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Rationale: Findings from animal studies and human PET imaging indicate that nicotine and cigarette smoking affect glutamate (Glu) and related neurochemical markers in the brain and imply that smoking reduces extracellular Glu. As Glu release is mediated by nicotinic acetylcholine receptors (nAChRs), which are present at high concentrations in the thalamus, we examined the effects of smoking on thalamic Glu. Objective: To determine the effects of tobacco smoking on thalamic glutamate levels. Methods: Thalamic Glu levels were measured in vivo in 18 smokers and 16 nonsmokers using proton magnetic resonance spectroscopic imaging (1H MRSI) at 1.5 T. Results: Mean Glu levels did not differ significantly between the subject groups. However, within smokers, Glu levels were negatively correlated with self-reports of both cigarettes/day over the last 30 days (r=-0.64, p=0.006) and pack-years of smoking (r=-0.66, p=0.005). Conclusions: Consistent with expectations based on preclinical studies, within smokers, cigarettes/day and pack-years are associated with reduced Glu in thalamus, a brain region rich in nAchRs. These results encourage work on candidate glutamatergic therapies for smoking cessation and suggest a noninvasive metric for their action in the brain. © 2014 Springer-Verlag.

Piezo1 mechanosensitive ion channel plays a important role in vascular physiology and disease. This study aimed to elucidate the altered signaling elicited by Piezo1 activation in the arteries of type 2 diabetes. Ten- to 12-week-old male C57BL/6 (control) and type 2 diabetic mice (db - /db - ) were used. The second-order mesenteric arteries (~ 150 μm) were used for isometric tension experiments. Western blot analysis and immunofluorescence staining were performed to observe protein expression. Piezo1 was significantly decreased in mesenteric arteries of type 2 diabetic mice compared to control mice, as analyzed by western blot and immunofluorescence staining. Piezo1 agonist, Yoda1, concentration-dependently induced relaxation of mesenteric arteries in both groups. Interestingly, the relaxation response was significantly greater in control mice than in db - /db - mice. The removal of endothelium reduced relaxation responses induced by Yoda1, which was greater in control mice than db - /db - mice. Furthermore, the relaxation response was reduced by pre-treatment with various types of K + channel blockers in endothelium-intact arteries in control mice. In endothelium-denuded arteries, pre-incubation with charybdotoxin, an Ca 2+ -activated K + channel (BK Ca channel) blocker, significantly attenuated Yoda1-induced relaxation in db - /db - mice, while there was no effect in control mice. Co-immunofluorescence staining showed co-localization of Piezo1 and BK Ca channel was more pronounced in db - /db - mice than in control mice. These results indicate that the vascular responses induced by Piezo1 activation are different in the mesenteric resistance arteries in type 2 diabetic mice., (© 2024. The Author(s).)

Background: Exposure to noxious particles, including cigarette smoke and fine particulate matter (PM 2.5 ), is a risk factor for chronic obstructive pulmonary disease (COPD) and promotes inflammation and cell death in the lungs. We investigated the combined effects of cigarette smoking and PM 2.5 exposure in patients with COPD, mice, and human bronchial epithelial cells., Methods: The relationship between PM 2.5 exposure and clinical parameters was investigated in patients with COPD based on smoking status. Alveolar destruction, inflammatory cell infiltration, and pro-inflammatory cytokines were monitored in the smoking-exposed emphysema mouse model. To investigate the mechanisms, cell viability and death and pyroptosis-related changes in BEAS-2B cells were assessed following the exposure to cigarette smoke extract (CSE) and PM 2.5 ., Results: High levels of ambient PM 2.5 were more strongly associated with high Saint George's respiratory questionnaire specific for COPD (SGRQ-C) scores in currently smoking patients with COPD. Combined exposure to cigarette smoke and PM 2.5 increased mean linear intercept and TUNEL-positive cells in lung tissue, which was associated with increased inflammatory cell infiltration and inflammatory cytokine release in mice. Exposure to a combination of CSE and PM 2.5 reduced cell viability and upregulated NLRP3, caspase-1, IL-1β, and IL-18 transcription in BEAS-2B cells. NLRP3 silencing with siRNA reduced pyroptosis and restored cell viability., Conclusions: PM 2.5 aggravates smoking-induced airway inflammation and cell death via pyroptosis. Clinically, PM 2.5 deteriorates quality of life and may worsen prognosis in currently smoking patients with COPD., (© 2024. The Author(s).)

Major depressive disorder (MDD) is a common mental illness worldwide and is triggered by an intricate interplay between environmental and genetic factors. Although there are several studies on common variants in MDD, studies on rare variants are relatively limited. In addition, few studies have examined the genetic contributions to neurostructural alterations in MDD using whole-exome sequencing (WES). We performed WES in 367 patients with MDD and 161 healthy controls (HCs) to detect germline and copy number variations in the Korean population. Gene-based rare variants were analyzed to investigate the association between the genes and individuals, followed by neuroimaging-genetic analysis to explore the neural mechanisms underlying the genetic impact in 234 patients with MDD and 135 HCs using diffusion tensor imaging data. We identified 40 MDD-related genes and observed 95 recurrent regions of copy number variations. We also discovered a novel gene, FRMPD3, carrying rare variants that influence MDD. In addition, the single nucleotide polymorphism rs771995197 in the MUC6 gene was significantly associated with the integrity of widespread white matter tracts. Moreover, we identified 918 rare exonic missense variants in genes associated with MDD susceptibility. We postulate that rare variants of FRMPD3 may contribute significantly to MDD, with a mild penetration effect., (© 2024. The Author(s).)

Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries. The left descending coronary arteries of 13-week-old male Sprague Dawley rats were cut into segments 2-3 mm long and mounted in a multi-wire myography system to measure isometric tension. Dapagliflozin effectively reduced blood vessel constriction induced by U-46619 (500 nM) in coronary arteries regardless of the endothelium. Treatment with an eNOS inhibitor (L-NNA, 100 μM), sGC inhibitor (ODQ, 5 μM), or COX inhibitor (indomethacin, 3 μM) did not affect the vasodilation induced by dapagliflozin. The application of a Ca 2+ -activated K + channel (K Ca ) blocker (TEA, 2 mM), voltage-dependent K + channel (K V ) blocker (4-AP, 2 mM), ATP-sensitive K + channel blocker (K ATP ) glibenclamide (3 μM), and inward-rectifier K + channel (K IR ) blocker (BaCl 2 , 30 μM) did not affect the dapagliflozin-induced vasodilation either. The treatment with dapagliflozin decreased contractile responses induced by the addition of Ca 2+ , which suggested that the extracellular Ca 2+ influx was inhibited by dapagliflozin. Treatment with dapagliflozin decreased the phosphorylation level of the 20 kDa myosin light chain (MLC 20 ) in vascular smooth muscle cells. In the present study, we found that dapagliflozin has a significant vasodilatory effect on rat coronary arteries. Our findings suggest a novel pharmacologic approach for the treatment of cardiovascular diseases in diabetic patients through the modulation of Ca 2+ homeostasis via dapagliflozin administration.

Ezetimibe is a lipid-lowering agent that selectively inhibits cholesterol absorption by binding to the Niemann-Pick C1-like 1 (NPC1L1) protein. Although it is well known that administration of ezetimibe in hypercholesterolemia patients reduces the risk of cardiovascular events through attenuation of atherosclerosis, studies on the direct effect of ezetimibe on vascular function are not sufficient. The aim of the present study was to investigate the vascular effects of ezetimibe in rat mesenteric arteries. In the present study, 12-week-old male Sprague Dawley rats were used. After the rats were sacrificed, the second branches of the mesenteric arteries were isolated and cut into 2-3 mm segments and mounted in a multi-wire myography system to measure isometric tension. Ezetimibe reduced vasoconstriction induced by U46619 (500 nM) in endothelium-intact and endothelium-denuded arteries. Ezetimibe-induced vasodilation was not affected by the endothelial nitric oxide synthase (eNOS) inhibitor N ω -Nitro-L-arginine (L-NNA, 300 μM) or the non-selective potassium channel blocker, tetraethylammonium (TEA, 10 mM). Moreover, ezetimibe also completely blocked the contraction induced by an increase in external calcium concentration. Ezetimibe significantly reduced vascular contraction induced by L-type Ca 2+ channel activator (Bay K 8644, 30 nM). Treatment with ezetimibe decreased the phosphorylation level of 20 kDa myosin light chain (MLC 20 ) in vascular smooth muscle cells. In the present study, we found that ezetimibe has a significant vasodilatory effect in rat mesenteric resistance arteries. These results suggest that ezetimibe may have beneficial cardiovascular effects beyond its cholesterol-lowering properties.

Owing to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, the development of effective and safe vaccines has become a priority. The measles virus (MeV) vaccine is an attractive vaccine platform as it has been administered to children for more than 40 years in over 100 countries. In this study, we developed a recombinant MeV expressing the full-length SARS-CoV-2 spike protein (rMeV-S) and tested its efficacy using mouse and hamster models. In hCD46Tg mice, two-dose rMeV-S vaccination induced higher Th1 secretion and humoral responses than one-dose vaccination. Interestingly, neutralizing antibodies induced by one-dose and two-dose rMeV-S immunization effectively blocked the entry of the α, β, γ, and δ variants of SARS-CoV-2. Furthermore, two-dose rMeV-S immunization provided complete protection against SARS-CoV-2 in the hamster model. These results suggest the potential of rMeV-S as a vaccine candidate for targeting SARS-CoV-2 and its variants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Molecular profiling of the hypothalamus in response to metabolic shifts is a critical cue to better understand the principle of the central control of whole-body energy metabolism. The transcriptional responses of the rodent hypothalamus to short-term calorie restriction have been documented. However, studies on the identification of hypothalamic secretory factors that potentially contribute to the control of appetite are lacking. In this study, we analyzed the differential expression of hypothalamic genes and compared the selected secretory factors from the fasted mice with those of fed control mice using bulk RNA-sequencing. We verified seven secretory genes that were significantly altered in the hypothalamus of fasted mice. In addition, we determined the response of secretory genes in cultured hypothalamic cells to treatment with ghrelin and leptin. The current study provides further insights into the neuronal response to food restriction at the molecular level and may be useful for understanding the hypothalamic control of appetite.

Vanillin is a phenolic aldehyde, which is found in plant species of the Vanilla genus. Although recent studies have suggested that vanillin has various beneficial properties, the effect of vanillin on blood vessels has not been studied well. In the present study, we investigated whether vanillin has vascular effects in rat mesenteric resistance arteries. To examine the vascular effect of vanillin, we measured the isometric tension of arteries using a multi-wire myograph system. After the arteries were pre-contracted with high K+ (70 mM) or phenylephrine (5 µM), vanillin was administered. Vanillin induced concentration-dependent vasodilation. Endothelial denudation or treatment of eNOS inhibitor (L-NNA, 300 μM) did not affect the vasodilation induced by vanillin. Treatment of K+ channel inhibitor (TEA, 10 mM) or sGC inhibitor (ODQ, 10 μM) or COX-2 inhibitor (indomethacin, 10 μM) did not affect the vanillin-induced vasodilation either. The treatment of vanillin decreased the contractile responses induced by Ca2+ addition. Furthermore, vanillin significantly reduced vascular contraction induced by BAY K 8644 (30 nM). Vanillin induced concentration-dependent vascular relaxation in rat mesenteric resistance arteries, which was endothelium-independent. Inhibition of extracellular Ca2+ influx was involved in vanillin-induced vasodilation. Treatment of vanillin reduced phopsho-MLC20 in vascular smooth muscle cells. These results suggest the possibility of vanillin as a potent vasodilatory molecule.

Background: Trachelospermi caulis ( T. caulis ) has been used as a traditional herbal medicine in Asian countries. Although it is well known that T. caulis has beneficial effects, no sufficient research data are available on the cardiovascular effect of T. caulis . We investigated whether T. caulis extract has vascular effects in rat resistance arteries in this study., Methods: To examine whether T. caulis extract affects vascular reactivity, we measured isometric tension of rat mesenteric resistance arteries using a multi-wire myograph system. T. caulis extract was administered after arteries were pre-contracted with high K + (70 mM) or phenylephrine (5 µM). Vanillin, a single active component of T. caulis , was used to treat mesenteric arteries., Results: T. caulis extract caused vascular relaxation in a concentration-dependent manner, which was endothelium-independent. To further identify the mechanism, we incubated the arteries in Ca 2+ -free solution containing high K + , followed by a cumulative administration of CaCl 2 (0.01-2.0 mM) with or without T. caulis extract (250 µg/mL). The treatment of T. caulis extract decreased contractile responses induced by the addition of Ca 2+ , which suggested that the extracellular Ca 2+ influx was inhibited by the T. caulis extract. Moreover, an active compound of T. caulis extract, vanillin, also induced vasodilation in mesenteric resistance arteries., Conclusion: T. caulis extract and its active compound, vanillin, concentration-dependently induced vascular relaxation in mesenteric resistance arteries. These results suggest that the administration of T. caulis extract could help decrease blood pressure.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is causing a global crisis. It is still unresolved. Although many therapies and vaccines are being studied, they are still in their infancy. As this pandemic continues, rapid and accurate research for the development of therapies and vaccines is needed. Therefore, it is necessary to understand characteristics of diseases caused by SARS-CoV-2 through animal models. Syrian hamsters are known to be susceptible to SARS-CoV-2. They were intranasally inoculated with SARS-CoV-2. At 2, 4, 8, 12, and 16 days post-infection (dpi), these hamsters were euthanized, and tissues were collected for ultrastructural and microstructural examinations. Microscopic lesions were prominent in the upper and lower respiratory tracts from 2 and 4 dpi groups, respectively. The respiratory epithelium in the trachea, bronchiole, and alveolar showed pathological changes. Inflammatory cells including neutrophils, lymphocytes, macrophages, and eosinophils were infiltrated in/around tracheal lamina propria, pulmonary vessels, alveoli, and bronchiole. In pulmonary lesions, alveolar wall was thickened with infiltrated inflammatory cells, mainly neutrophils and macrophages. In the trachea, epithelial damages started from 2 dpi and recovered from 8 dpi, consistent with microscopic results, High levels of SARS-CoV-2 nucleoprotein were detected at 2 dpi and 4 dpi. In the lung, lesions were most severe at 8 dpi. Meanwhile, high levels of SARS-CoV-2 were detected at 4 dpi. Electron microscopic examinations revealed cellular changes in the trachea epithelium and alveolar epithelium such as vacuolation, sparse micro-organelle, and poor cellular margin. In the trachea epithelium, the number of cytoplasmic organelles was diminished, and small vesicles were prominent from 2 dpi. Some of these electron-lucent vesicles were filled with virion particles. From 8 dpi, the trachea epithelium started to recover. Because of shrunken nucleus and swollen cytoplasm, the N/C ratio of type 2 pneumocyte decreased at 8 and 12 dpi. From 8 dpi, lamellar bodies on type 2 pneumocyte cytoplasm were increasingly observed. Their number then decreased from 16 dpi. However, there was no significant change in type 1 pneumocyte. Viral vesicles were only observed in the cytoplasm of type 2 pneumocyte. In conclusion, ultra- and micro-structural changes presented in this study may provide useful information for SARS-CoV-2 studies in various fields., (© 2021. The Author(s).)

Extracellular vesicles (EVs) are cell-released, nanometer-scaled, membrane-bound materials and contain diverse contents including proteins, small peptides, and nucleic acids. Once released, EVs can alter the microenvironment and regulate a myriad of cellular physiology components, including cell-cell communication, proliferation, differentiation, and immune responses against viral infection. Among the cargoes in the vesicles, small non-coding micro-RNAs (miRNAs) have received attention in that they can regulate the expression of a variety of human genes as well as external viral genes via binding to the complementary mRNAs. In this study, we tested the potential of EVs as therapeutic agents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. First, we found that the mesenchymal stem-cell-derived EVs (MSC-EVs) enabled the rescue of the cytopathic effect of SARS-CoV-2 virus and the suppression of proinflammatory responses in the infected cells by inhibiting the viral replication. We found that these anti-viral responses were mediated by 17 miRNAs matching the rarely mutated, conserved 3'-untranslated regions (UTR) of the viral genome. The top five miRNAs highly expressed in the MSC-EVs, miR-92a-3p, miR-26a-5p, miR-23a-3p, miR-103a-3p, and miR-181a-5p, were tested. They were bound to the complemented sequence which led to the recovery of the cytopathic effects. These findings suggest that the MSC-EVs are a potential candidate for multiple variants of anti-SARS-CoV-2.

We aimed to comprehensively understand the functional mechanisms of immunity, especially of the CD8 +/- subsets of gamma delta (γδ) T cells, using an RNA-sequencing analysis. Herein, γδ T cells were obtained from bronchial lymph node tissues of 38-day-old (after weaning 10-day: D10) and 56-day-old (after weaning 28-day: D28) weaned pigs and sorted into CD8 + and CD8 - groups. Differentially expressed genes (DEGs) were identified based on the CD8 groups at D10 and D28 time points. We confirmed 1699 DEGs between D10 CD8 + versus D10 CD8 - groups and 1784 DEGs between D28 CD8 + versus D28 CD8 - groups; 646 upregulated and 561 downregulated DEGs were common. The common upregulated DEGs were enriched in the cytokine-cytokine receptor interaction and T cell receptor (TCR) signaling pathway, and the common downregulated DEGs were enriched in the B cell receptor signaling pathway. Further, chemokine-related genes, interferon gamma, and CD40 ligand were involved in the cytokine-cytokine receptor interaction and TCR signaling pathway, which are associated with inter-regulation in immunity. We expect our results to form the basic data required for understanding the mechanisms of γδ T cells in pigs; however, further studies are required in order to reveal the dynamic changes in γδ T cells under pathogenic infections, such as those by viruses.

Since the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), various vaccines are being developed, with most vaccine candidates focusing on the viral spike protein. Here, we developed a previously unknown subunit vaccine comprising the receptor binding domain (RBD) of the spike protein fused with the tetanus toxoid epitope P2 (RBD-P2) and tested its efficacy in rodents and nonhuman primates (NHPs). We also investigated whether the SARS-CoV-2 nucleocapsid protein (N) could increase vaccine efficacy. Immunization with N and RBD-P2 (RBDP2/N) + alum increased T cell responses in mice and neutralizing antibody levels in rats compared with those obtained using RBD-P2 + alum. Furthermore, in NHPs, RBD-P2/N + alum induced slightly faster SARS-CoV-2 clearance than that induced by RBD-P2 + alum, albeit without statistical significance. Our study supports further development of RBD-P2 as a vaccine candidate against SARS-CoV-2. Also, it provides insights regarding the use of N in protein-based vaccines against SARS-CoV-2., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Vitamin D (VitD) has pleiotropic effects. VitD deficiency is closely involved with obesity and may contribute to the development of lung fibrosis and aggravation of airway hyperresponsiveness (AHR). We evaluated the causal relationship between VitD deficiency and the lung pathologies associated with obesity. In vivo effects of VitD supplementation were analyzed using high-fat diet (HFD)-induced obese mice and TGF-β1 (transforming growth factor-β1) triple transgenic mice. Effects of VitD supplementation were also evaluated in both BEAS-2B and primary lung cells from the transgenic mice. Obese mice had decreased 25-OH VitD and VitD receptor expressions with increases of insulin resistance, renin and angiotensin-2 system (RAS) activity, and leptin. In addition, lung pathologies such as a modest increase in macrophages, enhanced TGF-β1, IL-1β, and IL-6 expression, lung fibrosis, and AHR were found. VitD supplementation to HFD-induced obese mice recovered these findings. TGF-β1-overexpressing transgenic mice enhanced macrophages in BAL fluid, lung expression of RAS, epithelial-mesenchymal transition markers, AHR, and lung fibrosis. VitD supplementation also attenuated these findings in addition to the attenuation of the expressions of TGF-β1, and phosphorylated Smad-2/3 in lung. Supplementing in vitro -stimulated BEAS-2B and primary lung cells with VitD inhibited TGF-β1 expression, supporting the suppressive effect of VitD for TGF-β1 expression. These results suggest that obesity leads to VitD deficiency and worsens insulin resistance while enhancing the expression of leptin, RAS, TGF-β1, and proinflammatory cytokines. These changes may contribute to the development of lung fibrosis and AHR. VitD supplementation rescues these changes and may have therapeutic potential for asthma with obesity.

Background: Particulate matter 10 (PM10; airborne particles <10 μm) inhalation has been demonstrated to induce airway and lung diseases. In this study, we investigate the effects of PM10 inhalation on RNA expression in lung tissues using a murine model., Methods: Female BALB/c mice were affected with PM10, ovalbumin (OVA), or both OVA and PM10. PM10 was administered intranasally while OVA was both intraperitoneally injected and intranasally administered. Treatments occurred 4 times over a 2-week period. Two days after the final challenges, mice were sacrificed. Full RNA sequencing using lung homogenates was conducted., Results: While PM10 did not induce cell proliferation in bronchoalveolar fluid or lead to airway hyper-responsiveness, it did cause airway inflammation and lung fibrosis. Levels of interleukin 1β, tumor necrosis factor-α, and transforming growth factor-β in lung homogenates were significantly elevated in the PM10-treated group, compared to the control group. The PM10 group also showed increased RNA expression of Rn45a, Snord22, Atp6v0c-ps2, Snora28, Snord15b, Snora70, and Mmp12. Generally, genes associated with RNA splicing, DNA repair, the inflammatory response, the immune response, cell death, and apoptotic processes were highly expressed in the PM10-treated group. The OVA/PM10 treatment did not produce greater effects than OVA alone. However, the OVA/PM10-treated group did show increased RNA expression of Clca1, Snord22, Retnla, Prg2, Tff2, Atp6v0c-ps2, and Fcgbp when compared to the control groups. These genes are associated with RNA splicing, DNA repair, the inflammatory response, and the immune response., Conclusion: Inhalation of PM10 extensively altered RNA expression while also inducing cellular inflammation, fibrosis, and increased inflammatory cytokines in this murine mouse model.

Background: House dust mite (HDM) is a well-known cause of asthma. Allergen-specific immunotherapy (AIT) can only modify the natural course of the disease. Conventional routes of HDM AIT are subcutaneous or sublingual. Subcutaneous immunotherapy (SCIT) has a disadvantage of systemic hypersensitive reaction, and the sublingual immunotherapy has a disadvantage of local allergic reaction and low drug adherence., Objective: To overcome the weak points of conventional AIT, we developed a HDM loaded biodegradable microneedle patch (MNP) for transdermal immunotherapy (TDIT). We aim to demonstrate the efficacy of TDIT in murine asthma model triggered by HDM compared with conventional SCIT., Methods: To make HDM asthma mouse model, 5-week-old BALB/c female mice were sensitized and challenged by intranasal administration of HDM. The mice were divided into 5 groups: sham, asthma, low (10 µg) and high dose (100 µg) SCIT, and TDIT (10 µg). To make HDM loaded MNP, droplet-born air blowing method was used. Airway hyperresponsiveness and allergic inflammation markers were analysed by bronchoalveolar lavage fluid, immunohistochemistry, serum immunoglobulin (Ig) analysis, and lung cytokine assays., Results: Airway hyperresponsiveness was ameliorated by TDIT. Eosinophilic inflammation in bronchoalveolar lavage was improved without adverse reactions. Reduction of Th2 (IL-4, IL-5, and IL-13) cytokines, and HDM-specific IgE, induction of Treg (IL-10, TGF-β), Th1 (IFN-γ) cytokines were observed. Eosinophilic infiltration, goblet cell hyperplasia, and subepithelial fibrosis were also alleviated by TDIT. These changes were more significant in the TDIT group than in subcutaneous AIT group., Conclusion: In conclusion, HDM loaded biodegradable TDIT is a novel treatment option to treat asthma which showed more effectiveness and may have better safety profiles than conventional SCIT., (© 2020 John Wiley & Sons Ltd.)

CD93 has been shown critical roles in inflammatory and immune diseases. However, in allergic asthma, the potential roles of soluble CD93 (sCD93) have not been well studied. We conducted house dust mite (HDM) stimulation with Der p 1 in BEAS-2B and U937 cells, followed by treatment with dexamethasone or small interfering RNA against CD93. A HDM-induced murine allergic asthma model was also established. We estimated the power of sCD93 to predict allergic asthma in a retrospective post-hoc analysis containing 96 human samples. HDM-stimulated BEAS-2B cells showed increased mRNA expression levels of IL-6, IL-8, IL-33, TSLP, and CD93. The CD93 level in culture supernatants steadily increased for 24 h after allergen stimulation, which was significantly suppressed by both dexamethasone and CD93 silencing. CD93 silencing increased IL-6 and TSLP, but not IL-33 levels in culture supernatants. HDM-induced asthma mice showed significant airway hyperresponsiveness and inflammation with Th2 cytokine activation, along with decreased CD93 expression in bronchial epithelial cells and lung homogenates but increased serum CD93 levels. The sCD93 level in asthma patients was significantly higher than that in healthy controls and could predict asthma diagnosis with moderate sensitivity (71.4%) and specificity (82.4%) (AUC = 0.787, P < 0.001). The level of sCD93 which has potential role to predict asthma significantly increased after HDM stimulation via IL-6 and TSLP in vitro and in vivo.

Patients with asthma with obesity experience severe symptoms, are unresponsive to conventional asthma treatment, and lack proper pharmacotherapy. Empagliflozin and dulaglutide, developed for diabetes, reduce weight, decrease insulin resistance, and exert additive effects. We evaluated the efficacy of empagliflozin, dulaglutide, and their combination on obesity-induced airway hyperresponsiveness (AHR) and lung fibrosis using a murine model. We assigned C57BL/6J mice to five groups: control, high-fat diet (HFD), and HFD with empagliflozin, dulaglutide, or both. Mice received a 12-week HFD, empagliflozin (5 days/week, oral gavage), and dulaglutide (once weekly, intraperitoneally). Both drugs significantly attenuated HFD-induced weight increase, abnormal glucose metabolism, and abnormal serum levels of leptin and insulin, and co-treatment was more effective. Both drugs significantly alleviated HFD-induced AHR, increased macrophages in bronchoalveolar lavage fluid (BALF), and co-treatment was more effective on AHR. HFD-induced lung fibrosis was decreased by both drugs alone and combined. HFD induced interleukin (IL)-17, transforming growth factor (TGF)-β1, and IL-1β mRNA and protein expression, which was significantly reduced by empagliflozin, dulaglutide, and their combination. Tumour necrosis factor (TNF)-α and IL-6 showed similar patterns without significant differences. HFD-enhanced T helper (Th) 1 and Th17 cell differentiation was improved by both drugs. Empagliflozin and dulaglutide could be a promising therapy for obesity-induced asthma and showed additive effects in combination.

Prior studies have reported the presence of lung fibrosis and enhanced airway hyperresponsiveness (AHR) in mice with high-fat-diet (HFD)-induced obesity. This study evaluated the role of TGF-β1 in HFD-induced AHR and lung fibrosis in a murine model. We generated HFD-induced obesity mice and performed glucose and insulin tolerance tests. HFD mice with or without ovalbumin sensitization and challenge were also treated with an anti-TGF-β1 neutralizing antibody. AHR to methacholine, inflammatory cells in the bronchoalveolar lavage fluid (BALF), and histological features were evaluated. Insulin was intranasally administered to normal diet (ND) mice, and in vitro insulin stimulation of BEAS-2b cells was performed. HFD-induced obesity mice had increased insulin resistance, enhanced AHR, peribronchial and perivascular fibrosis, and increased numbers of macrophages in the BALF. However, they did not have meaningful eosinophilic or neutrophilic inflammation in the lungs compared with ND mice. The HFD enhanced TGF-β1 expression in the bronchial epithelium, but we found no differences in the expression of interleukin (IL)-4 or IL-5 in lung homogenates. Administration of the anti-TGF-β1 antibody attenuated HFD-induced AHR and lung fibrosis. It also attenuated goblet cell hyperplasia, but did not affect the AHR and inflammatory cell infiltration induced by OVA challenge. The intranasal administration of insulin enhanced TGF-β1 expression in the bronchial epithelium and lung fibrosis. Stimulating BEAS-2b cells with insulin also increased TGF-β1 production by 24 h. We concluded that HFD-induced obesity-associated insulin resistance enhances TGF-β1 expression in the bronchial epithelium, which may play an important role in the development of lung fibrosis and AHR in obesity.

This study was conducted to investigate the correlation between dietary taurine intake, nutrients intake, dietary attitudes, dietary behaviors, and life stress by depression in Korean female college students. Depression was measured by self-reported symptoms of depression on the CES-D (Center for Epidemiologic Studies Depression) scale. The subjects of this cross-sectional study included 56 female college students with depression (depression group, DG) and 122 female students without depression (control group, CG). Self-reported life stress score was determined using the life stress scale developed for Korean college students. Intakes of dietary taurine and nutrients were assessed using 3-day food records (2 weekdays and 1 weekend day) and evaluated using the computer aided nutrition program 4.0 version. Statistical analysis was performed using SPSS 24.0. We observed no significant difference in the average dietary taurine intake between DG (87.6 mg/day) and CG (92.3 mg/day). The average dietary intakes of vitamin A and calcium in DG were significantly lower as compared to CG (p < 0.05). The average total scores of dietary attitudes (p < 0.01) and dietary behaviors (p < 0.05) in DG were significantly lower as compared to CG. The average total life stress score (p < 0.001) and all stress categories were significantly higher in DG as compared to CG. No significant correlation was observed between the CES-D scale score and dietary taurine intake. However, there were significant negative correlations between the CES-D scale score and vitamin A, folic acid, vitamin C, and calcium intakes (p < 0.05), dietary attitudes, and dietary behaviors (p < 0.01). Scores of the CES-D scale and life stress showed a significantly positive correlation (p < 0.01). Therefore, continuous nutrition education and counseling for good dietary attitudes and behaviors are required. Future studies need to be undertaken to confirm the correlation between dietary taurine intake and depression by intervention with taurine.

Background: CD93 is a membrane-associated glycoprotein, which can be released in a soluble form (sCD93) into the serum. CD93 has received renewed attention as a candidate biomarker of inflammation in various inflammatory and immune-mediated diseases, including asthma., Objective: We aimed to evaluate the effects of airway inflammation on CD93 levels in murine models., Methods: We established an ovalbumin (OVA)-induced acute asthma murine model (OVA model) and a lipopolysaccharide (LPS)-induced airway inflammation murine model (LPS model). Dexamethasone was administered by gavage to attenuate the airway inflammation., Results: The OVA model demonstrated typical allergic asthma features with increased airway hyper-responsiveness, inflammatory cell infiltration, increased Th2 cytokine levels, compared to the control group. CD93 levels were decreased in lung homogenates and, respiratory epithelial cells, whereas serum sCD93 levels were increased in the OVA model, as compared to the control group. Dexamethasone reversed these effects of OVA. In contrast, in the LPS model, CD93 levels were not affected in neither respiratory epithelial cells nor serum., Conclusions: Our findings demonstrate the potential of using sCD93 as a biomarker for allergic asthma.

To overcome persistent disparities in oral health access and status, it is vital we adopt a paradigm shift from addressing symptoms to also addressing root causes. This article delineates why an equity lens and a collaborative systems change approach are essential elements., (©2017 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.)

Expansion microscopy (ExM), a method for improving the resolution of light microscopy by physically expanding a specimen, has not been applied to clinical tissue samples. Here we report a clinically optimized form of ExM that supports nanoscale imaging of human tissue specimens that have been fixed with formalin, embedded in paraffin, stained with hematoxylin and eosin, and/or fresh frozen. The method, which we call expansion pathology (ExPath), converts clinical samples into an ExM-compatible state, then applies an ExM protocol with protein anchoring and mechanical homogenization steps optimized for clinical samples. ExPath enables ∼70-nm-resolution imaging of diverse biomolecules in intact tissues using conventional diffraction-limited microscopes and standard antibody and fluorescent DNA in situ hybridization reagents. We use ExPath for optical diagnosis of kidney minimal-change disease, a process that previously required electron microscopy, and we demonstrate high-fidelity computational discrimination between early breast neoplastic lesions for which pathologists often disagree in classification. ExPath may enable the routine use of nanoscale imaging in pathology and clinical research.

In this paper, a photosensor-based latency measurement system for head-mounted displays (HMDs) is proposed. The motion-to-photon latency is the greatest reason for motion sickness and dizziness felt by users when wearing an HMD system. Therefore, a measurement system is required to accurately measure and analyze the latency to reduce these problems. The existing measurement system does not consider the actual physical movement in humans, and its accuracy is also very low. However, the proposed system considers the physical head movement and is highly accurate. Specifically, it consists of a head position model-based rotary platform, pixel luminance change detector, and signal analysis and calculation modules. Using these modules, the proposed system can exactly measure the latency, which is the time difference between the physical movement for a user and the luminance change of an output image. In the experiment using a commercial HMD, the latency was measured to be up to 47.05 ms. In addition, the measured latency increased up to 381.17 ms when increasing the rendering workload in the HMD.

The assessment of protein expression in immunohistochemistry (IHC) images provides important diagnostic, prognostic and predictive information for guiding cancer diagnosis and therapy. Manual scoring of IHC images represents a logistical challenge, as the process is labor intensive and time consuming. Since the last decade, computational methods have been developed to enable the application of quantitative methods for the analysis and interpretation of protein expression in IHC images. These methods have not yet replaced manual scoring for the assessment of IHC in the majority of diagnostic laboratories and in many large-scale research studies. An alternative approach is crowdsourcing the quantification of IHC images to an undefined crowd. The aim of this study is to quantify IHC images for labeling of ER status with two different crowdsourcing approaches, image-labeling and nuclei-labeling, and compare their performance with automated methods. Crowdsourcing- derived scores obtained greater concordance with the pathologist interpretations for both image-labeling and nuclei-labeling tasks (83% and 87%), as compared to the pathologist concordance achieved by the automated method (81%) on 5,338 TMA images from 1,853 breast cancer patients. This analysis shows that crowdsourcing the scoring of protein expression in IHC images is a promising new approach for large scale cancer molecular pathology studies.

Purpose: The purpose of this study was to examine the effects of a cognitive training program on neurocognitive task performance and activities of daily living (ADL) in patients who had a stroke., Methods: The research design for this study was a nonequivalent control group non-synchronized design. Patients were assigned to the experimental (n=21) or control group (n=21). The experimental group received a 4-week cognitive training program and usual care (i.e., rehabilitation service), while the control was received usual care only. Cognitive function was measured with a standardized neurocognitive test battery and ADL was assessed at baseline and one and two months after completion of the intervention. Repeated measures ANOVA was used to determine changes in cognitive function and ADL over 2 months., Results: The interaction of group and time was significant indicating that the experimental group showed improvement in attention, visuospatial function, verbal memory, and executive function compared to the control group which had a sustained or gradual decrease in test performance. A significant group by time interaction in instrumental ADL was also found between the experimental group with gradual improvement and the control group showing no noticeable change., Conclusion: Findings show that the cognitive training program developed in this study is beneficial in restoring cognitive function and improving ADL in patients following a stroke. Further study is needed to investigate the long-term relationship between cognitive training participation and cognitive improvement and effective functioning in daily living., Competing Interests: The author declared no conflict of interest., (© 2017 Korean Society of Nursing Science)

Sampling of formalin-fixed paraffin-embedded (FFPE) tissue blocks is a critical initial step in molecular pathology. Image-guided coring (IGC) is a new method for using digital pathology images to guide tissue block coring for molecular analyses. The goal of our study is to evaluate the use of IGC for both tissue-based and nucleic acid-based projects in molecular pathology. First, we used IGC to construct a tissue microarray (TMA); second, we used IGC for FFPE block sampling followed by RNA extraction; and third, we assessed the correlation between nuclear counts quantitated from the IGC images and RNA yields. We used IGC to construct a TMA containing 198 normal and breast cancer cores. Histopathologic analysis showed high accuracy for obtaining tumor and normal breast tissue. Next, we used IGC to obtain normal and tumor breast samples before RNA extraction. We selected a random subset of tumor and normal samples to perform computational image analysis to quantify nuclear density, and we built regression models to estimate RNA yields from nuclear count, age of the block, and core diameter. Number of nuclei and core diameter were the strongest predictors of RNA yields in both normal and tumor tissue. IGC is an effective method for sampling FFPE tissue blocks for TMA construction and nucleic acid extraction. We identify significant associations between quantitative nuclear counts obtained from IGC images and RNA yields, suggesting that the integration of computational image analysis with IGC may be an effective approach for tumor sampling in large-scale molecular studies.

Objectives: Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in carcinogenesis. Here, we investigated the role of morusin, the major prenylflavonoid, isolated from Chinese herbal medicine in abrogating the constitutive STAT3 activation in human pancreatic tumor cells., Methods: The effect of morusin on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was examined., Results: Morusin specifically inhibited constitutive STAT3 activation both at tyrosine residue 705 and serine residue 727 in 4 pancreatic tumor cells. The inhibition of STAT3 was mediated through the suppression of activation of upstream JAK1, JAK2, and c-Src kinases. Morusin led to the accumulation of the cells in different phases of the cell cycle and caused induction of apoptosis and loss of mitochondrial membrane potential. Morusin downregulated the expression of various STAT3-regulated gene products; this correlated with induction of caspase-3 activation and anti-invasive effects. Treatment with the protein tyrosine phosphatase inhibitor pervanadate reversed the morusin-induced downregulation of STAT3, thereby suggesting the involvement of a protein tyrosine phosphatase., Conclusions: Morusin is a novel blocker of STAT3 activation and thus may have potential in negative regulation of growth and metastasis of pancreatic tumor cells.

Brassinin (BSN), a type of indole compound derived from cruciferous vegetables, has shown anti-cancer effects in cells and animals. Capsaicin (CAP), an alkaloid derived from the chilli pepper, is also of interest in for its reported efficacy against various malignancies. The objective of our study was to analyze the potential synergistic anti-tumor effects of BSN combined with CAP on prostate cancer PC-3 cells. After treatment with BSN and CAP at various concentrations, the synergistic cytotoxic effect of PC-3 cells was analyzed by MTT method, proliferation, apoptosis, mitochondrial membrane potential, colony formation, and Western blotting. Moreover, the inhibitory effects of BSN and CAP on the constitutive expressions of MMP-9/2, their enzymatic activities, cellular migration, and cell invasion were also investigated. The cytotoxicity was synergistically increased in combination compared with the single drug used; moreover, proliferation, apoptosis, mitochondrial membrane potential, and colony formation were significantly suppressed and anti-apoptotic-, proliferative-, and metastatic-related proteins were clearly abolished in the combination group. Besides, constitutive MMP-9/2 expression, their enzymatic activities, cell migration, and tumor cell invasion were inhibited, and TIMP-1 was up-regulated in the combination group in PC-3 cells. Our results indicate, for the first time, that BSN and CAP in combination exert synergistic anticancer effects in prostate carcinoma., (Copyright © 2015 John Wiley & Sons, Ltd.)

Context: Metaplastic carcinomas arising in association with benign sclerosing lesions (BSLs) are rare malignancies in which a neoplastic spindle cell proliferation can be recognized extending beyond the boundaries of the complex sclerosing lesion or papilloma. However, in cases in which the metaplastic carcinoma is of the low-grade fibromatosis-like type or is a low-grade adenosquamous carcinoma, distinction from the background BSL can be a significant challenge. Cytokeratin (CK) and/or p63 immunostains are helpful in confirming the diagnosis of metaplastic carcinoma, but the expression patterns of these markers in the stromal cells of BSLs have not been well characterized., Objective: To characterize the expression patterns of CKs and p63 in BSLs., Design: We evaluated the spindle cell component of 55 BSLs using CK 5/6, CK 903, CK MNF116, and p63., Results: A total of 45 cases (81%) showed no staining for CKs or p63 in benign stromal cells. CK 5/6, CK 903, and p63 were positive in one case each. CK MNF116 stained spindle cells within 10 BSLs. No cases showed spindle cell reactivity for all 4 markers. Positive cases demonstrated very focal, weak staining of spindle cells; only 1 case showed focal, moderate CK staining. Spindle cell positivity was not associated with lesion type, growth pattern, spindle cell atypia, or mitoses., Conclusions: These findings suggest that although the presence or absence of expression of CK 5/6, CK 903, and p63 may be useful to distinguish BSL from metaplastic carcinomas arising in this setting, CK MNF116 positivity may be a diagnostic pitfall.

Background: Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis., Results: We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive rewiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, and estrogen receptor-positive and estrogen receptor-negative invasive breast cancer, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in invasive breast cancer mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas., Conclusions: Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially localized transcriptomic data. The analysis provides new biological insights into the rewiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer.

NFAT transcription factors are key regulators of gene expression in immune cells. In addition, NFAT1-induced genes play diverse roles in mediating the progression of various solid tumors. Here we show that NFAT1 induces the expression of the IL8 gene by binding to its promoter and leading to IL8 secretion. Thapsigargin stimulation of breast cancer cells induces IL8 expression in an NFAT-dependent manner. Moreover, we show that NFAT1-mediated IL8 production promotes the migration of primary human neutrophils in vitro and also promotes neutrophil infiltration in tumor xenografts. Furthermore, expression of active NFAT1 effectively suppresses the growth of nascent and established tumors by a non cell-autonomous mechanism. Evaluation of breast tumor tissue reveals that while the levels of NFAT1 are similar in tumor cells and normal breast epithelium, cells in the tumor stroma express higher levels of NFAT1 compared to normal stroma. Elevated levels of NFAT1 also correlate with increased neutrophil infiltrate in breast tumors. These data point to a mechanism by which NFAT1 orchestrates the communication between breast cancer cells and host neutrophils during breast cancer progression., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

The categorization of intraductal proliferative lesions of the breast based on routine light microscopic examination of histopathologic sections is in many cases challenging, even for experienced pathologists. The development of computational tools to aid pathologists in the characterization of these lesions would have great diagnostic and clinical value. As a first step to address this issue, we evaluated the ability of computational image analysis to accurately classify DCIS and UDH and to stratify nuclear grade within DCIS. Using 116 breast biopsies diagnosed as DCIS or UDH from the Massachusetts General Hospital (MGH), we developed a computational method to extract 392 features corresponding to the mean and standard deviation in nuclear size and shape, intensity, and texture across 8 color channels. We used L1-regularized logistic regression to build classification models to discriminate DCIS from UDH. The top-performing model contained 22 active features and achieved an AUC of 0.95 in cross-validation on the MGH data-set. We applied this model to an external validation set of 51 breast biopsies diagnosed as DCIS or UDH from the Beth Israel Deaconess Medical Center, and the model achieved an AUC of 0.86. The top-performing model contained active features from all color-spaces and from the three classes of features (morphology, intensity, and texture), suggesting the value of each for prediction. We built models to stratify grade within DCIS and obtained strong performance for stratifying low nuclear grade vs. high nuclear grade DCIS (AUC = 0.98 in cross-validation) with only moderate performance for discriminating low nuclear grade vs. intermediate nuclear grade and intermediate nuclear grade vs. high nuclear grade DCIS (AUC = 0.83 and 0.69, respectively). These data show that computational pathology models can robustly discriminate benign from malignant intraductal proliferative lesions of the breast and may aid pathologists in the diagnosis and classification of these lesions.

Ethnopharmacological Relevance: We isolated a single compound, 1-methoxyoctadecan-1-ol (MOD), from dried hooks and stems of Uncaria sinensis, which is used in traditional Korean medicine to provide relief from various nervous related symptoms., Materials and Methods: Neuroprotective effects of MOD against glutamate-induced oxidative stress in HT22 cells were investigated by analyzing cell viability, lactate dehydrogenase, flow cytometry, reactive oxygen species (ROS) and Western blot assays., Results: Exposure to glutamate alone resulted in remarkable hippocampal neuronal cell death; however, pretreatment with MOD resulted in suppression of neuronal death and ROS accumulation in connection with cellular Ca2+ level after exposure to glutamate. Stimulation by glutamate also caused significant protein level of phosphorylated p38 mitogen-activated protein kinases (MAPK), and dephosphorylated phosphatidylinositol-3 kinase (PI3K), however, pretreatment with MOD resulted in inhibition of these changes in protein level. Treatment with glutamate alone led to suppressed protein level of mature brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (CREB); however, pretreatment with MOD resulted in significant enhancement of this level of protein. Anti-oxidant N-acetyl-L-cysteine and both Ca2+ inhibitors, BAPTA and EGTA, showed effects similar to those of MOD in all proteins examined, except mature BDNF., Conclusions: Our results suggest that MOD mainly exerted neuroprotective effects in suppression of ROS accumulation and up-regulation of mature BDNF in association with p38 MAPK and PI3K signaling in hippocampal neuronal cells., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Chronic microglial activation endangers neuronal survival through the release of various toxic pro-inflammatory molecules; thus, negative regulators of microglial activation have been identified as potential therapeutic candidates for several neurological diseases. In this study, we investigated the inhibitory effects of an ethanol extract of Cnidium officinale rhizomes (EECO), which has been used as a herbal drug in Oriental medicine, on the production of lipopolysaccharide (LPS)-induced pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E₂ (PGE₂), as well as that of pro-inflammatory cytokines in BV2 microglia cells. EECO significantly inhibited the excess production of NO and PGE₂ in LPS-stimulated BV2 microglia cells. It also attenuated the expression of inducible NO synthase, cyclooxygenase-2, as well as that of pro-inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α. Moreover, EECO exhibited anti-inflammatory properties by suppressing nuclear factor-κB (NF-κB) translocation and the activation of the phosphoinositide 3-kinase/Akt pathway in LPS-stimulated BV2 cells. These results indicate that EECO exerts anti-inflammatory effects in LPS-stimulated BV2 microglial cells by inhibiting pro-inflammatory mediators and cytokine production by blocking the NF-κB pathway. These findings suggest that EECO has substantial therapeutic potential for the treatment of neurodegenerative diseases accompanied by microglial activation.

Purpose: Because impulsivity during adolescence predicts health-risk behaviors and associated harm, interventions that attenuate impulsivity may offer protection. We evaluated effects of the Youth Empowerment Seminar (YES!), a biopsychosocial workshop for adolescents that teaches skills of stress management, emotion regulation, conflict resolution, and attentional focus, on impulsive behavior., Methods: High school students (14-18 years of age) in the United States participated in YES! during their physical education classes. Students in a control group attended their usual curriculum and were tested in parallel. We used items from the Barratt Impulsiveness Scale (framed to reflect recent behavior) to assess students' behavior before and after they underwent the program., Results: Compared with the control group, YES! participants reported less impulsive behavior after the program., Conclusions: The results suggest that YES! can promote mental health in adolescents, potentially protecting them from harmful coping behaviors., (Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Thrombosis risk necessitates dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) receptor antagonist, in patients who have acute coronary syndrome. Current guidelines emphasize the critical role of dual antiplatelet therapy in both medical management and invasive strategy, especially in patients undergoing percutaneous coronary intervention. With the availability of multiple ADP-receptor antagonists, it is crucial to select the most appropriate agent for each patient., Areas Covered: The pertinent trials were identified through a MEDLINE search, in addition to a manual search from the articles retrieved. This review examines the differences between clopidogrel, prasugrel and ticagrelor in terms of their pharmacological/pharmacokinetic properties, clinical efficacy, drug interactions and safety parameters., Expert Opinion: Prasugrel and ticagrelor exhibit greater platelet inhibition and superior efficacy compared with clopidogrel, at the expense of higher bleeding risk. Prasugrel and ticagrelor should be preferred over clopidogrel in patients who are at a high risk of thrombotic events with low risk of bleeding. Additionally, these two agents may offer advantage over clopidogrel in those patients who might have risk for drug resistance due to CYP2C19 polymorphism. In selecting the ideal agent for patients, clinicians should tailor the antiplatelet regimen by considering individual risk factors and medication characteristics.

Objectives: Acetazolamide-challenged perfusion magnetic resonance imaging (MRI) has been shown as a method for assessment of cerebrovascular reserve (CVR) capacity in patients with atherosclerotic steno-occlusive disease of internal carotid artery. We have assessed the feasibility of the acetazolamide-challenged perfusion MRI for evaluating CVR in symptomatic patients with severe middle cerebral artery (MCA) stenosis (≥70%) by comparison with the acetazolamide-challenged technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single-photon emission computed tomography (SPECT)., Methods: Seventeen prospectively enrolled patients with symptomatic unilateral MCA stenosis underwent technetium-99m-hexamethylpropyleneamine oxime SPECT and perfusion MRI without and with acetazolamide challenge, respectively. Acetazolamide-challenged SPECT and perfusion MRI were compared quantitatively by Region of interest (ROI) analysis., Results: At all ROIs, there were no significant differences in percent change between SPECT and perfusion MRI. Patients with impaired CVR showed significant decreases in the percent changes of respective cerebral blood flow (P=.016) and respective cerebral blood volume (P=.029)., Conclusion: Acetazolamide-challenged perfusion MRI is feasible for evaluating CVR in symptomatic patients with severe MCA stenosis quantitatively., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer., Methods: We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI. The robustness and stability of activity/sleep circadian daily rhythms were measured by actigraphy. Fifty three of the patients in the study were starting their definitive therapy following diagnosis and thirty one patients were beginning second-line therapy. Among the patients who failed prior therapy, the median time between completing definitive therapy and baseline actigraphy was 4.3 months, (interquartile range 2.1 to 9.8 months)., Results: We found that circadian disruption is universal and severe among these patients compared to non-cancer-bearing individuals. We found that each of these patient's EORTC QLQ C30 domain scores revealed a compromised capacity to perform the routine activities of daily life. The severity of several, but not all, EORTC QLQ C30 symptom items correlate strongly with the degree of individual circadian disruption. In addition, the scores of all four Ferrans/Powers QLI domains correlate strongly with the degree of circadian disruption. Although Ferrans/Powers QLI domain scores show that cancer and its treatment spared these patients' emotional and psychological health, the QLI Health/Function domain score revealed high levels of patients' dissatisfaction with their health which is much worse when circadian disruption is severe. Circadian disruption selectively affects specific Quality of Life domains, such as the Ferrans/Powers Health/Function domain, and not others, such as EORTC QLQ C30 Physical Domain., Conclusions: These data suggest the testable possibility that behavioral, hormonal and/or light-based strategies to improve circadian organization may help patients suffering from advanced lung cancer to feel and function better.

The circadian clock exists in virtually every cell and regulates key biological processes in cells and tissues. Even in cancer cells, DNA synthesis, cell division and tumor growth are gated by the circadian clock. This study examined the gene expression profiles of transplanted mouse breast tumor cells under normal light-dark (LD) as well as constant dark (DD) conditions. It was found that the overall percentage of rhythmic transcripts in breast tumor tissue was lower than that in normal tissue. Few transcripts had unaltered rhythmic expression patterns under both LD and DD conditions. Most rhythmic transcripts in DD displayed 12h or shorter periods. These results suggest that in addition to the circadian clock control of gene transcription, altering light, feeding, physical activity and other factors characteristically affect the expression of many genes.

Aim of the Study: 1-O-methyl-fructofuranose (1-O-MFF) from the fruit of Schisandra chinensis is a traditional Korean medicinal herb that has a variety of beneficial properties. The effect of purified 1-O-MFF on melanogenesis including the activation of related signaling pathways was investigated., Materials and Methods: The inhibitory activities of 1-O-MFF were examined by melanin synthesis, tyrosinase activity assay, Western blot and flow cytometric analyses in B16F0 mouse melanoma cells., Results: 1-O-MFF significantly inhibited both melanin synthesis and tyrosinase activity in a concentration-dependent manner, and reduced the expression of melanogenic proteins including microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related protein-1. 1-O-MFF phosphorylated and activated melanogenesis inhibitory proteins such as mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and Akt. Flow cytometry confirmed that 1-O-MFF phosphorylated ERK and Akt proteins and recovered partially phosphorylated forms in cells treated with the MEK/ERK inhibitor compound PD98059 and the phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor compound LY294002., Conclusions: The suppressive effects of 1-O-MFF on melanogenesis may involve down-regulation of MITF and its downstream signal pathway via the activation of MEK/ERK or PI3K/Akt., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Human breast cancer incidence has seasonal patterns that seem to vary among global populations. The aggregate monthly frequency of breast cancer diagnosis was collected and examined for 2,921,714 breast cancer cases diagnosed across 64 global regions over spans from 2 to 53 years. Breast cancer is consistently diagnosed more often in spring and fall, both in the Northern and Southern Hemispheres, regardless of presumable menopausal status (50). This seasonality is increasingly more prominent as population distance from the equator increases and this latitude dependence is most pronounced among women living in rural areas. Moreover, the overall annual incidence (2005-2006), per 100,000 population, of breast cancer increased as the latitude of population residence increased. These data make it clear that human breast cancer discovery occurs non-randomly throughout each year with peaks near both equinoxes and valleys near both solstices. This stable global breast cancer seasonality has implications for better prevention, more accurate screening, earlier diagnosis, and more effective treatment. This complex latitude-dependent breast cancer seasonality is clearly related to predictable local day/night length changes which occur seasonally. Its mechanism may depend upon seasonal sunlight mediation of vitamin D and seasonal mediation of nocturnal melatonin peak level and duration.

Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. Experimental studies have shown that specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers. Experimental interference with circadian clock function increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integration. We must now determine whether strategies known to help synchronize the circadian clocks of normal individuals can do so in advanced cancer patients and whether doing so allows cancer patients to feel better and/or live longer. Several academic laboratories and at least 2 large pharmaceutical firms are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian organization, which in turn is likely to help prevent and control human cancer. These drugs and strategies can, in turn, be used to make cancer patients with advanced disease feel and function more normally.

Breast cancer relapse and death occur more often and sooner among young pre-menopausal women. Breast cancer resected during luteal phase cures about a quarter more women than if the operation is performed during follicular phase. We have identified candidate breast cancer gene signatures that may point to the potential mechanisms of cycle stage-dependent surgical cure. We performed whole murine genome microarrays on mammary tumors resected during pre-ovulatory (diestrus, follicular) and post-ovulatory (estrus, luteal) phases of the estrous cycle with known post-surgical cure or relapse (pulmonary metastasis) outcome. A set of genes whose expressions are differentially modulated by fertility cycle stage of tumor resection and also associate with prognosis were identified. These identified genes were validated by qRT-PCR. From two independent microarray studies, we identified 90 genes in mammary tumors whose expressions change significantly (up to 100-fold) across the estrous cycle, 69 genes that are associated with cure/relapse independent of cycle stage at resection, and 24 genes that change significantly (up to 12-fold) across the estrous cycle and also associate with the outcome. The mRNA expression patterns of these 24 identified genes were 100% validated by qRT-PCR in the same samples. We have identified candidate breast cancer genes and pathways that may point to the potential mechanisms by which the post-resection breast cancer outcome is influenced by the menstrual cycle phase of cancer resection. Since human breast cancer outcome is influenced by the menstrual cycle phase of breast cancer resection, we consider this study in a mouse breast cancer model to be a proof of principle that such signatures may well exist in human premenopausal breast cancer. It remains to be determined in human breast cancer whether woman to woman and/or tumor to tumor variability will mask cycle phase dependent and outcome predictive genomic signatures in human premenopausal breast cancer. The pathways identified by these studies are potential targets for the development of peri-surgical neoadjuvant therapies, which may delay or prevent relapse by preventing dormant micrometastatic tumor cells from escaping that dormant state post-operatively.

Cell cycle progression is tightly regulated. The expressions of cell cycle regulators, the products of which either promote or inhibit cell proliferation, oscillate during each cell cycle. Cellular proliferation and the expression of cell cycle regulators are also controlled by the circadian clock. Disruption of the circadian clock may thereby lead to deregulated cell proliferation. Mammalian Per2 is a core clock gene, the product of which suppresses cancer cell proliferation and tumor growth in vivo and in vitro. Because Per1, another key clock gene, is mutated in human breast cancers, and because its clock functions are similar and complementary to those of Per2, we have studied its role in modulating breast cancer cell proliferation and tumor growth. We find that breast cancer growth rate is gated by the circadian clock with two daily peaks and troughs, and that they are coupled to the daily expression patterns of clock-controlled genes that regulate cell proliferation. Down-regulation of the expression of tumor Per1 increases cancer cell growth in vitro and tumor growth in vivo by enhancing the circadian amplitude of the two daily tumor growth peaks. The data of the study suggest Per1 has tumor-suppressor function that diminishes cancer proliferation and tumor growth, but only at specific times of day.