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1.
J Geophys Res Atmos ; 125(22): e2020JD032794, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33777605

RESUMO

TanSat is the 1st Chinese carbon dioxide (CO2) measurement satellite, launched in 2016. In this study, the University of Leicester Full Physics (UoL-FP) algorithm is implemented for TanSat nadir mode XCO2 retrievals. We develop a spectrum correction method to reduce the retrieval errors by the online fitting of an 8th order Fourier series. The spectrum-correction model and its a priori parameters are developed by analyzing the solar calibration measurement. This correction provides a significant improvement to the O2 A band retrieval. Accordingly, we extend the previous TanSat single CO2 weak band retrieval to a combined O2 A and CO2 weak band retrieval. A Genetic Algorithm (GA) has been applied to determine the threshold values of post-screening filters. In total, 18.3% of the retrieved data is identified as high quality compared to the original measurements. The same quality control parameters have been used in a footprint independent multiple linear regression bias correction due to the strong correlation with the XCO2 retrieval error. Twenty sites of the Total Column Carbon Observing Network (TCCON) have been selected to validate our new approach for the TanSat XCO2 retrieval. We show that our new approach produces a significant improvement on the XCO2 retrieval accuracy and precision when compared to TCCON with an average bias and RMSE of -0.08 ppm and 1.47 ppm, respectively. The methods used in this study can help to improve the XCO2 retrieval from TanSat and subsequently the Level-2 data production, and hence will be applied in the TanSat operational XCO2 processing.

2.
Case Rep Pulmonol ; 2012: 595402, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23198240

RESUMO

We report a case of nephropleural fistula causing empyema and respiratory failure in a 68-year-old gentleman with a long history of urological problems including recurrent nephrolithiasis and urinary tract infections. He was admitted with sepsis, a productive cough, pyuria, and reduced breath sounds over the left hemithorax. Radiological imaging revealed a fistulous connection between a left-sided perinephric abscess and the pleural space. He was commenced on broad spectrum intravenous antibiotics but developed progressive respiratory failure requiring intensive care admission. Urinary and pleural aspirates cultured facultative anaerobic pathogens with identical resistance patterns. Drainage of thoracic and perinephric collections was carried out, allowing him to be extubated after 24 hours and discharged home after 18 days on an extended course of oral antibiotics. Left nephrectomy is now planned after a period of convalescence. Empyema developing in patients with known urolithiasis should alert the treating physician to the possibility that a pathological communication has formed especially if typical urinary tract pathogens are cultured from respiratory sampling.

3.
J Bone Joint Surg Br ; 91(1): 131-7, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19092018

RESUMO

In spite of extensive accounts describing the blood supply to the femoral head, the prediction of avascular necrosis is elusive. Current opinion emphasises the contributions of the superior retinacular artery but may not explain the clinical outcome in many situations, including intramedullary nailing of the femur and resurfacing of the hip. We considered that significant additional contribution to the vascularity of the femoral head may exist. A total of 14 fresh-frozen hips were dissected and the medial circumflex femoral artery was cannulated in the femoral triangle. On the test side, this vessel was ligated, with the femoral head receiving its blood supply from the inferior vincular artery alone. Gadolinium contrast-enhanced MRI was then performed simultaneously on both control and test specimens. Polyurethane was injected, and gross dissection of the specimens was performed to confirm the extraosseous anatomy and the injection of contrast. The inferior vincular artery was found in every specimen and had a significant contribution to the vascularity of the femoral head. The head was divided into four quadrants: medial (0), superior (1), lateral (2) and inferior (3). In our study specimens the inferior vincular artery contributed a mean of 56% (25% to 90%) of blood flow in quadrant 0, 34% (14% to 80%) of quadrant 1, 37% (18% to 48%) of quadrant 2 and 68% (20% to 98%) in quadrant 3. Extensive intra-osseous anastomoses existed between the superior retinacular arteries, the inferior vincular artery and the subfoveal plexus.


Assuntos
Artéria Femoral/fisiologia , Necrose da Cabeça do Fêmur/fisiopatologia , Cabeça do Fêmur/irrigação sanguínea , Imageamento por Ressonância Magnética/métodos , Cadáver , Meios de Contraste , Artéria Femoral/anatomia & histologia , Gadolínio DTPA , Humanos , Fluxo Sanguíneo Regional/fisiologia
5.
Environ Monit Assess ; 136(1-3): 227-38, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17370131

RESUMO

Eight sediment cores recovered from Tamaki Estuary were analysed for Cu, Pb, Zn, and Cd using downward cored sub-samples. The results indicate a significant upward enrichment in heavy metals with the highest concentrations found in the uppermost 0-10 cm layer. Assessment of heavy metal pollution in marine sediments requires knowledge of pre-anthropogenic metal concentrations to act as a reference against which measured values can be compared. Pristine values for the cored sediments were determined from flat "base-line" metal trends evident in lower core samples. Various methods for calculating metal enrichment and contamination factors are reviewed in detail and a modified and more robust version of the procedure for calculating the degree of contamination is proposed. The revised procedure allows the incorporation of a flexible range of pollutants, including various organic species, and the degree of contamination is expressed as an average ratio rather than an absolute summation number. Comparative data for normalized enrichment factors and the modified degree of contamination show that Tamaki Estuary sediments have suffered significant systematic heavy metal contamination following catchment urbanization. Compared to baseline values the uppermost sediment layers show four-fold enrichment averaged across eight cores and four analysed metals.


Assuntos
Sedimentos Geológicos/análise , Metais Pesados/análise , Água do Mar/química , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Humanos , Nova Zelândia
7.
Emerg Med J ; 22(11): 826, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16244353

RESUMO

A chest radiograph performed to check the position of a central venous catheter in a patient appeared to show a pneumothorax. Intercostal drain insertion was prepared. Reassessment of the patient and a further radiograph confirmed that the "pneumothorax" was an artefact from a prominent skin fold due to the patient's body habitus.


Assuntos
Cateterismo Venoso Central/efeitos adversos , Pneumotórax/etiologia , Idoso , Feminino , Humanos , Nefropatias/complicações , Sepse/complicações
8.
Int J Clin Pract Suppl ; (147): 31-3, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15875615

RESUMO

Heat illness is a common presentation to emergency departments during periods of high ambient temperatures. The thyroid axis is involved in thermoregulation, and its dysfunction dysfunction leads to loss of thermal homeostasis. Hyperthyroidism predisposes an individual to heat illness and hypothyroidism to hypothermia. For heat illness to be the presenting feature of hypothyroidism is very rare. In this report, a case is presented and a discussion of the thyroid axis, thermoregulation, its failure and possible mechanisms follows on.


Assuntos
Golpe de Calor/etiologia , Hipotireoidismo/complicações , Emergências , Feminino , Humanos , Hipotireoidismo/diagnóstico , Pessoa de Meia-Idade , Oximetria , Apneia Obstrutiva do Sono/etiologia
10.
Genome ; 45(5): 897-904, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12416622

RESUMO

The genetic diversity among Canadienne, Brown Swiss, Holstein, and Jersey cattle was estimated from relationships determined by genotyping 20 distantly related animals in each breed for 15 microsatellites located on separate chromosomes. The Canadienne, Holstein, and Jersey cattle had an average of six alleles per loci compared with five alleles for Brown Swiss. Furthermore, a number of potentially breed-specific alleles were identified. The allele size variance among breeds was similar, but varied considerably among loci. All of the loci studied were equally heterozygous, as were Brown Swiss, Canadienne, and Holstein cattle (0.68-0.69) whereas Jersey cattle showed lower heterozygosity (0.59). The within-breed estimates of genetic distance were greater than zero and significant. The genetic distance between Canadienne and Holstein (0.156), Brown Swiss (0.243), and Jersey (0.235) was negligible, suggesting close relationship. Concurrently, Brown Swiss and Holstein (0.211) cattle also demonstrated close relationship. In contrast, the Jersey breed was genetically distant from the Brown Swiss and Holstein cattle (0.427 and 0.320, respectively). The characterization of Canadienne cattle, as part of the genetic resource conservation effort currently underway in Canada, underscores the difficulty in scientifically establishing unique breeds. Therefore, the need to consider all relevant morphological characteristics and production performance in combination with available cultural, historical, pedigree, and molecular information becomes relevant when identifying breeds for conservation.


Assuntos
Bovinos/genética , Repetições de Microssatélites , Alelos , Animais , Sequência de Bases , Cruzamento , Primers do DNA/genética , Feminino , Variação Genética , Heterozigoto , Masculino , Filogenia , Especificidade da Espécie
11.
Appl Ergon ; 33(5): 395-403, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12236648

RESUMO

Forestry is among the most hazardous of all industry sectors internationally. In New Zealand, highest work-related morbidity and mortality incidence rates are found in the logging sector. The New Zealand Forest Industry Accident Reporting Scheme (ARS) is a forestry injury surveillance system maintained by the Centre for Human Factors and Ergonomics (COHFE). The paper highlights the pivotal role of an industry-wide injury surveillance system in an industry-specific strategic research programme, giving examples of the use of ARS data in identification of priority areas for ergonomics, safety and health research attention, for safety awareness feedback to the industry, and in the evaluation of injury countermeasures. An analysis of injury patterns and trends for one high-risk forestry operation (skid work) is presented to illustrate both the capabilities and limitations of the ARS in its present stage of development.


Assuntos
Acidentes de Trabalho/estatística & dados numéricos , Ergonomia , Agricultura Florestal , Saúde Ocupacional/estatística & dados numéricos , Vigilância da População , Ferimentos e Lesões/epidemiologia , Pesquisa sobre Serviços de Saúde , Humanos , Masculino , Nova Zelândia/epidemiologia , Gestão de Riscos
12.
Breast Cancer Res Treat ; 66(3): 225-37, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11510694

RESUMO

PURPOSE: To determine whether in vitro extreme drug resistance (EDR) assay results for patients with breast carcinoma were associated with clinical outcome after chemotherapy. PATIENTS AND METHODS: EDR assays were performed on tumor tissue obtained from 103 newly diagnosed breast cancer cases. EDR scores of 2 for low, 1 for intermediate, or 0 for extreme drug resistance were determined for each agent tested. In vitro EDR scores for 4-hydroxycyclophosphamide (4HC) and doxorubicin were summed for patients treated with AC, or for 4HC and 5-FU for patients treated with CMF. Treatment selection was blinded to assay results. RESULTS: Median time to progression was significantly shorter for patients with extreme or intermediate in vitro resistance (n = 55, 48 months), compared to patients with low in vitro resistance, (n = 41, 100 months, p = 0.022). Patients demonstrating extreme to intermediate drug resistance also showed poorer survival than the low resistance group (49.5 months vs. not reached, median follow-up 48 months, p =0.011). Summed EDR scores, stage, and number of lymph nodes were significantly associated with survival in univariate and multivariate analysis. Compared to EDR scores of 4, summed EDR scores of 0-1 and summed EDR scores of 2-3 were associated with a relative risk of death of 3.09 (95%, CI 1.05-9.06, Cox proportional hazards model, p = 0.040) and 2.35 (95%, CI 1.07-5.15, Cox proportional hazards model, p = 0.033), respectively. CONCLUSION: Extreme drug resistance testing identified patients with individual patterns of drug resistance prior to therapy. In this cohort of breast cancer patients treated with chemotherapy, summed EDR scores were significantly associated with time to tumor progression and overall survival. EDR results may offer a method for optimizing treatment selection.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ciclofosfamida/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bioensaio , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Progressão da Doença , Doxorrubicina/administração & dosagem , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Análise de Sobrevida
13.
Inorg Chem ; 40(18): 4696-704, 2001 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-11511218

RESUMO

Substitution of the weakly binding aqua ligand in [Cu(tren)OH2](2+) and [Cu(tpa)OH2](2+) (tren = tris(2-aminoethyl)amine; tpa = tris(2-pyridylmethyl)amine) by a cyano ligand on ferricyanide results in the assembly of heteropolynuclear cations around the cyanometalate core. In water, the reduction of the Fe(III) core to Fe(II) generates complexes that feature heteropolycations in which ferrocyanide is encapsulated by the Cu(II) moieties: [(Cu(tpa)CN)6Fe][ClO4]8-3H2O 1, [(Cu(tren)CN)6Fe][ClO4]8-10H2O 2, [(Cu(tren)CN)6Fe][Fe(CN)6]2[ClO4]2-15.8H2O 3, and [(Cu(tren)CN)6Fe][(Cu(tren)CN)4Fe(CN)2][Fe(CN)6)]4-6DMSO-21H2O 4. The formation of discrete molecules, in preference to extended networks or polymeric structures, has been encouraged through the use of branched tetradentate ligands in conjunction with copper(II), a metal center with the propensity to form five-coordinate complexes. Complex 3 crystallizes in the monoclinic space group P2(1)/c (#14) with a = 14.8674(10), b = 25.9587(10), c = 27.5617(10) A, beta = 100.8300(10) degrees, and Z = 4, and it is comprised of almost spherical heptanuclear cations, [(Cu(tren)CN)6Fe](8+), whose charge is balanced by two ferricyanide and two perchlorate counteranions. Complex 4 crystallizes in the triclinic space group P1 (# 1) with a = 14.8094(8), b = 17.3901(7), c = 21.1565(11) A, alpha = 110.750(3), beta = 90.206(2), gamma = 112.754(3) degrees, and Z = 1, and it is comprised of the heptanuclear [(Cu(tren)CN)6Fe](8+) cation and pentanuclear [(Cu(tren)CN)4Fe(CN)2](4+) cation, whose terminal cyano ligands are oriented trans to each other. The charge is balanced exclusively by ferricyanide counteranions. In both complexes, H-bonding interactions between hydrogens on primary amines of the tren ligand, terminal cyano groups of the ferricyanide counterions, and the solvent of crystallization generate intricate 3D H-bonding networks.

14.
J Toxicol Clin Toxicol ; 39(2): 135-42, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11407499

RESUMO

OBJECTIVE: Safety concerns have been raised over the possible effects of inappropriate exposure to transdermal nicotine patches. This study was initiated to determine whether placement of these products into the mouth could affect cardiovascular function. METHODS: In a series of 10 anesthetized beagle dogs, Nicoderm, Habitrol, ProStep I (Intact), ProStep D (Damaged) transdermal nicotine products or the Skoal Bandit smokeless tobacco plug were placed in the buccal cavity for 5 minutes. Systemic arterial blood pressure and the electrocardiogram were monitored for up to 90 minutes after exposure with blood samples at intervals during the first 10 minutes for plasma nicotine concentration. RESULTS: The systolic and diastolic arterial blood pressures and heart rate increased within 2 minutes of buccal exposure to either the intact or the damaged ProStep nicotine product. Ventricular arrhythmias were observed in 6 of 10 dogs exposed to the intact patch and 7 of 10 dogs exposed to the damaged patch during the period of maximal cardiovascular response. Modest increases in systemic blood pressure and heart rate were seen with the Nicoderm and Habitrol products but not with the Skoal Bandit. The increases in systemic arterial pressure and heart rate occurring after exposure to ProStep were significantly more severe than those observed after Nicoderm and Habitrol. Mean peak nicotine levels of 9.8 microg/mL (ProStep 1), 5.4 microg/mL (ProStep D), 3.4 microg/mL (Habitrol), 2.5 microg/mL (Nicoderm), and 0.12 microg/mL (Skoal Bandit) were detected within 2 to 10 minutes after buccal placement of the product. CONCLUSIONS: Certain transdermal nicotine patches, when applied to a nondermal site such as the buccal cavity for a short period (5 minutes) can rapidly provoke significant cardiovascular alterations (hypertension, tachycardia, and ventricular arrhythmias). The magnitude of the cardiovascular responses occurring after buccal exposure to a product such as ProStep could pose a risk to susceptible individuals.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Administração Oral , Animais , Pressão Sanguínea/fisiologia , Cães , Eletrocardiografia , Cromatografia Gasosa-Espectrometria de Massas , Frequência Cardíaca/fisiologia , Masculino , Nicotina/administração & dosagem , Nicotina/sangue , Plantas Tóxicas , Tabaco sem Fumaça/efeitos adversos
15.
J Neurooncol ; 55(3): 195-204, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11859975

RESUMO

Although several studies have examined brain tumor markers for prognostic value, few investigations have stratified analysis based on specific histologic grade. The objective of this study was to evaluate a single histologic grade of glioma, the grade IV glioma or glioblastoma (World Health Organization Classification), with a comprehensive panel of tumor markers in an attempt to identify those with prognostic significance. Tumor samples from a cohort of patients with glioblastoma multiforme (n = 32) were examined for tumor markers, DNA analysis, and clinical variables in an attempt to determine a 'profile' for this tumor. We used univariate and multivariate statistical analysis to determine the prognostic value of tumor cell ploidy, percent S-phase, DNA index, p53, and Ki-67 labeling index, as well as the variables of gender, race, age, location of tumor, history of chemotherapy, and primary versus recurrent tumor. Two additional tumor markers, multidrug resistance gene 1 and glutathione-S-transferase subtype pi, were included in the sample testing, but were not analyzed statistically. Univariate analysis indicated that increasing age had a strong association with decreased survival. Female gender, increasing Ki-67, no chemotherapy before sample collection, and primary glioblastoma showed some association with decreased survival in the univariate model. The univariate results indicated that race, side of tumor, ploidy, S-phase, DNA index, and p53 had no prognostic value. Multivariate modeling demonstrated that age, gender, and Ki-67 were the strongest factors associated with survival. The relevant literature is reviewed.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Glioblastoma/química , Proteínas de Neoplasias/análise , Proteínas do Tecido Nervoso/análise , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Neoplasias Encefálicas/mortalidade , Estudos de Coortes , DNA de Neoplasias/análise , Feminino , Glioblastoma/mortalidade , Glutationa S-Transferase pi , Glutationa Transferase/análise , Humanos , Isoenzimas/análise , Antígeno Ki-67/análise , Tábuas de Vida , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Fase S , Análise de Sobrevida , Proteína Supressora de Tumor p53/análise
16.
Oncol Rep ; 6(1): 155-9, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-9864420

RESUMO

Cadmium (Cd), a toxic heavy metal and probable carcinogen in humans, appears to have potential anti-cancer activity in pre-clinical systems. This observation led us to develop a method for measuring cellular Cd and DNA-bound Cd following micromolar exposures to cadmium dichloride. Cultured human ovarian cancer cell lines were used. Following low level exposures to cadmium dichloride (CdCl2), atomic absorption spectrometry with Zeeman background correction was used to measure total cell associated Cd in wet-ashed cells, and the lower limits of detection was at 100 pg of Cd per 106 cells. In cellular DNA isolated by cesium chloride density gradient centrifugation, levels of 1.5 Cd lesions (Cd molecules) per 106 nucleotides were reproducibly detected. Standard curves with samples yielded 76.4 6.7% recovery when using picogram quantities of Cd. Manipulation of the total amount of biological material used, can further improve detection limits. Thus, this method is suitable for the detection of Cd in biological matrixes after low levels of Cd exposure, and shows good performance in terms of the level of sensitivity and reproducibility.


Assuntos
Cádmio/análise , Espectrofotometria Atômica/métodos , Cloreto de Cádmio/farmacologia , Calibragem , DNA de Neoplasias/química , Feminino , Humanos , Neoplasias Ovarianas/química , Manejo de Espécimes , Espectrofotometria Atômica/instrumentação , Células Tumorais Cultivadas/química
17.
Am J Orthod Dentofacial Orthop ; 114(6): 677-83, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9844208

RESUMO

External apical root resorption is a multifactorial problem encountered in all disciplines of dentistry, but it is most commonly seen in cases treated orthodontically. Specific tooth movements that are most likely to exacerbate external apical root resorption are poorly understood. Purpose of the present investigation was twofold: (1) to quantify apical and incisal movements of the maxillary central incisor in the sagittal and vertical planes from cephalograms and (2) to use stepwise multivariate linear regression analyses to see which tooth movements and skeletodental relationships are most predictive of external apical root resorption. The sample consisted of 110 adolescents with similar pretreatment malocclusions (Class I crowded or bimaxillary protrusive) and treatment planned similarly (extraction of four first premolars) by experienced private practitioners. Each of three practitioners used a different orthodontic appliance; the sample was divided proportionately into cases treated with Tweed standard edgewise technique, Begg lightwire technique, and Roth-prescription straightwire technique. Lateral cephalograms were analyzed at the start, middle, and end of treatment. There was no statistical difference in average external apical root resorption between sexes or among techniques. Measures of tooth movement were highly predictive, explaining up to 90% of the variation in root resorption. Apical and incisal vertical movements and increase in incisor proclination were the strong predictors of external apical root resorption for each regression model. Incisor intrusion with increase in lingual root torque together were the strongest predictors of external apical root resorption. In contrast, distal bodily retraction, extrusion, or lingual crown tipping had no discernible effect.


Assuntos
Análise do Estresse Dentário , Incisivo/fisiopatologia , Aparelhos Ortodônticos/efeitos adversos , Reabsorção da Raiz/etiologia , Técnicas de Movimentação Dentária/efeitos adversos , Adolescente , Cefalometria , Criança , Feminino , Humanos , Modelos Lineares , Masculino , Má Oclusão/terapia , Valor Preditivo dos Testes , Análise de Regressão , Reabsorção da Raiz/patologia , Extração Dentária , Técnicas de Movimentação Dentária/instrumentação , Técnicas de Movimentação Dentária/métodos , Torque
18.
Chem Biol Interact ; 111-112: 277-305, 1998 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-9679561

RESUMO

L-buthionine-S,R-sulfoximine (L-S,R-BSO) was enriched for the active L-buthionine-S-sulfoximine (L-S-BSO) diastereomer. Comparative analysis was performed to determine if this enriched form possessed an increased capacity to deplete glutathione (GSH), and to inhibit the proliferation of tumor cell lines and fresh human tumor samples. Increased activity was observed for the enriched preparation of L-S-BSO in direct proportion to its increased L-S-diastereomeric percentage. Significant antitumor activity towards melanoma, breast and ovarian carcinoma specimens was noted, with the greatest activity directed against malignant melanoma. The activity of BSO on melanoma specimens was found to be correlated with their melanin content, suggesting that free radicals generated during melanin synthesis may become cytotoxic after GSH-dependent scavenging has been eliminated by BSO treatment. The antimelanoma activity of melphalan and BCNU were found to be significantly enhanced in combination with L-S-BSO. With respect to the mechanism of L-S-BSO synergy with alkylators, L-S-BSO treatment of M14 and ZAZ human melanoma cell lines resulted in decreased GSH levels and glutathione S-transferase (GST) activity. Western and Northern blot analyses indicated that GST-mu was the predominant isozyme downregulated after L-S-BSO treatment. Both M14 and ZAZ cell lines selected for resistance to L-S-BSO also showed decreased levels of GST-mu expression. However, in drug free media GST enzyme activity returned to pre-treatment levels without altering the BSO-resistance status of the cell lines. We conclude that L-S-BSO may be an active agent in the treatment of melanoma, and that it may enhance alkylator activity on melanoma through depletion of GSH and down-regulation of GST expression. Purified L-S-BSO should be explored clinically as an active agent for the treatment of melanoma.


Assuntos
Butionina Sulfoximina/farmacologia , Glutationa Transferase/metabolismo , Melaninas/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Butionina Sulfoximina/administração & dosagem , Carmustina/administração & dosagem , Regulação para Baixo , Resistência a Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Glutamato-Cisteína Ligase/antagonistas & inibidores , Glutationa Transferase/genética , Humanos , Melanoma/genética , Melfalan/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Células Tumorais Cultivadas
19.
Clin Cancer Res ; 4(2): 389-98, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9516927

RESUMO

To determine whether multidrug resistance (MDR1) P-glycoprotein (Pgp) expression correlated with clinical MDR1-related drug resistance, we established a protocol for quantitative measurement of Pgp expression and in vitro drug resistance in doxorubicin resistant MCF7 breast cancer cell lines and 359 freshly resected specimens of breast carcinoma. Pgp expression was detected with 4E3, UIC2, and JSB-1 monoclonal antibodies using flow cytometry and immunohistochemistry (IHC). Pgp function was determined using PSC833 in a drug resistance-reversal assay and with a three-dimensional agarose-based extreme drug resistance assay. MCF7 calibrator cell lines expressed Pgp, which was functional and in proportion to the degree of drug resistance. Flow cytometry, UIC2 shift assays, IHC scores, and determination of absorbance products by image analysis were all highly correlated (r > 0.9). Overall Pgp expression increased from 11% in untreated patients to 30% in patients who had previously received chemotherapy. Compared with Pgp-negative tumors, a significant increase in doxorubicin and Taxol resistance was seen for breast cancers that expressed Pgp, regardless of prior treatment. A strong correlation between the degree of Pgp expression and in vitro resistance to Taxol and doxorubicin (but not to 5-fluorouracil) was found when either IHC scores or image analysis-based methods were used to quantify Pgp expression (n = 185, P < 0.0001). The degree of Pgp expression strongly correlated with the degree of drug resistance in the clinical specimens studied. These data suggest that (a) Pgp contributes to clinical MDR1-related drug resistance, and (b) both intrinsic and acquired expression of Pgp in breast cancer may contribute in part to therapeutic failure and relapse.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Paclitaxel/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Células Tumorais Cultivadas
20.
Pigment Cell Res ; 10(4): 236-49, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9263331

RESUMO

L-buthionine-S,R-sulfoximine (BSO) selectivley inhibits glutathione (GSH) synthesis. Malignant melanoma may be uniquely dependent on GSH and its linked enzymes, glutathione S-transferase (GST) and GSH-peroxidase, for metabolism of reactive orthoquinones and peroxides produced during melanin synthesis. We compared the in vitro effects of BSO on melanoma cell lines and fresh melanoma specimens (n = 118) with breast and ovarian cell lines and solid tumors (n = 244). IC50 values (microM) for BSO on melanoma, breast and ovarian tumor specimens were 1.9, 8.6, and 29, respectively. The IC90 for melanoma was 25.5 microM, a level 20-fold lower than steady state levels achieved clinically. The sensitivity of individual specimens of melanoma correlated with their melanin content (r = 0.63). BSO synergistically enhanced BCNU activity against melanoma cell lines and human tumors. We followed GSH levels, GST enzyme activity, GST isoenzyme profiles and mRNA levels after BSO. BSO (50 microM) treatment for 48 hr resulted in a 95% decrease in ZAZ and M14 melanoma cell line GSH levels, and a 60% decrease in GST enzyme activity. GST-mu protein and mRNA levels were significantly reduced in both cell lines. GST-pi expression was unaffected. These data suggest that BSO action on melanoma may be related to GSH depletion, diminishing the capacity to scavenge toxic metabolites produced during melanin synthesis. We report here for the first time that BSO enhancement of alkylator action may be related in part to down regulation of GST. BSO may be a clinically useful adjunct in the treatment of malignant melanoma.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Butionina Sulfoximina/farmacologia , Glutationa Transferase/biossíntese , Melanoma/tratamento farmacológico , Antineoplásicos Alquilantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carmustina/farmacologia , Sinergismo Farmacológico , Feminino , Glutationa/metabolismo , Glutationa Transferase/antagonistas & inibidores , Glutationa Transferase/genética , Humanos , Melaninas/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Células Tumorais Cultivadas
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