ABSTRACT
Enforced expression of microRNA-155 (miR-155) in myeloid cells has been shown to have both oncogenic or tumour-suppressor functions in acute myeloid leukaemia (AML). We sought to resolve these contrasting effects of miR-155 overexpression using murine models of AML and human paediatric AML data sets. We show that the highest miR-155 expression levels inhibited proliferation in murine AML models. Over time, enforced miR-155 expression in AML in vitro and in vivo, however, favours selection of intermediate miR-155 expression levels that results in increased tumour burden in mice, without accelerating the onset of disease. Strikingly, we show that intermediate and high miR-155 expression also regulate very different subsets of miR-155 targets and have contrasting downstream effects on the transcriptional environments of AML cells, including genes involved in haematopoiesis and leukaemia. Furthermore, we show that elevated miR-155 expression detected in paediatric AML correlates with intermediate and not high miR-155 expression identified in our experimental models. These findings collectively describe a novel dose-dependent role for miR-155 in the regulation of AML, which may have important therapeutic implications.
Subject(s)
Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute/genetics , MicroRNAs/genetics , RNA Interference , Adolescent , Animals , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Child , Child, Preschool , Disease Models, Animal , Gene Expression , Hematopoiesis/genetics , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Mice , Prognosis , Tumor Stem Cell AssayABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0152310.].
ABSTRACT
BACKGROUND: Data regarding the viremia profile of chikungunya virus (CHIKV) infected patients especially during the pre-febrile period is limited. OBJECTIVE: To obtain virological kinetic data on CHIKV infections. STUDY DESIGN: A two-week community observation for dengue transmission was conducted in Bandung, Indonesia, from 2005 to 2009. Acute specimens from non-dengue febrile patients were screened by pan-alphavirus conventional RT-PCR. The positives were confirmed for CHIKV RNA by a specific RT-PCR followed by sequencing. Simultaneously these specimens were also cultured in Vero cells and tested for anti-CHIK IgM MAC-ELISA. All the available serial specimens,including the pre-febrile specimens, from confirmed CHIK cases, were tested by virus isolation, RT-PCR, qRT-PCR, and CHIK IgM ELISA. RESULTS: There were five laboratory confirmed CHIK cases identified and studied. Among these, viremia was determined to extend from as early as 6 days prior to until 13 days post fever onset. Quantitative RT-PCR showed viremia peaked at or near onset of illness. CONCLUSION: In this study, individuals were identified with viremia prior to fever onset and extending beyond the febrile phase. This extended viremic phase has the potential to impact transmission dynamics and thus the public health response to CHIK outbreaks.
Subject(s)
Chikungunya Fever/virology , Chikungunya virus/isolation & purification , Viral Load , Viremia/diagnosis , Adolescent , Adult , Antibodies, Viral/blood , Child , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin M/blood , Indonesia , Male , Middle Aged , RNA, Viral/blood , Real-Time Polymerase Chain Reaction , Time FactorsABSTRACT
In January 2005, a tetanus epidemic was discovered amongst survivors of the Boxing Day Tsunami in Aceh, Indonesia. Our aim was to describe the extent of the tetanus outbreak in tsunami survivors admitted and describe the case outcomes from one hospital. All clinicians were instructed to report suspected cases to a centralised organisation using a standardised data collection tool. Active case finding was carried out by a trained team that visited hospital wards in Aceh. Of the 106 cases, 79% was above 25 years old (the median age was 40 years) and 62% was male. The mortality rate in Aceh was 19% and that of in follow up cases was 17%. Fifteen of the follow-up cases were admitted with severe tetanus associated with superficial wounds, three of whom had a history of immersion. Supplies to treat the tetanus cases in this epidemic were initially limited as disaster relief agencies were not prepared for the resultant tetanus epidemic. The mortality rate of 17%, was significantly less than was usual for tetanus in adults (>50%) and children (80%) in underdeveloped countries. To reduce mortality and morbidity, rapid disaster relief organisations should include supplies for vaccination and treatment of tetanus cases and consider early tracheotomy for severe cases.
