Mutant p53 murine oviductal epithelial cells induce progression of high-grade serous carcinoma and are most sensitive to simvastatin therapy in vitro and in vivo.

High-grade serous carcinoma (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer, characterized by gain-of-function TP53 mutations originating in the fallopian tube epithelium. Therapeutic intervention occurs at advanced metastatic disease, due to challenges in early-stage diagnosis, with common disease recurrence and therapy resistance despite initial therapy success. The mevalonate pathway is exploited by many cancers and is potently inhibited by statin drugs. Statins have shown anti-cancer activity in many, but not all cancers. Here, we investigated the role of p53 status in relation to mevalonate pathway signaling in murine oviductal epithelial (OVE) cells and identified OVE cell sensitivity to statin inhibition. We found that p53R175H mutant and Trp53 knockout OVE cells have increased mevalonate pathway signaling compared to p53 wild-type OVE cells. Through orthotopic implantation to replicate the fallopian tube origin of HGSC, p53R175H mutant cells upregulated the mevalonate pathway to drive progression to advanced-stage ovarian cancer, and simvastatin treatment abrogated this effect. Additionally, simvastatin was more efficacious at inhibiting cell metabolic activity in OVE cells than atorvastatin, rosuvastatin and pravastatin. In vitro, simvastatin demonstrated potent effects on cell proliferation, apoptosis, invasion and migration in OVE cells regardless of p53 status. In vivo, simvastatin induced ovarian cancer disease regression through decreased primary ovarian tumor weight and increased apoptosis. Simvastatin also significantly increased cytoplasmic localization of HMG-CoA reductase in ovarian tumors. Downstream of the mevalonate pathway, simvastatin had no effect on YAP or small GTPase activity. This study suggests that simvastatin can induce anti-tumor effects and could be an important inhibitor of ovarian cancer progression.

A meta-analysis of the stony coral tissue loss disease microbiome finds key bacteria in unaffected and lesion tissue in diseased colonies.

Stony coral tissue loss disease (SCTLD) has been causing significant whole colony mortality on reefs in Florida and the Caribbean. The cause of SCTLD remains unknown, with the limited concurrence of SCTLD-associated bacteria among studies. We conducted a meta-analysis of 16S ribosomal RNA gene datasets generated by 16 field and laboratory SCTLD studies to find consistent bacteria associated with SCTLD across disease zones (vulnerable, endemic, and epidemic), coral species, coral compartments (mucus, tissue, and skeleton), and colony health states (apparently healthy colony tissue (AH), and unaffected (DU) and lesion (DL) tissue from diseased colonies). We also evaluated bacteria in seawater and sediment, which may be sources of SCTLD transmission. Although AH colonies in endemic and epidemic zones harbor bacteria associated with SCTLD lesions, and aquaria and field samples had distinct microbial compositions, there were still clear differences in the microbial composition among AH, DU, and DL in the combined dataset. Alpha-diversity between AH and DL was not different; however, DU showed increased alpha-diversity compared to AH, indicating that, prior to lesion formation, corals may undergo a disturbance to the microbiome. This disturbance may be driven by Flavobacteriales, which were especially enriched in DU. In DL, Rhodobacterales and Peptostreptococcales-Tissierellales were prominent in structuring microbial interactions. We also predict an enrichment of an alpha-toxin in DL samples which is typically found in Clostridia. We provide a consensus of SCTLD-associated bacteria prior to and during lesion formation and identify how these taxa vary across studies, coral species, coral compartments, seawater, and sediment.

Detection and impact of sewage pollution on South Kohala's coral reefs, Hawai'i.

Sewage pollution from on-site sewage disposal systems and injection wells is impacting coral reefs worldwide. Our study documented the presence and impact of sewage on South Kohala's coral reefs, on Hawai'i Island, through benthic water quality and macroalgal sampling (fecal indicator bacteria, nutrients, δ15N macroalgal tissue), NO3- stable isotope mixing models, water motion measurements, and coral reef surveys. Sewage pollution was moderate on the offshore reef from benthic seeps, and water motion mixed and diluted it across the benthos. These conditions likely contribute to the dominance of turf algae cover, and the severity and prevalence of growth anomalies and algal overgrowth on corals. Use of multiple indicators and studying water motion was necessary to assess sewage pollution and identify environmental drivers associated with impaired coral health conditions. Methods used in this study can be utilized by natural resource managers to identify and reduce anthropogenic stressors to coral reefs.

Understanding Sex Differences in Children's Injury Risk as Pedestrians.

OBJECTIVE: Boys experience more injuries as pedestrians than girls. The aim of this study was to compare how boys and girls cross streets in order to identify factors that differentially influence their injury risk as pedestrians. METHODS: Using a fully immersive virtual reality (VR) system interfaced with a 3D movement measurement system, various measures of children's street-crossing behaviors were taken. RESULTS: At the start of the crossing, boys selected smaller (riskier) inter-vehicle gaps to cross into than girls. Subsequently, as they crossed, they showed greater attention to traffic, shorter start delay, and more evasive action than girls, which are strategies that could reduce risk as a pedestrian. Despite these efforts, however, boys experienced more hits and close calls than girls. CONCLUSION: To enhance their safety as pedestrians, girls adopt a proactive approach and select larger inter-vehicle gaps to cross into, whereas boys apply a reactive approach aimed at managing the risk created by having selected smaller (riskier) gaps. Girls' proactive approach yielded safer outcomes than boys' reactive strategy.

Tolerability and benefit of a tetramethoxyluteolin-containing skin lotion.

As many as 40% of people have sensitive skin and at least half of them suffer from pruritus associated with allergies, atopic dermatitis (AD), chronic urticaria (CU), cutaneous mastocytosis (CM), and psoriasis. Unfortunately, the available topical formulations contain antihistamines that are often not as effective as those containing corticosteroids. Certain natural flavonoids have anti-inflammatory actions. We recently reported that the natural flavonoid tetramethoxyluteolin has potent antiallergic and anti-inflammatory actions in vitro and in vivo. This flavonoid was formulated in a skin lotion along with olive fruit extract and was first tested for tolerability in 25 patients with mastocytosis or mast cell activation syndrome and very sensitive skin who reported back through a questionnaire. The skin lotion was then used by eight patients, four with AD and four with psoriasis, who had not received any topical treatment for at least 2 months, twice daily for 2 weeks. The use of this tetramethoxyluteolin formulation resulted in significant improvement of the skin lesions and could be useful adjuvant treatment for allergic and inflammatory skin conditions.

Using Peer Communicated Norms About Safety to Reduce Injury-Risk Behaviors by Children.

Objective: This study examined whether exposure to a safety norm could counteract the increase in risk taking children show when in an elevated positive mood state. Methods: Risk taking (intentions, behaviors) was measured in a neutral and positive (induced experimentally) mood state. Before completing the tasks in a positive mood, 120 children 7-10 years were exposed to either a safety norm or a control audio. Results: The control audio had no effect: children showed an increase in risk taking and intentions when in a positive mood compared with a neutral mood, replicating past research. In contrast, exposure to the safety norm counteracted this effect: children showed a decrease in risk taking and intentions when in a positive mood compared with a neutral mood. Conclusion: Manipulating children's exposure to social norms can be an effective strategy for reducing injury-risk behaviors even when they are in an elevated positive mood state.

Neuroendocrinology of the skin.

The skin is considered the mirror of the soul and is affected by neurohormonal triggers, especially stress. Hair follicles, keratinocytes, mast cells, melanocytes, and sebocytes all express sex and stress hormones implicating them in a local "hypothalamic-pituitary-adrenal axis." In particular, the peptides corticotropin-releasing hormone (CRH) and neurotensin (NT) have synergistic action stimulating mast cells and are uniquely elevated in the serum of patients with skin diseases exacerbated by stress. Addressing the neurohormonal regulation of skin function could lead to new targets for effective treatment of inflammatory skin diseases.

Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells.

Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain affecting more women than men. Even though clinical studies have provided evidence of altered central pain pathways, the lack of definitive pathogenesis or reliable objective markers has hampered development of effective treatments. Here we report that the neuropeptides corticotropin-releasing hormone (CRH), substance P (SP), and SP-structurally-related hemokinin-1 (HK-1) were significantly (P = 0.026, P < 0.0001, and P = 0.002, respectively) elevated (0.82 ± 0.57 ng/ml, 0.39 ± 0.18 ng/ml, and 7.98 ± 3.12 ng/ml, respectively) in the serum of patients with FMS compared with healthy controls (0.49 ± 0.26 ng/ml, 0.12 ± 0.1 ng/ml, and 5.71 ± 1.08 ng/ml, respectively). Moreover, SP and HK-1 levels were positively correlated (Pearson r = 0.45, P = 0.002) in FMS. The serum concentrations of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF) were also significantly (P = 0.029 and P = 0.006, respectively) higher (2.97 ± 2.35 pg/ml and 0.92 ± 0.31 pg/ml, respectively) in the FMS group compared with healthy subjects (1.79 ± 0.62 pg/ml and 0.69 ± 0.16 pg/ml, respectively). In contrast, serum IL-31 and IL-33 levels were significantly lower (P = 0.0001 and P = 0.044, respectively) in the FMS patients (849.5 ± 1005 pg/ml and 923.2 ± 1284 pg/ml, respectively) in comparison with healthy controls (1281 ± 806.4 pg/ml and 3149 ± 4073 pg/ml, respectively). FMS serum levels of neurotensin were not different from controls. We had previously shown that CRH and SP stimulate IL-6 and TNF release from mast cells (MCs). Our current results indicate that neuropeptides could stimulate MCs to secrete inflammatory cytokines that contribute importantly to the symptoms of FMS. Treatment directed at preventing the secretion or antagonizing these elevated neuroimmune markers, both centrally and peripherally, may prove to be useful in the management of FMS.

Mast cells, brain inflammation and autism.

Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Mast cells (MCs) are located perivascularly close to neurons and microglia, primarily in the leptomeninges, thalamus, hypothalamus and especially the median eminence. Corticotropin-releasing factor (CRF) is secreted from the hypothalamus under stress and, together with neurotensin (NT), can stimulate brain MCs to release inflammatory and neurotoxic mediators that disrupt the blood-brain barrier (BBB), stimulate microglia and cause focal inflammation. CRF and NT synergistically stimulate MCs and increase vascular permeability; these peptides can also induce each other׳s surface receptors on MCs leading to autocrine and paracrine effects. As a result, brain MCs may be involved in the pathogenesis of "brain fog," headaches, and autism spectrum disorders (ASDs), which worsen with stress. CRF and NT are significantly increased in serum of ASD children compared to normotypic controls further strengthening their role in the pathogenesis of autism. There are no clinically affective treatments for the core symptoms of ASDs, but pilot clinical trials using natural-antioxidant and anti-inflammatory molecules reported statistically significant benefit.

Fibromyalgia syndrome in need of effective treatments.

Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain, affecting primarily women. It is clinically characterized by chronic, nonarticular pain and a heightened response to pressure along with sleep disturbances, fatigue, bowel and bladder abnormalities, and cognitive dysfunction. The diagnostic criteria have changed repeatedly, and there is neither a definitive pathogenesis nor reliable diagnostic or prognostic biomarkers. Clinical and laboratory studies have provided evidence of altered central pain pathways. Recent evidence suggests the involvement of neuroinflammation with stress peptides triggering the release of neurosenzitizing mediators. The management of FMS requires a multidimensional approach including patient education, behavioral therapy, exercise, and pain management. Here we review recent data on the pathogenesis and propose new directions for research and treatment.

Brain "fog," inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin.

Brain "fog" is a constellation of symptoms that include reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory. Brain "fog" characterizes patients with autism spectrum disorders (ASDs), celiac disease, chronic fatigue syndrome, fibromyalgia, mastocytosis, and postural tachycardia syndrome (POTS), as well as "minimal cognitive impairment," an early clinical presentation of Alzheimer's disease (AD), and other neuropsychiatric disorders. Brain "fog" may be due to inflammatory molecules, including adipocytokines and histamine released from mast cells (MCs) further stimulating microglia activation, and causing focal brain inflammation. Recent reviews have described the potential use of natural flavonoids for the treatment of neuropsychiatric and neurodegenerative diseases. The flavone luteolin has numerous useful actions that include: anti-oxidant, anti-inflammatory, microglia inhibition, neuroprotection, and memory increase. A liposomal luteolin formulation in olive fruit extract improved attention in children with ASDs and brain "fog" in mastocytosis patients. Methylated luteolin analogs with increased activity and better bioavailability could be developed into effective treatments for neuropsychiatric disorders and brain "fog."

Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation.

PURPOSE: Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. METHODS: Articles were identified with a search of Medline (starting in 1980) by using the key words anxiety, attention-deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, and stress. FINDINGS: Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic-pituitary-adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. IMPLICATIONS: Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation, and flavonoids are discussed.

Genitourinary mast cells and survival.

Mast cells (MCs) are ubiquitous in the body, but they have historically been associated with allergies, and most recently with regulation of immunity and inflammation. However, it remains a puzzle why so many MCs are located in the diencephalon, which regulates emotions and in the genitourinary tract, including the bladder, prostate, penis, vagina and uterus that hardly ever get allergic reactions. A number of papers have reported that MCs have estrogen, gonadotropin and corticotropin-releasing hormone (CRH) receptors. Moreover, animal experiments have shown that diencephalic MCs increase in number during courting in doves. We had reported that allergic stimulation of nasal MCs leads to hypothalamic-pituitary adrenal (HPA) activation. Interestingly, anecdotal information indicates that female patients with mastocytosis or mast cell activation syndrome may have increased libido. Preliminary evidence also suggests that MCs may have olfactory receptors. MCs may, therefore, have been retained phylogenetically not only to "smell danger", but to promote survival and procreation.

Exploring relations between positive mood state and school-age children's risk taking.

OBJECTIVE: To examine whether children engage in greater risk taking when in a positive versus neutral mood state, and whether positive urgency trait relates to risk taking. METHODS: Positive mood in 7-10-year-old children was induced experimentally, and children's risk-taking intentions and actual behaviors were measured when the child was in a positive and neutral mood state. RESULTS: Within-person comparisons revealed that children showed greater risk-taking intentions and actual risk behaviors when in a positive mood state compared with a neutral one. Positive urgency was associated with greater risk taking when in a positive mood state, and this effect was stronger in the actual risk taking than intentions to risk take task. CONCLUSIONS: Mood state affects children's risk taking. Positive mood is associated with greater risk taking in elementary-school children, and those high in positive urgency are especially likely to show this effect. Implications for injury prevention are discussed.

Spectrum of mast cell activation disorders.

Mast cell (MC) activation disorders present with multiple symptoms including flushing, pruritus, hypotension, gastrointestinal complaints, irritability, headaches, concentration/memory loss and neuropsychiatric issues. These disorders are classified as: cutaneous and systemic mastocytosis with a c-kit mutation and clonal MC activation disorder, allergies, urticarias and inflammatory disorders and mast cell activation syndrome (MCAS), idiopathic urticaria and angioedema. MCs are activated by IgE, but also by cytokines, environmental, food, infectious, drug and stress triggers, leading to secretion of multiple mediators. The symptom profile and comorbidities associated with these disorders, such as chronic fatigue syndrome and fibromyalgia, are confusing. We propose the use of the term 'spectrum' and highlight the main symptoms, useful diagnostic tests and treatment approaches.

Combined climate- and prey-mediated range expansion of Humboldt squid (Dosidicus gigas), a large marine predator in the California Current System.

Climate-driven range shifts are ongoing in pelagic marine environments, and ecosystems must respond to combined effects of altered species distributions and environmental drivers. Hypoxic oxygen minimum zones (OMZs) in midwater environments are shoaling globally; this can affect distributions of species both geographically and vertically along with predator-prey dynamics. Humboldt (jumbo) squid (Dosidicus gigas) are highly migratory predators adapted to hypoxic conditions that may be deleterious to their competitors and predators. Consequently, OMZ shoaling may preferentially facilitate foraging opportunities for Humboldt squid. With two separate modeling approaches using unique, long-term data based on in situ observations of predator, prey, and environmental variables, our analyses suggest that Humboldt squid are indirectly affected by OMZ shoaling through effects on a primary food source, myctophid fishes. Our results suggest that this indirect linkage between hypoxia and foraging is an important driver of the ongoing range expansion of Humboldt squid in the northeastern Pacific Ocean.

Examining parents' behaviors and supervision of their children in the presence of an unfamiliar dog: does The Blue Dog intervention improve parent practices?

OBJECTIVES: Young children are at particular risk for dog bite injuries. This study examined parents' supervision of and reactions to their children in the vicinity of an unfamiliar dog. METHODS: A pre/post intervention/control group randomized design assessed whether exposure to The Blue Dog, a dog bite prevention and education program, positively impacted parent behaviors. RESULTS: No group differences in pre or post-intervention measures emerged, indicating that The Blue Dog did not evoke improvements in parents' behaviors. Generally, parents showed risky reactions and encouraged children to interact with the dog, even though they knew very little about the dog's safety or disposition. Supervision measures (proximity, watching) remained unchanged (watching) or more lax (proximity) across sessions. CONCLUSIONS: The results highlight the importance of targeting parent behavior, not just child behavior, in programs that aim to reduce risk of childhood dog bites. The Blue Dog did not effectively change parent behavior.