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Retinoid X receptor α (RXRα) plays a vital role in multiple biological and pathological processes and represents a promising therapeutic target for anti-tumor drug design. Inspired by the marine-derived RXRα antagonist meroterpenthiazole A, 21 undescribed benzothiazole derivatives were designed and synthesized. The inhibitory effects of 21 derivatives on RXRα transactivation and their anti-tumor activities against MDA-MB-231 cells were evaluated. Compounds 4a–4h, 6a–6b, 7c–7f, and 7h–7i inhibited 9-cis-retinoic acid-induced RXRα transactivation, while compounds 3b, 4f–4h, 7a, 7c, 7f, and 7h–7i exhibited inhibitory effects on the proliferation of MDA-MB-231 cells. Meanwhile, the structure–activity relationships governing both the RXRα antagonist effects and the anti-proliferative activities against MDA-MB-231 cells were discussed. Compound 7i exhibited the most potent inhibitory effects on the proliferation of MDA-MB-231 cells with an IC50 value of 16.5 μM. Further mechanism studies revealed that compound 7i induced G2/M phase arrest in MDA-MB-231 cells, accompanied by dose-dependent downregulation of Cyclin B1 and CDK1 protein expression. However, these effects were abolished in RXRα-knockout MDA-MB-231 cells, indicating that the anti-proliferative and cell cycle arrest activities of 7i were RXRα-dependent. Cellular Thermal Shift Assay (CETSA) and molecular docking studies further confirmed that 7i directly bound to RXRα, thereby mediating its anti-cancer efficacy.

A polyphenol-enriched fraction (PEF) from Acalypha wilkesiana, whose leaves have been traditionally utilized for the treatment of diverse medical ailments, was investigated for the anti-inflammatory effect and molecular mechanisms by using lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages and acetaminophen- (APAP-) induced liver injury mouse model. Results showed that PEF significantly attenuated LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production and suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in RAW 264.7 macrophages. PEF also reduced the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1β, and IL-6 in LPS-stimulated RAW 264.7 macrophages. Moreover, PEF potently inhibited LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) as well as the activation of nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor κB-α (IκB-α). In vivo, PEF pretreatment ameliorated APAP-induced liver injury and hepatic inflammation, as presented by decreased hepatic damage indicators and proinflammatory factors at both plasma and gene levels. Additionally, PEF pretreatment remarkably diminished Toll-like receptor 3 (TLR3) and TLR4 expression and the subsequent MAPKs and NF-κB activation. HPLC analysis revealed that two predominantly polyphenolic compounds present in PEF were geraniin and corilagin. These results indicated that PEF has an anti-inflammatory effect, and its molecular mechanisms may be involved in the inactivation of the TLR/MAPK/NF-κB signaling pathway, suggesting the therapeutic potential of PEF for inflammatory diseases.

Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural modification and optimization of U12 were further investigated and twelve U12 derivatives were synthesized by substitution, esterification and amidation reactions. The evaluation of the cytotoxicity of synthetic derivatives against hepatoma cell lines (HepG2) indicated that U12-I, U12a-d and U12h showed more effective cytotoxic effects on the growth of HepG2 cells than U12, and the preliminary structure–activity relationship was discussed. Among them, U12a exhibited the most potent anti-hepatocellular carcinoma activity. Mechanism studies indicated that U12a inhibited HepG2 cell proliferation by arresting the G0/G1 phase, and suppressed the activation of the PI3K/AKT/mTOR pathway. Further studies showed that U12a induced HepG2 cells apoptosis through activating the caspase signaling pathway. Furthermore, U12a evidently inhibits the growth of HepG2-derived tumor xenografts in vivo without observable adverse effects. Thus, U12a might be considered as a promising candidate for the treatment of hepatocellular carcinoma.

In China, gastric cancer (GC) ranks second in incidence and mortality. Over 80% of patients with GC were diagnosed at an advanced stage with poor clinical outcome. Chemotherapy was the mainstream treatment with limited benefit. Apatinib, an inhibitor of targeting vascular endothelial growth factor receptor 2 (VEGFR2), has been approved for third-line treatment of advanced gastric cancer. However, the data of apatinib treatment in the real-world setting are limited. In this real-world study, we aimed to understand the current treatment pattern of apatinib, investigate the effectiveness and safety of apatinib in real-world settings, and explore the potential factors associated with the clinical outcomes. This was a prospective, multicenter observational study in a real-world setting. Patients aged ≥18 years with histologic diagnosis of advanced GC were eligible for enrollment. The eligible patients received either apatinib monotherapy or apatinib plus chemotherapy by physician's discretion. Apatinib treatment could be used as first-line, second-line, or third-line and above therapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), ORR, DCR, and safety profile. A total of 737 patients with advanced gastric cancer treated with apatinib were included in the FAS population. A total of 54.9% patients used apatinib monotherapy and 45.1% patients used apatinib combination therapy. A total of 44.1% patients received apatinib in first-line treatment, 28.2% in second-line, and 27.7% in third-line and above. In first-line treatment, the objective response rate (ORR) was 9.09% and 16.42% in apatinib monotherapy and combination therapy groups, and disease control rate (DCR) was 78.41% and 89.29%, respectively. Patients who received combination therapy achieved significantly longer median progression-free survival (mPFS; 6.18 vs 3.52 months, <0.01) and median overall survival (mOS; 8.72 vs 5.92 months, <0.01) compared with monotherapy. In second-line and third-line therapy, combination therapy showed a better trend in tumor response and survival outcomes compared with monotherapy. For all patients, apatinib combined with paclitaxel were associated with longer mPFS compared with other combinations (8.88 vs 6.62 months). Multivariate analysis showed that combination with paclitaxel ( =0.02) and experience of apatinib-related specific AEs ( <0.01) were independent predictors for PFS and OS. The safety profile was tolerable and no unexpected adverse events were reported. In a real-world setting, apatinib showed a favorable effectiveness and safety profile in patients with advanced gastric cancer. Apatinib combination therapy, especially combined with paclitaxel, might lead to better survival benefit in first-line treatment. Combination with paclitaxel and the occurrence of apatinib-specific AEs were independent factors associated with better survival outcomes. NCT03333967.

U12, one of 20 derivatives synthesized from ursodeoxycholic acid (UDCA), has been found to have anticancer effects in liver cancer cell lines (SMMC-7721 and HepG2) and to protect normal liver cells from deoxycholic acid (DCA) damage (QSG-7701). Its anticancer mechanism was investigated using computer-aided network pharmacology and comparative proteomics. Results showed that its anti-malignancy activities were activated by mTOR/S6K1, cyclinD1/CDK2/4 and caspase-dependent apoptotic signaling pathways in hepatocellular carcinoma cells (HCC). The action of U12 may be similar to that of rapamycin. Animal testing confirmed that U12 exerted better anti-tumor activity than UDCA and had less severe side effects than fluorouracil (5-Fu). These observations indicate that U12 differs from UDCA and other derivatives and may be a suitable lead for the development of compounds useful in the treatment of HCC.

Peng W, Zhang F, Wang Z, et al. Cancer Manag Res. 2020;12:6977-6985. Page 6980, Effectiveness, second paragraph, last sentence, the text \"In third-line and above, the DCR was 81.82% vs 76.59% with no significant difference between the two treatment groups (Table 2)\" should read \"In third-line and above, the DCR was 74.23% vs 81.82% with no significant difference between the two treatment groups (Table 2)\". The data in Table 2 on page 6980 is incorrect. The correct Table 2 is shown below. The authors apologize for these errors and advise they do not affect the results of the paper. Read the original article

BackgroundClear cell renal cell carcinoma (ccRCC) is a highly lethal malignancy with few therapeutic options. Cyclin‑dependent kinase 9 (CDK9), a potential therapeutic target of many cancers, has been recently observed to be upregulated in ccRCC patients. Therefore, we aimed to investigate the therapeutic potential of CDK9 in ccRCC and develop a novel CDK9 inhibitor with low toxicity for ccRCC treatment.MethodsThe expression of CDK9 in ccRCC was checked using the online database and tissue microarray analysis. shRNA-mediated CDK9 knockdown and CDK inhibitor were applied to evaluate the effect of CDK9 on ccRCC. Medicinal chemistry methods were used to develop a new CDK9 inhibitor with drugability. RNA-seq and ChIP-seq experiments were conducted to explore the mechanism of action. MTS, western blotting, and colony formation assays were performed to evaluate the anti-ccRCC effects of CDK9 knockdown and inhibition in vitro. The in vivo anti-tumour efficacy was evaluated in a xenograft model.ResultsCDK9 is overexpressed and associated with poor survival in ccRCC. Knockdown or inhibition of CDK9 significantly suppressed ccRCC cells. XPW1 was identified as a new potent and selective CDK9 inhibitor with excellent anti-ccRCC activity and low toxicity. In mechanism, XPW1 transcriptionally inhibited DNA repair programmes in ccRCC cells, resulting in an excellent anti-tumour effect. CDK9 and BRD4 were two highly correlated transcriptional regulators in ccRCC patients, and the BRD4 inhibitor JQ1 enhanced XPW1’s anti-ccRCC effects in vitro and in vivo.ConclusionsThis work provides valuable insights into the therapeutic potential of CDK9 in ccRCC. The CDK9 inhibitor XPW1 would be a novel therapeutic agent for targeting ccRCC, alone or in rational combinations.

The effects of UV-ozone (UVO) treatment on the sensing behaviours of extended-gate field-effect transistors (EGFETs) that use Al2O3 as the sensing film have been investigated. The Al2O3 sensing films are UVO-treated with various duration times and the corresponding EGFET sensing behaviours, such as sensitivity, hysteresis, and long-term stability, are electrically evaluated under various measurement conditions. Physical analysis is also performed to characterize the surface conditions of the UVO-treated sensing films using X-ray photoelectron spectroscopy and atomic force microscopy. It is found that UVO treatment effectively reduces the buried sites in the Al2O3 sensing film and subsequently results in reduced hysteresis and improved long-term stability of EGFET. Meanwhile, the observed slightly smoother Al2O3 film surface post UVO treatment corresponds to decreased surface sites and slightly reduced pH sensitivity of the Al2O3 film. The sensitivity degradation is found to be monotonically correlated with the UVO treatment time. A treatment time of 10 min is found to yield an excellent performance trade-off: clearly improved long-term stability and reduced hysteresis at the cost of negligible sensitivity reduction. These results suggest that UVO treatment is a simple and facile method to improve the overall sensing performance of the EGFETs with an Al2O3 sensing film.

The aim of the current study was to assess the expression and clinical significance of serum microRNA (miR)-484 in patients with non-small cell lung cancer (NSCLC). Reverse transcription-quantitative polymerase chain reaction was performed to determine the expression of miR-484 in the serum of patients with NSCLC and NSCLC cell lines. Cell counting kit-8, flow cytometry, cell migration and cell invasion assays were performed to assess the role of miR-484 in the malignant changes associated with NSCLC cells. Furthermore, to assess the diagnostic value of miR-484, receiver operating curve (ROC) analysis was performed and the clinical relevance of serum miR-484 expression in patients with NSCLC was determined. A Kaplan-Meier analysis with the log-rank test was performed to assess the overall survival rate patients. To the best of our knowledge, the current study demonstrates for the first time that serum miR-484 was increased in patients with NSCLC compared with healthy controls. Additionally, serum miR-484 was revealed to be positively associated with histological grade, lymph node metastasis, distant metastasis and clinical stage. Patients with NSCLC and high serum miR-484 levels demonstrated significantly poorer overall survival rates compared with those exhibiting lower serum miR-484 expressions. ROC analysis revealed that serum miR-484 could screen patients with NSCLC patients from healthy controls with a high sensitivity and specificity. In vitro analysis also demonstrated that miR-484 was significantly upregulated in NSCLC cell lines, including 95D and H358 cells. Furthermore, the suppression of miR-484 decreased cell proliferation, cell migration and invasion. In summary, the results of the present study demonstrated that increased serum miR-484 expression is associated with the diagnosis and prognosis of patients with NSCLC.

Objective Thymidine kinase 1 (TK1) is a key enzyme in the pyrimidine salvage pathway. Increased TK1 concentration correlates with cell division. TK1 is an emerging biomarker in cancer diagnosis; however, its effectiveness in diagnosis and management for malignant pleural effusion (MPE) is unclear. We evaluated the diagnostic efficiency and prognostic value of pleural effusion TK1 (pTK1) concentration for MPE. Methods From 2013 to 2017, 210 pleural effusion samples were collected from 160 patients diagnosed with MPE and 50 patients diagnosed with benign pleural effusion (BPE). TK1 concentrations in pleural effusion were measured by chemiluminescence dot blot assays. The median follow‐up was 12 months. We constructed a receiver‐operating characteristic (ROC) curve to find the optimal cutoff value for MPE diagnosis. The hazard ratios were estimated using a multivariable Cox proportional hazard model. A nomogram was drawn to illustrate the prognostic characteristics of MPE. Results The TK1 concentration in pleural effusion was significantly higher in MPE than BPE (P < 0.001), and patients with MPE could be distinguished by an optimal cutoff value of 3.10 pmol/L with a sensitivity of 0.894 and a specificity of 0.800. The multivariate analysis suggested that pTK1 concentration was an independent predictor of survival in patients with MPE. Conclusions The diagnostic and prognostic prediction of MPE may be improved by measuring pTK1 concentration and utilizing a multivariate nomogram.