The physiology of sleep-wakefulness melatonin receptor agonists may be affected as a result of changes in ovarian hormone synthesis. The menopause and the reduction in the availability of endogenous estradiol, that occur within the climacteric, have been considered risk factors for SD. The effect could be directly influenced by changes in the steroid profile, as a result of variations in body temperature by the presence of hot flashes, circadian rhythm disturbances or higher reactivity to stress [11–14].
There is controversy about whether severity criteria should be assessed in the presence of insomnia or in the functional impairment that this could entailed, which always should be considered due to they could affect the quality of life further than sleep disturbances [15]. The diagnostic method of SD is the polysomnography, considered the gold standard; however, it has some limitations due to it does not evaluate quality of sleep and the impact of SD on daily activities. In additionally, to carry out the procedure is necessary to have a quiet room, as close as possible to the home address, where the patient could sleep and another room where the necessary sleep equipment could be installed [16].
Sleep scales are tools to identify, in a subjective way, SD [9,17]. They offer advantages as easy application and interpretation and the availability to study different disorders [5,18]. These scales must have been validated in populations and checked in the age groups. Since the high prevalence of SD in climacteric is necessary to know the differences among scales that are available to study adequately these women, and to establish the deterioration of the quality of sleep or the presence of any different types of SD [18–21]. The aim is to identify and to describe the different scales that have been used to assess SD in climacteric.
Methods
Discussion
The SD are very important problems with many expressions, complex etiology with associated factors [6,39]. There are many scales that have been developed and validated in several areas of the health; they are available to analyze the sleep behavior and to establish subjectively the presence of SD. To study the general population in specific groups like elderly, children and adolescent patients with dementia and other diseases has been proposed.
The most widely used scales to study climacteric are Insomnia Severity Index (ISI), Athens Insomnia Scale (AIS) and Pittsburgh Quality of Sleep Index (PSQI), with validation in several countries and languages, which make them attractive to assess the prevalence and factors associated with SD. The first two of them allow setting aspects specifically related to insomnia, whose prevalence increases in postmenopausal women, increasing in 60% while in premenopausal women 40%. The four major causes proposed to explain the poor quality of sleep are: sleep disruption associated with hot flashes, increase of sleep apnea, mood disorder and inadequate sleep hygiene leading to chronic insomnia [40].
The PSQI was developed to provide a reliable, valid and standardized measure of quality of sleep, to discriminate between “good” and “poor” sleepers, to procure an easy index to use in patients, clinicians and researchers to understand and to provision a brief, clinical and useful assessment of a variety of sleep disturbances that might affect quality of sleep. It has been widely used in 
climacteric and it is a proper tool to be applied [5,9,28].
The Insomnia Severity Index, Athens Insomnia Scale, Pittsburgh Quality of sleep Index (PSQI) and Basic Nordic Sleep Questionnaire (BNSQ) have been used to check modifications in the prevalence of SD in women with hormonal therapy for the treatment of menopause symptoms, demonstrating its efficacy in these scenes [5,9,18,36].
The PSQI could be difficult to apply as a self-administered instrument in patients with low educational levels. The internal consistency determined by Cronbach\’s alpha was appropriated for the 19 items and 7 components. The scores of the items, the components and the total value remained stable during the time of Test-retest. The cutoff point of five has been used to define the population with poor quality of sleep [25].
The Post Keynesian theory of the banking firm originally
The Post Keynesian theory of the banking firm, originally developed by Oreiro (2004) and Silva and Oreiro (2007), advances in the analysis of the determinants of bank spread in Brazil as it demonstrates that “a permanent pilocarpine hydrochloride of banking spreads can be obtained through a policy of lower interest rates and/or through a change in social conventions regarding the “safe” or “normal” value of the interest rate” (Silva and Oreiro, 2007, p. 43).
Silva et al. (2007) make the macroeconomic aspects more relevant because they consider the history of macroeconomic instability of the Brazilian economy and its high levels of bank spreads in international terms. An extremely used variable to measure the stability of the Brazilian economy is the interest rate, which is believed to be largely responsible for the high levels of bank spread. Below this comparison is made, where it is found that, in fact, the trajectories of these two variables have similar behavior (see Graph 1).
Empirically, an important part of the papers on the determinants of bank spread in the Brazilian economy uses the two-stage method of Ho and Saunders (1981) to separate the macroeconomic determinants of the microeconomic. An example of a study using this methodology is developed by Afanasieff et al. (2002), which makes use of panel data to uncover the main determinants of bank spread in Brazil. In this paper, the authors take into account the variables that address the characteristics of banks, macroeconomic conditions, the deposit insurance regulation, overall financial structure and the legal and institutional indicators. The results show that “the pure spreads are sensitive to both, market structure and volatility effects, and also that the effects are quite heterogeneous across countries” (Afanasieff et al., 2002, p. 10). Note that despite the downward trend observed in the banking spread in Brazil, these rates remain extremely high when compared to international standards and that this difference cannot be explained by inflation, as shown in Chart 2.
The work developed by Nakane (2001) and Belaisch (2003) closely follow the microeconomic approach. Both sought, although using different methodologies to analyze the determinants of bank spread in Brazil. Their conclusions are similar: the market structure in the Brazilian banking sector is not in any of the two extremes, i.e., corresponds neither to a monopoly/cartel nor to a model of perfect competition. Thus, the structure turns out to be not perfectly delimited, being acknowledged as a structure of oligopoly, since studies show evidence of some market power in this industry. To Belaisch (2003), the Brazilian banking system has a non-competitive market structure, which may be the explanatory factor for the low rate of banking intermediation and for the relative inefficiency of the Brazilian banking sector. Belaisch\’s (2003) hypothesis is that a non-competitive market structure may justify high ra
tes of bank spread, discouraging deposit volumes and higher loans. The results show that Brazilian banks have oligopolistic behavior, given that the hypotheses of monopolistic behavior and a perfectly competitive demeanor in the banking system are rejected.
Nakane (2001) also conducts an empirical test that allows him to analyze the degree of competition in the Brazilian banking sector. The result found was that the market structure of this industry is highly competitive, although not perfectly competitive, but it is also not a monopoly or cartel as advocated by the general thought. The methodology used to identify and measure the degree of competition in an industry was an adaptation of the methodology developed by Bresnahan–Lau which seeks to test the significance of market power in banking intermediation in Brazil. The demand function for long-term bank loans is represented by the following expression:where L is the aggregate amount of bank loans in real terms, r is the interest rate of the loan market in real terms, Y is an indicator of economic activity, and α1, α2 and α3 are coefficients to be estimated. The interaction term between r and L rotates the demand curve for bank loans, which allows the identification of the parameter of market power.
Our findings have implications on the site
Our findings have implications on the site of origin of serous extra-uterine Müllerian carcinomas, which until recently were thought to originate primarily from metaplastic foci within the ovarian surface mesothelium (Dubeau, 1999, 2008). The fallopian tube is currently regarded as the most important site of origin of these tumors, the type associated with the BRCA1 mutation carrier state. We argued earlier that other extra-uterine Müllerian structures, including endosalpingiosis, endometriosis, and endocervicosis are also important in the histogenesis of the serous, endometrioid, and mucinous subtypes, respectively (Dubeau, 1999, 2008; Ahmed et al., 2010; Dubeau and Drapkin, 2013). All pelvic tumors seen in our mouse cohort appeared to have originated from endosalpingiosis, indicating that such extra-uterine structures are at risk of cancer development in mice carrying mutations mimicking those present in human with familial extra-uterine Müllerian carcinoma in support of our hypothesis.
In summary, we developed a mouse model that recapitulates the cell-autonomous and cell-nonautonomous mechanisms of cancer predisposition in human BRCA1 carriers. This model should facilitate elucidation of the menstrual factors associated with cell-nonautonomous mechanisms, which could represent attractive targets for cancer prevention strategies. Characterization of this model led to insights into the role of endosalpingiosis in the histogenesis of high grade serous extra-uterine Müllerian tumors, previously called ovarian, which should be considered in developing early detection and risk-reducing surgical strategies for these tumors. Our findings also shed light on the differentiation lineage of Müllerian clear cell carcinomas, which may facilitate the development of novel therapeutic approaches.
Funding Source Statement
Author\’s Contributions
Ying Liu developed the mouse model, made the Mis2r-Cre and Mis2r-Hsp68-LacZ constructs, maintained the mouse colonies, performed all autopsies, performed most of the experiments, and participated in the overall planning. Hai-Yun Yen performed the immunostains for purchase RG7112 and progesterone receptor proteins. Theresa Austria performed the studies on Her-2/neu expression. Jonas Pettersson performed studies on loss of heterozygosity. Janos Peti-Peterdi helped with the imaging studies of the kidney and helped in the redaction of the manuscript. Robert Maxson helped in the designing of the transgenic constructs and participated in the redaction of the manuscript. Martin Widschwendter helped in the analysis of the data and in the redaction of the manuscript. Louis Dubeau conceived and supervised the entire project and wrote the initial draft of the manuscript.
Acknowledgments
This work was aided by grants R01 CA119078 and R01 CA133117 from the US National Institutes of Health and by a gift from the Ovarian Cancer Coalition of Greater California to LD. Part of this work was funded by the Eve Appeal and undertaken at UCLH/UCL, which received a proportion of its funding from the Department of Health NIHR Biomedical Research Centers (BRC) funding scheme.
Introduction
Risk factors for breast cancer development include genetic predisposition and exposure to elevated sex steroid hormones. Germline mutations in BRCA1/2 account for elevated sex steroid hormones and 2%–10% of breast cancer cases depending on ethnic origin (Fackenthal and Olopade, 2007). Hormonal risk factors include early menarche, late menopause or first full pregnancy, weight gain, and combined hormone replacement therapy (HRT) (Veronesi et al., 2005). Evidence suggests a potential relationship between BRCA mutations, sex hormone levels, and end-organ effects to hormones, and cancer risk (Kim and Oktay, 2013; Segev et al., 2015; Titus et al., 2013; Widschwendter et al., 2013). High breast cancer risk in BRCA-mutation carriers is particularly evident premenopausally (relative risk 32 and 10 for 40–49-year-old BRCA1/2-mutation carriers, respectively) (Robson and Offit, 2007), whilst removal of both ovaries in premenopausal BRCA1/2-mutation carriers markedly reduces breast cancer risk (Domchek et al., 2010). Studies in BRCA1/p53-deficient mice indicate a direct role for progesterone (P) in mediating mammary tumourigenesis (Poole et al., 2006). Specific signalling pathways mediating interactions between BRCA-associated risk and sex steroid exposure have not been identified.
elastase Interestingly all three antihistamines emerging as
Interestingly, all three antihistamines emerging as putative anti-cancer drugs in our studies have extremely high apparent volumes of distribution (VD) ranging from 48 to over 100L/kg for astemizole (Tillement, 2000), loratadine (Tillement, 2000) and ebastine (Del Cuvillo et al., 2006) (Table 3). High VD values reflect the efficient distribution of drugs to tissues. Accordingly, the reported concentrations of astemizole in e.g. lungs, kidneys, liver and pancreas of Beagle dogs treated for six weeks with 1mg/kg astemizole are over 1000-fold higher than the corresponding plasma concentrations (Tillement, 2000, Michiels et al., 1986). Notably, astemizole and other CADs, which per definition are weak bases, are likely to accumulate in acidic tumors even more efficiently than in healthy tissues with neutral pH. Data for tissue distribution of loratadine and ebastine are unfortunately not available, but their higher VD values suggest even more efficient tissue distribution than observed for astemizole. On the other hand, the approximately 50-fold lower VD (Tillement, 2000) and less efficient tissue distribution of terfenadine (Leeson et al., 1982) may explain the discrepancy between its potent anti-cancer activity in vitro and lack of effect in the pharmacoepidemilogical study. Contrary to the other CADs studied here, clemastine use was associated with increased cancer mortality. Notably, clemastine is commonly used in prevention and treatment of hypersensitivity reactions associated with cancer therapy at Danish hospitals and its use increased over six-fold after cancer diagnosis in our patient cohort. Such a prescription bias towards high-risk patients may thus explain the poor prognosis associated with the use of clemastine. It should also be noted that clemastine has a relatively low VD value (Schran et al., 1996) (Table 3), and its ability to augment chemotherapy in parental and MDR cancer elastase in vitro is inferior to that of astemizole, loratadine and ebastine. Over-the-counter sale of loratadine (<35% of the total sale) and ebastine (<25%) could create another potential source of bias. Such exposure misclassification is, however, considered negligible.
Funding Sources
This work was supported by grants from the European Research Council (Advanced grant number 340751), the Danish N
ational Research Foundation (grant number DNRF125), the Danish Cancer Society (grant number R90-A5783), the Danish Medical Research Council (grant number DFF4004-00465), the Novo Nordisk Foundation (grant number NNF12OC0001341) and the Danish Cancer Research Foundation (project grant from 2011) to MJ.
Conflict of Interest Statement
Author Contributions
A.M.E. designed and performed most of the cell culture experiments, analyzed the data and contributed to the writing of the manuscript. C.D. designed and performed the analyses of all registry-based data. A.C.V. performed experiments presented in Fig. 3c and Fig. S2e. A.A. designed and performed the experiment presented in Fig. S1b. L.C. assisted in the design of the registry-based studies, N.H.T.P. and J.N. contributed to the design of cell culture experiments, J.S. designed the experiments and analyzed the data presented in Fig. 3c and Fig. S2e. A.M. and K.Ø. provided important insight into the clinical practice and possible confounding factors. S.F. designed the epidemiological analyses, analyzed the data and contributed to the writing the manuscript. M.J. designed the study, analyzed the biological data and wrote the first draft of the manuscript. All authors contributed to the final text and approved it.
Acknowledgements
Introduction
Almost one million new cases of gastric cancer were estimated to have occurred throughout the world in 2012 (952,000 cases, 6.8% of total new cancer cases), making RNA transcript the fifth most common malignancy after cancers of the lung, breast, colorectum and prostate (GLOBOCAN, 2012). Gastric cancer is the third leading cause of death from cancer among both sexes worldwide (723,000 deaths, 8.8% of total cancer deaths). Most patients with gastric cancer are diagnosed at an advanced stage, with an overall 5-year survival rate of approximately 28% (American Cancer Society. Cancer facts and figures, 2014). Early detection is the key to improving the survival of gastric cancer patients (Leung et al., 2008). Upper gastrointestinal endoscopy is a widely accepted procedure for early detection of gastric cancer. However, in many countries, endoscopists have limited opportunities to acquire the techniques, knowledge and experience which are imperative for the endoscopic detection of early gastric cancer (EGC) when only subtle mucosal morphology is apparent (Veitch et al., 2015). In contrast, endoscopists in Japan have more such opportunities thereby enabling them to detect subtle lesions that suggest EGC.
Fourth our findings could impact the most widely used
Fourth, our findings could impact the most widely used pharmacokinetic models of maturation as commonly recommended by regulatory authorities (European Medicines Agency, 2007). Several methods are used to examine the effect of maturation on pharmacokinetic parameters, with the two most common being allometric scaling based on the ¾ fractal geometry law and physiologically-based pharmacokinetic modeling (Hope et al., 2007). These methods use specific drug clearance rates derived in adults to estimate drug clearances in children, with ontogeny effects scaled based on dry tissue weight of the organ clearing the drug. The central assumption is that xenobiotic metabolism enzyme reaction rates are the same between adults and children, and that what varies is the quantity of the saha inhibitor Supplier proportional to organ weight and size. It is recognized in some cases, as for example sirolimus, that there could be different fetal isoform enzymes that get replaced by others after birth, thereby leading to altered clearance (Emoto et al., 2015); nevertheless the reaction kinetic constants of each of the different isoforms are assumed fixed. Moreover, the development of clearance with maturation is described by a single mathematical function. Our data suggests that non-linear functions and analyses, with no a priori assumptions, could be more accurate.
The following are the supplementary data related to this article.
Author Contributions
Conception and design: T. Gumbo, B.M., J. Pasipanodya, P. Jeena, W. Bishai.
Development of methodology: Z. Rogers, H. Hiruy, J. G. Pasipanodya, J. Adamson, P. Jeena, W. Bishai, T. Gumbo
Acquisition of data: Z. Rogers, H. Hiruy, C. Mbowane, J. Adamson, L. Ngotho, F. Karim, P. Jeena, W. Bishai
Analysis and interpretation of data: Z. Rogers, J. Pasipanodya, P. Jeena, W. Bishai, T. Gumbo
Writing, review and/or revision of the manuscript: Z. Rogers, H. Hiruy, J. Pasipanodya, P. Jeena, W. Bishai, T. Gumbo
Study supervision: P. Jeena, W. Bishai
Conflict of Interest
Acknowledgements
The support of the Howard Hughes Medical Institute and NIH grants AI37856, AI36973, 97138, R56AI111985 is gratefully acknowledged.
Introduction
Gaucher disease (GD), a common lysosomal storage disease (LSD), is caused by mutations in GBA1 with resultant defective glucocerebrosidase (GCase) function and the consequent accumulation of its substrate glucosylceramide (β-GlcCer) in macrophages and other cell types (Platt, 2014). There are three types of GD based on its neurological complications (type 1 is non-neuropathic, type 2 is acute neuropathic and type 3 is chronic neuropathic). Extra-neurologic systematic features include hepatosplenomegaly, pancytopenia, and osteoporosis as a consequence of Gaucher cell infiltration in target organs. GD has been regarded as wholly attributable to GBA1 mutations. However, clinical manifestations may have huge variations among patients carrying the same GBA1 mutations, ranging from very early disease onset to very mild clinical presentations (Biegstraaten et al., 2011; Elstein et al., 2010). It has therefore been speculated that additional disease modifiers exist in GD patients.
Progranulin (PGRN), also known as granulin epithelin precursor (GEP), is recognized for its roles in a variety of physiologic and disease processes, including immunomodulation (Jian et al., 2013a), cell growth, wound healing (He and Bateman, 2003), host defense (Park et al., 2011) and inflammation (Park et al., 2011; Tang et al., 2011; He et al., 2003). PGRN acts as an anti-inflammation molecule by direct binding to TNF receptors (Tang et al., 2011; Jian et al., 2013b). PGRN also functions as an important neurotrophic factor and mutations of the GRN gene (coding PGRN) are directly linked to frontotemporal dementia (Baker et al., 2006; Cruts et al., 2006), as well as considered contributory to other neurological diseases (Mateo et al., 2013; Perry et al., 2013). PGRN has been shown to play an important role in lysosomes, and homozygous mutation of the GRN gene results in neuronal ceroid lipofuscinosis (Smith et al., 2012; Gotzl et al., 2014). In this study we reported PGRN as a novel disease modifier in GD. In addition, recombinant PGRN is therapeutic against GD in various preclinical models.
Inulin Advax poly fructo furanosyl glucose is a plant derived
Inulin (Advax™, β–[2→1] poly(fructo-furanosyl) α–glucose) is a plant-derived carbohydrate. It has no immunological activity in soluble form; however, once it is formulated into delta inulin microparticles, its adjuvanting activity is widely acknowledged (). Inulin was applied to enhance vaccine efficacy against influenza, hepatitis B, West Nile virus, Japanese encephalitis, human immunodeficiency virus, SARS, and anthrax, amongst others. The carbohydrate was effective and safe in both experimental animals, as well as in humans. Yet, despite the large number of studies performed, its mechanism of action is still unclear. This prompted Ishii and coworkers to investigate the potential mode of action of inulin microparticles. At first, they investigated its adjuvanting capacity when administered together with cp-690550 already bearing danger signals. It has been reported that influenza split vaccine (SV) elicits Th2, while whole virion influenza vaccine (WV) triggers a Th1 response. When antigens were delivered with inulin, immune responses were significantly increased and the Th1/Th2 direction remained unchanged. And when inulin was delivered with “danger signal free” ovalbumin as an antigen, nothing happened. No antibody production against ovalbumin was detected. Moreover, inulin on its own was not able to stimulate dendritic cell (DC) maturation . Maturation of DCs is the crucial step before adaptive immunity can be activated. Just taking into account these observations, it might be assumed that inulin acts as a delivery system, possibly by preventive antigen degradation or through improved delivery to APCs, but without its own immune stimulating abilities.
Is inulin really just a delivery platform for vaccines, without adjuvanting properties? The answer is no. In contrast to testing, DC maturation experiments showed that inulin acted as an adjuvant and enhanced the expression of maturation markers on these cells. The reason for such unique behavior of inulin is yet to be determined. In addition, Ishii and coworkers demonstrated that DCs and phagocytic macrophages, as well as tumor necrosis factor (TNF)-α played a crucial role in the adjuvanting ability of inulin. It is of note that the ability of inulin to enhance adaptive immune responses when injected a day earlier than an antigen was reported previously (). Thus, inulin acts as an unusual adjuvant, as it did not force the direction of immune response (Th1 Th2), as typical adjuvants do. For example, commercially-approved alum is a well-known Th-2 pathway stimulator, while CpG-ODN triggers Th1 response ().
Primary biliary cholangitis, formerly designated primary biliary cirrhosis, represents a model cholestatic liver disease characterized by chronic, progressive immune-mediated bile duct destruction mainly affecting middle-aged women. Though its distinct pathogenesis remains to be fully defined, complex environmental-host immunogenic interactions have been highlighted by large-scale genome-wide association studies (GWAS) identifying a total of at least 27 disease-associated human leukocyte antigen (HLA) and non-HLA risk loci (). The diagnosis can be firmly assumed in the presence of at least two of three criteria including biochemical evidence of chronic cholestasis, presence of pathognomonic anti-mitochondrial antibodies (AMA, targeting the E2 and/or E3BP subunits of the pyruvate dehydrogenase complex) and/or supportive liver histology including florid bile duct lesions. The well-established standard of care consists of the oral hydrophilic bile acid (BA) ursodeoxycholic acid (UDCA), the hitherto only Food and Drug Administration (FDA)-approved agent for PBC treatment, with proven beneficial effects on disease progression as well as transplant-free survival and liver-related mortality. A convincing long-term response to UDCA identifies a low-risk subgroup without disease progression and survival rates comparable to the general population. By contrast, an estimated one in three PBC individuals reveals UDCA suboptimal or non-response as assessed by variable biochemical surrogate endpoints with a special emphasis on serum alkaline phosphatase (ALP) activity (e.g. or criteria), thus conferring high risk of continued disease progression despite treatment (“”). Novel prognostic tools, such as the score, predictive of transplant-free survival in a large cohort of 4119 UDCA-treated individuals, or the score have recently been reported (). The major drawback, however, remains the nature of determining UDCA response, traditionally after one year, although smaller studies reported adequate reflection of long-term prognosis assessing UDCA response as early as after six months (). Therefore, an unmet clinical need in PBC research lies in the identification of adequate biomarkers for high-risk disease at diagnosis and prediction criteria of UDCA response applicable early on or even before treatment (). The reliable identification of non-responders represents an opportunity to actively alter future disease trajectories and may be of key importance in prioritizing patients for novel and/or re-purposed second-line treatments. The changing and vital landscape of second-line options in PBC treatment is underscored by the recent conditional FDA licensing of obeticholic acid (OCA) as the first-in-class farnesoid X receptor (FXR) agonist, regulating BA synthesis and transport, after phase III randomized data () demonstrated biochemical improvement in approximately 40% of UDCA non-responders ().
When first launched in late the world watched
When first launched in late 2014, the world watched in horror as an Ebola virus outbreak claimed the lives of thousands of West Africans. The outbreak spurred a massive response by researchers around the world to develop effective therapeutics and a protective vaccine. As we embark upon our third full year here at the journal, we can now indeed celebrate the success of an Ebola vaccine which appears to be completely protective in humans. In a trial published in December 2016 in , this recombinant respiratory syncytial virus (rRSV)-based vaccine was administered to more than 5800 people in Guinea, all of whom were protected from disease. We praise the large-scale collaborative effort of both clinical and basic science researchers which has brought us closer to preventing further Ebola outbreaks. Moving forward in 2017, we hope a similar mobilization of efforts will lead us towards better diagnostic and therapeutic options for patients affected by Zika virus. Although quite different from Ebola virus in its clinical presentation, this emergent and wide-spread public health threat will require the same degree of scientific collaboration across basic and clinical disciplines.
Chronic lymphocytic leukemia (CLL) is an incurable common B-cell malignancy with a spectrum of clinical outcomes. Over the past decade, our increasing understanding of the drivers of CLL progression has led to the development and use of novel therapeutics. For example, B-cell receptor (BCR) signaling was shown to be overactive in CLL, and subsequently the kinase inhibitors ibrutinib (BTK inhibitor) and idelalisib (PI3K delta inhibitor) were found to have clinical efficacy in this malignancy (). Despite these new treatments, CLL remains incurable and there remains a need to identify new therapeutic targets.
The therapeutic target of interest for in their article is lipid metabolism. It has been appreciated for many years that lipids have importance in CLL progression and outcomes. Most notably, lipoprotein lipase is a well-known (although not routinely measured clinically) prognostic factor in CLL, with higher levels associated with inferior clinical outcomes. LPL is not expressed in normal lymphocytes, but its TG101348 is increased in CLL cells, particularly in the IGHV unmutated subset (). LPL catalyzes hydrolysis of VLDL and chylomicrons, releasing fatty acids. LPL also has non-catalytic functions, for example co-localizing with lipoproteins at the cell surface. In CLL cells, the exact function of LPL and the reason for its overexpression compared to normal B-cells is not fully understood. However, recent work has demonstrated that inhibition of LPL with orlistat induces CLL apoptosis, and that LPL expression is increased by BCR cross-linking, by binding of STAT3 to the LPL promoter, and by certain CLL stimulants that induce demethylation of the LPL gene (). Together, this previous work has suggested that free fatty acids, liberated by LPL, may be a protective factor for CLL lymphocytes.
Within this context, provide a compelling argument for the role of lipids in inducing second messenger signaling in CLL. The authors were intrigued by a recent case-control study in Canada that demonstrated that CLL patients have more dyslipidemia than age-matched controls, and that CLL patients who took HMG-CoA reductase inhibitors (“statins”) had improved survival compared to CLL patients who did not take these medications, which confirmed similar results in smaller CLL cohorts (). Together with the story regarding lipoprotein lipase, these clinical data beg the question of if and how LDLs affect CLL cells.
In their paper, focus on LDL potentiation of cytokine-induced STAT3 phosphorylation. The authors demonstrate that LDLs are able to increase STAT3 phosphorylation within the context of cytokine stimulation, not BCR cross-linking. The induced STAT3 phosphorylation was suppressed by anti-IL10 antibodies and by small molecule JAK inhibition, suggesting overlapping pathways with IL10 and JAK mediated signaling. The authors evaluated which of the different components of LDL contributed to the effect on STAT3 phosphorylation, and they found that long-chain fatty acids and free cholesterol were the main actors. Lastly, the authors found a negative correlation between the extent of LDL-potentiated STAT3 phosphorylation and HMGCoA reductase expression. Since HMGCoA reductase is the rate limiting step in cholesterol synthesis, this suggests that the subset of CLL cells with lower intracellular cholesterol synthesis are affected more by LDL incubation, and that this mechanism may be important for disease progression amongst these patients.
Despite viral etiologies driving most cases of acute
Despite viral etiologies driving most cases of acute respiratory infection, definitive diagnostic tools for these syndromes are lacking. Even highly sensitive pathogen-specific tests such as PCR are dependent upon proper sampling technique and inclusion of virus-type-specific reagents and processing methods. Moreover, detection of a specific microbe in a clinical sample does not necessarily indicate the cause of the acute clinical syndrome. For example, it has been reported that HRV has been detected in up to 44% of asymptomatic individuals (Byington et al., 2015; Johnston et al., 1993). Therefore, better tools that help providers define the etiology of a susp
ected infectious syndrome in a safe, rapid, accurate, and cost-effective manner are of paramount importance for both individual and public health as recently noted by the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (House, 2014), and others (O\’Neill, 2015; Organization, 2015). A complementary diagnostic strategy to pathogen detection could focus on utilizing the varied (but pathogen-class specific) host-response to infection (Ramilo and Mejias, 2009; Zaas et al., 2014). This approach discriminates between infection and colonization. It is pathogen-agnostic and therefore circumvents another limitation of pathogen detection assays, which due to technical limitations are only capable of detecting a 
limited subset of microorganisms. Furthermore, categorizing infection based on host response provides additional insights into the mechanisms of infection and disease response, and may offer new targets, pathways, or strategies for therapeutic intervention.
We recently identified gene Cyt 387 manufacturer patterns in peripheral whole blood capable of differentiating (Zaas et al., 2009; Woods et al., 2013; McClain et al., 2016; Tsalik et al., 2016; Huang et al., 2011) individuals with symptomatic infection due to influenza H3N2, HRV, or RSV from uninfected individuals with >90% accuracy. Moreover, this ARV signature was validated in an independent population of patients with influenza A infection, demonstrating an ability to distinguish from bacterial respiratory infections (93% accuracy) and healthy controls (100% accuracy) (Zaas et al., 2009). Thus, host derived biomarkers are capable of making these types of distinction. However, considering the technical challenges inherent in developing peripheral blood host gene expression classifiers as a diagnostic tool – including semi-invasive venipuncture, RNA instability, processing complexity, relatively high cost of RNA profiling, and time to result – we sought to extend this host response paradigm for ARV diagnosis to an alternative and potentially more suitable sample matrix and analyte class.
Upon contact with the respiratory epithelium, respiratory viruses incite activation of type I interferons (IFNs) and pro-inflammatory cytokines, orchestrate proliferation of inflammatory cells and the innate immune response, and regulate induction of adaptive immunity (Yoneyama and Fujita, 2010; Koyama et al., 2008; Bhoj et al., 2008). Based on the prominent role of the nasopharyngeal epithelium in mediating ARV infections, we hypothesized that nasopharyngeal lavage (NPL) would reflect the in situ host response and serve as a potential target for diagnostic development. Furthermore, the NPL protein fraction represents an accessible sample matrix, providing a highly tractable diagnostic analyte class. Multiple reaction monitoring (MRM), a quantitative mass spectrometry (MS) platform for facile development of multiplexed, quantitative assays for measuring specific protein levels in biologic fluids and is routinely used for biomarker verification in clinical cohorts (Kiyonami et al., 2011; Gerszten et al., 2010; Boja and Rodriguez, 2011). In addition to being customizable for nearly any target protein, MRM assays provide a more specific quantitation of individual proteins and protein isoforms by targeting multiple unique peptides per protein target. Combined with internal stable-isotope labeled (SIL) peptide standards, these assays match or exceed the quantitative precision of ELISA assays with low femtomole limits of quantitation and analytical precision coefficient of variation<10% across clinically sized cohorts (Addona et al., 2009; Aebersold et al., 2013).
Calcium Ionophore I A special subpopulation of cancer
A special subpopulation of cancer cells, known as cancer stem Calcium Ionophore I (CSCs), drive cancer progression. CSCs self-renew, uncontrollably proliferate, differentiate, and form the bulk of the tumor (Majumdar et al., 2012; Chandler and Lagasse, 2010). CSCs also regulate the development, progression, and metastasis of cancer (da Silva-Diz et al., 2016, S
ampetrean and Saya, 2013, Nguyen et al., 2012). Multiple studies reported evidence of CSCs in CRC (Patman, 2016; Zeuner et al., 2014). Epithelial cell adhesion molecule (Ep-CAM), also known as epithelial-specific antigen (ESA) or CD326, is a transmembrane glycoprotein cell adhesion molecule that is encoded by the Ep-CAM gene mapped to chromosomal region 4q (Balzar et al., 1999; Linnenbach et al., 1989). This cell adhesion molecule plays a key role in Ca-independent cell-to-cell adhesion (Litvinov et al., 1994). Ep-CAM correlates with cell proliferation, migration, invasion, motility, and signal transduction (Subramanian et al., 2015; Maetzel et al., 2009). Studies suggest that Ep-CAM is associated with epithelial-to-mesenchymal transition (EMT) and enhances tumor-initiating capacity (Gupta et al., 2009; Morel et al., 2008). Ep-CAM is overexpressed in many types of cancers, such as breast cancer, ovarian cancer, and head and neck squamous cell cancer (Moldenhauer et al., 2012). Some studies demonstrated that Ep-CAM overexpression was an unfavorable prognostic marker in breast cancer and gallbladder carcinoma (Varga et al., 2004; Gastl et al., 2000). Ep-CAM is a CSC marker, and it is frequently expressed or overexpressed in CRC (Dalerba et al., 2007; Mosolits et al., 2004). Ep-CAM is defined as a universal molecular marker for circulating tumor cell (CTC) detection, which is termed the “post-Ep-CAM era” (Nicolazzo et al., 2015; Raimondi et al., 2015). Therefore, it is important to investigate Ep-CAM further.
Some studies demonstrated inconsistent and controversial conclusions of Ep-CAM expression in CRC patients. For example, Kuhn et al. reported that Ep-CAM expression was not associated with tumor stage or grade (Kuhn et al., 2007). Gosens et al. reported that the loss of Ep-CAM expression was significantly associated with tumor grade and trended towards a correlation with tumor stage (Gosens et al., 2007). Therefore, the present study assessed whether Ep-CAM expression correlated with an increased risk of CRC vs. benign colonic lesions and normal controls. We also analyzed whether Ep-CAM overexpression or the loss of Ep-CAM expression was associated with the prognostic effect and clinicopathological features of CRC. Finally, we evaluated the use of Ep-CAM expression as a biomarker for the early diagnosis of CRC.
Materials and Methods
Results
Discussion
Cancer stem cells (CSCs) are a special subpopulation of cells within a tumor. Ep-CAM overexpression is a CSC marker of tumor cells that closely correlates with tumor progression, including colorectal cancer cell lines (Liao et al., 2015). Ep-CAM overexpression is a poor prognostic factor in some cancers, such as breast and gallbladder carcinomas (Schmidt et al., 2010; Varga et al., 2004), but its overexpression is a favorable prognostic factor in ovarian cancer (Battista et al., 2014). The present study found that Ep-CAM was commonly expressed in CRC, and its expression was significantly higher in CRC than in normal controls (Chai et al., 2015; Zhou et al., 2015; Paret et al., 2007; Kuhn et al., 2007; Karanikiotis et al., 2005). Ep-CAM was slightly less frequently expressed in CRC than in benign lesions (Kuhn et al., 2007), but its expression level was notably higher in CRC than in benign lesions (Zhou et al., 2015). The current results revealed that the frequency of Ep-CAM expression was significantly more common in CRC compared with normal controls, which suggests that Ep-CAM expression is associated with the carcinogenesis of CRC. Ep-CAM expression stimulates cell differentiation and cell proliferation via up-regulation of the proto-oncogene c-myc, which causes carcinogenic effects (Munz et al., 2004). However, no correlation in Ep-CAM expression was found between CRC and benign colonic lesions because the sample size was small. No association between Ep-CAM expression and DNA mismatch repair protein expression was reported in 218 microsatellite instability (MSI-high) CRCs (Kim et al., 2016).
br Experimental design materials and methods br Acknowledgments This work
Experimental design, materials and methods
Acknowledgments
This work was supported by the project “Seeding production of eel Anguilla japonica by artificial induction of sexual maturation” (R2016011) of the NIFS, Korea, and the Export Strategical Item of KIMST, Korea.
Data
The dataset presents a comprehensive inventory of the medicinal plants used by a Tashelhit-speaking sorafenib tosylate in the N’Fiss valley, including linguistic, ecological and ethnomedicinal data (High Atlas, Marrakech; Supplementary Table S1). Details for the herbarium specimens collected during the study and a comprehensive glossary of the Tashelhit vocabulary used are also provided (Supplementary Table S2 and Table 1).
Experimental design, materials and methods
Fieldwork was conducted in the rural community of Imegdale, High Atlas, Morocco, between March and June 2015, as detailed in [1]. Ethical guidelines of the American Anthropological Association (2012), the Code of Ethics of the International Society of Ethnobiology (2006) and University of Reading ethical protocols were followed. Approval from the Ethics Committee of the School of Biological Sciences, University of Reading, was obtained (Research Ethics Project Submission SBS 14-15 05). In Supplementary Table S1, quantitative data and relevant ethnobotanical indices are also presented for each plant, including the number of Use Reports (UR), the highest Fidelity Level [5] and Use Value [6,7].
Acknowledgements
This work has received funding from the European Union׳s Seventh Framework Programme for Research, Technological Development And Demonstration under the Grant agreement no. 606895. We would like to acknowledge in kind support provided by the Darwin Initiative (Project number 20-013: Medicinal root trade, plant conservation and local livelihoods in Morocco).
Data
In this article are presented the data analyses (figures) from leaf count and rosette diameter for three lines AtFTOE (2.1, 3.1 an 4.3) compared with WT Arabidopsis plants (Fig. 2A and B respectively). Data corresponding to differential expression (log2 fold change) from AtFTOE 2.1 line vs WT Arabidopsis are visualized by Mapman (Fig. 3). Some data corresponding to down-regulated genes are presented in Table 3.
Experimental design, materials and methods
Acknowledgments
This work was supported by Departmental funds from CINVESTAV-IPN, by CONACyT grants nos. 156162 to RR-M and 105985 to BX-C, and a SENASICA-SAGARPA grant to BX-C and RR-M. LD-B was supported by a doctoral fellowship from CONACyT no 388937. This research was partially supported by the Intramural Research Program of the NIH, NLM, NCBI.
Specifications Table
Value of the data
Data
Supplementary material S1reports the UV absorption spectra in the range 252–360nm of 8 standard phenolic compounds – belonging to different chemical classes: benzoic acid derivatives (hydroxybenzoic acid, protocathecuic acid, vanillic acid), cinnamic acid derivatives (p-coumaric acid, caffeic acid), phenyl-ethyl alcohols (tyrosol), flavonoids (apigenin), lignans (pinoresinol) – after solubilization in the DES based on lactic acid and glucose.
Supplementary material S2 reports the phenolic compounds content, expressed in mg gallic acid/kg oil, of the 65 EVOO samples.
Supplementary material S3 and Fig. 1 report the UV absorption spectra in the range 252–360nm of the DES extracts of the 65 EVOO samples. Mean spectra of the two independent extractions after sample weight normalization are reported.
Experimental design, materials and methods
Data
In order to obtain the most representative dataset as well as to eliminate any regional effect on the milk of two pure Greek goat breeds (Capra prisca and Skopelos), animals from flocks across Greece were analyzed. The geographical distribution of animal flocks used for milk sample collection is shown in Fig. 1. The flowchart of the strategy followed including the end-process for protein identification approaches used is schematically shown in Fig. 2. A total of 822 proteins were identified in the analyzed goat milk samples (Table 1). In Table 1 identified proteins are shown by their accession number and their description according to Uniprot database.