54 research outputs found
Long 3âČ-UTRs target wild-type mRNAs for nonsense-mediated mRNA decay in Saccharomyces cerevisiae
The nonsense-mediated mRNA decay (NMD) pathway, present in most eukaryotic cells, is a specialized pathway that leads to the recognition and rapid degradation of mRNAs with premature termination codons and, importantly, some wild-type mRNAs. Earlier studies demonstrated that aberrant mRNAs with artificially extended 3âČ-untranslated regions (3âČ-UTRs) are degraded by NMD. However, the extent to which wild-type mRNAs with long 3âČ-UTRs are degraded by NMD is not known. We used a global approach to identify wild-type mRNAs in Saccharomyces cerevisiae that have longer than expected 3âČ-UTRs, and of these mRNAs tested, 91% were degraded by NMD. We demonstrate for the first time that replacement of the natural, long 3âČ-UTR from wild-type PGA1 mRNA, which encodes a protein that is important for cell wall biosynthesis, with a short 3âČ-UTR renders it immune to NMD. The natural PGA1 3âČ-UTR is sufficient to target a NMD insensitive mRNA for decay by the NMD pathway. Finally, we show that nmd mutants are sensitive to Calcofluor White, which suggests that the regulation of PGA1 and other cell wall biosynthesis proteins by NMD is physiologically significant
Worldwide comparison of survival from childhood leukaemia for 1995â2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89â828 children from 198 registries in 53 countries
Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia.
Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML).
Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls.
Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival
Lancet
BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation
Worldwide trends in population-based survival for children, adolescents, and young adults diagnosed with leukaemia, by subtype, during 2000â14 (CONCORD-3) : analysis of individual data from 258 cancer registries in 61 countries
Background Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed
data for children (aged 0â14 years) and adults (aged 15â99 years) diagnosed with a haematological malignancy
during 2000â14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and
morphology, in young patients (aged 0â24 years).
Methods We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3
that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0â14 years),
adolescents (15â19 years), and young adults (20â24 years). We categorised leukaemia subtypes according to the
International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases
for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs,
using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by
country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age
survival estimates were standardised to the marginal distribution of young people with leukaemia included in the
analysis.
Findings 164563 young people were included in this analysis: 121328 (73·7%) children, 22963 (14·0%) adolescents, and
20272 (12·3%) young adults. In 2010â14, the most common subtypes were lymphoid leukaemia (28205 [68·2%] patients)
and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and
young adults for all leukaemias combined during 2010â14 varied widely, ranging from 46% in Mexico to more than
85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better
age-standardised survival (from 43% in Ecuador to â„80% in parts of Europe, North America, Oceania, and Asia) than
those with acute myeloid leukaemia (from 32% in Peru to â„70% in most high-income countries in Europe,
North America, and Oceania). Throughout 2000â14, survival from all leukaemias combined remained consistently
higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young
adults in most countries.
Interpretation This study offers the first worldwide picture of population-based survival from leukaemia in children,
adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower
survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators
of the quality of cancer management in this age group.peer-reviewe
Couvent Saint-François : Corse-du-Sud (2A), Sainte-Lucie-de-Tallano: Rapport de diagnostic
Le couvent est Ă©difiĂ© Ă partir de 1492 pour lâordre mendiant des franciscains. A partir du XVIe siĂšcle et jusquâĂ la rĂ©volution il sera occupĂ© par les frĂšres observantins. Le couvent a Ă©tĂ© vendu comme bien national le 29 septembre 1803, et les bĂątiments conventuels seront par la suite occupĂ©s par lâarmĂ©e ou par des privĂ©s (et serviront mĂȘme de bergerie). LâĂ©glise et les bĂątiments seront classĂ©s au titre des Monuments Historiques le 11 novembre 1980. La dĂ©cision dâintervenir rĂ©pond au projet de restauration et dâamĂ©nagement dâun centre culturel. Au terme de cette opĂ©ration de diagnostic archĂ©ologique, plusieurs informations sont sorties des sondages et des observations du bĂąti. A lâest, la structure retrouvĂ©e constituĂ©e dâune fosse et d'un mur nâest pas datĂ©e de maniĂšre absolue mais intervient avant la mise en terrasse de la parcelle. Il sâagit dâun amĂ©nagement liĂ© Ă un chantier. Il pourrait sâagir dâĂ©lĂ©ments attachĂ©s Ă la construction du couvent, ou aux amĂ©nagements antĂ©rieurs.Lâaile est a livrĂ© une information importante qui est Ă prendre en considĂ©ration lors du projet dâamĂ©nagement du centre culturel. Il sâagit du niveau de sol du rez-de-chaussĂ©e qui permet de restituer un niveau de circulation initial Ă cet espace.Enfin, lâobservation du bĂąti et un des sondages ont permis de proposer une chronologie de lâĂ©volution de cette aile du cloitre et de documenter un peu plus la prĂ©sence de la tour du seigneur de la Rocca, mĂ©cĂšne du couvent. Cette derniĂšre a Ă©tĂ© localisĂ©e Ă lâouest du bĂątiment conventuel nord, dont elle constitue une partie des fondations
Ăglise Saint Jean-Baptiste : Ă©tude archĂ©ologique d'une Ă©glise piĂ©vane de l'Alta Rocca : Corse, Corse-du-Sud (2A), Sainte-Lucie-de-Tallano: Rapport de fouille
LâĂ©glise de Saint Jean Baptiste, a Ă©tĂ© bĂątie sur les terres du hameau de Poggio qui dĂ©pend de la commune de Sainte Lucie de Tallano, au lieu dit Pieve e San Giovani. Construite sur les terres de lâancienne piĂšve dâAttalĂ ,, elle est isolĂ©e et Ă©loignĂ©e des villages alentours. Le cours dâeau du Rizzanese, coule en contrebas de lâĂ©glise Ă environ 500 m. LâĂ©difice est construit sur un promontoire « poggio », au sommet aplani, reprĂ©sentant une surface dâenviron 400 mÂČ culminant Ă environ 325 m..Le cadre historique de cette fouille sâinscrit dans ce que les textes du bas-Moyen Ăge dĂ©signent comme lâAu-delĂ des Monts (A Tirra Dila Da Monti) et qui correspond Ă lâactuel dĂ©partement de Corse-du-Sud. Câest Ă lâintĂ©rieur de cet espace historique intimement liĂ© Ă la gĂ©ographie physique que prend place cette Ă©tude.San Ghuvan Battista est traditionnellement datĂ©e de la pĂ©riode pisane (XIIe siĂšcle) et sâinscrit dans une politique de construction et de reconstruction sur lâensemble du territoire initiĂ©e par la commune de Pise et rĂ©alisĂ©e sous le contrĂŽle de lâĂ©glise.LâĂ©glise San Ghuvan Battista, adopte le plan dâune Ă©glise Ă nef unique, sans transept avec une seule abside semi circulaire et chĆur en cul de four. Le matĂ©riau employĂ© : le granit, est une source dont lâapprovisionnement est manifestement local, bien quâil paraisse de prime abord exogĂšne au substrat local qui se caractĂ©rise plus souvent par un granit Ă gros grains visible dans de nombreuses constructions. Le grain fin du matĂ©riau, sa composition minĂ©rale et son apparente homogĂ©nĂ©itĂ© chromatique donnent Ă lâĂ©difice la vision dâune construction harmonieuse.Lâobservation du bĂąti a montrĂ© un problĂšme de stabilitĂ© de lâĂ©difice qui semble existĂ© depuis sa construction. En effet, on observe sur le parement externe du mur gouttereau nord, une cĂ©sure verticale, qui marque une rupture dans le bĂątiment se caractĂ©risant par un Ă©largissement anormal des joints.A travers lâĂ©tude des quelques sources Ă©crites, lâanalyse du bĂąti et des deux campagnes de fouilles (2013 et 2014) menĂ©es Ă lâextĂ©rieur et dans le chĆur de lâĂ©glise, il a Ă©tĂ© possible de retracer une partie de lâhistoire du site de Saint Jean Baptiste. De plus, cette histoire sâest largement enrichie dâune importante Ă©tude anthropologique.Peu dâĂ©glises de piĂšve ont Ă©tĂ© fouillĂ©es en Corse et lâexemple de Saint Jean Baptiste permet de documenter un type de site qui a jouĂ© un rĂŽle important dans la gestion de lâĂźle de Corse.LâĂ©glise comme bĂątiment est un monument signe architecturalement, mais pas seulement. Elle est aussi le marqueur fort en Corse de la prĂ©sence pisane et de lâĂ©glise sur un territoire nouvellement conquis ou au moins « pacifiĂ© ».Ces fouilles ont permis dâĂ©tudier une partie de la construction et de proposer une Ă©volution de celle-ci. La provenance locale des matĂ©riaux, et la mise en Ćuvre que lâon retrouve dans beaucoup dâautres Ă©difices contemporains sont les signes dâun savoir-faire insulaire, couplĂ© Ă une architecture trĂšs caractĂ©ristique venant des rivages orientaux de la mer TyrrhĂ©nienne. Elle est la marque de la prĂ©sence italienne sur la Corse, qui imprĂ©gnera lâĂźle de ses modĂšles architecturaux tout au long du Moyen Ăge et de lâĂ©poque moderne
Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women : an attempt to maintain immune homeostasis and vascular tone
Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3Δ, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension.9 page(s
Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride-rich lipoprotein metabolism
BACKGROUND: NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. APPROACH AND RESULTS: To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F (APOF) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated aâ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo, and reduced hepatocyte VLDL uptake by ~15% in vitro. Transcriptomic analysis of APOF-overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1, among others. CONCLUSION: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance
Early feeding practices in infants with phenylketonuria across Europe
BACKGROUND: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. METHODS: We sent a cross sectional, survey monkeyÂź questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. RESULTS: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6âŻmonths.53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (nâŻ=âŻ35/95), whereas 44% (nâŻ=âŻ42/95) advised mixing both formulas together. Weaning commenced between 17 and 26âŻweeks in 85% centres, â„26âŻweeks in 12% andâŻ<âŻ17âŻweeks in 3%. DISCUSSION: This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development
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