Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas.

Non-coding microRNAs (miRs) are a vital component of post-transcriptional modulation of protein expression and, like coding mRNAs harbour oncogenic properties. However, the mechanisms governing miR expression and the identity of the affected transcripts remain poorly understood. Here we identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR-155. We demonstrate that in diffuse large B cell lymphoma (DLBCL) elevated levels of miR-155, and consequent diminished SHIP1 expression are the result of autocrine stimulation by the pro-inflammatory cytokine tumour necrosis factor a (TNFalpha). Anti-TNFalpha regimen such as eternacept or infliximab were sufficient to reduce miR-155 levels and restored SHIP1 expression in DLBCL cells with an accompanying reduction in cell proliferation. Furthermore, we observed a substantial decrease in tumour burden in DLBCL xenografts in response to eternacept. These findings strongly support the concept that cytokine-regulated miRs can function as a crucial link between inflammation and cancer, and illustrate the feasibility of anti-TNFalpha therapy as a novel and immediately accessible (co)treatment for DLBCL

Rebellious Chiefs and the Operation of the Department of Indian Affairs in Ahkwesáhsne from 1880-1899

During an election of chiefs in the summer of 1899, Indian Agent George Long was locked until evening in the schoolhouse where the polls were stationed by the bandmembers of the St. Regis reserve. The event was not a random coincidence, but an organized protest by the people of the community, whose relationship with the agent had grown increasingly hostile since he was stationed at the reserve in 1887. Elections for chiefs were an ongoing issue in St. Regis (known today as Ahkwesáhsne) ever since the implementation of the electoral system imposed by the Indian Act of 1876. The current research investigates the operation of the Department of Indian Affairs in Ahkwesáhsne during a twenty-year period, from 1880 to 1900, a decisive period for the bureaucratic and administrative formation of the Department. Through a reading of the agent’s letterbooks, and other archival materials, this research provides a micro historical lens into the operation of four different agents stationed at the St. Regis agency. The thesis focuses on the agents’ management of the reserve and their implementation of election. It aims to show how the agents acted in self-interest, and that their authoritative supervision produced hostile relations with the band. This research tells not only the story of state formation and the professionalization of government employees, but it also reveals the collective activism and resistance with which the Department and its agents were met

Predictors of oedema among children hospitalized with severe acute malnutrition in Jimma University Hospital, Ethiopia:a cross sectional study

BACKGROUND: Severe acute malnutrition has two main clinical manifestations, i.e., oedematous and non-oedematous. However, factors associated with oedema are not well established. METHODS: Children 0.5-14 years of age with SAM (MUAC < 11.0 cm or weight-for-height < 70 % of median and/or nutritional oedema) admitted to the nutrition unit were included. Information on infections before and during admission was collected together with anthropometry. Predictors of oedema was analysed separately for younger (< 60 months) and older children (≥ 60 months). RESULTS: 351 children were recruited (median age: 36 months (interquartile range 24 to 60); 43.3% females). Oedema was detected in 61.1%. The prevalence of oedema increased with age, peaked at 37–59 months (75%) and declined thereafter. Infection was more common in the younger group (33% vs. 8.9%, p < 0.001) and in this group children with oedema had less infections (25.2% vs. 45.1%, p = 0.001). In the older group the prevalence of infections was not different between oedematous and non-oedematous children (5.5% v. 14.3%, p = 0.17). In the younger group oedema was less common in children with TB (OR = 0.20, 95% CI: 0.06, 0.70) or diarrhea (OR = 0.40, 95% CI: 0.21, 0.73). CONCLUSIONS: The proportion of oedema in SAM peaked at three to five years of age and a considerable proportion was above 5 years. Furthermore, the prevalence of infection seemed to be lower among children with oedema. Further studies are needed to better understand the role of infection-immunity interaction

The Role of Fish in the First 1,000 Days in Zambia

Fish is especially rich in essential omega-3 long-chain polyunsaturated fatty acids and micronutrients, including bioavailable calcium, iron and zinc. Fish features prominently in the diet of most, especially poor, Zambians. Despite this, its significance in the diet of women and children in the first 1,000 days is not well understood. Our current knowledge of the nutrient content of commonly consumed fish species in Zambia is synthesised. The importance of fish in food and nutrition security of rural and urban households and the impact of intra-household distribution on nutrient intake from fish, especially among pregnant and lactating women and children 6–23 months of age, are explored in this article. Key knowledge gaps are identified, and research priorities are highlighted. Recommendations are provided on policy, communications and technological initiatives to maximise the role fish can play in the First 1000 Most Critical Days Programme in Zambia

Cardiac dysfunction in a porcine model of pediatric malnutrition

Half a million children die annually of severe acute malnutrition and cardiac dysfunction may contribute to the mortality. However, cardiac function remains poorly examined in cases of severe acute malnutrition.To determine malnutrition-induced echocardiographic disturbances and longitudinal changes in plasma pro-atrial natriuretic peptide and cardiac troponin-T in a pediatric porcine model.Five-week old piglets (Duroc-x-Danish Landrace-x-Yorkshire) were fed a nutritionally inadequate maize-flour diet to induce malnutrition (MAIZE, n = 12) or a reference diet (AGE-REF, n = 12) for 7 weeks. Outcomes were compared to a weight-matched reference group (WEIGHT-REF, n = 8). Pro-atrial natriuretic peptide and cardiac troponin-T were measured weekly. Plasma pro-atrial natriuretic peptide decreased in both MAIZE and AGE-REF during the first 3 weeks but increased markedly in MAIZE relative to AGE-REF during week 5-7 (p ≤ 0.001). There was overall no difference in plasma cardiac troponin-T between groups. However, further analysis revealed that release of cardiac troponin-T in plasma was more frequent in AGE-REF compared with MAIZE (OR: 4.8; 95%CI: 1.2-19.7; p = 0.03). However, when release occurred, cardiac troponin-T concentration was 6.9-fold higher (95%CI: 3.0-15.9; p < 0.001) in MAIZE compared to AGE-REF. At week 7, the mean body weight in MAIZE was lower than AGE-REF (8.3 vs 32.4 kg, p < 0.001), whereas heart-weight relative to body-weight was similar across the three groups. The myocardial performance index was 86% higher in MAIZE vs AGE-REF (p < 0.001) and 27% higher in MAIZE vs WEIGHT-REF (p = 0.025).Malnutrition associates with cardiac dysfunction in a pediatric porcine model by increased myocardial performance index and pro-atrial natriuretic peptide and it associates with cardiac injury by elevated cardiac troponin-T. Clinical studies are needed to see if the same applies for children suffering from malnutrition

Equitoxic Doses of 5-Azacytidine and 5-Aza-2′Deoxycytidine Induce Diverse Immediate and Overlapping Heritable Changes in the Transcriptome

The hypomethylating agent 5-Azacytidine (5-Aza-CR) is the first drug to prolong overall survival in patients with myelodysplastic syndrome (MDS). Surprisingly, the deoxyribonucleoside analog 5-Aza-2′deoxycytidine (5-Aza-CdR) did not have a similar effect on survival in a large clinical trial. Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase (DNMT). While 5-Aza-CdR is incorporated into only DNA, 5-Aza-CR is also incorporated into RNA. Here, we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs (miRNA), which may potentially affect the activities of the drugs in patients.A hematopoietic (HL-60; acute myeloid leukemia) and a solid (T24; transitional cell carcinoma) cancer cell line were treated with equitoxic doses of 5-Aza-CR and 5-Aza-CdR for 24 hrs, and the immediate (day 2) and lasting (day 8) effects on RNA expression examined. There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog. Both drugs strongly induced expression of cancer testis antigens. On day 2 more RNAs were downregulated by 5-Aza-CR, particularly at higher doses. A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells.Overall, this suggests that significant differences exist in the immediate action of the two drugs, however the dominant pattern of the lasting, and possible heritable changes, is overlapping

miR-449 inhibits cell proliferation and is down-regulated in gastric cancer

<p>Abstract</p> <p>Background</p> <p>Gastric cancer is the fourth most common cancer in the world and the second most prevalent cause of cancer related death. The development of gastric cancer is mainly associated with <it>H. Pylori </it>infection leading to a focus in pathology studies on bacterial and environmental factors, and to a lesser extent on the mechanistic development of the tumour. MicroRNAs are small non-coding RNA molecules involved in post-transcriptional gene regulation. They are found to regulate genes involved in diverse biological functions and alterations in microRNA expression have been linked to the pathogenesis of many malignancies. The current study is focused on identifying microRNAs involved in gastric carcinogenesis and to explore their mechanistic relevance by characterizing their targets.</p> <p>Results</p> <p>Invitrogen NCode miRNA microarrays identified miR-449 to be decreased in 1-year-old <it>Gastrin </it>KO mice and in <it>H. Pylori </it>infected gastric tissues compared to tissues from wild type animals. Growth rate of gastric cell lines over-expressing miR-449 was inhibited by 60% compared to controls. FACS cell cycle analysis of miR-449 over-expressing cells showed a significant increase in the sub-G₁fraction indicative of apoptosis. ß-Gal assays indicated a senescent phenotype of gastric cell lines over-expressing miR-449. Affymetrix 133v2 arrays identified <it>GMNN</it>, <it>MET, CCNE2, SIRT1 </it>and <it>CDK6 </it>as miR-449 targets. Luciferase assays were used to confirm <it>GMNN</it>, <it>MET</it>, <it>CCNE2 </it>and <it>SIRT1 </it>as direct targets. We also show that miR-449 over-expression activated p53 and its downstream target p21 as well as the apoptosis markers cleaved CASP3 and PARP. Importantly, qPCR analyses showed a loss of miR-449 expression in human clinical gastric tumours compared to normal tissues.</p> <p>Conclusions</p> <p>In this study, we document a diminished expression of miR-449 in <it>Gastrin </it>KO mice and further confirmed its loss in human gastric tumours. We investigated the function of miR-449 by identifying its direct targets. Furthermore we show that miR-449 induces senescence and apoptosis by activating the p53 pathway.</p

Fishery Associated Changes in the Whelk Buccinum undatum Stock in the Southwest Irish Sea, 1995-2003

The whelk fishery of the southwest Irish Sea had a turnover of approximately €18 million and employed 250 people directly and indirectly in catching and processing in 2003. In the nine years, 1995-2003 inclusive, whelk landings to Ireland from the southwest Irish Sea fluctuated between 3,800 and almost 10,000 tonnes(t) per year; from an estimated 5,000 – 15,000 boat-days annually. A collapse in landings was recorded in 1997 and again in the spring of 2004. The fishery is divided for assessment purposes into four sectors, the central two consisting largely of nursery area and the north and south extremities of the fishery populated by more older, larger and mature whelk. Logbooks were not completed by fishermen participating in this fishery which was, in theory, managed by size limit, but the regulations were not enforced. Boats fishing whelk made daily fishing trips and daily weights recorded by processors were used to estimate biomass in each of the sectors by depletion regressions. Total biomass fluctuated between 12,720 t in 1999 and 37,319 t in 2002. The estimates based on a full season’s landings are used to compare the fishery from one year to the next and to supply weighting factors for other parameters of the population. Exploitation rates were lowest in one of the central sectors of the fishery (where they averaged 27% annually). At the southern extremity they averaged 39%. Depletion estimates based on landings records from approximately April to 15 June provided higher exploitation rates and lower biomass. The mortality coefficient Z, calculated from a catch curve, peaked in two years, 1998 and 2002, as did an index of recruitment. The age at full recruitment declined after 2000. Throughout nine years of documented history, one of the central sectors of the fishery assumed progressively greater dominance over the others, providing 77% of the landings from the entire fishery to its ports in 2003. Some sectoral changes to the whelk population may be irreversible: the oldest animals have been removed from the northern extremity of the fishery and while the whelks which are exploited at the southern end between 2000 and 2003 were similar in size to those exploited in the mid-1990s, their tonnage between 1999 and 2003 decreased from 47 to 4% of the landings in 1995. A substantial recruitment in 2001 or 2002 was followed by an increase in fishing effort of 42% between 2002 and 2003 and this is identified as the reason for the collapse in 2004.Funder: Marine Institut

Corn-Soy-Blend Fortified with Phosphorus to Prevent Refeeding Hypophosphatemia in Undernourished Piglets

<div><p>Background</p><p>Phosphorus (P) levels in refeeding diets are very important as undernourished children are at risk of hypophosphatemia during refeeding. For this reason, conventional corn-soy-blends (CSB) have been reformulated by the World Food Programme to obtain a mono-calcium-phosphate fortified product (CSB+) and a product further fortified with skim milk powder (CBS++).</p><p>Methods</p><p>Using a piglet model of undernourished children, we hypothesized that feeding of CSB+, CSB++ or CSB+ with added whey permeate (CSB+/wp) would help to prevent refeeding hypophosphatemia. Pigs were weaned at 4 weeks of age and undernutrition was induced with a nutritionally inadequate pure maize diet for 7 weeks, after which they were refed for 3 weeks with either CSB+ (n = 10), CSB++ (n = 10) or CSB+/wp (n = 10). For reference, a fourth group continued on the maize diet (REF, n = 10).</p><p>Results</p><p>Following induction of undernutrition, body weight and length were 29±5% and 67±4% (means±SD) of values in age-matched pigs fed a nutritionally adequate diet, and the mean serum P level was 1.77±0.34 mmol/l. During the first week of refeeding, P levels in the CSB+ pigs decreased to 55% of values before refeeding (P < 0.05) while values in the CSB++ and CSB+/wp pigs were able to maintain their plasma phosphate at a similar level as before refeeding.</p><p>Conclusion</p><p>We conclude that fortification of CSB with only monocalcium-phosphate does not prevent hypophosphatemia. Dairy products like skim milk powder or whey permeate may represent relevant sources of phosphorus during refeeding. The content and form of phosphorus in such diets need to be carefully evaluated, and the undernourished piglet may be used to test the efficacy of such diets.</p></div

Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial

Background &amp; Aims: Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced attacks and other disease manifestations, compared with placebo. Here we report data from the 36-month final analysis of ENVISION. Methods: Ninety-four patients with AHP (age ≥12 years) and recurrent attacks were randomized 1:1 to monthly double-blind subcutaneous givosiran 2.5 mg/kg (N=48) or placebo (N=46) for 6 months. In the open-label extension (OLE) period, 93 patients received givosiran 2.5 or 1.25 mg/kg for 6 months or more before transitioning to 2.5 mg/kg. Endpoints were exploratory unless otherwise noted. Results: During givosiran treatment, median annualized attack rate (AAR) was 0.4. Through Month 36, annualized days of hemin use remained low in the continuous givosiran group (median, 0.0 to 0.4) and decreased in the placebo crossover group (16.2 to 0.4). At end of OLE, in the continuous givosiran and placebo crossover groups, 86% and 92%, respectively, had 0 attacks. AAR was lower than historical AAR in 98% and 100%, respectively (post hoc analysis), and there were 0 days of hemin use in 88% and 90%, respectively. The 12-item Short Form Health Survey physical and mental component scores increased by 8.6 and 8.1, respectively (continuous givosiran) and 9.4 and 3.2, respectively (placebo crossover). EQ-5D health-related questionnaire scores increased by 18.9 (continuous givosiran) and 9.9 (placebo crossover). Lowering of urinary delta-aminolevulinic acid and porphobilinogen levels was sustained. Safety findings demonstrated a continued positive risk/benefit profile for givosiran