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Hybrid waveguides consisting of two-dimensional layered materials pad on the surface of optical waveguides suffer from a nonuniform and loose contact between the two-dimensional material and the waveguide, which can reduce the efficiency of the pulsed laser. Here, we present high-performance passively Q-switched pulsed lasers in three distinct structures of monolayer graphene-Nd:YAG hybrid waveguides irradiated by energetic ions. The ion irradiation enables the monolayer graphene a tight contact and strong coupling with the waveguide. As a result, Q-switched pulsed lasers with narrow pulse width and high repetition rate are obtained in three designed hybrid waveguides. The narrowest pulse width is 43.6â ns, provided by the ion-irradiated Y-branch hybrid waveguide. This study paves the way toward developing on-chip laser sources based on hybrid waveguides by using ion irradiation.
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Raman enhancement on a flat nonmetallic surface has attracted increasing attention, ever since the discovery of graphene enhanced Raman scattering. Recently, diverse two-dimensional layered materials have been applied as a flat surface for the Raman enhancement, attributed to different mechanisms. Looking beyond these isolated materials, atomic layers can be reassembled to design a heterostructure stacked layer by layer with an arbitrary chosen sequence, which allows the flow of charge carriers between neighboring layers and offers novel functionalities. Here, we demonstrate the heterostructure as a novel Raman enhancement platform. The WSe2 (W) monolayer and graphene (G) were stacked together to form a heterostructure with an area of 10 mm × 10 mm. Heterostructures with different stacked structuress are used as platforms for the enhanced Raman scattering, including G/W, W/G, G/W/G/W, and W/G/G/W. On the surface of the heterostructure, the intensity of the Raman scattering is much stronger compared with isolated layers, using the copper phthalocyanine (CuPc) molecule as a probe. It is found that the Raman enhancement effect on heterostructures depends on stacked methods. Phonon modes of CuPc have the strongest enhancement on G/W. W/G and W/G/G/W have a stronger enhancement than that on the isolated WSe2 monolayer, while lower than the graphene monolayer. The G/W/G/W/substrate demonstrated a comparable Raman enhancement effect than the G/W/substrate. These differences are due to the different interlayer couplings in heterostructures related to electron transition probability rates, which are further proved by first-principle calculations and probe-pump measurements.
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Owing to their unique properties, graphene-like two dimensional semiconducting materials, including Tungsten Disulfide (WS2) and Black Phosphorous (BP), have attracted increasing interest from basic research to practical applications. Herein, we demonstrated the ultrafast nonlinear saturable absorption response of WS2 and BP films in the waveguide structure. Through fabricating WS2 and BP films by evaporating the solutions on glass wafers. Saturable absorber films were attached onto the end-facet of the waveguide, which therefore constitutes a resonant cavity for the waveguide laser. Under a pump laser at 810 nm, we could obtain a stable Q-switched operation in the waveguide structure. This work indicated the significant potential of WS2 and BP for the ultrafast waveguide laser.
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The tribological behavior of traditional oil-in-water (O/W) lubricants (1.0 wt.%) and nano-TiO2 additive lubricants (1.0-9.0 wt.%) during micro rolling of titanium foils were analyzed. In this study, the surface morphologies of titanium foils under various lubrication conditions were assessed, and the corresponding lubrication mechanisms were revealed. The tribological behavior of nano-TiO2 additive lubricants during micro rolling of titanium foils was also explored through a series of characterization methods. The utilization of nano-TiO2 additive lubricants in micro rolling reduces the surface roughness of titanium foils. Moreover, it effectively inhibits the generation of indentations and cracks during rolling processes, enhancing the surface quality of rolled specimens. Additionally, owing to the synergism of rolling, tribo-film, mending and polishing effects of the nanoparticles, both the rolling force and surface roughness were minimized by using lubricants containing 3.0 wt.% TiO2 nanoparticles. Overall, an optimal concentration (3.0 wt.%) of TiO2 nanoparticles in water-based nanolubricants was obtained with enhanced tribological properties and lubrication performance during micro rolling of titanium foils.
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Surface-enhanced Raman spectroscopy (SERS) can boost the pristine Raman signal significantly which could be exploited for producing innovative sensing devices with advanced properties. However, the inherent complexity of SERS systems restricts their further applications in rapid detection, especially in situ detection in narrow areas. Here, we construct an efficient and flexible SERS-based Lab-on-Fiber (LOF) sensor by integrating Ag/Au nanocap arrays obtained by Ag/Au coating polystyrene nanospheres on the optical fiber face. We obtain rich "hot spots" at the nanogaps between neighboring nanocaps, and further achieve SERS performance with the assistance of laser-induced thermophoresis on the metal film that can achieve efficiency aggregation of detected molecules. We achieve a high Raman enhancement with a low detection limitation of 10-7 mol/L for the most efficient samples based on the above sensor. This sensor also exhibits good repeatability and stability under multiple detections, revealing the potential application for in situ detection based on the reflexivity of the optical fiber.
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Water-based lubricants with different fractions of TiO2 nanoparticles ranging from 1.0 to 9.0 wt.% were utilized to study the lubrication mechanisms during micro rolling tests and the tribological behaviour of nanolubricants during the micro rolling of copper foils. The results indicate that the application of TiO2 nanolubricants remarkably improves the surface quality of rolled copper foils during rolling processes. For lubricants with inadequate TiO2 nanoparticles, it is found that few TiO2 nanoparticles enter the contact regions between the rolls and foils, causing insufficient lubrication during rolling processes. Instead, for lubricants with excessive TiO2 nanoparticles, obvious agglomeration occurs at the contact regions and promotes the generation of voids on the surface of the rolled foils, thereby deteriorating the surface quality of the rolled copper foils. In addition, it is found that the surface quality of rolled foils is improved by utilizing a large reduction ratio. Overall, the fraction of 3.0 wt.% TiO2 nanolubricants is optimal to improve the lubrication conditions at the contact regions, thereby improving the surface quality of the rolled copper foils.
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Here we report stable gene transfer in cord blood-derived CD34(+) hematopoietic stem cells using a hyperactive nonviral Sleeping Beauty (SB) transposase (SB100X). In colony-forming assays, SB100X mediated the highest efficiency (24%) of stable Discosoma sp red fluorescent protein (DsRed) reporter gene transfer in committed hematopoietic progenitors compared with both the early-generation hyperactive SB11 transposase and the piggyBac transposon system (1.23% and 3.8%, respectively). In vitro differentiation assays further demonstrated that SB100X-transfected CD34(+) cells can develop into DsRed(+) CD4(+)CD8(+) T (3.17%-21.84%; median, 7.97%), CD19(+) B (3.83%-18.66%; median, 7.84%), CD56(+)CD3(-) NK (3.53%-79.98%; median, 7.88%), and CD33(+) myeloid (7.59%-15.63%; median, 9.48%) cells. SB100X-transfected CD34(+) cells achieved approximately 46% engraftment in NOD-scid IL2gammac(null) (NOG) mice. Twelve weeks after transplantation, 0.57% to 28.96% (median, 2.79%) and 0.49% to 34.50% (median, 5.59%) of total human CD45(+) cells in the bone marrow and spleen expressed DsRed, including CD19(+) B, CD14(+) monocytoid, and CD33(+) myeloid cell lineages. Integration site analysis revealed SB transposon sequences in the human chromosomes of in vitro differentiated T, B, NK, and myeloid cells, as well as in human CD45(+) cells isolated from bone marrow and spleen of transplanted NOG mice. Our results support the continuing development of SB-based gene transfer into human hematopoietic stem cells as a modality for gene therapy.
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Antígenos CD34 , Trasplante de Células Madre de Sangre del Cordón Umbilical , Elementos Transponibles de ADN , Sangre Fetal , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Células Madre Hematopoyéticas , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/metabolismo , Diferenciación Celular/genética , Femenino , Expresión Génica , Supervivencia de Injerto/genética , Humanos , Proteínas Luminiscentes/biosíntesis , Proteínas Luminiscentes/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Factores de Tiempo , Trasplante Heterólogo , Proteína Fluorescente RojaRESUMEN
In previous studies, we reported that indole-3-carbinol (I3C) and myo-inositol (MI) inhibit lung adenoma induced by tobacco smoke carcinogens in A/J mice. In this paper, we extended our work and examined the effects of I3C (70 or 30 micromol/g diet) and MI (56 micromol/g diet) against vinyl carbamate (VC)-induced lung adenocarcinoma by administering the agents from 1 week after the second of two injections of VC until termination of the study at week 18. The higher dose of I3C decreased multiplicities of tumors on the surface of the lung (26%, P = 0.0005), carcinoma incidence (38%), multiplicity (67%, P < 0.0001) and size (complete abolition of carcinoma with an area of >1.0 cm(2)) as well as adenoma with cellular pleomorphism (46%, P < 0.0001). The lower dose of I3C was less effective. MI decreased multiplicities of pulmonary surface tumors (20%, P = 0.0005), adenoma with cellular pleomorphism (40%, P < 0.0001) and lung adenoma (52%, P < 0.0001) and the proportion of the biggest carcinoma (carcinoma with an area of >1.0 cm(2), P < 0.05). Immunoblot analyses of lung tissues for potential target identification showed that I3C (70 micromol/g diet) inhibits IkappaBalpha degradation, nuclear factor-kappaB activation, expression of cyclooxygenase-2, phospho-Akt and fatty acid synthase (FAS) and activates caspase-3 and poly ADP ribose polymerase cleavage. The effect of MI was limited to inhibition of phospho-Akt and FAS expression. Our data show that I3C and MI inhibit lung carcinoma and provide a basis for future evaluation of these compounds in clinical trials as chemopreventive agents for current and former smokers.
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Adenocarcinoma/tratamiento farmacológico , Anticarcinógenos/farmacología , Indoles/farmacología , Inositol/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Uretano/análogos & derivados , Adenocarcinoma/inducido químicamente , Adenocarcinoma/metabolismo , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Caspasa 3/metabolismo , Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Femenino , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos A , Poli(ADP-Ribosa) Polimerasas/metabolismo , Uretano/toxicidad , Complejo Vitamínico BRESUMEN
O(6)-alkyldeoxyguanine adducts induced by tobacco-specific nitrosamines are repaired by O(6)-alkylguanine DNA alkyltransferase (AGT), which transfers the O(6)-alkyl group from the damaged base to a cysteine residue within the protein. In the present study, a mass spectrometry-based approach was used to analyze the effects of cytosine methylation on the kinetics of AGT repair of O(6)-methyldeoxyguanosine (O(6)-Me-dG) adducts placed within frequently mutated 5'-CG-3' dinucleotides of the p53 tumor suppressor gene. O(6)-Me-dG-containing DNA duplexes were incubated with human recombinant AGT protein, followed by rapid quenching, acid hydrolysis, and isotope dilution high pressure liquid chromatography-electrospray ionization tandem mass spectrometry analysis of unrepaired O(6)-methylguanine. Second-order rate constants were calculated in the absence or presence of the C-5 methyl group at neighboring cytosine residues. We found that the kinetics of AGT-mediated repair of O(6)-Me-dG were affected by neighboring 5-methylcytosine ((Me)C) in a sequence-dependent manner. AGT repair of O(6)-Me-dG adducts placed within 5'-CG-3' dinucleotides of p53 codons 245 and 248 was hindered when (Me)C was present in both DNA strands. In contrast, cytosine methylation within p53 codon 158 slightly increased the rate of O(6)-Me-dG repair by AGT. The effects of (Me)C located immediately 5' and in the base paired position to O(6)-Me-dG were not additive as revealed by experiments with hypomethylated sequences. Furthermore, differences in dealkylation rates did not correlate with AGT protein affinity for cytosine-methylated and unmethylated DNA duplexes or with the rates of AGT-mediated nucleotide flipping, suggesting that (Me)C influences other kinetic steps involved in repair, e.g. the rate of alkyl transfer from DNA to AGT.
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Citosina/metabolismo , Reparación del ADN/fisiología , Fosfatos de Dinucleósidos/metabolismo , Guanina/análogos & derivados , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Codón/genética , Metilación de ADN , Reparación del ADN/genética , Fosfatos de Dinucleósidos/genética , Ensayo de Cambio de Movilidad Electroforética , Genes p53/genética , Guanina/metabolismo , Humanos , Unión Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Rayos UltravioletaRESUMEN
Concurrent indoor-outdoor fine particulate matter (PM2.5) measurements were conducted at urban, suburban, and rural sites in Harbin, a megacity in the northeast of China. Chemical constituents of indoor-outdoor PM2.5 were determined. Infiltration factors (FINF) of all sites were calculated according to the indoor to outdoor (I/O) ratios of PM2.5 based on the regression analysis. Linear discriminant analysis (LDA) is applied to determine the indoor-outdoor relationship. Secondary organic carbon (SOC) was calculated on the basis of organic carbon to elemental carbon (OC/EC) ratios. The mean concentrations of indoor and outdoor PM2.5 were 166.4 ± 32.5 µg/m3 and 228.4 ± 83.7 µg/m3, respectively, during the heating period. OC/EC and potassium ion to elemental carbon (K+/EC) ratios verified that biomass was an important source in Harbin especially for rural sites. The nitrate to sulfate (NO3-/SO42-) ratio indicates the higher contribution of traffic emissions in urban sites. Cr was the only species that exceeded the guidelines of WHO 2002, which was mainly emitted from coal and oil combustion. SOC/OC and NO3-/SO42- ratios, and ion-balanced acidity (the ratio of cation to anion, R+/-) showed a large urban-rural and indoor-outdoor difference. The highest SOC/OC ratio was found at urban sites, up to 38.3% for indoors. SOC/OC ratios and R+/- values of indoor environments were higher, which is attributed to the conducive condition of forming the secondary pollutants during the heating period. The results of LDA indicated that the distributions of the chemical components of PM2.5 at three sites were statistically dissimilar. Graphical abstract.
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Contaminación del Aire Interior/análisis , Material Particulado/análisis , Contaminantes Atmosféricos , Carbono , China , Ciudades , Monitoreo del Ambiente , Calefacción , Tamaño de la Partícula , Estaciones del AñoRESUMEN
INTRODUCTION: We examined effects of state statutory changes in DUI fine or jail penalties for firsttime offenders from 1976 to 2002. METHODS: A quasi-experimental time-series design was used (n=324 monthly observations). Four outcome measures of drivers involved in alcohol-related fatal crashes are: single-vehicle nighttime, low BAC (0.01-0.07g/dl), medium BAC (0.08-0.14g/dl), high BAC (>/=0.15g/dl). All analyses of BAC outcomes included multiple imputation procedures for cases with missing data. Comparison series of non-alcohol-related crashes were included to efficiently control for effects of other factors. Statistical models include state-specific Box-Jenkins ARIMA models, and pooled general linear mixed models. RESULTS: Twenty-six states implemented mandatory minimum fine policies and 18 states implemented mandatory minimum jail penalties. Estimated effects varied widely from state to state. Using variance weighted meta-analysis methods to aggregate results across states, mandatory fine policies are associated with an average reduction in fatal crash involvement by drivers with BAC>/=0.08g/dl of 8% (averaging 13 per state per year). Mandatory minimum jail policies are associated with a decline in single-vehicle nighttime fatal crash involvement of 6% (averaging 5 per state per year), and a decline in low-BAC cases of 9% (averaging 3 per state per year). No significant effects were observed for the other outcome measures. CONCLUSIONS: The overall pattern of results suggests a possible effect of mandatory fine policies in some states, but little effect of mandatory jail policies.
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Accidentes de Tránsito/legislación & jurisprudencia , Consumo de Bebidas Alcohólicas/legislación & jurisprudencia , Intoxicación Alcohólica/prevención & control , Aplicación de la Ley , Policia , Prisiones/legislación & jurisprudencia , Consumo de Bebidas Alcohólicas/efectos adversos , Intoxicación Alcohólica/sangre , Humanos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Política Pública , Estados UnidosRESUMEN
PROBLEM: Hundreds of laws have been implemented in the United States over the past few decades designed to reduce alcohol-impaired driving and the crashes that often result. One approach has been to lower the legally allowable alcohol concentration for drivers. We examined the effects of changes in legal BAC limit in 28 U.S. states from January, 1976 to December, 2002. METHOD: An interrupted time-series quasi-experimental design was used, incorporating non-alcohol-related crashes as comparisons. Four outcome measures of alcohol-related crash involvement were examined: single-vehicle nighttime, BAC=0.01-0.07, BAC=0.08-0.14, and BAC>/=0.15. Missing BAC test result data were handled by using multiple imputations. Analyses involved estimation of state-specific ARIMA models, controlling for other factors affecting overall crash rates and other major DUI policy changes. Inverse variance weighting methods were used to pool results across states for the most precise underlying estimate of effect of legal BAC limits. RESULTS: Considerable state by state variability in estimated effects was observed, but results from the pooled analyses were clear and consistent. Changes in legal BAC limits significantly affected alcohol-related fatal crash involvement for both the SVN and BAC test result measures, and the laws affected drivers at all drinking levels. SUMMARY: An estimated 360 deaths are prevented each year in the United States as a result of the move from a 0.10 to 0.08 legal limit in recent years, and an additional 538 lives could be saved each year if the United States reduced the limit to 0.05, consistent with limits in most countries worldwide. IMPACT ON INDUSTRY: Given the significant effects of lower legal BAC limits on fatal crash involvement, businesses should support implementation of laws that further reduce the legal BAC limit for all drivers. Furthermore, all companies should set higher standards for employees, such as a zero allowable BAC limit for driving during work time.
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Accidentes de Tránsito/mortalidad , Consumo de Bebidas Alcohólicas/legislación & jurisprudencia , Conducción de Automóvil/legislación & jurisprudencia , Accidentes de Tránsito/tendencias , Empleo/legislación & jurisprudencia , Humanos , Evaluación de Resultado en la Atención de Salud , Gobierno Estatal , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: To evaluate the outcome of endovascular stent graft placement in patients with acute thoracic aortic syndromes. METHODS: Emergency stent-graft implantations were performed in 57 patients with acute thoracic aortic syndromes from May 2001 to December 2005 (45 Stanford B aortic dissections, 9 acute penetrating aortic ulcers or pseudoaneurysms. 3 traumatic thoracic aneurysms). The clinical data, efficacy and follow-up results were analyzed. RESULTS: Procedures were successful in all patients. Type I endoleaks were evidenced in 5 patients and ascending aortic dissection occurred in 1 patient during operation, 5 patients with acute penetrating aortic ulcer complicating with coronary artery disease received successful PCI immediately post endovascular stent graft placement. Adynamia in extremities occurred in 1 patient and recovered two days later post anisodamine and mcnicol treatments. Left vertebral artery ischemia was found in 1 patient due to coated subclavian artery by stent-graft and the patient recovered spontaneously after two days lethargy without special treatment. The mean ICU time after surgery was 3.5 days (1 - 8 days) and the mean hospitalization time was 10 days. The mean follow-up time was 25.30 +/- 13.1 months (1 - 47 months). Two patients died within 30 days after operation, 1 patient died of rupture of the ascending aortic dissection (7 days post operation), 1 patient died of acute renal failure at the 2nd day post operation. One patient died of empsyxis 3 months after procedure, 1 patient died at the 4th month post procedure for unknown reason, 1 patient received second stent-graft implantation because of a newly formed endoleak at the proximal end of the stent-graft, 5 patients received second stent-graft implantation because of newly formed leaks at the remote end of the stent-graft. No paraplegia or stent migration or stenosis was observed during the follow up period. Total mortality during hospitalization and follow-up was 7.0%. CONCLUSION: Patients with acute thoracic aortic syndrome could be effectively and safely treated by coated stent-graft endovascular placement.
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Aneurisma Falso/cirugía , Aneurisma de la Aorta Torácica/cirugía , Disección Aórtica/cirugía , Implantación de Prótesis Vascular/métodos , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Aorta Torácica , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Stents , SíndromeRESUMEN
We demonstrate a tunable hybrid Graphene-Nd:YAG cladding waveguide laser exploiting the electro-optic and the Joule heating effects of Graphene. A cladding Nd:YAG waveguide was fabricated by the ion irradiation. The multi-layer graphene were transferred onto the waveguide surface as the saturable absorber to get the Q-switched pulsed laser oscillation in the waveguide. Composing with appropriate electrodes, graphene based capacitance and heater were formed on the surface of the Nd:YAG waveguide. Through electrical control of graphene, the state of the hybrid waveguide laser was turned on or off. And the laser operation of the hybrid waveguide was electrically tuned between the continuous wave laser and the nanosecond pulsed laser.
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Chitosan (CS) is widely used as a scaffold material in tissue engineering. The objective of this study was to test whether porous chitosan membrane (PCSM) coating for Nafion used in implantable sensor reduced fibrous capsule (FC) density and promoted superior vascularization compared with PCSM coating for polytetrafluoroethylene (PTFE). PCSM was fabricated with solvent casting/particulate leaching method using silica gel as porogen and characterized in vitro. Then, PCSM-Nafion and PCSM-PTFE composites were assembled with hydrated PCSM and implanted subcutaneously in rats. The histological analysis was performed in comparison with Nafion and PTFE. Implants were explanted 35, 65, and 100 days after the implantation. Histological assessments indicated that both composites achieved presumed effects of porous coatings on decreasing collagen deposition and promoting angiogenesis. PCSM-PTFE exerted higher collagen deposition by area ratio, both within and outside, compared with that of PCSM-Nafion. Angiogenesis within and outside the PCSM-Nafion both increased over time, but that of the PCSM-PTFE within decreased.
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Materiales Biocompatibles/química , Quitosano/química , Polímeros de Fluorocarbono/química , Politetrafluoroetileno/química , Andamios del Tejido/química , Animales , Materiales Biocompatibles/efectos adversos , Quitosano/efectos adversos , Reacción a Cuerpo Extraño/etiología , Reacción a Cuerpo Extraño/patología , Politetrafluoroetileno/efectos adversos , Porosidad , Ratas , Ratas Sprague-Dawley , Andamios del Tejido/efectos adversosAsunto(s)
Infecciones Bacterianas/etiología , Complicaciones de la Diabetes , Trasplante de Riñón , Anciano , Infecciones Bacterianas/economía , Complicaciones de la Diabetes/inmunología , Femenino , Supervivencia de Injerto/inmunología , Costos de la Atención en Salud , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Humanos , Huésped Inmunocomprometido , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/inmunología , Masculino , Medicare , Persona de Mediana Edad , Complicaciones Posoperatorias/economía , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de RiesgoRESUMEN
Few studies have examined the quality of life (QOL) in survivors of non-Hodgkin lymphoma (NHL). A total of 109 patients with NHL (58 aggressive [AGG], 51 indolent [IND]) completed two health-related QOL assessments using the Medical Outcomes Study 36-Item Short-Form Healthy Survey (MOS SF-36) and the Functional Assessment in Cancer Therapy - Fatigue (FACT-F). Scores between IND and AGG were compared using a two-sample t-test. Multiple linear regression was performed to account for any potentially explanatory variables. Overall, 70.6% had received chemotherapy and 55% had received immunotherapy. Some 17.6% of the IND group had received no therapy. The overall physical and mental component QOL scores of the SF-36 did not differ between survivors. Physical function in survivors of IND was significantly better when compared with that of AGG NHL. Our study reports a similar overall QOL between survivors of IND and AGG NHL. Physical function, however, may be more impaired in survivors of AGG NHL.
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Linfoma no Hodgkin/psicología , Calidad de Vida/psicología , Encuestas y Cuestionarios , Sobrevivientes/psicología , Adulto , Anciano , Fatiga/psicología , Femenino , Encuestas Epidemiológicas , Humanos , Modelos Lineales , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) enables cancer cells to develop resistance to multiple anticancer drugs. Functional inhibitors of P-gp have shown promising efficacy in early clinical trials, but their long-term safety is yet to be established. A novel approach to overcome drug resistance is to use siRNA-mediated RNA interference to silence the expression of the efflux transporter. Because P-gp plays an important role in the physiological regulation of endogenous and xenobiotic compounds in the body, it is important to deliver P-gp targeted siRNA and anticancer drug specifically to tumor cells. Further, for optimal synergy, both the drug and siRNA may need to be temporally colocalized in the tumor cells. In the current study, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel, along with P-gp targeted siRNA, using poly(D,L-lactide-co-glycolide) nanoparticles to overcome tumor drug resistance. Nanoparticles were surface functionalized with biotin for active tumor targeting. Dual agent nanoparticles encapsulating the combination of paclitaxel and P-gp targeted siRNA showed significantly higher cytotoxicity in vitro than nanoparticles loaded with paclitaxel alone. Enhanced therapeutic efficacy of dual agent nanoparticles could be correlated with effective silencing of the MDR1 gene that encodes for P-gp and with increased accumulation of paclitaxel in drug-resistant tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and P-gp targeted siRNA at a paclitaxel dose that was ineffective in the absence of gene silencing. These results suggest that that the combination of P-gp gene silencing and cytotoxic drug delivery using targeted nanoparticles can overcome tumor drug resistance.
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Sistemas de Liberación de Medicamentos/métodos , Resistencia a Antineoplásicos , Silenciador del Gen , Nanopartículas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Biotina/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Ratones , Nanopartículas/ultraestructura , Paclitaxel/farmacología , Tamaño de la Partícula , ARN Interferente Pequeño/metabolismo , Propiedades de Superficie/efectos de los fármacosRESUMEN
Poor oral bioavailability limits the use of curcumin and other dietary polyphenols in the prevention and treatment of cancer. Minimally invasive strategies that can provide effective and sustained tissue concentrations of these agents will be highly valuable tools in the fight against cancer. The objective of this study was to investigate the use of an injectable sustained release microparticle formulation of curcumin as a novel approach to breast cancer chemoprevention. A biodegradable and biocompatible polymer, poly(d,l-lactide-co-glycolide), was used to fabricate curcumin microparticles. When injected s.c. in mice, a single dose of microparticles sustained curcumin levels in the blood and other tissues for nearly a month. Curcumin levels in the lungs and brain, frequent sites of breast cancer metastases, were 10- to 30-fold higher than that in the blood. Further, curcumin microparticles showed marked anticancer efficacy in nude mice bearing MDA-MB-231 xenografts compared with other controls. Repeated systemic injections of curcumin were not effective in inhibiting tumor growth. Treatment with curcumin microparticles resulted in diminished vascular endothelial growth factor expression and poorly developed tumor microvessels, indicating a significant effect on tumor angiogenesis. These results suggest that sustained delivery of chemopreventives such as curcumin using polymeric microparticles is a promising new approach to cancer chemoprevention and therapy.