High Overexpression of SiAAP9 Leads to Growth Inhibition and Protein Ectopic Localization in Transgenic Arabidopsis.

Amino acid permeases (AAPs) transporters are crucial for the long-distance transport of amino acids in plants, from source to sink. While Arabidopsis and rice have been extensively studied, research on foxtail millet is limited. This study identified two transcripts of SiAAP9, both of which were induced by NO3- and showed similar expression patterns. The overexpression of SiAAP9L and SiAAP9S in Arabidopsis inhibited plant growth and seed size, although SiAAP9 was found to transport more amino acids into seeds. Furthermore, SiAAP9-OX transgenic Arabidopsis showed increased tolerance to high concentrations of glutamate (Glu) and histidine (His). The high overexpression level of SiAAP9 suggested its protein was not only located on the plasma membrane but potentially on other organelles, as well. Interestingly, sequence deletion reduced SiAAP9's sensitivity to Brefeldin A (BFA), and SiAAP9 had ectopic localization on the endoplasmic reticulum (ER). Protoplast amino acid uptake experiments indicated that SiAAP9 enhanced Glu transport into foxtail millet cells. Overall, the two transcripts of SiAAP9 have similar functions, but SiAAP9L shows a higher colocalization with BFA compartments compared to SiAAP9S. Our research identifies a potential candidate gene for enhancing the nutritional quality of foxtail millet through breeding.

Arecoline promotes Akt-c-Myc-driven aerobic glycolysis in esophageal epithelial cells.

Aerobic glycolysis is a typical metabolic rearrangement for tumorigenesis. Arecoline is of explicit carcinogenicity, numerous works demonstrate its mutagenicity, genotoxicity, and cytotoxicity. However, the effects of arecoline on aerobic glycolysis of esophageal epithelial cells remain unclear. In the present study, 5 µM arecoline efficiently increased HK2 expression to induce aerobic glycolysis in Het-1A-Are and NE2-Are cells. The mechanistic analysis showed that arecoline activated the Akt-c-Myc signaling pathway and reduced the GSK3ß-mediated phosphorylation of c-Myc on Thr58 to prevent its ubiquitination and destruction, subsequently promoting HK2 transcription and expression. Taken together, these results suggest that arecoline can induce aerobic glycolysis of esophageal epithelial cells and further confirm that arecoline is a carcinogen harmful to human health.

Identification and validation of a 4-extracellular matrix gene signature associated with prognosis and immune infiltration in lung adenocarcinoma.

Background: The extracellular matrix (ECM) plays a crucial role in the development and tumor microenvironment of lung adenocarcinoma (LUAD). This study aimed to establish a risk score of ECM-related genes in LUAD and explore the association between the risk score and patient survival as well as immune cell infiltration, somatic mutations, and therapy response. Methods: Gene expression data from The Cancer Genome Atlas (TGCA) and eight Gene Expression Omnibus (GEO) databases were used to analyze and identify differentially expressed genes (DEGs). Prognostic ECM-related genes were identified and utilized to formulate a prognostic signature. A nomogram was constructed using TCGA dataset and validated in two GEO datasets. Differences between high- and low-risk patients were analyzed for function enrichment, immune cell infiltration, somatic mutations, and therapy response. Finally, Quantitative real-time PCR (qRT-PCR) was used to detect the mRNA expression of DEGs in LUAD. Results: A risk score based on four ECM-related genes, ANOS1, CD36, COL11A1, and HMMR, was identified as an independent prognostic factor for overall survival (OS) compared to other clinical variables. Subsequently, a nomogram incorporating the risk score and TNM staging was developed using the TCGA dataset. Internal and external validation of the nomogram, conducted through calibration plots, C-index, time-dependent receiver operating characteristics (ROC), integrated discrimination improvement (IDI), and decision curve analyses (DCA), demonstrated the excellent discriminatory ability and clinical practicability of this nomogram. The risk score correlated with the distribution of function enrichment, immune cell infiltration, and immune checkpoint expression. More somatic mutations occurred in the high-risk group. The risk score also demonstrated a favorable ability to predict immunotherapy response and drug sensitivity. Conclusion: A novel signature based on four ECM-related genes is developed to help predict LUAD prognosis. This signature correlates with tumor immune microenvironment and can predict the response to different therapies in LUAD patients.

Construction and validation of a novel prognostic model of neutrophil­related genes signature of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) remains an incurable disease with a poor prognosis. This study aimed to explore neutrophil­related genes (NRGs) and develop a prognostic signature for predicting the prognosis of LUAD. NRGs were obtained by intersecting modular genes identified by weighted gene co-expression network analysis (WGCNA) using bulk RNA-seq data and the marker genes of neutrophils identified from single-cell RNA-sequencing(scRNA-seq) data. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses were run to construct a prognostic signature, follow by delineation of risk groups, and external validation. Analyses of ESTIMAT, immune function, Tumor Immune Dysfunction and Exclusion (TIDE) scores, Immune cell Proportion Score (IPS), and immune checkpoint genes between high- and low-risk groups were performed, and then analyses of drug sensitivity to screen for sensitive anticancer drugs in high-risk groups. A total of 45 candidate NRGs were identified, of which PLTP, EREG, CD68, CD69, PLAUR, and CYP27A1 were considered to be significantly associated with prognosis in LUAD and were used to construct a prognostic signature. Correlation analysis showed significant differences in the immune landscape between high- and low-risk groups. In addition, our prognostic signature was important for predicting drug sensitivity in the high-risk group. Our study screened for NRGs in LUAD and constructed a novel and effective signature, revealing the immune landscape and providing more appropriate guidance protocols in LUAD treatment.

BACH1 promotes lung adenocarcinoma cell metastasis through transcriptional activation of ITGA2.

BACH1 plays an important role in promoting cancer. This study aims to further verify the relationship between the expression level of BACH1 in lung adenocarcinoma prognosis, as well as the influence of BACH1 expression on lung adenocarcinoma and the potential mechanism. The expression level of BACH1 in lung adenocarcinoma and its relationship with prognosis was evaluated by lung adenocarcinoma tissue microarray analysis combined with bioinformatics approaches. Gene knockdown and overexpression were used to investigate the functions and molecular mechanisms of BACH1 in lung adenocarcinoma cells. The regulatory downstream pathways and target genes of BACH1 in lung adenocarcinoma cells were explored by bioinformatics and RNA sequencing data analysis, real-time PCR, western blot analysis, and cell immunofluorescence and cell adhesion assays. Chromatin immunoprecipitation and dual-luciferase reporter assays were carried out to verify the target gene binding site. In the present study, BACH1 is abnormally highly expressed in lung adenocarcinoma tissues, and high BACH1 expression is negatively correlated with patient prognosis. BACH1 promotes the migration and invasion of lung adenocarcinoma cells. Mechanistically, BACH1 directly binds to the upstream sequence of the ITGA2 promoter to promote ITGA2 expression, and the BACH1-ITGA2 axis is involved in cytoskeletal regulation in lung adenocarcinoma cells by activating the FAK-RAC1-PAK signaling pathway. Our results indicated that BACH1 positively regulates the expression of ITGA2 through a transcriptional mechanism, thereby activating the FAK-RAC1-PAK signaling pathway to participate in the formation of the cytoskeleton in tumor cells and then promoting the migration and invasion of tumor cells.

Multifeature analysis of age-related microbiome structures reveals defense mechanisms of Populus tomentosa trees.

Root microbiota composition shifts during the development of most annual plants. Although some perennial plants can live for centuries, the host-microbiome partnerships and interaction mechanisms underlying their longevity remain unclear. To address this gap, we investigated age-related changes in the root metabolites, transcriptomes, and microbiome compositions of 1- to 35-yr-old Populus tomentosa trees. Ten co-response clusters were obtained according to their accumulation patterns, and members of each cluster displayed a uniform and clear pattern of abundance. Multi-omics network analysis demonstrated that the increased abundance of Actinobacteria with tree age was strongly associated with the flavonoid biosynthesis. Using genetic approaches, we demonstrate that the flavonoid biosynthesis regulator gene Transparent Testa 8 is associated with the recruitment of flavonoid-associated Actinobacteria. Further inoculation experiments of Actinobacteria isolates indicated that their colonization could significantly improve the host's phenotype. Site-directed mutagenesis revealed that the hyBl gene cluster, involved in biosynthesis of an aminocyclitol hygromycin B analog in Streptomyces isolate bj1, is associated with disease suppression. We hypothesize that interactions between perennial plants and soil microorganisms lead to gradual enrichment of a subset of microorganisms that may harbor a wealth of currently unknown functional traits.

Effect of Segmental Abutting Esophagus-Sparing Technique to Reduce Severe Esophagitis in Limited-Stage Small-Cell Lung Cancer Patients Treated with Concurrent Hypofractionated Thoracic Radiation and Chemotherapy.

The aim of the current study is to evaluate the effect of segmental abutting esophagus-sparing (SAES) radiotherapy on reducing severe acute esophagitis in patients with limited-stage small-cell lung cancer treated with concurrent chemoradiotherapy. Thirty patients were enrolled from the experimental arm (45 Gy in 3 Gy daily fractions in 3 weeks) of an ongoing phase III trial (NCT02688036). The whole esophagus was divided into the involved esophagus and the abutting esophagus (AE) according to the distance from the edge of the clinical target volume. All dosimetric parameters were significantly reduced for the whole esophagus and AE. The maximal and mean doses of the esophagus (47.4 ± 1.9 Gy and 13.5 ± 5.8 Gy, respectively) and AE (42.9 ± 2.3 Gy and 8.6 ± 3.6 Gy, respectively) in the SAES plan were significantly lower than those (esophagus 48.0 ± 1.9 Gy and 14.7± 6.1 Gy, AE 45.1 ± 2.4 Gy and 9.8 ± 4.2 Gy, respectively) in the non-SAES plan. With a median follow-up of 12.5 months, only one patient (3.3%) developed grade 3 acute esophagitis, and no grade 4-5 events happened. SAES radiotherapy has significant dosimetric advantages, which are successfully translated into clinical benefits and provide good feasibility for dose escalation to improve local control and prognosis in the future.

Dosimetric and clinical analysis of pseudo-progression versus recurrence after hypo-fractionated radiotherapy for brain metastases.

BACKGROUND: The main challenge in follow-up duration of patients with brain metastases after stereotactic radiotherapy is to distinguish between pseudo-progression and tumor recurrence. The objective of this study is to retrospectively analyze the predictive factors. METHODS: The study included 123 patients with enlarged brain metastases after hypo-fractionated radiotherapy in our center from March 2009 to October 2019, and the baseline clinical features, radiotherapy planning parameters, and enhanced magnetic resonance imaging before and after radiation therapy were analyzed. Logistic regression was performed to compare the differences between groups. Independent risk factors with P < 0.05 and associated with recurrence were used to establish a nomogram prediction model and validated by Bootstrap repeated sampling, which was validated in an internal cohort (n = 23) from October 2019 to December 2021. RESULTS: The median follow-up time was 68.4 months (range, 8.9-146.2 months). A total of 76 (61.8%) patients were evaluated as pseudo-progression, 47 patients (38.2%) were evaluated as tumor recurrence. The median time to pseudo-progression and tumor recurrence were 18.3 months (quartile range, 9.4-27.8 months) and 12.9 months (quartile range, 8.7-19.6 months) respectively. Variables associated with tumor recurrence included: gross tumor volume ≥ 6 cc, biological effective dose < 60 Gy, target coverage < 96% and no targeted therapy. The area under curve values were 0.730 and 0.967 in the training and validation cohorts, respectively. Thirty-one patients received salvage therapy in the tumor recurrence group. The survival time in pseudo-progression and tumor recurrence groups were 66.3 months (95% CI 56.8-75.9 months) and 39.6 months (95% CI 29.2-50.0 months, respectively; P = 0.001). CONCLUSIONS: Clinical and dosimetry features of hypo-fractionated radiation therapy based on enhanced brain magnetic resonance can help distinguish pseudo-progression from tumor recurrence after hypo-fractionated radiotherapy for brain metastases. Gross tumor volume, biological effective dose, target coverage, and having received targeted therapy or not were factors associated with the occurrence of tumor recurrence, and the individual risk could be estimated by the nomogram effectively.

Improved Cancer-Specific Risk Stratification by the Lymph Node Ratio-Based Nomogram: A Potential Role in Guiding Postoperative Management Decisions for Oral Cavity Carcinoma.

PURPOSE: To develop and validate a nomogram integrating lymph node ratio (LNR) to predict cancer-specific survival (CSS) and assist decision making for postoperative management in nonmetastatic oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHODS: We retrospectively retrieved 6,760 patients with OCSCC primarily treated with surgery from surveillance, epidemiology, and end results database between 2010 and 2015. They were randomly divided into training and validation cohorts. Performance of the nomogram was evaluated by calibration curve, consistency index, area under the curve, and decision curve analysis and was compared with that of the LNR, positive lymph nodes (PLN) and tumor node metastasis (TNM) staging. According to the individualized nomogram score, patients were classified into three risk cohorts. The therapeutic efficacy of postoperative radiotherapy and chemotherapy was evaluated in each cohort. RESULTS: The nomogram incorporated six independent variables, including race, tumor site, grade, T stage, PLN, and LNR. Calibration plots demonstrated a good match between the predicted and observed CSS. C-indices for training and validation cohorts were 0.746 (95% CI, 0.740 to 0.752) and 0.726 (95% CI, 0.713 to 0.739), compared with 0.687, 0.695, and 0.669 for LNR, PLN, and TNM staging, respectively (P < .001). Decision curve analyses confirmed that nomogram showed the best performance in clinical utility. Postoperative radiotherapy presented survival benefit in medium-and high-risk groups but showed a negative effect in the low-risk group. Chemotherapy was only beneficial in the high-risk group. CONCLUSION: The LN status-incorporated nomogram demonstrated good discrimination and predictive accuracy of CSS for patients with OCSCC and could identify those most likely to benefit from adjuvant therapy.

NOD2 inhibits the proliferation of esophageal adenocarcinoma cells through autophagy.

AIM: To study the regulatory mechanism of NOD2 in the inhibition of esophageal adenocarcinoma cell proliferation. METHODS: Cell experiments: after confirming the decrease in NOD2 expression in esophageal adenocarcinoma, we overexpressed NOD2 in esophageal adenocarcinoma cells via lentivirus, compared and verified the changes in esophageal adenocarcinoma cell proliferation before and after NOD2 overexpression, and compared the overexpression group with the control group by mRNA sequencing to identify pathways that may affect cell proliferation. Then, the autophagy level of multiple groups were assessed, and the results were verified by rescue experiments. In vivo experiments: we administered esophageal adenocarcinoma cells to nude mice to form tumors under their skin and then injected the tumors with NOD2 overexpression lentivirus and negative control lentivirus. After a period of time, the growth curve of the tumor was generated, and the tumor was removed to generate sections. Ki67 was labeled with immunohistochemistry to verify cell proliferation, and the protein was extracted from the tissue to detect the molecular indices of the corresponding pathway. RESULTS: Upregulation of NOD2 expression inhibited the proliferation of esophageal adenocarcinoma cells. Upregulation of NOD2 expression increased the autophagy level of esophageal adenocarcinoma cells via ATG16L1. After ATG16L1 was inhibited, NOD2 had no significant effect on autophagy and proliferation of esophageal adenocarcinoma cells. Enhanced autophagy in esophageal adenocarcinoma cell lines inhibited cell proliferation. In vivo, the upregulation of NOD2 expression improved the autophagy level of tumor tissue and inhibited cells proliferation. CONCLUSION: NOD2 can activate autophagy in esophageal adenocarcinoma cells through the ATG16L1 pathway and inhibit cell proliferation.

Distinctive physiological and molecular responses of foxtail millet and maize to nicosulfuron.

Introduction: Nicosulfuron is the leading acetolactate synthase inhibitor herbicide product, and widely used to control gramineous weeds. Here, we investigated the metabolic process of nicosulfuron into foxtail millet and maize, in order to clarify the mechanism of the difference in sensitivity of foxtail millet and maize to nicosulfuron from the perspective of physiological metabolism and provide a theoretical basis for the breeding of nicosulfuron-resistant foxtail millet varieties. Methods: We treated foxtail millet (Zhangzagu 10, Jingu 21) and maize (Nongda 108, Ditian 8) with various doses of nicosulfuron in both pot and field experiments. The malonaldehyde (MDA) content, target enzymes, detoxification enzymes, and antioxidant enzymes, as well as related gene expression levels in the leaf tissues of foxtail millet and maize were measured, and the yield was determined after maturity. Results: The results showed that the recommended dose of nicosulfuron caused Zhangzagu 10 and Jingu 21 to fail to harvest; the yield of the sensitive maize variety (Ditian 8) decreased by 37.09%, whereas that of the resistant maize variety (Nongda 108) did not decrease. Nicosulfuron stress increased the CYP450 enzyme activity, MDA content, and antioxidant enzyme activity of foxtail millet and maize, reduced the acetolactate synthase (ALS) activity and ALS gene expression of foxtail millet and Ditian 8, and reduced the glutathione S-transferase (GST) activity and GST gene expression of foxtail millet. In conclusion, target enzymes, detoxification enzymes, and antioxidant enzymes were involved in the detoxification metabolism of nicosulfuron in plants. ALS and GST are the main factors responsible for the metabolic differences among foxtail millet, sensitive maize varieties, and resistant maize varieties. Discussion: These findings offer valuable insights for exploring the target resistance (TSR) and non-target resistance (NTSR) mechanisms in foxtail millet under herbicide stress and provides theoretical basis for future research of develop foxtail millet germplasm with diverse herbicide resistance traits.

Association between trauma exposure and respiratory disease-A Mendelian randomization study.

Background: Trauma is a well-known risk factor for many disease, but the effect of trauma on respiratory disease is unclarified. In the present study, we aimed to evaluate the association between trauma and respiratory disease. Method: Using both United Kingdom biobank and Finnish biobank genome-wide association study data (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to evaluate the relationship between trauma and respiratory disease. We used four methods including inverse-variance weighted (IVW), weighted median, Maximum likelihood, and MR-Egger in this MR analysis. The IVW MR was selected as the main method. We also performed multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of trauma exposure on respiratory disease. Results: In the main two-sample MR analysis, trauma exposure was significantly associated with increased risk of respiratory disease (OR 1.15, 95%CI: 1.05-1.25). Besides, there was no heterogeneity and horizontal pleiotropy observed in the sensitivity analysis. After adjusting for pack years of smoking and body mass index (BMI), trauma exposure retained its association with respiratory disease (OR, 1.13, 95%CI, 1.04-1.23 adjusted by pack years of smoking; and OR, 1.11, 95%CI, 1.04-1.18 adjusted by BMI). Conclusion: Our study discovered the association between trauma exposure and the increased risk of respiratory disease, suggesting the prevention and treatment with trauma to reduce the risk of respiratory disease.

Lymph node ratio-dependent prognosis stratification and postoperative radiotherapy utilization in T1-2N1 oral cavity carcinoma.

OBJECTIVE: Pathological T1-2N1 oral cavity squamous cell carcinoma (pT1-2N1 OCSCC) is a setting with intermediate prognosis whilst without consensus regarding the utilization of postoperative radiotherapy (PORT). This study aimed to investigate the prognostic value of lymph node ratio (LNR) and to further examine its clinical validity for guiding PORT in pT1-2N1 OCSCC. METHODS: OCSCC patients who received surgery between 2010 and 2015 with at least 6 lymph nodes dissection were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Time-dependent receiver operating characteristic (ROC) analysis was used to identify the optimal cutoff of LNR. Multivariable Cox regression analysis was employed to assess the prognostic value of LNR. Impact of PORT was evaluated in respective subgroups stratified by LNR. RESULTS: A total of 870 OCSCC patients with pT1-2N1 diseases were eligible for analysis. The 5-year overall survival (OS) and disease-specific survival (DSS) was 57.2% and 67.9% respectively. Time-dependent ROC analyses for OS and DSS concordantly revealed 5.5% as the optimal cutoff of LNR. Significantly higher risks of death (HR = 1.610, 95% CI: 1.139-2.276) and disease-specific death (HR = 1.731, 95% CI: 1.101-2.723) were unveiled in patients with LNR > 5.5%. PORT related improvement on OS (5-year rate: 57.6% vs. 47.3%, p = 0.095) and DSS (5-year rate: 71.0% vs. 53.8%, p = 0.030) was only found in LNR > 5.5% subgroup. CONCLUSIONS: LNR > 5.5% is indicative of inferior outcome in pT1-2N1 OCSCC, warranting the utilization of PORT in this sub-setting.

Management of BMI Is a Potential New Approach for the Prevention of Idiopathic Pulmonary Fibrosis.

Aims: Current idiopathic pulmonary fibrosis (IPF) therapies usually show a poor outcome or treatment efficacy. The search for new risk factors has significant implications in preventing, delaying, and treating IPF. The association between obesity and the risk of IPF is not clear. This study aimed to investigate the role of different obesity types in IPF risk, which provides the possibility of weight loss as a new approach for IPF prevention. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effect of obesity on IPF risk. We collected summary data of genetically determined obesity-related traits, including body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) from large-scale consortia (the sample size ranging from 232,101 to 681,275), and genetic association with IPF from one of the largest meta-analyses including 2,668 cases. A total of 35-469 single nucleotide polymorphisms were selected as instrumental variables for obesity-related traits. We further performed multivariable MR to estimate the independent effect of BMI and WC on the risk of IPF. Results: Increased BMI and WC were associated with higher risk of IPF [odds ratio (OR) = 1.51, 95% confidence interval (CI) (1.22-1.87), p = 1.27 × 10-4, and OR = 1.71, 95% CI (1.08-2.72), p = 2.33 × 10-2, respectively]. Similar results for the BMI and WC were obtained in the replicated analysis. Subsequently, only the result for BMI survived following the multiple testing correction and showed good consistency with the weighted median estimator. Sensitivity analyses indicated that there was no heterogeneity or horizontal pleiotropy for MR estimations. Further multivariable MR suggested that the BMI showed the same direction and similar magnitude with that in the univariable MR analysis. There was little evidence to support the causal role of WHR on the risk of IPF in this study. Conclusion: Genetically determined BMI demonstrates a causal risk for IPF, which offers a novel insight into probing potential mechanisms. Meanwhile, these results also suggest that weight loss may be beneficial to IPF prevention.

Xanthohumol inhibits non-small cell lung cancer by activating PUMA-mediated apoptosis.

Deregulation of apoptosis signaling is an important feature of cancer cells and plays an essential role in tumorigenesis. Xanthohumol is an active ingredient in Traditional Chinese Medicines Hops (Humulus lupulus L.). Recently studies have shown the profound anti-tumor activities of Xanthohumol in multiple cancer models. However, its potency in non-small cell lung cancer (NSCLC) and the underlying mechanisms are still elusive. Here, we have investigated the potency of Xanthohumol against NSCLC cells in vitro and xenograft mouse models. Xanthohumol suppressed cell viability, colony formation and induced apoptosis in A549, H520, and H358 cells. Xanthohumol activated mitochondrial apoptosis through upregulation of (p53-upregulated modulator of apoptosis) PUMA expression. After Xanthohumol treatment, the Akt activity was inhibited, which resulted in dephosphorylation of FOXO3a and PUMA induction. Silent PUMA or FOXO3a impaired Xanthohumol-induced apoptosis in NSCLC cells. In nude mice, Xanthohumol administration suppressed NSCLC xenograft tumor growth and increased PUMA expression in tumor tissues. Briefly, our studies revealed a novel mechanism by which Xanthohumol exerted its anti-tumor activity in a PUMA-dependent manner in NSCLC cells.

Simplified Synthetic Approach to Tetrabrominated Spiro-Cyclopentadithiophene and the Following Derivation to A-D-A Type Acceptor Molecules for Use in Polymer Solar Cells.

4,4'-Spiro-bis[cyclopenta[2,1-b;3,4-b']dithiophene] (SCT) is a versatile building block for constructing three-dimensional (3D) π-conjugated molecules for use in organic electronics. In this paper, we report a more convenient synthetic route to SCT and its derivatives, where a structurally symmetric 3,3'-dibromo-5,5'-bis(trimethylsilyl)-2,2'-bithiophene (2) serves as the precursor for both the synthesis of 4H-cyclopenta[2,1-b:3,4-b']dithiophen-4-one (4) and 4-(5,5'-bis(trimethylsilyl)-2,2'-bithiophen-3-yl)-2,6-bis(trimethylsilyl)-4-hydroxy-cyclopenta[2,1-b;3,4-b']dithiophene (5). The later one is the key intermediate for the final brominated SCT building block. Such a "two birds with one stone" strategy simplifies the synthetic approach to the SCT core. Functionalization on the SCT core with different terminal electron-deficient groups, including 1H-indene-1,3(2H)-dione (ID), 2-(3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile (IC), and 2-(5,6-difluoro-3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile (FIC), was carried out, yielding three spiro-conjugated A-D-A type molecules, SCT-(TID)4, SCT-(TIC)4, SCT-(TFIC)4, respectively. The optical spectroscopy and electrochemical properties of these three compounds were investigated and compared to the corresponding linear oligomers. Results revealed that the IC and TFIC terminated compounds showed low-lying HOMO/LUMO energy levels with reduced optical bandgap, making them more suitable for use in polymer solar cells. A power conversion efficiency of 3.73% was achieved for the SCT-(TFIC)4 based cell, demonstrating the application perspective of 3D molecules.

Lymph node ratio-based nomogram for prognosis evaluation and treatment optimization of non-metastatic oral cavity squamous cell carcinoma.

BACKGROUND: Lymph node ratio (LNR) has been increasingly reported as a prognostic factor in oral cavity squamous cell carcinoma (OCSCC). This study aimed to develop and validate a prognostic nomogram integrating LNR and to further assess its role in guiding adjuvant therapy for OCSCC. METHODS: A total of 8703 OCSCC patients treated primarily with surgery in the Surveillance, Epidemiology and End Results (SEER) database were retrieved and randomly divided into training and validation cohorts. The nomogram was created based on the factors identified by Cox model. The value of PORT and chemotherapy was respectively evaluated in each prognostic group according to nomogram-deduced individualized score. RESULTS: The final nomogram included tumor site, grade, T stage, number of positive lymph nodes and LNR. Calibration plots demonstrated a good match between predicted and observed rates of overall survival (OS). The concordance indexes for training and validation cohorts were 0.720 (95% confidence interval (CI): 0.708, 0.732) and 0.711 (95% CI: 0.687, 0.735), both significantly higher than did TNM stage (p< 0.001). According to individualized nomogram score, patients were stratified into three subgroups with significantly distinct outcome. PORT presented survival benefit among medium- and high-risk groups whereas a near-detrimental effect in low-risk group. Chemotherapy was found to be beneficial only in high-risk group. CONCLUSION: This LNR-incorporated nomogram surpassed the conventional TNM stage in predicting prognosis of patients with non-metastatic OCSCC and identified sub-settings that could gain survival benefit from adjuvant thearpy.

Hsa_circ_0005576 promotes osimertinib resistance through the miR-512-5p/IGF1R axis in lung adenocarcinoma cells.

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for lung adenocarcinoma (LUAD) harboring activating mutations, but patients ultimately develop acquired resistance. Circular RNAs are involved in EGFR-TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remains unknown. In this study, we demonstrated that hsa_circ_0005576 could facilitate osimertinib-resistant LUAD cells. Briefly, knockdown of hsa_circ_0005576 not only suppressed the proliferation and promoted the apoptosis of resistant LUAD cells, but also increased their sensitivity to osimertinib. Mechanistically, hsa_circ_0005576, serving as an miRNA sponge, could directly interact with miR-512-5p and subsequently upregulate the miR-512-5p-targeted insulin-like growth factor 1 receptor. Rescue assays indicated that miR-512-5p inhibition could reverse the effects of hsa_circ_0005576 knockdown in LUAD cells resistant to osimertinib. Overall, our study revealed that hsa_circ_0005576 regulates proliferation and apoptosis through miR-512-5p/IGF1R signaling, which contributes further to the resistance of LUAD cells to osimertinib. In addition, this study provides a novel insight into the mechanisms underlying osimertinib resistance of LUAD.

The Sequence of Intracranial Radiotherapy and Systemic Treatment With Tyrosine Kinase Inhibitors for Gene-Driven Non-Small Cell Lung Cancer Brain Metastases in the Targeted Treatment Era: A 10-Year Single-Center Experience.

PURPOSE: The high intracranial efficacy of targeted therapeutic agents poses a challenge in determining the optimal sequence of local radiation therapy (RT) and systemic treatment with tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). Therefore, we conducted a cohort study to elucidate the appropriate treatment strategy, either upfront RT or deferred RT including a toxicity assessment, in these patients. PATIENTS AND METHODS: We retrospectively evaluated patients with gene-driven BMs from a single institution and divided them into deferred and upfront RT groups. Survival was estimated using a log-rank test. Intracranial progression was estimated using Fine-Gray competing risks model. Cox proportional hazards regression was performed for multivariable analysis in the entire group and subgroups. RESULTS: Among the 198 eligible patients, 94 and 104 patients received deferred and upfront RT, respectively. The upfront RT group showed a lower intracranial progression risk with an adjusted sub-distribution hazard ratios of 0.41 (95% CI, 0.30-0.57) than did the deferred RT group (median intracranial progression-free survival [iPFS], 19.9 months vs. 11.1 months; p < 0.001). The median overall survival (OS; 43.2 months vs. 49.1 months, p = 0.377) and BM-specific survival (92.1 months vs. 82.9 months, p = 0.810) after salvage therapy were not significantly different between the upfront and deferred groups. Among patients with progressed extracranial disease, the deferred RT group showed significantly better OS than did the upfront RT group (44.0 vs. 28.1 months, p = 0.022). Grade 3-4 treatment-related adverse events were rare, and similar toxicities were observed between the two groups. CONCLUSION: Compared to the deferred RT group, the upfront RT group achieved longer iPFS and similar survival outcomes in most patients with gene-driven NSCLC BM, although patients with progression of extracranial disease might benefit from deferred RT. Both groups showed well-tolerated toxicities. TRIAL REGISTRATION ID: NCT04832672.

Effect of surgery on survival in patients with stage III N2 small cell lung cancer: propensity score matching analysis and nomogram development and validation.

BACKGROUND: The standard treatment of stage III N2 small cell lung cancer (SCLC) is concurrent chemoradiation, and surgery is not recommended. This study was aimed to evaluate whether surgery has survival benefits in patients with stage III N2 SCLC and investigate the factors influencing survival of surgery. METHODS: Patients diagnosed with stage T1-4N2M0 SCLC from 2004 to 2015 were selected from the Surveillance Epidemiology End Results database. Propensity score matching (PSM) was used to balance confounders between patients who underwent surgery and those treated with radiation and/or chemotherapy. We compared overall survival (OS) of the two groups using Kaplan-Meier curves and a Cox proportional hazard model. We also identified prognostic factors in patients with surgical resection, and a nomogram was developed and validated for predicting postoperative OS. RESULTS: -A total of 5576 patients were included in the analysis; of these, 211 patients underwent surgery. PSM balanced the differences between the two groups. The median OS was longer in the surgery group than in the non-surgery group (20 vs. 15 months; p = 0.0024). Surgery was an independent prognostic factor for longer OS in the multivariate Cox regression analysis, and subgroup analysis revealed a higher survival rate in T1 stage patients treated with surgery (hazard ratio = 0.565, 95% confidence interval: 0.401-0.798; p = 0.001). In patients who underwent surgery, four prognostic factors, including age, T stage, number of positive lymph nodes, and radiation, were selected into nomogram development for predicting postoperative OS. C-index, decision curve analyses, integrated discrimination improvement, and time-dependent receiver operating characteristics showed better performance in nomogram than in the tumor-node-metastasis staging system. Calibration plots demonstrated good consistency between nomogram predicted survival and actual observed survival. The patients were stratified into three different risk groups by prognostic scores and Kaplan-Meier curves showed significant difference between these groups. CONCLUSIONS: These results indicate that surgery can prolong survival in patients with operable stage III N2 SCLC, particularly those with T1 disease. A nomogram that includes age, T stage, number of positive lymph nodes, and radiation can be used to predict their long-term postoperative survival.