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1.
Indian J Dent Res ; 31(4): 546-549, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33107454

RESUMO

Background: Diabetes is a metabolic disorder, which affects almost all parts of body. Dental problems remain neglected among diabetics which could have negative impact on health and if untreated could lead to financial loss in treatment of diseases. Aims: To compare the risk, quality of life (QOL), and direct cost of dental problems between cases and controls. Methods: A hospital-based case control study in a tertiary care hospital of Uttarakhand, India. Results: The risk of comorbidities of dental problem was 1.8 times higher as compared with controls. Twenty-six percent of cases were found to be suffering from one or the other type of dental problems as compared with 16.4% among controls. The direct cost expenditure among cases was significantly higher as compared with controls. Limitations: The QOL scores and the cost of treatment obtained could be an overestimate as some of the participants with dental problems also had comorbidities related to other systems of the body. Conclusion: The risk of dental problems and the direct cost was reported to be significantly higher among cases as compared with controls.


Assuntos
Diabetes Mellitus , Qualidade de Vida , Estudos de Casos e Controles , Comorbidade , Diabetes Mellitus/epidemiologia , Humanos , Índia/epidemiologia
2.
BMC Infect Dis ; 20(1): 720, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004004

RESUMO

BACKGROUND: Children living with sputum smear-positive adult tuberculosis (TB) patients are vulnerable to acquire tubercular infection. Contact tracing is an important strategy to control tubercular infection in the community. This study was done to find out prevalence of tuberculosis and tubercular infection in children living with sputum smear-positive adult patients receiving DOTS at recruitment and to find out incidence of tubercular infection and disease in these children on follow up. METHOD: Children (< 15 years) living in contact with adults on DOTS were grouped as < 6 years and 6-14 years. They were further sub grouped as being - uninfected, infected, diseased and on prophylaxis and were followed at 3, 6 and 9 months. Tuberculin skin test (TST) and chest X-ray were done. RESULTS: At recruitment 152 children were enrolled and 21.1% (n = 32) had TB. On follow up, 4.3% (n = 5), 5.8% (n = 6) and 11.6% (n = 11) children developed TB after 3, 6 and 9 months respectively.9 children did not come for the last follow up so the overall prevalence of TB disease at 9 months was 37.7% (n = 54). Out of the 128 children with TST reading 23.4% (n = 30) child contacts were found to be infected already at recruitment. The incidence of TST conversion was 20.7% (n = 18), 26.9% (n = 18) and 16.3% (n = 7) respectively. The overall prevalence of tubercular infection in the children, who were in contact with TB patients for 9 months was 74.5% (n = 73). CONCLUSION: About half the children were either suffering from TB or tubercular infection on recruitment. During 9 months follow up 22 unaffected children developed disease and 43acquired infection.


Assuntos
Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Características da Família , Feminino , Seguimentos , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Escarro/microbiologia , Teste Tuberculínico , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologia , Adulto Jovem
3.
Front Oncol ; 10: 1226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850364

RESUMO

The polycomb repressive complex 2 (PRC2) maintains the transcriptional repression of target genes through its catalytic component enhancer of zeste homolog 2 (EZH2). Through modulating critical gene expression, EZH2 also plays a role in cancer development and progression by promoting cancer cell survival and invasion. Mutations in EZH2 are prevalent in certain B-cell lymphoma subtypes such as diffuse large cell lymphoma and follicular lymphoma; while no EZH2 mutation has been reported in the mantle cell lymphoma (MCL). Here we demonstrate that the PRC2 components EZH2, EED and SUZ12 are upregulated in the MCL cells as compared to normal B-cells. Moreover, stably transfected cells with wild-type EZH2 or-EED showed increased cell growth and H3K27-trimehtylation. However, unlike wild-type EZH2, ectopic expression of a deletion construct of EZH2 (EZH2Δ550-738 lacking SET domain) had no growth advantage over control cells. Pharmacological inhibition of EZH2 suppressed H3K27me3 and had significant inhibitory effect on cell growth and colony forming capacity (p < 0.05) of MCL cells, and this effect was more or less comparable to the anti-proliferative effects of EZH2 inhibition in cells harboring EZH2-mutation. Mechanistically, EZH2 appears to downregulate expression of cdkn2b gene via enhanced H3K27me3, a well-known suppressive epigenetic mark, at the cdkn2b promoter region. Overall, these results highlight that deregulation of PRC2/EZH2 is associated with epigenetic suppression of cdkn2b in MCL, and in part responsible for increased cell growth, thus the EZH2 inhibitors may have therapeutic potential in the patients with MCL.

4.
BMJ Open ; 10(5): e034330, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32385060

RESUMO

INTRODUCTION: Depression is a common mental disorder in the elderly population, which significantly impacts their quality of life. However, correct estimates of its magnitude are not available in the elderly in India. The present systematic review and meta-analysis would attempt to estimate the prevalence of depression using diagnostic instruments among elderly persons aged 60 years and above. METHODS AND ANALYSIS: Searches will be performed in PubMed, Scopus, Embase, Web of Science, CINAHL and PsycINFO. Community-based cross-sectional and cohort studies (2001 to September 2019) reporting the prevalence of depression in the elderly, using diagnostic instruments will be included. Studies conducted among chronic disease patients, in-hospital patients and special groups such as with disaster-stricken populations, and studies reporting the only one or two subcategories of depression, will be excluded. Disagreements in study selection and data abstraction will be resolved by consensus and arbitration by a third reviewer. AXIS critical appraisal tool will be used for quality assessment of individual studies. Findings of eligible studies will be pooled using fixed-effects or random-effects meta-analysis whichever is appropriate. Heterogeneity between studies will be examined by Cochran's Q test and quantified by I² statistic. A cumulative meta-analysis will be used to detect temporal trends in the prevalence of depression and the effect of poor-quality studies on the pooled estimate. Publication bias will be assessed by visual inspection of funnel plots and the Egger test. ETHICS AND DISSEMINATION: No ethical approval will be needed because it will be a systematic review. Data from previously published studies will be retrieved and analysed. Findings will be disseminated through a peer-reviewed publication in a scientific journal and conferences. PROSPERO REGISTRATION NUMBER: CRD42019138453.

5.
Chemistry ; 26(19): 4396-4402, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31943447

RESUMO

Herein, the RhIII -catalyzed selective monoarylation and diarylation (symmetrical and unsymmetrical) of 8-methylquinolines with organoboron reagents are disclosed. The selective monoarylation of primary C(sp3 )-H bonds is achieved by using 7-substituted 8-methylquinolines or by changing the quantity of the aryl boronic acids. The method is also applicable for the arylation of 2-ethylpyridines, and the heteroarylation with thiophene-2-ylboronic acids. Symmetrical and unsymmetrical diarylation of 8-methylquinolines have been carried out in one-pot and sequential manner, respectively. Late-stage monoarylation of oxime derivatives and gram-scale synthesis of monoarylated products has also been carried out. A mechanistic study revealed that the current reaction is first order with respect to both reactants and a five-membered rhodacycle intermediate may be involved in the catalytic cycle.

6.
ACS Omega ; 5(1): 904-913, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31956844

RESUMO

Herein, we disclose Ru(II)-catalyzed regioselective distal C(sp2)-H arylation of quinoline N-oxide with arylboronic acids to 8-arylquinolines. In the developed method, the Ru(II)-catalyst shows dual activity, that is, distal C-H activation of quinoline N-oxides followed by in situ deoxygenation of arylated quinoline N-oxide in the same pot. The current catalytic method features use of Ru metal as the catalyst and arylboronic acids as the arylating source under mild reaction conditions. Use of the Rh(III)-catalyst in place of Ru(II) under the same conditions afforded 8-arylquinoline N-oxides with excellent regioselectivity. Furthermore, the developed Ru(II) catalytic system is also extended for the C(sp2)-H arylation of indolines, N-tert-butylbenzamide, and 6-(5H)-phenanthridinone. Formation of the quinoline N-oxide coordinated ruthenium adduct is found to be the key reaction intermediate, which has been characterized by single crystal X-ray diffraction and NMR spectroscopy.

7.
Med Chem ; 16(1): 4-23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31203807

RESUMO

BACKGROUND: Thiazole is a good nucleus owing to its various pharmaceutical applications. Thiazole containing compounds (thiazoles) have shown various biological activities like antioxidant, analgesic, antibacterial, anticancer, antiallergic, antihypertensive, antiinflammatory, antimalarial, antifungal and antipsychotic. The scaffold is present in more than 18 FDA approved drugs and also in more than 70 experimental drugs. Only a few reviews are available in the literature despite its great medicinal importance. During the course of time, this scaffold has been studied extensively for its antiviral activities and provided compounds with activity in the nM range. However, no focused review is available on the compilation of antiviral activities shown by this scaffold. OBJECTIVE: In the present review, we have made an effort to compile antiviral literature of thiazoles reported from the year 2011 to till date. METHODS: We searched the SciFinder database (excluding patent literature) with keywords like "antiviral", "anti-HIV" and "virus". Further filters were applied for the year of publication and keywords thiazole, reviews etc. to find relevant literature reported on the antiviral activities of thiazoles. RESULTS: Nearly, 50 research articles were selected to compile and review the antiviral literature of thiazoles reported from the year 2011 to till date. Compounds 8, 25, 40, 62, 72, 73, 91, 112, 113, 131, 137, 175, 198, 200, 201 and 213 were reported in the literature with potent antiviral activity against CVB, SARS, RSV, HCV, HRV, VZV, TMV, FMDV, DENV, YFV, influenza virus, Junin virus, HIV-1, HSV, VV and EBV, respectively. CONCLUSION: There is further scope for the synthesis and evaluation of novel thiazole compounds by taking the most active compounds as lead structures. In conclusion, this review provides an overview of antiviral activities of thiazole compounds reported from the year 2011 to till date.


Assuntos
Antivirais/farmacologia , Tiazóis/farmacologia , Vírus/efeitos dos fármacos , Antivirais/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química
8.
J Org Chem ; 85(2): 1181-1192, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31842545

RESUMO

Herein, [RuCl2(p-cymene)]2/[Cp*RhIIICl2]2-catalyzed direct alkylation of C(sp3)-H bond of 8-methylquinolines with olefins (acrylates, styrenes, and aliphatic) is reported. The alkylation also proceeds with other conjugated systems such as malemides and α,ß-unsaturated ketones. The reaction is highly regioselective, forms only a linear product, and tolerates a variety of functional groups on quinoline and olefin moieties. Control experiments, deuterium labeling, and kinetic studies have been carried out for preliminary understanding of the reaction pathway. The reaction possibly proceeds through five-membered metallacycle under redox-neutral condition. Diversification of alkylated product and late-stage functionalization of ketoxime derivatives of (-)-santonin have also been carried out to demonstrate the applicability of the developed method.

9.
Diabetes Metab Syndr ; 14(6): 2153-2159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33395775

RESUMO

BACKGROUND AND AIMS: The objective of present study was to estimate and compare the direct cost between diabetics and age and gender matched non-diabetics. It also aimed to estimate and compare the effect of various comorbidities on direct cost between cases and controls, while simultaneously trying to determine the predictors of direct cost among T2DM patients. METHODS: A hospital-based pair matched case-control study was conducted in a tertiary care hospital in Garhwal division of Uttarakhand, India to accomplish the objectives of study. Regression analysis was applied to determine the predictors of direct cost among diabetics. RESULTS: Mean annual direct cost among diabetics was estimated to be US$ 104.6 (Indian Rupees (INR) 7338.9)) in comparison to US$ 27.8 (INR 1905.8) among non-diabetics. The total cost among cases was significantly higher than controls, if they had comorbidities from CVS, nervous, ophthalmic, respiratory and musculoskeletal system. Gender, education, duration of diabetes and number of comorbidities were significant predictors in estimating the direct cost among cases. For each one-year increase in duration of diabetes, direct cost increased by 13.1 unit. CONCLUSIONS: The study provides us conclusive evidence of significantly higher expenditure among diabetics in comparison to non-diabetics. An effect on direct cost among diabetics was observed with types and increasing number of comorbidities.

11.
Eur J Med Chem ; 183: 111714, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557609

RESUMO

In our continuing efforts to find novel anti-HIV compounds, we have synthesized sixteen novel pyrazolo[4,3-c]pyridin-4-one derivatives. All the synthesized compounds were screened for anti-HIV activity against HIV-1VB59 (R5, subtype C). Compounds 12a-12c and 12e were also tested against HIV-1UG070 (X4, subtype D) in TZM-bl cell line. Compound 12c was found to be the most active against HIV-1VB59 and HIV-1UG070 with IC50 value 3.67 µM and 2.79 µM, and therapeutic indices 185 and 243, respectively. The lead compound 12c inhibited the HIV-192/BR/018 (R5, subtype B) and drug resistant isolates, NIH-119 (X4/R5, subtype B) and NARI-DR (R5, subtype C) effectively. The activity of the lead compound was further confirmed by PBMC assays. The molecular docking data showed that the most active compound 12c binds in the non-nucleoside binding pocket of HIV-1 reverse transcriptase, which was confirmed by the ToA assay. Thus the study indicated that 12c may be considered as a NNRTI and further explored as a lead for anti-HIV drug development.


Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/síntese química , Piridinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/farmacologia , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Pirazóis/farmacologia , Piridinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
12.
Neuro Oncol ; 21(11): 1458-1469, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31346613

RESUMO

BACKGROUND: Glioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)-wildtype GBM long-term survivors (LTS) to date. METHODS: Retrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression. RESULTS: Of the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks. CONCLUSIONS: While our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Mutação , Sobreviventes/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Epigênese Genética , Feminino , Seguimentos , Perfilação da Expressão Gênica , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transcriptoma , Adulto Jovem
13.
J Org Chem ; 84(20): 12871-12880, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31257883

RESUMO

A highly efficient and regioselective Rh(III)-catalyzed protocol for C8-bromination and amidation of quinoline N-oxide was developed. The transformation was found to be successful up to gram scale with excellent functional group tolerance and wide substrate scope. The mechanistic study revealed five-membered rhodacycle with quinoline N-oxide as a key intermediate for regioselective C8-functionalization. In addition, NFSI (N-fluorobis(phenylsulfonyl)-imide) was explored as an amidating reagent for C8-amidation of quinoline N-oxide for the first time.

14.
J Hematol Oncol ; 12(1): 73, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288832

RESUMO

Double/triple-hit lymphomas (DHL/THL) account for 5-10% of diffuse large B cell lymphoma (DLBCL) with rearrangement of MYC and BCL2 and/or BCL6 resulting in MYC overexpression. Despite the poor prognosis of DHL, R-CHOP chemotherapy remains the treatment backbone and new targeted therapy is needed. We performed comprehensive cytogenetic studies/fluorescence in situ hybridization on DLBCL and Burkitt lymphoma cell lines (n = 11) to identify the DHL/THL DLBCL in vitro model. We identified MYC/IG in Raji and Ramos (single hit); MYC/IG-BCL2 (DHL) in DOHH2, OCI-LY1, SUDHL2, and OCI-LY10; MYC/IG-BCL2/BCL6 (THL) in VAL; and no MYC rearrangement in U2932 and HBL1 (WT-MYC). Targeting MYC in the DHL/THL DLBCLs through bromodomain extra-terminal inhibitors (BETi) (JQ1, I-BET, and OTX015) significantly (p < 0.05) reduced proliferation, similar to WT-MYC cells, accompanied by decreased MYC but not BCL2 protein. Moreover, BETi suppressed MYC transcription and decreased BRD4 binding to MYC promoter in DHL cells. CD47 and PD-L1 are immunoregulatory molecules often expressed on tumors and regulated by MYC. High levels of surface CD47 but not surface PD-L1 was observed in DHL/THL, which was reduced by JQ1 treatment. BETi in combination with Pan-HDAC inhibitor had a limited effect on survival of DHL/THL, while combination of BETi and BCL2 inhibitor (ABT-199) had a significant (p < 0.005) inhibitory effect on survival followed by BCL-XL inhibition. Overall, the data suggests that MYC-expressing DLBCLs are probably addicted to the MYC-oncogenic effect regardless of MYC rearrangements. In summary, we identified an in vitro model for DHL/THL DLBCLs and provide evidence for the therapeutic potential of BET inhibitor alone or in combination with BCL2 inhibitor.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Feminino , Humanos , Masculino , Transfecção
15.
BMC Public Health ; 19(1): 832, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248394

RESUMO

BACKGROUND: There is lack of information on the magnitude of depression among elderly population in India. This systematic review and meta-analysis aimed to estimate the prevalence of depression among elderly population in India. METHODS: PubMed, Scopus, Web of Science, Embase, PsycINFO, IndMed, and Google Scholar were searched to identify articles reported community-based prevalence of depression among elderly population using screening tools. This study included the articles published during the years 1997 to 2016. Studies conducted in the special population groups, hospitals, reported only a subcategory of depression, and not specified the screening tool were excluded. Data were extracted from published reports and any missing information was requested from authors. Estimates were pooled using random-effects meta-analyses. Subgroup and sensitivity analysis were performed. The publication bias was evaluated by using Egger's test and visual inspection of the symmetry in funnel plots. RESULTS: Fifty-one studies from 16 States of India were included as 56 datasets, which estimated the prevalence of depression among Indian elderly population as 34.4% (95% CI: 29.3-39.7). In sub-group analysis, the pooled prevalence was higher among females, rural populations, and in the eastern part of the country. Studies using non-probability sampling, and GDS and CES-D screening tool showed higher prevalence. Exclusion of the studies with sample size less than 100 and low-quality studies (score < 5/8) had no effect on the estimate of the prevalence. The studies that excluded dementia before assessment of depression had lower prevalence. CONCLUSION: About one third elderly population of India suffered from depression with female preponderance. The estimates varied with type of study tool, geographic region, sampling methods, and presence of dementia. The pooled estimate should be interpreted with caution as the studies included in this review had varied methodological approach and screening tools.


Assuntos
Depressão/epidemiologia , Idoso , Humanos , Índia/epidemiologia , Pessoa de Meia-Idade , Prevalência
16.
Front Oncol ; 9: 92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873381

RESUMO

Diffuse Midline Gliomas with Histone 3-Lysine-27-Methionine (H3K27M) mutation constitute the majority of Diffuse Intrinsic Pontine Glioma (DIPG), which is the most aggressive form of pediatric glioma with a dire prognosis. DIPG are lethal tumors found in younger children with a median survival <1 year from diagnosis. Discovery of the characteristic H3K27M mutations offers opportunity and hope for development of targeted therapies for this deadly disease. The H3K27M mutation, likely through epigenetic alterations in specific H3 lysine trimethylation levels and subsequent gene expression, plays a significant role in pathogenesis of DIPG. Animal models accurately depicting molecular characteristics of H3K27M DIPG are important to elucidate underlying pathologic events and for preclinical drug evaluation. Here we review the past and present DIPG models and describe our efforts developing patient derived cell lines and xenografts from pretreated surgical specimens. Pre-treated surgical samples retain the characteristic genomic and phenotypic hallmarks of DIPG and establish orthotopic tumors in the mouse brainstem that recapitulate radiographic and morphological features of the original human DIPG tumor. These models that contain the H3K27M mutation constitute a valuable tool to further study this devastating disease and ultimately may uncover novel therapeutic vulnerabilities.

17.
Med Chem ; 15(5): 561-570, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30398119

RESUMO

BACKGROUND: Natural products have shown potent anti-HIV activity, but some of these also possess toxicity. The pharmacophoric fragments of these natural products have scope of combination with other pharmacophoric fragment and derivatization to reduce toxicity and increase the potency. Combination of natural product fragments from different classes of anti-HIV compounds may lead to a new class of potent anti-HIV agents. OBJECTIVE: Design, in silico prediction of drug-likeness, ADMET properties and synthesis of pyrazol- pyridones. Evaluation of the anti-HIV-1 activity of synthesized pyrazol-pyridones. METHODS: Pyrazol-pyridones were designed by combining reported anti-HIV pharmacophoric fragments. Designed molecules were synthesized after in silico prediction of drug-likeness and ADMET properties. Compounds were evaluated for activity against HIV-1VB59 and HIV-1UG070. RESULTS: QED value of designed pyrazol-pyridones was greater than the known drug zidovudine. The designed compounds were predicted to be noncarcinogenic and nonmutagenic in nature. Seventeen novel pyrazol-pyridones were synthesized with good yield. Compound 6q and 6l showed activity with IC50 values 6.14 µM and 15.34 µM against HIV-1VB59 and 16.21 µM and 18.21 µM against HIV-1UG070, respectively. CONCLUSION: Compound 6q was found to be most potent among the synthesized compounds with a therapeutic index of 54.31against HIV-1VB59. This is the first report of anti-HIV-1 activity of pyrazol-pyridone class of compounds. Although the anti-HIV-1 activity of these compounds is moderate, this study opens up a new class for exploration of chemical space for anti-HIV-1 activity.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirazóis/farmacologia , Piridonas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/toxicidade , Desenho de Fármacos , Células HeLa , Humanos , Pirazóis/síntese química , Pirazóis/farmacocinética , Pirazóis/toxicidade , Piridonas/síntese química , Piridonas/farmacocinética , Piridonas/toxicidade
18.
Nat Commun ; 9(1): 4904, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30464169

RESUMO

Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling.


Assuntos
Antineoplásicos/farmacocinética , Cloridrato de Erlotinib/farmacocinética , Glioblastoma/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/administração & dosagem , Feminino , Imagem por Ressonância Magnética , Camundongos Nus , Transplante de Neoplasias , Proteínas Tirosina Quinases/metabolismo , Análise de Sequência de RNA , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
19.
Reprod Health ; 15(1): 3, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29304867

RESUMO

BACKGROUND: In India, community based studies and media reports indicate a surge in the number of young women undergoing hysterectomy in the past few years. This has led to suspicion on the misuse of procedure, and intense debates on its potential ill health-effects on young women. However, there are no population-based studies that provide insights into hysterectomy prevalence and its determinants at the national level. DATA AND METHODS: This study used data from India's District Level Household Survey that involved a sample of 3, 16,361 married women in the age group of 15-49 years spread across 21 States and Union Territories of India. Bivariate and multivariate regression analysis was performed to estimate hysterectomy prevalence and identify its predictors. RESULTS: The study estimated hysterectomy prevalence of 17 per 1000 ever married women. The number of women undergoing hysterectomy ranged from 2 to 63/1000 across different states. A little more than one-third of women who had undergone hysterectomy were under the age of 40 years. The proportion of women below 40 years of age who had had hysterectomy was much higher in southern states of Andhra Pradesh (42%) and Telangana (47%). The likelihood of hysterectomy was higher among women belonging to households with health insurance (OR: 1.88, CI: 1.77-2.00) and women who were sterilized (OR 1.55; CI 1.45-1.67) than uninsured and unsterilized women, and lower among women with education level of matriculation and above (OR 0.47; CI 0.42-0.50) than those with no and/or low education. CONCLUSIONS: A sizable proportion of young women undergoing hysterectomy in India may have severe ill-health effects on their physical, reproductive and socio-psycho health. As women with low or no education are also more prone to hysterectomy, providing more information and education to them on the possible after-effects of hysterectomy and alternative options will enable them to make more informed choices.


Assuntos
Histerectomia/estatística & dados numéricos , Casamento/estatística & dados numéricos , Adolescente , Adulto , Características da Família , Feminino , Humanos , Histerectomia/psicologia , Índia/epidemiologia , Seguro Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Pobreza , Prevalência , Fatores de Risco , População Rural/estatística & dados numéricos , Fatores Socioeconômicos , Adulto Jovem
20.
Front Oncol ; 8: 670, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30723695

RESUMO

Prognosis of patients with glioblastoma (GBM) remains dismal despite maximal surgical resection followed by aggressive chemo-radiation therapy. Almost every GBM, regardless of genotype, relapses as aggressive recurrent disease. Sensitization of GBM cells to chemo-radiation is expected to extend survival of patients with GBM by enhancing treatment efficacy. The PARP family of enzymes has a pleiotropic role in DNA repair and metabolism and has emerged as an attractive target for sensitization of cancer cells to genotoxic therapies. However, despite promising results from a number of preclinical studies, progress of clinical trials involving PARP inhibitors (PARPI) has been slower in GBM as compared to other malignancies. Preclinical in vivo studies have uncovered limitations of PARPI-mediated targeting of base excision repair, considered to be the likely mechanism of sensitization for temozolomide (TMZ)-resistant GBM. Nevertheless, PARPI remain a promising sensitizing approach for at least a subset of GBM tumors that are inherently sensitive to TMZ. Our PDX preclinical trial has helped delineate MGMT promoter hyper-methylation as a biomarker of the PARPI veliparib-mediated sensitization. In clinical trials, MGMT promoter hyper-methylation now is being studied as a potential predictive biomarker not only for response to TMZ therapy alone, but also PARPI-mediated sensitization of TMZ therapy. Besides the combination approach being investigated, IDH1/2 mutant gliomas associated with 2-hydroxygluterate (2HG)-mediated homologous recombination (HR) defect may potentially benefit from PARPI monotherapy. In this article, we discuss existing results and provide additional data in support of potential alternative mechanisms of sensitization that would help identify potential biomarkers for PARPI-based therapeutic approaches to GBM.

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