Aris T . Alexandrou

The majority of women with ovarian cancer are diagnosed with metastatic disease, therefore elucidating molecular events that contribute to successful metastatic dissemination may identify additional targets for therapeutic intervention and thereby positively impact survival. Using two human high grade serous ovarian cancer cell lines with inactive TP53 and multiple rounds of serial in vivo passaging, we generated sublines with significantly accelerated intra-peritoneal (IP) growth. Comparative analysis of the parental and IP sublines identified a common panel of differentially expressed genes. The most highly differentially expressed gene, upregulated by 60-65-fold in IP-selected sublines, was the type I transmembrane protein AMIGO2. As the role of AMIGO2 in ovarian cancer metastasis remains unexplored, CRISPR/Cas9 was used to reduce AMIGO2 expression, followed by in vitro and in vivo functional analyses. Knockdown of AMIGO2 modified the sphere-forming potential of ovarian cancer cells, reduced adhesion and invasion in vitro, and significantly attenuated IP metastasis. These data highlight AMIGO2 as a new target for a novel anti-metastatic therapeutic approach aimed at blocking cohesion, survival, and adhesion of metastatic tumorspheres.

The Implicit Theory of Intelligence, first proposed by Carol Dweck in 1995, states that individuals may possess an entity theory (Fixed Mindset) or an incremental theory (Growth Mindset) about their own intelligence. Accordingly, individuals with fixed mindsets perceive their intelligence as constant and not subject to growth, while individuals with growth mindsets perceive their intelligence as malleable and strive to expand it (Blackwell, Trzesniewski, & Dweck, 2007). Implicit Theories have also been extended to thoughts, emotions and behavior (Schleider,& Weisz, 2016).
A large portion of the existing research focuses on academic achievement, elucidating the benefits of adopting a growth mindset for students of all ages (Bostwick, Collie, Martin, & Durksen, 2017; Hellmich & Hoya, 2017; Renaud-Dube, Guay, Talbot, Taylor, &Koestner, 2015; Tempelaar, Rienties, Giesbergs, & Gijselaers, 2015; Shively & Ryan, 2013; Shih, 2011; Ahmavaara & Houston, 2007; Leondari & Gialamas, 2002). Consequently, only a few studies address the relationship between implicit theories and stress regulation (Gal & Szamoskozi, 2016). A 2013 study found that a growth mindset predicts stronger challenge confronting tendencies for students with a relatively low fear of being laughed at (Liu, Chiu, Chen, & Lin, 2013). Another study found evidence that students with a fixed mindset of intelligence have a stronger association with negative affective states, while growth mindsets of intelligence are associated with positive affective states and less psychiatric disorders (Gal & Szamoskozi, 2016).
This study aims to elucidate the relationship between four types of implicit theories (intelligence, thoughts, emotions and behavior) and stress regulation. Hence, the study aims to investigate the impact of mindset on subjects’ salivary cortisol and self-reported anxiety under the impact of induced social stress. We hypothesize that an incremental theory (growth mindset) of intelligence, thoughts, emotions and behavior will contribute to better regulation of psychological and physiological anxiety and to more positive affective states expressed by relatively lower anxiety and depression.

Circadian clocks are intimately involved in the homeostatic maintenance of metabolic and physiological processes that may have increasingly important roles to enhance bone marrow transplantation success in cancer patients; to protect normal tissue surrounding tumors from the harmful effects of radio/chemotherapy; and to enhance the quality of diet and sleep for astronauts during space exploration. Herein, we report that expression of PERIOD2 (PER2; a core circadian clock component and "the inherent driver" of radioprotection) is required for adaptive protection against environmental radiation stress. PER2 expression is induced by exposure to low dose radiation (LDR; 10cGy) and siRNA blockade of PER2 ablates LDR-induced adaptive radioprotection. In addition, melatonin (N-acetyl-5-methoxytryptamine), a natural anti-oxidant and hypothalamic circadian synchronizer, stimulates PER2 expression and confers mice radioprotection through weight maintenance and increased survival. LDR-induced PER2 transcription is regulated by NF-κB and βcatenin and is released from phospho-glycogen synthase kinase-3ß (p-GSK3ß) in the WNT/β-catenin pathway. Unbound β-catenin interacts with the TCF/LEF domain on the Per2 promoter to promote feed-forward PER2-pGSK3β complex formation. Mitochondrial bioenergetics measured by oxygen consumption and ATP generation was attenuated in bone marrow isolated from PER2 mutant () mice. Furthermore, RNA-seq profiling of bone marrow-derive progenitor hematopoietic stem cells (BM-pHSCs; Lin-/Sca1+/cKit+; LSK) cells isolated form LDR-treated wild-type (WT) versus mice showed a cluster of genes involved in mitochondrial bioenergetics and DNA repair capacity. These results demonstrate that a core circadian regulator plays an indispensable role in defending mammalian cells against environmental genotoxic stress through the PER2/β-catenin pathway, a potential therapeutic target to enhance cell survival under radiation.

Circulating biomarkers reflecting the development, progression, and rupture of abdominal aortic aneurysm (AAA) are needed. AAA is the most common arterial aneurysm and is characterized by a degradation of elastin fibers in the media and collagen fibers in the adventitia, leading to >50% expansion of the diameter of the aorta. 1,2 The incidence of AAA is increasing with an aging population around the world. 3,4 Evidence from epidemiologic and experimental investigations suggest that the pathogenesis of AAA is often related to atherosclerosis risk factors, particularly smoking, genetic influence,

Significance: There are accruing concerns on potential genotoxic agents present in the environment including low-dose ionizing radiation (LDIR) that naturally exists on earth's surface and atmosphere and is frequently used in medical diagnosis and nuclear industry. Although its long-term health risk is being evaluated and remains controversial, LDIR is shown to induce temporary but significant adaptive responses in mammalian cells and animals. The mechanisms guiding the mitochondrial function in LDIR-induced adaptive response represent a unique communication between DNA damage and cellular metabolism. Elucidation of the LDIRregulated mitochondrial activity may reveal new mechanisms adjusting cellular function to cope with hazardous environmental stress. Recent Advances: Key cell cycle regulators, including Cyclin D1/CDK4 and Cyclin B1/ cyclin-dependent kinase 1 (CDK1) complexes, are actively involved in the regulation of mitochondrial functions via phosphorylation of their mitochondrial targets. Accumulating new evidence supports a concept that the Cyclin B1/CDK1 complex acts as a mediator in the cross talk between radiation-induced DNA damage and mitochondrial functions to coordinate cellular responses to low-level genotoxic stresses. Critical Issues: The LDIR-mediated mitochondrial activity via Cyclin B1/CDK1 regulation is an irreplaceable network that is able to harmonize vital cellular functions with adjusted mitochondrial metabolism to enhance cellular homeostasis. Future Directions: Further investigation of the coordinative mechanism that regulates mitochondrial activities in sublethal stress conditions, including LDIR, will reveal new insights of how cells cope with genotoxic injury and will be vital for future targeted therapeutic interventions that reduce environmental injury and cancer risk.

Breast cancer is the leading cause of cancer death among women worldwide. Accumulating evidence indicates that the local recurrent and/or distant metastatic tumors, the major causes of lethality in the clinic, are related to the aggressive phenotype of a small fraction of cancer cells loosely termed as cancer stem cells (CSCs), tumor initiating cells (TICs), or cancer metastasis-initiating cells (CMICs). Breast cancer stem cells (BCSCs) are shown to exhibit unique growth abilities including self-renewal, differentiation potential, and resistance to most anti-cancer agents including chemo-and/or radiotherapy, all of which are believed to contribute to the development and overall aggressiveness of the recurrent or metastatic lesions. It is in the urgent need not only to further define the nature of heterogeneity in each tumor but also to characterize the precise mechanisms governing tumor-host cross-talk which is assumed to be initiated by BCSCs. In this review, we will focus on recently identified key factors, including the BCSCs among circulating tumor cells, interaction of BCSCs with the host, epithelial mesenchymal transition (EMT), tumor microenvironment, the intrinsic resistance due to HER2 expression, potential biomarkers of BCSCs and cancer cell immune signaling. We believe that new evidence coming from both bench and clinical research will help to develop more effective approaches to control or significantly reduce the aggressiveness of metastatic tumors.