Design, synthesis, and biological evaluation of 1,6-naphthyridine-2-one derivatives as novel FGFR4 inhibitors for the treatment of colorectal cancer.

Aberrant FGFR4 signaling has been implicated in the development of several cancers, making FGFR4 a promising target for cancer therapy. Several FGFR4-selective inhibitors have been developed, yet none of them have been approved. Herein, we report a novel series of 1,6-naphthyridine-2-one derivatives as potent and selective inhibitors targeting FGFR4 kinase. Preliminary structure-activity relationship analysis was conducted. The screening cascades revealed that 19g was the preferred compound among the prepared series. 19g demonstrated excellent kinase selectivity and substantial cytotoxic effect against all tested colorectal cancer cell lines. 19g induced significant tumor inhibition in a HCT116 xenograft mouse model without any apparent toxicity. Notably, 19g exhibited excellent potency in disrupting the phosphorylation of FGFR4 and downstream signaling proteins mediated by FGF18 and FGF19. Compound 19g might be a potential antitumor drug candidate for the treatment of colorectal cancer.

The transcription factor VaNAC72-regulated expression of the VaCP17 gene from Chinese wild Vitis amurensis enhances cold tolerance in transgenic grape (V. vinifera).

Papain-like cysteine proteases (PLCP) play diverse roles in plant biology. In our previous studies, a VaCP17 gene from the cold-tolerant Vitis amurensis accession 'Shuangyou' was isolated and its role in cold tolerance was preliminarily verified in Arabidopsis. Here, we confirmed the function of VaCP17 in cold tolerance by stably overexpressing VaCP17 in the cold-sensitive Vitis vinifera cultivar 'Thompson Seedless' and transiently silencing VaCP17 in 'Shuangyou' leaves. The results showed that overexpression of VaCP17 improved the cold tolerance in 'Thompson Seedless' as manifested by reduced electrolyte leakage and malondialdehyde accumulation, chlorophyll homeostasis, increased antioxidant enzymes (superoxide dismutase, peroxidase, and catalase) activitiy, and rapid up-regulation of stress-related genes (VvKIN2, VvRD29B, and VvNCED1) compared with wild-type line. Conversely, RNA interfere-mediated knockdown of VaCP17 in 'Shuangyou' leaves resulted in opposite physiological and biochemical responses and exacerbated leaves wilting compared with control. Subsequently, by yeast one-hybrid, dual-luciferase assays, and transient overexpression of VaNAC72 in 'Shuangyou' leaves, a VaCP17-interacting protein VaNAC72 was confirmed to promote the expression of VaCP17 under cold stress, which depends on abscisic acid, methyl jasmonate, and salicylic acid signaling. By yeast two-hybrids, bimolecular fluorescence complementation and luciferase complementation assays, it was found that VaNAC72 could form homodimers or heterodimers with VaCBF2. Furthermore, co-expression analysis confirmed that VaNAC72 works synergistically with VaCBF2 or VaCP17 to up-regulate the expression of VaCP17. In conclusion, the study revealed that the VaNAC72-VaCP17 module positively regulated cold tolerance in grapevine, and this knowledge is useful for further revealing the cold-tolerance mechanism of V. amurensis and grape molecular breeding.

Discovery of ß-cyclocitral-derived mono-carbonyl curcumin analogs as anti-hepatocellular carcinoma agents via suppression of MAPK signaling pathway.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high recurrence and mortality rate. In this study, a series of ß-cyclocitral-derived mono-carbonyl curcumin analogs were synthesized and their anticancer properties were evaluated. Among the series, A19 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest and cell apoptosis of HCC HepG2 and Huh-7 cells, while having almost no cytotoxicity on normal liver MIHA cells. Mechanistically, our results demonstrated that A19 triggered intense DNA damage via suppression of the ERK/JNK/p38 MAPK signaling pathway. Additionally, a combination of A19 with sorafenib significantly induced synergistic cytotoxicity in HCC cells. Overall, our results indicate the potential of A19 as a novel chemotherapeutic drug administered either separately or in combined therapy for HCC treatment.

cyy260 suppresses the proliferation, migration and tumor growth of osteosarcoma by targeting PDGFR-ß signaling pathway.

Osteosarcoma (OS) is a group of malignant tumors with high rates of malignancy and metastasis. OS most commonly affects adolescents and young individuals. However, owing to the lack of effective targeted treatments, the 5-year survival rate for OS is still around 20%. Thus, it is essential to develop effective drugs with low toxicity for OS treatment. In the present study, we investigated the antitumor effect and underlying mechanism of cyy260 in OS via suppressing PDGFR-ß and its downstream pathway. We demonstrated that cyy260 inhibits OS cell proliferation and promotes apoptosis via inducing DNA damage and causing cell cycle arrest. More importantly, cyy260 also significantly inhibits tumor migration. Further analysis of molecular mechanisms confirmed that PDGFR-ß and its downstream AKT, STAT3, and ERK were involved in the cyy260-mediated antitumor effect. Analysis of subcutaneously transplanted tumors in mice showed that cyy260 suppressed tumor cell growth and exhibited low toxicity in vivo. Collectively, these findings proved that cyy260 could serve as a promising PDGFR-ß inhibitor for the treatment of OS.

SGEResU-Net for brain tumor segmentation.

The precise segmentation of tumor regions plays a pivotal role in the diagnosis and treatment of brain tumors. However, due to the variable location, size, and shape of brain tumors, the automatic segmentation of brain tumors is a relatively challenging application. Recently, U-Net related methods, which largely improve the segmentation accuracy of brain tumors, have become the mainstream of this task. Following merits of the 3D U-Net architecture, this work constructs a novel 3D U-Net model called SGEResU-Net to segment brain tumors. SGEResU-Net simultaneously embeds residual blocks and spatial group-wise enhance (SGE) attention blocks into a single 3D U-Net architecture, in which SGE attention blocks are employed to enhance the feature learning of semantic regions and reduce possible noise and interference with almost no extra parameters. Besides, the self-ensemble module is also utilized to improve the segmentation accuracy of brain tumors. Evaluation experiments on the Brain Tumor Segmentation (BraTS) Challenge 2020 and 2021 benchmarks demonstrate the effectiveness of the proposed SGEResU-Net for this medical application. Moreover, it achieves DSC values of 83.31, 91.64 and 86.85%, as well as Hausdorff distances (95%) of 19.278, 5.945 and 7.567 for the enhancing tumor, whole tumor, and tumor core on BraTS 2021 dataset, respectively.

Chromosome-level assembly of the Neolamarckia cadamba genome provides insights into the evolution of cadambine biosynthesis.

Neolamarckia cadamba (Roxb.), a close relative of Coffea canephora and Ophiorrhiza pumila, is an important traditional medicine in Southeast Asia. Three major glycosidic monoterpenoid indole alkaloids (MIAs), cadambine and its derivatives 3ß-isodihydrocadambine and 3ß-dihydrocadambine, accumulate in the bark and leaves, and exhibit antimalarial, antiproliferative, antioxidant, anticancer and anti-inflammatory activities. Here, we report a chromosome-scale N. cadamba genome, with 744.5 Mb assembled into 22 pseudochromosomes with contig N50 and scaffold N50 of 824.14 Kb and 29.20 Mb, respectively. Comparative genomic analysis of N. cadamba with Co. canephora revealed that N. cadamba underwent a relatively recent whole-genome duplication (WGD) event after diverging from Co. canephora, which contributed to the evolution of the MIA biosynthetic pathway. We determined the key intermediates of the cadambine biosynthetic pathway and further showed that NcSTR1 catalyzed the synthesis of strictosidine in N. cadamba. A new component, epoxystrictosidine (C27H34N2O10, m/z 547.2285), was identified in the cadambine biosynthetic pathway. Combining genome-wide association study (GWAS), population analysis, multi-omics analysis and metabolic gene cluster prediction, this study will shed light on the evolution of MIA biosynthetic pathway genes. This N. cadamba reference sequence will accelerate the understanding of the evolutionary history of specific metabolic pathways and facilitate the development of tools for enhancing bioactive productivity by metabolic engineering in microbes or by molecular breeding in plants.

Second-order ResU-Net for automatic MRI brain tumor segmentation.

Tumor segmentation using magnetic resonance imaging (MRI) plays a significant role in assisting brain tumor diagnosis and treatment. Recently, U-Net architecture with its variants have become prevalent in the field of brain tumor segmentation. However, the existing U-Net models mainly exploit coarse first-order features for tumor segmentation, and they seldom consider the more powerful second-order statistics of deep features. Therefore, in this work, we aim to explore the effectiveness of second-order statistical features for brain tumor segmentation application, and further propose a novel second-order residual brain tumor segmentation network, i.e., SoResU-Net. SoResU-Net utilizes a number of second-order modules to replace the original skip connection operations, thus augmenting the series of transformation operations and increasing the non-linearity of the segmentation network. Extensive experimental results on the BraTS 2018 and BraTS 2019 datasets demonstrate that SoResU-Net outperforms its baseline, especially on core tumor and enhancing tumor segmentation, illuminating the effectiveness of second-order statistical features for the brain tumor segmentation application.

Application value of ERAS in perioperative period of precise hepatectomy for hepatocellular carcinoma patients.

PURPOSE: To explore the efficacy and reliability of enhanced recovery after surgery (ERAS) applied in the perioperative period of precise hepatectomy for hepatocellular carcinoma (HCC). METHODS: The propensity score matching and a retrospective cohort study were employed. The clinical and pathological data of 122 hepatocellular carcinoma (HCC) patients with surgical indications admitted to our hospital from March 2014 to March 2016 were collected. These 122 patients were subjected to propensity score matching and divided into ERAS group and Control group. The surgical situation, postoperative recovery [postoperative alanine aminotransferase (ALT), total bilirubin (TBiL) and C-reactive protein (CRP) levels], postoperative complications, postoperative hospital stay, hospitalization costs and patient satisfaction score were observed and compared between the two groups. All patients were followed up to record their postoperative survival. RESULTS: The average drainage tube removal time, bowel sound time, postoperative flatus time and postoperative hospital stay of patients were overtly shorter in ERAS group than in Control group. Besides, the postoperative numerical rating scale (NRS) score and the incidence rate of moderate and severe pain after surgery were lower in ERAS group than in Control group. The total hospitalization cost was significantly lower in ERAS group than in Control group. The patient satisfaction score was obviously higher in ERAS group than in Control group. ERAS group had fewer cases of postoperative vomiting, abdominal distension, biliary fistula, intestinal obstruction, large-volume ascites, liver failure, wound infection, pulmonary infection and abdominal infection than Control group, but the differences were not statistically significant. The ALT, TBiL and CRP levels of patients were notably lower in ERAS group than in Control group at d 7 after surgery. Based on the follow-up results, there was no significant difference in overall survival between the two groups. CONCLUSION: ERAS applied in the perioperative period of HCC patients receiving precise hepatectomy is reliable and effective and has positive significance for the promotion of postoperative rehabilitation, which is worthy of popularization in clinical practice.