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Treatment at academic cancer centers (ACs) is associated with improved survival across hematologic malignancies, though the benefit in multiple myeloma (MM) has not been examined. This study aims to evaluate survival outcomes at Commission on Cancer accredited ACs compared to non-academic centers (NACs) for patients receiving MM-directed therapy. The National Cancer Database (NCDB) was used to identify demographics and overall survival (OS) of MM patients diagnosed from 2004 to 2017 and to compare outcomes by facility type. Survival analysis was repeated in a propensity score matched cohort, with NACs matched 1:1 to ACs by age, race, comorbidity score, insurance, year of diagnosis, distance traveled, and income. Of 163 375 MM patients, 44.5% were treated at ACs. Patients at ACs were more likely to receive MM-directed therapy compared to NACs (81% vs. 73%, p < .001). For patients receiving treatment, median OS at ACs was 71.3 months versus 41.2 months at NACs (p < .001). When adjusted for baseline demographics, patients treated at ACs had reduced mortality; hazard ratio (HR) 0.79 (95% CI 0.78-0.81, p < .001). The propensity score matched cohort maintained this survival benefit with a median OS of 59.9 months at ACs versus 37.0 months at NACs (p < .001), HR of 0.66 (95% CI 0.64-0.67, p < .001). ACs treated younger patients with fewer comorbidities and were more likely to treat racial minorities and patients with Medicaid or private insurance, and the uninsured. In this analysis, MM patients treated at ACs have significantly improved survival. While potentially related to access to specialized care, socioeconomic factors that drive facility selection may also contribute.
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Mieloma Múltiplo , Estados Unidos/epidemiologia , Humanos , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Medicaid , Centros Médicos Acadêmicos , Análise de SobrevidaRESUMO
Staphylococcus aureus is an important and leading cause of foodborne diseases worldwide. Prompt detection and recall of contaminated foods are crucial to prevent untoward health consequences caused by S. aureus. Helix loop-mediated isothermal amplification (HAMP) is an exciting recent addition to the array of available isothermal-based nucleic acid amplification techniques. This study aimed to develop and evaluate a HAMP assay for detecting S. aureus in milk and milk products. The assay is completed in 75 minutes of isothermal temperature incubation (64 ËC) and dye-based visual interpretation of results based on colour change. The specificity of the developed assay was ascertained using 27 S. aureus and 17 non S. aureus bacterial strains. The analytical sensitivity of the developed HAMP assay was 9.7 fg/µL of pure S. aureus DNA. The detection limit of the HAMP assay in milk (86 CFU/mL) was 1000x greater than the routinely used endpoint PCR (86 × 103 CFU/mL). The practicality of applying the HAMP assay was also assessed by analysing milk and milk product samples (n = 95) obtained from different dairy farms and retail outlets. The developed test is a more rapid, sensitive, and user-friendly method for the high-throughput screening of S. aureus in food samples and may therefore be suitable for field laboratories. To our knowledge, this is the first study to develop and evaluate the HAMP platform for detecting S. aureus.
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Leite , Infecções Estafilocócicas , Humanos , Animais , Staphylococcus aureus/genética , Colorimetria , Técnicas de Amplificação de Ácido Nucleico , HepcidinasRESUMO
Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.
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Doença de Erdheim-Chester , Neoplasias Hematológicas , Histiocitose de Células de Langerhans , Histiocitose Sinusal , Adulto , Doença de Erdheim-Chester/tratamento farmacológico , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/patologia , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/tratamento farmacológico , Histiocitose Sinusal/patologia , Humanos , PrognósticoRESUMO
Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p.R15L and p.G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p.P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p.R15L and p.G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p.R15L, but not of CHCHD10 p.G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p.G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p.P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.
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Haploinsuficiência/fisiologia , Proteínas Mitocondriais/metabolismo , Doença dos Neurônios Motores/metabolismo , Animais , DNA Complementar/genética , DNA Complementar/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Haploinsuficiência/genética , Humanos , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Doença dos Neurônios Motores/genética , Mutação/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Brucellosis is an important zoonosis worldwide. In livestock, it frequently causes chronic disease with reproductive failures that contribute to production losses, and in humans, it causes an often-chronic febrile illness that is frequently underdiagnosed in many low- and middle-income countries, including India. India has one of the largest ruminant populations in the world, and brucellosis is endemic in the country in both humans and animals. In November 2017, the International Livestock Research Institute invited experts from government, national research institutes, universities, and different international organizations to a one-day meeting to set priorities towards a "One Health" control strategy for brucellosis in India. Using a risk prioritization exercise followed by discussions, the meeting agreed on the following priorities: collaboration (transboundary and transdisciplinary); collection of more epidemiological evidence in humans, cattle, and in small ruminants (which have been neglected in past research); Economic impact studies, including cost effectiveness of control programmes; livestock vaccination, including national facilities for securing vaccines for the cattle population; management of infected animals (with the ban on bovine slaughter, alternatives such as sanctuaries must be explored); laboratory capacities and diagnostics (quality must be assured and better rapid tests developed); and increased awareness, making farmers, health workers, and the general public more aware of risks of brucellosis and zoonoses in general. Overall, the meeting participants agreed that brucellosis control will be challenging in India, but with collaboration to address the priority areas listed here, it could be possible.
Assuntos
Brucelose Bovina/prevenção & controle , Brucelose , Controle de Doenças Transmissíveis , Doenças das Cabras/prevenção & controle , Prioridades em Saúde , Doenças dos Ovinos/prevenção & controle , Zoonoses/prevenção & controle , Animais , Brucelose/prevenção & controle , Brucelose/veterinária , Bovinos , Controle de Doenças Transmissíveis/economia , Controle de Doenças Transmissíveis/métodos , Cabras , Humanos , Índia , Saúde Única , OvinosRESUMO
Purpose Hand-foot syndrome is a common dose limiting toxicity of vascular endothelial growth factor receptor tyrosine kinase inhibitors used for treatment of patients with metastatic renal cell carcinoma. The effect of treatment dose reductions, in the context of hand-foot syndrome, on survival outcomes is reported. Methods This was a retrospective case series of patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors from 1 January 2004 to 31 October 2013. The main outcomes were progression-free and overall survival in these patients experiencing hand-foot syndrome and undergoing treatment dose reductions. Univariate and multivariate analyses were conducted utilizing Kaplan-Meier method and COX Proportional Hazard model with landmark analyses at 2 months. Results Of the 120 patients evaluated, treatment dose reductions for any reason were required in 68 (56.7%) patients. The most common reasons for treatment dose reductions were mucositis, hand-foot syndrome, and fatigue. The median progression-free survival and overall survival were significantly longer in patients with hand-foot syndrome with or without treatment dose reductions as compared to those without hand-foot syndrome. Conclusions An improvement in survival outcomes was observed in metastatic renal cell carcinoma patients with treatment-associated hand-foot syndrome despite treatment dose reductions. These data need validation in a larger cohort to confirm the hypothesis that treatment dose reductions in the setting of hand-foot syndrome do not negatively impatient survival.
Assuntos
Carcinoma de Células Renais/mortalidade , Síndrome Mão-Pé/mortalidade , Neoplasias Renais/mortalidade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/tratamento farmacológico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting â¼5000 cell signaling genes into K562(R), a CML cell line with BCR-ABL1 kinase-independent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562(R) cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34(+) cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34(+) cells from normal cord blood or from a patient harboring the BCR-ABL1(T315I) mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML.
Assuntos
Transporte Ativo do Núcleo Celular , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , RNA Interferente Pequeno/genética , Transporte Ativo do Núcleo Celular/genética , Benzamidas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Técnicas de Silenciamento de Genes , Biblioteca Gênica , Humanos , Hidrazinas/farmacologia , Mesilato de Imatinib , Células K562 , Carioferinas/antagonistas & inibidores , Carioferinas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais , Triazóis/farmacologia , Ensaio Tumoral de Célula-Tronco , Proteína ran de Ligação ao GTP/antagonistas & inibidores , Proteína ran de Ligação ao GTP/genética , Proteína Exportina 1RESUMO
A simple and efficient method for the selective synthesis of 2-pyrdones from 4H-pyrans using iodine as catalyst and ethanol as solvent was developed. The present method is equally effective for both aromatic and hetero aromatic ring containing 4H-pyrans. The compatibility with various functional groups, mild reaction conditions, high yields and application of inexpensive, readily and easily available iodine as catalyst and formation of 2-pyridones as major products are the advantages of the present procedure. In vitro antiproliferative activity of the final synthesized compounds was evaluated with four different human cancer cell lines (Lung adenocarcinoma-A549, Hepatocarcinoma-HepG2, Breast carcinoma-MCF-7 and Ovarian carcinoma-SKOV3) and normal human lung fibroblast cell line (MRC-5). Compounds 2b showed better inhibition against MCF-7, HepG2 and A549 cell lines (IC50 8.00 ± 0.11, 11.93 ± 0.01 and 15.85 ± 0.04 µM, respectively) as compared with doxorubicin and also 2e showed moderate inhibition against MCF-7, HepG2 (IC50 9.32 ± 0.21 and 20.22 ± 0.01 µM, respectively, cell lines, respectively) as compared with doxorubicin. As many clinically used antiproliferative agents induce apoptosis in cancer cells hence, the 2-pyridone analogues were also tested for their ability to induce apoptosis in MCF-7 cells using the caspases-3 and -9 assays.
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Antineoplásicos/síntese química , Iodo/química , Piridonas/síntese química , Inibidores da Topoisomerase II/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Catálise , Linhagem Celular Tumoral , DNA Girase/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Piridonas/farmacologia , Piridonas/toxicidade , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/toxicidadeRESUMO
A series of eleven novel bisindole derivatives were synthesized and screened for anticancer and antiobesity potentials in in vitro mode. The reaction of 1-ethoxy carbonyl 4-pyperidone 1a with indole-3-carboxaldehyde 1b in presence of catalytic amount of piperidine gave 2 which was N-alkylated with different benzyl halides in the presence of potassium carbonate to afford compounds 3a-3k in quantitative yields. Among the compounds tested for anticancer activity against different human cancer cell lines, 3f significantly inhibited HepG2 cell line (IC50 7.33 µM) when compared with standard doxorubicin (IC50 10.15 µM). Compounds 3e (IC50 2.75 µM), 3f (IC50 4.21 µM) and 3i (IC50 15.98 µM) showed better activity than the standard curcumin (IC50 23.54 µM) against A549 cell line. Also, among the synthesized compounds, 3g (IC50 14.89 µM), 3c (IC50 56.41 µM) and 3i (IC50 30.88 µM) have potentially inhibited enzyme lipase when compared to standard Orlistat (IC50 62.25 µM). In in silico docking assays, piperidones 3e, 3f, 3i, 3c and 3a showed higher binding affinity towards anti-cancer target of A549 (3e: -11.1, 3f: -10.3, 3c: -11.3, 3i: -11.2 kcal/mol), HepG2 (3f: -10.5 kcal/mol), HeLa (3d: -10.0 kcal/mol) and SKOV3 (3f: -8.4 kcal/mol) cell lines better than standard drug doxorubicin. Docking to lipase protein for compounds 3i, 3g and 3c showed scores of -11.1, -10.7 and -10.5 kcal/mol when compared to that of standard drug Orlistat with -6.9 kcal/mol.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Lipase/antagonistas & inibidores , Piperidonas/síntese química , Piperidonas/farmacologia , Fármacos Antiobesidade/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Lipase/metabolismo , Estrutura Molecular , Piperidonas/química , Relação Estrutura-AtividadeRESUMO
The aim of this study was to report the success of maintaining reduced distal radius fractures with cast immobilisation and analyse risk factors for redisplacement. A retrospective analysis of distal radius fracture manipulated between April 2011 and 2013 was conducted. Age, gender, fracture classification, ulna fracture, dorsal comminution and volar alignment were recorded. Reduction and redisplacement were measured using Sarmiento's modification of Lidstrom's system. 110 patients were includedâ; mean age 62.8 years and 83.4% female. The AO classification was used to grade initial fractures A2 (44%), A3 (25%), C1 (20%) and C2 (10%). 86.4% of cases were improved following manipulation, although 48.4% redisplaced and 27.4% required surgical intervention. The radial length (60%) was harder to maintain than dorsal alignment (44%) in cases of redisplacement. Successful alignment of the volar cortices was associated with a statistically significant reduction in redisplacement (pâ=â0.024). Manipulation of distal -radius fractures is initially beneficial but half of cases redisplace.
Assuntos
Redução Fechada , Serviço Hospitalar de Emergência , Fraturas do Rádio/terapia , Idoso , Moldes Cirúrgicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Fraturas do Rádio/diagnóstico por imagem , Recidiva , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND & OBJECTIVES: Improving quality of life (QOL) of healthy people living with HIV (PLHIV) is critical needing home-based, long-term strategy. Sudarshan Kriya yoga (SKY) intervention is acknowledged for its positive impact on health. It is hypothesised that SKY would improve PLHIV's QOL, justifying an evaluation. METHODS: In this open label randomized controlled pilot trial, 61 adult PLHIV with CD4 count more than 400 cells/µl and Karnofsky scale score above 70 were enrolled. Those with cardiac disease, jaundice, tuberculosis, or on antiretroviral therapy/yoga intervention were excluded. All were given standard care, randomized to SKY intervention (31: I-SKY) and only standard of care in control (30: O-SOC) arms. The I-SKY participants were trained for six days to prepare for daily practice of SKY at home for 30 min. A validated 31-item WHOQOL-HIVBREF questionnaire was used to document effect in both arms from baseline to three visits at 4 wk interval. RESULTS: Baseline QOL scores, hypertension and CD4 count were similar in both arms. An overall 6 per cent improvement of QOL scores was observed in I-SKY group as compared to O-SOC group, after controlling for baseline variables like age, gender, education and occupation ( p =0.016); 12 per cent for physical ( p =0.004), 11 per cent psychological (p =0.023) and 9 per cent level of independence (p =0.001) domains. Improvement in I-SKY observed at post-training and in the SKY adherence group showed increase in these two domains. CONCLUSIONS: A significant improvement in QOL scores was observed for the three health related QOL domains in SKY intervention arm. This low cost strategy improved physical and psychological state of PLHIV calling for upscaling with effective monitoring for sustainability of quality of life.
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Infecções por HIV/fisiopatologia , Qualidade de Vida , Yoga , Adulto , Contagem de Linfócito CD4 , Feminino , Humanos , Avaliação de Estado de Karnofsky , Masculino , Projetos PilotoRESUMO
OBJECTIVE: The aim of this study is to establish the sensitivity and specificity of MRA in the investigation of patients with traumatic anterior shoulder dislocations. MATERIALS AND METHODS: A retrospective analysis of consecutive patients undergoing both magnetic resonance arthrography and arthroscopic assessment after a traumatic anterior shoulder dislocation between January 2011 and 2014 was performed. Demographic data were collected from electronic records. Images were interpreted by 8 musculoskeletal radiologists and patients were treated by 8 consultant orthopaedic surgeons. Arthroscopic findings were obtained from surgical notes and these findings were used as a reference for MRA. The sensitivity, specificity, and positive predictive value were calculated for the different injuries. RESULTS: Sixty-nine patients underwent both an MRA and shoulder arthroscopy during the study period; however, clinical notes were unavailable in 9 patients. Fifty-three patients (88 %) were male, the mean age was 28 years (range 18 to 50) and 16 subjects (27 %) had suffered a primary dislocation. The overall sensitivity and specificity of MRA to all associated injuries was 0.9 (CI 0.83-0.95) and 0.94 (CI 0.9-0.96) retrospectively. The lowest sensitivity was seen in osseous Bankart 0.8 (CI 0.44-0.96) and superior labral tear (SLAP) lesions 0.5 (CI 0.14-0.86). The overall positive predictive value was 0.88 (CI 0.76-0.91) with the lowest values found in rotator cuff 0.4 (CI 0.07-0.83) and glenohumeral ligament (GHL) lesions 0.29 (CI 0.05-0.7). CONCLUSION: Magnetic resonance angiography has a high sensitivity when used to identify associated injuries in shoulder dislocation, although in 8 patients (13 %) arthroscopy identified an additional injury. The overall agreement between MRA and arthroscopic findings was good, but the identification of GHL and rotator cuff injuries was poor.
Assuntos
Artroscopia/métodos , Imageamento por Ressonância Magnética/métodos , Luxação do Ombro/patologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
INTRODUCTION: The majority of displaced distal radius fractures are managed by closed reduction and cast immobilisation. Redisplacement is associated with initial displacement, imperfect reduction and quality of cast. The aim of this study was to establish which factors predict the risk of redisplacement. MATERIALS AND METHODS: A retrospective analysis between September 2010 and April 2013 of children who underwent closed manipulation and cast immobilisation for a distal third radius fracture was performed. Open fractures, those treated with fixation, and cases with associated dislocations or physeal injuries were excluded. Initial fracture translation and angulation, the distance from the physis and the presence of an ulna fracture were recorded. Intra-operative radiographs were analysed to assess reduction, the cast index and gap index. Clinic records and post-operative radiographs were reviewed to identify redisplacement or further surgical intervention. RESULTS: During the study period, 107 children underwent closed reduction and casting: 82 boys (76.6 %) and 25 girls (23.4 %), and the mean age of the group was 10 years. Twenty-nine children (27 %) suffered a radiographic redisplacement although only five children underwent a second surgical intervention. Statistically significant risk factors for redisplacement were initial fracture translation (p < 0.001), success of reduction (p < 0.001) and associated ulna fracture (p = 0.021). Both the mean cast index (0.81 vs. 0.78) and mean gap index (0.16 vs. 0.14) were higher in the redisplaced group, but this did not reach statistical significance. CONCLUSION: Closed reduction and immobilisation of paediatric distal radius fractures is associated with a high redisplacement rate. Initial fracture type and success of reduction are key risk factors.
Assuntos
Moldes Cirúrgicos , Fixação de Fratura/métodos , Fraturas do Rádio/terapia , Criança , Feminino , Fixação de Fratura/efeitos adversos , Humanos , Masculino , Radiografia , Fraturas do Rádio/diagnóstico por imagem , Recidiva , Estudos Retrospectivos , Fatores de RiscoRESUMO
Non-canonical NF-κB signaling is controlled by the precise regulation of NF-κB inducing kinase (NIK) stability. NIK is constitutively ubiquitylated by cellular inhibitor of apoptosis (cIAP) proteins 1 and 2, leading to its complete proteasomal degradation in resting cells. Following stimulation, cIAP-mediated ubiquitylation of NIK ceases and NIK is stabilized, allowing for inhibitor of κB kinase (IKK)α activation and non-canonical NF-κB signaling. Non-canonical NF-κB signaling is terminated by feedback phosphorylation of NIK by IKKα that promotes NIK degradation; however, the mechanism of active NIK protein turnover remains unknown. To address this question, we established a strategy to precisely distinguish between basal degradation of newly synthesized endogenous NIK and induced active NIK in stimulated cells. Using this approach, we found that IKKα-mediated degradation of signal-induced activated NIK occurs through the proteasome. To determine whether cIAP1 or cIAP2 play a role in active NIK turnover, we utilized a Smac mimetic (GT13072), which promotes degradation of these E3 ubiquitin ligases. As expected, GT13072 stabilized NIK in resting cells. However, loss of the cIAPs did not inhibit proteasome-dependent turnover of signal-induced NIK showing that unlike the basal regulatory mechanism, active NIK turnover is independent of cIAP1 and cIAP2. Our results therefore establish that the negative feedback control of IKKα-mediated NIK turnover occurs via a novel proteasome-dependent and cIAP-independent mechanism.
Assuntos
Retroalimentação Fisiológica/fisiologia , Regulação da Expressão Gênica/fisiologia , Quinase I-kappa B/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células 3T3 , Animais , Ativação Enzimática , Células HeLa , Humanos , Camundongos , Quinase Induzida por NF-kappaBRESUMO
The complete DNA A genome of a virus isolate associated with yellow mosaic disease of a medicinal plant, Hemidesmus indicus, from India was cloned and sequenced. The length of DNA A was 2825 nucleotides, 35 nucleotides longer than the unit genome of monopartite begomoviruses. Comparison of the nucleotide sequence of DNA A of the virus isolate with those of other begomoviruses showed maximum sequence identity of 69 % to DNA A of ageratum yellow vein China virus (AYVCNV; AJ558120) and 68 % with tomato yellow leaf curl virus- LBa4 (TYLCV; EF185318), and it formed a distinct clade in phylogenetic analysis. The genome organization of the present virus isolate was found to be similar to that of Old World monopartite begomoviruses. The genome was considered to be monopartite, because association of DNA B and ß satellite DNA components was not detected. Based on its sequence identity (<70 %) to all other begomoviruses known to date and ICTV (International Committee on Taxonomy of Viruses) species demarcating criteria (<89 % identity), it is considered a member of a novel begomovirus species, and the tentative name "Hemidesmus yellow mosaic virus" (HeYMV) is proposed.
Assuntos
Begomovirus/genética , Begomovirus/isolamento & purificação , Hemidesmus/virologia , Sequência de Aminoácidos , Sequência de Bases , Genoma Viral , Índia , FilogeniaRESUMO
The study examined the effects of herb drying, salt concentration, pH, and sampling approach on essential oil yield and composition in Pimenta dioica (L.) Merr. Fresh samples yielded higher essential oil (EO) (1.25%) than shade-dried ones. Increasing NaCl concentration correlated with higher EO yields, while a basic pH favoured superior yields. Gas Chromatography identified Eugenol and ß-myrcene as primary constituents. Eugenol content peaked at 10% NaCl (56.429%) and was lowest at pH 4 (42.850%). ß-myrcene content was highest at pH 4 (31.476%). Hydro distillation with systematic sampling evaluated the effects of 14 fractions in different time frames. Phenylpropanoids (mainly eugenol) and acyclic monoterpene (mainly ß-myrcene) dominated all fractions, with cyclic monoterpene (mainly limonene) enriched in the first four fractions. Fractions 10 to 14 showed significant increases in eugenol compared to the control. These findings provide insights for meeting market demands, enhancing the commercial potential of P. dioica EO.
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Nanogels offer hope for precise drug delivery, while addressing drug delivery hurdles is vital for effective prostate cancer (PCa) management. We developed an injectable elastin nanogels (ENG) for efficient drug delivery system to overcome castration-resistant prostate cancer (CRPC) by delivering Decursin, a small molecule inhibitor that blocks Wnt/ßcatenin pathways for PCa. The ENG exhibited favourable characteristics such as biocompatibility, flexibility, and low toxicity. In this study, size, shape, surface charge, chemical composition, thermal stability, and other properties of ENG were used to confirm the successful synthesis and incorporation of Decursin (DEC) into elastin nanogels (ENG) for prostate cancer therapy. In vitro studies demonstrated sustained release of DEC from the ENG over 120 h, with a pH-dependent release pattern. DU145 cell line induces moderate cytotoxicity of DEC-ENG indicates that nanomedicine has an impact on cell viability and helps strike a balance between therapeutics efficacy and safety while the EPR effect enables targeted drug delivery to prostate tumor sites compared to free DEC. Morphological analysis further supported the effectiveness of DEC-ENG in inducing cell death. Overall, these findings highlight the promising role of ENG-encapsulated decursin as a targeted drug delivery system for CRPC.
Assuntos
Elastina , Nanogéis , Neoplasias de Próstata Resistentes à Castração , Masculino , Elastina/química , Humanos , Linhagem Celular Tumoral , Nanogéis/química , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Sistemas de Liberação de Medicamentos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Benzopiranos , ButiratosRESUMO
Toxoplasma gondii and Trichinella spp. are critical tissue-dwelling foodborne zoonotic parasites associated with pork consumption and pig rearing. Despite being a major pig-rearing region in the country, Northeastern India has not undergone any investigation regarding the presence of T. gondii and Trichinella spp. in pigs. Therefore, this study aims to determine the seroprevalence of T. gondii and Trichinella spp. and identify associated risk factors in pigs reared by tribal communities and small-holder livestock farmers in the northeastern region of India. In a cross-sectional serological survey, 400 pigs from 400 households across five northeastern states of India underwent testing for the seroprevalence of porcine toxoplasmosis and trichinellosis. Serum samples (80 from each state) were analyzed using commercially available ELISA assays. Data on backyard farm characteristics and various management aspects were collected, and risk factors linked with prevalence were analyzed through univariate and multivariate logistic regression analysis. The findings revealed that the apparent and true prevalence of anti-T. gondii antibodies were 45% (40.12-49.88, 95% CI) and 45.7% (40.7-50.69, 95% CI), respectively. As for anti- Trichinella antibodies, both the apparent and true prevalence were 0.75% (-0.1-1.6, 95% CI). The univariate and multivariate analyses indicated that age above 24 months (OR 7.20, 95% CI 2.45-23.71), exposure to cats (OR = 5.87, 95% CI 2.55-14.05), and farms operating for breeding purposes (OR = 5.60, 95% CI 3.01-11.04) were significant risk factors associated with the seroprevalence of T. gondii. This study marks the initial documentation of the seroprevalence of T. gondii and Trichinella spp. in pigs reared by tribal communities in Northeastern India. The results emphasize the significance of these parasites as foodborne zoonotic threats in the region, potentially posing substantial public health risks, especially within tribal and rural communities. The insights derived from this research could be valuable in formulating targeted preventive and control strategies against T. gondii and Trichinella spp. in pigs, not only in this region but also in areas with similar rearing practices.