159 research outputs found

    Inhibition of a new AXL isoform (AXL3) induces apoptosis of mantle cell lymphoma cells

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    Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma having a poor overall survival that is in need for the development of new therapeutics. In this study, we report the identification and expression of a new isoform splice variant of the tyrosine kinase receptor AXL in MCL cells. This new AXL isoform, called AXL3, lacks the ligand-binding domain of the commonly described AXL splice variants and is constitutively activated in MCL cells. Interestingly, functional characterization of AXL3, using CRISPRi, revealed that only the knockdown of this isoform leads to apoptosis of MCL cells. Importantly, pharmacological inhibition of AXL activity resulted in a significant decrease in the activation of well-known pro-proliferative and survival pathways activated in MCL cells (i.e.b-catenin, AKT, and NF-kB). Therapeutically, pre-clinical studies using a xenograft mouse model of MCL indicated that bemcentinib is more effective than ibrutinib in reducing the tumour burden and to increase the overall survival. Our study highlights the importance of a previously unidentified AXL splice variant in cancer and the potential of bemcentinib as a targeted therapy for MCL

    Serum microRNA array analysis identifies miR-140-3p, miR-33b-3p and miR-671-3p as potential osteoarthritis biomarkers involved in metabolic processes.

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    Background: MicroRNAs (miRNAs) in circulation have emerged as promising biomarkers. In this study, we aimed to identify a circulating miRNA signature for osteoarthritis (OA) patients and in combination with bioinformatics analysis to evaluate the utility of selected differentially expressed miRNAs in the serum as potential OA biomarkers. Methods: Serum samples were collected from 12 primary OA patients, and 12 healthy individuals were screened using the Agilent Human miRNA Microarray platform interrogating 2549 miRNAs. Receiver Operating Characteristic (ROC) curves were constructed to evaluate the diagnostic performance of the deregulated miRNAs. Expression levels of selected miRNAs were validated by quantitative real-time PCR (qRT-PCR) in all serum and in articular cartilage samples from OA patients (n = 12) and healthy individuals (n = 7). Bioinformatics analysis was used to investigate the involved pathways and target genes for the above miRNAs. Results: We identified 279 differentially expressed miRNAs in the serum of OA patients compared to controls. Two hundred and five miRNAs (73.5%) were upregulated and 74 (26.5%) downregulated. ROC analysis revealed that 77 miRNAs had area under the curve (AUC) > 0.8 and p < 0.05. Bioinformatics analysis in the 77 miRNAs revealed that their target genes were involved in multiple signaling pathways associated with OA, among which FoxO, mTOR, Wnt, pI3K/akt, TGF-β signaling pathways, ECM-receptor interaction, and fatty acid biosynthesis. qRT-PCR validation in seven selected out of the 77 miRNAs revealed 3 significantly downregulated miRNAs (hsa-miR-33b-3p, hsa-miR-671-3p, and hsa-miR-140-3p) in the serum of OA patients, which were in silico predicted to be enriched in pathways involved in metabolic processes. Target-gene analysis of hsa-miR-140-3p, hsa-miR-33b-3p, and hsa-miR-671-3p revealed that InsR and IGFR1 were common targets of all three miRNAs, highlighting their involvement in regulation of metabolic processes that contribute to OA pathology. Hsa-miR-140-3p and hsa-miR-671-3p expression levels were consistently downregulated in articular cartilage of OA patients compared to healthy individuals. Conclusions: A serum miRNA signature was established for the first time using high density resolution miR-arrays in OA patients. We identified a three-miRNA signature, hsa-miR-140-3p, hsa-miR-671-3p, and hsa-miR-33b-3p, in the serum of OA patients, predicted to regulate metabolic processes, which could serve as a potential biomarker for the evaluation of OA risk and progression.Peer reviewedFinal Published versio

    JunB Inhibits ER Stress and Apoptosis in Pancreatic Beta Cells

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    Cytokines contribute to pancreatic β-cell apoptosis in type 1 diabetes (T1D) by modulation of β-cell gene expression networks. The transcription factor Activator Protein-1 (AP-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated β-cell dysfunction and death. The cytokines IL-1β+IFN-γ induced an early and transitory upregulation of JunB by NF-κB activation. Knockdown of JunB by RNA interference increased cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (INS-1E) and in purified rat primary β-cells. JunB knockdown β-cells and junB−/− fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected β-cells from cytokine-induced cell death. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis

    The relationship between maternal education and mortality among women giving birth in health care institutions: Analysis of the cross sectional WHO Global Survey on Maternal and Perinatal Health

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    Background: Approximately one-third of a million women die each year from pregnancy-related conditions. Three-quarters of these deaths are considered avoidable. Millennium Development Goal five calls for a reduction in maternal mortality and the establishment of universal access to high quality reproductive health care. There is evidence of a relationship between lower levels of maternal education and higher maternal mortality. This study examines the relationship between maternal education and maternal mortality among women giving birth in health care institutions and investigates the association of maternal age, marital status, parity, institutional capacity and state-level investment in health care with these relationships.Methods: Cross-sectional information was collected on 287,035 inpatients giving birth in 373 health care institutions in 24 countries in Africa, Asia and Latin America, between 2004-2005 (in Africa and Latin America) and 2007-2008 (in Asia) as part of the WHO Global Survey on Maternal and Perinatal Health. Analyses investigated associations between indicators measured at the individual, institutional and country level and maternal mortality during the intrapartum period: from admission to, until discharge from, the institution where women gave birth. There were 363 maternal deaths.Results: In the adjusted models, women with no education had 2.7 times and those with between one and six years of education had twice the risk of maternal mortality of women with more than 12 years of education. Institutional capacity was not associated with maternal mortality in the adjusted model. Those not married or cohabiting had almost twice the risk of death of those who were. There was a significantly higher risk of death among those aged over 35 (compared with those aged between 20 and 25 years), those with higher numbers of previous births and lower levels of state investment in health care. There were also additional effects relating to country of residence which were not explained in the model.Conclusions: Lower levels of maternal education were associated with higher maternal mortality even amongst women able to access facilities providing intrapartum care. More attention should be given to the wider social determinants of health when devising strategies to reduce maternal mortality and to achieve the increasingly elusive MDG for maternal mortality

    Ethnic Identity of Older Chinese in Canada

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    In Canada’s multicultural society, ethnic identity is important to the elderly and can influence areas such as access to services, health promotion and care. Often, the complex nature of ethnic identity is underestimated when looking at cultural groups. This study aims to: (a) validate the factor structure of a Chinese ethnic identity measure for older Chinese in Canada, (b) examine the level of ethnic identity of the participants, and (c) examine the correlates of ethnic identity in these older individuals. Using data from a large, national research project on the elderly Chinese in Canada, this study analyzed the results gathered from a total of 2,272 participants. Principal component analysis, maximum-likelihood confirmatory factor analysis, and multiple regression analysis were performed. The results indicated that ethnic identity of the older Chinese is a multi-dimensional construct made up of three factors: (a) culture related activities, (b) community ties, (c) linkage with country of origin, and (d) cultural identification. The findings have provided a better understanding of how ethnic identity can be measured among the aging Chinese population in Canada

    Distribution Patterns of Infection with Multiple Types of Human Papillomaviruses and Their Association with Risk Factors

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    Background: Infection with multiple types of human papillomavirus (HPV) is one of the main risk factors associated with the development of cervical lesions. In this study, cervical samples collected from 1, 810 women with diverse sociocultural backgrounds, who attended to their cervical screening program in different geographical regions of Colombia, were examined for the presence of cervical lesions and HPV by Papanicolau testing and DNA PCR detection, respectively. Principal Findings: The negative binomial distribution model used in this study showed differences between the observed and expected values within some risk factor categories analyzed. Particularly in the case of single infection and coinfection with more than 4 HPV types, observed frequencies were smaller than expected, while the number of women infected with 2 to 4 viral types were higher than expected. Data analysis according to a negative binomial regression showed an increase in the risk of acquiring more HPV types in women who were of indigenous ethnicity (+37.8%), while this risk decreased in women who had given birth more than 4 times (-31.1%), or were of mestizo (-24.6%) or black (-40.9%) ethnicity. Conclusions: According to a theoretical probability distribution, the observed number of women having either a single infection or more than 4 viral types was smaller than expected, while for those infected with 2-4 HPV types it was larger than expected. Taking into account that this study showed a higher HPV coinfection rate in the indigenous ethnicity, the role of underlying factors should be assessed in detail in future studies.This project was funded by Asociacion Investigacion Solidaria SADAR, Caja Navarra (Navarra, Spain) and the Spanish Agency for International Development Cooperation (AECID) (Project 08-CAP2-0609)

    Effects of lay support for pregnant women with social risk factors on infant development and maternal psychological health at 12 months postpartum

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    Background The ELSIPS (Evaluation of Lay Support in Pregnant Women with Social Risk) RCT showed that lay support for women with social risk had a positive effect on maternal mental health and mother-infant bonding. This exploratory study examined whether these observed benefits would impact infant development at 1 year. Methods A sub-sample of women whose infants were under one year who had participated in the ELSIPS RCT which randomised women to receive either standard care or the services of a Pregnancy Outreach Worker (POW), and who were contactable, were eligible to participate in the follow up. At home visits, the Bayley Scales of Infant Development (3rd Edition) and standardised measures of depression, self efficacy, mind-mindedness and bonding were completed. Results 486 women were eligible for follow up, of whom 154 agreed to participate. 61/273 were successfully followed up in the standard maternity care arm and 51/213 in the POW arm. Women who completed follow up were less depressed and had higher selfefficacy scores at 8–12 weeks postpartum than those who did not complete follow up. There were no significant differences in maternal outcomes, infant cognitive development, receptive communication, expressive communication, fine motor development or social/emotional functioning between groups at 12 month follow up. Infants of mothers who received the POW intervention had significantly better gross motor development than infants whose mothers received standard care (p<0.03)

    Human papillomavirus detected in female breast carcinomas in Japan

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    To investigate the aetiological role of human papillomavirus (HPV) in breast cancer, we examined the presence, genotype, viral load, and physical status of HPV in 124 Japanese female patients with breast carcinoma. Human papillomavirus presence was examined by PCR using SPF10 primers, and primer sets targeting the E6 region of HPV-16, -18, and -33. The INNO-LiPA HPV genotyping kit was used to determine genotype. Human papillomavirus DNA was detected in 26 (21%) breast carcinomas. The most frequently detected HPV genotype was HPV-16 (92%), followed by HPV-6 (46%), HPV-18 (12%), and HPV-33 (4%). In 11 normal epithelium specimens adjacent to 11 HPV-16-positive carcinomas, 7 were HPV-16-positive. However, none of the normal breast tissue specimens adjacent to HPV-negative breast carcinomas were HPV-positive. The real-time PCR analysis suggested the presence of integrated form of viral DNA in all HPV-16-positive samples, and estimated viral load was low with a geometric mean of 5.4 copies per 104 cells. In conclusion, although HPV DNA was detected in 26 (21%) breast carcinomas and, in all HPV-16-positive cases, the HPV genome was considered integrated into the host genome, their low viral loads suggest it is unlikely that integrated HPV is aetiologically involved in the development of Japanese breast carcinomas that we examined
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