MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

Myelofibros is (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAK(V617F) mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK(V617F) inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-S43 was significantly upregulated in non responders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2(V617F) mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options

Noncoding RNA Profiles in Tobacco- and Alcohol-Associated Diseases

Tobacco and alcohol are the leading environmental risk factors in the development of human diseases, such as cancer, cardiovascular disease, and liver injury. Despite the copious amount of research on this topic, by 2030, 8.3 million deaths are projected to occur worldwide due to tobacco use. The expression of noncoding RNAs, primarily microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), is modulated by tobacco and alcohol consumption. Drinking alcohol and smoking cigarettes can modulate the expression of miRNAs and lncRNAs through various signaling pathways, such as apoptosis, angiogenesis, and inflammatory pathways—primarily interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), which seems to play a major role in the development of diseases associated with these risk factors. Since they may be predictive and prognostic biomarkers, they can be used both as predictors of the response to therapy and as a targeted therapy. Further, circulating miRNAs might be valuable noninvasive tools that can be used to examine diseases that are related to the use of tobacco and alcohol. This review discusses the function of noncoding RNAs in cancer and other human tobacco- and alcohol-associated diseases

Plasmodium vivax and Plasmodium falciparum ex vivo susceptibility to anti-malarials and gene characterization in Rondônia, West Amazon, Brazil.

Submitted by Nuzia Santos ([email protected]) on 2015-02-09T18:31:12Z No. of bitstreams: 1 2014_064.pdf: 497580 bytes, checksum: 316e9d474b23be75c14c54a2ed6320ab (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-02-09T18:31:20Z (GMT) No. of bitstreams: 1 2014_064.pdf: 497580 bytes, checksum: 316e9d474b23be75c14c54a2ed6320ab (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-02-09T18:35:37Z (GMT) No. of bitstreams: 1 2014_064.pdf: 497580 bytes, checksum: 316e9d474b23be75c14c54a2ed6320ab (MD5)Made available in DSpace on 2015-02-09T18:35:37Z (GMT). No. of bitstreams: 1 2014_064.pdf: 497580 bytes, checksum: 316e9d474b23be75c14c54a2ed6320ab (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária.Belo Horizonte, MG, Brazil/Universidade Federal de Minas Gerais. Faculdade de Medicina. Belo Horizonte, MG, BrazilCentro de Pesquisas em Medicina Tropical de Rondônia. Porto Velho, RO, BrazilUniversidade Federal de Minas Gerais. Faculdade de Medicina. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Faculdade de Medicina. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, Brazil/Universidade Federal de Minas Gerais. Faculdade de Medicina. Belo Horizonte, MG, BrazilBackground: Chloroquine (CQ), a cost effective antimalarial drug with a relatively good safety profile and therapeutic index, is no longer used by itself to treat patients with Plasmodium falciparum due to CQ-resistant strains. P. vivax, representing over 90% of malaria cases in Brazil, despite reported resistance, is treated with CQ as well as with primaquine to block malaria transmission and avoid late P. vivax malaria relapses. Resistance to CQ and other antimalarial drugs influences malaria control, thus monitoring resistance phenotype by parasite genotyping is helpful in endemic areas. Methods: A total of 47 P. vivax and nine P. falciparum fresh isolates were genetically characterized and tested for CQ, mefloquine (MQ) and artesunate (ART) susceptibility in vitro. The genes mdr1 and pfcrt, likely related to CQ resistance, were analyzed in all isolates. Drug susceptibility was determined using short-term parasite cultures of ring stages for 48 to 72 hour and thick blood smears counts. Each parasite isolate was tested with the antimalarials to measure the geometric mean of 50% inhibitory concentration. Results; The low numbers of P. falciparum isolates reflect the species prevalence in Brazil; most displayed low sensitivity to CQ (IC50 70 nM). However, CQ resistance was rare among P. vivax isolates (IC50 of 32 nM). The majority of P. vivax and P. falciparum isolates were sensitive to ART and MQ. One hundred percent ofP. falciparum isolates carried non-synonymous mutations in the pfmdr1 gene in codons 184, 1042 and 1246, 84% in codons 1034 and none in codon 86, a well-known resistance mutation. For the pfcrt gene, mutations were observed in codons 72 and 76 in all P. falciparum isolates. One P. falciparum isolate from Angola, Africa, showing sensitivity to the antimalarials, presented no mutations. In P. vivax, mutations of pvmdr1 and the multidrug resistance gene 1 marker at codon F976 were absent. Conclusion: All P. falciparum Brazilian isolates showed CQ resistance and presented non-synonymous mutations inpfmdr1 and pfcrt. CQ resistant genotypes were not present among P. vivax isolates and the IC50 values were low in all samples of the Brazilian West Amazon

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy

Angiogenesis and co-optive vascular remodeling are prerequisites of solid tumor growth. Vascular heterogeneity, notably perivascular composition, may play a critical role in determining the rate of cancer progression. The contribution of vascular pericyte heterogeneity to cancer progression and therapy response is unknown. Here, we show that angiopoietin-2 (Ang2) orchestrates pericyte heterogeneity in breast cancer with an effect on metastatic disease and response to chemotherapy. Using multispectral imaging of human breast tumor specimens, we report that perivascular composition, as defined by the ratio of PDGFR beta(-) and desmin(+) pericytes, provides information about the response to epirubicin but not paclitaxel. Using 17 distinct patient-derived breast cancer xenografts, we demonstrate a cancer cell-derived influence on stromal Ang2 production and a cancer cell-defined control over tumor vasculature and perivascular heterogeneity. The aggressive features of tumors and their distinct response to therapies may thus emerge by the cancer cell-defined engagement of distinct and heterogeneous angiogenic programs.NIH [CA155370]University of Texas Faculty Science and Technology Acquisition and Retention (STARs) ProgramNIH/National Cancer institute Cancer Center Support Grant New Faculty Award [P30CA016672]UT MD Anderson Cancer Center through the Khalifa Bin Zayed Al Nahyan FoundationHelse VestBergen Medical Research FoundationNorwegian Cancer SocietyRieber Foundation, NorwayUniv Texas MD Anderson Canc Ctr, Dept Canc Biol, 1881 East Rd,Unit 1906, Houston, TX 77054 USAUniv Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USAUniv Texas MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX 77030 USARoche Innovat Ctr, Discovery Oncol, Roche Pharmaceut Res & Early Dev, pRED, Munich, GermanyAC Camargo Canc Ctr, Dept Anat Pathol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Gynecol, Mol Gynecol Lab, Sao Paulo, BrazilUniv Bergen, Sect Oncol, Dept Clin Sci, Bergen, NorwayHaukeland Hosp, Dept Oncol, Bergen, NorwayUniv Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Houston, TX 77030 USAMolecular Gynecology Laboratory, Gynecology Department, Universidade Federal de São Paulo (UNIFESP), Brazil.Web of Scienc

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy

Angiogenesis and co-optive vascular remodeling are prerequisites of solid tumor growth. Vascular heterogeneity, notably perivascular composition, may play a critical role in determining the rate of cancer progression. The contribution of vascular pericyte heterogeneity to cancer progression and therapy response is unknown. Here, we show that angiopoietin-2 (Ang2) orchestrates pericyte heterogeneity in breast cancer with an effect on metastatic disease and response to chemotherapy. Using multispectral imaging of human breast tumor specimens, we report that perivascular composition, as defined by the ratio of PDGFR beta(-) and desmin(+) pericytes, provides information about the response to epirubicin but not paclitaxel. Using 17 distinct patient-derived breast cancer xenografts, we demonstrate a cancer cell-derived influence on stromal Ang2 production and a cancer cell-defined control over tumor vasculature and perivascular heterogeneity. The aggressive features of tumors and their distinct response to therapies may thus emerge by the cancer cell-defined engagement of distinct and heterogeneous angiogenic programs.NIH [CA155370]University of Texas Faculty Science and Technology Acquisition and Retention (STARs) ProgramNIH/National Cancer institute Cancer Center Support Grant New Faculty Award [P30CA016672]UT MD Anderson Cancer Center through the Khalifa Bin Zayed Al Nahyan FoundationHelse VestBergen Medical Research FoundationNorwegian Cancer SocietyRieber Foundation, NorwayUniv Texas MD Anderson Canc Ctr, Dept Canc Biol, 1881 East Rd,Unit 1906, Houston, TX 77054 USAUniv Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USAUniv Texas MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX 77030 USARoche Innovat Ctr, Discovery Oncol, Roche Pharmaceut Res & Early Dev, pRED, Munich, GermanyAC Camargo Canc Ctr, Dept Anat Pathol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Gynecol, Mol Gynecol Lab, Sao Paulo, BrazilUniv Bergen, Sect Oncol, Dept Clin Sci, Bergen, NorwayHaukeland Hosp, Dept Oncol, Bergen, NorwayUniv Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Houston, TX 77030 USAMolecular Gynecology Laboratory, Gynecology Department, Universidade Federal de São Paulo (UNIFESP), Brazil.Web of Scienc

Plasma Viral Mirnas Indicate A High Prevalence Of Occult Viral Infections

Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P < 0.001). The prevalence of KSHV infection based on miRNAs qPCR is significantly higher than the prevalence determined by seropositivity, and this ismore obvious for immuno-depressed patients. Plasma viral miRNAs quantification proved that EBV infection is ubiquitous. Measurement of viral miRNAs by qPCR has the potential to become the "gold" standard method to detect certain viral infections in clinical practice. (C) 2017 Elsevier B. V