Hydroxymethylation hydroxylation of 1,3-diarylpropene through a catalytic diastereoselective Prins reaction: cyclization logic and access to brazilin core.

A catalytic diastereoselective Prins reaction for hydroxymethylation and hydroxylation of 1,3-diarylpropene was successfully utilized to prepare various 1,3-dioxanes 7 in 14-88% yields. Take advantage of the synthetic intermediate 7h, the key B/C rings in brazilin core could be constructed by the sequential of Friedel-Crafts/Ullmann-Ma rather than Ullmann-Ma/Friedel-Crafts reactions.

Genome-wide identification and characterization of long non-coding RNA in barley roots in response to Piriformospora indica colonization.

Currently, there is very limited information about long noncoding RNAs (lncRNAs) found in barley. It remains unclear whether barley lncRNAs are responsive to Piriformospora indica (P. indica) colonization.We found that barley roots exhibited fast development and that large roots branched after P. indica colonization. Genome-wide high-throughput RNA-seq and bioinformatic analysis showed that 4356 and 5154 differentially expressed LncRNAs (DELs) were found in response to P. indica at 3 and 7 days after colonization (dai), respectively, and 2456 DELs were found at 7 dai compared to 3 dai. Based on the coexpression correlation of lncRNAmRNA, we found that 98.6% of lncRNAs were positively correlated with 3430 mRNAs at 3 dai and 7 dai. Further GO analysis showed that 30 lncRNAs might be involved in the regulation of gene transcription; 23 lncRNAs might participate in cell cycle regulation. Moreover, the metabolite analysis indicated that chlorophyll a, sucrose, protein, gibberellin, and auxin were in accordance with the results of the transcriptome, and the respective lncRNAs were positively correlated with these target RNAs. Gene silencing suggested that lncRNA TCONS_00262342 is probably a key regulator of GA3 synthesis pathway, which participates in P. indica and barley interactions. We concluded that acting as a molecular material basis and resource, lncRNAs respond to P. indica colonization by regulating metabolite content in barley and coordinate the complex regulatory process of higher life by constructing highly positive correlations with their target mRNAs.

Ferroptosis-related STEAP3 acts as predictor and regulator in diffuse large B cell lymphoma through immune infiltration.

Diffuse large B cell lymphoma (DLBCL) is a usual-seen hematological malignant tumor possessing molecular and genetic heterogeneity. Ferroptosis induction has been increasingly acknowledged to be an advantageous therapeutic method in tumor treatment by triggering cell death of tumor cells. However, studies on the function of ferroptosis in DLBCL remain scarce, especially the interaction with the tumor immune microenvironment (TIME). The clinical and biological functions of ferroptosis-related genes in DLBCL were still warranted to be explored. A ferroptosis-related risk model was constructed, followed by functional enrichment analyses and evaluation of immune profile. Quantitative real-time PCR, western blotting, and immunohistochemistry were conducted to examine the RNA and protein levels. Dysregulated expression of the major ferroptosis-related genes was found in DLBCL. A prognostic risk model based on 10 ferroptosis-related genes was constructed. The risk score served as an independent prognostic indicator for DLBCL patients in univariate and multivariate Cox regression analysis. Patients with low-risk scores presented a more favorable prognosis. Functional enrichment analysis revealed that immune-related pathways were significantly enriched, and the high-risk group exhibited less immunocyte infiltration, lower immunoscore, and downregulated PD-L1 expression relative to the low-risk group. Two molecular subtypes were determined through consensus clustering of the expression of ferroptosis-related genes. Cluster 1 was relevant to favorable prognosis, higher immunoscore, and elevated PD-L1 expression. More importantly, STEAP3 was screened as a reliable biomarker for DLBCL, and its enhanced expression levels of mRNA and protein were verified in public databases and clinical specimens. Our study demonstrated the crucial role of ferroptosis-related genes including STEAP3 in the TIME of DLBCL and identified promising novel molecular targets for DLBCL treatment.

CTP synthase 2 predicts inferior survival and mediates DNA damage response via interacting with BRCA1 in chronic lymphocytic leukemia.

BACKGROUND: Cytidine triphosphate synthase 2 (CTPS2) is an essential metabolic enzyme that catalyzes the biosynthesis of CTP. CTP synthases contribute to lymphocytes proliferation and tumorigenesis, but the role of CTPS2 in chronic lymphocytic leukemia (CLL) remains undefined. METHODS: In silico analysis was performed to quantified the expression and clinical analysis of CTPS2 and BRCA1. The expression was then validated on the internal sets. Loss-and gain-of-function assays were conducted to investigate the physiological phenotypes in CLL. RNA-seq was employed to probe the molecular mechanism of CTPS2. RESULTS: Herein, significant elevated expression of CTPS2 was observed in CLL patients compared to normal CD19 + B cells, which was verified in three independent cohorts. Furthermore, overexpression of CTPS2 was closely associated with undesired prognostic indicators, including unmutated IGHV status and chromosome 11q23 deletion. Additionally, elevated CTPS2 expression predicted adverse overall survival and treatment-free survival with independent prognostic significance. Downregulation of CTPS2 in CLL cells exhibited attenuated cell proliferation, arrested G2/M cell cycle and increased apoptosis. The addition of CTP or glutamine could reverse the above effects. Since RNA-seq showed the enrichment in DNA damage and response signaling, we subsequently found that silence of CTPS2 remarkably elevated DNA damage and decreased DNA repair. It was demonstrated that CTPS2 mediated DNA damage response via interacting with Breast Cancer 1 (BRCA1) protein in CLL through CoIP assays and rescued experiments. CONCLUSIONS: Collectively, our study generated the novel findings that CTPS2 promoted CLL progression via DNA damage response and repair pathway. Targeting nucleotide metabolism potentially became an attractive strategy for treatment against CLL.

Competing endogenous RNA networks related to prognosis in chronic lymphocytic leukemia: comprehensive analyses and construction of a novel risk score model.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy that lacks specific biomarkers and drug targets. Competing endogenous RNAs (ceRNAs) play vital roles in oncogenesis and tumor progression by sponging microRNAs (miRNAs). Nevertheless, the regulatory mechanisms of survival-related ceRNA networks in CLL remain to be uncovered. METHODS: We included 865 de novo CLL patients to investigate RNA expression profiles and Illumina sequencing was performed on four CLL patients, two CLL cell lines and six healthy donors in our center. According to univariate Cox regression, LASSO regression as well as multivariate Cox regression analyses, we established a novel risk score model in CLL patients. Immune signatures were compared between the low- and high-risk groups with CIBERSORT and ESTIMATE program. Afterwards, we analyzed the relationship between differentially expressed miRNAs (DEmiRNAs) and IGHV mutational status, p53 mutation status and del17p. Based on the survival analyses and differentially expressed RNAs with targeting relationships, the lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed. In addition, the circRNA circ_0002078/miR-185-3p/TCF7L1 axis was verified and their interrelations were delineated by dual-luciferase reporter gene assay. RESULTS: Totally, 57 differentially expressed mRNAs (DEmRNAs) and 335 DEmiRNAs were identified between CLL patient specimens and normal B cells. A novel risk score model consisting of HTN3, IL3RA and NCK1 was established and validated. The concordance indexes of the model were 0.825, 0.719 and 0.773 in the training, test and total sets, respectively. The high-risk group was related to del(13q14) as well as shorter overall survival (OS). Moreover, we identified DEmiRNAs that related to cytogenetic abnormality of CLL patients, which revealed that miR-324-3p was associated with IGHV mutation, p53 mutation and del17p. The survival-related lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed to further facilitate the development of potential predictive biomarkers. Besides, the expression of circ_0002078 and TCF7L1 were significantly elevated and miR-185-3p was obviously decreased in CLL patients. Circ_0002078 regulated TCF7L1 expression by competing with TCF7L1 for miR-185-3p. CONCLUSIONS: The comprehensive analyses of RNA expression profiles provide pioneering insights into the molecular mechanisms of CLL. The novel risk score model and survival-related ceRNA networks promote the development of prognostic biomarkers and potential therapeutic vulnerabilities for CLL.

An Extended Prognostic Index of the ISSWM Score Based on Thyroid Complications in Waldenström Macroglobulinemia/Lymphoplasmacytoid Lymphoma.

Waldenström macroglobulinemia/lymphoplasmacytoid lymphoma (WM/LPL) is a rare lymphoproliferative neoplasm characterized by clonally related lymphocytes, lymphoplasmacytic cells, and plasma cell proliferation. WM/LPL patients commonly present with elevated immunoglobulin, predominantly immunoglobulin M (IgM). Previous studies reported that thyroid dysfunction was associated with the development and progression of solid tumors. However, only limited information is available on the correlation between thyroid complications and lymphoid malignancies. The aim of our study was to explore the prognostic significance of thyroid complications in WM/LPL. Herein, 13.3% of WM/LPL patients were diagnosed with thyroid complications, which were significantly associated with unfavorable progression-free survival (PFS), overall survival (OS), and adverse treatment response. Co-existing thyroid disease was significantly related to alleviated serum IgM levels, providing an answer to practical problems. Furthermore, the presence of thyroid complications was identified as an independent prognostic indicator for PFS in WM/LPL. Incorporating the ISSWM score with thyroid complications was superior to ISSWM alone in risk stratification and prognostic prediction. Furthermore, subgroup analyses of WM/LPL patients revealed that subclinical hypothyroidism predicted undesirable outcomes at the early stage. These results were also supported by independent microarray dataset analyses. In conclusion, the primary strength of this study is that it provides robust real-world evidence on the prognostic role of thyroid complications, highlighting further clinical concerns in the management of WM/LPL patients.

Nucleolar and spindle associated protein 1 enhances chemoresistance through DNA damage repair pathway in chronic lymphocytic leukemia by binding with RAD51.

Nucleolar and spindle-associated protein 1 (NUSAP1) is an essential regulator of mitotic progression, spindle assembly, and chromosome attachment. Although NUSAP1 acts as an oncogene involved in the progression of several cancers, the exact role of chronic lymphocytic leukemia (CLL) remains elusive. Herein, we first discovered obvious overexpression of NUSAP1 in CLL associated with poor prognosis. Next, the NUSAP1 level was modulated by transfecting CLL cells with lentivirus. Silencing NUSAP1 inhibited the cell proliferation, promoted cell apoptosis and G0/G1 phase arrest. Mechanistically, high expression of NUSAP1 strengthened DNA damage repairing with RAD51 engagement. Our results also indicated that NUSAP1 knockdown suppressed the growth CLL cells in vivo. We further confirmed that NUSAP1 reduction enhanced the sensitivity of CLL cells to fludarabine or ibrutinib. Overall, our research investigates the mechanism by which NUSAP1 enhances chemoresistance via DNA damage repair (DDR) signaling by stabilizing RAD51 in CLL cells. Hence, NUSAP1 may be expected to be a perspective target for the treatment of CLL with chemotherapy resistance.

Prognostic and Therapeutic Value of Apolipoprotein A and a New Risk Scoring System Based on Apolipoprotein A and Adenosine Deaminase in Chronic Lymphocytic Leukemia.

Lipid metabolism is related to lymphomagenesis, and is a novel therapeutic target in some hematologic tumors. Apolipoprotein A (ApoA), the major protein of high-density lipoprotein (HDL), plays a crucial role in lipid transportation and protecting against cardiovascular disease, and takes effect on anti-inflammation and anti-oxidation. It is correlated with the prognosis of some solid tumors. Yet, there is no investigation involving the role of ApoA plays in chronic lymphocytic leukemia (CLL). Our retrospective study focuses on the prognostic value of ApoA in CLL and its therapeutic potential for CLL patients. Herein, ApoA is a favorable independent prognostic factor for both overall survival (OS) and progression-free survival (PFS) of CLL patients. ApoA is negatively associated with ß2-microglobulin (ß2-MG) and advanced stage, which are poor prognostic factors in CLL. Age, Rai stage, ApoA, and adenosine deaminase (ADA) are included in a new risk scoring system named ARAA-score. It is capable of assessing OS and PFS of CLL patients. Furthermore, cell proliferation assays show that the ApoA-I mimetic L-4F can inhibit the proliferation of CLL cell lines and primary cells. In conclusion, ApoA is of prognostic value in CLL, and is a potential therapy for CLL patients. The ARAA-score may optimize the risk stratification of CLL patients.

Casualty risk of e-bike rider struck by passenger vehicle using China in-depth accident data.

Objective: Traffic deaths involving e-bike (electric bike) riders are increasing in China. This study aims to quantitatively investigate the association between e-bike rider casualty and impact speed in electric bike-passenger vehicle collisions based on China in-depth accident study data.Methods: According to the collision location and driving direction of the e-bike and the vehicle, electric bike-passenger vehicle collisions are divided into five collision types: frontal collision, e-bike side collision, vehicle side collision, scrape collision and rear-end collision. Since e-bike side collision (the side of e-bike impacted with the front of vehicle) is the leading type and has the highest likelihood of severe or fatal injury in all collision types, e-bike side collisions are further selected to build the casualty risk functions of e-bike rider in relation to the rider age and the impact speed (vehicle impact speed and e-bike impact speed).Results: The analysis results show that, as for e-bike side collisions and e-bike impact speed is 20 km/h, the fatality risk of riders is approximately 2.9% at vehicle impact speed of 30 km/h, 23% at 50 km/h, 50% at 60 km/h, and 90% at 80 km/h. Rider age is also significantly associated with a higher risk of severe and fatality injury. The e-bike impact speed is not significantly associated with the severe and fatality risk in e-bike side collisions.Conclusions: The findings of this study provide meaningful insights to formulate effective policies especially for speed limit management to improve the safety of e-bikes.

The injury epidemiology of adult riders in vehicle-two-wheeler crashes in China, Ningbo, 2011-2015.

INTRODUCTION: We used road crashes between vehicles and two-wheelers from Yinzhou District Ningbo in 2011-2015 from the China In-depth Accident Study (CIDAS) as sample cases. The risk factors of different injury severity grades were analyzed. METHOD: The classification tree model was used to screen the possible interaction items, and the corresponding regression model was constructed according to the results of the tree model to explore the influencing factors of cyclist injury. RESULTS: The road types, weather types, gender, age of the riders, and vehicle speed were significantly correlated with the dependent variables. The interaction effect of gender*road type, weather*age, weather*speed and speed*age were obtained through a tree model. CONCLUSIONS: The risk of male casualties at the crossroads was 3.31 times higher than that of female casualties at the straight roads. On sunny days, the risk of crash casualties in Ningbo was low, and the fatality risk when the speed reached 38 km/h was 10%. Under the interaction effect of weather and age, the fatality risk in cloudy/foggy and rainy days was almost coincident, and the serious risk in cloudy/foggy conditions was the highest. Practical applications: Through factor analysis, it is confirmed that there is interaction effect among the factors, and it can provide reference for relevant departments to formulate more targeted and effective governance strategies.

Dually crosslinked self-healing hydrogels originating from cell-enhanced effect.

A new cell-loading strategy is proposed to improve the self-healing properties of hydrogels prepared by free-radical polymerization. The introduction of normal human dermal fibroblast (NHDF) cells enables the formation of dually crosslinked hydrogels through hydrogen interactions between cell secretions (mainly the secretory proteins) and polymer chains. This allows an enhancement of the self-healing efficiency from 73% to 92% and an acceleration of the self-healing rate (12 times). Based on the excellent biocompatibility, antibacterial property and low toxicity, we extended the use of dually crosslinked hydrogels as wound dressings to expedite wound healing. This cell-loading concept for constructing dually crosslinked hydrogels offers an available pathway to design smart materials useful for biomedical applications.

Quercetin protects gastric epithelial cell from oxidative damage in vitro and in vivo.

Epithelial injury caused by reactive oxygen species (ROS) including H2O2 plays a critical role in the pathogenesis of gastric disorders. Therefore, pharmacological intervention targeting reactive oxygen species elimination has highly clinical values in therapy of gastric diseases. Although quercetin has been found to possess gastroprotective activity, whether it has a protective activity againress related injury to gastric epithelial cells remains unknown. The aim of the study is herein to investigate a possible protective effect of quercetin against oxidative stress in vitro and vivo. Human gastric epithelial GES-1 cells were pretreated with quercetin and then challenged with H2O2. In vivo reactive oxygen species production in acute gastric mocosa injury was assessed using a chemiluminescent probe L-012 (8-amino-5-chloro-7-phenylpyrido [3,4-d]pyridazine-1,4-(2H,3H)dione) after quercetin was administered to mice. In GES-1 cells, pretreatment of quercetin can significantly diminish H2O2-induced cell viability loss; decrease intracellular reactive oxygen species and Ca(2+) influx; restore H2O2-induced ΔΨm dissipation. It also upregulates peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) expression under the state of oxidative stress, and the downstream cell apoptosis significantly decreased. In vivo, chemiluminescence imaging shows that quercetin attenuates reactive oxygen species production and gastric damages in acute gastric mucosal injury. We first reported the evidence that quercetin can protect gastric epithelial GES-1 cells from oxidative damage and ameliorate reactive oxygen species production during acute gastric mucosal injury in mice. This might be ascribed to its inhibition of oxidative stress, regulation of mitochondrial dysfunction, initiation of antioxidant defense and inhibition of apoptosis.