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1.
PLoS One ; 18(6): e0283082, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37384663

RESUMO

In recent years measles has been one of the most critical public health problem in Bangladesh. Although the Ministry of Health in Bangladesh employs a broad extension of measles control policies, logistical challenges exist, and there is significant doubt regarding the disease burden. Mathematical modelling of measles is considered one of the most effective ways to understand infection transmission and estimate parameters in different countries, such as Bangladesh. In this study, a mathematical modelling framework is presented to explore the dynamics of measles in Bangladesh. We calibrated the model using cumulative measles incidence data from 2000 to 2019. Also, we performed a sensitivity analysis of the model parameters and found that the contact rate had the most significant influence on the basic reproduction number R0. Four hypothetical intervention scenarios were developed and simulated for the period from 2020 to 2035. The results show that the scenario which combines enhanced treatment for exposed and infected population, first and second doses of vaccine is the most effective at rapidly reducing the total number of measles incidence and mortality in Bangladesh. Our findings also suggest that strategies that focus on a single interventions do not dramatically affect the decline in measles incidence cases; instead, those that combine two or more interventions simultaneously are the most effective in decreasing the burden of measles incidence and mortality. In addition, we also evaluated the cost-effectiveness of varying combinations of three basic control strategies including distancing, vaccination and treatment, all within the optimal control framework. Our finding suggested that combines distancing, vaccination and treatment control strategy is the most cost-effective for reducing the burden of measles in Bangladesh. Other strategies can be comprised to measles depending on the availability of funds and policymakers' choices.


Assuntos
Efeitos Psicossociais da Doença , Sarampo , Humanos , Bangladesh/epidemiologia , Número Básico de Reprodução , Emoções , Sarampo/epidemiologia , Sarampo/prevenção & controle
2.
Front Bioeng Biotechnol ; 10: 992708, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36185432

RESUMO

Cell-free gene expression (CFE) systems are an attractive tool for engineering within synthetic biology and for industrial production of high-value recombinant proteins. CFE reactions require a cell extract, energy system, amino acids, and DNA, to catalyse mRNA transcription and protein synthesis. To provide an amino acid source, CFE systems typically use a commercial standard, which is often proprietary. Herein we show that a range of common microbiology rich media (i.e., tryptone, peptone, yeast extract and casamino acids) unexpectedly provide an effective and low-cost amino acid source. We show that this approach is generalisable, by comparing batch variability and protein production in the following range of CFE systems: Escherichia coli (Rosetta™ 2 (DE3), BL21(DE3)), Streptomyces venezuelae and Pichia pastoris. In all CFE systems, we show equivalent or increased protein synthesis capacity upon replacement of the commercial amino acid source. In conclusion, we suggest rich microbiology media provides a new amino acid source for CFE systems with potential broad use in synthetic biology and industrial biotechnology applications.

3.
J Neurosci Rural Pract ; 13(3): 550-553, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35946001

RESUMO

Presence of the artery of Desproges-Gotteron is extremely rare. It has seldom been mentioned in the literature as well. The authors have dealt with a case of a dural arteriovenous malformation (AVM ) of conus medullaris fed by the artery of Desproges-Gotteron in a young female of 19 years. The patient presented with a tingling sensation of lower limbs, progressive difficulty walking, and incontinence of the bladder. There was weakness in all groups of muscle of both lower limbs and definite sensory level on examination. Magnetic resonance imaging revealed multiple flow voids at the level of conus medullaris. Spinal digital subtraction angiography (DSA) revealed dural AVM at the level of conus. The patient underwent transarterial embolization with 30% Endocryl( n -butyl cyanoacrylate) in two stages, and repeated spinal DSA revealed no evidence of residual AVM. Patient's neurology gradually improved. Almost 2 years down the line, the follow-up revealed gradual but complete motor and sensory deficits recovery except for occasional burning pain in lower limbs. Spinal AVM supplied by the artery of Desproges-Gotteron is a unique variation. Moreover, the authors believe that it is the first reported case in Bangladesh.

4.
Biomaterials ; 283: 121423, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35220018

RESUMO

Growth factors (GF) regulate normal development to cancer progression. GFs interact with extracellular matrix (ECM) biomolecules, such as heparin sulfate (HS) glycosaminoglycan (GAG), to enhance their stability and angiogenic signaling. Biomaterials that modulate GF activity by mimicking interactions observed in the native ECM could be designed as an effective treatment strategy. However, these materials failed to attenuate angiogenic signaling site-specifically without sparing normal tissues. In this work, we investigated the effect of a GAG-based biomaterial, which binds to the tumor endothelial cells (TEC), on the interaction among vascular endothelial growth factor (VEGF), its receptors-VEGFR2 and HS-and angiogenesis. Heparin-bile acid based conjugates, as ECM-mimicking component, were synthesized to selectively target the TEC marker doppel and doppel/VEGFR2 axis. The most effective compound LHbisD4 (low molecular weight heparin conjugated with 4 molecules of dimeric dexocholic acid) reduced tumor volume concentrated over doppel-expressing EC, and decreased tumor-interstitial VEGF without affecting its plasma concentration. Doppel-destined LHbisD4 captured VEGF, formed an intermediate complex with doppel, VEGFR2, and VEGF but did not induce active VEGFR2 dimerization, and competitively inhibited HS for VEGF binding. We thus show that GAG-based materials can be designed to imitate and leverage to control tumor microenvironment via bio-inspired interactions.


Assuntos
Células Endoteliais , Glicosaminoglicanos , Neoplasias , Células Endoteliais/metabolismo , Glicosaminoglicanos/farmacologia , Humanos , Neoplasias/patologia , Neovascularização Patológica/patologia , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-34367649

RESUMO

BACKGROUND: Subjective wellbeing in terms of objective outcome can be useful to determine the level of progress in clinical practice as well as research studies in Bangladesh. Besides, cultural understanding of well-being for Bangladeshi population is also equally important to report. A valid Bangla version of the five-item WHO Well-being Index can be a suitable measure to achieve the purposes. Therefore, the present study aimed at validating the WHO-5 Well-being Index for general population in Bangladesh. METHODS: After following the standard procedures for translation, back-translation, and committee translation, the initial Bangla version of the scale was developed and pretested. Based on the feedback during pretesting, a slight modification was made and the final version was developed. This final version was administered to 269 participants of different socioeconomic backgrounds to find out the reliability and validity of the scale from March 2019 to May 2019. The data analysis was conducted using SPSS 24. RESULTS: The scale demonstrated acceptable internal consistency (α = 0.754) and test-retest reliability (r = 0.713), divergent validity (r = -0.443, p < 0.01 with the Bangla version of Perceived Stress Scale-10) and convergent validity (r = 0.542, p < 0.01 with the Bangla version of Warwick-Edinburgh Mental Well-Being Scale). The data also yielded one-factor structure for the scale in exploratory factor analysis explaining 38.68% of total variance. The factor-structure was further supported in the confirmatory factor analysis (χ2 = 295.852, χ2/df = 2.017, RMSEA = 0.062, CFI = 0.986, TLI = 0.964, and SRMR = 0.0255). CONCLUSION: The findings suggested the Bangla version of the WHO-5 Well-being Index is a psychometrically valid and reliable tool for general adult population in Bangladeshi when it comes to measuring subjective well-being both in clinical practice and research studies.

6.
J Control Release ; 334: 237-247, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33915222

RESUMO

ROCK, one of the downstream regulators of Rho, controls actomyosin cytoskeleton organization, stress fiber formation, smooth muscle contraction, and cell migration. ROCK plays an important role in the pathologies of cerebral and coronary vasospasm, hypertension, cancer, and arteriosclerosis. Pharmacological-induced systemic inhibition of ROCK affects both the pathological and physiological functions of Rho-kinase, resulting in hypotension, increased heart rate, decreased lymphocyte count, and eventually cardiovascular collapse. To overcome the adverse effects of systemic ROCK inhibition, we developed a bioreductive prodrug of a ROCK inhibitor, fasudil, that functions selectively under hypoxic conditions. By masking fasudil's active site with a bioreductive 4-nitrobenzyl group, we synthesized a prodrug of fasudil that is inactive in normoxia. Reduction of the protecting group initiated by hypoxia reveals an electron-donating substituent that leads to fragmentation of the parent molecule. Under normoxia the fasudil prodrug displayed significantly reduced activity against ROCK compared to its parent compound, but under severe hypoxia the prodrug was highly effective in suppressing ROCK activity. Under hypoxia the prodrug elicited an antiproliferative effect on disease-afflicted pulmonary arterial smooth muscle cells and pulmonary arterial endothelial cells. The prodrug displayed a long plasma half-life, remained inactive in the blood, and produced no drop in systemic blood pressure when compared with fasudil-treated controls. Due to its selective nature, our hypoxia-activated fasudil prodrug could be used to treat diseases where tissue-hypoxia or hypoxic cells are the pathological basis of the disease.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina , Hipóxia , Pró-Fármacos , Inibidores de Proteínas Quinases , Quinases Associadas a rho , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/efeitos adversos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Células Endoteliais , Humanos , Hipóxia/tratamento farmacológico , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores
7.
BMJ Open Respir Res ; 6(1): e000393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179000

RESUMO

Introduction: To evaluate WHO chest radiograph interpretation processes during a pneumococcal vaccine effectiveness study of children aged 3-35 months with suspected pneumonia in Sylhet, Bangladesh. Methods: Eight physicians masked to all data were standardised to WHO methodology and interpreted chest radiographs between 2015 and 2017. Each radiograph was randomly assigned to two primary readers. If the primary readers were discordant for image interpretability or the presence or absence of primary endpoint pneumonia (PEP), then another randomly selected, masked reader adjudicated the image (arbitrator). If the arbitrator disagreed with both primary readers, or concluded no PEP, then a masked expert reader finalised the interpretation. The expert reader also conducted blinded quality control (QC) for 20% of randomly selected images. We evaluated agreement between primary readers and between the expert QC reading and the final panel interpretation using per cent agreement, unadjusted Cohen's kappa, and a prevalence and bias-adjusted kappa. Results: Among 9723 images, the panel classified 21.3% as PEP, 77.6% no PEP and 1.1% uninterpretable. Two primary readers agreed on interpretability for 98% of images (kappa, 0.25; prevalence and bias-adjusted kappa, 0.97). Among interpretable radiographs, primary readers agreed on the presence or absence of PEP in 79% of images (kappa, 0.35; adjusted kappa, 0.57). Expert QC readings agreed with final panel conclusions on the presence or absence of PEP for 92.9% of 1652 interpretable images (kappa, 0.75; adjusted kappa, 0.85). Conclusion: Primary reader performance and QC results suggest the panel effectively applied the WHO chest radiograph criteria for pneumonia.


Assuntos
Vacinas Pneumocócicas , Pneumonia Pneumocócica/diagnóstico por imagem , Pneumonia Pneumocócica/prevenção & controle , Radiografia Torácica , Bangladesh , Pré-Escolar , Estudos de Coortes , Humanos , Lactente , Variações Dependentes do Observador , Distribuição Aleatória
8.
Bioconjug Chem ; 29(11): 3757-3767, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30372043

RESUMO

Tumor-derived exosomes are bound and internalized to organ-specific cells, affecting metastasis. Heparan sulfate proteoglycans mediate the interaction between cells and exosomes. Exosome transfer to the recipient cell can be competitively blocked by heparinoids, because heparin is structurally similar to heparan sulfate. It is hypothesized that there may be structural requirements of heparinoids to attenuate the cellular uptake and metastatic activity of tumor-derived exosomes. Here, we compared the properties of unfractionated heparin (UFH), glycol-split UFH, low-molecular-weight heparin (LMWH), glycol-split LMWH, and ultra-LMWH premixed with A549-derived exosomes. Uptake of A549-derived exosomes (0.1 mg/mL) into BEAS-2B cells was significantly blocked by 0.4 mg/mL of heparinoids. Heparinoids attenuated migration of BEAS-2B cells stimulated by A549-derived exosomes. Glycol-split LMWH with no antifactor Xa activity exhibited the strongest antimigratory effects than other heparinoids. Thus, heparinoids with proper molecular weight and structure can inhibit tumor-derived exosomes, not proportionally to the anticoagulant activity.


Assuntos
Anticoagulantes/farmacologia , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Heparina/farmacologia , Neoplasias/metabolismo , Células A549 , Anticoagulantes/química , Linhagem Celular , Exossomos/patologia , Heparina/química , Heparina de Baixo Peso Molecular/química , Heparina de Baixo Peso Molecular/farmacologia , Heparinoides/química , Heparinoides/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia
9.
J Control Release ; 284: 160-170, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-29908222

RESUMO

There is a growing interest in preclinical research to consider low-dose metronomic chemotherapy as antiangiogenic cancer treatment. Oral metronomic therapy, in particular, has shown much promise with its ease of daily administration and higher therapeutics window. In that regard, we developed oral pemetrexed using the physical complex with the bile acid enhancers (DCK). In a caco-2 permeability study, the oral pemetrexed/DCK complex had significantly higher drug uptake, and inhibited efflux transporter activity as well. We further observed that the mechanism of oral drug uptake was related to transcellular along with bile acid transporter mediated pathways. The oral administration of drug complex in rats revealed high bioavailability (22.37%) and extended mean residence time. Using SCC7 and A549 xenograft models, we demonstrated that antitumor effects from daily oral metronomic pemetrexed significantly reduced tumor in a dose-dependent manner. The antitumor activity of oral pemetrexed/DCK complex plus cisplatin was superior to both monotherapies. The xenograft study also revealed that oral metronomic therapy markedly reduced microvessel density, proliferation and increased apoptosis in the tumor tissues. Oral metronomic doses were significantly correlated with the elevation of plasma deoxyuridine level, an essential biomarker for pemetrexed therapy. One-month toxicity study confirmed that daily dosing of oral pemetrexed is safe by investigating apoptosis in the gut tissues from mice. Moreover, we analyzed different biochemical parameters and enzymes from the blood to prove that our newly developed oral pemetrexed complex is well tolerated.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/administração & dosagem , Células A549 , Administração Metronômica , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Apoptose , Ácidos e Sais Biliares/química , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Pemetrexede/farmacocinética , Pemetrexede/uso terapêutico , Veículos Farmacêuticos/química , Ratos Sprague-Dawley
10.
J Cardiovasc Pharmacol Ther ; 23(5): 472-480, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29756460

RESUMO

INTRODUCTION: Pulmonary hypertension (PH) is a potentially deadly disease for infants and adults with few existing medical interventions and no cure. In PH, increased blood pressure in the pulmonary artery eventually leads to heart failure. Fasudil, an antagonist of Rho-kinase, causes vasodilation leading to decreased systemic artery pressure and pulmonary artery pressure (PAP). This study compared the effects of fasudil administered as either an intravenous infusion or inhaled aerosol in newborn lambs. HYPOTHESIS: Inhaled aerosol delivery of fasudil will provide selective pulmonary vasodilation when compared with intravenous administration. METHODS: Newborn lambs (∼11 days) were surgically instrumented and mechanically ventilated under anesthesia. A pulmonary artery catheter and ultrasonic flow probe were inserted to measure hemodynamics. Acute PH was pharmaceutically induced via continuous intravenous infusion of thromboxane. After achieving a 2- to 3-fold elevation of PAP, fasudil was administered either as intravenous infusion (2.5 mg/kg) or inhaled aerosol (100 mg of fasudil in 2 mL of saline). Changes in PAP, mean systemic arterial pressure (MABP), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), cardiac output, and heart rate were assessed. In addition, plasma concentrations of fasudil were measured. RESULTS: Both routes of fasudil delivery produced significant decreases in PAP and PVR but also produced similar decreases in MABP and SVR. The Cmax for intravenous fasudil was greater than that for inhaled fasudil. CONCLUSIONS: These results suggest inhaled fasudil lacks pulmonary selectivity when compared with intravenous fasudil.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Anti-Hipertensivos/administração & dosagem , Pressão Arterial/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Artéria Pulmonar/efeitos dos fármacos , Tromboxanos , Vasodilatadores/administração & dosagem , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , Administração por Inalação , Aerossóis , Animais , Animais Recém-Nascidos , Débito Cardíaco/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Infusões Intravenosas , Masculino , Artéria Pulmonar/enzimologia , Artéria Pulmonar/fisiopatologia , Carneiro Doméstico , Resistência Vascular/efeitos dos fármacos , Quinases Associadas a rho/metabolismo
11.
Int J Pharm ; 544(1): 285-296, 2018 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-29680281

RESUMO

Three-dimensional printing (3DP), though developed for nonmedical applications and once regarded as futuristic only, has recently been deployed for the fabrication of pharmaceutical products. However, the existing feeding materials (inks and filaments) that are used for printing drug products have various shortcomings, including the lack of biocompatibility, inadequate extrudability and printability, poor drug loading, and instability. Here, we have sought to develop a filament using a single pharmaceutical polymer, with no additives, which can be multi-purposed and manipulated by computational design for the preparation of tablets with desired release and absorption patterns. As such, we have used hydroxypropyl-methylcellulose (HPMC) and diltiazem, a model drug, to prepare both drug-free and drug-impregnated filaments, and investigated their thermal and crystalline properties, studied the cytotoxicity of the filaments, designed and printed tablets with various infill densities and patterns. By alternating the drug-free and drug-impregnated filaments, we fabricated various types of tablets, studied the drug release profiles, and assessed oral absorption in rats. Both diltiazem and HPMC were stable at extrusion and printing temperatures, and the drug loading was 10% (w/w). The infill density, as well as infill patterns, influenced the drug release profile, and thus, when the infill density was increased to 100%, the percentage of drug released dramatically declined. Tablets with alternating drug-free and drug-loaded layers showed delayed and intermittent drug release, depending on when the drug-loaded layers encountered the dissolution media. Importantly, the oral absorption patterns accurately reproduced the drug release profiles and showed immediate, extended, delayed and episodic absorption of the drug from the rat gastrointestinal tract (GIT). Overall, we have demonstrated here that filaments for 3D printers can be prepared from a pharmaceutical polymer with no additives, and the novel computational design allows for fabricating tablets with the capability of producing distinct absorption patterns after oral administration.


Assuntos
Portadores de Fármacos/administração & dosagem , Derivados da Hipromelose/administração & dosagem , Impressão Tridimensional , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Diltiazem/administração & dosagem , Diltiazem/sangue , Diltiazem/química , Diltiazem/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Mucosa Gástrica/metabolismo , Humanos , Derivados da Hipromelose/química , Derivados da Hipromelose/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Comprimidos
12.
Int J Pharm ; 535(1-2): 38-46, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29097141

RESUMO

Heparin-like sulfated polysaccharides are potential drug candidates owing to their ability to interact with angiogenic factors and inhibit angiogenesis, tumor growth, and metastasis. This study aimed to improve the delivery of heparin-like anticancer polysaccharides for accumulation at the tumor site. We designed a nanocarrier system using protamine attached to polyethylene glycol (PEG) and evaluated the stability, tumor targeting, and tumor growth inhibition of the nanocarrier loaded with heparin derivatives. When mixed with various polyanionic heparin derivatives, the polycationic PEG-protamine formed stable self-assembled nanocomplexes via ionic interactions, with flexible PEG chains located on the outside. Among the complexes, a nanocomplex loaded with a low-molecular-weight heparin-suramin conjugate (LHsura) had the most suitable average size (101.9nm) for the enhanced permeability and retention effect and allowed accumulation of LHsura at the tumor site for up to 48h. In a tumor-bearing mouse model, the PEG-protamine and LHsura nanocomplex (10mg/kg/3days, intravenously), which could be extravasated through the tumor vasculature, significantly inhibited tumor growth, more than LHsura alone did. Overall, the self-assembled nanocomplexation of PEG-protamine and LHsura helped control the release and extravasation of LHsura, which resulted in an antitumor effect on the target tumor cells.


Assuntos
Portadores de Fármacos/química , Heparina de Baixo Peso Molecular/química , Nanoconjugados/química , Neoplasias Experimentais/metabolismo , Protaminas/química , Suramina/química , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Heparina de Baixo Peso Molecular/farmacocinética , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Tamanho da Partícula , Polietilenoglicóis/química , Protaminas/farmacocinética , Suramina/farmacocinética , Propriedades de Superfície , Distribuição Tecidual
13.
Biomaterials ; 139: 56-66, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28586719

RESUMO

Clinical studies have found that the incidence of cancer metastasis through the lymphatic vessels are 3-5 times higher than that through the blood vessels. These findings suggest the potency of anti-lymphangiogenic therapy in reducing the incidence of cancer metastasis. Previously, we reported LHbisD4, which is the conjugate of low molecular weight heparin (LMWH) and four bis-deoxycholates as a potent anti-angiogenic drug with less toxicity and orally active property. Here, we show that LHbisD4 could also suppress the formation of new lymphatic vessels and attenuate the incidence of metastasis by blocking VEGF-C signaling pathway. LHbisD4 significantly enhanced binding affinity with VEGF-C when compared with LMWH, which enables LHbisD4 to suppress the proliferation, migration and formation of tubular structures of human dermal lymphatic endothelial cells(HDLECs) in in vitro condition even in the presence of excessive amounts of VEGF-C. Similarly, we found that the density of lymphatic vessels in the primary tumor tissue in breast cancer bearing mice was significantly diminished when LHbisD4 was administered compared with the control group. Also, the incidence of axillary lymph nodes and distant organ metastasis was significantly reduced in the LHbisD4 administered group, which demonstrates that LHbisD4 could successfully lower the incidence of metastasis through blocking VEGF-C induced lymphangiogenesis. Based on these results, we propose LHbisD4 as a potent anti-cancer drug that can reduce the incidence of metastasis by suppressing lymphangiogenesis through blocking VEGF-C signaling pathway.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Heparina de Baixo Peso Molecular/química , Linfangiogênese/efeitos dos fármacos , Fator C de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Movimento Celular , Proliferação de Células , Ácido Desoxicólico/química , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Metástase Linfática , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Neovascularização Patológica/tratamento farmacológico
14.
Ultrasonics ; 80: 22-33, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28499122

RESUMO

Using a large set of ultrasound features does not necessarily ensure improved quantitative classification of breast tumors; rather, it often degrades the performance of a classifier. In this paper, we propose an effective feature reduction approach in the transform domain for improved multi-class classification of breast tumors. Feature transformation methods, such as empirical mode decomposition (EMD) and discrete wavelet transform (DWT), followed by a filter- or wrapper-based subset selection scheme are used to extract a set of non-redundant and more potential transform domain features through decorrelation of an optimally ordered sequence of N ultrasonic bi-modal (i.e., quantitative ultrasound and elastography) features. The proposed transform domain bi-modal reduced feature set with different conventional classifiers will classify 201 breast tumors into benign-malignant as well as BI-RADS⩽3, 4, and 5 categories. For the latter case, an inadmissible error probability is defined for the subset selection using a wrapper/filter. The classifiers use train truth from histopathology/cytology for binary (i.e., benign-malignant) separation of tumors and then bi-modal BI-RADS scores from the radiologists for separating malignant tumors into BI-RADS category 4 and 5. A comparative performance analysis of several widely used conventional classifiers is also presented to assess their efficacy for the proposed transform domain reduced feature set for classification of breast tumors. The results show that our transform domain bimodal reduced feature set achieves improvement of 5.35%, 3.45%, and 3.98%, respectively, in sensitivity, specificity, and accuracy as compared to that of the original domain optimal feature set for benign-malignant classification of breast tumors. In quantitative classification of breast tumors into BI-RADS categories⩽3, 4, and 5, the proposed transform domain reduced feature set attains improvement of 3.49%, 9.07%, and 3.06%, respectively, in likelihood of malignancy and 4.48% in inadmissible error probability compared to that of the original domain optimal subset. In summary, the construction of a transform domain reduced feature set by extracting complementary information from a large set of available bi-modal features and use of qualitative bi-modal BI-RADS can contribute to improved quantitative classification of breast tumors and thereby help reduce the number of unnecessary biopsies, securing a nearly minimum chance of a life-endangering diagnosis.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Interpretação de Imagem Assistida por Computador/métodos , Ultrassonografia Mamária/métodos , Adolescente , Adulto , Idoso , Biópsia por Agulha Fina , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Análise de Ondaletas
15.
J Control Release ; 249: 42-52, 2017 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-28093298

RESUMO

Metronomic chemotherapy has translated into favorable toxicity profile and capable of delaying tumor progression. Despite its promise, conventional injectable chemotherapeutics are not meaningful to use as metronomic due to the necessity of frequent administration for personalized therapy in long-term cancer treatments. This study aims to exploit the benefits of the oral application of carboplatin as metronomic therapy for non-small cell lung cancer (NSCLC). We developed an orally active carboplatin by physical complexation with a deoxycholic acid (DOCA). The X-ray diffraction (XRD) patterns showed the disappearance of crystalline peaks from carboplatin by forming the complex with DOCA. In vivo pharmacokinetic (PK) study confirmed the oral absorption of carboplatin/DOCA complex. The oral bioavailability of carboplatin/DOCA complex and native carboplatin were calculated as 24.33% and 1.16%, respectively, when a single 50mg/kg oral dose was administered. Further findings of oral bioavailability during a low-dose daily administration of the complex (10mg/kg) for 3weeks were showed 19.17% at day-0, 30.27% at day-7, 26.77% at day-14, and 22.48% at day-21, demonstrating its potential for metronomic chemotherapy. The dose dependent antitumor effects of oral carboplatin were evaluated in SCC7 and A549 tumor xenograft mice. It was found that the oral carboplatin complex exhibited potent anti-tumor activity at 10mg/kg (74.09% vs. control, P<0.01) and 20mg/kg dose (86.22% vs. control, P<0.01) in A549 tumor. The number of TUNEL positive cells in the tumor sections was also significantly increased during oral therapy (3.95% in control, whereas 21.37% and 32.39% in 10mg/kg and 20mg/kg dose, respectively; P<0.001). The enhanced anti-tumor efficacy of oral metronomic therapy was attributed with its antiangiogenic mechanism where new blood vessel formation was notably decreased. Finally, the safety of oral complex was confirmed by three weeks toxicity studies; there were no significant systemic or local abnormalities found in mice at 10mg/kg daily oral dose. Our study thus describes an effective and safe oral formulation of carboplatin as a metronomic chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ácido Desoxicólico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/efeitos dos fármacos , Administração Metronômica , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina/administração & dosagem , Carboplatina/análogos & derivados , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Ácido Desoxicólico/administração & dosagem , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/farmacocinética , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos Nus , Modelos Moleculares , Ratos Sprague-Dawley
16.
J Clin Invest ; 126(4): 1251-66, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26950422

RESUMO

Controlled and site-specific regulation of growth factor signaling remains a major challenge for current antiangiogenic therapies, as these antiangiogenic agents target normal vasculature as well tumor vasculature. In this article, we identified the prion-like protein doppel as a potential therapeutic target for tumor angiogenesis. We investigated the interactions between doppel and VEGFR2 and evaluated whether blocking the doppel/VEGFR2 axis suppresses the process of angiogenesis. We discovered that tumor endothelial cells (TECs), but not normal ECs, express doppel; tumors from patients and mouse xenografts expressed doppel in their vasculatures. Induced doppel overexpression in ECs enhanced vascularization, whereas doppel constitutively colocalized and complexed with VEGFR2 in TECs. Doppel inhibition depleted VEGFR2 from the cell membrane, subsequently inducing the internalization and degradation of VEGFR2 and thereby attenuating VEGFR2 signaling. We also synthesized an orally active glycosaminoglycan (LHbisD4) that specifically binds with doppel. We determined that LHbisD4 concentrates over the tumor site and that genetic loss of doppel in TECs decreases LHbisD4 binding and targeting both in vitro and in vivo. Moreover, LHbisD4 eliminated VEGFR2 from the cell membrane, prevented VEGF binding in TECs, and suppressed tumor growth. Together, our results demonstrate that blocking doppel can control VEGF signaling in TECs and selectively inhibit tumor angiogenesis.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Príons/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sistemas de Liberação de Medicamentos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Príons/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biomaterials ; 86: 56-67, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26890038

RESUMO

Targeting multiple stages in metastatic breast cancer is one of the effective ways to inhibit metastatic progression. To target human metastatic breast cancer as well as improving patient compliance, we developed an orally active low molecular weight heparin (LMWH)-taurocholate conjugated with tetrameric deoxycholic acid, namely LHTD4, which followed by physical complexation with a synthetic bile acid enhancer, DCK. In breast cancer, both transforming growth factor-ß1 (TGF-ß1) and CXCL12 exhibit enhanced metastatic activity during the initiation and progression stages of breast cancer, thus we direct the focus on investigating the antimetastatic effect of LHTD4/DCK complex by targeting TGF-ß1 and CXCL12. Computer simulation study and SPR analysis were performed for the binding confirmation of LHTD4 with TGF-ß1 and CXCL12. We carried out in vitro phosphorylation assays of the consecutive receptors of TGF-ß1 and CXCL12 (TGF-ß1R1 and CXCR4, respectively). Effects of LHTD4 on in vitro cell migration (induced by TGF-ß1) and chemotaxis (mediated by CXCL12) were investigated. The in vivo anti-metastatic effect of LHTD4 was evaluated in an accelerated metastasis model and an orthotopic MDA-MB-231 breast cancer model. The obtained KD values of TGF-ß1 and CXCL12 with LHTD4 were 0.85 and 0.019 µM respectively. The simulation study showed that binding affinities of LHTD4 fragment with either TGF-ß1 or CXCL12 through additional electrostatic interaction was more stable than that of LMWH fragment. In vitro phosphorylation assays of TGF-ß1R1 and CXCR4 showed that the effective inhibition of receptor phosphorylation was observed with the treatment of LHTD4. The expressions of epithelial to mesenchymal transition (EMT) marker proteins such as vimentin and Snail were prevented by LTHD4 treatment in in vitro studies with TGF-ß1 treated MDA-MB-231 cells. Moreover, we observed that LHTD4 negatively regulated the functions of TGF-ß1 and CXCL12 on migration and invasion of breast cancer cell. In several advanced orthotopic and experimental breast cancer metastasis murine models, the treatment with LHTD4 (5 mg/kg daily, p.o.) significantly inhibited metastasis compared to the control. Overall, LHTD4 exhibited anti-metastatic effects by inhibiting TGF-ß1 and CXCL12, and the clinically relevant dose of orally active LHTD4 was found to be effective in preclinical studies without any apparent toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ácido Desoxicólico/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Metástase Neoplásica/prevenção & controle , Ácido Taurocólico/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Heparina de Baixo Peso Molecular/análogos & derivados , Heparina de Baixo Peso Molecular/farmacologia , Humanos , Camundongos SCID , Terapia de Alvo Molecular , Metástase Neoplásica/patologia , Fosforilação/efeitos dos fármacos , Ácido Taurocólico/análogos & derivados , Ácido Taurocólico/farmacologia , Fator de Crescimento Transformador beta1/metabolismo
18.
Drug Dev Ind Pharm ; 42(8): 1247-57, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26612099

RESUMO

CONTEXT: As a class of angiogenesis inhibitors, heparin conjugates have shown significant effectiveness in several studies. OBJECTIVES: The purpose of our current study is to evaluate the effectiveness and safety of infusing the conjugate of low molecular weight heparin and taurocholate (LHT7), which has been developed as a potent angiogenesis inhibitor. METHODS: To evaluate its safety, the method of intravenous infusion was compared with its i.v. bolus administration. Intravenous infusion was administered at a rate of 400 µl/min/kg of body weight for 30 min. Pharmacokinetic (PK) analysis, organ accumulation, and plasma concentration profiles of LHT7 were measured. The anticancer effect of LHT7 was evaluated in murine and human xenograft models, and preclinical studies were performed in SD rats and beagle dogs. RESULTS: The results of the PK studies showed reduced organ accumulation in mice and the AUC(0-96 h) (area under the curve) was increased up to 1485 ± 125 h × µg/ml. The efficacy, at dose 1 mg/kg/2 d was higher for i.v. infusion than for i.v. bolus administration in both murine and human cancer models. The preclinical studies showed the safety dose of LHT7 is less than 20 mg/kg in SD rats and in the next safety analysis in beagle dogs showed that there were no organ-specific adverse effects in higher doses, such as, 12 mg/kg. LHT7 showed sustained effects with minimized adverse events when administered through i.v. infusion. CONCLUSIONS: LHT7 (i.v. infusion) could be safely used for further clinical development as a multi-targeting anti-angiogenic agent.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/efeitos adversos , Ácido Taurocólico/administração & dosagem , Ácido Taurocólico/efeitos adversos , Animais , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Infusões Intravenosas/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Nus , Ratos , Ratos Sprague-Dawley , Segurança , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
Int J Environ Res Public Health ; 13(1): ijerph13010043, 2015 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-26703643

RESUMO

Depression is very common in reproductive women particularly with premenstrual dysphoric disorder (PMDD), which is a severe form of premenstrual syndrome (PMS). Beta-arrestins were previously implicated in the pathophysiology, diagnosis and treatment for mood disorders. This study examined whether a measurement for beta-arrestin1 levels in peripheral blood mononuclear leukocytes (PBMC), could aid to distinguish between PMDD and PMS. Study participants (n = 25) were non-pregnant women between 18-42 years of age with the symptoms of PMS/PMDD, but not taking any antidepressants/therapy and at the luteal phase of menstruation. The levels of beta-arrestin1 protein in the PBMCs were determined by ELISA using human beta-arrestin1 kit. The beta-arrestin1 levels were compared with the Hamilton Depression Rating Scale scores among these women. The magnitude of the different parameters for Axis 1 mental disorders were significantly higher and beta arrestin1 protein levels in PBMCs were significantly lower in women with PMDD as compared to PMS women. The reduction in beta arrestin1 protein levels was significantly correlated with the severity of depressive symptoms. Beta-arrestin1 measurements in women may potentially serve for biochemical diagnostic purposes for PMDD and might be useful as evidence-based support for questionnaires.


Assuntos
Arrestinas/sangue , Depressão/sangue , Depressão/fisiopatologia , Leucócitos Mononucleares/metabolismo , Transtorno Disfórico Pré-Menstrual/sangue , Transtorno Disfórico Pré-Menstrual/fisiopatologia , Síndrome Pré-Menstrual/sangue , Síndrome Pré-Menstrual/fisiopatologia , Adolescente , Adulto , Feminino , Humanos , Inquéritos e Questionários , Adulto Jovem , beta-Arrestinas
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