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1.
Journal of Experimental Hematology ; (6): 671-676, 2022.
Article in Chinese | WPRIM | ID: wpr-939674

ABSTRACT

OBJECTIVE@#To investigate the effects of paclitaxel, quizartinib and their combination on proliferation, apoptosis and FLT3/STAT5 pathway of human leukemia cell line MV4-11 (FLT3-ITD+).@*METHODS@#MV4-11 cells were treated with paclitaxel and quizartinib at different concentrations for 24 h, 48 h and 72 h, respectively, and then the two drugs were combined at 48 h to compare the inhibition of proliferation, the apoptosis rate was detected by flow cytometry, the expression of FLT3 and STAT5 mRNA was determined by fluorescence quantitative PCR, and the protein expression of FLT3, p-FLT3, STAT5 and p-STAT5 was determined by Western blot.@*RESULTS@#Different combination groups of paclitaxel and quizartinib had synergistic inhibitory effect. The cell survival rate in the combination group was significantly lower than that in the single drug group (P<0.05). The cell apoptosis rate in the combination group was significantly higher than that in the single drug group (P<0.001). The expression of FLT3 mRNA in combination group was significantly higher than that in two single drugs (P<0.01). The expression of STAT5 mRNA in combination group was significantly higher than that in quizartinib group (P<0.001); increased compared with paclitaxel group, but there was no statistical significance. The expression level of p-FLT3、p-STAT5 protein in the combination group was significantly lower than that in the single drug group (P<0.05, P<0.05).@*CONCLUSION@#Paclitaxel combined with quizartinib can synergistically inhibit the proliferation of MV4-11 cell line and promote the apoptosis of MV4-11 cell line by inhibiting the activity of FLT3/STAT5 pathway.


Subject(s)
Humans , Apoptosis , Benzothiazoles , Cell Line, Tumor , Leukemia, Myeloid, Acute/genetics , Paclitaxel/therapeutic use , Phenylurea Compounds , RNA, Messenger , STAT5 Transcription Factor/pharmacology , Signal Transduction , fms-Like Tyrosine Kinase 3
3.
Clinics ; 76: e2498, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153964

ABSTRACT

OBJECTIVES: To evaluate the efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma (HCC). METHODS: We analyzed data from a cohort of patients with advanced HCC treated using systemic treatment according to the local institutional protocol. Patients were divided into two groups, Group A, individuals <70 years of age, and Group B, individuals 70 years of age or older at the time of treatment initiation. Efficacy, measured based on overall survival (OS) and time to treatment failure (TTF), and toxicity were compared between groups. RESULTS: A total of 238 patients with advanced HCC who received sorafenib between 2007 and 2018 were evaluated. The median age for Group A was 59.1 years and that for Group B 73.6 years. The major prognostic characteristics were balanced between the groups. There were no significant differences in OS between Group A (8.0 months, 95%CI 6.34-9.3) and Group B (9.0 months, 95%CI 5.38-12.62), p=0.433, or in TTF between Group A (3.0 months, 95%CI 2.39-3.60) and Group B (3.0 months, 95%CI 1.68-4.32), p=0.936. There were no significant differences between Groups A and B with respect to the incidence of adverse events or treatment discontinuation because of toxicity. CONCLUSION: Efficacy and safety of sorafenib did not differ significantly between younger and older patients with HCC. Our data suggest that age alone should not restrict clinical decision-making for patients with advanced HCC.


Subject(s)
Humans , Middle Aged , Aged , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Phenylurea Compounds/adverse effects , Prognosis , Niacinamide/adverse effects , Sorafenib/adverse effects
4.
Rev. bras. parasitol. vet ; 30(1): e025220, 2021. tab, graf
Article in English | LILACS | ID: biblio-1156219

ABSTRACT

Abstract Southern cattle tick resistance to pour-on and injectable acaricides has yet to be evaluated on a broader scope, and the paucity of information on the subject may hinder efforts to control this parasite. The objective of this study was to evaluate the resistance profile of ten populations of Rhipicephalus microplus to the acaricides fluazuron, fipronil and ivermectin in cattle herds in Mato Grosso do Sul, Brazil. The larval immersion test (LIT) was used to evaluate susceptibility to ivermectin and fipronil and the adult immersion test (AIT) was performed to evaluate fluazuron. Samples were randomly obtained in ten farms, and in general, we found resistance in five samples to fluazuron and in four samples to ivermectin and fipronil. Six samples showed incipient resistance to ivermectin and fipronil. Five of the ten evaluated samples showed resistance and/or incipient resistance to all the active ingredients, and the other five to two active ingredients. Among the samples classified as resistant, the average resistance ratio for ivermectin was 2.75 and 3.26 for fipronil. These results demonstrate the advanced status of resistance to the most modern chemical groups for the control of R. microplus in the state of Mato Grosso do Sul.


Resumo A resistência do carrapato-do-boi a acaricidas com modo de aplicação "pour-on" e injetáveis é pouco avaliada em estudos mais abrangentes, e essa escassez de informação pode resultar falhas no seu controle. Este estudo teve como objetivo avaliar o perfil de resistência em dez populações de Rhipicephalus microplus aos acaricidas fluazuron, fipronil e ivermectina, em rebanhos bovinos em Mato Grosso do Sul, Brasil. A caracterização fenotípica da resistência foi realizada por meio do teste de imersão de adultos (AIT) para o fluazuron, e teste de imersão de larvas (LIT) para fipronil e ivermectina. As amostras foram obtidas aleatoriamente em dez fazendas, sendo diagnosticada resistência em cinco amostras ao fluazuron e em quatro amostras à ivermectina e fipronil. Seis amostras apresentaram resistência incipiente à ivermectina e fipronil. Cinco das dez amostras avaliadas apresentaram resistência e / ou resistência incipiente a todos os princípios ativos, e as outras cinco a dois princípios ativos. Entre as amostras classificadas como resistentes, a média do fator de resistência para ivermectina foi de 2,75 e de 3,26 para fipronil. Esses resultados demonstram o avançado estado de resistência aos mais modernos grupos químicos para o controle de R. microplus em Mato Grosso do Sul.


Subject(s)
Animals , Tick Infestations/parasitology , Tick Infestations/veterinary , Drug Resistance , Cattle Diseases/parasitology , Rhipicephalus/drug effects , Acaricides/pharmacology , Phenylurea Compounds/pharmacology , Pyrazoles/pharmacology , Ivermectin/pharmacology , Brazil , Cattle
5.
Salud pública Méx ; 62(4): 424-431, jul.-ago. 2020. tab, graf
Article in English | LILACS | ID: biblio-1377334

ABSTRACT

Abstract: Objective: To compare the efficacy of three modern larvicides with the organophosphate temephos for control of Aedes aegypti in water tanks in Chiapas. Materials and methods: Trials were performed to compare the efficacy of pyriproxyfen, novaluron, two formulations of spinosad (granules and tablets) and temephos in oviposition traps and domestic water tanks. Results: Pyriproxyfen and temephos provided 2-3 weeks of complete control of larvae in oviposition traps, whereas spinosad granules and novaluron provided 7-12 weeks of control. Treatment of water tanks resulted in a significant reduction in oviposition by Ae. aegypt in houses (p<0.001). Higher numbers of larvae were present in temephos and pyriproxyfen-treated water tanks compared to novaluron and spinosad tablet treatments during most of the study. Conclusion: Spinosad formulations and novaluron were effective larvicides in this region. The poor performance of temephos may be indicative of reduced susceptibility in Ae. aegypti populations in Chiapas.


Resumen: Objetivo: Comparar la eficacia de tres larvicidas modernos para el control de Aedes aegypti en tanques de agua doméstica en Chiapas. Material y métodos: Se comparó la eficacia de piriproxifeno, novalurón, dos formulaciones de spinosad (gránulos y tabletas) y temefos en ovitrampas y tanques domésticos de agua. Resultados: El piriproxifeno y el temefos proporcionaron de 2 a 3 semanas de control de larvas en ovitrampas, mientras que los gránulos de spinosad y novaluron proporcionaron de 7 a12 semanas. Los tanques de agua tratados produjeron una reducción significativa en la oviposición por Ae. aegypti en las casas (p<0.001). Se encontró gran cantidad de larvas en los tanques tratados con temefos y piriproxifeno en comparación con los tratados con novaluron y tabletas de spinosad durante la mayor parte del estudio. Conclusión: Las formulaciones de spinosad en tabletas y novaluron fueron larvicidas efectivos en esta región. El bajo desempeño de temefos puede indicar una susceptibilidad reducida en poblaciones de Ae. aegypti en Chiapas.


Subject(s)
Animals , Female , Phenylurea Compounds , Pyridines , Temefos , Macrolides , Aedes , Insecticides , Oviposition , Water/parasitology , Mosquito Control/methods , Aedes/anatomy & histology , Drug Combinations , Housing , Larva , Mexico
6.
Journal of Southern Medical University ; (12): 1488-1492, 2020.
Article in Chinese | WPRIM | ID: wpr-880773

ABSTRACT

OBJECTIVE@#To compare the effects of medical ozone oil and urea ointment for prevention and treatment of hand-foot skin reaction (HFSR) caused by sorafenib in patients with hepatocellular carcinoma (HCC).@*METHODS@#A total of 99 patients diagnosed with advanced HCC according to National Comprehensive Cancer Network (NCCN) who were scheduled to receive sorafenib treatment for the first time were enrolled in this study between April, 2018 and January, 2020. The patients were randomized into medical ozone oil group (@*RESULTS@#Eight patients were excluded for poor compliance or protocol violations, leaving a total of 91 patients for analysis, including 44 in medical ozone oil group and 47 in urea ointment group. Sixteen (36.4%) of patients in ozone oil group developed HFSR, a rate significantly lower than that in urea ointment group (57.4%; @*CONCLUSIONS@#Medical ozone oil can significantly reduce the incidence and severity of HFSR to improve the quality of life of HCC patients receiving sorafenib treatment.


Subject(s)
Humans , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Hand-Foot Syndrome/prevention & control , Liver Neoplasms/drug therapy , Niacinamide/therapeutic use , Ozone/therapeutic use , Phenylurea Compounds/adverse effects , Quality of Life , Sorafenib/therapeutic use
7.
Electron. j. biotechnol ; 40: 45-51, July. 2019. ilus, tab
Article in English | LILACS | ID: biblio-1053457

ABSTRACT

Background: This research is intended to determine suitable types and concentrations of plant growth regulators (PGRs) to induce callus on stem and leaf sections of 4 species of the genus Garcinia, namely, Garcinia mangostana, Garcinia schomburgkiana, Garcinia cowa, and Garcinia celebica. The base medium was MS medium containing 30 g l -1 sucrose, 0.5 g l-1 polyvinylpyrrolidone (PVP), and 7 g l-1 agar, and for the different treatments, PGRs were added to the medium as follows: thidiazuron (TDZ) at concentrations of 0, 0.1, 0.5, 1, and 2 mg l-1; 6-(3- hydroxybenzylamino) purine (meta-topolin) at concentrations of 0, 0.5, 2.5, and 5 mg l-1; 4-amino-3,5,6- trichloro-2-pyridinecarboxylic acid (picloram) at concentrations of 0, 0.5, 2.5, and 5 mg l-1; and 2,4- dichlorophenoxyacetic acid (2,4-D) at concentrations of 0, 0.5, 1, 2, and 4 mg l-1. The occurrence of callus was observed after 4 weeks. Results: A maximum of 100% and 93% of G. mangostana leaf explants formed callus in the 0.5 mg l-1 and 1 mg l-1 TDZ treatments, respectively, while 100% of G. schomburgkiana stem explants formed callus in the 1 mg l-1 TDZ treatment and 89% of G. schomburgkiana leaf explants formed callus in the 0.5 mg l-1 picloram treatment. The highest callus induction rate for G. cowa was 62% in the 1 mg l-1 TDZ treatment and for G. celebica was 56% in the 0.5 mg l-1•mT-1 treatment. Conclusions: For all 4 species, the greatest amount of large nodular callus was observed in the TDZ treatments. White, friable callus was observed on most of the 2,4-D and picloram treatment groups. Most meta-topolin treatments resulted in minimal callus formation.


Subject(s)
Plant Growth Regulators/metabolism , Garcinia/growth & development , Phytochemicals/metabolism , Phenylurea Compounds , Thiadiazoles , Time Factors , Transformation, Genetic , Clusiaceae/growth & development , Garcinia/physiology , Tissue Culture Techniques
8.
Journal of Southern Medical University ; (12): 875-882, 2019.
Article in Chinese | WPRIM | ID: wpr-773518

ABSTRACT

OBJECTIVE@#To investigate the role of E26 transformation-specific variant 4 (ETV4) in sorafenib and cisplatin resistance in hepatocellular carcinoma (HCC).@*METHODS@#HCC cell lines SMMC-7721 and HCC-LM3 were transfected with an ETV4- overexpressing plasmid or small interfering RNAs (siRNAs) targeting ETV4. The cells with ETV4 overexpression or ETV4 interference were treated with DMSO, sorafenib (5 μmol/L) or cisplatin (5 μmol/L) for 48 h, and the total protein and total RNA were collected. Western blotting, flow cytometry, EdU proliferation assay were used to analyze the apoptosis and proliferation of the cells. We also obtained clinical specimens of HCC tissues and paired adjacent tissues from 11 patients for detecting ETV4 mRNA expression levels using real-time fluorescence quantitative PCR (q-PCR). The effect of ETV4 interference on the mRNA expression levels of immediate early response gene 3 (IER3) was examined in HCC cells that were treated with DMSO, sorafenib or cisplatin for 48 h.@*RESULTS@#The expression of ETV4 mRNA was significantly higher in HCC tissues than in the paired adjacent tissues. Overexpression of ETV4 in the HCC cell lines obviously inhibited cell apoptosis induced by sorafenib or cisplatin. Conversely, ETV4 interference significantly enhanced the apoptosis and inhibited the proliferation of the HCC cells following treatments with sorafenib or cisplatin. In addition, ETV4 regulated the mRNA expression levels of IER3 in the cells treatmed with sorafenib and cisplatin.@*CONCLUSIONS@#ETV4 promotes resistance of HCC cells to sorafenib or cisplatin .


Subject(s)
Humans , Apoptosis , Apoptosis Regulatory Proteins , Carcinoma, Hepatocellular , Cell Line, Tumor , Cell Proliferation , Cisplatin , Drug Resistance, Neoplasm , Liver Neoplasms , Membrane Proteins , Niacinamide , Phenylurea Compounds , Sorafenib
9.
Biol. Res ; 52: 3, 2019. tab, graf
Article in English | LILACS | ID: biblio-1011433

ABSTRACT

BACKGROUND: Gymnema sylvestre is a medicinal woody perennial vine known for its sweetening properties and antidiabetic therapeutic uses in the modern and traditional medicines. Its over-exploitation for the therapeutic uses and to meet the demand of pharmaceutical industry in raw materials supply for the production of anti-diabetic drugs has led to considerable decline in its natural population. RESULTS: An efficient system of shoot bud sprouting from nodal segment explants and indirect plant regeneration from apical meristem-induced callus cultures of G. sylvestre have been developed on Murashige and Skoog (MS) medium amended with concentrations of cytokinins. Of the three growth regulators tested, N6-benzylaminopurine (BAP) was the most efficient and 2.0 mg L-1 gave the best shoot formation efficiency. This was followed by thidiazuron (TDZ) and kinetin (Kin) but, most of the TDZ-induced micro shoots showed stunted growth. Multiple shoot formation was observed on medium amended with BAP or TDZ at higher concentrations. The produced micro shoots were rooted on half strength MS medium amended with auxins and rooted plantlets acclimatized with 87% survival of the regenerates. CONCLUSIONS: The developed regeneration system can be exploited for genetic transformation studies, particularly when aimed at producing its high yielding cell lines for the anti-diabetic phytochemicals. It also offers opportunities for exploring the expression of totipotency in the anti-diabetic perennial vine.


Subject(s)
Plant Growth Regulators/pharmacology , Regeneration/drug effects , Plant Shoots/growth & development , Gymnema sylvestre/growth & development , Morphogenesis/drug effects , Phenylurea Compounds/pharmacology , Purines/pharmacology , Thiadiazoles/pharmacology , Benzyl Compounds/pharmacology , Plant Shoots/drug effects , Gymnema sylvestre/drug effects , Kinetin/pharmacology
10.
Arch. endocrinol. metab. (Online) ; 62(6): 636-640, Dec. 2018. tab, graf
Article in English | LILACS | ID: biblio-983805

ABSTRACT

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Young Adult , Piperidines/adverse effects , Quinazolines/adverse effects , Carcinoma/drug therapy , Carcinoma, Medullary/drug therapy , Protein Kinase Inhibitors/adverse effects , Antineoplastic Agents/adverse effects , Oophoritis/chemically induced , Phenylurea Compounds/adverse effects , Quinolines/adverse effects , Thrombocytopenia/chemically induced , Time Factors , Thyroid Neoplasms/drug therapy , Retrospective Studies , Risk Factors , Follow-Up Studies , Kaplan-Meier Estimate , Sorafenib/adverse effects , Heart Failure/chemically induced , Intestinal Perforation/chemically induced
11.
Arch. endocrinol. metab. (Online) ; 62(3): 370-375, May-June 2018. graf
Article in English | LILACS | ID: biblio-950060

ABSTRACT

Summary Total thyroidectomy, radioiodine (RAI) therapy, and TSH suppression are the mainstay treatment for differentiated thyroid carcinomas (DTCs). Treatments for metastatic disease include surgery, external-beam radiotherapy, RAI, and kinase inhibitors for progressive iodine-refractory disease. Unresectable locoregional disease remains a challenge, as standard therapy with RAI becomes unfeasible. We report a case of a young patient who presented with unresectable papillary thyroid carcinoma (PTC), and treatment with sorafenib allowed total thyroidectomy and RAI therapy. A 20-year-old male presented with severe respiratory distress due to an enlarging cervical mass. Imaging studies revealed an enlarged multinodular thyroid gland, extensive cervical adenopathy, severe tracheal stenosis, and pulmonary micronodules. He required an urgent surgical intervention and underwent tracheostomy and partial left neck dissection, as the disease was deemed unresectable; pathology revealed PTC. Treatment with sorafenib was initiated, resulting in significant tumor reduction allowing near total thyroidectomy and bilateral neck dissection. Postoperatively, the patient underwent radiotherapy for residual tracheal lesion, followed by RAI therapy for avid cervical and pulmonary disease. The patient's disease remains stable 4 years after diagnosis. Sorafenib has been approved for progressive RAI-refractory metastatic DTCs. In this case report, we describe a patient with locally advanced PTC in whom treatment with sorafenib provided sufficient tumor reduction to allow thyroidectomy and RAI therapy, suggesting a potential role of sorafenib as an induction therapy of unresectable DTC.


Subject(s)
Humans , Male , Young Adult , Phenylurea Compounds/administration & dosage , Thyroid Neoplasms/therapy , Carcinoma, Papillary/therapy , Niacinamide/analogs & derivatives , Iodine Radioisotopes/administration & dosage , Antineoplastic Agents/administration & dosage , Thyroidectomy , Thyroid Neoplasms/diagnostic imaging , Carcinoma, Papillary/diagnostic imaging , Tomography, X-Ray Computed , Treatment Outcome , Niacinamide/administration & dosage , Neoadjuvant Therapy , Sorafenib , Thyroid Cancer, Papillary
12.
Medicina (B.Aires) ; 78(1): 29-32, feb. 2018. tab
Article in English | LILACS | ID: biblio-894543

ABSTRACT

Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.


El hepatocarcinoma (HCC) es la segunda causa de muerte relacionada con el cáncer en el mundo y es la principal causa de muerte en pacientes cirróticos. Desafortunadamente, la incidencia de HCC ha crecido significativamente en la última década. Los tratamientos curativos como la cirugía, el trasplante de hígado o la ablación solo pueden aplicarse en menos del 30% de los casos. El sorafenib es el tratamiento de primera línea para el HCC avanzado, mientras que el regorafenib se reserva como segunda línea. Sin embargo, todavía son necesarios nuevos enfoques terapéuticos potentes y más específicos para el HCC avanzado. El hígado constituye un microambiente inmunológico único, aunque la inmunidad antitumoral parece ser factible mediante el uso de inhibidores de punto de control como nivolumab. La eficacia puede aumentarse adicionalmente combinando inhibidores de puntos de control inmunitario o aplicando tratamientos loco-regionales. En este sentido, el éxito del uso de anticuerpos monoclonales, que bloquean el control inmunitario, ha renovado el interés en la inmunoterapia para el HCC.


Subject(s)
Humans , Carcinoma, Hepatocellular/drug therapy , Antineoplastic Agents, Immunological/therapeutic use , Immunotherapy/methods , Liver Neoplasms/drug therapy , Antibodies, Monoclonal/therapeutic use , Phenylurea Compounds/therapeutic use , Pyridines/therapeutic use , Clinical Trials as Topic , Sorafenib/therapeutic use , Nivolumab/therapeutic use
13.
Chinese Journal of Hematology ; (12): 143-147, 2018.
Article in Chinese | WPRIM | ID: wpr-1011712

ABSTRACT

Objective: To explore the effects and possible mechanisms of the novel pan-FGFR inhibitor BGJ398 on KG-1 cells in vitro. Methods: Effects of BGJ398 on cells proliferation were detected by CCK-8, the apoptosis was assessed by Annexin V-FITC. Reverse transcriptionquantitative polymerase chain reaction (q-PCR) analysis was used to detect the expression of apoptosis-related genes B cell lymphoma-2 (Bcl-2) and caspase-3. Western blotting analysis was performed to explore the proteins expression levels of Bcl-2, caspase-3 and the expression of p-AKT, p-S6K, p-ERK and FGFR1. Results: BGJ398 effectively inhibited cell proliferation by dose-dependent manners. BGJ398(1.4 µmol/L) induced apoptosis of KG-1 cells by 36.4%, compared with 4.5% in the control group(P<0.001). Treatment with BGJ398 at 1.4 µmol/L led to significant increases in the expression levels of caspase-3, and decreases in the expression of Bcl-2 (P<0.005). In accordance with these results, Western blot analysis further confirmed the increased expression of Bcl-2 protein along with elevated caspase-3 activity. In addition, BGJ398 markedly down-regulated FGFR1OP2-FGFR1 fusion protein, p-AKT and p-S6K expression, but not p-ERK expression. Conclusion: Novel pan-FGFR inhibitor BGJ398 substantially suppressed KG-1 cell growth and induced apoptosis by inhibiting the expression of FGFR1, p-AKT, p-S6K and regulating apoptosis-related proteins.


Subject(s)
Humans , Apoptosis , Caspase 3 , Cell Line, Tumor , Cell Proliferation , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology
14.
Neuroscience Bulletin ; (6): 98-108, 2018.
Article in English | WPRIM | ID: wpr-777072

ABSTRACT

Increasing evidence suggests that spinal microglia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain following intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID (a caspase-6 inhibitor) and the astroglial inhibitors L-α-aminoadipate (L-AA, an astroglial toxin) and carbenoxolone (a connexin 43 inhibitor), as well as U0126 (an ERK kinase inhibitor) and D-JNKI-1 (a c-Jun N-terminal kinase inhibitor). We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflammatory pain in both sexes. Intrathecal U0126 and D-JNKI-1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.


Subject(s)
Animals , Female , Male , Mice , 2-Aminoadipic Acid , Toxicity , Anti-Inflammatory Agents , Therapeutic Uses , Astrocytes , Pathology , Carbenoxolone , Pharmacology , Caspase 6 , Metabolism , Connexin 43 , Metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors , Pharmacology , Glial Fibrillary Acidic Protein , Metabolism , Mice, Transgenic , Microglia , Pathology , Minocycline , Therapeutic Uses , Neuralgia , Drug Therapy , Pathology , Pain Measurement , Phenylurea Compounds , Pharmacology , Sex Characteristics , Spinal Cord , Pathology , Time Factors
15.
An. acad. bras. ciênc ; 89(4): 3103-3110, Oct.-Dec. 2017. tab, graf
Article in English | LILACS | ID: biblio-886869

ABSTRACT

ABSTRACT The low fruit set is one of the main factors leading to poor yield of pear orchards in Brazil. The exogenous application of thidiazuron (TDZ) and aminoethoxyvinilglycine (AVG) has shown promising results in some pear cultivars and other temperate fruit trees. The objective of this study was to evaluate the effect of TDZ and AVG on fruit set, yield, and fruit quality of 'Hosui' and 'Packham's Triumph' pears. The study was performed in a commercial orchard located in São Joaquim, SC. Plant material consisted of 'Hosui' and 'Packham's Triumph' pear trees grafted on Pyrus calleryana. Treatments consisted on different rates of TDZ (0 mg L-1, 20 mg L-1, 40 mg L-1 and 60 mg L-1) sprayed at full bloom for both cultivars. An additional treatment of AVG 60 mg L-1 was sprayed one week after full bloom in 'Hosui'. The fruit set, number of fruit per tree, yield, fruit weight, seed number, and fruit quality attributes were assessed. Fruit set and yield of both cultivars are consistently increased by TDZ, within the rates of 20 to 60 mg L-1. Besides, its application increased fruit size of 'Hosui' and did not negatively affect fruit quality attributes of both cultivars.


Subject(s)
Phenylurea Compounds/pharmacology , Thiadiazoles/pharmacology , Pyrus/drug effects , Glycine/analogs & derivatives , Phenylurea Compounds/administration & dosage , Thiadiazoles/administration & dosage , Pyrus/growth & development , Crop Production , Glycine/administration & dosage , Glycine/pharmacology
16.
Einstein (Säo Paulo) ; 15(3): 355-358, July-Sept. 2017.
Article in English | LILACS | ID: biblio-891404

ABSTRACT

ABSTRACT Acute myeloid leukemia is a hematopoietic stem cell neoplastic disease associated with high morbidity and mortality. The presence of FLT3 internal tandem duplication mutations leads to high rates of relapse and decreased overall survival. Patients with FLT3 internal tandem duplication are normally treated with hematopoietic stem cell transplantation in first complete remission. Nevertheless, the incidence of post-transplant relapse is considerable in this group of patients, and the management of this clinical condition is challenging. The report describes the outcomes of patients with FLT3 internal tandem duplication positive acute myeloid leukemia who relapsed after allogeneic hematopoietic stem cell transplantation and were treated with the combination of re-induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Three cases are described and all patients achieved prolonged complete remission with the combined therapy. The combination of induction chemotherapy followed by donor lymphocyte infusion, and the maintenance with azacitidine and sorafenib can be effective approaches in the treatment of post-hematopoietic stem cell transplant and relapsed FLT3 internal tandem duplication positive acute myeloid leukemia patients. This strategy should be further explored in the context of clinical trials.


RESUMO A leucemia mieloide aguda é uma doença neoplásica de células-tronco hematopoiéticas com alta morbimortalidade. A presença de mutações de duplicação em tandem de FLT3 leva a altas taxas de recorrência e a menor sobrevida global. Os pacientes com duplicação em tandem de FLT3 são normalmente tratados com transplante de células-tronco hematopoiéticas na primeira remissão completa. No entanto, a incidência de recidiva pós-transplante é considerável neste grupo de pacientes, e a conduta, nestes casos, é um desafio. O relato descreve os resultados do tratamento de pacientes com leucemia mieloide aguda positiva e duplicação em tandem de FLT3 que recidivaram depois do transplante alogênico de células-tronco hematopoiéticas e que foram tratados com combinação de quimioterapia de reindução, infusão de linfócitos de doador, sorafenib e azacitidina. São descritos três casos, e todos os pacientes apresentaram remissão completa prolongada com a terapia combinada. A combinação de quimioterapia de indução, seguida de infusão de linfócitos do doador, e a manutenção com azacitidina e sorafenib podem ser abordagens eficazes no tratamento da recorrência pós-transplante em pacientes com leucemia mieloide aguda e duplicação em tandem de FLT3. Essa estratégia deve ser mais explorada no contexto de ensaios clínicos.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Phenylurea Compounds/administration & dosage , Azacitidine/administration & dosage , Leukemia, Myeloid, Acute/therapy , Niacinamide/analogs & derivatives , Lymphocyte Transfusion , fms-Like Tyrosine Kinase 3/genetics , Induction Chemotherapy , Antineoplastic Agents/administration & dosage , Recurrence , Leukemia, Myeloid, Acute/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Treatment Outcome , Niacinamide/administration & dosage , Combined Modality Therapy/methods , Neoplasm Recurrence, Local/therapy
18.
Ann. hepatol ; 16(2): 263-268, Mar.-Apr. 2017. tab, graf
Article in English | LILACS | ID: biblio-887231

ABSTRACT

ABSTRACT Background and Aims. The presence of dermatologic reaction as an adverse event to sorafenib treatment in patients with unresectable hepatocellular carcinoma has been indicated as a prognostic factor for survival in a recent prospective analysis. To date, this is the only clinical predictor of treatment response, which can be evaluated earlier in the treatment and, therefore, contribute to a better and more individualized patient management. Material and methods. This retrospective study included 127 patients treated with sorafenib under real-life practice conditions in two hepatology reference centers in Brazil. Demographic data, disease/medical history and time of sorafenib administration as well as adverse events related to the medication were recorded in a database. Results. Cirrhosis was present in 94% of patients, 85.6% were Child-Pugh A, 80.3%BCLC-C, 81% had vascular invasion and/or extrahepatic spread and 95% had a performance status 0 to 1.The median duration of treatment was 10.1 months (range: 0.1-47 months).The most common adverse event within the first 60 days of treatment were diarrhea (62.2%) and dermatological reaction (42%).The median overall survival for the cohort was 20 months, and it was higher for patients who developed dermatological reactions within the first 60 days compared to those who did not present this adverse event. Conclusion. This retrospective analysis showed the use of sorafenib in patients selected according to BCLC staging, and it is the first external validation of early dermatologic adverse events as a predictor of overall survival in patients with advanced hepatocellular carcinoma.


Subject(s)
Humans , Phenylurea Compounds/adverse effects , Niacinamide/analogs & derivatives , Drug Eruptions/etiology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Time Factors , Proportional Hazards Models , Retrospective Studies , Risk Factors , Treatment Outcome , Niacinamide/adverse effects , Drug Eruptions/diagnosis , Drug Eruptions/mortality , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Kaplan-Meier Estimate , Sorafenib , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Neoplasm Staging
19.
Ann. hepatol ; 16(2): 255-262, Mar.-Apr. 2017. tab, graf
Article in English | LILACS | ID: biblio-887230

ABSTRACT

ABSTRACT Background. Hepatocellular carcinoma (HCC) is the most common malignancy that develops in cirrhotic livers. Its clinical and epidemiological characteristics and mortality rates vary according to geographical region. The objective of this study was to evaluate the clinical profile, epidemiological characteristics, laboratory parameters, treatment and survival of patients with HCC. Material and methods. Patients with HCC seen between 2000 and 2012 were studied. The Kaplan-Meier method was used for survival analysis according to variables in question. Results. The study included 247 patients with a mean age of 60 ± 10 years. There was a predominance of males (74%). The main etiologies of HCC were HCV infection (55%), excessive alcohol consumption (12%), and HBV infection (8%). Liver cirrhosis was present in 92% of cases. The mean tumor number and diameter were 2 and 5 cm, respectively. Patients meeting the Milan criteria corresponded to 43% of the sample. Liver transplantation was performed in 22.4% of patients of the Milan subset and in 10% of the whole sample. The overall mean survival was 60 months, with a 1-, 3- and 5-year survival probability of 74%, 40% and 29%, respectively. Lower survival was observed among patients with alcoholic etiology. Survival was higher among patients submitted to liver transplantation (P < 0.001), TACE (P < 0.001), or any kind of treatment (P < 0.001). However, no difference was found for surgical resection (P = 0.1) or sorafenib (P = 0.1). Conclusion. Patients with HCC were mainly older men diagnosed at an advanced stage. Treatment was associated with better overall survival, but few patients survived to be treated.


Subject(s)
Humans , Liver Transplantation , Chemoembolization, Therapeutic , Carcinoma, Hepatocellular/therapy , Ablation Techniques , Hepatectomy , Liver Neoplasms/therapy , Antineoplastic Agents/therapeutic use , Phenylurea Compounds/therapeutic use , Time Factors , Brazil/epidemiology , Risk Factors , Treatment Outcome , Chemoembolization, Therapeutic/adverse effects , Chemoembolization, Therapeutic/mortality , Niacinamide/analogs & derivatives , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Tumor Burden , Kaplan-Meier Estimate , Tertiary Care Centers , Hepatectomy/adverse effects , Hepatectomy/mortality , Liver Neoplasms/etiology , Neoplasm Staging , Antineoplastic Agents/adverse effects
20.
Ann. hepatol ; 16(2): 247-254, Mar.-Apr. 2017. tab, graf
Article in English | LILACS | ID: biblio-887229

ABSTRACT

ABSTRACT Background & Aim. Transarterial chemoembolization (TACE) or sorafenib is recommended for hepatocellular carcinoma BCLC stages B and C respectively. We studied the role of combination of TACE and sorafenib in BCLC stages B/C. Material and methods. We undertook an observational study on a cohort of cirrhotics with HCC from August 2010 through October 2014. Patients in BCLC stages B/C who had received TACE and/or sorafenib were included. mRECIST criteria were used to assess tumor response. The primary end point was overall survival. Results. Out of 124 patients, 47.6% were in BCLC-B and 52.4% in BCLCC. Baseline characteristics were comparable. The predominant etiology was cryptogenic (37.2% and 38.5%, p = NS). 49.1% in BCLC-B and 56.9% in BCLC-C had received TACE+sorafenib. In BCLC-B, the overall survival improved from 9 months (95% CI 6.3-11.7) using TACE only to 16 months (95% CI 12.9-19.1) using TACE+sorafenib (p < 0.05). In BCLC-C, addition of TACE to sorafenib improved the overall survival from 4 months (95%CI 3-5) to 9 months (95%CI 6.8-11.2) (p < 0.0001). As per mRECIST criteria, patients on TACE+sorafenib had reduced progressive disease (37.8% vs. 83.3%), improved partial response (43.2% vs. 3.3%) and one had complete response compared to those on sorafenib alone (p < 0.0001) in BCLC-C but not in BCLC-B group. Hand foot syndrome was noted in 27.7% patients on sorafenib and post TACE syndrome in 80.2% patients, but both were reversible. No major adverse events were noted. Conclusion. TACE+sorafenib was more effective than TACE or sorafenib alone in HCC BCLC stages B or C with a significant survival benefit and improved tumour regression especially in BCLC-C patients.


Subject(s)
Humans , Phenylurea Compounds/therapeutic use , Niacinamide/analogs & derivatives , Carcinoma, Hepatocellular/therapy , Protein Kinase Inhibitors/therapeutic use , Liver Neoplasms/therapy , Antineoplastic Agents/therapeutic use , Phenylurea Compounds/adverse effects , Time Factors , Treatment Outcome , Chemoembolization, Therapeutic/adverse effects , Chemoembolization, Therapeutic/mortality , Niacinamide/adverse effects , Niacinamide/therapeutic use , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Protein Kinase Inhibitors/adverse effects , Tumor Burden , Kaplan-Meier Estimate , Liver Neoplasms/etiology , Liver Neoplasms/mortality , Neoplasm Staging , Antineoplastic Agents/adverse effects
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