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Using an ab initio methodology and mass spectrometric study we identify AuO2+ as a metastable species in the gas phase. This represents the first characterization of a gas phase compound of gold with the oxidation state +4. Computations show that this dication exhibits deep potential wells with long lived electronic states. Its electronic ground state is of 4∑- symmetry, which is known for very few molecular ground states. We also discussed the O + Au2+ collision dynamics, which leads mostly to charge transfer to form Au+ and O+ species. This identification may help in identifying new routes for the reactivity of gold in the gas phase, in solution and in the condensed phase.
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Isocyanogen, CNCN, was discovered very recently in the interstellar medium (ISM). At present, the rate coefficients for the rotational (de-)excitation of CNCN by collisions with He are determined. First, we mapped the interaction potential between CNCN and He in Jacobi coordinates using highly correlated ab initio methodology. Then, an analytical expansion of the CNCN-He potential energy surface is derived. Later on, quantum dynamical treatments of nuclear motions are performed using the close coupling technique. We obtained the cross sections for the rotational (de-)excitation of CNCN after a collision by He up to 2000 cm-1 total energies. These cross sections are used to deduce the collision rates in the 10-300 K range. These data are needed for modeling the CNCN abundances in the ISM. This work should help for determining the abundance of such non-symmetrical dicyanopolyynes in astrophysical media and indirectly the symmetric one [Cyanogen (NCCN)].
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BACKGROUND AND AIMS: One of the priorities in public health policy for the control of Cutaneous Leishmaniasis (CL) is to investigate associations between disease distribution, socio-demographical and environmental risk factors, so that rational prevention and control strategies can be developed. Assessment of baseline awareness of the disease amongst the endemic population would be one of the first steps in this direction. This study aims to provide qualitative information on lay perceptions of CL in an endemic area in Saudi Arabia. We also attempted to correlate these perceptions with associated socio-demographical backgrounds. METHODS: This was a cross-sectional descriptive survey carried out in Al-Hassa, located in the Eastern Province of Saudi Arabia. The study included 1824 participants, age ranging from 15 to 63 years (mean 35.86±9.54 years). RESULTS: Over 76% of the studied population recognized the infectious nature of CL. There was also good awareness regarding the clinical features of CL, but the awareness regarding the vector, transmission, risk factors and preventive methods were very poor. Our study demonstrated a significantly higher knowledge score correlated with regard to male gender, higher family income, age and a previous history of CL. CONCLUSION: In our study we found low awareness for important epidemiological aspects like transmission of the disease, risk factors and prevention. Our study provides a baseline to understand and correct deficits in the perceptions and knowledge regarding CL in Saudi Arabia and would provide a template to design interventions.
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Conscientização , Doenças Endêmicas , Leishmaniose Cutânea/psicologia , Opinião Pública , Adolescente , Adulto , Estudos Transversais , Feminino , Humanos , Leishmaniose Cutânea/epidemiologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Risco , Arábia Saudita/epidemiologia , Adulto JovemRESUMO
Chikungunya virus (CHIKV) infection is the cause of acute symptoms and chronic symmetrical polyarthritis associated with long-term morbidity and mortality. Currently, there is no available licensed vaccine or particularly useful drug for human use against CHIKV infection. This study was conducted to evaluate the efficacy of antibodies produced by papaya mosaic virus (PapMV) nanoparticles fused to E2EP3 peptide of CHIKV envelope as a recombinant CHIKV vaccine. PapMV, PapMV-C- E2EP3, and E2EP3-N-PapMV were produced in E. coli with an approximate size of 27 to 30 kDa. ICR mice (5 to 6 weeks of age) were injected subcutaneously with 25 micrograms of vaccine construct, and ELISA measured the titer of CHIKV specific IgG antibodies. The results showed that both recombinant proteins E2EP3-N-PapMV and PapMVC-E2EP3 were able to induce IgG antibodies production in immunized mice against CHIKV while immunization with recombinant PapMV showed no IgG antibodies induction. The neutralizing activity of the antibodies generated by either E2EP3-N-PapMV or PapMV-C-E2EP3 exhibited similar inhibition to CHIKV replication in Vero cells using the cells based antibody neutralizing assay and analyzed by plaque formation assay. This study showed the effectiveness of nanoparticles vaccine generated by fusing epitope peptide of CHIKV envelope to papaya mosaic virus envelope in inducing a robust immune response in mice against CHIKV. The data showed that levels of neutralizing antibodies correlate with a protective immune response CHIKV replication.
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Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vírus Chikungunya/imunologia , Proteínas do Envelope Viral/imunologia , Sequência de Aminoácidos , Animais , Febre de Chikungunya/imunologia , Febre de Chikungunya/prevenção & controle , Epitopos/imunologia , Camundongos Endogâmicos ICR , Nanopartículas , Peptídeos , PotexvirusRESUMO
The immature and mature heart differ from each other in terms of excitability, action potential properties, contractility, and relaxation. This includes upregulation of repolarizing K(+) currents, an enhanced inward rectifier K(+) (Kir) current, and changes in Ca(2+), Na(+), and Cl(-) currents. At the molecular level, the developmental regulation of ion channels is scantily described. Using a large-scale real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay, we performed a comprehensive analysis of ion channel transcript expression during perinatal development in the embryonic (embryonic day 17.5), neonatal (postnatal days 1-2), and adult Swiss-Webster mouse hearts. These data are compared with publicly available microarray data sets (Cardiogenomics project). Developmental mRNA expression for several transcripts was consistent with the published literature. For example, transcripts such as Kir2.1, Kir3.1, Nav1.5, Cav1.2, etc. were upregulated after birth, whereas others [e.g., Ca(2+)-activated K(+) (KCa)2.3 and minK] were downregulated. Cl(-) channel transcripts were expressed at higher levels in immature heart, particularly those that are activated by intracellular Ca(2+). Defining alterations in the ion channel transcriptome during perinatal development will lead to a much improved understanding of the electrophysiological alterations occurring in the heart after birth. Our study may have important repercussions in understanding the mechanisms and consequences of electrophysiological alterations in infants and may pave the way for better understanding of clinically relevant events such as congenital abnormalities, cardiomyopathies, heart failure, arrhythmias, cardiac drug therapy, and the sudden infant death syndrome.
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Coração/embriologia , Coração/crescimento & desenvolvimento , Canais Iônicos/genética , Miocárdio/metabolismo , Animais , Canais de Cálcio/genética , Canais de Cloreto/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Expressão Gênica , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Canais Iônicos/metabolismo , Camundongos , Camundongos Transgênicos , Canais de Potássio/genética , Canais de Potássio Cálcio-Ativados/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Análise Serial de Proteínas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Canais de Sódio/genéticaRESUMO
We investigated the use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of advanced Hodgkin lymphoma (HL). Sixty-two consecutive HL patients underwent haplo-HSCT. Unmanipulated stem cells and post-transplant cyclophosphamide were given to all patients as GVHD prophylaxis. At 100 days, the cumulative incidence of grades 2-3 and grades 3-4 acute GVHD was 23% and 4%, respectively. The chronic GVHD (cGVHD) cumulative incidence was 16%, with one patient experiencing severe cGVHD. The 3-year OS, PFS, relapse rates and 1-year non-relapse mortality (NRM) were 63%, 59%, 21% and 20%, respectively. Uncontrolled disease status and high hematopoietic cell transplantation comorbidity index (HCT-CI) were associated with lower OS, whereas PBSC was an independent protective factor. Uncontrolled disease and HCT-CI >2 was predictive for NRM. Finally, disease status other than CR was predictive of relapse. In conclusion, haplo-HSCT is a valid treatment in advanced HL, offering excellent rates of survival and acceptable toxicities.
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Ciclofosfamida/uso terapêutico , Doença de Hodgkin/terapia , Transplante Haploidêntico/métodos , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Doença de Hodgkin/mortalidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico , Prognóstico , Análise de Sobrevida , Transplante Haploidêntico/mortalidade , Adulto JovemRESUMO
Unmanipulated haploidentical transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy) represents an alternative for patients with high-risk diseases lacking HLA-identical donor. Although it provides low incidences of GVHD, the efficacy of Haplo-SCT is still questioned, especially for patients with myeloid malignancies. Thus, we analyzed 60 consecutive patients with refractory (n=30) or high-risk CR (n=30) AML or myelodysplastic syndromes (MDSs) who underwent PT-Cy Haplo-SCT. The median age was 57 years (22-73 years), hematopoietic cell transplantation comorbidity index was ⩾3 in 38 patients (63%) and Haplo-SCT was the second allogeneic transplantation for 10 patients (17%). Although most of patients received PBSC as graft source (n=48, 80%), we found low incidences of grade 3-4 acute (2%) and severe chronic GVHD (4%). Among patients with high-risk CR diseases, 1-year non-relapse mortality, cumulative incidence of relapse, progression-free and overall survivals were 20%, 32%, 47% and 62%, respectively. In patients with refractory disease, corresponding results were 34%, 35%, 32% and 37%, respectively. We conclude that PT-Cy Haplo-SCT could provide promising anti-leukemic effect even in the setting of very advanced diseases. Thus, it represents a viable alternative for high-risk AML/MDS patients without HLA-identical donor.
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Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Transplante de Células-Tronco , Doença Aguda , Adulto , Idoso , Aloenxertos , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidadeRESUMO
Overexpression of anti-apoptotic BCL-2 family members is a hallmark of many lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) that can be targeted with small molecule inhibitors. ABT-199 is a rationally designed BCL-2 homology (BH)-3 mimetic that specifically binds to BCL-2, but not to MCL-1 and BCL-xL. Although the thrombocytopenia that occurs with navitoclax treatment has not been a problem with ABT-199, clinical trials in CLL could benefit by lowering the ABT-199 concentration through targeting other survival pathways. In this study, we investigated the mechanisms of resistance that develops to ABT-199 therapy by generating ABT-199-resistant (ABT199-R) cell lines via chronic exposure of NHL cell lines to ABT-199. Acquired resistance resulted in substantial AKT activation and upregulation of MCL-1 and BCL-xL levels that sequestered BIM. ABT199-R cells exhibited increased MCL-1 stability and failed to activate BAX in response to ABT-199. The ABT-199 acquired and inherent resistant cells were sensitized to treatment with ABT-199 by inhibitors of the PI3K, AKT, and mTOR pathways, NVP-BEZ235 and GS-1101. NVP-BEZ235, a dual inhibitor of p-AKT and mTOR, reduced MCL-1 levels causing BIM release from MCL-1 and BCL-xL, thus leading to cell death by BAX activation. The PI3Kδ inhibitor GS-1101 (idelalisib) downregulated MCL-1 and sensitized ABT199-R cells through AKT-mediated BAX activation. A genetic approach, through siRNA-mediated down-regulation of AKT, MCL-1, and BCL-xL, significantly decreased cell survival, demonstrating the importance of these cell survival factors for ABT-199 resistance. Our findings suggest a novel mechanism that modulates the expression and activity of pro-survival proteins to confer treatment resistance that could be exploited by a rational combination therapeutic regimen that could be effective for treating lymphoid malignancies.
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Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma/enzimologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfonamidas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteína bcl-X/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Linfoma/genética , Linfoma/patologia , Proteínas de Membrana/metabolismo , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Purinas/farmacologia , Quinazolinonas/farmacologia , Quinolinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/genéticaRESUMO
Investigation of B lymphocytes and T-lymphocyte subsets in patients with homozygous sickle cell disease (SCD) who were not in crisis and who did not demonstrate infectious complications showed these cell populations to be abnormal. The proportion of total T cells (CD2+) was significantly reduced (P = 0.002) when compared with controls. B cells (CD19+) were significantly elevated in sicklers (P = 0.029). Helper/inducer (CD4+) and suppressor/cytotoxic (CD8+) cells were significantly reduced (P = 0.019 and P = 0.0001, respectively). The average ratio of T cells/B cells in SCD patients was 3.7:1, while controls showed a ratio of 7.2:1. Since patients with SCD are abnormally susceptible to severe infections, we discussed the implications of low levels of CD4+ and CD8+ cells and the consequent cytokine imbalance in SCD patients which may lead to impairment of immunity.
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Anemia Falciforme/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Receptores Imunológicos/imunologia , Subpopulações de Linfócitos T , Antígenos CD/imunologia , Linfócitos B/imunologia , Antígenos CD2 , Linfócitos T CD4-Positivos , Feminino , Humanos , Imunofenotipagem , Contagem de Leucócitos , Masculino , Linfócitos T ReguladoresRESUMO
Circulating lymphocyte subset imbalance is associated with type-1 insulin-dependent diabetes mellitus (IDDM). To examine the imbalance in these immunoregulatory cells in Kuwaitis with type-1 diabetes and their first-degree relatives we analysed T-lymphocyte subsets and HLA-DR expression (activation) in 18 IDDM patients with a family history of IDDM and 18 non-diabetic first-degree relatives of the IDDM patients. Both IDDM patients and their first-degree relatives showed a mild lymphopenia. Total T lymphocytes, CD3+ cells, in IDDM patients and their first-degree relatives were reduced compared to control subjects (P < 0.001). Total B lymphocytes, CD19+ cells, was increased in IDDM patients (P = 0.001), but was comparable to controls in IDDM patients' first-degree relatives. No quantitative abnormality was demonstrated in CD4+ cells in IDDM patients; however, these cells were higher in their first-degree relatives (P = 0.0089). Suppressor T lymphocytes, CD8+ cells, in first-degree relatives and controls were not significantly different; however, these cells were significantly reduced in IDDM patients (P = 0.001). The ratio of CD4+/CD8+ cells was higher in IDDM patients and their first-degree relatives compared to controls (P = 0.0007 and 0.0103, respectively). Activated T lymphocytes, HLA-DR+ CD3+ cells, were significantly increased in IDDM patients and their first-degree relatives. HLA-DR3 was the most common antigen found in IDDM patients (77% vs. 20% in controls, P = 0.00021). The second most common antigen was HLA-DR4 (55% vs. 24% in controls, P = 0.0566). However, no relationship was found in the levels of CD3+, CD4+ or CD8+ cells in patients possessing either DR3 or DR4. These results suggest that T-lymphocyte subset imbalance not only characterizes the cellular autoimmunity in the pathogenesis of IDDM but may also be significant in early pre-diabetic stages in those with a family history of IDDM.