Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors.

The targeting of cyclin-dependent kinase 7 (CDK7) has become a highly desirable therapeutic approach in the field of oncology due to its dual role in regulating essential biological processes, encompassing cell cycle progression and transcriptional control. We have previously identified a highly selective thieno[3,2-d]pyrimidine-based CDK7 inhibitor with demonstrated efficacy and safety in animal model. In this study, we sought to optimize the thieno[3,2-d]pyrimidine core to discover a novel series of CDK7 inhibitors with improved potency and pharmacokinetic (PK) properties. Through extensive structure-activity relationship (SAR) studies, compound 20 has emerged as the lead candidate due to its potent inhibitory activity against CDK7 and remarkable efficacy on MDA-MB-453 cells, a representative triple negative breast cancer (TNBC) cell line. Furthermore, 20 has demonstrated favorable oral bioavailability and exhibited highly desirable pharmacokinetic (PK) properties, making it a promising lead candidate for further structural optimization.

Discovery of LHQ490 as a highly selective fibroblast growth factor receptor 2 (FGFR2) inhibitor.

Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC50 of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC50 value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.

Design and Synthesis of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-Dependent Kinase 7 Inhibitors.

The duality of function (cell cycle regulation and gene transcription) of cyclin-dependent kinase 7 (CDK7) makes it an attractive oncology target and the discovery of CDK7 inhibitors has been a long-term pursuit by academia and pharmaceutical companies. However, achieving selective leading compounds is still difficult owing to the similarities among the ATP binding pocket. Herein, we detail the design and synthesis of a series of macrocyclic derivatives with pyrazolo[1,5-a]-1,3,5-triazine core structure as potent and selective CDK7 inhibitors. The diverse manners of macrocyclization led to distinguished selectivity profiles of the CDK family. Molecular dynamics (MD) simulation explained the binding difference between 15- and 16-membered macrocyclic compounds. Further optimization generated compound 37 exhibiting good CDK7 inhibitory activity and high selectivity over other CDKs. This work clearly demonstrated macrocyclization is a versatile method to finely tune the selectivity profile of small molecules and MD simulation can be a valuable tool in prioritizing designs of the macrocycle.

Discovery of novel macrocyclic derivatives as potent and selective cyclin-dependent kinase 2 inhibitors.

Cyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over-activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1, a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22, exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.

Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol.

Taxol is a widely-applied anticancer drug that inhibits microtubule dynamics in actively replicating cells. Although a minimum 19-step biosynthetic pathway has been proposed and 16 enzymes likely involved have been characterized, stepwise biosynthetic reactions from the well-characterized di-oxygenated taxoids to Taxol tetracyclic core skeleton are yet to be elucidated. Here, we uncover the biosynthetic pathways for a few tri-oxygenated taxoids via confirming the critical reaction order of the second and third hydroxylation steps, unearth a taxoid 9α-hydroxylase catalyzing the fourth hydroxylation, and identify CYP725A55 catalyzing the oxetane ester formation via a cascade oxidation-concerted acyl rearrangement mechanism. After identifying a acetyltransferase catalyzing the formation of C7-OAc, the pathway producing the highly-oxygenated 1ß-dehydroxybaccatin VI with the Taxol tetracyclic core skeleton is elucidated and its complete biosynthesis from taxa-4(20),11(12)-diene-5α-ol is achieved in an engineered yeast. These systematic studies lay the foundation for the complete elucidation of the biosynthetic pathway of Taxol.

A novel transcriptomic signature associated with lymphovascular invasion predicts clinical outcomes, tumor microenvironment, and therapeutic response in lung adenocarcinoma.

PURPOSE: Since TNM staging has limitations for predicting post-operative outcomes and relapse, more effective prediction tools need to be researched and developed. Lymphovascular invasion, LVI, as a histopathological feature, has been widely shown to have a correlation with poor prognosis and early recurrence of lung adenocarcinoma (LUAD). However, LVI assessment is limited by subjective bias, and therefore its efficacy in practical clinical application needs further clarification. The aim of this study was to formulate a new signature based on LVI-related genes to predict prognosis and recurrence in patients with lung adenocarcinoma. METHODS: Clinicopathological information, gene sequencing data and whole slide images (WSIs) of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA) databases. LVI statue were evaluated by professional pathologists, and then the differentially expressed genes (LVI DEGs) associated with LVI were screened. The least absolute shrinkage and selection operator (LASSO) and Step Cox regression models were used to construct LVI-associated risk scores (LVRS), including PAQR4, ARGHEF6, CKS1B, CFTR and SEC14L4. The validity of the LVRS score was evaluated on multiple external datasets and our JSSZL cohort dataset. Using LVRS scores and clinical information, nomogram were constructed for use by clinicians. In addition, we further explored the relationship between LVRS score and clinicopathological features, immune infiltration, tumor mutational load, and immunotherapy response, and confirmed the expression of key genes in LVRS score in lung adenocarcinoma tissues using qRT-PCR and immunohistochemistry (IHC) techniques. RESULTS: Based on the LVRS, patients could be classified into high-LVRS and low-LVRS groups. It was found that OS and PFS were significantly worse in the high-LVRS group than in the low-LVRS group (p < 0.001). By ROC curve analysis, it could be found that the nomogram combining LVRS and clinical information could accurately predict the prognosis of LUAD patients with the area under the curve of 1,3,5-year survival rate could reach 0.754, 0.741 and 0.735. The results of univariate and multivariate analysis showed that LVRS was an independent prognostic factor. At the same time, there were significant differences in the mutation profiles and immune microenvironment between the high-LVRS and low-LVRS groups, with the high-LVRS group having a significantly higher mutation rate than the low-LVRS group and exhibiting immunological "cold" features. By the experimental results, higher expression levels of PAQR4 and CKS1B were found in LUAD tissues, while lower expression levels of ARGHEF6, CFTR and SEC14L4 were observed. CONCLUSIONS: The LVRS established in this study serves as a valid tool to predict the prognosis and recurrence status of lung adenocarcinoma patients and has a predictive effect on the response to postoperative treatment. The establishment of LVRS may offer some theoretical support to clinical treatment strategies for patients with lung adenocarcinoma following surgical intervention.

The molecular, immune features, and risk score construction of intraductal papillary mucinous neoplasm patients.

Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precancerous lesion, with increasing incidence in recent years. However, the mechanisms of IPMN progression into invasive cancer remain unclear. The mRNA expression data of IPMN/PAAD patients were extracted from the TCGA and GEO databases. First, based on GSE19650, we analyzed the molecular alterations, tumor stemness, immune landscape, and transcriptional regulation of IPMN progression. The results indicated that gene expression changed dramatically, specifically at the intraductal papillary-mucinous adenoma (IPMA) stage. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Kyoto Encyclopedia of Genes and Genomes (GSEA) pathway analyses showed that glycoprotein-related, cell cycle, and P53 pathways displayed the most significant changes during progression. With IPMN progression, tumor stemness increased continuously, and KRAS, ERBB3, RUNX1, and ELF3 are essential driver genes affecting tumor stemness. Motif analysis suggested that KLF4 may be a specific transcription factor that regulates gene expression in the IPMA stage, while MYB and MYBL1 control gene expression in the IPMC and invasive stages, respectively. Then, GSE19650 and GSE71729 transcriptome data were combined to perform the least absolute shrinkage and selection operator (LASSO) method and Cox regression analysis to develop an 11-gene prediction model (KCNK1, FHL2, LAMC2, CDCA7, GPX3, C7, VIP, HBA1, BTG2, MT1E, and LYVE1) to predict the prognosis of pancreatic cancer patients. The reliability of the model was validated in the GSE71729 and TCGA databases. Finally, 11 additional IPMN patients treated in our hospital were included, and the immune microenvironment changes during IPMN progression were analyzed by immunohistochemistry (IHC). IHC results suggest that Myeloid-derived suppressor cells (MDSCs) and macrophages may be key in the formation of immunosuppressive microenvironment of IPMN progression. Our study deepens our understanding of IPMN progression, especially the changes in the immune microenvironment. The findings of this work may contribute to the development of new therapeutic strategies for IPMN.

Recent advances in the synthesis of ent-kaurane diterpenoids.

Covering: 2015 to 2020The ent-kaurane diterpenoids are integral parts of tetracyclic natural products that are widely distributed in terrestrial plants. These compounds have been found to possess interesting bioactivities, ranging from antitumor, antifungal and antibacterial to anti-inflammatory activities. Structurally, the different tetracyclic moieties of ent-kauranes can be seen as the results of intramolecular cyclizations, oxidations, C-C bond cleavages, degradation, or rearrangements, starting from their parent skeleton. During the past decade, great efforts have been made to develop novel strategies for synthesizing these natural products. The purpose of this review is to describe the recent advances in the total synthesis of ent-kaurane diterpenoids covering the period from 2015 to date.

90-Gene Expression Profiling for Tissue Origin Diagnosis of Cancer of Unknown Primary.

Cancer of unknown primary (CUP), in which metastatic diseases exist without an identifiable primary location, accounts for about 3-5% of all cancer diagnoses. Successful diagnosis and treatment of such patients are difficult. This study aimed to assess the expression characteristics of 90 genes as a method of identifying the primary site from CUP samples. We validated a 90-gene expression assay and explored its potential diagnostic utility in 44 patients at Jiangsu Cancer Hospital. For each specimen, the expression of 90 tumor-specific genes in malignant tumors was analyzed, and similarity scores were obtained. The types of malignant tumors predicted were compared with the reference diagnosis to calculate the accuracy. In addition, we verified the consistency of the expression profiles of the 90 genes in CUP secondary malignancies and metastatic malignancies in The Cancer Genome Atlas. We also reported a detailed description of the next-generation coding sequences for CUP patients. For each clinical medical specimen collected, the type of malignant tumor predicted and analyzed by the 90-gene expression assay was compared with its reference diagnosis, and the overall accuracy was 95.4%. In addition, the 90-gene expression profile generally accurately classified CUP into the cluster of its primary tumor. Sequencing of the exome transcriptome containing 556 high-frequency gene mutation oncogenes was not significantly related to the 90 genes analysis. Our results demonstrate that the expression characteristics of these 90 genes can be used as a powerful tool to accurately identify the primary sites of CUP. In the future, the inclusion of the 90-gene expression assay in pathological diagnosis will help oncologists use precise treatments, thereby improving the care and outcomes of CUP patients.

Case Report: Extragonadal Yolk Sac Tumors Originating From the Endometrium and the Broad Ligament: A Case Series and Literature Review.

Yolk sac tumors (YSTs) of the endometrium and the broad ligament are very rare, with only 29 cases and one case of each other reported before in the English literature. Due to lack of standard guidelines, the treatment strategies of these diseases are controversial. Here, we share two cases of YSTs originating from the endometrium and the broad ligament respectively and review related literature. A 35-year-old woman was diagnosed with endometrial YST in our center and underwent surgery followed by chemotherapy with BEP (bleomycin, cisplatin and etoposide) regimen for six courses. After follow-up for 21 months, there is still no evidence of relapse. Another 36-year-old woman was admitted to our department with YST of the broad ligament. She was treated with surgery followed by chemotherapy with BEP regimen and was lost to follow-up after completing therapy. The case of endometrial YST we shared was similar to cases reported before, while the case with YST of the broad ligament we shared was the second case reported worldwide. Both of these two cases were treated with surgery combined with chemotherapy with BEP regimen.

Long Non-coding RNA RUNDC3A-AS1 Promotes Lung Metastasis of Thyroid Cancer via Targeting the miR-182-5p/ADAM9.

Long non-coding RNAs (lncRNAs) have been identified as influential indicators in variety of malignancies. Among which, LncRNA RUNDC3A-AS1 is reported to upregulate in thyroid cancer. However, the expression pattern and the pathological function of lncRNA RUNDC3A-AS1 in thyroid cancer is unclear. In this study, we examined the expression levels of lncRNA RUNDC3A-AS1 in the thyroid cancer tissues and cell lines via RT-qPCR analysis. The effects of RUNDC3A-AS1 on thyroid cancer cell metastasis were detected by transwell chamber assay, scratch assay in vitro and lung metastasis model in vivo. The results indicated that RUNDC3A-AS1 was highly expressed in the thyroid cancer tissues and cell lines. Functionally, knockdown of RUNDC3A-AS1 could repress the migration and invasion of thyroid cancer cells in vitro, and inhibit thyroid cancer metastasis to lung in vivo. Mechanistically, RUNDC3A-AS1 served as an inhibitor of miR-182-5p in tumor tissues and cell lines. RUNDC3A-AS1 inhibited the expression of miR-182-5p to increase the expression level of ADAM9, thus further aggravating the malignancy of thyroid cancer. Therefore, the RUNDC3A-AS1/miR-182-5p/ADAM9 axis may be a potential therapeutic target for the treatment of thyroid cancer metastasis.

PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression.

Background: Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that symmetrically di-methylates arginine residues on both histone and non-histone protein substrates. Accumulating evidence suggests that PRMT5 exerts its oncogenic properties in a wide spectrum of human malignancies. However, the underlying mechanisms by which PRMT5 contributes to the progression of colorectal cancer (CRC) remain to be defined. Methods: Western blot and real-time PCR were used to analyze the expression of CDKN2B. Co-immunoprecipitation (Co-IP), immunofluorescence and GST pulldown assays were employed to investigate the interaction between PRMT5 and EZH2. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to validate CDKN2B as a direct target of PRMT5/EZH2. DNA methylation status at the CpG islands of promoter region of CDKN2B gene was analyzed by bisulfite sequencing. The effect of PRMT5/EZH2 on malignant phenotypes was examined through in vitro and in vivo assays. PRMT5 and EZH2 protein expression levels in CRC tissues were analyzed by immunohistochemistry (IHC) staining. Results: We observed that PRMT5-deficient CRC cells exhibit proliferation defects in vitro. PRMT5 was identified as a major transcriptional repressor of CDKN2B (p15INK4b) for determining CRC progression. Mechanistically, PRMT5-mediated histone marks H4R3me2s and H3R8me2s were predominantly deposited at the promoter region of CDKN2B gene in CRC cells. Knockdown of PRMT5 in CRC cells decreased the accumulation of H4R3me2s and H3R8me2s marks and reduced the CpG methylation level of CDKN2B promoter, then re-activated CDKN2B expression. Strikingly, silencing of CDKN2B partially abrogated the proliferation defects caused by PRMT5 depletion in vitro and in vivo. Furthermore, we proved that PRMT5 interacted with Enhancer of zeste homolog 2 (EZH2), leading to enhanced EZH2 binding and H3K27me3 deposition together with decreased transcriptional output of CDKN2B gene. Importantly, we found that the combined interventions exerted a synergistic inhibitory effect of combined treatment with PRMT5i (GSK591) and EZH2i (GSK126) on the growth of CRC cells/xenografts in vitro and in vivo. Moreover, PRMT5 and EZH2 were found to be significantly elevated and associated with poor prognosis in CRC patients. Conclusion: PRMT5 functionally associates with EZH2 to promote CRC progression through epigenetically repressing CDKN2B expression. Thus, our findings raise the possibility that combinational intervention of PRMT5 and EZH2 may be a promising strategy for CRC therapy.

In Pursuit of Synthetic Efficiency: Convergent Approaches.

The field of total synthesis has reached a stage in which emphasis has been increasingly focused on synthetic efficiency rather than merely achieving the synthesis of a target molecule. The pursuit of synthetic efficiency, typically represented by step count and overall yield, is a rich source of inspiration and motivation for synthetic chemists to invent innovative strategies and methods. Among them, convergent strategy has been well recognized as an effective approach to improve efficiency. This strategy generally involves coupling of fragments with similar complexity to furnish the target molecule via subsequent cyclization or late-stage functionalization. Thus, methodologies that enable effective connection of fragments are critical to devising a convergent plan. In our laboratory, convergent strategy has served as a long-standing principle for pursuing efficient synthesis during the course of planning and implementing synthetic projects. In this Account, we summarize our endeavors in the convergent synthesis of natural products over the last ten years. We show how we identify reasonable bond disconnections and employ enabling synthetic methodologies to maximize convergency, leading to the efficient syntheses of over two-dozen highly complex molecules from eight disparate families.In detail, we categorize our work into three parts based on the diverse reaction types for fragment assembly. First, we demonstrate the application of a powerful single-electron reducing agent, SmI2, in a late-stage cyclization step, forging the polycyclic skeletons of structurally fascinating Galbulimima alkaloids and Leucosceptrum sesterterpenoids. Next, we showcase how three different types of cycloaddition reactions can simultaneously construct two challenging C-C bonds in a single step, providing concise entries to three distinct families, namely, spiroquinazoline alkaloids, gracilamine, and kaurane diterpenoids. In the third part, we describe convergent assembly of ent-kaurane diterpenoids, gelsedine-type alkaloids, and several drug molecules via employing some bifunctional synthons. To access highly oxidized ent-kaurane diterpenoids, we introduce the hallmark bicyclo[3.2.1]octane ring system at an early stage, and then execute coupling and cyclization by means of a Hoppe's homoaldol reaction and a Mukaiyama-Michael-type addition, respectively. Furthermore, we showcase how the orchestrated combination of an asymmetric Michael addition, a tandem oxidation-aldol reaction and a pinacol rearrangement can dramatically improve the efficiency in synthesizing gelsedine-type alkaloids, with nary a protecting group. Finally, to address the supply issue of several drugs, including anti-influenza drug zanamivir and antitumor agent Et-743, we exploit scalable and practical approaches to provide advantages over current routes in terms of cost, ease of execution, and efficiency.

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export.

Therapeutic monoclonal antibodies against the PD-L1/PD-1 (programmed death ligand-1/programmed cell death protein-1) axis have achieved great successes in cancer treatments, but the development of small-molecule immunomodulators of the pathway has lagged far behind. We established a cellular coculture assay with two stable transfectant cell lines, a PD-L1-expressing tumor cell line PC9/PD-L1 and a PD-1-expressing T cell line Jurkat/PD-1. Western blotting analyses were used to monitor the PD-L1/PD-1 interaction and signaling. We analyzed PD-L1 glycosylation by lectin binding assay and glycosidase digestion, and examined subcellular localization of PD-L1 by immunocytochemical staining. Luciferase assay and real-time PCR were used to evaluate T cell activation in the coculture experiments. We found that coculturing of the PC9/PD-L1 cells with the Jurkat/PD-1 cells induced a lysosomal degradation of PD-1. A small-molecule PD-L1 inhibitor BMS1166 developed by Bristol-Myers Squibb inhibited the coculture-induced PD-1 degradation through a unique mechanism. BMS1166 specifically affected PD-L1 glycosylation and prevented transporting of the under-glycosylated form of PD-L1 from endoplasmic reticulum (ER) to Golgi, leading to accumulation of PD-L1 in ER. In doing so, BMS1166 blocked PD-L1/PD-1 signaling. Coculturing PD-L1-expressing cells with PD-1-expressing cells induced degradation of PD-1, which could be used as a readout to identify inhibitors of PD-L1/PD-1 signaling. The small-molecule PD-L1 inhibitor BMS1166 abolished the glycosylation and maturation of PD-L1 by blocking its exporting from ER to Golgi. Our study discovered a new strategy to identify inhibitors of the PD-L1/PD-1 signaling pathway and to develop new drugs for the treatment of cancer.

Pre-miR-27a rs895819 polymorphism and risk of diffuse large B-cell lymphoma.

BACKGROUND: Recently, several studies have investigated the relationship between Pre-miR-27a rs895819 polymorphism and risk of various cancers. However, the relationship between rs895819 and diffuse large B-cell lymphoma (DLBCL) has not been well known. METHODS: In this study, we conducted a case-control study to explore the role of Pre-miR-27a rs895819 in risk of DLBCL. The PCR-TaqMan and luciferase assays and in vitro experiments were used to evaluate polymorphism function. RESULTS: As a result, we found subjects carrying with rs895819 AG/GG genotype had a significantly decreased risk when compared with those carrying the AA genotype. Further qPCR assay showed that the DLBCL patients carrying AG/GG genotypes showed a lower level of mature miR-27a when compared with patients carrying AA genotype. Moreover, miR-27a levels were upregulated in DLBCL tissues compared with normal lymphoid tissues. Further in vitro experiments showed that miR-27a might function as an oncogene through target TGFBR1. In addition, TGFBR1 overexpression rescues effects of miR-27a inhibitor on DLBCL cells phenotypes. CONCLUSIONS: In conclusion, these findings indicate that rs895819 A > G might reduce the expression of mature miR-27a, and leading a higher level of TGFBR1, ultimately inhibiting the development of DLBCL.

Over-expression of miR-206 decreases the Euthyrox-resistance by targeting MAP4K3 in papillary thyroid carcinoma.

PURPOSE: microRNAs (miRNAs) play a critical role in drug resistance of multiple cancers including papillary thyroid carcinoma (PTC), indicating the potential of miRNAs as chemoresistance regulators in cancer treatment. The aim of this paper is to explore the relationship between miR-206 and chemoresistance of PTC. METHODS: qRT-PCR was conducted to examine the expression of miR-206 in PTC tissues, parental and TPC-1/euthyrox. The CCK-8 assay, EdU assay and flow cytometry were performed to test cells viability, proliferation and apoptosis, respectively. Luciferase reporter assay was used to confirm the potential target of miR-206. Western blotting analysis was performed to evaluate the expressions of related-proteins. RESULTS: miR-206 was significantly down-regulated in PTC tissues, parental and TPC-1/euthyrox. Moreover, the expression of miR-206 was exceptionally lower in TPC-1/euthyrox cells than that in TPC-1 cells. Furthermore, we found that over-expression of miR-206 could notably decrease the IC50 values both in TPC-1 and TPC-1/euthyrox cells, which indicated that miR-206 played an essential role in the euthyrox resistance in PTC. In addition, up-regulation of miR-206 inhibited the proliferation, induced apoptosis, suppressed the expressions of multidrug resistance-related proteins, including p-gp, MRP, BCRP and LRP, in euthyrox-resistant PTC cells. Besides, over-expression of miR-206 could notably promoted the expression of NIS, an intrinsic membrane protein that mediates the active transport of iodide into the thyroid and other tissues, playing a critical role in the progress. Further, miR-206 was demonstrated to be able to bind to MAP4K3 and negatively regulated the expression of MAP4K3. Besides, MAP4K3 was clearly up-regulated in PTC tissues, parental and TPC-1/euthyrox cells, and down-regulation of miR-206 attenuated the effect of si-MAP4K3 on the euthyrox sensitivity in euthyrox-resistant PTC cells. Moreover, TPC-1/euthyrox cells transfected with miR-206 mimics could significantly inhibit the expressions of p-p38, p-JNK and p-Erk, which indicated that miR-206 might play an essential role in the euthyrox resistance in PTC by negatively regulating the p38 and JNK signaling pathway. CONCLUSION: miR-206 contributed to euthyrox resistance in PTC cells through blockage p38 and JNK signaling pathway by targeting MAP4K3, providing a potential therapeutic application for the treatment of patients with euthyrox-resistant PTC in the further.

A Scalable Total Synthesis of the Antitumor Agents Et-743 and Lurbinectedin.

An efficient and scalable approach is described for the total synthesis of the marine natural product Et-743 and its derivative lubinectedin, which are valuable antitumor compounds. The method delivers 1.6 % overall yield in 26 total steps from Cbz-protected (S)-tyrosine. It features the use of a common advanced intermediate to create the right and left parts of these compounds, and a light-mediated remote C-H bond activation to assemble a benzo[1,3]dioxole-containing intermediate.

The analysis of cell-free DNA concentrations and integrity in serum of initial and treated of lymphoma patients.

OBJECTIVE: To evaluate cell-free DNA (cfDNA) in plasma as a promising biomarker for lymphoma, altered levels of cfDNA and its association with clinical parameters are investigated in patients suffered from lymphomas. METHODS: Peripheral blood specimens were collected from 60 patients with lymphoma during initial diagnosis and those of another 107 patients with lymphoma during treated stage were also collected, 93 healthy volunteers were selected as control group. Quantitative PCR was used to detect cfDNA level in each group, cfDNA level in different groups was analyzed to understand its relationship with lymphoma patients' clinical features. After correlation analysis between cfDNA and clinical characteristics, Receiver operator characteristic curve was performed to analyze sensitivity and specificity of cfDNA and LDH. RESULTS: cfDNA concentration and integrity in initial stage of lymphoma patients were significantly higher than those in treated stage, and cfDNA concentration in treated phase was significantly higher than cfDNA concentration in control group. There was no significant difference in cfDNA integrity at treated stage compared with control group. There was no significant correlation between patient's age, gender, extranodal invasion and lymphoma pathological type and cfDNA concentration and integrity; In contrast, there was a significant correlation between ECOG score, LDH content, Ann Arbor stage, IPI, B-symptoms, Ki-67 expression and radiotherapy and cfDNA concentration and integrity, both at the time of initial diagnosis and treated stage. cfDNA concentration detection is an optimal diagnostic indicator, followed by cfDNA integrity detection, the sensitivity and specificity of both are superior to the traditional LDH detection. CONCLUSION: cfDNA level is significantly increased in lymphomas patient plasma and may help lymphoma screening. cfDNA level may serve as a potential indicator of lymphomas treatment efficacy.

Association of serum lipids and severity of epithelial ovarian cancer: an observational cohort study of 349 Chinese patients.

While obesity and fat intake have been associated with the risk and prognosis of epithelial ovarian cancer, the association between the lipid levels and epithelial ovarian cancer phenotype remains controversial. We conducted a retrospective study of 349 epithelial ovarian cancer patients who received treatment at Jiangsu Cancer Hospital, China between 2011 and 2017. We analyzed age at diagnosis, blood pressure, plasma glucose content, body mass index (BMI), lipid levels and clinical parameters. Severity of epithelial ovarian cancer was classified according to the International Federation of Gynecology and Obstetrics (FIGO) grading system. Univariate analysis of the clinical factors according to the severity of epithelial ovarian cancer was followed by logistic regression analysis to identify clinical factors significantly associated with epithelial ovarian cancer severity. Univariate analysis indicated that age, BMI, triglyceride (TG), and high density lipoproteins (HDL) differed significantly among different stages of epithelial ovarian cancer (P<0.05). In the logistic regression model, elevated TG (OR: 1.883; 95% CI= 1.207-2.937), and low HDL (OR: 0.497; 95% CI= 0.298-0.829) levels were significantly associated with the high severity epithelial ovarian cancer. Our data indicate that high TG and low HDL levels correlate with a high severity of epithelial ovarian cancer. These data provide important insight into the potential relationship between the lipid pathway and epithelial ovarian cancer phenotype and development.

Potential effects of ultraviolet radiation reduction on tundra nitrous oxide and methane fluxes in maritime Antarctica.

Stratospheric ozone has begun to recover in Antarctica since the implementation of the Montreal Protocol. However, the effects of ultraviolet (UV) radiation on tundra greenhouse gas fluxes are rarely reported for Polar Regions. In the present study, tundra N2O and CH4 fluxes were measured under the simulated reduction of UV radiation in maritime Antarctica over the last three-year summers. Significantly enhanced N2O and CH4 emissions occurred at tundra sites under the simulated reduction of UV radiation. Compared with the ambient normal UV level, a 20% reduction in UV radiation increased tundra emissions by an average of 8 µg N2O m-2 h-1 and 93 µg CH4 m-2 h-1, whereas a 50% reduction in UV radiation increased their emissions by an average of 17 µg N2O m-2 h-1 and 128 µg CH4 m-2 h-1. No statistically significant correlation (P > 0.05) was found between N2O and CH4 fluxes and soil temperature, soil moisture, total carbon, total nitrogen, NO3--N and NH4+-N contents. Our results confirmed that UV radiation intensity is an important factor affecting tundra N2O and CH4 fluxes in maritime Antarctica. Exclusion of the effects of reduced UV radiation might underestimate their budgets in Polar Regions with the recovery of stratospheric ozone.