RESUMO
Berkeleylactone A is a potent 16-membered macrolactone antibiotic, recently isolated from a coculture of Berkeley Pit Lake fungi. Although its antimicrobial activity has already been investigated, little is known about the structure-activity relationship. Based on our previous synthetic studies, a series of berkeleylactone A derivatives were synthesized and evaluated for their in vitro antimicrobial activities against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) strains. Our data confirmed the essential role of the embedded conjugated system and suggest a reversible sulfa-protection of the Michael acceptor as a viable option. Structurally simplified achiral macrolactam 8 showed the best inhibitory activity against S. aureus L12 (MRSA) with MIC50 values of 0.39 µg mL-1, 8-fold lower than those of berkeleylactone A. These studies may be of value in the development of more advanced candidates for antibiotic applications.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Antibacterianos/farmacologia , Macrolídeos , Meticilina , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Relação Estrutura-AtividadeRESUMO
Richter syndrome represents the transformation of the chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most frequently the diffuse large B-cell lymphoma (DLBCL). In this report we describe a patient with CLL, who developed a clonally-related pleomorphic highly-aggressive mantle cell lymphoma (MCL) after five cycles of a fludarabine-based second-line therapy for the first relapse of CLL. Molecular cytogenetic methods together with whole-exome sequencing revealed numerous gene alterations restricted to the MCL clone (apart from the canonical t(11;14)(q13;q32) translocation) including gain of one copy of ATM gene or emergence of TP53, CREBBP, NUP214, FUBP1 and SF3B1 gene mutations. Similarly, gene expression analysis revealed vast differences between the MCL and CLL transcriptome, including overexpression of cyclin D1, downregulation of cyclins D2 and D3, or downregulation of IL4R in the MCL clone. Backtracking analysis using quantitative PCR specifically detecting an MCL-restricted focal deletion of TP53 revealed that the pre-MCL clone appeared in the bone marrow and peripheral blood of the patient approximately 4 years before the clinical manifestation of MCL. Both molecular cytogenetic and sequencing data support the hypothesis of a slow development of the pre-MCL clone in parallel to CLL over several years, and thereby exclude the possibility that the transformation event occurred at the stage of the CLL relapse clone by mere t(11;14)(q13;q32) acquisition.
Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/metabolismo , Perda de Heterozigosidade , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Célula do Manto/metabolismo , Pessoa de Meia-Idade , Translocação Genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Healthcare-associated infections (HAIs) are caused by nosocomial pathogens. HAIs have an immense impact not only on developing countries but also on highly developed parts of world. They are predominantly device-associated infections that are caused by the planktonic form of microorganisms as well as those organized in biofilms. This review elucidates the impact of HAIs, focusing on device-associated infections such as central line-associated bloodstream infection including catheter infection, catheter-associated urinary tract infection, ventilator-associated pneumonia, and surgical site infections. The most relevant microorganisms are mentioned in terms of their frequency of infection on medical devices. Standard care bundles, conventional therapy, and novel approaches against device-associated infections are briefly mentioned as well. This review concisely summarizes relevant and up-to-date information on HAIs and HAI-associated microorganisms and also provides a description of several useful approaches for tackling HAIs.
RESUMO
GATA-1 and PU.1 are two important hematopoietic transcription factors that mutually inhibit each other in progenitor cells to guide entrance into the erythroid or myeloid lineage, respectively. PU.1 controls its own expression during myelopoiesis by binding to the distal URE enhancer, whose deletion leads to acute myeloid leukemia (AML). We herein present evidence that GATA-1 binds to the PU.1 gene and inhibits its expression in human AML-erythroleukemias (EL). Furthermore, GATA-1 together with DNA methyl Transferase I (DNMT1) mediate repression of the PU.1 gene through the URE. Repression of the PU.1 gene involves both DNA methylation at the URE and its histone H3 lysine-K9 methylation and deacetylation as well as the H3K27 methylation at additional DNA elements and the promoter. The GATA-1-mediated inhibition of PU.1 gene transcription in human AML-EL mediated through the URE represents important mechanism that contributes to PU.1 downregulation and leukemogenesis that is sensitive to DNA demethylation therapy.
Assuntos
Fator de Transcrição GATA1/genética , Leucemia Eritroblástica Aguda/genética , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Diferenciação Celular/genética , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Elementos Facilitadores Genéticos , Fator de Transcrição GATA1/metabolismo , Regulação Leucêmica da Expressão Gênica , Histonas/genética , Humanos , Leucemia Eritroblástica Aguda/patologia , Leucemia Mieloide Aguda/patologia , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/biossíntese , Transativadores/metabolismo , Transcrição GênicaRESUMO
The transcription factor PU.1 and its inhibitory microRNA-155 (miR-155) are important regulators of B-cell differentiation. PU.1 downregulation coupled with oncogenic miR-155 upregulation has been reported in lymphoid malignancies; however, these data have not been studied across different subtypes in relation to clinical outcomes. We studied expression of miR-155 and PU.1 in the six most prevalent human B-cell lymphomas (n = 131) including aggressive (DLBCL, HL, MCL) and indolent (B-CLL/SLL, MZL, FL) types. Levels of miR-155 and PU.1 inversely correlated in DLBCL, B-CLL/SLL, and FL tumor tissues. In HL tissues, an exceptionally high level of miR-155 was found in patients with unfavorable responses to first-line therapy and those who had shorter survival times. PU.1 downregulation was noted in B-CLL/SLL samples positive for the adverse prognostic markers CD38 and ZAP-70. Upregulation of miR-155 and downregulation of PU.1 expression are integral aspects of lymphoma biology that could mark aggressive behavior of some, but not all, lymphoma types.
Assuntos
Biomarcadores Tumorais/biossíntese , Regulação Neoplásica da Expressão Gênica , Linfoma/metabolismo , Linfoma/mortalidade , MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , RNA Neoplásico/biossíntese , Transativadores/biossíntese , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Proteína-Tirosina Quinase ZAP-70/metabolismoRESUMO
CCCTC-binding factor (CTCF) can both activate as well as inhibit transcription by forming chromatin loops between regulatory regions and promoters. In this regard, Ctcf binding on non-methylated DNA and its interaction with the Cohesin complex results in differential regulation of the H19/Igf2 locus. Similarly, a role for CTCF has been established in normal hematopoietic development; however its involvement in leukemia remains elusive. Here, we show that Ctcf binds to the imprinting control region of H19/Igf2 in AML blasts. We also demonstrate that Smarca5, which also associates with the Cohesin complex, facilitates Ctcf binding to its target sites on DNA. Furthermore, Smarca5 supports Ctcf functionally and is needed for enhancer-blocking effect at ICR. We next asked whether CTCF and SMARCA5 control the expression of key hematopoiesis regulators. In normally differentiating myeloid cells both CTCF and SMARCA5 together with members of the Cohesin complex are recruited to the SPI1 gene, a key hematopoiesis regulator and leukemia suppressor. Due to DNA methylation, CTCF binding to the SPI1 gene is blocked in AML blasts. Upon AZA-mediated DNA demethylation of human AML blasts, CTCF and SMARCA5 are recruited to the -14.4 Enhancer of SPI1 gene and block its expression. Our data provide new insight into complex SPI1 gene regulation now involving additional key epigenetic factors, CTCF and SMARCA5 that control PU.1 expression at the -14.4 Enhancer.
Assuntos
Adenosina Trifosfatases/genética , Proteínas Cromossômicas não Histona/genética , Epigênese Genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Transativadores/genética , Doença Aguda , Adenosina Trifosfatases/metabolismo , Animais , Azacitidina/farmacologia , Fator de Ligação a CCCTC , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/metabolismo , Metilação de DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Impressão Genômica , Células HeLa , Humanos , Immunoblotting , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Células K562 , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patologia , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Microscopia Confocal , Ligação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/metabolismoRESUMO
Nucleosome movement is, at least in part, facilitated by ISWI ATPase Smarca5 (Snf2h). Smarca5 gene inactivation in mouse demonstrated its requirement at blastocyst stage; however its role at later stages is not completely understood. We herein determined nuclear distribution of Smarca5 and histone marks associated with actively transcribed and repressed chromatin structure in embryonic and adult murine tissues and in tumor cells. Confocal microscopy images demonstrate that Smarca5 is localized mainly in euchromatin and to lesser extent also in heterochromatin and nucleoli. Smarca5 heterozygous mice for a null allele display decreased levels of histone H3 modifications and defects in heterochromatin foci supporting role of Smarca5 as a key regulator of global chromatin structure.