emission tomography (PET) scans are the only means of functional assessment prior to treatment. We aimed to predict the presence of LVI and PNI in esophageal squamous cell carcinoma using PET imaging data by training a three-dimensional convolution neural network (3D-CNN)., Methods: Seven hundred and ninety-eight PET scans of patients with esophageal squamous cell carcinoma and 309 PET scans of patients with stage I lung cancer were collected. In the first part of this study, we built a 3D-CNN based on a residual network, ResNet, for a task to classify the scans into esophageal cancer or lung cancer. In the second stage, we collected the PET scans of 278 patients undergoing esophagectomy for a task to classify and predict the presence of LVI/PNI., Results: In the first part, the model performance attained an area under the receiver operating characteristic curve (AUC) of 0.860. In the second part, we randomly split 80%, 10%, and 10% of our dataset into training set, validation set and testing set, respectively, for a task to classify the scans into the presence of LVI/PNI and evaluated the model performance on the testing set. Our 3D-CNN model attained an AUC of 0.668 in the testing set, which shows a better discriminative ability than random guessing., Conclusions: A 3D-CNN can be trained, using PET imaging datasets, to predict LNV/PNI in esophageal cancer with acceptable accuracy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-1419). JCYY is the CEO of aetherAI, Co., Ltd. WHY and CKY are the employees of aetherAI, Co., Ltd. PKH serves as a current Editorial Team member. The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

The plant hormone abscisic acid (ABA) plays a central role in the regulation of stomatal movements under water-deficit conditions. The identification of ABA receptors and the ABA signaling core consisting of PYR/PYL/RCAR ABA receptors, PP2C protein phosphatases and SnRK2 protein kinases has led to studies that have greatly advanced our knowledge of the molecular mechanisms mediating ABA-induced stomatal closure in the past decade. This review focuses on recent progress in illuminating the regulatory mechanisms of ABA signal transduction, and the physiological importance of basal ABA signaling in stomatal regulation by CO 2 and, as hypothesized here, vapor-pressure deficit. Furthermore, advances in understanding the interactions of ABA and other stomatal signaling pathways are reviewed here. We also review recent studies investigating the use of ABA signaling mechanisms for the manipulation of stomatal conductance and the enhancement of drought tolerance and water-use efficiency of plants., (© 2020 Society for Experimental Biology and John Wiley & Sons Ltd.)

Introduction: Few studies have investigated the impact of active surveillance on pathological outcome ground-glass nodules (GGNs). We focused on GGNs that needed preoperative localization before resection and compared the pathological results between GGNs that underwent early resection or active surveillance., Methods: We retrospectively reviewed data of resected GGNs between January 2017 and December 2018. GGNs were classified by early resection (Group A) and active surveillance (Group B). Group B was subclassified as no (Group B1) and with (Group B2) growth, and intergroup comparison of pathological results was undertaken., Results: In total, 509 GGNs (124, 275, and 110 in Groups A, B1, and B2, respectively) were included. Malignancy (primary lung cancer) ratios were 68% and 72% in Groups A and B (p = .312) and 65% and 92% in Groups B1 and B2, respectively (p < .001). The ratios of invasive carcinoma were 21.4%, 9.6%, and 35.6% in Groups A, B1, and B2, respectively. Predictors for invasive carcinoma included history of lung cancer, GGN size ≥ 10 mm, solid size ≥ 6 mm, and GGN growth., Conclusions: The pathological findings were similar for GGNs in the early resection and active surveillance groups. However, rates of malignancy and invasive carcinoma increased in the group that manifested growth during active surveillance., (© 2020 Wiley Periodicals LLC.)

Competing Interests: Declaration of Competing Interest The authors have no conflict of interest.

Background: Nonintubated video-assisted thoracic surgery (VATS) is widely used due to its acceptable postoperative outcomes. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) has been successfully applied in cases of prolonged difficult intubation and intensive respiratory care in patients receiving VATS lobectomy. Thopaz Digital Chest Drainage System (THOPAZ) provides regulated negative pressure close to the patient's chest, optimizing drainage of the pleural and mediastinum. We explored the surgical outcomes of nonintubated VATS lung wedge resection and traditional wedge resection with a double-lumen endotracheal tube., Methods: Patients who received nonintubated VATS lung wedge resection (group A, n = 81) and traditional wedge resection with double-lumen endotracheal tube (group B, n = 79) during the period of November 2015 to April 2018 were enrolled in the study. Demographic data and operation outcomes were obtained and analyzed from review of patient medical charts., Results: Group B had significantly longer mean induction and operative times than group A. Similarly, group B suffered greater intraoperative blood loss, longer postoperative hospital stays, and increased chest tube retention times than group A. Group A had higher partial pressure of carbon dioxide levels in both the pre-one-lung and during one-lung ventilation periods than group B. Furthermore, group A showed lower serum pH levels during one-lung ventilation period. However; group A had significantly higher partial pressure of oxygen levels during one-lung ventilation than group B, although the differences in peripheral oxygen saturation were not statistically significant., Conclusion: Our study demonstrated that nonintubated VATS using THRIVE and THOPAZ in lung wedge resection provides measurable benefits to patients.

Background: Adenocarcinoma is the most common type of lung cancer, and pre-operative biopsy plays an important role to determine its major subtypes. As proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) in 2011, the predominant histological subtype of adenocarcinoma is an indicator of outcomes and recurrence rate. However, the value of CT-guided core biopsy in predicting the predominant subtype and detecting the presence of an aggressive subtype of adenocarcinoma, peripheral sub-solid nodule, has less been discussed., Methods: We retrospectively reviewed 318 consecutive peripheral sub-solid nodules that underwent percutaneous CT-guided lung biopsy and surgical resection, between October 2015 and December 2018 and were diagnosed as adenocarcinoma with histological subtype. The subtyping results from biopsy and surgical pathology were compared to evaluate the concordance rate., Results: The overall concordance rate between biopsy and surgical pathology in determining the predominant histological subtype was 64%. Better concordance was found in small tumors (≤ 2 cm), in predicting either predominant histology (χ 2  = 7.091, P = 0.008) or high grade adenocarcinoma, micropapillary and/or solid subtype, MIP-SOL (χ 2  = 22.301, P < 0.001). The analysis of ground glass opacity (GGO) component (C/T ratio) obtained significantly higher accuracy in the pure GGO group than in the other two groups in predicting predominant histology or high grade adenocarcinoma (χ 2  = 17.560, P < 0.001 and χ 2  = 61.938, P < 0.001, respectively)., Conclusions: CT-guided core biopsies provide additional value in predicting the histological subtype of lung adenocarcinoma after surgical resection, especially in small tumors (≤ 2 cm) or an initially pure GGO group.

The prognostic impact of circumferential resection margin (CRM) in surgically resected esophageal squamous cell carcinoma (ESCC) has been controversial. This investigation assessed the prognostic impact of CRM in surgically resected pathologic T3 ESCC patients with or without neoadjuvant chemoradiotherapy (nCRT). We reviewed consecutive p/yp T3 ESCC patients undergoing esophagectomy from two medical centers between January 2009 and December 2016. The cohort was divided into two groups: upfront esophagectomy (upfront surgery) and nCRT followed by esophagectomy (nCRT + surgery). CRM status was assessed and divided into CRM > 1 mm, 0 < CRM < 1 mm, and tumor at CRM. A total of 217 p/yp T3 ESCC patients undergoing esophagectomy (138 patients in the upfront surgery group and 79 in the nCRT + surgery group) were enrolled. In the upfront surgery group, patients with 0 < CRM < 1 mm showed equivalent overall survival to those with CRM > 1 mm (log-rank P = 0.817) and significantly outlived those with tumor at CRM (log-rank P < 0.001). However, in the nCRT + surgery group, CRM > 1 mm failed to show survival superiority to CRM between 0 and 1 mm or involved by cancer (log-rank P = 0.390). In conclusion, a negative CRM, even though being <1 mm, is adequate for pT3 ESCC patients undergoing upfront esophagectomy. In contrast, the CRM status is less prognostic in ypT3 ESCC patients undergoing nCRT followed by esophagectomy., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Tubeless uniportal video-assisted thoracic surgery (VATS), using a uniportal approach and non-intubated anaesthesia while avoiding postoperative chest drain insertion, for patients undergoing thoracoscopic surgery has been demonstrated to be feasible in selected cases. However, to date, the safety of the procedure has not been studied., Methods: We reviewed consecutive patients undergoing non-intubated uniportal VATS for pulmonary wedge resection at 2 medical centres between August 2016 and October 2019. The decision to avoid chest drain insertion was made in selected candidates. For those candidates in whom a tubeless procedure was performed, postoperative chest X-rays (CXRs) were taken on the day of the surgery [operation (OP) day], on postoperative day 1 and 1-2 weeks later. The factors associated with abnormal CXR findings were studied., Results: Among 135 attempts to avoid chest drain insertion, 13 (9.6%) patients ultimately required a postoperative chest drain. Among 122 patients in which a tubeless procedure was performed, 26 (21.3%) and 47 (38.5%) had abnormal CXR findings on OP day and postoperative day 1, respectively. Among them, 3 (2.5%) patients developed clinically significant abnormal CXRs and required intercostal drainage. Primary spontaneous pneumothorax was independently associated with a higher risk of postoperative abnormal CXRs., Conclusions: Tubeless uniportal VATS for pulmonary wedge resection can be safely performed in selected patients. Most patients with postoperative abnormal CXRs presented subclinical symptoms that spontaneously resolved; only 2.5% of patients with postoperative abnormal CXRs required drainage., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: An optimal method for preoperative localization of small lung nodules is yet to be established, and there are few comparative studies in the literature. In the present study, we aimed to compare electromagnetic navigation-guided and computed tomography (CT)-guided methods of percutaneous transthoracic localization., Methods: The clinical, radiographic, surgical and pathological data of patients who underwent electromagnetic navigation-guided localization (EMNGL) and CT-guided localization (CTGL) before uniportal video-assisted thoracic surgery (VATS) were reviewed. Propensity score matching analysis was performed to compare the localization and surgical results., Results: After matching, 25 EMNGL and 50 CTGL patients were included in the analysis. In the CTGL group, pulmonary haemorrhage and pneumothorax were noted in 56% and 34% of patients, respectively, on postprocedural CT scans. Successful localization was achieved in 96% and 100% of patients in the EMNGL and CTGL groups, respectively (P = 0.333). The median time in the operation room was significantly shorter in the CTGL group {142.5 [interquartile range (IQR) 123.8-175.0] vs 205.0 [IQR 177.5-290.0] min, P < 0.001}. In contrast, EMNGL significantly decreased the total time [205.0 (IQR 177.5-290.0) vs 324.0 (IQR 228.3-374.0) min, P = 0.002]. The median duration of chest drainage was 1 day shorter in the EMNGL group [2.0 (IQR 1.5-2.5) vs 3.0 (IQR 2.0-3.0), P = 0.002]; the surgical complication rates were comparable between the 2 groups., Conclusions: The localization and surgical results were similar between the EMNGL and CTGL groups. EMNGL is comparable to conventional CTGL with respect to preoperative localization of small lung nodules before uniportal VATS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: The role of extracapsular lymph node involvement (ELNI) in esophageal cancer has not been fully investigated. We aim to assess its incidence and prognostic significance in patients with esophageal squamous cell carcinoma (ESCC) treated with and without neoadjuvant treatments., Methods: Data of patients who underwent esophagectomy for ESCC in a single medical center was retrospectively reviewed. Patients with positive lymph node involvement were classified as either with ELNI or without ELNI (intracapsular lymph node involvement, ILNI). The impact of ELNI on overall survival (OS), disease-free survival (DFS), and disease recurrence was analyzed., Results: A total of 336 patients, including 179 without (NCRT -) and 157 with (NCRT +) neoadjuvant chemoradiotherapy, were included. Seventy-two of 179 (40.2%) patients in NCRT - group were with positive lymph node, of whom 19 (26.4%) had ELNI, whereas 49 (31.2%) patients in NCRT + group had positive lymph node, of whom 25 (51.0%) had ELNI. In NCRT + group, patients with ELNI had worse outcome compared to those with ILNI in 5-year OS (10.4 vs. 13.8%, p = 0.008), and DFS (5.3 vs. 17.5%, p = 0.008). The presence of ELNI was also associated with more distant recurrence (p = 0.03). In contrast, there was no survival difference between patients with ELNI and ILNI in NCRT - group., Conclusions: Compared with ILNI, ELNI is a significant poor prognostic factor in patients with ESCC treated with neoadjuvant treatments, but not in those with primary surgery.

Purpose: To evaluate whether preoperative biopsy affects the outcomes of patients undergoing at least lobectomy for stage I lung adenocarcinoma., Methods: We reviewed the medical records of patients who underwent surgery for stage I lung adenocarcinoma between 2006 and 2013. Tumor recurrence and survival were compared between patients who underwent preoperative biopsy, including computed tomographic-guided needle biopsy and transbronchial biopsy, and those who underwent intraoperative frozen section., Results: Among 509 patients, 229 patients (44.9%) underwent preoperative biopsy and 280 patients had lung adenocarcinoma diagnosed by intraoperative frozen section (reference group). Recurrence developed in 65 (12.8%) patients within a median follow-up period of 54.4 months. Multivariate analysis demonstrated that preoperative biopsy (OR 1.97, p = 0.045), radiological solid appearance (OR 5.43, p < 0.001), and angiolymphatic invasion (OR 2.48, p = 0.010) were independent predictors of recurrence. In the overall cohort, preoperative biopsy appeared to worsen 5-year disease-free and overall survival significantly (76.6% vs. 93.0%, p < 0.001; and 83.8% vs. 94.5%, p = 0.002, respectively) compared with the reference group. After propensity matching, multivariable logistic regression still identified preoperative biopsy as an independent predictor of overall recurrence (OR 2.21, p = 0.048) after adjusting for tumor characteristics., Conclusion: Preoperative biopsy might be considered a prognosticator of recurrence of stage I adenocarcinoma of the lungs in patients who undergo at least anatomic lobectomy without postoperative adjuvant chemotherapy.

Background: Studies addressing both lymphovascular invasion (LVI) and perineural invasion (PNI) in patients with esophageal squamous cell carcinoma (ESCC) treated with or without neoadjuvant therapy are limited. We aimed to analyze the incidence and prognostic significance of LVI and PNI in patients with thoracic ESCC., Methods: This retrospective study included 520 patients with ESCC: 174 patients after neoadjuvant treatment followed by surgery and 346 after primary esophagectomy, from two medical centers. The relationships between LVI, PNI, and other histological factors were evaluated. The Cox regression model was used for survival analysis., Results: Positive LVI and PNI were noted in 35.6% and 22.4% of patients with residual primary tumor after neoadjuvant treatment and in 39.6% and 24.0% of patients who underwent primary esophagectomy, respectively. In patients with neoadjuvant treatments, the 5-year overall survival rates were 12.7% and 28.3% in patients with positive LVI and negative LVI, respectively (p = 0.001). The 5-year overall survival rates were 6.4% and 29.9% in patients with positive PNI and negative PNI, respectively (p < 0.001). In patients who did not receive neoadjuvant treatment, the 5-year overall survival rates were 28.2% and 61.1% in patients with positive LVI and negative LVI, respectively (p < 0.001). The 5-year overall survival rates were 30.2% and 52.5% in patients with positive PNI and negative PNI (p < 0.001). In subgroup analysis, the presence of PNI was an independent prognostic factor in patients with neoadjuvant treatments, whereas the presence of LVI had more significant prognostic impact in patients with node-negative ESCC after primary esophagectomy., Conclusions: Both LVI and PNI statuses are significant prognostic factors for patients with ESCC. However, the prognostic impact of LVI was majorly in the subgroup of node-negative patients who received primary esophagectomy.

Lineage tracing aims to identify the progeny of a defined population of dividing progenitor cells, a daunting task in the developing central nervous system where thousands of cell types are generated. In mice, lineage analysis has been accomplished using Cre recombinase to indelibly label a defined progenitor population and its progeny. However, the interpretation of historical recombination events is hampered by the fact that driver genes are often expressed in both progenitors and postmitotic cells. Genetically inducible approaches provide temporal specificity but are afflicted by mosaicism and toxicity. Here, we present PRISM, a progenitor-restricted intersectional fate mapping approach in which Flp recombinase expression is both dependent on Cre and restricted to neural progenitors, thus circumventing the aforementioned confounds. This tool can be used in conjunction with existing Cre lines making it broadly applicable. We applied PRISM to resolve two developmentally important, but contentious, lineages-Shh and Cux2., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sucrose-non-fermenting-1-related protein kinase-2s (SnRK2s) are critical for plant abiotic stress responses, including abscisic acid (ABA) signaling. Here, we develop a genetically encoded reporter for SnRK2 kinase activity. This sensor, named SNACS, shows an increase in the ratio of yellow to cyan fluorescence emission by OST1/SnRK2.6-mediated phosphorylation of a defined serine residue in SNACS. ABA rapidly increases FRET efficiency in N. benthamiana leaf cells and Arabidopsis guard cells. Interestingly, protein kinase inhibition decreases FRET efficiency in guard cells, providing direct experimental evidence that basal SnRK2 activity prevails in guard cells. Moreover, in contrast to ABA, the stomatal closing stimuli, elevated CO 2 and MeJA, did not increase SNACS FRET ratios. These findings and gas exchange analyses of quintuple/sextuple ABA receptor mutants show that stomatal CO 2 signaling requires basal ABA and SnRK2 signaling, but not SnRK2 activation. A recent model that CO 2 signaling is mediated by PYL4/PYL5 ABA-receptors could not be supported here in two independent labs. We report a potent approach for real-time live-cell investigations of stress signaling., Competing Interests: LZ, YT, PH, HK, EM, PK, JS No competing interests declared, (© 2020, Zhang et al.)

Background: Thoracoscopic resection of small pulmonary nodules can be challenging, which highlights the importance of preoperative localization. We report our experience with electromagnetic navigation-guided localization., Methods: The clinical, radiographic, surgical, and pathologic data of patients who underwent electromagnetic navigation-guided preoperative localization for pulmonary tumors smaller than 2 cm were reviewed. Successful localization was defined as successful identification of target lesions during the thoracoscopic procedure without palpation., Result: Included were 30 patients with 35 nodules. There were 31 transthoracic and 5 transbronchial approaches performed. One patient received both approaches for the same tumor, and 3 received both approaches for localization of multiple targets. The median nodule size was 1.0 cm (interquartile range [IQR], 0.8-1.2 cm), and the median distance from the pleural surface was 1.1 cm (IQR, 0.6-2.0 cm). The most commonly used marker for localization was dye (n = 18), followed by microcoils (n =15). In nodules located with microcoils, the median distance between the microcoil and nodule was 1 mm (IQR, 0-3 mm). There were no complications related to the localization procedure. Successful localization was achieved in 27 of 30 patients (90.0%) and in 32 of 35 nodules (91.4%). The pathologic diagnosis was primary pulmonary malignancy in 29 nodules and secondary pulmonary malignancy in 6., Conclusions: Our experience with electromagnetic navigation-guided transbronchial and transthoracic preoperative localization of small, malignant pulmonary tumors shows this technique is feasible and appears to be a viable option for preoperative localization of pulmonary nodules that may be difficult to locate thoracoscopically., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

This study was conducted to test the effectiveness of a particular bitter melon peptide (BMP), with a specific sequence of 19 amino acids (mcIRBP-19), in regulating diabetic patients' blood glucose. In order to test the product with the specially processed BMP, a total of 142 diabetic patients were solicited as study subjects, of which 64 were assigned to an experiment group and 78 to a control group. Biochemical data were compared with a paired t- test to verify the significance of changes over different time periods. The clinical results showed that BMP started to improve the subjects' glycated hemoglobin (HbA1c) levels at the end of the second month (T2), with mean values being significantly lowered from 7.8 ± 1.4% (T0) to 7.5 ± 1.4% (T2) ( p = 0.004). The values reduced continuously, eventually reaching 7.4 ± 1.1% ( p = 0.000) at the end of the experiment (T3). HbA1c levels for the control group were 7.5 ± 1.2% in T0 and 7.5 ± 1.1% (T3), and not significantly different ( p = 0.852) over the same period. This study provides clinical evidence that helps to verify the effectiveness of the new BMP product in regulating diabetic patients' blood sugar levels., Competing Interests: The authors declare no conflict of interest.

Background: This study aimed to compare survival between standard lobectomy and surgeons' preference sublobar resection among patients with stage I non-small cell lung cancer (NSCLC)., Methods: Medical records of patients undergoing pulmonary resection between 2006 and 2016 were reviewed retrospectively. Differences in disease-free survival (DFS) and DFS-associated factors between patients receiving lobectomy and surgeons' preference sublobar resection were analyzed after 1-1 propensity score-matching (n = 119 per group)., Results: In total, 1064 pathological stage I NSCLC patients were identified, including 816 (76.7%) who underwent lobectomy, 111 (10.4%) who underwent sublobar resection as a compromised procedure (medically unfit), and 137 (12.9%) who underwent surgeons' preference sublobar resection. Rates of five-year DFS for patients undergoing lobectomy, medically unfit, and surgeons' preference sublobar resection were 88.7%, 71.0%, and 93.4%, respectively (P < 0.001). Multivariable Cox regression analysis demonstrated that radiological solid-appearance (adjusted hazard [aHR] = 2.908, P = 0.003), PL2 invasion (aHR = 1.970, P = 0.024), and angiolymphatic invasion (aHR = 2.202, P = 0.005) were significantly associated with lower DFS after adjusting for surgeons' preference sublobar resection (aH = 1.031, P = 0.939). Subgroup analysis of all 403 solid-dominant patients demonstrated equivalent five-year DFS between surgeons' preference sublobar resection and lobectomy (87.7% and 84.1%, respectively, P = 0.721). Propensity-matched analysis showed no differences in five-year DFS in stage I NSCLC patients undergoing lobectomy or surgeons' preference sublobar resection (90.5% vs. 93.4% P = 0.510), and DFS for surgeons' preference sublobar resection remained an insignificant factor (aHR = 0.894, P = 0.834)., Conclusions: Carefully selected patients who have undergone surgeons' preference sublobar resection have comparable outcomes to those receiving lobectomy for stage I NSCLC <3 cm., Key Points: Significant findings of the study Intended sublobar resection has a good outcome. What this study adds Sublobar resection is applicable for stage I NSCLC <3 cm., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Lobectomy plus lymph node dissection is the standard treatment of early-stage lung cancer, but the low lymph node metastasis rate with ground-glass opacity (GGO) makes surgeons not perform lymphadenectomy. This study aimed to re-evaluate the lymph node metastasis rate of GGO to help make a clinical judgment., Methods: We performed this retrospective study to enroll patients who received lung cancer surgery from 2011 to 2016. Patient characteristics collected included tumor size, solid part size and lymph node metastasis rate. These patients were categorized into pure GGO and part solid GGO groups to undergo analysis., Results: Lymph node metastasis rates were 0%, 3.8% and 6.9% in order of the pure GGO group, the GGO predominant group and the solid predominant group. In the lobectomy patients, the solid predominant group still showed to have the highest lymph node metastasis rate and recurrence rate (8.3% and 10.1%)., Conclusion: It is unnecessary to perform lymphadenectomy for patients with pure GGO in view of the 0% lymph node metastasis rate. The higher lymph node metastasis rate in the patients with the solid predominant group, 6.9%, suggested that surgeons should choose a rational lymphadenectomy method according to their GGO property and clinical judgment.

Background: The impact of delayed surgery on clinical outcomes after histologic or radiologic diagnosis of clinical stage I adenocarcinoma remains controversial. We evaluated the effects of delayed surgery on outcomes of patients with early-stage lung cancer., Methods: Associations between time intervals of "histologic diagnosis-to-surgery" (HDS), "radiologic diagnosis-to-surgery" (RDS), and overall survival in clinical stage I adenocarcinoma were assessed using multivariable Cox proportional hazard analysis., Results: A total of 561 consecutive patients with preoperative histologic confirmation of stage I lung cancer between 2006 and 2016 were included. Median time to HDS and RDS were 20 (2-267) and 58 (38-2,983) days. Higher Charlson comorbidity score, receiving brain magnetic resonance imaging screening, and video-assisted thoracoscopic surgery approach were significantly associated with increased risk of late HDS (>21 days). Smaller tumor size and non-radiologic solid-dominant pattern were significantly associated with increased risk of late RDS (>60 days). In the overall cohort, worse 5-year overall survival was associated with late HDS compared to early HDS (75.9% vs . 85.5%, P=0.003). No significant differences were found in later late vs . early RDS (83.7% vs . 83.3%, P=0.570). In 286 propensity-score matched patients, late HDS [adjusted hazard ratio (aHR) =2.031, P=0.038], higher Charlson comorbidity score (aHR=1.610, P=0.023), larger tumor size (aHR=2.164, P=0.031), without brain magnetic resonance imaging screening (aHR=2.051, P=0.045), and tumor with angiolymphatic invasion (aHR=4.638, P=0.001) were significantly associated with lower overall survival., Conclusions: In patients with stage I lung adenocarcinoma, delayed surgery after a histologic diagnosis is an independent predictor of overall survival after adjusting for clinical risk factors, suggesting meaningful differences in clinical outcomes between timely vs . delayed surgeries., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Abiotic stresses, including drought and salinity, trigger a complex osmotic-stress and abscisic acid (ABA) signal transduction network. The core ABA signalling components are snf1-related protein kinase2s (SnRK2s), which are activated by ABA-triggered inhibition of type-2C protein-phosphatases (PP2Cs). SnRK2 kinases are also activated by a rapid, largely unknown, ABA-independent osmotic-stress signalling pathway. Here, through a combination of a redundancy-circumventing genetic screen and biochemical analyses, we have identified functionally-redundant MAPKK-kinases (M3Ks) that are necessary for activation of SnRK2 kinases. These M3Ks phosphorylate a specific SnRK2/OST1 site, which is indispensable for ABA-induced reactivation of PP2C-dephosphorylated SnRK2 kinases. ABA-triggered SnRK2 activation, transcription factor phosphorylation and SLAC1 activation require these M3Ks in vitro and in plants. M3K triple knock-out plants show reduced ABA sensitivity and strongly impaired rapid osmotic-stress-induced SnRK2 activation. These findings demonstrate that this M3K clade is required for ABA- and osmotic-stress-activation of SnRK2 kinases, enabling robust ABA and osmotic stress signal transduction.

Introduction: Digital thoracic drainage systems are a new technology in minimally invasive thoracic surgery. However, the criteria for chest tube removal in digital thoracic drainage systems have never been evaluated. We aim to investigate the incidence and predictive factors of complications and reinterventions after drainage tube removal in patients with a digital drainage system., Method: Patients who received lung resection surgery and had their chest drainage tubes connected with a digital drainage system were retrospectively reviewed., Results: A total of 497 patients were monitored with digital drainage systems after lung resection surgery. A total of 175 (35.2%) patients had air leak-related complications after drainage tube removals, whereas 25 patients (5.0%) required reintervention. We identified that chest drainage duration of five days was an optimal cut-off value in predicting air leak-related complications and reinterventions. In multiple logistic regression analysis, previous chest surgery history; small size (16 Fr.) drainage tubes; the presence of initial air leaks, defined as air leaks recorded by the digital drainage system immediately after operation; and duration of chest drainage ≥5 days were independent factors of air leak-related complications, whereas the presence of initial air leaks and duration of chest drainage ≥5 days were independent predictive factors of reintervention after drainage tube removal., Conclusion: Air leak-related complications and reinterventions after drainage tube removals happened in 35.2% and 5.0% of patients with digital thoracic drainage systems. The management of chest drainage tubes in patients with predictive factors, i.e., the presence of initial air leaks and duration of chest drainage of more than five days, should be treated with caution.

This study presents the preparation, characterization, and properties of a new composite containing cerium oxide nanoparticles and a conjugated polymer. CeO 2 nanoparticles prepared using the co-precipitation method were dispersed into the conjugated polymer, prepared using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The interface interactions between the two components and the resultant optoelectronic properties of the composite are demonstrated. According to transmission electron microscopy and X-ray absorption spectroscopy, the dispersion of CeO 2 nanoparticles in the polymer matrix strongly depends on the CeO 2 nanoparticle concentration and results in different degrees of charge transfer. The photo-induced charge transfer and recombination processes were studied using steady-state optical spectroscopy, which shows a significant fluorescence quenching and red shifting in the composite. The higher photo-activity of the composite as compared to the single components was observed and explained. Unexpected room temperature ferromagnetism was observed in both components and all composites, of which the origin was attributed to the topology and defects., Competing Interests: Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1, Figure S1: The schematic picture of the polymer synthesis procedure. The chemical formulas of polymers are also shown. Figure S2: TEM investigation of polymer composite with different amount of CeO2, (a) bright image of composite with 20 wt% CeO2, (b) bright image of composite with 50 wt% CeO2, (c) HRTEM of composite with 20 wt% CeO2, (d) HRTEM of composite with 50 wt% CeO2. The insert figures were corresponding diffraction patterns. Aggregation of nanoparticles was observed in composite with 50 wt% CeO2.

Sensing and responding to environmental water deficiency and osmotic stresses are essential for the growth, development, and survival of plants. Recently, an osmolality-sensing ion channel called OSCA1 was discovered that functions in sensing hyperosmolality in Arabidopsis Here, we report the cryo-electron microscopy (cryo-EM) structure and function of an OSCA1 homolog from rice ( Oryza sativa ; OsOSCA1.2), leading to a model of how it could mediate hyperosmolality sensing and transport pathway gating. The structure reveals a dimer; the molecular architecture of each subunit consists of 11 transmembrane (TM) helices and a cytosolic soluble domain that has homology to RNA recognition proteins. The TM domain is structurally related to the TMEM16 family of calcium-dependent ion channels and lipid scramblases. The cytosolic soluble domain possesses a distinct structural feature in the form of extended intracellular helical arms that are parallel to the plasma membrane. These helical arms are well positioned to potentially sense lateral tension on the inner leaflet of the lipid bilayer caused by changes in turgor pressure. Computational dynamic analysis suggests how this domain couples to the TM portion of the molecule to open a transport pathway. Hydrogen/deuterium exchange mass spectrometry (HDXMS) experimentally confirms the conformational dynamics of these coupled domains. These studies provide a framework to understand the structural basis of proposed hyperosmolality sensing in a staple crop plant, extend our knowledge of the anoctamin superfamily important for plants and fungi, and provide a structural mechanism for potentially translating membrane stress to transport regulation., Competing Interests: The authors declare no conflict of interest.

In esophageal cancer, few prediction tools can be confidently used in current clinical practice. We developed a deep convolutional neural network (CNN) with 798 positron emission tomography (PET) scans of esophageal squamous cell carcinoma and 309 PET scans of stage I lung cancer. In the first stage, we pretrained a 3D-CNN with all PET scans for a task to classify the scans into esophageal cancer or lung cancer. Overall, 548 of 798 PET scans of esophageal cancer patients were included in the second stage with an aim to classify patients who expired within or survived more than one year after diagnosis. The area under the receiver operating characteristic curve (AUC) was used to evaluate model performance. In the pretrain model, the deep CNN attained an AUC of 0.738 in identifying patients who expired within one year after diagnosis. In the survival analysis, patients who were predicted to be expired but were alive at one year after diagnosis had a 5-year survival rate of 32.6%, which was significantly worse than the 5-year survival rate of the patients who were predicted to survive and were alive at one year after diagnosis (50.5%, p < 0.001). These results suggest that the prediction model could identify tumors with more aggressive behavior. In the multivariable analysis, the prediction result remained an independent prognostic factor (hazard ratio: 2.830; 95% confidence interval: 2.252-3.555, p < 0.001). We conclude that a 3D-CNN can be trained with PET image datasets to predict esophageal cancer outcome with acceptable accuracy.

Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (h TIM ) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP., Competing Interests: The authors declare no conflict of interest.

Objectives: The 8th edition American Joint Committee on Cancer Tumour-Nodes-Metastasis (TNM) staging system distinguishes between the clinical (c), pathological (p) and post-neoadjuvant pathological (yp) stage groups. However, the ability to discriminate between ypStage II and ypStage III is poor. We aim to identify prognostic factors in patients with ypStage II/III oesophageal squamous cell carcinoma., Methods: The data of 150 patients with ypStage II/III oesophageal squamous cell carcinoma from 2 medical centres were retrospectively reviewed. The neoadjuvant treatments included chemotherapy with cisplatin and 5-fluorouracil, administered concurrently with external beam radiation. The determination of perineural invasion (PNI) was based on pathological reports. Survival curves were compared using the log-rank test, and multivariable survival analysis was performed with a Cox regression model., Results: The 3-year/5-year overall survival rate/median survival in ypStages II, IIIa and IIIb were 35.3%/26.9%/21.9 [95% confidence interval (CI) 14.9-28.8] months, 33.8%/22.5%/22.4 (95% CI 20.1-24.7) months and 21.7%/14.0%/14.4 (95% CI 11.1-17.7) months, respectively (P = 0.07). The 3-year/5-year overall survival rate/median survival was 36.7%/26.4%/22.8 (95% CI 19.2-26.5) months in the absence of PNI and 6.9%/3.4%/9.1 (95% CI 8.9-9.4) months in the presence of PNI (P < 0.001). In the multivariable survival analysis, tumour location in the upper third of the thoracic oesophagus [hazard ratio (HR) 1.692, 95% CI 1.087-2.635; P = 0.020] and positive PNI (HR 3.316, 95% CI 2.005-4.905; P < 0.001) remained as independent prognostic factors., Conclusions: The existence of PNI after neoadjuvant treatment is closely associated with poor prognosis and could be incorporated into the TNM staging system for better discrimination between patients with ypStage II/III oesophageal squamous cell carcinoma., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: The benefits of neoadjuvant chemoradiation (NCRT) compared to upfront esophagectomy (UE) in esophageal squamous cell carcinoma (ESCC) is controversial. Our purpose was to determine whether clinical stages based on the 8th edition American Joint Committee on Cancer Tumor-Node-Metastasis staging system could guide treatment decision., Methods: Data from 2503 patients with clinical stages II and III ESCC diagnosed between 2008 and 2014 were obtained from a nationwide database. Propensity score matching was used to identify well-balanced pairs of patients. Cox proportional hazards regression and log-rank test were used in the survival analysis. The outcomes of patients receiving "NCRT followed by surgery" or "UE" strategies were compared., Results: The treatment modality (UE or NCRT) was not a prognostic factor in clinical stage II ESCC (HR: 0.97; p = 0.778). In contrast, the UE group demonstrated a significantly worse outcome compared with the NCRT group in clinical stage III ESCC (HR: 1.39; p < 0.001). After matching, patients who underwent UE for clinical stage II ESCC had median survival/3-year overall survival (OS) rates of 27.8 months/39.2% compared with 32.7 months/49.8% in the NCRT group (p = 0.508). The patients who underwent UE for clinical stage III ESCC had median survival/3-year OS rates of 17.9 months/28.2% in the UE group compared with 24.0 months/41.8% in the NCRT group (p < 0.001)., Conclusions: Our data suggest that NCRT strategy improved survival compared with UE in clinical stage III ESCC but not in clinical stage II tumors.