Cobalt-Catalyzed Enantioselective Cross-Electrophile Couplings: Stereoselective Syntheses of 5-7-Membered Azacycles.

Cobalt complexes of chiral pyrox ligands catalyzed enantioselective reductive couplings of nonconjugated iododienes with aryl iodides or alkenyl bromides. The reaction enabled stereoselective syntheses of 5-7-membered azacycles carrying quaternary stereocenters. Mechanistically, cross-electrophile selectivity originated from selective coupling of alkylcobalt(I) complexes generated after cyclization with aryl iodides.

Catalytic enantioselective alkenylation-heteroarylation of olefins: stereoselective syntheses of 5-7 membered azacycles and oxacycles.

Catalytic enantioselective domino alkenylation-heteroarylation of nonconjugated iododienes proceeded with excellent stereoselectivity and broad scope of substrates. The reaction enables stereoselective syntheses of substituted azacycles such as piperidine, pyrrolidine azepine and dihydropyrans carrying new quaternary stereocenters. Mechanistically, C-H bonds of heterocycles were activated by lithium alkoxides via reversible deprotonation, rather than conventional palladium(ii)-assisted metalation processes. Many types of heteroarenes can be used, including not only azoles (such as thiazoles, oxazoles, imidazoles and oxadiazoles), but also nonazoles (thiophene, furan and azine N-oxides).

Nickel-Catalyzed Enantioselective Reductive Conjugate Arylation and Heteroarylation via an Elementary Mechanism of 1,4-Addition.

A nickel complex of isoquinox promoted enantioselective conjugate arylation and heteroarylation of enones using aryl and heteroaryl halides directly. The reaction was successfully applied to stereoselective syntheses of ar-turmerone, chiral fragments of (+)-tolterodine and AZD5672. Mechanistically, experiments and calculations supported that an arylnickel(I) complex inserted to enones via an elementary 1,4-addition.

Design of GSH-Responsive Curcumin Nanomicelles for Oesophageal Cancer Therapy.

Oesophageal cancer is a malignant tumor with high morbidity and mortality. Surgical treatment, radiotherapy, and chemotherapy are the most common treatment methods for oesophageal cancer. However, traditional chemotherapy drugs have poor targeting performance and cause serious adverse drug reactions. In this study, a GSH-sensitive material, ATRA-SS-HA, was developed and self-assembled with curcumin, a natural polyphenol antitumor drug, into nanomicelles Cur@ATRA-SS-HA. The micelles had a suitable particle size, excellent drug loading, encapsulation rate, stability, biocompatibility, and stable release behaviour. In the tumor microenvironment, GSH induced disulfide bond rupture in Cur@ATRA-SS-HA and promoted the release of curcumin, improving tumor targeting. Following GSH-induced release, the curcumin IC50 value was significantly lower than that of free curcumin and better than that of 5-FU. In vivo pharmacokinetic experiments showed that the drug-loaded nanomicelles exhibited better metabolic behaviour than free drugs, which greatly increased the blood concentration of curcumin and increased the half-life of the drug. The design of the nanomicelle provides a novel clinical treatment for oesophageal cancer.

Prognostic Value of MUC16 Mutation and Its Correlation with Immunity in Hepatocellular Carcinoma Patients.

Objective: Identifying gene mutation signatures will enable a better understanding for the occurrence, development, and prognosis of hepatocellular carcinoma (HCC) and provide some potential biomarkers for clinical practice. This study investigated the mutated genes in HCC patients and assessed their relationship with tumor mutation burden (TMB) and prognosis. Methods: The somatic mutation annotation format (MAF) document, mRNA expression matrix, and clinical information of HCC patients were obtained from the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA) database. The differences of TMB between the mutant type and the wild-type genes were detected using the Mann-Whitney U test. The link of gene mutations with prognosis was explored by the Kaplan-Meier analysis. The proportion of 22 immune cells' composition was measured using CIBERSORT algorithm. Results: The two databases screened 16 common mutated genes, which included TP53, TTN, LRP1B, ZFHX4, MUC16, OBSCN, CSMD3, FLG, CSMD1, SYNE1, SPTA1, USH2A, KMT2C, PCLO, HMCN1, and FAT3. After a series of analysis, MUC16 mutation was found to be highly correlated with TMB and was regarded as an independent factor predicting HCC. Furthermore, gene set enrichment analysis (GSEA) indicated that the MUC16 mutation was significantly involved in HCC cell metabolism. Conclusions: MUC16 mutation seems to be a valuable potential biomarker for HCC development and its overall survival.

Prognosis assessment of CD44+/CD24- in breast cancer patients: a systematic review and meta-analysis.

PURPOSE: This meta-analysis investigated the relationships between the CD44+/CD24- phenotype and tumor size, lymph node metastasis, distant metastasis, disease-free survival (DFS), and overall survival (OS) in 8036 postoperative breast cancer patients enrolled in 23 studies. METHODS: A literature search of PubMed, Medline, Cochrane, Embase, and PMC was conducted to identify eligible studies. The combined odds ratios (ORs) and 95% confidence intervals (95% CIs) were analyzed to evaluate the relationships between the CD44+/CD24- phenotype and the pathological and biological characteristics of breast cancer patients, and the combined hazard ratios (HRs) and 95% CIs were calculated to evaluate the relationships between CD44+/CD24- and DFS and OS of breast cancer patients using Stata12.0 software. RESULTS: The CD44+/CD24- phenotype were not related to the tumor size (tumor size > 2.0 vs ≤ 2.0 cm, combined OR = 0.98, 95% CI 0.68-1.34, p = 0.792) and did not promote lymph node metastasis (lymph node metastasis vs. no lymph node metastasis, OR = 0.92, 95% CI 0.67-1.27, p = 0.626) and distant metastasis (distant metastasis vs no distant metastasis, combined OR = 3.88, 95% CI 0.93-16.24, p = 0.064). The CD44+/CD24- phenotype was negatively correlated with postoperative DFS (HR = 1.67, 95% CI 1.35-2.07, p < 0.00001) and OS (combined HR = 1.52, 95% CI 1.21-1.91, p = 0.0004). CONCLUSION: These results suggested expression of the CD44+/CD24- phenotype cannot be used as a reliable indicator of the tumor size, lymph node metastasis, and distant metastasis, however, it can be used be a potential therapeutic targets of DFS, OS in breast cancer patients.

FAT1 and PTPN14 Regulate the Malignant Progression and Chemotherapy Resistance of Esophageal Cancer through the Hippo Signaling Pathway.

BACKGROUND: Esophageal cancer (EC) is a common malignant tumor, which brings heavy economic burden to patients and society. Therefore, it is important to understand the molecular mechanism of recurrence, metastasis, and drug resistance of esophageal cancer. METHODS: Human esophageal cancer cell line TE13 (poorly differentiated squamous cell carcinoma) and normal human esophageal epithelial cell line het-1a were selected for aseptic culture. At the same time, 6 bottles of TE13 cell line were inoculated in logarithmic phase. Cell apoptosis was analyzed by flow cytometry (FCM). Cell clone formation assay was used to analyze the proliferation. Fibronectin-coated dishes were used to detect the characteristics of cell adhesion to extracellular matrix. The Transwell method was used to detect the cell invasion ability. Western blot was used to analyze the expression of Yap1, PTPN14, FAT1, and Myc. RESULTS: Results showed that FAT1 and PTPN14 were downregulated, while Yap1 was upregulated in esophageal cancer tissues. FAT1 inhibited the proliferation, adhesion, and invasion of human esophageal cancer cell lines, which might be associated with the upregulation of PTPN14 and the inhibition of Yap1 and Myc. CONCLUSION: The results suggested that PTPN14 and FAT1 could regulate malignant progression and chemotherapy resistance of esophageal cancer based on the Hippo signaling pathway.

Analysis of gene co­expression network reveals prognostic significance of CNFN in patients with head and neck cancer.

In patients with head and neck cancer (HNC), lymph node (N) metastases are associated with cancer aggressiveness and poor prognosis. Identifying meaningful gene modules and representative biomarkers relevant to the N stage helps predict prognosis and reveal mechanisms underlying tumor progression. The present study used a step­wise approach for weighted gene co­expression network analysis (WGCNA). Dataset GSE65858 was subjected to WGCNA. RNA sequencing data of HNC downloaded from the Cancer Genome Atlas (TCGA) and dataset GSE39366 were utilized to validate the results. Following data preprocessing, 4,295 genes were screened, and blue and black modules associated with the N stage of HNC were identified. A total of 16 genes [keratinocyte differentiation associated protein, suprabasin, cornifelin (CNFN), small proline rich protein 1B, desmoglein 1 (DSG1), chromosome 10 open reading frame 99, keratin 16 pseudogene 3, gap junction protein ß2, dermokine, LY6/PLAUR domain containing 3, transmembrane protein 79, phospholipase A2 group IVE, transglutaminase 5, potassium two pore domain channel subfamily K member 6, involucrin, kallikrein related peptidase 8] that had a negative association with the N­stage in the blue module, and two genes (structural maintenance of chromosomes 4 and mutS homolog 6) that had a positive association in the black module, were identified to be candidate hub genes. Following further validation in TCGA and dataset GSE65858, it was identified that CNFN and DSG1 were associated with the clinical stage of HNC. Survival analysis of CNFN and DSG1 was subsequently performed. Patients with increased expression of CNFN displayed better survival probability in dataset GSE65858 and TCGA. Therefore, CNFN was selected as the hub gene for further verification in the Gene Expression Profiling Interactive Analysis database. Finally, functional enrichment and gene set enrichment analyses were performed using datasets GSE65858 and GSE39366. Three gene sets, namely 'P53 pathway', 'estrogen response early' and 'estrogen response late', were enriched in the two datasets. In conclusion, CNFN, identified via the WGCNA algorithm, may contribute to the prediction of lymph node metastases and prognosis, probably by regulating the pathways associated with P53, and the early and late estrogen response.

STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma.

The radioresistance of esophageal squamous cell carcinoma (ESCC) remains an obstacle for the effective radiotherapy of ESCC. This study aimed to investigate the radiosensitization of ESCC by signal transducer and activator of transcription 3 (STAT3) inhibitor stattic. ECA109, TE13, and KYSE150 cell lines were exposed to hypoxia and treated with stattic or radiation, alone or in combination. Cell proliferation, colony formation, apoptosis, and double-stranded DNA breaks (DSBs) were examined. In addition, ECA109 cells were xenografted into nude mice and treated with radiation and/or stattic. The levels of STAT3, p-STAT3, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) in ESCC cells and xenografts were detected by Western blot and immunohistochemical analysis. Our results showed that stattic efficiently radiosensitized ESCC cells and xenografts, especially under hypoxia. Moreover, stattic inhibited STAT3 activation and downregulated HIF-1α and VEGF expression. In conclusion, stattic confers radiosensitivity in ESCC cells in vitro and in vivo and is a potential adjuvant for the radiotherapy of ESCC in the clinical setting.

Targets and molecular mechanisms of triptolide in cancer therapy.

Triptolide (TPL/TL) is a natural drug with novel anticancer effects. Preclinical studies indicated that TPL inhibits cell proliferation, induces cell apoptosis, inhibits tumor metastasis and enhances the effect of other therapeutic methods in various cancer cell lines. Multiple molecules and signaling pathways, such as caspases, heat-shock proteins, NF-κB, and deoxyribonucleic acid (DNA) repair-associated factors, are associated with the anti-cancer effect. TPL also improves chemoradiosensitivity in cancer therapy. Phase I trials indicate the potential clinical value of TPL use. However, further trials with larger sample sizes are needed to confirm these results.

Berberine inhibits the expression of hypoxia induction factor-1alpha and increases the radiosensitivity of prostate cancer.

BACKGROUND: The radiation resistance of prostate cancer remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of berberine, a commonly used natural product, on the radiosensitivity of prostate cancer. METHODS: Prostate cancer cell line LNCaP and DU-145 were subjected to hypoxia and/or ionizing radiation (IR), in the presence or absence of berberine treatment. Cell growth and colony formation, and apoptosis were evaluated. Moreover, LNCaP cells were xenografted into nude mice and subjected to IR and/or berberine treatment. The expression of HIF-1α and VEGF in prostate cancer cells and xenografts was detected by Western blot analysis. RESULTS: Berberine increased radiosensitivity of prostate cancer cells and xenografts in a dose dependent manner, and this was correlated with the inhibition of HIF-1α and VEGF expression. CONCLUSIONS: Berberine may inhibit the expression of HIF-1α and VEGF and thus confer radiosensitivity on prostatic cancer cells. Berberine has potential application as an adjuvant in radiotherapy of prostatic cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1519827543125021.