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Background: The epithelial-mesenchymal transition (EMT) promotes cell signaling and morphology alterations, contributing to cancer progression. Exosomes, extracellular vesicles containing proteins involved in cell-cell communication, have emerged as a potential source of biomarkers for several diseases. Methods: Our aim was to assess the proteome content of exosomes secreted after EMT-induction to identify potential biomarkers for ovarian cancer classification. EMT was induced in the ovarian cancer cell line CAOV3 by treating it with EGF (10 ng/mL) for 96 h following 24 h of serum deprivation. Subsequently, exosomes were isolated from the supernatant using selective centrifugation after decellularization, and their characteristics were determined. The proteins present in the exosomes were extracted, identified, and quantified using Label-Free-Quantification (LFQ) via Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). To identify potential biomarkers, the obtained proteomic data was integrated with the TGGA database for mRNA expression using principal component analysis and a conditional inference tree. Results: The exosomes derived from CAOV3 cells exhibited similar diameter and morphology, measuring approximately 150 nm, regardless of whether they were subjected to EMT stimulation or not. The proteomic analysis of proteins from CAOV3-derived exosomes revealed significant differential regulation of 157 proteins, with 100 showing upregulation and 57 downregulation upon EMT induction. Further comparison of the upregulated proteins with the TCGA transcriptomic data identified PLAU, LAMB1, COL6A1, and TGFB1 as potential biomarkers of the mesenchymal HGSOC subtype. Conclusions: The induction of EMT, the isolation of exosomes, and the subsequent proteomic analysis highlight potential biomarkers for an aggressive ovarian cancer subtype. Further investigation into the role of these proteins is warranted to enhance our understanding of ovarian cancer outcomes. [ABSTRACT FROM AUTHOR]

Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17–11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment. [ABSTRACT FROM AUTHOR]

The disease COVID-19 caused by the coronavirus SARS-CoV-2 translates, in individuals affected by this virus, from mild respiratory symptoms, sometimes imperceptible to serious respiratory and multiorgan implications, especially if associated with risk groups such as people with hypertension, diabetes or those with more than 65 years, among others. For the most severely affected patients, hospitalization in intensive care units due to severe respiratory distress syndrome may be a reality, with increased hospitalization time compared to normal pneumonia, and which will translate into motor and functional sequelae where the physiotherapist will have an essential role to develop. In any of the different stages of evolution of this disease (critical and acute, post-acute, ambulatory, and home), the physiotherapist acts in order to restore maximum functional capacity in individuals affected by COVID-19. The purpose of this text is thus to show the role of the physiotherapist in each of these intervention stages. [ABSTRACT FROM AUTHOR]

Lipid rafts are ordered membrane domains, which provide an environment for the proteins participating in signal transduction. Perifosine is an alkylphospholipid (APL) that inhibits the AKT pathway, cytotoxic to neoplastic cells. We have shown that the lipid raft adaptor protein NTAL is a target of APLs in leukemic cells. Using human mantle cell lymphoma (MCL) Granta-519 cell line we showed here that perifosine decreased NTAL in lipid raft fractions reducing AKT phosphorylation before apoptosis. We also showed that the NTAL-knockdown by shRNA induced a state of reduced AKT activation. Experimental NTAL-knockdown in NSG mouse MCL xenografts reduced AKT activity, increased the basal apoptotic rate by 3-fold (n = 8) and decreased tumor weight by 2.7-fold (n = 5), indicating that NTAL participates in tumor growth. NTAL protein was detected by western blotting in circulating cells of 7 of 8 MCL patients in the leukemic phase, suggesting involvement in the progression of the disease. [ABSTRACT FROM AUTHOR]

Multipotent mesenchymal stromal cells (MSC) are imbued with an immunosuppressive phenotype that extends to several immune system cells. In this study, we evaluated how distinct Toll-like receptor (TLR) agonists impact immunosuppressive properties of bone marrow (BM)-MSC and explored the potential mechanisms involved. We show that TLR4 stimulation by lipopolysaccharide (LPS) restricted the ability of MSC to suppress the proliferation of T lymphocytes, increasing the gene expression of interleukin (IL)-1β and IL-6. In contrast, stimulation of TLR9 by DSP30 induced proliferation and the suppressive potential of BM-MSC, coinciding with reducing tumor necrosis factor (TNF)-α expression, increased expression of transforming growth factor (TGF)-β1, increased percentages of BM-MSC double positive for the ectonucleotidases CD39+CD73+ and adenosine levels. Importantly, following simultaneous stimulation with LPS and DSP30, BM-MSC's ability to suppress T lymphocyte proliferation was comparable with that of non-stimulated BM-MSC levels. Moreover, stimulation of BM-MSC with LPS reduced significantly the gene expression levels, on co-cultured T lymphocyte, of IL-10 and interferon (IFN)γ, a cytokine with potential to enhance the immunosuppression mediated by MSC and ameliorate the clinical outcome of patients with graft-versus-host disease (GVHD). Altogether, our findings reiterate the harmful effects of LPS on MSC immunosuppression, besides indicating that DSP30 could provide a protective effect against LPS circulating in the blood of GVHD patients who receive BM-MSC infusions, ensuring a more predictable immunosuppressive effect. The novel effects and potential mechanisms following the stimulation of BM-MSC by DSP30 might impact their clinical use, by allowing the derivation of optimal "licensing" protocols for obtaining therapeutically efficient MSC. [ABSTRACT FROM AUTHOR]

Introduction - The benefits of physical exercise in cancer survivors have been reported, although it's practice remains low, becoming important the acknowledgement of the factors that promote the motivation and adhesion of physical exercise in this population. Objectives - To identify the preferences about programming and counseling of physical exercise inside a population-based sample of Portuguese women who have survived breast cancer. We also intend to investigate the influence of demographic and medical variables in those preferences. Method - A questionnaire was applied to a non-probabilistic sequential sample of 26 women that have survived breast cancer. Results - Our sample was mainly composed by women aged between 45 and 62, married or in a cohabitation state, with basic instruction, employed and with a Body Mass Index (BMI)> 24.4. Most of them have had radical mastectomy for at least one month, had the Stage I of the tumor, and had done chemotherapy as an adjuvant treatment and some of them were practicing post-surgery physical therapy. The majority of participants showed interest in receiving counseling, felt able to participate in an exercise program, preferred receiving face-to-face counseling, at the hospital and with other cancer patients. The exercise should be supervised and with a moderate intensity. Walking was their preferred choice of exercise. It was not statistically possible to establish the relationship between demographic and medical variables and those preferences. Conclusion - Some results are in agreement with previous studies; however, others diverge from these. The results obtained can provide important information for future construction of exercise programs for this population. [ABSTRACT FROM AUTHOR]

Summary: Despite advancements in utilizing genetic markers to enhance acute myeloid leukaemia (AML) outcome prediction, significant disease heterogeneity persists, hindering clinical management. To refine survival predictions, we assessed the transcriptome of non‐acute promyelocytic leukaemia chemotherapy‐treated AML patients from five cohorts (n = 975). This led to the identification of a 4‐gene prognostic index (4‐PI) comprising CYP2E1, DHCR7, IL2RA and SQLE. The 4‐PI effectively stratified patients into risk categories, with the high 4‐PI group exhibiting TP53 mutations and cholesterol biosynthesis signatures. Single‐cell RNA sequencing revealed enrichment for leukaemia stem cell signatures in high 4‐PI cells. Validation across three cohorts (n = 671), including one with childhood AML, demonstrated the reproducibility and clinical utility of the 4‐PI, even using cost‐effective techniques like real‐time quantitative polymerase chain reaction. Comparative analysis with 56 established prognostic indexes revealed the superior performance of the 4‐PI, highlighting its potential to enhance AML risk stratification. Finally, the 4‐PI demonstrated to be potential marker to reclassified patients from the intermediate ELN2017 category to the adverse category. In conclusion, the 4‐PI emerges as a robust and straightforward prognostic tool to improve survival prediction in AML patients. [ABSTRACT FROM AUTHOR]

Prescription-event monitoring (PEM) is a non-interventional intensive method for post-marketing drug safety monitoring of newly licensed medicines. PEM studies are cohort studies where exposure is obtained from a centralised service and outcomes from simple questionnaires completed by general practitioners. Follow-up forms are sent for selected events.Because PEM captures all events and not only the suspected adverse drug reactions, PEM cohorts potentially differ in respect to the distribution of number of events per person depending on the nature of the drug under study. This variance can be related either with the condition for which the drug is prescribed (e.g. a condition causing high morbidity will have, in average, a higher number of events per person compared with a condition with lower morbidity) or with the drug effect itself.This paper describes an exploratory investigation of the distortion caused by product-related variations of the number of events to the interpretation of the proportional reporting ratio (PRR) values (“the higher the PRR, the greater the strength of the signal”) computed using drug-cohort data.We studied this effect by assessing the agreement between the PRR based on events (event of interest vs all other events) and PRR based on cases (cases with the event of interest vs cases with any other events). PRR were calculated for all combinations reported to ten selected drugs against a comparator of 81 other drugs. Three of the ten drugs had a cohort with an apparent higher proportion of patients with lower number of events. The PRRs based on events were systematically higher than the PRR based on cases for the combinations reported to these three drugs. Additionally, when applying the threshold criteria for signal screening (n ≥3, PRR ≥1.5 and Chi-squared ≥4), the binary agreement was generally high but apparently lower for these three drugs.In conclusion, the distribution of events per patient in drug cohorts shall be examined when comparing the ‘strength of the signals’ across drugs using PRR values. Further research will be required to address the sensitivity and specificity of the two ways of calculating PRR using data derived from drug cohorts. [ABSTRACT FROM AUTHOR]

Objective: To report the experience of nurses in the use of mobile technology for nursing care for users in primary and special care during the COVID-19 pandemic. Method: Use the method of systematization of experiments studied by Holliday, which enabled the reflexive reconstruction of the collective experience lived, through five steps for an explanation of the experience. Results: It enabled the development of new tools for monitoring users served by health services through remote technologies that mediate nursing care. Conclusions: The use of mobile technology makes it possible to recover nursing care during a COVID-19 pandemic, the way care can be taken to vulnerable users, without interruption or health compromise in the current epidemiological context in which the disease is in progress full process of propagation and dissemination. [ABSTRACT FROM AUTHOR]

Introduction: S. pneumoniae can cause a wide spectrum of diseases, including invasive pneumococcal disease and pneumonia. Two types of pneumococcal vaccines are indicated for use in adults: 23-valent pneumococcal polysaccharide vaccines (PPV23) and a 13-valent pneumococcal conjugate vaccine (PCV13). Objective: To systematically review the literature assessing pneumococcal vaccine effectiveness (VE) against community-acquired pneumonia (CAP) in adults among the general population, the immunocompromised and subjects with underlying risk factors in real-world settings. Methods: We searched for peer-reviewed observational studies published between 1980 and 2015 in Pubmed, SciELO or LILACS, with pneumococcal VE estimates against CAP, pneumococcal CAP or nonbacteremic pneumococcal CAP. Meta-analyses and meta-regression for VE against CAP requiring hospitalization in the general population was performed. Results: 1159 unique articles were retrieved of which 33 were included. No studies evaluating PCV13 effectiveness were found. Wide ranges in PPV23 effectiveness estimates for any-CAP were observed among adults ≥65 years (-143% to 60%). The meta-analyzed VE estimate for any-CAP requiring hospitalization in the general population was 10.2% (95%CI: -12.6; 33.0). The meta-regression indicates that VE against any-CAP requiring hospitalization is significantly lower in studies with a maximum time since vaccination ≥60 months vs. <60 months and in countries with the pediatric PCV vaccine available on the private market. However, these results should be interpreted cautiously due to the high influence of two studies. The VE estimates for pneumococcal CAP hospitalization ranged from 32% (95%CI: -18; 61) to 51% (95%CI: 16; 71) in the general population. Conclusions: Wide ranges in PPV23 effectiveness estimates for any-CAP were observed, likely due to a great diversity of study populations, circulation of S. pneumoniae serotypes, coverage of pediatric pneumococcal vaccination, case definition and time since vaccination. Despite some evidence for short-term protection, effectiveness of PPV23 against CAP was not consistent in the general population, the immunocompromised and subjects with underlying risk factors. [ABSTRACT FROM AUTHOR]

A literature survey and analysis was conducted to describe the epidemiology of dengue disease in Brazil reported between 2000 and 2010. The protocol was registered on PROSPERO (CRD42011001826: http://www.crd.york.ac.uk/prospero/display%5frecord.asp?ID=CRD42011001826). Between 31 July and 4 August 2011, the published literature was searched for epidemiological studies of dengue disease, using specific search strategies for each electronic database. A total of 714 relevant citations were identified, 51 of which fulfilled the inclusion criteria. The epidemiology of dengue disease in Brazil, in this period, was characterized by increases in the geographical spread and incidence of reported cases. The overall increase in dengue disease was accompanied by a rise in the proportion of severe cases. The epidemiological pattern of dengue disease in Brazil is complex and the changes observed during this review period are likely to have been influenced by multiple factors. Several gaps in epidemiological knowledge regarding dengue disease in Brazil were identified that provide avenues for future research, in particular, studies of regional differences, genotype evolution, and age-stratified seroprevalence. Systematic Review Registration: PROSPERO registration number: CRD42011001826. Author Summary: Dengue disease is the most prevalent arthropod-borne viral disease in humans and is a global and national public health concern in Brazil. We conducted this review to consolidate and describe the existing evidence on the epidemiology of dengue disease in Brazil, between 2000 and 2011, to gauge the recent national and regional impact of dengue disease and provide a basis for setting research priorities and prevention efforts. We used well-defined methods to search and identify relevant research, according to predetermined inclusion criteria. Despite control measures, the increased territorial distribution of the mosquito vector and the co-circulation of multiple dengue virus serotypes have resulted in increases in the incidence and distribution of dengue disease. The number of disease-related hospitalizations and deaths has also increased. Efforts to control the increasing disease incidence have been unsuccessful. This review of dengue disease epidemiology will help enhance knowledge and future disease management. Despite the high volume of research retrieved, we have identified several avenues for future research, in particular studies of regional differences, genotype evolution and age-stratified seroprevalence that will improve our knowledge of dengue disease, contribute to a more accurate estimate of global disease incidence, and also inform evidence-based policies for dengue disease prevention. [ABSTRACT FROM AUTHOR]

: A literature survey and analysis was conducted to describe the epidemiology of dengue disease in Brazil reported between 2000 and 2010. The protocol was registered on PROSPERO (CRD42011001826: http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42011001826). Between 31 July and 4 August 2011, the published literature was searched for epidemiological studies of dengue disease, using specific search strategies for each electronic database. A total of 714 relevant citations were identified, 51 of which fulfilled the inclusion criteria. The epidemiology of dengue disease in Brazil, in this period, was characterized by increases in the geographical spread and incidence of reported cases. The overall increase in dengue disease was accompanied by a rise in the proportion of severe cases. The epidemiological pattern of dengue disease in Brazil is complex and the changes observed during this review period are likely to have been influenced by multiple factors. Several gaps in epidemiological knowledge regarding dengue disease in Brazil were identified that provide avenues for future research, in particular, studies of regional differences, genotype evolution, and age-stratified seroprevalence. Systematic Review Registration: PROSPERO registration number: CRD42011001826. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OvCA) is the most lethal neoplasia among gynecologic malignancies and faces high rates of new cases particularly in South America. In special, the High Grade Serous Ovarian Carcinoma (HGSC) presents very poor prognosis with deaths caused mainly by metastasis. Among several mechanisms involved in metastasis, the Epithelial to Mesenchymal Transition (EMT) molecular reprogramming represents a model for latest stages of cancer progression. EMT promotes important cellular changes in cellular adhesion and cell-cell communication, which particularly depends on the paracrine signaling from neighbor cells. Considering the importance of cellular communication during EMT and metastasis, here we analyzed the changes in the secretome of the ovarian cancer cell line Caov-3 induced to EMT by Epidermal Growth Factor (EGF). Using a combination of GEL-LC-MS/MS and stable isotopic metabolic labelling (SILAC), we identified up-regulated candidates during EMT as a starting point to identify relevant proteins for HGSC. Based on public databases, our candidate proteins were validated and prioritized for further analysis. Importantly, several of the protein candidates were associated with cellular vesicles, which are important to the cell-cell communication and metastasis. Furthermore, the association of candidate proteins with gene expression data uncovered a subset of proteins correlated with the mesenchymal subtype of ovarian cancer. Based on this relevant molecular signature for aggressive ovarian cancer, supported by protein and gene expression data, we developed a targeted proteomic method to evaluate individual OvCA clinical samples. The quantitative information obtained for 33 peptides, representative of 18 proteins, was able to segregate HGSC from other tumor types. Our study highlighted the richness of the secretome and EMT to reveal relevant proteins for HGSC, which could be used in further studies and larger patient cohorts as a potential stratification signature for ovarian cancer tumor that could guide clinical conduct for patient treatment. Schematic experimental approach. Secretome of Caov-3 cells induced to EMT by EGF (10 ng/mL) for 96 h and respective control (not induced) were combined with the secretome of Caov-3 cells cultured in heavy SILAC medium and analyzed by LC-MS/MS. The mRNA expression levels of differentially quantified proteins were retrieved from the TCGA and only up-regulated proteins at maximum value on Mesenchymal subtype gene expression were select to be used in our final verification panel. The final MRM method covering 18 proteins was used to analyze selected tumor samples. Individual figures adapted from https://smart.servier.com/ [Display omitted] • We explored the model of inducing EMT in Caov-3 ovarian cancer cell lines using EGF. • Our quantitative proteomic approach identified proteins up-regulated in the secretome of Caov-3 cells during EMT. • Selected up-regulated proteins were mainly associated with mechanisms of vesicle-mediated transport. • Up-regulated proteins were prioritized based on gene expression signature of mesenchymal subtype of HGSC tumors. • Secretome-gene expression associated proteins were used to develop a targeted proteomics method to analyze clinical samples. • The final method was able to stratify high grade ovarian cancer patient tumor samples from other subtypes. [ABSTRACT FROM AUTHOR]

Background: Norovirus is the leading cause of community-acquired and nosocomial acute gastroenteritis. Routine testing for norovirus is seldom undertaken, and diagnosis is mainly based on presenting symptoms. This makes understanding the burden of medically attended norovirus-attributable gastroenteritis (MA-NGE) and targeting care and prevention strategies challenging.Methods: We used linked population-based healthcare datasets (Clinical Practice Research Datalink General Practice OnLine Database linked with Hospital Episode Statistics Admitted Patient Care) to model the incidence of MA-NGE associated with primary care consultations or hospitalizations according to age groups in England in the period July 2007-June 2013.Results: Mean annual incidence rates of MA-NGE were 4.9/1000 person-years and 0.7/1000 person-years for episodes involving primary care or hospitalizations, respectively. Incidence rates were highest in children aged <5 years: 34.0 consultations/1000 person-years and 3.3 hospitalizations/1000 person-years. Medically attended norovirus-attributable gastroenteritis hospitalization rates were second highest in adults aged >65 years (1.7/1000 person-years).Conclusions: In this particular study, the burden of MA-NGE estimated from healthcare datasets was higher than previously estimated in small cohort studies in England. Routinely collected primary care and hospitalization datasets are useful resources to estimate and monitor the burden of MA-NGE in a population over time. [ABSTRACT FROM AUTHOR]

Summary Background Dengue surveillance data in India are limited and probably substantially underestimate the burden of disease. A community-based study was undertaken to assess the prevalence of dengue-specific immunoglobulin G (IgG) antibodies in children across India and to examine historical dengue exposure rates. Potential associations between socio-economic factors and dengue seroprevalence were also assessed (registered at ctri.nic.in: CTRI/2011/12/002243). Methods A convenience sample of 2609 healthy children aged 5–10 years was enrolled; these children were registered at or were living in the vicinity of eight centres located at six geographically distinct sites across India. Blood samples were drawn to test for the presence of dengue IgG antibodies using ELISA. Serotype-specific neutralizing antibody titres were measured in dengue IgG-positive children using dengue plaque reduction neutralization tests. Socio-demographic and household information was collected using a questionnaire. Results Overall, 2558/2609 children had viable samples with laboratory results for dengue IgG. Dengue IgG seroprevalence across all sites was 59.6% (95% confidence interval 57.7–61.5%): the lowest (23.2%) was in Kalyani, West Bengal, and the highest (80.1%) was in Mumbai. Seroprevalence increased with age. Multivariate analysis suggested associations with household water storage/supply and type of housing. Half of the subjects with positive IgG results presented a multitypic profile, indicating previous exposure to more than one serotype. Conclusions The overall dengue seroprevalence suggests that dengue endemicity in India is comparable to that in highly endemic countries of Southeast Asia. Additional prospective studies are required to fully quantify the disease burden, in order to support evidence-based policies for dengue prevention and control in India. [ABSTRACT FROM AUTHOR]

Background Annual seasonal influenza vaccination is recommended for transplant recipients. No formal pharmacoepidemiology study has been published on the association between solid organ transplant (SOT) rejection and vaccination with seasonal trivalent inactivated influenza vaccines (TIIVs). Methods The risk of SOT (liver, kidney, lung, heart or pancreas) rejection after TIIV vaccination was assessed using a self-controlled case-series method ( NCT01715792 ). SOT recipients in England with transplant rejection were selected from the Clinical Practice Research Datalink and linked Hospital Episode Statistics inpatient data. The study period (September 2006 to August 2009) encompassed three consecutive influenza seasons. We calculated the relative incidence (RI) of SOT rejection between the 30- and 60-day post-vaccination risk periods and the control periods (any follow-up period excluding risk periods), using a Poisson regression model. Results In seasons 2006/07, 2007/08, 2008/09 and pooled seasons, 132, 136, 168 and 375 subjects, respectively, experienced at least one transplant rejection; approximately half (45%–51%) of these subjects had received a TIIV. For season 2006/07, the RI of rejection of any organ, adjusted for time since transplantation, was 0.74 (95% CI: 0.24–2.28) and 0.58 (95% CI: 0.24–1.38) during the 30-day and 60-day risk periods, respectively. Corresponding RIs for season 2007/08 were 1.21 (95% CI: 0.55–2.64) and 1.31 (95% CI: 0.69–2.48); for season 2008/09, 0.99 (95% CI: 0.43–2.28) and 0.64 (95% CI: 0.31–1.33); and for pooled seasons 1.01 (95% CI: 0.58–1.76) and 0.88 (95% CI: 0.56–1.38). The results of a separate analysis of kidney rejections and analyses that took into account additional potential confounders were consistent with those of the main analyses, with 95% CIs including 1 and upper limits below 3. Conclusion This study provides reassuring evidence of the safety profile of TIIVs in SOT recipients, thus supporting current recommendations to vaccinate this risk group annually. [ABSTRACT FROM AUTHOR]

Background: An increase in narcolepsy cases was observed in Finland and Sweden towards the end of the 2009 H1N1 influenza pandemic. Preliminary observational studies suggested a temporal link with the pandemic influenza vaccine Pandemrix™, leading to a number of additional studies across Europe. Given the public health urgency, these studies used readily available retrospective data from various sources. The potential for bias in such settings was generally acknowledged. Although generally advocated by key opinion leaders and international health authorities, no systematic quantitative assessment of the potential joint impact of biases was undertaken in any of these studies. Methods: We applied bias-level multiple-bias analyses to two of the published narcolepsy studies: a pediatric cohort study from Finland and a case-control study from France. In particular, we developed Monte Carlo simulation models to evaluate a potential cascade of biases, including confounding by age, by indication and by natural H1N1 infection, selection bias, disease- and exposure misclassification. All bias parameters were evidence-based to the extent possible. Results: Given the assumptions used for confounding, selection bias and misclassification, the Finnish rate ratio of 13.78 (95% CI: 5.72–28.11) reduced to a median value of 6.06 (2.5th- 97.5th percentile: 2.49–15.1) and the French odds ratio of 5.43 (95% CI: 2.6–10.08) to 1.85 (2.5th—97.5th percentile: 0.85–4.08). Conclusion: We illustrate multiple-bias analyses using two studies on the Pandemrix™-narcolepsy association and advocate their use to better understand the robustness of study findings. Based on our multiple-bias models, the observed Pandemrix™-narcolepsy association consistently persists in the Finnish study. For the French study, the results of our multiple-bias models were inconclusive. [ABSTRACT FROM AUTHOR]

Background: Antimalarial treatment strategies have changed much in the last 15 years, resulting in an increased variety of medicines available. Active pharmacovigilance methods are important for continued safety surveillance of these medicines, particularly in environments in which there is variability in treatments prescribed and limited confirmatory diagnostic capacity as well as limited ability of spontaneous reporting pharmacovigilance systems to generate much needed safety information quickly and efficiently.Objective: Our objective was to use the cohort-event monitoring (CEM) technique to gather drug utilization and adverse event data for patients prescribed antimalarial medicines in an outpatient setting.Methods: The characteristics of a large urban African cohort of outpatients (n = 2,831) receiving antimalarial medications are described. The cohort was actively surveyed over the subsequent week to record adverse events, using follow-up phone calls, paper reports, and/or voluntary return clinic visits. Adverse events reported in the cohort were analysed overall and by clinically relevant age and medication groupings.Results: At least one event was reported in 29.4 % of patients. Adverse events were more likely to be reported in subjects older than 12 years of age, and by patients prescribed an artesunate-amodiaquine combination. A range of adverse events were reported, the most frequent higher level terms being asthenic conditions (10.1 % of total cohort), neurological signs and symptoms (4.5 %), headaches (3.1 %), appetite disorders (2.1 %), and disturbances in consciousness (1.6 %). There were three reports of possible extrapyramidal events (two cases of tremor "hand and back shaking all over" and one case of tongue protrusion), which may appear to be related to combinations including amodiaquine and an artemisinin.Conclusion: The CEM methodology is a useful tool for monitoring the safety of widely available and utilized medicines, particularly in an urban environment where spontaneous reporting yields poor results and where the availability of various regimens and high levels of medicine usage can give valuable 'real-life' safety data. The types and frequencies of events reported reflected the types of events expected in patients prescribed antimalarials and nearly all events reported are listed in the summary of product characteristics of the medicines involved. [ABSTRACT FROM AUTHOR]

Gliomas are responsible for more than 60% of all primary brain tumors. Glioblastoma multiforme (GBM), a grade IV tumor (WHO), is one of the most frequent and malignant gliomas. Despite two decades of advances in the discovery of new markers for GBM, the chemotherapy of choice falls to temozolomide after surgery and radiotherapy, which are not enough to increase the survival of patients to more than 15 months. It is urgent to discover new anti-glioma compounds. Many compounds derived from natural products have been used in the development of anti-tumor drugs. In this work, we have screened six low molecular weight sesquiterpene lactones, isolated from Eremanthus spp., and studied their function as anti-proliferative agents against GBM strains. We demonstrated that two of them, goyazensolide and lychnofolide, were effective in reducing cell viability, preventing the formation of anchorage-dependent colony and were able to pass through a mimetic blood-brain barrier making them candidates for glioma therapy, being more potent than temozolomide, according to in vitro assays for the cell lines tested. Proteomic analysis revealed a number of altered proteins involved in glycolytic metabolism and cellular catabolism. [ABSTRACT FROM AUTHOR]

Epithelial to Mesenchymal Transition (EMT) is a normal cellular process that is also triggered during cancer progression and metastasis. EMT induces cellular and microenviromental changes, resulting in loss of epithelial features and acquisition of mesenchymal phenotypes. The growth factor TGFβ and the transcription factor SNAIL1 (SNAIL) have been described as inducers of EMT. Here, we carried out an EMT model with non-tumorigenic cell line MCF-10A induced with the TGFβ2 specific isoform of TGF protein family. The model was validated by molecular, morphological and functional experiments and showed correlation with the up-regulation of SNAIL. In order to identify additional regulators of EMT in this non-tumorigenic model, we explored quantitative proteomics, which revealed the Ubiquitin carboxyl-terminal hydrolase 47 (USP47) as one of the top up-regulated proteins. USP47 has a known role in cell growth and genome integrity, but not previously correlated to EMT. After validating USP47 alterations using MRM and antibody-based assays, we demonstrated that the chemical inhibition of USP47 with the inhibitor P5091 reduced expression of EMT markers and reverted morphological changes in MCF-10A cells undergoing EMT. These results support the involvement of USP47 in our EMT model as well as potential applications of deubiquitinases as therapeutic targets for cancer progression management. Metastasis is responsible for most cancer-associated mortality. Additionally, metastasis requires special attention, as the cellular transformations make treatment at this stage very difficult or occasionally impossible. Early steps in cancer metastasis involve the ability to detach from the solid tumor mass and invade the surrounding stromal tissues through cohesive migration, or a mesenchymal or amoeboid invasion. One of the first steps for metastatic cascade is denominated epithelial to mesenchymal transition (EMT), which can be triggered by different factors. Here, our efforts were directed to better understand this process and identify new pathways that contributes for acquisition of EMT, mainly focused on post translational modifications related to ubiquitin proteasome system. Our model of EMT induction by TGFβ2 mimics early stage of metastatic cancer in epithelial breast cells and a proteomic study carried out for such model demonstrates that the deubiquitinase enzyme USP47 acts in SNAIL stabilization, one of the most important transcription factors for EMT phenotype acquisition and consequent metastasis. In addition, the inhibiton of USP47 with P5091, reverted the EMT phenotype. Together the knowledge of such processes of cancer progression and regulation can help in designing new strategies for combined therapies for control of cancer in early stages. Unlabelled Image • TGFβ2 induces EMT in non-tumorigenic epithelial cells derived from breast tissue (MCF-10A). • Ubiquitin carboxyl-terminal hydrolase 47 (USP47) was up-regulated in a proteomics study carried out with the TGFβ2-induced EMT model. • Inhibition of USP47 with chemical inhibitor P5091 reduced expression of EMT markers and reverted morphological changes in MCF-10A cells undergoing EMT. [ABSTRACT FROM AUTHOR]