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In 2012, the World Health Assembly (WHA) endorsed the Global Vaccine Action Plan (GVAP), (1) with the objective of eliminating measles (2) in 5 of the 6 WHO regions by [...]

In 2010, the World Health Assembly (WHA) set the following 3 milestones for measles control to be achieved by 2015: 1) increase routine coverage with the first dose of measles-containing [...]

In 2010, the World Health Assembly (WHA) set 3 milestones for measles control, to be achieved by 2015: 1) increase routine coverage with the first dose of measles-containing vaccine (MCV1) [...]

Somatic mutations in the isocitrate dehydrogenase 2 gene (IDH2) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG).sup.1-8. Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants.sup.9,10. In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML.sup.11. Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans, such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant disease alleles alone did not induce the production of 2HG; however, the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH-mutant malignancies. A new mechanism of acquired clinical resistance in two patients with acute myeloid leukaemia driven by mutant IDH2 is described, in which a second-site mutation on the wild-type allele induces therapeutic resistance to IDH2 inhibitors., Author(s): Andrew M. Intlekofer [sup.1] [sup.2] [sup.3] [sup.4] , Alan H. Shih [sup.1] [sup.2] [sup.4] [sup.5] , Bo Wang [sup.1] [sup.2] [sup.6] , Abbas Nazir [sup.1] [sup.2] , Ariën S. [...]

In 2013, the Regional Committee of the WHO South-East Asia Region (SEAR) (1) at its 66th session adopted the goals of measles elimination and control of rubella and congenital rubella [...]

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of [Jak2.sup.V617F] and mutant [IDH1.sup.R132H] or [Idh2.sup.R140Q] induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. [Jak2.sup.V617F] [Idh2.sup.R140Q]-mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both [JAK2.sup.mut] and [IDH2.sup.mut] mutations. Taken together, these data suggest that combined JAK and IDH inhibition may offer a therapeutic advantage in this high-risk MPN subtype., Introduction Myeloproliferative neoplasms (MPNs) are clonal myeloid malignancies characterized by somatic mutations acquired in hematopoietic stem/progenitor cells, which drive the expansion of 1 or more myeloid lineages. Although patients with [...]

Rubella is the leading vaccine-preventable cause of birth defects. Whereas rubella virus infection usually causes a mild fever and rash in children and adults, infection during pregnancy, especially during the [...]

N[sup.6]-methyladenosine (m[sup.6]A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m[sup.6]A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m[sup.6]A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m[sup.6]A coupled with ribosome profiling reveals that m[sup.6]A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia., Author(s): Ly P Vu [1, 12]; Brian F Pickering [2, 12]; Yuanming Cheng [1, 12]; Sara Zaccara [2]; Diu Nguyen [1]; Gerard Minuesa [1]; Timothy Chou [1]; Arthur Chow [1]; [...]

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 546% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells., Author(s): Helena Kilpinen [1]; Angela Goncalves [2]; Andreas Leha [2]; Vackar Afzal [3]; Kaur Alasoo [2]; Sofie Ashford [4]; Sendu Bala [2]; Dalila Bensaddek [3]; Francesco Paolo Casale [1]; Oliver [...]

The Fourth United Nations Millennium Development Goal 4 (MDG4), adopted in 2000, set a target to reduce child mortality by two thirds by 2015. One of the indicators towards this [...]

Patients with advanced HIV infection commonly present with esophageal symptomatology most frequently due to Candida, cytomegalovirus, or herpes simplex virus. We present a case of a 53-year-old man with AIDS and prior esophageal candidiasis and oral aphthous ulcerations, who developed actinomycosis of the esophagus. This article aims to review clinical characteristics of this and seven previously reported cases occurring in HIV-infected patients. Esophageal actinomycosis is frequently preceded by other esophageal disease that likely results in breach of the mucosal barrier, allowing establishment of the infection. Health care providers should be aware of this rare entity, particularly in those with recurring symptoms, so that a timely diagnosis can be made. DOI: 10.1089/apc.2009.0185

Objectives. We examined the relationship between students' tobacco use and the density and proximity of tobacco retailers near their schools. Methods. We used data from the 2003-2004 California Student Tobacco Survey and California retail licensing data. Measures included students' self- reported tobacco use and geocoded state-reported locations of tobacco retailers. We used random-intercept generalized linear mixed modeling to jointly evaluate individual-level and school-level predictors. Results. Density of retailers was associated with experimental smoking (odds ratio [OR]=1.11; 95% confidence interval [CI]=1.02, 1.21) but not established smoking (OR = 1.06; 95% CI = 0.94, 1.20). The effects on experimental smoking were confined to high school students (OR=1.17; 95% CI=1.06, 1.29) in urban areas (OR=1.11; 95% CI=1.01, 1.21); no effects were observed among middle school students or in rural schools. High school students were more likely to obtain cigarettes from a retailer; middle school students relied more heavily on social sources. Conclusions. Our results support the plausibility of reducing rates of students' experimental smoking, but not established smoking, by restricting their access to commercial sources of tobacco in urban areas. (Am J Public Health. 2009;99: 2006-2013. doi: 10.2105/AJPH.2008.145128)

Background Severe trauma induces a widespread response of the immune system. This 'genomic storm' can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS. Methods and findings We performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] [greater than or equal to] 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS [less than or equal to] 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses. In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts. Conclusions In this study, we showed how the hyperacute postinjury time window contained a focused, specific signature of the response to critical injury that led to widespread genomic activation. A transcriptomic signature for later development of MODS was present in this hyperacute window; it showed a strong signal for cell death and survival pathways and implicated NK cells and neutrophil populations in this differential response., Author(s): Claudia P. Cabrera 1, Joanna Manson 2, Joanna M. Shepherd 2,*, Hew D. Torrance 3, David Watson 1, M. Paula Longhi 4, Mimoza Hoti 5, Minal B. Patel 1, [...]

Author(s): Helena Kilpinen; Angela Goncalves; Andreas Leha; Vackar Afzal; Kaur Alasoo; Sofie Ashford; Sendu Bala; Dalila Bensaddek; Francesco Paolo Casale; Oliver J. Culley; Petr Danecek; Adam Faulconbridge; Peter W. Harrison; [...]

Craig B. Thompson's conflict-of-interest statement was not included in the manuscript. The authors apologize for the oversight. The correct statement is below. CBT is a founder of Agios Pharmaceuticals and [...]

Byline: Bhavna. Puwar, Vaibhavi. Patel, Minal. Patel Introduction: Various socio demographic factors play role in sterilization operation. Materials and Methods: A record-based study was conducted in Jetalpur, rural area of [...]

Discovery Intuition and self-awareness: Excellent guides. Take a feel inside you with their help. Caves and Nooks filled with energy. Waiting to be discovered. Caves where Gremlins have made their [...]