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1.
Pediatr Blood Cancer ; 67(6): e28283, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32285998

RESUMO

PURPOSE: To study the efficacy and tolerability of valproic acid (VPA) and radiation, followed by VPA and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG). METHODS: Children 3 to 21 years of age received radiation therapy and VPA at 15 mg/kg/day and dose adjusted to maintain a trough range of 85 to 115 µg/mL. VPA was continued post-radiation, and bevacizumab was started at 10 mg/kg intravenously biweekly, four weeks after completing radiation therapy. RESULTS: From September 2009 through August 2015, 20 DIPG and 18 HGG patients were enrolled (NCT00879437). During radiation and VPA, grade 3 or higher toxicities requiring discontinuation or modification of VPA dosing included grade 3 thrombocytopenia (1), grade 3 weight gain (1), and grade 3 pancreatitis (1). During VPA and bevacizumab, the most common grade 3 or higher toxicities were grade 3 neutropenia (3), grade 3 thrombocytopenia (3), grade 3 fatigue (3), and grade 3 hypertension (4). Two patients discontinued protocol therapy prior to disease progression (one grade 4 thrombosis and one grade 1 intratumoral hemorrhage). Median event-free survival (EFS) and overall survival (OS) for DIPG were 7.8 (95% CI 5.6-8.2) and 10.3 (7.4-13.4) months, and estimated one-year EFS was 12% (2%-31%). Median EFS and OS for HGG were 9.1 (6.4-11) and 12.1 (10-22.1) months, and estimated one-year EFS was 24% (7%-45%). Four patients with glioblastoma and mismatch-repair deficiency syndrome had EFS of 28.5, 16.7, 10.4, and 9 months. CONCLUSION: Addition of VPA and bevacizumab to radiation was well tolerated but did not appear to improve EFS or OS in children with DIPG or HGG.

2.
ChemMedChem ; 2020 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-32281263

RESUMO

We have synthesized 50 benzimidazole (BMZ) derivatives with 1,2-phenylenediamines and aromatic aldehydes under mild oxidation conditions by using inexpensive, nontoxic inorganic salt sodium metabisulfite in a one-pot condensation reaction and screened their ability to interfere with Zika virus (ZIKV) infection utilizing a cell-based phenotypic assay. Seven BMZs inhibited an African ZIKV strain with a selectivity index (SI=CC50 /EC50 ) of 9-37. Structure-activity relationship analysis demonstrated that substitution at the C-2, N-1, and C-5 positions of the BMZ ring were important for anti-ZIKV activity. The hybrid structure of BMZ and naphthalene rings was a structural feature responsible for the high anti-ZIKV activity. Importantly, BMZs inhibited ZIKV in human neural stem cells, a physiologically relevant system considering the severe congenital anomalies, like microcephaly, caused by ZIKV infection. Compound 39 displayed the highest antiviral efficacy against the African ZIKV strain in Huh-7 (SI>37) and neural stem cells (SI=12). Compound 35 possessed the highest activity in Vero cells (SI=115). Together, our data indicate that BMZs derivatives have to be considered for the development of ZIKV therapeutic interventions.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32165040

RESUMO

BACKGROUND: Metastatic colorectal cancer (CRC) outcomes continue to improve, but they vary significantly by race and ethnicity. We hypothesize that these disparities arise from unequal access to care. MATERIALS AND METHODS: The Harris Health System (HHS) is an integrated health delivery network that provides medical care to the underserved, predominantly minority population of Harris County, Texas. As the largest HHS facility and an affiliate of Baylor College of Medicine's Dan L. Duncan Comprehensive Cancer Center, Ben Taub Hospital (BTH) delivers cancer care through multidisciplinary subspecialty that prioritize access to care, adherence to evidence-based clinical pathways, integration of supportive services, and mitigation of financial toxicity. We performed a retrospective analysis of minority patients diagnosed with and treated for metastatic CRC at BTH between January 2010 and December 2012. Kaplan-Meier survival curves were compared with survival curves from randomized control trials reported during that time period. RESULTS: We identified 103 patients; 40% were black, 49% were Hispanic, and 12% were Asian or Middle Eastern. Thirty-five percent reported a language other than English as their preferred language. Seventy-four percent of patients with documented coverage status were uninsured. Eighty-four percent of patients received standard chemotherapy with a clinician-reported response rate of 63%. Overall survival for BTH patients undergoing chemotherapy was superior to that of subjects enrolled in the CRYSTAL (Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial (median, 24.0 vs. 19.9 months; P = .014). CONCLUSION: HHS provides a health delivery infrastructure through which minority patients with socioeconomic challenges experience clinical outcomes comparable with highly selected patients enrolled in randomized control trials. Efforts to resolve CRC disparities should focus on improving access of at-risk populations to high-quality comprehensive cancer care.

4.
Talanta ; 210: 120639, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987175

RESUMO

The application of dried blood spots in clinical research is becoming increasingly popular owing to its convenient collection, storage, and transportation compared to that of conventional biological samples. The potential of trimethylamine N-oxide and its related compounds as biomarkers for various cardiovascular diseases, such as atherosclerosis, stroke, thrombosis, and heart failure, was recently highlighted, which was the driving force behind the development of an analytical method to identify trimethylamine N-oxide and eight related compounds in dried blood spots. In the proposed method, a novel "on-spot reaction" approach was introduced to overcome the low loading efficiency of trimethylamine in dried blood spots. Upon the addition of 50 µL of blood onto the filter paper pretreated with dilute HCl, an acid-base neutralization reaction in the blood spots transformed the volatile trimethylamine to a salt. Next, a punched disc with a diameter of 6.0 mm was eluted by agitation with 20 mM ammonium formate for 10 min and derivatized with 1.0 M ethyl bromoacetate at 80 °C for 60 min. A surrogate analyte approach was employed for quantification of these endogenous compounds in the complex matrix. Analysis was carried out using zwitterionic hydrophilic interaction liquid chromatography-high-resolution mass spectrometry. The established method was validated and applied to monitor real samples from 30 clinical cases. The proposed new methodology based on dried blood spots could greatly improve the convenience, analytical sensitivity, and selectivity of cardiovascular disease testing.

5.
J Pharm Biomed Anal ; 181: 113092, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31915107

RESUMO

Phthalates are commonly used as plasticizers and are known as risk factors toward several conditions such as cancer, birth defects, and endocrine disruption. Biomonitoring of phthalates is necessary to assess the potentially harmful effects of long-term exposure. In this work, we have developed a novel QuEChERS method to determine eight phthalate metabolites-mono-(3-carboxypropyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-n-butyl phthalate, mono-benzyl phthalate, mono-(carboxyloctyl) phthalate, and mono-(carboxynonyl) phthalate-in human milk. The extraction process was optimized by comparing three different QuEChERS methods, and a further purification step was used to eliminate interferential lipid. In this process, several factors, such as the pH based on QuEChERS additive salts, acid dissociation constant, and distribution coefficient of the analyte, were found to have a significant effect on the extraction efficiency of the QuEChERS method. Target compounds were determined using liquid chromatography-tandem mass spectrometry equipped with electrospray ionization in the multiple-reaction monitoring mode. The developed method was verified by evaluating the selectivity, linearity, lower limit of quantification, accuracy, precision, and recovery, and applied to monitor real milk samples from 26 people. It is expected that the established method can be utilized not only to monitor phthalate metabolites in biological samples but also to identify the correlation between phthalate concentrations observed for the mother and the newborn.

6.
Antiviral Res ; 175: 104709, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31940474

RESUMO

Currently, therapies to treat chronic hepatitis B (CHB) infection are based on the use of interferon-α or nucleos(t)ide analogs (NAs) to prevent viral DNA synthesis by inhibiting the reverse transcriptase activity of the hepatitis B virus (HBV) polymerase (Pol). However, these therapies are not curative; thus, the development of novel anti-HBV agents is needed. In accordance with this unmet medical need, we devised a new target- and cell-based, high-throughput screening assay to identify novel small molecules that block the initial interaction of the HBV Pol with its replication template the viral pregenomic RNA (pgRNA). We screened approximately 110,000 small molecules for the ability to prevent HBV Pol recognition of the pgRNA 5' epsilon (ε) stem-loop structure, identifying (Z)-2-(allylamino)-4-amino-N'-cyanothiazole-5-carboximidamide (AACC). Viral nucleocapsid-captured quantitative RT-PCR and Western blot results revealed that AACC significantly decreased encapsidated pgRNA levels and blocked capsid assembly without affecting core protein expression in stable HBV-replicating cells. As a result, both intra- and extracellular accumulation of viral DNA was strongly reduced. AACC treatment of HepG2-sodium taurocholate transporting polypeptide (NTCP) cells and primary human hepatocytes infected with cell culture- or patient-derived HBV isolates showed both time- and dose-dependent inhibition of infectious viral progeny and rcDNA production. Furthermore, AACC showed cross-genotypic activity against genotypes B, C, and D. Of note, AACC inhibited the viral replication of lamivudine and a capsid inhibitor-resistant HBV, and showed synergistic effects with NAs and a capsid inhibitor. In conclusion, we identified a novel class of compounds specifically targeting the ε-Pol interaction and thereby preventing the encapsidation of pgRNAs into viral capsids. This promising new HBV inhibitor class potently inhibits HBV amplification with distinct characteristics from existing NAs and other drugs currently under development, promising to add value to existing therapies for CHB.

7.
Viruses ; 11(10)2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31635418

RESUMO

Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Repurposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FLUAV), niclosamide against HSV-2, brequinar against human immunodeficiency virus 1 (HIV-1), and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vitro and in vivo tests.

8.
J Immunother Cancer ; 7(1): 268, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639056

RESUMO

BACKGROUND: The aim of this study is to profile the cytokines and immune cells of body fluid from metastatic gastric cancer (mGC), and evaluate the potential role as a prognostic factor and the feasibility as a predictive biomarker or monitoring source for immune checkpoint inhibitor. METHODS: Body fluid including ascites and pleural fluid were obtained from 55 mGC patients and 24 matched blood. VEGF-A, IL-10, and TGF-ß1 were measured and immune cells were profiled by fluorescence assisted cell sorting (FACS). RESULTS: VEGF-A and IL-10 were significantly higher in body fluid than in plasma of mGC. Proportion of T lymphocytes with CD69 or PD-1, memory T cell marked with CD45RO, and number of Foxp3+ T regulatory cells (Tregs) were significantly higher in body fluid than those in blood of mGC. Proportion of CD8 T lymphocyte with memory marker (CD45RO) and activation marker (HLA-DR), CD3 T lymphocyte with PD-1, and number of FoxP3+ Tregs were identified as independent prognostic factors. When patients were classified by molecular subgroups of primary tumor, VEGF-A was significantly higher in genomically stable (GS)-like group than that in chromosomal instability (CIN)-like group while PD-L1 positive tumor cells (%) showed opposite results. Monitoring immune dynamics using body fluid was also feasible. Early activated T cell marked with CD25 was significantly increased in chemotherapy treated group. CONCLUSIONS: By analyzing cytokines and proportion of immune cells in body fluid, prognosis of patients with mGC can be predicted. Immune monitoring using body fluid may provide more effective treatment for patients with mGC.

9.
J Pain Symptom Manage ; 58(4): 678-684, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31195079

RESUMO

CONTEXT: Methadone has been reported to prolong the corrected QT (QTc) interval and increase the risk of torsades de pointes. OBJECTIVES: Our study examined the frequency of QTc prolongation among pediatric and young adult patients starting methadone for cancer pain. METHODS: All patients followed a standardized protocol. Electrocardiograms (ECGs) were obtained at baseline (methadone starting day to 14 days prior), 1-2 weeks, and 4-6 weeks later. QTc values were manually calculated using the Bazett formula. QTc prolongation was defined as ≥460 milliseconds (ms) for prepubertal children, ≥470 ms for pubertal males, and ≥480 ms for pubertal females. RESULTS: Baseline ECGs were completed in 42 patients. Follow-up ECGs were completed in 38 of 42 (91%) and 31 of 42 (74%) patients at 1-2 weeks and 4-6 weeks, respectively. No patients had prolongation of the QTc at baseline, and 1 of 38 (3%) patients had a prolonged QTc at weeks 1-2. This patient had a history of prolonged QTc that the family did not initially report. No patients had prolongation of the QTc at weeks 4-6. No patients had torsades de pointes or ventricular fibrillation, and none died suddenly. Median (interquartile range [IQR]) baseline QTc was 391 (377-400) ms; median (IQR) 1-2 week follow-up QTc was 399 (374-411) ms (P = .05), and median (IQR) 4-6 week follow-up QTc was 393 (379-423) ms (P = .01). CONCLUSION: Clinically significant prolongation of the QTc interval occurred only in one patient who had a history of prolonged QTc. Prolonged QTc is rare in this population.

10.
J Hepatol ; 71(2): 289-300, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077792

RESUMO

BACKGROUND & AIMS: As hepatitis B virus (HBV) spreads through the infected liver it is simultaneously secreted into the blood. HBV-susceptible in vitro infection models do not efficiently amplify viral progeny or support cell-to-cell spread. We sought to establish a cell culture system for the amplification of infectious HBV from clinical specimens. METHODS: An HBV-susceptible sodium-taurocholate cotransporting polypeptide-overexpressing HepG2 cell clone (HepG2-NTCPsec+) producing high titers of infectious progeny was selected. Secreted HBV progeny were characterized by native gel electrophoresis and electron microscopy. Comparative RNA-seq transcriptomics was performed to quantify the expression of host proviral and restriction factors. Viral spread routes were evaluated using HBV entry- or replication inhibitors, visualization of viral cell-to-cell spread in reporter cells, and nearest neighbor infection determination. Amplification kinetics of HBV genotypes B-D were analyzed. RESULTS: Infected HepG2-NTCPsec+ secreted high levels of large HBV surface protein-enveloped infectious HBV progeny with typical appearance under electron microscopy. RNA-seq transcriptomics revealed that HBV does not induce significant gene expression changes in HepG2-NTCPsec+, however, transcription factors favoring HBV amplification were more strongly expressed than in less permissive HepG2-NTCPsec-. Upon inoculation with HBV-containing patient sera, rates of infected cells increased from 10% initially to 70% by viral spread to adjacent cells, and viral progeny and antigens were efficiently secreted. HepG2-NTCPsec+ supported up to 1,300-fold net amplification of HBV genomes depending on the source of virus. Viral spread and amplification were abolished by entry and replication inhibitors; viral rebound was observed after inhibitor discontinuation. CONCLUSIONS: The novel HepG2-NTCPsec+ cells efficiently support the complete HBV life cycle, long-term viral spread and amplification of HBV derived from patients or cell culture, resembling relevant features of HBV-infected patients. LAY SUMMARY: Currently available laboratory systems are unable to reproduce the dynamics of hepatitis B virus (HBV) spread through the infected liver and release into the blood. We developed a slowly dividing liver-derived cell line which multiplies infectious viral particles upon inoculation with patient- or cell culture-derived HBV. This new infection model can improve therapy by measuring, in advance, the sensitivity of a patient's HBV strain to specific antiviral drugs.

11.
Front Microbiol ; 10: 706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057494

RESUMO

There is a high demand for novel approaches to counter the various challenges of conventional drug susceptibility testing (DST) for tuberculosis, the most prevalent infectious disease with significant global mortality. The QMAC-DST system was recently developed for rapid DST using image technology to track the growth of single cells of Mycobacterium tuberculosis (MTB). The purpose of this study was to clinically validate the QMAC-DST system compared to conventional DST. In total, 178 MTB isolates recovered from clinical specimens in Asan Medical Center in 2016 were tested by both QMAC-DST and absolute concentration methods using Lowenstein-Jensen media (LJ-DST). Among the isolates, 156 were subjected to DST using BACTEC MGIT 960 SIRE kits (BD, Sparks, MD, United States) (MGIT-DST). The susceptibility/resistance results obtained by QMAC-DST were read against 13 drugs after 7 days of incubation and compared with those of LJ-DST. Based on the gold standard LJ-DST, the agreement rates of QMAC-DST for all drugs were 97.8%, 97.9%, and 97.8% among susceptible, resistant, and total isolates, respectively, while the overall agreement of MGIT-DST tested for 156 isolates against first-line drugs was 95.5%. QMAC-DST showed the highest major error of 6.4% for rifampin, however, it could be corrected by a revised threshold of growth since false-resistant isolates showed grew only half than the true-resistant isolates. The rapid and accurate performance of QMAC-DST warrants ideal phenotypic DST for a wide range of first-line and second-line drugs.

12.
J Ethnopharmacol ; 239: 111912, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029758

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Acer tegmentosum Maxim (AT), the East Asian stripe maple, is an herb used to treat liver disease and is approved as a functional food in Korea. AT protects against hepatic disorders, atopic dermatitis, and diabetes mellitus. AIM OF THE STUDY: We explored the mechanism of the hepatoprotective effects of AT extract in in vitro and in vivo levels. MATERIALS AND METHODS: AT extract from Acer tegmentosum Maxim was extracted by hot water. Hepatoprotective effects of AT extract were confirmed using carbon tetrachloride (CCl4)- or alcohol-induced mouse model, and H2O2- or alcohol-induced HepG2 (liver hepatocellular carcinoma cell line) cells by measuring GOT, GPT, TG, and MDA levels. Hematoxylin and eosin (H&E) staining was used to observe the pathological analysis. Cytotoxicity or protective effect of AT extract was confirmed using MTT assay in HepG2 cells. Antioxidant effect of AT extract was measured using DPPH or H2DCFDA assay. Mechanism study of antioxidant and autophagy was carried out using western blotting and immunofluorescence analysis. RESULTS: AT extract increased the viability of HepG2 cells treated with H2O2 and ethanol, and protected the liver against damage induced by CCl4 and alcohol. The AT extract increased the levels of nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1 (HO-1). The level of microtubule-associated protein light chain 3 (LC3)-Ⅱ, beclin-1, autophagy-related genes (Atg) such as Atg3 and Atg12-5 as markers of autophagy activation was also increased. Moreover, the AT extract increased activation of mitogen-activated protein kinase (MAPK), which regulated autophagy and HO-1. CONCLUSION: Therefore, these results indicate that the AT extract has a hepatoprotective effect by increasing antioxidant activity and inducing autophagy.


Assuntos
Acer , Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Tetracloreto de Carbono , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Extratos Vegetais/farmacologia , Caules de Planta , Espécies Reativas de Oxigênio/metabolismo
13.
Cancer Chemother Pharmacol ; 83(2): 349-360, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30488179

RESUMO

PURPOSE: High-dose methotrexate (HDMTX) is critical to the successful treatment of pediatric acute lymphoblastic leukemia (ALL) but can cause significant toxicities. This study prospectively evaluated the effectiveness of a fixed algorithm which requires no real-time pharmacokinetic modeling and no previous patient exposure to HDMTX, to individualize HDMTX dosing for at-risk patients with the aim of avoiding methotrexate-related toxicities. METHODS: We developed a simple algorithm to individualize HDMTX infusions with 0-2 rate adjustments based on methotrexate levels during the infusion. This was a prospective, open-label, study; eligible patients were identified and referred by their oncologist. RESULTS: Fifty-four evaluable cycles of HDMTX (5 g/m2 over 24 h) were administered to 22 patients. Blood samples were obtained in 21 patients to examine single nucleotide polymorphisms (SNPs) related to methotrexate disposition. Twelve (54.5%) subjects had a history of previous HDMTX toxicities including seven (31.8%) who previously required glucarpidase rescue and seven (31.8%) with an entry glomerular filtration rate < 80 ml/min/1.73 m2. 107/110 (97.2%) of methotrexate levels were drawn properly and 100% of algorithm dosing instructions were performed correctly at the bedside. Thirty-five (64.8%) of all cycles and 24 of 33 (72.7%) cycles that required a dose-adjustment had an end 24-h methotrexate level (Cpss) within our goal range of 65 ± 15 µM with only 3 (5.6%) resulting in Cpss higher than goal. Grade 3/4 toxicities were rare; no patients developed > Grade 1 acute kidney injury. CONCLUSION: This algorithm is a simple, safe and effective method for individualizing HDMTX in pediatric patients with ALL. CLINICALTRIALS. GOV REGISTRY: NCT02076997.


Assuntos
Algoritmos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Distribuição Tecidual , Adulto Jovem
14.
J Infect Dis ; 219(7): 1044-1048, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30358855

RESUMO

Hepatitis B virus (HBV) infection is considered a major public health problem worldwide, and a significant number of reports on nosocomial and occupational outbreaks have been reported. This systematic investigation of HBV stability and susceptibility to different antiseptics revealed that HBV infectivity was very stable, with a half-life of >22 days at 37°C. At 4°C, infectivity was barely reduced for up to 9 months. Different alcohols and commercially available hand antiseptics had a virucidal effect against HBV. We propose that very strict compliance with established hygienic guidelines should be mandatory to avoid and prevent HBV infections.


Assuntos
Anti-Infecciosos Locais/farmacologia , Infecção Hospitalar/prevenção & controle , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/prevenção & controle , Doenças Profissionais/prevenção & controle , 1-Propanol/farmacologia , 2-Propanol/farmacologia , Linhagem Celular , Infecção Hospitalar/virologia , Meio Ambiente , Etanol/farmacologia , Higiene das Mãos/normas , Higienizadores de Mão/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Doenças Profissionais/virologia , Soro , Temperatura , Fatores de Tempo
15.
Cancer Res ; 79(1): 61-71, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30401712

RESUMO

There are distinct cell subpopulations in normal epithelial tissue, including stem cells, progenitor cells, and more differentiated cells, all of which have been extensively studied for their susceptibility to tumorigenesis. However, normal cells usually have to progress through a precancerous lesion state before becoming a full-blown tumor. Precancerous early lesions are heterogeneous, and the cell subset that is the primary source of the eventual tumor remains largely unknown. By using mouse models that are tailored to address this question, we identified a keratin 6a-expressing precancerous stem cell (PcSC) subset and a more differentiated whey acidic protein-positive (WAP+) cell subset in mammary precancerous lesions initiated by the Wnt1 oncogene. Both cell subsets rapidly progressed to cancer upon introduction of constitutively active versions of either HRAS or BRAF. However, the resulting tumors were dramatically different in protein profiles and histopathology: keratin 6a+ precancerous cells gave rise to adenocarcinoma, whereas WAP+ cells yielded metaplastic carcinoma with severe squamous differentiation and more robust activation of MEK/ERK signaling. Therefore, both stem and non-stem cells in mammary precancerous lesions can contribute to the eventual cancers, but their differentiation status determines the resulting cancer phenotype. This work identifies a previously unknown player in cancer heterogeneity and suggests that cancer prevention should target precancerous cells broadly and not be limited to PcSC. SIGNIFICANCE: This work uses a novel mouse mammary gland cancer model to show that tumors initiated from different precancerous mammary epithelial cells are distinct.


Assuntos
Transformação Celular Neoplásica/patologia , Glândulas Mamárias Animais/citologia , Neoplasias Mamárias Animais/classificação , Neoplasias Mamárias Animais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Lesões Pré-Cancerosas/patologia , Células-Tronco/citologia , Animais , Diferenciação Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Feminino , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/genética , Camundongos , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Análise Serial de Proteínas , Células-Tronco/metabolismo , Proteína Wnt1/genética
16.
Adv Sci (Weinh) ; 5(8): 1800494, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30128257

RESUMO

Although protein nanoparticles (PNPs) (e.g., viral capsids) capable of delivering a broad range of drug agents have shown distinctive advantages over synthetic nanomaterials, PNPs have an intrinsic drawback that hampers their clinical application, that is, potential immunogenicity. Here, a novel method for resolving the immunogenicity problem of PNPs, which is based on the genetic presentation of albumin-binding peptides (ABPs) on the surface of PNP, is reported. ABPs are inserted into the surface of a viral capsid (hepatitis B virus capsid/HBVC) while preserving the native self-assembly function of HBVC. The ABPs effectively gather human serum albumins around HBVC and significantly reduce both inflammatory response and immunoglobulin titer in live mice compared to ABP-free HBVC. Furthermore, ABP-conjugated HBVCs remain within tumors for a longer period than HBVCs conjugated to tumor cell receptor-bindingpeptides, indicating that the ABPs are also capable of enhancing tumor-targeting performance. Although applied to HBVC for proof of concept, this novel approach may provide a general platform for resolving immunogenicity and cancer-targeting problems of PNPs, which enables the development of a variety of PNP-based drug delivery carriers with high safety and efficacy.

17.
Sci Rep ; 8(1): 8651, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29872060

RESUMO

The Disc Agarose Channel (DAC) system utilizes microfluidics and imaging technologies and is fully automated and capable of tracking single cell growth to produce Mycobacterium tuberculosis (MTB) drug susceptibility testing (DST) results within 3~7 days. In particular, this system can be easily used to perform DSTs without the fastidious preparation of the inoculum of MTB cells. Inoculum effect is one of the major problems that causes DST errors. The DAC system was not influenced by the inoculum effect and produced reliable DST results. In this system, the minimum inhibitory concentration (MIC) values of the first-line drugs were consistent regardless of inoculum sizes ranging from ~103 to ~108 CFU/mL. The consistent MIC results enabled us to determine the critical concentrations for 12 anti-tuberculosis drugs. Based on the determined critical concentrations, further DSTs were performed with 254 MTB clinical isolates without measuring an inoculum size. There were high agreement rates (96.3%) between the DAC system and the absolute concentration method using Löwenstein-Jensen medium. According to these results, the DAC system is the first DST system that is not affected by the inoculum effect. It can thus increase reliability and convenience for DST of MTB. We expect that this system will be a potential substitute for conventional DST systems.


Assuntos
Antituberculosos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Testes de Sensibilidade Microbiana/normas , Mycobacterium tuberculosis/efeitos dos fármacos , Contagem de Colônia Microbiana , Meios de Cultura/química , Reprodutibilidade dos Testes
18.
Biotechnol Bioeng ; 115(6): 1437-1449, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29460954

RESUMO

The endocytosis-mediating performances of two types of peptide ligands, cell receptor binding peptide (CRBP) and cell membrane penetrating peptide (CMPP), were analyzed and compared using a common carrier of peptide ligands-human ferritin heavy chain (hFTH) nanoparticle. Twenty-four copies of a CMPP(human immunodeficiency virus-derived TAT peptide) and/or a CRBP (peptide ligand with strong and specific affinity for either human integrin(αv ß3 ) or epidermal growth factor receptor I (EGFR) that is overexpressed on various cancer cells) were genetically presented on the surface of each hFTH nanopariticle. The quantitative level of endocytosis and intracellular localization of fluorescence dye-labeled CRBP- and CMPP-presenting nanoparticles were estimated in the in vitro cultures of integrin- and EGFR-overexpressing cancer and human dermal fibroblast cells(control). From the cancer cell cultures treated with the CMPP- and CRBP-presenting nanoparticles, it was notable that CRBPs resulted in quantitatively higher level of endocytosis than CMPP (TAT) and successfully transported the nanoparticles to the cytosol of cancer cells depending on concentration and treatment period of time, whereas TAT-mediated endocytosis localized most of the nanoparticles within endosomal vesicles under the same conditions. These novel findings provide highly useful informations to many researchers both in academia and in industry who are interested in developing anticancer drug delivery systems/carriers.


Assuntos
Membrana Celular/metabolismo , Endocitose , Nanopartículas/metabolismo , Peptídeos/metabolismo , Receptores de Superfície Celular/metabolismo , Apoferritinas/metabolismo , Células Cultivadas , Receptores ErbB/metabolismo , Humanos , Integrina alfaVbeta3/metabolismo , Nanopartículas/química , Ligação Proteica , Propriedades de Superfície
19.
Korean J Physiol Pharmacol ; 22(1): 35-42, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29302210

RESUMO

Ascorbic acid is one of the most well-known nutritional supplement and antioxidant found in fruits and vegetables. Calcium ascorbate has been developed to mitigate the gastric irritation caused by the acidity of ascorbic acid. The aim of this study was to compare calcium ascorbate and ascorbic acid, focusing on their antioxidant activity and effects on gastric juice pH, total acid output, and pepsin secretion in an in vivo rat model, as well as pharmacokinetic parameters. Calcium ascorbate and ascorbic acid had similar antioxidant activity. However, the gastric fluid pH was increased by calcium ascorbate, whereas total acid output was increased by ascorbic acid. In the rat pylorus ligation-induced ulcer model, calcium ascorbate increased the gastric fluid pH without changing the total acid output. Administration of calcium ascorbate to rats given a single oral dose of 100 mg/kg as ascorbic acid resulted in higher plasma concentrations than that from ascorbic acid alone. The area under the curve (AUC) values of calcium ascorbate were 1.5-fold higher than those of ascorbic acid, and the Cmax value of calcium ascorbate (91.0 ng/ml) was higher than that of ascorbic acid (74.8 ng/ml). However, their Tmax values were similar. Thus, although calcium ascorbate showed equivalent antioxidant activity to ascorbic acid, it could attenuate the gastric high acidity caused by ascorbic acid, making it suitable for consideration of use to improve the side effects of ascorbic acid. Furthermore, calcium ascorbate could be an appropriate antioxidant substrate, with increased oral bioavailability, for patients with gastrointestinal disorders.

20.
Nat Prod Res ; 32(16): 1963-1966, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28722505

RESUMO

In this study, 19 known compounds were isolated from mulberry (Morus alba L.) leaves. The lipid accumulation inhibitory activity of the isolated compounds was investigated. Compounds 4 and 12 showed good anti-adipogenic activity based on 3T3-L1 adipocytes with values of 36.6 ± 9.0 and 34.7 ± 4.0%, respectively. In addition, compounds 3, 6 and 15 showed significant inhibitory activity with values from 15.4 to 21.2% and compounds 2, 8-9 and 17-18 exhibited weak activity with values ranging from 2.1 to 10.7% at a concentration of 40.0 µM. These results show the potentiality that mulberry leaf is an excellent inhibitory phytochemical source against lipid accumulation.


Assuntos
Adipócitos/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Morus/química , Extratos Vegetais/química , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Lipogênese/efeitos dos fármacos , Camundongos , Folhas de Planta/química
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