Arnicolide C Suppresses Tumor Progression by Targeting 14-3-3θ in Breast Cancer.

Background: Arnicolide C, which is isolated from Centipeda minima, has excellent antitumor effects. However, the potential impacts and related mechanisms of action of arnicolide C in breast cancer remain unknown. Methods: The viability of breast cancer cells was measured using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and colony formation assays. For analysis of apoptosis and the cell cycle, flow cytometry was used. A molecular docking approach was used to explore the possible targets of arnicolide C. Western blot analysis was used to detect changes in the expression of 14-3-3θ and proteins in related pathways after arnicolide C treatment in breast cancer cells. The anti-breast cancer effect of arnicolide C in vivo was evaluated by establishing cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Results: Arnicolide C inhibited proliferation, increased apoptosis, and induced G1 arrest. In particular, molecular docking analysis indicated that arnicolide C binds to 14-3-3θ. Arnicolide C reduced 14-3-3θ expression and inhibited its downstream signaling pathways linked to cell proliferation. Similar results were obtained in the CDX and PDX models. Conclusion: Arnicolide C can have an anti-breast cancer effect both in vitro and in vivo and can induce cell cycle arrest and increase apoptosis in vitro. The molecular mechanism may be related to the effect of arnicolide C on the expression level of 14-3-3θ. However, the specific mechanism through which arnicolide C affects 14-3-3θ protein expression still needs to be determined.

A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.

BACKGROUND: The microtubule protein inhibitor C118P shows excellent anti-breast cancer effects. However, the potential targets and mechanisms of C118P in breast cancer remain unknown. METHODS: Real-time cellular analysis (RTCA) was used to detect cell viability. Apoptosis and the cell cycle were detected by flow cytometry. Computer docking simulations, surface plasmon resonance (SPR) technology, and microscale thermophoresis (MST) were conducted to study the interaction between C118P and alanine-serine-cysteine transporter 2 (ASCT2). Seahorse XF technology was used to measure the basal oxygen consumption rate (OCR). The effect of C118P in the adipose microenvironment was explored using a co-culture model of adipocytes and breast cancer cells and mouse cytokine chip. RESULTS: C118P inhibited proliferation, potentiated apoptosis, and induced G2/M cell cycle arrest in breast cancer cells. Notably, ASCT2 was validated as a C118P target through reverse docking, SPR, and MST. C118P suppressed glutamine metabolism and mediated autophagy via ASCT2. Similar results were obtained in the adipocyte-breast cancer microenvironment. Adipose-derived interleukin-6 (IL-6) promoted the proliferation of breast cancer cells by enhancing glutamine metabolism via ASCT2. C118P inhibited the upregulation of ASCT2 by inhibiting the effect of IL-6 in co-cultures. CONCLUSION: C118P exerts an antitumour effect against breast cancer via the glutamine transporter ASCT2.

Strain Quantum Sensing with Spin Defects in Hexagonal Boron Nitride.

Hexagonal boron nitride is not only a promising functional material for the development of two-dimensional optoelectronic devices but also a good candidate for quantum sensing thanks to the presence of quantum emitters in the form of atom-like defects. Their exploitation in quantum technologies necessitates understanding their coherence properties as well as their sensitivity to external stimuli. In this work, we probe the strain configuration of boron vacancy centers (VB-) created by ion implantation in h-BN flakes thanks to wide-field spatially resolved optically detected magnetic resonance and submicro Raman spectroscopy. Our experiments demonstrate the ability of VB- for quantum sensing of strain and, given the omnipresence of h-BN in 2D-based devices, open the door for in situ imaging of strain under working conditions.

Excited-State Optically Detected Magnetic Resonance of Spin Defects in Hexagonal Boron Nitride.

Negatively charged boron vacancy (V_{B}^{-}) centers in hexagonal boron nitride (h-BN) are promising spin defects in a van der Waals crystal. Understanding the spin properties of the excited state (ES) is critical for realizing dynamic nuclear polarization. Here, we report zero-field splitting in the ES of D_{ES}=2160 MHz and its associated optically detected magnetic resonance (ODMR) contrast of 12% at cryogenic temperature. In contrast to nitrogen vacancy (NV^{-}) centers in diamond, the ODMR contrast of V_{B}^{-} centers is more prominent at cryotemperature than at room temperature. The ES has a g factor similar to the ground state. The ES photodynamics is further elucidated by measuring the level anticrossing of the V_{B}^{-} defects under varying external magnetic fields. Our results provide important information for utilizing the spin defects of h-BN in quantum technology.

Contribution of adipocytes in the tumor microenvironment to breast cancer metabolism.

Breast cancer is considered the most common malignancy, with the profound ability to perform a wide range of metabolic reprogramming. Within the breast cancer microenvironment, highly available cancer-associated adipocytes interact with cancer cells by releasing various adipocytokines and metabolites. Obesity is also an important factor in this manner, where the accumulation of adipose tissue next to tumor tissue is linked to the increased incidence, progression, and metastasis of breast cancer. The metabolic changes caused by the crosstalk between breast cancer cells and dysfunctional adipose tissue include glucose, lipid, and amino acid metabolism. Thus, preventing this interaction between breast cancer cells and dysfunctional adipose tissue might develop a promising therapeutic strategy against breast cancer. This review focused on the metabolic changes responsible for inducing the crosstalk between breast cancer cells and adipocytes. We also reviewed the recent updates in therapeutics designed to disrupt this interaction.

Autophagy in cancer: The cornerstone during glutamine deprivation.

Over the past two decades, researchers have revealed the crucial functions of glutamine in supporting the hyperproliferation state of cancer cells. Glutamine acts on maintaining high energy production, supporting redox status and amino acid homeostasis. Therefore, cancer cells exhibit excessive uptake of the extracellular glutamine, synthesize it in some cases, and recycle intracellular and extracellular proteins to provide an additional source of glutamine to satisfy the increasing glutamine demand. On the other hand, autophagy's role is still debated regarding tumor initiation and progression. However, most cancer cells urgently need autophagy to overcome the existential threats during glutamine restriction stress. Downstream to various stress pathways induced during such a condition, autophagy is considered an indispensable cytoprotective tool to maintain cell integrity and survival. However, the overactivation of the autophagy process is related to lethal consequences. This review summarized glutamine pathways to control autophagy and highlighted autophagy's primary activation pathways, and discussed the roles during glutamine deprivation.

Interactive Web-based Data Visualization and Analysis Tool for Synthetizing on-farm Research Networks Data.

The on-farm research network concept enables a group of farmers to test new agricultural management practices under local conditions with support from local researchers or agronomists. Different on-farm trials based on the same experimental design are conducted over several years and sites to test the effectiveness of different innovative management practices aimed at increasing crop productivity and profitability. As a larger amount of historical trial data are being accumulated, data of all the trials require analyses and summarization. Summaries of on-farm trials are usually presented to farmers as individual field reports, which are not optimal for the dissemination of results and decision making. A more practical communication method is needed to enhance result communication and decision making. R Shiny is a new rapidly developing technology for turning R data analyses into interactive web applications. For the first time for on-farm research networks, we developed and launched an interactive web tool called ISOFAST using R Shiny. ISOFAST simultaneously reports all trial results about the same management practice to simplify interpretation of multi-site and multi-year summaries. We used a random-effects model to synthetize treatment differences at both the individual trial and network levels and generate new knowledge for farmers and agronomists. The friendly interface enables users to explore trial summaries, access model outputs, and perform economic analysis at their fingertips. This paper describes a case-study to illustrate how to use the tool and make agronomic management decisions based on the on-farm trial data. We also provided technical details and guidance for developing a similar interactive visualization tool customized for on-farm research network. ISOFAST is currently available at https://analytics.iasoybeans.com/cool-apps/ISOFAST/.

Empirical Bayes small area prediction under a zero-inflated lognormal model with correlated random area effects.

Many variables of interest in agricultural or economical surveys have skewed distributions and can equal zero. Our data are measures of sheet and rill erosion called Revised Universal Soil Loss Equation - 2 (RUSLE2). Small area estimates of mean RUSLE2 erosion are of interest. We use a zero-inflated lognormal mixed effects model for small area estimation. The model combines a unit-level lognormal model for the positive RUSLE2 responses with a unit-level logistic mixed effects model for the binary indicator that the response is nonzero. In the Conservation Effects Assessment Project (CEAP) data, counties with a higher probability of nonzero responses also tend to have a higher mean among the positive RUSLE2 values. We capture this property of the data through an assumption that the pair of random effects for a county are correlated. We develop empirical Bayes (EB) small area predictors and a bootstrap estimator of the mean squared error (MSE). In simulations, the proposed predictor is superior to simpler alternatives. We then apply the method to construct EB predictors of mean RUSLE2 erosion for South Dakota counties. To obtain auxiliary variables for the population of cropland in South Dakota, we integrate a satellite-derived land cover map with a geographic database of soil properties. We provide an R Shiny application called viscover (available at https://lyux.shinyapps.io/viscover/) to visualize the overlay operations required to construct the covariates. On the basis of bootstrap estimates of the mean square error, we conclude that the EB predictors of mean RUSLE2 erosion are superior to direct estimators.

IDH mutations associated impact on related cancer epidemiology and subsequent effect toward HIF-1α.

Particular mutations in the isocitrate dehydrogenase gene (IDH) were discovered in several gliomas citing astrocytoma, oligodendroglioma, and glioblastoma multiform, but also in leukemia; these mutations were discovered in nearly all cases of secondary glioblastomas, they evolve from lower-grade gliomas, but are limited in primary high-grade glioblastoma multiform. These mutations distinctively produce (D)-2-hydroxyglutarate (D-2-HG) from alpha-ketoglutarate (α-KG). (D)-2-hydroxyglutarate is accumulated to very high concentrations which inhibit the function of enzymes that are dependent on alpha-ketoglutarate. This modification leads to a hyper-methylated state of DNA and histones, resulting in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes. In our work we review the impact of the mutations that occur in IDH genes, we focus on their impact on distribution in cancer. As IDH mutations appear in many different conditions we expose the extent of IDH mutations and derivate their impact on cancer prognosis, diagnosis, and even their oncogenicity, we will also link their impact to HIF-1α and derivate some target and finally, we present some of the therapeutics under research and out on market.

Using landscape habitat associations to prioritize areas of conservation action for terrestrial birds.

Predicting species distributions has long been a valuable tool to plan and focus efforts for biodiversity conservation, particularly because such an approach allows researchers and managers to evaluate species distribution changes in response to various threats. Utilizing data from a long-term monitoring program and land cover data sets, we modeled the probability of occupancy and colonization for 38 bird Species of Greatest Conservation Need (SGCN) in the robust design occupancy modeling framework, and used results from the best models to predict occupancy and colonization on the Iowa landscape. Bird surveys were conducted at 292 properties from April to October, 2006-2014. We calculated landscape habitat characteristics at multiple spatial scales surrounding each of our surveyed properties to be used in our models and then used kriging in ArcGIS to create predictive maps of species distributions. We validated models with data from 2013 using the area under the receiver operating characteristic curve (AUC). Probability of occupancy ranged from 0.001 (SE < 0.001) to 0.995 (SE = 0.004) for all species and probability of colonization ranged from 0.001 (SE < 0.001) to 0.999 (SE < 0.001) for all species. AUC values for predictive models ranged from 0.525-0.924 for all species, with 17 species having predictive models considered useful (AUC > 0.70). The most important predictor for occupancy of grassland birds was percentage of the landscape in grassland habitat, and the most important predictor for woodland birds was percentage of the landscape in woodland habitat. This emphasizes the need for managers to restore specific habitats on the landscape. In an era during which funding continues to decrease for conservation agencies, our approach aids in determining where to focus limited resources to best conserve bird species of conservation concern.

Lactate-activated macrophages induced aerobic glycolysis and epithelial-mesenchymal transition in breast cancer by regulation of CCL5-CCR5 axis: a positive metabolic feedback loop.

Aberrant energy metabolism is critical for cancer progression. Tumor-associated macrophages (TAMs) can stimulate tumor angiogenesis and enhance cancer metastasis; however, the metabolic interaction between cancer cells and macrophages characterized by lactate shuttles remains unclear. Here, we showed that lactate activated human macrophages to a TAM-like phenotype and stimulated the secretion of CCL5 by activation of Notch signaling in macrophages. Reciprocally, CCL5 increased cell migration, induced cancer cell EMT, and promoted aerobic glycolysis in breast cancer cells, suggesting a positive metabolic feedback loop in the co-culture system. Inhibition of CCR5, the cognate receptor of CCL5, or neutralization of CCL5, broke the metabolic loop and decreased cancer cell migration and EMT. Inhibition of aerobic glycolysis significantly reduced breast cancer cell EMT, indicated that aerobic glycolysis was necessary for the invasive phenotype of cancer cells. We further showed that TGF-ß signaling regulated the expression of CCR5 in the co-culture system, and CCL5 induced glycolysis by mediation of AMPK signaling. The expression of CCL5-CCR5 axis was highly associated with macrophage infiltration, TGF-ß and p-AMPK in clinical samples. CCL5-CCR5 axis promoted breast cancer metastasis in vivo. Our findings suggested a pivotal role of CCL5-CCR5 axis in the metabolic communication between cancer cells and macrophages.

MHP-1 inhibits cancer metastasis and restores topotecan sensitivity via regulating epithelial-mesenchymal transition and TGF-ß signaling in human breast cancer cells.

BACKGROUND: Cordyceps has long been used to treat cancer. However, its pharmacologically active components as well as the molecular mechanisms underlying its effects are still unclear. PURPOSE: To investigate the effect of MHP-1, a newly isolated polysaccharide from Mortierella hepialid (the asexual structure of C. sinensis), on breast cancer metastasis. STUDY DESIGN: The effect of MHP-1 on breast cancer cell migration, epithelial-mesenchymal transition (EMT) and TGF-ß signaling were investigated in vitro and in vivo. The effect of MHP-1 against topotecan-resistant MCF-7 cells that developed an EMT-like phenotype was also examined. METHODS: The in vitro effect of MHP-1 on breast cancer cell proliferation and migration was evaluated by CCK8 and transwell assay. Morphological changes were observed and EMT markers were detected by western blot. The production of MMPs was measured by quantitative PCR and ELISA assay. To further investigate the mechanism that MHP-1 inhibited breast cancer EMT, western blot, ELISA, luciferase reporter gene assay, siRNA, quantitative PCR, immunohistochemistry, and xenograft tumor model were performed. RESULTS: MHP-1 inhibited breast cancer cell migration but did not cause any cytotoxicity. MHP-1 significantly surpressed breast cancer EMT, and slightly decreased MMP-9 secretion. TGF-ß signaling was selectively inhibited after MHP-1 treatment, and other EMT-related pathways, like Wnt and Notch, were not affected. MHP-1 reduced the secretion of TGF-ß1, but rarely affected other EMT-induced cytokines. Dual luciferase assay and Smad2/3 phosphorylation analysis indicated that MHP-1 suppressed TGF-ß signaling. We further showed that MHP-1 restored sensitivity in topotecan (TPT)-resistant MCF-7 cells that developed an EMT-like phenotype. Similarly, the effect of TPT on resistant MCF-7 cells was also increased either by ALK5 (TGFßRI) siRNA or by a small molecular inhibitor of ALK5, SB-431542. MHP-1 inhibited breast cancer metastasis in the MDA-MB-231 xenograft model, and the immunohistochemical staining showed dramatically decreased expression of ALK5 and vimentin, and increased expression of E-cadherin. CONCLUSION: MHP-1 significantly inhibited breast cancer metastasis and restored drug sensitivity in TPT-resistant cells via down-regulation of TGF-ß signaling and EMT program. The combination of non-toxic agents like MHP-1 and current anti-cancer drugs should be considered in the future treatment of cancer.