Dual mutations in the whitefly nicotinic acetylcholine receptor ß1 subunit confer target-site resistance to multiple neonicotinoid insecticides.

Neonicotinoid insecticides, which target insect nicotinic acetylcholine receptors (nAChRs), have been widely and intensively used to control the whitefly, Bemisia tabaci, a highly damaging, globally distributed, crop pest. This has inevitably led to the emergence of populations with resistance to neonicotinoids. However, to date, there have been no reports of target-site resistance involving mutation of B. tabaci nAChR genes. Here we characterize the nAChR subunit gene family of B. tabaci and identify dual mutations (A58T&R79E) in one of these genes (BTß1) that confer resistance to multiple neonicotinoids. Transgenic D. melanogaster, where the native nAChR Dß1 was replaced with BTß1A58T&R79E, were significantly more resistant to neonicotinoids than flies where Dß1 were replaced with the wildtype BTß1 sequence, demonstrating the causal role of the mutations in resistance. The two mutations identified in this study replace two amino acids that are highly conserved in >200 insect species. Three-dimensional modelling suggests a molecular mechanism for this resistance, whereby A58T forms a hydrogen bond with the R79E side chain, which positions its negatively-charged carboxylate group to electrostatically repulse a neonicotinoid at the orthosteric site. Together these findings describe the first case of target-site resistance to neonicotinoids in B. tabaci and provide insight into the molecular determinants of neonicotinoid binding and selectivity.

Genomic and transcriptomic profiling of inflammatory breast cancer reveals distinct molecular characteristics to non-inflammatory breast cancers.

PURPOSE: Inflammatory breast cancer (IBC), a rare and highly aggressive form of breast cancer, accounts for 10% of breast cancer-related deaths. Previous omics studies of IBC have focused solely on one of genomics or transcriptomics and did not discover common differences that could distinguish IBC from non-IBC. METHODS: Seventeen IBC patients and five non-IBC patients as well as additional thirty-three Asian breast cancer samples from TCGA-BRCA were included for the study. We performed whole-exon sequencing (WES) to investigate different somatic genomic alterations, copy number variants, and large structural variants between IBC and non-IBC. Bulk RNA sequencing (RNA-seq) was performed to examine the differentially expressed genes, pathway enrichment, and gene fusions. WES and RNA-seq data were further investigated in combination to discover genes that were dysregulated in both genomics and transcriptomics. RESULTS: Copy number variation analysis identified 10 cytobands that showed higher frequency in IBC. Structural variation analysis showed more frequent deletions in IBC. Pathway enrichment and immune infiltration analysis indicated increased immune activation in IBC samples. Gene fusions including CTSC-RAB38 were found to be more common in IBC. We demonstrated more commonly dysregulated RAS pathway in IBC according to both WES and RNA-seq. Inhibitors targeting RAS signaling and its downstream pathways were predicted to possess promising effects in IBC treatment. CONCLUSION: We discovered differences unique in Asian women that could potentially explain IBC etiology and presented RAS signaling pathway as a potential therapeutic target in IBC treatment.

Tissue factor regulates autophagy in pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension rats via the p38 MAPK-FoxO1 pathway.

AIMS: To detect the expression of autophagy components, p38 MAPK (p38) and phosphorylated forkhead box transcription factor O-1 (pFoxO1) in pulmonary vascular endothelial cells of chronic thromboembolic pulmonary hypertension (CTEPH) rats and to investigate the possible mechanism through which tissue factor (TF) regulates autophagy. METHODS: Pulmonary artery endothelial cells (PAECs) were isolated from CTEPH (CTEPH group) and healthy rats (control group (ctrl group)) which were cocultured with TF at different time points including 12 h, 24 h, 48 h and doses including 0 nM,10 nM, 100 nM, 1µM, 10µM, 100µM and cocultured with TFPI at 48 h including 0 nM, 2.5 nM, 5 nM. The expression of forkhead box transcription factor O-1 (FoxO1), pFoxO1, p38, Beclin-1 and LC3B in PAECs was measured. Coimmunoprecipitation (co-IP) assays were used to detect the interaction between FoxO1 and LC3. RESULTS: The protein expression of p-FoxO1/FoxO1 was significantly lower in the CTEPH groups (cocultured with TF from 0 nM to 100 µM) than in the ctrl group at 12 h, 24 h, and 48 h (P < 0.05) and was significantly lower in the CTEPH groups (cocultured with TFPI from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of p38 in the CTEPH groups treated with 0 nM, 10 nM, 100 nM or 1 µM TF for 48 h significantly increased than ctrl groups (P < 0.05) and was significantly increased in the CTEPH groups (cocultured with TFPI concentration from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of Beclin1 at the same concentration (cocultured with TF from 0 nM to 100 µM) was significantly lower in the CTEPH groups than ctrl groups after 24 h and 48 h (P < 0.05) and was significantly decreased in the CTEPH groups (cocultured with TFPI concentration from 2.5 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of LC3-II/LC3-I at the same concentration (cocultured with TF 0 nM, 1 µM, 10 µM, and 100 µM) was significantly lower in the CTEPH than in the ctrl groups after 12 h (P < 0.05) and was significantly lower in the CTEPH groups (cocultured with TFPI concentration from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). There were close interactions between FoxO1 and LC3 in the control and CTEPH groups at different doses and time points. CONCLUSION: The autophagic activity of PAECs from CTEPH rats was disrupted. TF, FoxO1 and p38 MAPK play key roles in the autophagic activity of PAECs. TF may regulate autophagic activity through the p38 MAPK-FoxO1 pathway.

Leveraging real-world data to conduct externally controlled trial for rare diseases with count-type endpoints: utilizing multiple entries - a simulation study.

Conducting randomized controlled trials for medications targeting rare diseases presents significant challenges, due to the scarcity of participants and ethical considerations. Under such circumstances, leveraging real-world data (RWD) to generate supporting evidence may be accepted by the regulatory agency. Constructing an external control arm (ECA) from RWD for a single-arm trial has been conducted occasionally. A complication in this design is that patients from RWD may be eligible at multiple time points. Most studies approach this by selecting one time point as the index date for ECA patients. Here, we propose a novel design for externally controlled trials that permits the inclusion of ECA patients at various entry points. Accompanying this design, we make recommendations for statistical methods to account for measured confounders, limited sample size, within-subject correlation, and potential overdispersion inherent in count data. Furthermore, we present an idea for the blinding process for this type of study. We have conducted a series of simulations to assess the performance of the design and statistical methods in terms of bias, type I error, and efficiency, as compared to the approach of selecting only one entry per ECA patient. The study and parameter setup were based on a hypothetical case inspired by a rare disease study. The results indicate that allowing multiple entries for ECA patients can lead to enhanced performance in many aspects. It provides a controlled type I error, robustness against certain model misspecifications, and a moderate power improvement compared with selecting a single entry per ECA patient.

Network pharmacology-based approach to understand the effect and mechanism of chrysophanol against cognitive impairment in Wilson disease.

Wilson disease (WD) is a rare hereditary copper metabolism disorder, wherein cognitive impairment is a common clinical symptom. Chrysophanol (CHR) is an active compound with neuroprotective effects. The study aims to investigate the neuroprotective effect of CHR in WD and attempted to understand the potential mechanisms. Network pharmacology analysis was applied to predict the core target genes of CHR against cognitive impairment in WD. The rats fed with copper-laden diet for 12 weeks, and the effect of CHR on the copper content in liver and 24-h urine, the learning and memory ability, the morphological changes and the apoptosis level of neurons in hippocampal CA1 region, the expression level of Bax, Bcl-2, Cleaved Caspase-3, p-PI3K, PI3K, p-AKT, and AKT proteins were detected. Network pharmacology analysis showed that cell apoptosis and PI3K-AKT signaling pathway might be the main participants in CHR against cognitive impairment in WD. The experiments showed that CHR could reduce the copper content in liver, increase the copper content in 24-h urine, improve the ability of the learning and memory, alleviate the damage and apoptosis level of hippocampal neurons, down-regulate the expression of Bax, Cleaved Caspase-3, and up-regulate the expressions of Bcl-2, p-PI3K/PI3K, p-AKT/AKT. These results suggested that CHR could alleviate cognitive impairment in WD by inhibiting cell apoptosis and triggering the PI3K-AKT signaling pathway.

Detection of continuous hierarchical heterogeneity by single-cell surface antigen analysis in the prognosis evaluation of acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) is characterised by the malignant accumulation of myeloid progenitors with a high recurrence rate after chemotherapy. Blasts (leukaemia cells) exhibit a complete myeloid differentiation hierarchy hiding a wide range of temporal information from initial to mature clones, including genesis, phenotypic transformation, and cell fate decisions, which might contribute to relapse in AML patients. METHODS: Based on the landscape of AML surface antigens generated by mass cytometry (CyTOF), we combined manifold analysis and principal curve-based trajectory inference algorithm to align myelocytes on a single-linear evolution axis by considering their phenotype continuum that correlated with differentiation order. Backtracking the trajectory from mature clusters located automatically at the terminal, we recurred the molecular dynamics during AML progression and confirmed the evolution stage of single cells. We also designed a 'dispersive antigens in neighbouring clusters exhibition (DANCE)' feature selection method to simplify and unify trajectories, which enabled the exploration and comparison of relapse-related traits among 43 paediatric AML bone marrow specimens. RESULTS: The feasibility of the proposed trajectory analysis method was verified with public datasets. After aligning single cells on the pseudotime axis, primitive clones were recognized precisely from AML blasts, and the expression of the inner molecules before and after drug stimulation was accurately plotted on the trajectory. Applying DANCE to 43 clinical samples with different responses for chemotherapy, we selected 12 antigens as a general panel for myeloblast differentiation performance, and obtain trajectories to those patients. For the trajectories with unified molecular dynamics, CD11c overexpression in the primitive stage indicated a good chemotherapy outcome. Moreover, a later initial peak of stemness heterogeneity tended to be associated with a higher risk of relapse compared with complete remission. CONCLUSIONS: In this study, pseudotime was generated as a new single-cell feature. Minute differences in temporal traits among samples could be exhibited on a trajectory, thus providing a new strategy for predicting AML relapse and monitoring drug responses over time scale.

Phosphorylation of MAP 1A regulates hyperphosphorylation of Tau in Alzheimer's disease model.

BACKGROUND AND PURPOSE: Hyperphosphorylation of Tau is one of the important pathological features of Alzheimer's disease (AD). Therefore, studying the mechanisms behind Tau hyperphosphorylation is crucial in exploring the pathogenesis of neurological damage in AD. METHODS: In this study, after the establishment of rat models of AD, quantitative phosphoproteomics and proteomics were performed to identify proteins, showing that phosphorylation of microtubule associated protein 1A (MAP 1A) was lower in the model group. Western blot confirmed the changes of MAP 1A in the SD rats, APP/PS1 transgenic mice and cell AD models. To further study the molecular mechanism of recombinant MAP 1A phosphorylation affecting Tau phosphorylation, interfering siRNA-MAP 1A and protein immunoprecipitation reaction analysis were performed in AD cell models. RESULTS: Cyclin-dependent kinase 5 (CDK5) showed reduced binding to MAP 1A and increased binding to Tau, resulting in a decrease in phosphorylated MAP 1A (p-MAP 1A) and an increase in phosphorylated Tau (p-Tau), and MAP 1A silencing promoted binding of CDK5-Tau and increased Tau phosphorylation, thereby reducing the cell survival rate. CONCLUSIONS: In summary, we found that p-MAP 1A downregulation associated with p-Tau upregulation was due to their altered binding forces to CDK5, and MAP 1A could enhance autophosphorylation by competitive binding to CDK5 and antagonise Tau phosphorylation. This leads to neuronal protection and reducing tissue damage levels in AD, which can help better understand the mechanisms of AD pathogenesis.

The effects of N6-methyladenosine RNA methylation on the nervous system.

Epitranscriptomics, also known as "RNA epigenetics", is a type of chemical modification that regulates RNA. RNA methylation is a significant discovery after DNA and histone methylation. The dynamic reversible process of m6A involves methyltransferases (writers), m6A binding proteins (readers), as well as demethylases (erasers). We summarized the current research status of m6A RNA methylation in the neural stem cells' growth, synaptic and axonal function, brain development, learning and memory, neurodegenerative diseases, and glioblastoma. This review aims to provide a theoretical basis for studying the mechanism of m6A methylation and finding its potential therapeutic targets in nervous system diseases.

The Application of Mixed Reality to Sentinel Lymph Node Biopsy in Breast Cancer.

OBJECTIVE: To explore the value of mixed reality (MR) in sentinel lymph node biopsy (SLNB) in patients with breast cancer. METHODS: A total of 300 patients with breast cancer who underwent SLNB enrolled and were randomly divided into two groups. In group A, only dye (an injection of methylene blue) was used to detect sentinel lymph nodes, while in group B MR was used for positioning in addition to dye. (MR localization method: Before the surgery, we built a 1:1 3D reconstruction model based on the patient's CT or MRI original data, and after the patient was injected with dye, we completed MR localization by overlapping the pre-marked image with the model.) RESULTS: During surgery, the detection time in group B was significantly shorter than in group A (3.62 ± 1.20 vs.7.87 ± 1.86; p < 0.001). At 1-month post-surgery follow-up, the incidence of pain in group B was lower than that in group A (2.70 vs. 8.28%, p = 0.036). The incidence of upper limb dysfunction was lower in group B than in group A (2.03 vs. 8.97%, p = 0.009). In terms of the incidence of pain, group B was better than group A (0.68 vs. 3.45%, p = 0.094). The satisfaction of the two groups was scored, and the results showed that group B was better than group A (4.04 ± 0.91 vs.3.32 ± 0.94, p < 0.001). CONCLUSION: The application of MR to SLNB in breast cancer can significantly reduce the detection time and the occurrence of complications and improve patient satisfaction.

Lnc NR2F1-AS1 Promotes Breast Cancer Metastasis by Targeting the MiR-25-3p/ZEB2 Axis.

Background: Long noncoding RNAs (lncRNAs) substantially affect tumor metastasis and are aberrantly expressed in various cancers. However, its role in breast cancer (BC) remains unclear. Methods: A microarray assay of differentially expressed lncRNAs in epithelial-mesenchymal transition (EMT) and non-EMT cells was performed. The prognostic value of lnc NR2F1-AS1 expression in patients with BC was analyzed using The Cancer Genome Atlas database. Lnc NR2F1-AS1 expression levels in different BC cell lines were assessed using quantitative real-time PCR. The role of lnc NR2F1-AS1 in BC cell metastasis was investigated in vitro and in vivo. Dual luciferase reporter assay and RNA immunoprecipitation were performed to investigate the relationship between lnc NR2F1-AS1, miR-25-3p, and ZEB2. Results: High levels of lnc NR2F1-AS1 were observed in BC cells undergoing EMT and were closely correlated with adverse prognosis in patients with BC. Lnc NR2F1-AS1 knockdown significantly inhibited BC cell migration, invasiveness in vitro, and metastasis in vivo. Mechanistically, lnc NR2F1-AS1 competitively binds to miR-25-3p to impede ZEB2 degradation, a positive EMT transcription factor in BC. Conclusions: Our study revealed a novel lnc NR2F1-AS1/miR-25-3p/ZEB2 axis in BC metastasis and that lnc NR2F1-AS1 may serve as a potential therapeutic target for BC metastasis.

π-hole bonding: A new retention mechanism for the solid phase extraction of polycyclic aromatic hydrocarbons from the hexane extracts of soil samples.

In this work, the perfluorobenzene-bonded silica sorbent was tested to adsorb polycyclic aromatic hydrocarbons in hexane. In the comparison experiments, the perfluorobenzene-bonded sorbent's performance was better than octadecyl silica sorbent and phenyl-bonded silica sorbents, which indicated that the π-hole···π bonds between perfluorobenzene and the polycyclic aromatic hydrocarbons were stronger than π···π interactions and hydrophobic interactions in hexane. Then the perfluorobenzene-bonded silica sorbent was applied to solid-phase extraction of 15 polycyclic aromatic hydrocarbons from the hexane extracts of soil samples directly without the solvent replacement, which simplified the soil pretreatment process. And the results showed that under the optimal conditions, the proposed method for the determination of polycyclic aromatic hydrocarbons in the environment soil presented good recoveries and stabilities for the 10 heavier polycyclic aromatic hydrocarbons with the recoveries ranging from 75.1% to 104.6% and the relative standard deviations being in the range of 1.4%-5.8%. The limits of detection of the method varied from 0.1 to 2 ng/g. This work reveals the great application potential of the π-hole bond as a new retention mechanism in the field of solid-phase extraction.

The Efficacy of Low-Kilovoltage X-Rays Intraoperative Radiation as Boost for Breast Cancer: A Systematic Review and Meta-Analysis.

Background: Intraoperative radiotherapy (IORT) is a novel promising technology that may replace external beam radiation therapy (EBRT) as boost for patients receiving breast-conserving surgery. To better evaluate the efficacy of IORT using low-kilovoltage (low-kV) X-rays as boost, we presented this meta-analysis according to the PRISMA checklist. Methods: Studies reported survival outcomes of intraoperative radiation using low-kilovoltage X-rays system (Intrabeam®, Carl Zeiss Meditec, Dublin, CA, USA) as boost were identified through electronic bibliographic database: PUBMED. The meta-analysis module in Stata (16.0) is used to pool the studies. A Poisson regression model is used to predict a 5-year local recurrence rate. Results: Twelve studies including 3006 cases were included in the final analysis, with a median follow-up of 55 months weighted by sample size. The pooled local recurrence rate is 0.39% per person-year (95% CI: 0.15%-0.71%), with a low degree of heterogeneity (I2 = 0%). The predicted 5-year local recurrence rate was 3.45%. No difference in pooled local recurrence rate was found between non-neoadjuvant patients studies and neoadjuvant patients studies (0.41% per person-year vs. 0.58% per person-year, P = 0.580). Conclusions: This study shows that low-kV IORT is an effective method as boost in breast cancer patients, with a low pooled local recurrence rate and low predicted 5-year local recurrence rate. Besides, no difference in the local recurrence rate was found between non-neoadjuvant patients studies and neoadjuvant patients studies. Low-kV IORT boost may be a promising alternative to EBRT boost in the future, which is being tested in the ongoing TARGIT-B trial.

Novel_miR-1517 mediates CYP6CM1 to regulate imidacloprid resistance in Bemisia tabaci (Hemiptera: Gennadius).

Bemisia tabaci (Hemiptera: Gennadius) is a notorious pest that is capable of feeding on >600 kinds of agricultural crops. Imidacloprid is critical in managing pest with sucking mouthparts, such as B. tabaci. However, the field population of B. tabaci has evolved resistance because of insecticide overuse. The overexpression of the detoxification enzyme cytochrome P450 monooxygenase is considered the main mechanism of imidacloprid resistance, but the mechanism underlying gene regulation remains unclear. MicroRNAs are a type of endogenous small molecule compounds that is fundamental in regulating gene expression at the post-transcriptional level. Whether miRNAs are related to the imidacloprid resistance of B. tabaci remains unknown. To gain deep insight into imidacloprid resistance, we conducted on miRNAs expression profiling of two B. tabaci Mediterranean (MED) strains with 19-fold resistance through deep sequencing of small RNAs. A total of 8 known and 1591 novel miRNAs were identified. In addition, 16 miRNAs showed significant difference in expression levels between the two strains, as verified by quantitative reverse transcription PCR. Among these, novel_miR-376, 1517, and 1136 significantly expressed at low levels in resistant samples, decreasing by 36.9%, 60.2%, and 15.6%, respectively. Moreover, modulating novel_miR-1517 expression by feeding with 1517 inhibitor and 1517 mimic significantly affected B. tabaci imidacloprid susceptibility by regulating CYP6CM1 expression. In this article, miRNAs related to imidacloprid resistance of B. tabaci were systematically screened and identified, providing important information for the miRNA-based technological innovation for this pest management.

Over-expression of UDP-glycosyltransferase UGT353G2 confers resistance to neonicotinoids in whitefly (Bemisia tabaci).

The whitefly, Bemisia tabaci, comes up high metabolic resistance to most neonicotinoids in long-term evolution, which is the key problem of pest control. UGT glycosyltransferase, as a secondary detoxification enzyme, plays an indispensable role in detoxification metabolism. In this study, UGT inhibitors, 5-nitrouracil and sulfinpyrazone, dramatically augmented the toxic damage of neonicotinoids to B. tabaci. A UGT named UGT353G2 was identified in whitefly, which was notably up-regulated in resistant strain (3.92 folds), and could be induced by most neonicotinoids. Additionally, the using of RNA interference (RNAi) suppresses UGT353G2 substantially increased sensitivity to neonicotinoids in resistant strain. Our results support that UGT353G2 may be involved in the neonicotinoids resistance of whitefly. These findings will help further verify the functional role of UGTs in neonicotinoid resistance.

[Huangdi Anxiao Capsules-containing serum protects cell model from cognitive dysfunction in diabetes via inhibiting NLRP3-mediated pyroptosis].

This study aims to investigate the effects and the molecular mechanism of Huangdi Anxiao Capsules(HDAX)-containing serum in protecting the rat adrenal pheochromocytoma(PC12) cells from diabetes-associated cognitive dysfunction induced by high glucose and whether the mechanism is related to the regulation of NOD-like receptor thermal protein domain associated protein 3(NLRP3)-mediated pyroptosis. The PC12 cell model of diabetes-associated cognitive dysfunction induced by high glucose was established and mcc950 was used to inhibit NLRP3. PC12 cells were randomized into control, model, HDAX-containing serum, mcc950, and HDAX-containing serum+mcc950 groups. Methyl thiazolyl tetrazolium(MTT) assay was employed to determine the viability, and Hoechst 33258/PI staining to detect pyroptosis of PC12 cells. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of interleukin-1 beta(IL-1ß) and IL-18. Western blot was employed to determine the protein levels of postsynaptic density protein 95(PSD-95), NLRP3, apoptosis-associated speck-like protein containing a CARD(ASC), gasdermin D(GSDMD), GSDMD-N, and cleaved cysteinyl aspartate specific proteinase-1(caspase-1), and RT-PCR to determine the mRNA levels of NLRP3, ASC, GSDMD, and caspase-1. The immunofluorescence assay was adopted to measure the levels and distribution of NLRP3 and GSDMD-N in PC12 cells. Compared with the control group, the model group showed decreased cell proliferation, increased PI positive rate, down-regulated protein level of PSD-95, up-regulated protein levels of NLRP3, ASC, GSDMD-N, GSDMD, and cleaved caspase-1, up-regulated mRNA levels of NLRP3, ASC, GSDMD, and caspase-1, and elevated levels of IL-1ß and IL-18. Compared with the model group, HDAX-containing serum, mcc950, and the combination of them improved cell survival rate and morphology, decreased the PI positive rate, down-regulated the protein levels of NLRP3, ASC, GSDMD-N, GSDMD, and cleaved caspase-1 and the mRNA levels of NLRP3, ASC, GSDMD, and caspase-1, and promoted the secretion of IL-1ß and IL-18. The findings demonstrated that HDAX-containing serum can inhibit the pyroptosis-mediated by NLRP3 and protect PC12 cells from the cognitive dysfunction induced by high glucose.

DLGAP1-AS2 promotes estrogen receptor signalling and confers tamoxifen resistance in breast cancer.

BACKGROUND: Tamoxifen is a first-line endocrine agent and is often used to treat estrogen receptor-positive (ER+) breast cancer. Unfortunately, approximately 30-40% of patients who received tamoxifen therapy experience recurrence or progression to a fatal advanced stage due to tamoxifen resistance. However, the mechanisms of tamoxifen resistance remain unclear. METHODS: The expression of lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) was detected by qPCR. The effect of DLGAP1-AS2 on tamoxifen resistance was evaluated by MTT, colony formation, TUNEL and flow cytometric assays. The mechanisms by which DLGAP1-AS2 regulates tamoxifen resistance were investigated through qPCR, RNA pull-down assays and RNA immunoprecipitation (RIP) assays. RESULTS: Our results showed that DLGAP1-AS2 is significantly upregulated in breast cancer and that tamoxifen can induce DLGAP1-AS2 expression. Further investigation suggested that upregulation of DLGAP1-AS2 can increase cell viability and inhibit apoptosis, while downregulation of DLGAP1-AS2 results in the opposite effects. Mechanistically, DLGAP1-AS2 can bind to the AFF3 protein to inhibit its degradation, which further promotes ER signalling. CONCLUSIONS: Our research clarified that DLGAP1-AS2 promotes ER signalling to induce tamoxifen resistance and that targeting DLGAP1-AS2 might be a promising strategy to overcome tamoxifen resistance in breast cancer.

Clinical characteristics and prognostic value of EGFR mutation in stage I lung adenocarcinoma with spread through air spaces after surgical resection.

The clinical data of stage I invasive lung adenocarcinoma patients with spread through air spaces (STAS) who underwent lobectomy from January 1, 2013 to January 1, 2016 at the Department of Thoracic Surgery of Hebei Medical University were analyzed retrospectively, and statistical analysis was carried out to explore their clinical features and prognostic value of EGFR mutation. A total of 280 patients were included in the study cohort, and EGFR mutations were detected in 154 patients. EGFR mutations were more common in non-smokers (p=0.045), females (p<0.001), without vascular tumor thrombus (p=0.037), and histological subtype LPA/APA/PPA (p=0.001). Multivariate analysis of the Cox risk regression model showed that EGFR gene mutation (p=0.807) was not an independent influencing factor of recurrence-free survival (RFS), but EGFR mutation was an independent influencing factor of overall survival (OS) (p=0.012), and OS of patients with EGFR mutation was better. The EGFR mutation also significantly increased the progression-free survival (PFS) of relapsed patients (p<0.001), but the PFS of relapsed EGFR mutation patients who received adjuvant chemotherapy after the operation was worse than that of patients who did not receive adjuvant chemotherapy (p=0.029). EGFR gene mutation is not a risk factor for postoperative recurrence in patients with stage I lung adenocarcinoma with STAS but the 5-year survival rate of patients with EGFR gene mutation is better than that of wild-type. Postoperative adjuvant chemotherapy for patients with EGFR mutation should be carefully considered.

Cystathionine ß-synthase expression correlates with tumor development and poor prognosis in lung squamous cell carcinoma patients.

The purpose of this study was to investigate the correlation between the expression of cystathionine ß-synthase (CBS) in lung squamous cell carcinoma (LUSC) and the microvascular density (MVD) and clinicopathological features. Firstly, the expression status of CBS in diffuse carcinoma and LUSC was searched through the public bioinformatics database. Subsequently, immunohistochemical staining and scoring were performed on tumor tissues and matched normal tissues from 108 LUSC patients to assess CBS expression; the MVD of tumor tissues was also detected. The results showed that CBS was overexpressed in some tumor tissues, including LUSC. Immunohistochemical results showed that the positive expression rate of CBS in tumor tissues (63.0%) was higher than that in normal tissues (17.6%). The expression of CBS was correlated with T (p=0.01), N (p=0.004), TNM (p=0.011) stages, and tumor differentiation degrees (p<0.001), with the increase of T, N, and TNM stages or the decrease of differentiation, the expression level of CBS also increased. In addition, the expression level of CBS was positively correlated with MVD (r=0.6997, p<0.0001). Survival analysis showed that the survival rate of the CBS negative expression group was better than that of the positive expression group (p=0.004). Cox multivariate analysis showed that CBS expression status (p<0.001), T stages (p=0.020), and TNM stages (p=0.021) were independent factors affecting the prognosis of LUSC. In conclusion, the high expression of CBS affects tumor development and is associated with the poor prognosis of LUCS, which may be used as a biomarker to evaluate prognosis and find a new direction for the treatment of LUSC.

A Mechanism Study for Self-Cleaving Chlorotetrafluoroethylsulfinyl (-SOCF2CF2Cl)-Directed Pd(II)-Catalyzed C-H Activation.

A mechanism study for Pd(II)-catalyzed C(sp3)-H activation using a self-cleaving chlorotetrafluoroethylsulfinyl (-SOCF2CF2Cl) auxiliary as a directing group is reported. Mechanistic studies reveal that (1) the auxiliary group is crucial for C(sp3)-H activation, (2) the reaction undergoes a C(sp3)-H olefination-Michael addition-removal of the auxiliary sequence, (3) the removal of the auxiliary (SORf) is most likely the alcoholic solvolysis of the -SOCF2CF2Cl group on the N-tri-substituted sulfonamides, and (4) the C(sp3)-H cleavage is involved in the rate-determining step.

Thioredoxin-interacting protein (TXNIP) as a target for Alzheimer's disease: flavonoids and phenols.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid plaques and tangles that have become the fifth leading cause of death worldwide. Previous studies have found that thioredoxin interacting protein (TXNIP) expression was increased during the development of AD neurons. TXNIP separates from the TXNIP-thioredoxin complex, and the TXNIP-NLRP3 complex assembles ASC and pro-caspase-1 to form the NLRP3 inflammasome, which triggers AD inflammation and apoptosis. CB-dock was used to explore whether 21 natural flavonoids and phenols target TXNIP based on references. Docking results showed that rutin, puerarin, baicalin, luteolin and quercetin are the most potent TXNIP inhibitors, and among them, rutin as the most effective flavonoid. And rosmarinic acid is the most potent TXNIP inhibitor of phenols. These phytochemicals could be helpful to find the lead compounds in designing and developing novel agents for Alzheimer's disease.