Cav1 Suppresses Tumor Growth and Metastasis in a Murine Model of Cutaneous SCC through Modulation of MAPK/AP-1 Activation

Caveolin-1 (Cav1) is a scaffolding protein that serves to regulate the activity of several signaling molecules. Its loss has been implicated in the pathogenesis of several types of cancer, but its role in the development and progression of cutaneous squamous cell carcinoma (cSCC) remains largely unexplored. Herein, we use the keratinocyte cell line PAM212, a murine model of cSCC, to determine the function of Cav1 in skin tumor biology. We first show that Cav1 overexpression decreases cell and tumor growth, whereas Cav1 knockdown increases these attributes in PAM212 cells. In addition, Cav1 knockdown increases the invasive ability and incidence of spontaneous lymph node metastasis. Finally, we demonstrate that Cav1 knockdown increases extracellular signaling–related kinase 1/2 mitogen-activated protein kinase/activator protein-1 pathway activation. We attribute the growth and invasive advantage conferred by Cav1 knockdown to increased expression of activator protein-1 transcriptional targets, including cyclin D1 and keratin 18, which show inverse expression in PAM212 based on the expression level of Cav1. In summary, we demonstrate that loss of Cav1 affects several characteristics associated with aggressive human skin tumors and that this protein may be an important modulator of tumor growth and invasion in cSCC

CAV1 inhibits metastatic potential in melanomas through suppression of the Integrin/Src/FAK signaling pathway.

Caveolin-1 (CAV1) is the main structural component of Caveolae which are plasma membrane invaginations that participate in vesicular trafficking and signal transduction events. Although, evidence has recently accumulated describing the function of CAV1 in several cancer types, its role in melanoma tumor formation and progression remains poorly explored. Here, by employing B16F10 melanoma cells as an experimental system, we directly explore the function of CAV1 in melanoma tumor growth and metastasis. We first show that CAV1 expression promotes proliferation while it suppresses migration and invasion of B16F10 cells in vitro. When orthotopically implanted in the skin of mice, B16F10 cells expressing CAV1 form tumors that are similar in size to their control counterpart. An experimental metastasis assay demonstrates that CAV1 expression suppresses the ability of B16F10 cells to form lung metastases in C57Bl/6 syngeneic mice. Additionally, CAV1 protein and mRNA levels are found to be significantly reduced in human metastatic melanoma cell lines and human tissue from metastatic lesions. Finally, we demonstrate that following integrin activation, B16F10 cells expressing CAV1 display reduced expression levels and activity of FAK and Src proteins. CAV1 expression also markedly reduces the expression levels of beta3 Integrin in B16F10 melanoma cells. In summary, our findings provide experimental evidence that CAV1 may function as an antimetastatic gene in malignant melanoma

A transcriptomic atlas of mammalian olfactory mucosae reveals an evolutionary influence on food odor detection in humans.

The mammalian olfactory system displays species-specific adaptations to different ecological niches. To investigate the evolutionary dynamics of olfactory sensory neuron (OSN) subtypes across mammalian evolution, we applied RNA sequencing of whole olfactory mucosa samples from mouse, rat, dog, marmoset, macaque, and human. We find that OSN subtypes, representative of all known mouse chemosensory receptor gene families, are present in all analyzed species. Further, we show that OSN subtypes expressing canonical olfactory receptors are distributed across a large dynamic range and that homologous subtypes can be either highly abundant across all species or species/order specific. Highly abundant mouse and human OSN subtypes detect odorants with similar sensory profiles and sense ecologically relevant odorants, such as mouse semiochemicals or human key food odorants. Together, our results allow for a better understanding of the evolution of mammalian olfaction in mammals and provide insights into the possible functions of highly abundant OSN subtypes

Identifying Treatments for Taste and Smell Disorders: Gaps and Opportunities.

The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the Identifying Treatments for Taste and Smell Disorders conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders

Carbohydrate Dose Influences Liver and Muscle Glycogen Oxidation and Performance during Prolonged Exercise

This study investigated the effect of carbohydrate (CHO) dose and composi-tion on fuel selection during exercise, specifically exogenous and endogenous(liver and muscle) CHO oxidation. Ten trained males cycled in a double-blindrandomized order on 5 occasions at 77%_VO2maxfor 2 h, followed by a30-min time-trial (TT) while ingesting either 60 g�h�1(LG) or 75 g�h�113C-glucose (HG), 90 g�h�1(LGF) or 112.5 g�h�113C-glucose-13C-fructose ([2:1]HGF) or placebo. CHO doses met or exceed reported intestinal transportersaturation for glucose and fructose. Indirect calorimetry and stable mass iso-tope [13C] tracer techniques were utilized to determine fuel use. TT perfor-mance was 93% “likely/probable” to be improved with LGF compared withthe other CHO doses. Exogenous CHO oxidation was higher for LGF andHGF compared with LG and HG (ES>1.34,P<0.01), with the relative con-tribution of LGF (24.5�5.3%)moderatelyhigher than HGF (20.6�6.2%,ES=0.68). Increasing CHO dose beyond intestinal saturation increased abso-lute (29.2�28.6 g�h�1,ES=1.28,P=0.06) and relative muscle glycogenutilization (9.2�6.9%, ES=1.68,P=0.014) for glucose-fructose ingestion.Absolute muscle glycogen oxidation between LG and HG was not significantlydifferent, but wasmoderatelyhigher for HG (ES=0.60). Liver glycogen oxida-tion was not significantly different between conditions, but absolute and rela-tive contributions weremoderatelyattenuated for LGF (19.3�9.4 g�h�1,6.8�3.1%) compared with HGF (30.5�17.7 g�h�1, 10.1�4.0%, ES=0.79& 0.98). Total fat oxidation was suppressed in HGF compared with all otherCHO conditions (ES>0.90,P=0.024–0.17). In conclusion, there was no lin-ear dose response for CHO ingestion, with 90 g�h�1of glucose-fructose beingoptimal in terms of TT performance and fuel selectio

Minimising fear and anxiety in working dogs:a review

The causes of fear and anxiety in working dogs are multifactorial and may include inherited characteristics that differ between individuals (e.g. Goddard and Beilharz, 1982; 1984a,b ), influences of the environment ( Lefebvre et al., 2007 ), and learned experiences during particular sensitive periods ( Appleby et al., 2002 ) and throughout life. Fear-related behavior compromises performance, leads to significant numbers of dogs failing to complete training (e.g., Murphy, 1995; Batt et al., 2008 ), early withdrawals from working roles ( Caron-Lormier et al., 2016 ), and can jeopardize dog and handler safety. Hence, amelioration of fear and anxiety is critical to maintain dogs in working roles and to ensure their well-being. Although current methods of selection and training are seemingly effective at producing many dogs which work in a remarkable array of environments, some dogs do not make the grade, and longevity of service is not always maximized. Programs should strive for optimal efficiency and they need to continually analyze the value of each component of their program, seek evidence for its value and explore potential evidence-based improvements. Here we discuss scientific evidence for methods and strategies which may be of value in reducing the risk of fear behaviors developing in the working dog population and suggest potentially valuable techniques and future research to explore the benefit of these approaches. The importance of environmental influences, learning opportunities, and effects of underlying temperament on the outward expression of fear and anxiety should not be underestimated. Identification of characteristics which predict resilience to stress are valuable, both to enable careful breeding for these traits and to develop predictive tests for puppies and procured animals. It is vitally important to rear animals in optimal environments and introduce them to a range of stimuli in a positive, controlled, and gradual way, as these can all help minimize the number of dogs which develop work-inhibiting fears. Future research should explore innovative methods to best measure the relative resilience of dogs to stressful events. This could include developing optimal exposure protocols to minimize the development of fear and anxiety, and exploring the influence of social learning and the most effective elements of stimulus presentation

Environmental Constraints on the Mechanics of Crawling and Burrowing Using Hydrostatic Skeletons

Mechanics, kinematics, and energetics of crawling and burrowing by limbless organisms using hydrostatic skeletons depend on the medium and mode in which the organism is moving. Whether the animal is moving over or through a solid has long been considered important enough to distinguish crawling and burrowing as different terms, and in fact the mechanics are very different. Crawlers use mechanisms to increase friction to generate thrust while reducing resistive friction. Burrowers in elastic muds extend their burrows by fracture, whereas sands are fluidized by burrowers much larger than grain sizes and smaller burrowers displace individual grains. Gravitational forces depend on how closely the density of the organism matches that of its fluid surroundings, therefore frictional forces depend on whether the organism is moving through air or water and fluidization on whether sands are saturated or unsaturated

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

New Insights into the Molecular and Cellular Functions of Caveolin-1 in Skin Cancer

As the main protein component of caveolae structures, Caveolin-1 has many functions, including an important role in the inhibition of cellular signal transduction events regulated through its scaffolding domain. Loss of Cav1 expression through mutation or misregulation has been implicated in the pathogenesis of several types of cancer, and Cav1 is a negative regulator of many malignant phenotypes, including proliferation, anchorage-independent growth, and invasion. Although previous studies suggest a role for Cav1 in cutaneous squamous cell carcinoma (cSCC) pathogenesis, little is known about the function of Cav1 in this malignancy. cSCC is the second most-commonly diagnosed malignancy among white populations, and its incidence is rising worldwide, making a better understanding of its pathogenesis essential for predicting disease outcome and developing better therapeutics. Herein, Cav1 is demonstrated to suppress benign tumorigenesis and inhibit epidermal proliferation both in primary keratinocytes in vitro and promoter-treated epidermis in vivo. In addition, Cav1 functions to suppress proliferation, invasion, and metastasis in a murine model of cSCC, attributed in part to its ability to inhibit signaling along the Ras/Erk/AP-1 pathway. Furthermore, decreased Cav1 expression correlates with increasing tumor grade in human tumors. This work provides evidence that Cav1 functions in both the promotion and progression stages of cSCC development, and is therefore a valid target for therapeutic intervention. In addition, the contribution of Cav1 to metastatic progression illustrates its potential value as a biomarker to predict aggressive tumor behavior. Although further work is needed to elucidate the mechanisms of Cav1 action in skin cancer, the research discussed herein makes it evident that Cav1 is a worthwhile avenue to pursue in cSCC research