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1.
Chemosphere ; 287(Pt 1): 132073, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34478964

RESUMO

Fomesafen is an herbicide used in soybean production, and sugar beet is a sensitive crop to fomesafen. When the herbicide is sprayed in the field, it is easy to cause floating and depositing on non-target crops, resulting in crop poisoning and reducing yield. There are few on the phenomenon and mechanism of fomesafen herbicide drift on sugar beet. There are few reports on the phenomenon and mechanism of ether herbicide migration on phytotoxicity of sugar beet. Therefore, in this experiment, indoor potted plants were used to simulate the dose of fomesafen drift deposited on sugar beet in the field to study the effects of fomesafen on the growth, photosynthetic system, and physiological indexes of seedlings for sugar beet were studied. The results showed that fomesafen at the dose of 225 g a.i. ha-1 significantly inhibited the plant height, root length, and biomass of sugar beet. Compared with the control, the net photosynthetic rate, stoma conductance, transpiration rate, and total chlorophyll pigment content of leaves were reduced by 77.16%, 83.84%, 64.00%, and 28.13%, respectively. Treatment with a dose of 225 g a.i. ha-1 also damaged the photosynthetic system II of the leaves, lowering the performance index on absorption energy, maximum quantum yield and, the energy of electron transfer, causing photoinhibition and photodamage. In addition, fomesafen significantly increased the content of malondialdehyde and the activity of peroxidase in leaves of sugar beet, reducing the activities of superoxide dismutase and catalase. Overall, this study is helpful to understand the drift and deposition of fomesafen on sugar beet and to discuss the phytotoxicity risk and dose of fomesafen on the beet, as a result of controlling the dose of fomesafen sprayed in the field.


Assuntos
Beta vulgaris , Benzamidas , Clorofila , Folhas de Planta , Açúcares
2.
Chemosphere ; 286(Pt 3): 131830, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34388432

RESUMO

Fluopyram, a succinate dehydrogenase inhibitor fungicide and nematicide, has been used extensively for agricultural pest control and toxicologically affects non-target organisms. In the present study, Caenorhabditis elegans, a well-established model organism, was used to evaluate the toxic effect of fluopyram and the possible molecular mechanisms. C. elegans was exposed to fluopyram for 24 h at three sublethal concentrations (0.01, 0.05 and 0.25 mg/L) and the physiological, biochemical, and molecular indicators were examined. The results showed that sublethal exposure to fluopyram could cause damage to growth, locomotion behavior, feeding, lifespan and reproduction of the nematodes. Fluopyram exposure induced oxidative stress as indicated by increase of ROS production, lipofuscin and lipid accumulation, and MDA level in the nematodes. In contrast, exposure to fluopyram significantly decreased the activities of target enzyme SDH and antioxidant enzymes including SOD, CAT and GST. Moreover, the expression of genes associated with oxidative stress (e.g., gst-4, sod-3, fat-7, mev-1 and daf-16), intestinal damage (e.g., mtm-6, nhx-2, opt-2, pkc-3, par-6, act-5 and egl-8), and cell apoptosis (e.g., ced-13, ced-3, egl-38, efl-2, cep-1 and lgg-1) was significantly influenced after exposure to fluopyram. According to Pearson correlation analyses, significant correlation existed between 190 pairs of parameters, which indicated that fluopyram induced multiple toxic related effects in C. elegans. These findings suggest that oxidative stress, intestinal damage, and cell apoptosis may play major roles in toxicity of fluopyram in the nematodes.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Apoptose , Benzamidas , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Estresse Oxidativo , Piridinas , Espécies Reativas de Oxigênio
3.
J Headache Pain ; 22(1): 132, 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34742230

RESUMO

BACKGROUND: Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). METHODS: Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. RESULTS: Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. CONCLUSION: In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. TRIAL REGISTRATION: NCT03670810.


Assuntos
Transtornos de Enxaqueca , Agonistas do Receptor de Serotonina , Adulto , Benzamidas , Método Duplo-Cego , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas , Piridinas , Resultado do Tratamento
4.
Int J Mol Sci ; 22(19)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34639155

RESUMO

The dysregulation of fibroblast growth factor (FGF) signaling has been implicated in tumorigenesis, tumor progression, angiogenesis, and chemoresistance. The small-molecule AZD4547 is a potent inhibitor of FGF receptors. This study was performed to investigate the antitumor effects and determine the mechanistic details of AZD4547 in ovarian cancer cells. AZD4547 markedly inhibited the proliferation and increased the apoptosis of ovarian cancer cells. AZD4547 also suppressed the migration and invasion of ovarian cancer cells under nontoxic conditions. Furthermore, it attenuated the formation of spheroids and the self-renewal capacities of ovarian cancer stem cells and exerted an antiangiogenic effect. It also suppressed in vivo tumor growth in mice. Collectively, this study demonstrated the antitumor effect of AZD4547 in ovarian cancer cells and suggests that it is a promising agent for ovarian cancer therapy.


Assuntos
Benzamidas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Piperazinas/farmacologia , Pirazóis/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Apoptose , Movimento Celular , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Med Case Rep ; 15(1): 535, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34696808

RESUMO

BACKGROUND: Permanent neonatal diabetes mellitus (PNDM) presents with dehydration and hyperglycemia, which usually occurs during the first 12 months of life. Activating mutations of beta-cell adenosine triphosphate-sensitive potassium [KATP] channel subunits that cause opening of the channel are associated with PNDM. Some patients with PNDM respond to administration of a sulfonylurea derivative, which has long action on blood glucose even during hypoglycemia and has an apoptotic effect on beta cells. However, there have been no reports regarding treatment with meglitinide (repaglinide), which has rapid and short duration of action during the rise in blood glucose after meals that is more similar to beta cell function. It has no effects during hypoglycemia, so it does not cause neurological damage, and has no apoptotic effect on beta cells. We report herein the effects of repaglinide administration in the management and clinical outcome of two patients with PNDM during 9 and 10 years of follow-up. CASE PRESENTATION: Two Iranian infants were brought to our institution with poor general condition, dehydration, lethargy, and poor feeding. They had diabetic ketoacidosis at 52 days and 3.5 months of age, respectively. Their genetic analysis revealed mutations in the KCNJ11 gene encoding KIR6.2, so they both had PNDM. After treatment of diabetic ketoacidosis with insulin, they responded to sulfonylurea (glibenclamide) treatment, but were switched to repaglinide because of blood sugar fluctuations in terms of hyper- and hypoglycemia. Repaglinide was administered with the dosage of 0.04 mg/kg/day divided before every meal. RESULTS: The patients were 10 and 9 years old at the last visit, with normal growth parameters. The values of self-monitored blood glucose were well-controlled, and the hemoglobin A1C (HbA1C) levels ranged from 3.6 to 6.4% during the follow-up period. There was no complication of diabetes, neurological disorder, or adverse effects related to repaglinide. CONCLUSION: In every neonate or infant < 6 months of age with diabetes mellitus, PNDM should be considered. A trial of oral repaglinide can be performed and substituted for glibenclamide for prevention of hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration.


Assuntos
Diabetes Mellitus , Hipoglicemiantes , Benzamidas , Carbamatos , Humanos , Hipoglicemiantes/uso terapêutico , Irã (Geográfico) , Mutação , Piperidinas
6.
Int J Mol Sci ; 22(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34639012

RESUMO

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.


Assuntos
Benzamidas/farmacologia , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Piridinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Radiossensibilizantes/farmacologia , Rabdomiossarcoma/genética , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/radioterapia
7.
BMJ Open ; 11(10): e052610, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34697119

RESUMO

INTRODUCTION: This paper presents a study protocol for a comparative effectiveness evaluation of abiraterone acetate against enzalutamide in clinical practice, two cancer drugs given to patients suffering from advanced prostate cancer. METHOD AND ANALYSIS: The protocol designs a comparative-effectiveness analysis of abiraterone acetate against enzalutamide. With the substantial number of covariates a two-step procedure is suggested in choosing relevant covariates in the matching design. In the first step, an exploratory factor analysis reduces the dimension of a large set of continuous covariates to nine factors. In the second step, we reduce the dimension of the covariates, interactions and second order terms for the continuous covariates using propensity score estimation. The final design makes use of a genetic matching algorithm. The study protocol provides a detailed statistical analysis plan of the analysis sample derived from the matching design. The analysis will make use of linear regression and robust inference adjusted for multisignificance testing. DISCUSSION: As in a randomised experiment the focus is on the design of the assignment to treatment. This allows the publication of this preanalysis plan before having access to outcome data. This means that the p values will be correct if the maintained assumption of uncounfoundedness is valid. Given that is p-hacking is substantial problem in empirical research, this is a substantial strength of this study. However, while design yields, balance on the observed covariates one cannot discard the possibility that unobserved confounders are not balanced. For that reason, sensitivity tests for the maintained assumption of uncounfoundedness are presented. ETHICS AND DISSEMINATION: The study was approved by the Regional Ethical Review Board in Uppsala, Sweden (Dnr 2017/482). Results will be published in a peer-reviewed journal and distributed to relevant stakeholders in healthcare.


Assuntos
Acetato de Abiraterona , Neoplasias de Próstata Resistentes à Castração , Benzamidas , Humanos , Estudos Longitudinais , Masculino , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Suécia , Resultado do Tratamento
8.
Chem Biol Interact ; 350: 109686, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34627785

RESUMO

Colorectal cancer (CRC) is the third leading type of adult cancer in both genders with high morbidity and mortality worldwide. Even though the discovery of many antineoplastic drugs for CRC, the current therapy is not adequately efficient.This study was designed to investigate the effect and mechanism of Piclamilast (PIC), a selective PDE4 inhibitor, on a DMH-induced colorectal cancer (CRC) rat model. The rats were grouped (n = 10) into group 1 (control), group 2 (PIC 3 mg/kg, p.o.), groups 3-5 received DMH (20 mg/kg/week, S.C.), and groups 4 and 5 received PIC (1 and 3 mg/kg/day, p.o.) for 15 weeks. The DMH treatment increased aberrant crypt foci (ACF), Proliferating cell nuclear antigen (PCNA), and TBARS levels, along with decreased antioxidant defenses (GSH, GSH-Px, and catalase). Increased NF-κß expression and inflammatory cytokines were also evident. PIC dose-dependently reduced ACF and restored oxidative stress and inflammatory markers favorably. Moreover, PIC in its large, tested dose only significantly increased the intracellular level of cAMP and suppressed the activation of Ras and PI3K and its downstream Akt/mTOR signaling. Furthermore, PIC promoted CRC apoptosis, and increased the gene expression of the apoptotic factors, caspase-3 and Bax, and decreased the anti-apoptotic factor Bcl-2. The results of this study show that PIC may be a promising therapeutic agent for the treatment of CRC. PIC might inhibit the proliferation of CRC cells and induce apoptosis via multiple mechanisms that involve its antioxidant effect and inhibition of NF-κß and Ras/PI3K/Akt/mTOR signaling.


Assuntos
1,2-Dimetilidrazina/antagonistas & inibidores , 1,2-Dimetilidrazina/toxicidade , Benzamidas/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Piridinas/farmacologia , Focos de Criptas Aberrantes/tratamento farmacológico , Focos de Criptas Aberrantes/metabolismo , Focos de Criptas Aberrantes/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/induzido quimicamente , Modelos Animais de Doenças , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas ras/metabolismo
9.
PLoS One ; 16(10): e0258160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34597353

RESUMO

BACKGROUND: There was no clear evidence whether the initial dose of enzalutamide affects the incidence of adverse events (AEs), and oncological outcome in patients with castration-resistant prostate cancer (CRPC). METHODS: The clinical charts of 233 patients with CRPC treated with enzalutamide were reviewed retrospectively. After 1:3 propensity score matching (PSM), 124 patients were divided into a reduced dose group and a standard dose group, and the prostate specific antigen (PSA) response and the incidence of AEs were compared. RESULTS: 190 patients with CRPC initiated with standard dose enzalutamide were younger and better performance status compared with 43 patients beginning with reduced dose. After PSM, the baseline characteristics were not different between the standard and the reduced dose group. In the PSM cohort, the PSA response rate was significantly lower in the reduced dose group than in the standard dose group (-66.3% and -87.4%, p = 0.02). The incidence rates of AEs were not statistically different between the groups (22.6% and 34.4%, respectively, p = 0.24). CONCLUSION: Initiating treatment with a reduced dose of enzalutamide did not significantly decrease the incidence rate of AEs, and it showed poorer PSA response rate. There is no clear rationale for treating with a reduced initial dose of enzalutamide to reduce the incidence of AEs.


Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Humanos , Masculino , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Resultado do Tratamento
10.
Curr Hematol Malig Rep ; 16(5): 422-432, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34599723

RESUMO

PURPOSE OF REVIEW: The treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed over the last few years with the introduction of novel targeted agents. Physicians are now faced with several equally effective therapy options when treating patients with CLL. Here, we review the role of Bruton tyrosine kinase (BTK) inhibitors in treating patients with treatment-naïve and relapsed or refractory CLL. We review recent approvals of BTK inhibitors as well as reported and ongoing clinical trial data. RECENT FINDINGS: The approval of ibrutinib rapidly led to a paradigm shift in the management of CLL. Randomized trials have now compared ibrutinib to several chemoimmunotherapy approaches, which were in favor of ibrutinib. Second-generation more selective BTK inhibitors, including acalabrutinib and zanubrutinib, have been developed, and recent data have led to the approval of acalabrutinib in CLL. Ongoing and future studies focus on either combining BTK inhibitors with other novel agents (e.g., venetoclax, obinutuzumab, or ublituximab) or developing next-generation non-covalent reversible BTK inhibitors that may be effective in treating patients with CLL harboring BTK-resistant mutations. The field of CLL continues to evolve rapidly with new and evolving combination treatments and novel BTK agents, which will continue to change the standard of care for CLL.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Benzamidas/uso terapêutico , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Humanos , Piperidinas/uso terapêutico , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
11.
FASEB J ; 35(10): e21874, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34486176

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations of PKD1 or PKD2 genes, is characterized by development and growth of cysts causing progressive kidney enlargement. Reduced resting cytosolic calcium and increased cAMP levels associated with the tonic action of vasopressin are two central biochemical defects in ADPKD. Here we show that co-targeting two GPCRs, the vasopressin V2 receptor (V2R) and the calcium sensing receptor, using the novel V2R antagonist lixivaptan in combination with the calcimimetic R-568, reduced cyst progression in two animal models of human PKD. Lixivaptan is expected to have a safer liver profile compared to tolvaptan, the only drug approved to delay PKD progression, based on computational model results and initial clinical evidence. PCK rat and Pkd1RC/RC mouse littermates were fed without or with lixivaptan (0.5%) and R-568 (0.025% for rats and 0.04% for mice), alone or in combination, for 7 (rats) or 13 (mice) weeks. In PCK rats, the combined treatment strongly decreased kidney weight, cyst and fibrosis volumes by 20%, 49%, and 73%, respectively, compared to untreated animals. In Pkd1RC/RC mice, the same parameters were reduced by 20%, 56%, and 69%, respectively. In both cases the combined treatment appeared nominally more effective than the individual drugs used alone. These data point to an intriguing new application for two existing drugs in PKD treatment. The potential for synergy between these two compounds suggested in these animal studies, if confirmed in appropriate clinical investigations, would represent a welcome advancement in the treatment of ADPKD.


Assuntos
Benzamidas/farmacologia , Fenetilaminas/farmacologia , Rim Policístico Autossômico Dominante/tratamento farmacológico , Propilaminas/farmacologia , Pirróis/farmacologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Vasopressinas/química , Animais , AMP Cíclico , Quimioterapia Combinada , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Ratos , Ratos Sprague-Dawley
13.
Bull Environ Contam Toxicol ; 107(5): 961-966, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34515822

RESUMO

The research portrays the fate of a new herbicide mixture of fomesafen and quizalofop-ethyl. The soil samples viz. red lateritic soil (A), coastal saline soil (B) and black soil (C) were fortified separately for fomesafen and quizalofop-ethyl at 0.5 (T1) and 1.0 mg kg-1 (T2) doses and incubated at 20, 30 and 40°C. A satisfactory mean recovery, precision and linearity proved that the methods were accurate. Both the herbicides followed first + first order kinetics. Higher persistence of fomesafen was observed in Soil C than Soil B and Soil A with 22.38-53.75 days half-life, whereas quizalofop-ethyl showed higher stability in Soil A than Soils B and C with half-life of 0.93-12.07 days. Both compounds showed faster rates of dissipation at increased temperature, irrespective of soil type. The current study will help to predict the effect of temperature on the dissipation of herbicides in different soil under real field scenario.


Assuntos
Herbicidas , Poluentes do Solo , Benzamidas , Herbicidas/análise , Cinética , Propionatos , Quinoxalinas , Solo , Poluentes do Solo/análise , Temperatura
14.
ESMO Open ; 6(5): 100261, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34509804

RESUMO

BACKGROUND: Abiraterone and enzalutamide use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude and clinical relevance of this association in real-world prostate cancer (PC) population remain unknown. MATERIALS AND METHODS: We retrospectively reviewed the MarketScan claims databases (1 January 2013 to 30 September 2018) to identify adults with diagnosis of metastatic PC who received treatment with androgen deprivation therapy (ADT) and novel antiandrogen agents (abiraterone or enzalutamide). The primary CV outcome measure was composite outcome of acute myocardial infarction (MI) or stroke. Secondary outcomes were individual risks of MI or stroke. We used an intention-to-treat approach to analyze the CV outcomes associated with drug exposure among patients with metastatic PC. Cox regression model was used to estimate the independent association of two drugs with CV risk after adjustment for age, baseline atrial fibrillation, and Charlson Comorbidity Index. RESULTS: A total of 6294 patients with metastatic PC who were treated with ADT and either abiraterone or enzalutamide were included in the final analysis. Of these, 4017 (63.8%) patients used abiraterone and 2217 (32.2%) patients used enzalutamide. During the study period, 255 (6.3%) primary endpoint events occurred, resulting in an incidence rate of 4.3 per 100 patient-years. In multivariable analysis, abiraterone use was associated with a 31% increased risk of MI or stroke compared to enzalutamide (hazard ratio 1.31; 95% confidence interval 1.05-1.63; P = 0.01). The incidence rate was similar in patients who switched initial therapy from abiraterone to enzalutamide or vice versa (5.0 versus 5.6 per 100 patient-years, respectively). CONCLUSIONS: To our knowledge, this is the first real-world assessment of MI and stroke among metastatic PC patients receiving novel anti-androgens. Our findings of increased MI and stroke risk with abiraterone compared with enzalutamide are consistent with data from clinical trials and suggest that enzalutamide may be preferable for prostate cancer patients at high CV risk.


Assuntos
Infarto do Miocárdio , Neoplasias de Próstata Resistentes à Castração , Acidente Vascular Cerebral , Adulto , Antagonistas de Androgênios/efeitos adversos , Androstenos , Benzamidas , Humanos , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/epidemiologia , Nitrilas , Feniltioidantoína , Estudos Retrospectivos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/epidemiologia
15.
Nat Commun ; 12(1): 5307, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489465

RESUMO

Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.


Assuntos
Cromatina/química , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Transcriptoma , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Análise de Sobrevida , Sequenciamento Completo do Exoma
16.
J Am Soc Nephrol ; 32(9): 2159-2174, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34465607

RESUMO

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous cysts originating from renal tubules and is associated with significant tubular epithelial cell proliferation. Focal adhesion kinase (FAK) promotes tumor growth by regulating multiple proliferative pathways. METHODS: We established the forskolin (FSK)-induced three-dimensional (3D) Madin-Darby Canine Kidney cystogenesis model and 8-bromoadenosine-3`,5`-cyclic monophosphate-stimulated cyst formation in ex vivo embryonic kidney culture. Cultured human renal cyst-lining cells (OX-161) and normal tubular epithelial cells were treated with FAK inhibitors or transfected with green fluorescent protein-tagged FAK mutant plasmids for proliferation study. Furthermore, we examined the role of FAK in two transgenic ADPKD animal models, the kidney-specific Pkd1 knockout and the collecting duct-specific Pkd1 knockout mouse models. RESULTS: FAK activity was significantly elevated in OX-161 cells and in two ADPKD mouse models. Inhibiting FAK activity reduced cell proliferation in OX-161 cells and prevented cyst growth in ex vivo and 3D cyst models. In tissue-specific Pkd1 knockout mouse models, FAK inhibitors retarded cyst development and mitigated renal function decline. Mechanically, FSK stimulated FAK activation in tubular epithelial cells, which was blocked by a protein kinase A (PKA) inhibitor. Inhibition of FAK activation by inhibitors or transfected cells with mutant FAK constructs interrupted FSK-mediated Src activation and upregulation of ERK and mTOR pathways. CONCLUSIONS: Our study demonstrates the critical involvement of FAK in renal cyst development, suggests that FAK is a potential therapeutic target in treating patients with ADPKD, and highlights the role of FAK in cAMP-PKA-regulated proliferation.


Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Células Epiteliais/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Rim Policístico Autossômico Dominante/prevenção & controle , Pirazinas/farmacologia , Sulfonamidas/farmacologia , Animais , Técnicas de Cultura de Células , Proliferação de Células , Modelos Animais de Doenças , Cães , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Rim Policístico Autossômico Dominante/etiologia , Rim Policístico Autossômico Dominante/patologia , Transdução de Sinais
17.
Rev Cardiovasc Med ; 22(3): 1037-1045, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34565105

RESUMO

Histone deacetylase (HDAC) inhibitors have shown cardioprotective or renoprotective effects in various animal models. Our study proposed that the HDAC inhibitor, mocetinostat, regulates cardiac remodelling and renin-angiotensin system (RAS) activity in rats with transverse aortic constriction (TAC)-induced pressure overload cardiac hypertrophy. Cardiac remodelling was evaluated using echocardiography. Cardiac hypertrophy was visualized with haematoxylin and eosin staining, and related gene (Nppa and Nppb) expression was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Cardiac and renal fibrosis were visualized with picrosirius red and trichrome staining, respectively. Fibrosis related gene (Collagen-1, Collagen-3, Ctgf, and Fibronectin) expression was determined by qRT-PCR. Serum concentrations of RAS components (renin, angiotensin II, and aldosterone) were quantified by enzyme-linked immunosorbent assay and related gene (Renin and Agtr1) expression was determined by qRT-PCR. TAC-induced pressure overload cardiac hypertrophy, which mimics hypertensive heart disease, increased cardiac remodelling, cardiac hypertrophy, and fibrosis in our rat models. Upon treatment with mocetinostat, there was a significant regression in cardiac remodelling, cardiac hypertrophy, and fibrosis in TAC rats. Additionally, pressure overload-induced renal fibrosis and activity of RAS-related components were increased in TAC rats, and were decreased on treatment with mocetinostat. The present study indicates that mocetinostat, an HDAC inhibitor, has cardiorenal protective effects in rats with TAC-induced pressure overload cardiac hypertrophy and offers a promising therapeutic agent for hypertension-related diseases.


Assuntos
Inibidores de Histona Desacetilases , Remodelação Ventricular , Animais , Benzamidas , Cardiomegalia/tratamento farmacológico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Constrição , Fibrose , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Miocárdio/patologia , Pirimidinas , Ratos , Sistema Renina-Angiotensina
18.
Chemistry ; 27(63): 15628-15633, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34519367

RESUMO

The Rh-catalyzed ortho-C(sp2 )-H functionalization of 8-aminoquinoline-derived benzamides with aliphatic acyl fluorides generated in situ from the corresponding acids has been developed. This reaction initiated with 8-aminoquinoline-directed ortho-C(sp2 )-H acylation, which was accompanied by subsequent intramolecular nucleophilic acyl substitution of amide group to produce alkylidene phthalides This approach exhibits high stereo-selectivity for Z-isomer products, and tolerates a variety of functional groups as well as aliphatic carboxylic acids with diverse structural scaffolds.


Assuntos
Ródio , Acilação , Benzamidas , Benzofuranos , Ácidos Carboxílicos , Catálise
19.
Leuk Res ; 110: 106707, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34563945

RESUMO

PURPOSE: Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL. EXPERIMENTAL DESIGN: Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m2/day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy. RESULTS: Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined. CONCLUSION: Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem da Célula , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/tratamento farmacológico , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Idoso , Benzamidas/administração & dosagem , Clofarabina/administração & dosagem , Feminino , Seguimentos , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Piridinas/administração & dosagem , Terapia de Salvação , Adulto Jovem
20.
Cancer Sci ; 112(11): 4641-4654, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34510663

RESUMO

Screening custom-made libraries of inhibitors may reveal novel drugs for treating pancreatic cancer. In this manner, we identified ispinesib as a candidate and attempted to determine its clinical efficacy and the biological significance of its functional target Eg5 in pancreatic cancer. One hundred compounds in our library were screened for candidate drugs using cell cytotoxicity assays. Ispinesib was found to mediate effective antitumor effects in pancreatic cancer. The clinical significance of the expression of the ispinesib target Eg5 was investigated in 165 pancreatic cancer patients by immunohistochemical staining and in Eg5-positive pancreatic cancer patient-derived xenograft (PDX) mouse models. Patients with Eg5-positive tumors experienced significantly poorer clinical outcomes than those not expressing Eg5 (overall survival; P < .01, recurrence-free survival; P < .01). Ispinesib or Eg5 inhibition with specific siRNA significantly suppressed cell proliferation and induced apoptosis in pancreatic cancer cell lines. Mechanistically, ispinesib acted by inducing incomplete mitosis with nuclear disruption, resulting in multinucleated monoastral spindle cells. In the PDX mouse model, ispinesib dramatically reduced tumor growth relative to vehicle control (652.2 mm3 vs 18.1 mm3 in mean tumor volume, P < .01 by ANOVA; 545 mg vs 28 mg in tumor weight, P < .01, by ANOVA). Ispinesib, identified by inhibitor library screening, could be a promising novel therapeutic agent for pancreatic cancer. The expression of its target Eg5 is associated with poorer postoperative prognosis and is important for the clinical efficacy of ispinesib in pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Cinesina/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Quinazolinas/farmacologia , Análise de Variância , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Descoberta de Drogas , Feminino , Inativação Gênica , Humanos , Cinesina/genética , Cinesina/metabolismo , Bibliotecas Especializadas , Metáfase/efeitos dos fármacos , Camundongos , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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