The microenvironment reprograms circuits in tumor cells

In the course of multistep oncogenesis, initially normal cells acquire several new functions that render them malignant. We have recently demonstrated that the peritoneal microenvironment promotes resistance to anoikis in ovarian cancer cells by reprogramming SRC/AKT/ERK signaling and metabolism. These findings have prognostic and therapeutic implications

FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer

Lysophosphatidic acid (LPA), a prototypical ligand for G protein coupled receptors, and Forkhead box protein M1 (FOXM1), a transcription factor that regulates expression of a wide array of genes involved in cancer initiation and progression, are two important oncogenic signaling molecules in human epithelial ovarian cancers (EOC). We conducted in vitro mechanistic studies using pharmacological inhibitors, genetic forms of the signaling molecules, and RNAi-mediated gene knock-down to uncover the molecular mechanisms of how these two molecules interact in EOC cells. Additionally, in vivo mouse studies were performed to confirm the functional involvement of FOXM1 in EOC tumor formation and progression. We show for the first time that LPA up-regulates expression of active FOXM1 splice variants in a time- and dose-dependent manner in the human EOC cell lines OVCA433, CAOV3, and OVCAR5. Gi-PI3K-AKT and G12/13-Rho-YAP signaling pathways were both involved in the LPA receptor (LPA1-3) mediated up-regulation of FOXM1 at the transcriptional level. In addition, down-regulation of FOXM1 in CAOV3 xenografts significantly reduced tumor and ascites formation, metastasis, and expression of FOXM1 target genes involved in cell proliferation, migration, or invasion. Collectively, our data link the oncolipid LPA, the oncogene YAP, and the central regulator of cell proliferation/mutagenesis FOXM1 in EOC cells. Moreover, these results provide further support for the importance of these pathways as potential therapeutic targets in EOC

Hypoxic conditions differentially regulate TAZ and YAP in cancer cells

The Hippo-YAP pathway is altered and implicated as an oncogenic signaling pathway in many human cancers. Hypoxia is an important microenvironmental factor that promotes tumorigenesis. However, the effects of hypoxia on the two most important Hippo-YAP effectors, YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), have not been reported. In this work, we demonstrated that TAZ was functionally involved in cell proliferation and/or migration in epithelial ovarian cancer (EOC) or human ovarian surface epithelial (HOSE) cells. Hypoxic conditions (1% O2 or hypoxia mimics) induced a reduction of YAP phosphorylation (S127) and total YAP expression in EOC cell lines OVCAR5 and SKOV3. However, these conditions up-regulated levels of S69 phosphorylated TAZ in EOC cells. The known TAZ kinases, Lats1 and Akt, were unlikely to be involved in up-regulated pTAZ by hypoxic conditions. Together, our data revealed new and differential regulating mechanisms of TAZ and YAP in cancer cells by hypoxia conditions

LPA induced FOXM1 up-regulation in ovarian cancer cells via both the PI3K and YAP pathways

poster abstractThe cure rate for late stage epithelial ovarian cancer (EOC) has not significantly improved for patients over the past 20 years. The current standard of care is aggressive surgery followed by platinum/paclitaxel chemotherapy. However, approximately 25% of patients will develop platinum resistant cancer within 6 months and the overall 5-year survival is only 31%. Therefore, new and more effective treatment modalities that target additional molecular pathways are urgently needed. The functional and mechanistic studies presented here clearly support that the FOXM1 network is an important target for developing new EOC therapeutics. This network includes the newly identified LPA as an up-stream regulator of FOXM1 and down-stream targets. Tumor cell specific targeting may be necessary and tumor and/or tumor-host interactions generating secreted factors, such as amphiregulin (AREG) and/or VEGF, may be used as follow-up factors to monitor treatment and disease progression

Structure design and surface interference analysis of double crown surface configuration of multistage face gears

A novel transmission using the multistage face gears as the core component is used to realize variable speed with differential gear shifting, there are multiple face gears superimposed on the radial direction, meshing with planetary wheel at the same time, which achieves different outputs speed through braking different face gears. In order to solve the interference problems caused by asynchronous meshing motion between several face gears and the same cylinder gear, this study mainly focuses on the meshing theory study based on the double crown surfaces in tooth profile and tooth orientation. The surface structure of straight tooth and double crown are constructed according to the related surface equations, the corresponding interference conditions are obtained by comparison, every single stage face gear model is designed and assembled. This study shows that the double crown configuration surface structure can easily improve contact characteristics compared with straight tooth surface structure of face gear. In addition, the double crown configuration surface structure can improve the distribution and direction of contact path. This study is expected to establish a new tooth surface model, which can provide the best machining parameters for the face gears

Describing Strong Correlation with Block-Correlated Coupled Cluster Theory

A block-correlated coupled cluster (BCCC) method based on the generalized valence bond (GVB) wave function (GVB-BCCC in short) is proposed and implemented at the ab initio level, which represents an attractive multireference electronic structure method for strongly correlated systems. The GVB-BCCC method is demonstrated to provide accurate descriptions for multiple bond breaking in small molecules, although the GVB reference function is qualitatively wrong for the studied processes. For a challenging prototype of strongly correlated systems, tridecane with all 12 single C-C bonds at various distances, our calculations have shown that the GVB-BCCC2b method can provide highly comparable results as the density matrix renormalization group method for potential energy surfaces along simultaneous dissociation of all C-C bonds

Pharmacokinetics, tissue distribution, and antitumor activity of a novel compound, NY-2, in non-small cell lung cancer

Introduction: ZLDI-8, which has a relatively strong antitumor activity, is an inhibitor of ADAM-17 and acts on the Notch signaling pathway. To further optimize its structure and improve its activity, a series of derivatives of ZLDI-8 was synthesized. NY-2 was the most effective derivative based on preliminary activity screening in vitro, with no obvious toxicity after administration in vivo.Method: The study aimed to determine the pharmacokinetics, tissue distribution, hepatotoxicity, nephrotoxicity, and antitumor activity of compound NY-2 on non-small cell lung cancer (NSCLC) in vitro and in vivo.Results: The in vivo pharmacokinetics parameters of NY-2 were better than those of ZLDI-8. The tissue distribution analysis showed that tail vein injection of 6 mg/kg of NY-2 in rats resulted in the highest concentration in the lung, so we hypothesized that NY-2 might be effective in the treatment of non-small cell lung cancer. In vitro assays showed that NY-2 significantly inhibited tumor colony formation, invasion, and migration and increased LDH activity and apoptosis in a concentration-dependent manner in non-small cell lung cancer cells. NY-2 also inhibited the formation of lung metastases without significant toxicity to major organs in nude mice.Conclusion: Compared with the parent compound, ZLDI-8, the activity and safety of NY-2 were higher. NY-2 acts on ADAM17 and simultaneously affects the downstream Notch1 and integrinβ1 signaling pathways resulting in antitumor activity. Thus, NY-2 could be a potential antitumor agent, inhibiting the organization and development of non-small cell lung cancer

SELECTOR: Heterogeneous graph network with convolutional masked autoencoder for multimodal robust prediction of cancer survival

Accurately predicting the survival rate of cancer patients is crucial for aiding clinicians in planning appropriate treatment, reducing cancer-related medical expenses, and significantly enhancing patients' quality of life. Multimodal prediction of cancer patient survival offers a more comprehensive and precise approach. However, existing methods still grapple with challenges related to missing multimodal data and information interaction within modalities. This paper introduces SELECTOR, a heterogeneous graph-aware network based on convolutional mask encoders for robust multimodal prediction of cancer patient survival. SELECTOR comprises feature edge reconstruction, convolutional mask encoder, feature cross-fusion, and multimodal survival prediction modules. Initially, we construct a multimodal heterogeneous graph and employ the meta-path method for feature edge reconstruction, ensuring comprehensive incorporation of feature information from graph edges and effective embedding of nodes. To mitigate the impact of missing features within the modality on prediction accuracy, we devised a convolutional masked autoencoder (CMAE) to process the heterogeneous graph post-feature reconstruction. Subsequently, the feature cross-fusion module facilitates communication between modalities, ensuring that output features encompass all features of the modality and relevant information from other modalities. Extensive experiments and analysis on six cancer datasets from TCGA demonstrate that our method significantly outperforms state-of-the-art methods in both modality-missing and intra-modality information-confirmed cases. Our codes are made available at https://github.com/panliangrui/Selector.Comment: Accepted on Computers in Biology and Medicin

Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice

Acknowledgments and Disclosures This work was supported by the National Institutes of Health (Grant Nos. R01DK093587 and R01DK101379 [to YX], R01DK092605 to [QT], R01DK078056 [to MM]), the Klarman Family Foundation (to YX), the Naman Family Fund for Basic Research (to YX), Curtis Hankamer Basic Research Fund (to YX), American Diabetes Association (Grant Nos. 7-13-JF-61 [to QW] and 1-15-BS-184 [to QT]), American Heart Association postdoctoral fellowship (to PX), Wellcome Trust (Grant No. WT098012 [to LKH]), and Biotechnology and Biological Sciences Research Council (Grant No. BB/K001418/1 [to LKH]). The anxiety tests (e.g., open-field test, light-dark test, elevated plus maze test) were performed in the Mouse Neurobehavior Core, Baylor College of Medicine, which was supported by National Institutes of Health Grant No. P30HD024064. PX and YH were involved in experimental design and most of the procedures, data acquisition and analyses, and writing the manuscript. XC assisted in the electrophysiological recordings; LV-T assisted in the histology study; XY, KS, CW, YY, AH, LZ, and GS assisted in surgical procedures and production of study mice. MGM, QW, QT, and LKH were involved in study design and writing the manuscript. YX is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors report no biomedical financial interests or potential conflicts of interest.Peer reviewedPublisher PD

An Obligate Role of Oxytocin Neurons in Diet Induced Energy Expenditure

Oxytocin neurons represent one of the major subsets of neurons in the paraventricular hypothalamus (PVH), a critical brain region for energy homeostasis. Despite substantial evidence supporting a role of oxytocin in body weight regulation, it remains controversial whether oxytocin neurons directly regulate body weight homeostasis, feeding or energy expenditure. Pharmacologic doses of oxytocin suppress feeding through a proposed melanocortin responsive projection from the PVH to the hindbrain. In contrast, deficiency in oxytocin or its receptor leads to reduced energy expenditure without feeding abnormalities. To test the physiological function of oxytocin neurons, we specifically ablated oxytocin neurons in adult mice. Our results show that oxytocin neuron ablation in adult animals has no effect on body weight, food intake or energy expenditure on a regular diet. Interestingly, male mice lacking oxytocin neurons are more sensitive to high fat diet-induced obesity due solely to reduced energy expenditure. In addition, despite a normal food intake, these mice exhibit a blunted food intake response to leptin administration. Thus, our study suggests that oxytocin neurons are required to resist the obesity associated with a high fat diet; but their role in feeding is permissive and can be compensated for by redundant pathways