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1.
Planta ; 259(1): 11, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38047928

RESUMO

MAIN CONCLUSION: Overexpression of SlBRI1 driven by the Atrd29A promoter could increase the cold resistance of tomato plants during chilling stress but did not improve the expression of SlBRI1 and plant growth under normal conditions. Low temperature is the main limiting factor severely affecting tomato plant development, growth, and fruit quality in winter and spring. Brassinosteroids (BRs) and key BR signaling genes positively regulate tomato plant development and response to chilling stress. Brassinosteroid-insensitive 1 (BRI1) is a major BR receptor that initiates BR signaling. Our results showed that overexpression of SlBRI1 driven by the Atrd29A promoter in transgenic plants did not increase the expression of SlBRI1 under normal conditions but rapidly induced the expression of SlBRI1 during chilling stress. The degree of wilting was lower in Atrd29A promoter-transgenic plants than in wild-type (WT) plants after chilling stress. Atrd29A promoter-transgenic plants exhibited low relative electrolyte leakage and reactive oxygen species (ROS) accumulation under chilling stress. Transgenic plants showed higher photosynthetic ability and antioxidant enzyme activity than WT plants under chilling stress. The BR content and expression levels of key genes involved in BR biosynthesis in Atrd29A-promoter transgenic plants were significantly lower than those in WT plants during chilling stress. The abscisic acid (ABA) content and expression levels of key ABA biosynthesis genes in the Atrd29A promoter-transgenic plants were significantly higher than those in the WT plants during chilling stress. In addition, Atrd29A promoter-transgenic plants positively enhanced the expression levels of ICE-CBF-COR cold-responsive pathway genes. Therefore, the overexpression of SlBRI1 driven by the Atrd29A promoter in transgenic plants can be a valuable tool for reducing chilling stress.


Assuntos
Solanum lycopersicum , Plantas Geneticamente Modificadas , Solanum lycopersicum/genética , Temperatura Baixa , Ácido Abscísico , Antioxidantes , Brassinosteroides
2.
Angew Chem Int Ed Engl ; 59(20): 7738-7742, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31999040

RESUMO

A novel triphenylphosphine (TPP) treatment strategy was developed to prepare the near-infrared emission CsPbI3 nanocrystal (NC)-polymer composite thin-film luminescent solar concentrators (LSCs) featuring high absolute photoluminescence quantum yield (PLQY), low reabsorption, and high stability. The PL emission of the LSCs is centered at about 700 nm with 99.4±0.4 % PLQY and narrow full width at half maximum (FWHM) of 75 meV (30 nm). Compared with LSCs prepared with classic CsPbI3 NCs, the stability of the LSCs after TPP treatments has been greatly improved, even after long-term (30 days) immersion in water and strong mercury-lamp irradiation (50 mW cm-2 ). Owing to the presence of lone-pair electrons on the phosphorus atom, TPP is also used as a photoinitiator, with higher efficiency than other common photoinitiators. Large-area (ca. 75 cm2 ) infrared LSCs were achieved with a high optical conversion efficiency of 3.1 % at a geometric factor of 10.

3.
Cancer ; 125(5): 807-817, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561757

RESUMO

BACKGROUND: The management of most solid tumors of the anterior mediastinum involves complete resection. Because of their location near mediastinal structures, wide resection is not possible; therefore, surgeons must use subjective visual and tactile cues to determine disease extent. This clinical trial explored intraoperative near-infrared (NIR) imaging as an approach to improving tumor delineation during mediastinal tumor resection. METHODS: Twenty-five subjects with anterior mediastinal lesions suspicious for malignancy were enrolled in an open-label feasibility trial. Subjects were administered indocyanine green (ICG) at a dose of 5 mg/kg, 24 hours before resection (via a technique called TumorGlow). The NIR imaging systems included Artemis (Quest, Middenmeer, the Netherlands) and Iridium (VisionSense Corp, Philadelphia, Pennsylvania). Intratumoral ICG uptake was evaluated. The clinical value was determined via an assessment of the ability of NIR imaging to detect phrenic nerve involvement or incomplete resection. Clinical and histopathologic variables were analyzed to determine predictors of tumor fluorescence. RESULTS: No drug-related toxicity was observed. Optical imaging added a mean of 10 minutes to case duration. Among the subjects with solid tumors, 19 of 20 accumulated ICG. Fluorescent tumors included thymomas (n = 13), thymic carcinomas (n = 4), and liposarcomas (n = 2). NIR feedback improved phrenic nerve dissection (n = 4) and identified residual disease (n = 2). There were no false-positives or false-negatives. ICG preferentially accumulated in solid tumors; this was independent of clinical and pathologic variables. CONCLUSIONS: NIR imaging for anterior mediastinal neoplasms is safe and feasible. This technology may provide a real-time tool capable of determining tumor extent and specifically identify phrenic nerve involvement and residual disease.


Assuntos
Verde de Indocianina/administração & dosagem , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/cirurgia , Imagem Óptica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Período Intraoperatório , Masculino , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Neoplasia Residual , Sensibilidade e Especificidade
4.
BMC Plant Biol ; 19(1): 256, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196007

RESUMO

BACKGROUND: Appropriate brassinosteroid (BR) signal strength caused by exogenous application or endogenous regulation of BR-related genes can increase crop yield. However, precise control of BR signals is difficult and can cause unstable effects and failure to reach full potential. Phosphorylated BRASSINOSTEROID INSENSITIVE1 (BRI1), the rate-limiting receptor in BR signalling, transduces BR signals, and we recently demonstrated that modifying BRI1 phosphorylation sites alters BR signal strength and botanical characteristics in Arabidopsis. However, the functions of such phosphorylation sites in agronomic characteristics of crops remain unclear. RESULTS: In this work, we investigated the roles of tomato SlBRI1 threonine-1050 (Thr-1050). SlBRI1 mutant cu3-abs1 plants expressing SlBRI1 with a non-phosphorylatable Thr-1050 (T1050A), with a wild-type SlBRI1 transformant used as a control, were examined. The results showed enhanced autophosphorylation of SlBRI1 and BR signal strength for cu3-abs1 harbouring T1050A, which promoted yield through increased plant expansion, leaf area, fruit weight and fruit number per cluster but reduced nutrient contents, including ascorbic acid and soluble sugar levels. Moreover, plant height, stem diameter, and internodal distance were similar between the transgenic plants. CONCLUSION: Our results reveal the biological role of Thr-1050 in tomato and provide a molecular basis for establishing high-yield crops by precisely controlling BR signal strength via phosphorylation site modification.


Assuntos
Brassinosteroides/metabolismo , Frutas/crescimento & desenvolvimento , Proteínas de Plantas/fisiologia , Proteínas Quinases/fisiologia , Transdução de Sinais , Solanum lycopersicum/crescimento & desenvolvimento , Solanum lycopersicum/genética , Mutação , Fosforilação , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Proteínas Quinases/genética , Proteínas Quinases/metabolismo
5.
Proc Natl Acad Sci U S A ; 113(15): 4164-9, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-27035960

RESUMO

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Apoptose , Linhagem Celular Tumoral , Humanos , Metástase Neoplásica , Neoplasias/patologia , Esferoides Celulares
6.
J Surg Oncol ; 118(2): 344-355, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30098293

RESUMO

Intraoperative fluorescence imaging (IFI) can improve real-time identification of cancer cells during an operation. Phase I clinical trials in thoracic surgery have demonstrated that IFI with second window indocyanine green (TumorGlow® ) can identify subcentimeter pulmonary nodules, anterior mediastinal masses, and mesothelioma, while the use of a folate receptor-targeted near-infrared agent, OTL38, can improve the specificity for diagnosing tumors with folate receptor expression. Here, we review the existing preclinical and clinical data on IFI in thoracic surgery.


Assuntos
Imagem Óptica/métodos , Cirurgia Assistida por Computador/métodos , Neoplasias Torácicas/diagnóstico por imagem , Neoplasias Torácicas/cirurgia , Procedimentos Cirúrgicos Torácicos/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Ensaios Clínicos como Assunto , Corantes Fluorescentes , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/cirurgia , Mesotelioma/diagnóstico por imagem , Mesotelioma/cirurgia , Monitorização Intraoperatória/métodos , Nódulo Pulmonar Solitário/diagnóstico por imagem , Nódulo Pulmonar Solitário/cirurgia
7.
Cancer ; 123(6): 1051-1060, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28263385

RESUMO

BACKGROUND: Complete tumor resection is the most important predictor of patient survival with non-small cell lung cancer. Methods for intraoperative margin assessment after lung cancer excision are lacking. This study evaluated near-infrared (NIR) intraoperative imaging with a folate-targeted molecular contrast agent (OTL0038) for the localization of primary lung adenocarcinomas, lymph node sampling, and margin assessment. METHODS: Ten dogs with lung cancer underwent either video-assisted thoracoscopic surgery or open thoracotomy and tumor excision after an intravenous injection of OTL0038. Lungs were imaged with an NIR imaging device both in vivo and ex vivo. The wound bed was re-imaged for retained fluorescence suspicious for positive tumor margins. The tumor signal-to-background ratio (SBR) was measured in all cases. Next, 3 human patients were enrolled in a proof-of-principle study. Tumor fluorescence was measured both in situ and ex vivo. RESULTS: All canine tumors fluoresced in situ (mean Fluoptics SBR, 5.2 [range, 2.7-8.1]; mean Karl Storz SBR 1.9 [range, 1.4-2.6]). In addition, the fluorescence was consistent with tumor margins on pathology. Three positive lymph nodes were discovered with NIR imaging. Also, a positive retained tumor margin was discovered upon NIR imaging of the wound bed. Human pulmonary adenocarcinomas were also fluorescent both in situ and ex vivo (mean SBR, > 2.0). CONCLUSIONS: NIR imaging can identify lung cancer in a large-animal model. In addition, NIR imaging can discriminate lymph nodes harboring cancer cells and also bring attention to a positive tumor margin. In humans, pulmonary adenocarcinomas fluoresce after the injection of the targeted contrast agent. Cancer 2017;123:1051-60. © 2016 American Cancer Society.


Assuntos
Receptores de Folato com Âncoras de GPI/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Imagem Molecular , Imagem Óptica , Espectroscopia de Luz Próxima ao Infravermelho , Idoso , Animais , Meios de Contraste , Modelos Animais de Doenças , Cães , Feminino , Corantes Fluorescentes , Humanos , Cuidados Intraoperatórios , Neoplasias Pulmonares/cirurgia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Imagem Molecular/métodos , Estadiamento de Neoplasias , Imagem Óptica/métodos , Razão Sinal-Ruído , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Tomografia Computadorizada por Raios X
8.
Bioconjug Chem ; 28(5): 1351-1355, 2017 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-28448116

RESUMO

Targeted and nontargeted biopolymeric nanoparticles with identical hydrodynamic sizes and surface charges were quantitatively examined in terms of the pharmacokinetic and biodistribution differences in detail. In adding cancer cell targeting folate molecules to the surface of the heparin nanocarriers, the amount of drug delivered to the tumor is doubled, and tumor growth inhibition is significantly enhanced. The folate-targeted heparin particles offered similar therapeutic potentials compared to their synthetic long-circulating analogues, thus presenting a viable alternative for drug-delivery vehicle construction using biological polymers, which are easier for the body to eliminate.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Nanopartículas/química , Polímeros/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Cisplatino/química , Heparina/química , Humanos , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Distribuição Tecidual
9.
Bioconjug Chem ; 28(1): 244-252, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-27341302

RESUMO

The development of sophisticated nanoplatforms for in vivo targeted delivery of therapeutic agents to solid tumors has the potential for not only improving therapeutic efficacy but also minimizing systemic toxicity. However, the currently low delivery efficiency (about 1% of the injected dose) and the limited tumor penetration of nanoparticles remain two major challenges. Here we report a class of functionalized, long-circulating, and ultrasmall gold nanocarriers (5 nm gold core and 20 nm overall hydrodynamic diameter) for improved drug delivery and deep tumor penetration. By using doxorubicin as a model drug, our design also includes a pH-sensitive hydrazone linkage that is stable at neutral or slightly basic pH but is rapidly cleaved in the acidic tumor microenvironments and intracellular organelles. With a circulation halftime of 1.6 days, the small particle size is an important feature not only for efficient extravasation and accumulation via the enhanced permeability and retention (EPR) effect, but also for faster nanoparticle diffusion and improved tumor penetration. In xenograft animal models, the results demonstrate that up to 8% of the injected nanoparticles can be accumulated at the tumor sites, among the highest nanoparticle delivery efficiencies reported in the literature. Also, histopathological and direct visual examinations reveal dark-colored tumors with deep nanoparticle penetration and distribution throughout the tumor mass. In comparison with pure doxorubicin which is known to cause considerable heart, kidney, and lung toxicity, in vivo animal data indicate that this class of functionalized and ultrasmall gold nanoparticles indeed provides better therapeutic efficacies with no apparent toxicity in vital organs.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Ouro/química , Nanopartículas Metálicas/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Humanos , Espectrometria de Massas , Camundongos , Microscopia Eletrônica de Transmissão , Polietilenoglicóis/química , Distribuição Tecidual
10.
Int J Mol Sci ; 18(9)2017 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-28902164

RESUMO

Bri1-associated kinase 1 (BAK1)-interacting receptor-like kinase (BIR) proteins have been shown to play important roles in regulating growth and development, pathogen associated molecular pattern (PAMP)-triggered immunity (PTI) responses, and cell death in the model plant, Arabidopsis thaliana. We identified four BIR family members in tomato (Solanum lycopersicum), including SlBIR3, an ortholog of AtBIR3 from A. thaliana. SlBIR3 is predicted to encode a membrane localized non-arginine-aspartate (non-RD) kinase that, based on protein sequence, does not have autophosphorylation activity but that can be phosphorylated in vivo. We established that SlBIR3 interacts with SlBAK1 and AtBAK1 using yeast two-hybrid assays and co-immunoprecipitation and maltose-binding protein pull down assays. We observed that SlBIR3 overexpression in tomato (cv. micro-tom) and A. thaliana has weak effect on growth and development through brassinosteroid (BR) signaling. SlBIR3 overexpression in A. thaliana suppressed flg22-induced defense responses, but did not affect infection with the bacterial pathogen Pseudomonas syringae (PstDC3000). This result was confirmed using virus-induced gene silencing (VIGS) in tomato in conjunction with PstDC3000 infection. Overexpression of SlBIR3 in tomato (cv. micro-tom) and A. thaliana resulted in enhanced susceptibility to the necrotrophic fungus Botrytis cinerea. In addition, co-silencing SlBIR3 with SlSERK3A or SlSERK3B using VIGS and the tobacco rattle virus (TRV)-RNA2 vector containing fragments of both the SlSERK3 and SlBIR3 genes induced spontaneous cell death, indicating a cooperation between the two proteins in this process. In conclusion, our study revealed that SlBIR3 is the ortholog of AtBIR3 and that it participates in BR, PTI, and cell death signaling pathways.


Assuntos
Morte Celular/efeitos dos fármacos , Moléculas com Motivos Associados a Patógenos/imunologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Arabidopsis/genética , Arabidopsis/imunologia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Clorofila/análise , Resistência à Doença/imunologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Inativação Gênica , Genes de Plantas/genética , Hipocótilo/crescimento & desenvolvimento , Imunoprecipitação , Solanum lycopersicum/imunologia , Solanum lycopersicum/microbiologia , Proteínas Ligantes de Maltose , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Doenças das Plantas/virologia , Reguladores de Crescimento de Plantas , Imunidade Vegetal/efeitos dos fármacos , Imunidade Vegetal/genética , Proteínas de Plantas/imunologia , Raízes de Plantas/crescimento & desenvolvimento , Vírus de Plantas/patogenicidade , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Pseudomonas syringae/patogenicidade , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Análise de Sequência , Transdução de Sinais/efeitos dos fármacos , Técnicas do Sistema de Duplo-Híbrido
11.
Anal Chem ; 88(10): 5489-97, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27067749

RESUMO

Nanozymes, the nanostructures with enzymatic activities, have attracted considerable attention because, in comparison with natural enzymes, they offer the possibility of lowered cost, improved stability, and excellent recyclability. However, the specificity and catalytic activity of current nanozymes are still far lower than that of their natural counterparts, which in turn has limited their use such as in bioanalysis. To address these challenges, herein we report the design and development of integrated nanozymes (INAzymes) by simultaneously embedding two cascade catalysts (i.e., a molecular catalyst hemin and a natural enzyme glucose oxidase, GOx) inside zeolitic imidazolate framework (ZIF-8) nanostructures. Such integrated design endowed the INAzymes with major advantage in improved catalytic efficiency as the first enzymatic reaction occurred in close (nanoscale) proximity to the second enzyme, so products of the first reaction can be used immediately as substrates for the second reaction, thus overcoming the problems of diffusion-limited kinetics and product instability. The considerable high catalytic activity and stability enabled the INAzymes to efficiently draw a colorimetric detection of glucose with good sensitivity and selectivity. When facilitated with in vivo microdialysis, the INAzyme was successfully used for facile colorimetric visualization of cerebral glucose in the brain of living rats. Moreover, when further combined with microfluidic technology, an integrative INAzyme-based online in vivo analytical platform was constructed. The promising application of the platform was successfully illustrated by continuously monitoring the dynamic changes of striatum glucose in living rats' brain following ischemia/reperfusion. This study developed a useful approach to not only functional nanomaterial design but also advanced platforms developments for diverse targets monitoring.


Assuntos
Encéfalo/metabolismo , Glucose/análise , Nanoestruturas/química , Espectrofotometria , Animais , Catálise , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Hemina/química , Hemina/metabolismo , Ratos , Zeolitas/química
12.
Anal Chem ; 88(1): 858-67, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26587976

RESUMO

Intraoperative cancer imaging and fluorescence-guided surgery have attracted considerable interest because fluorescence signals can provide real-time guidance to assist a surgeon in differentiating cancerous and normal tissues. Recent advances have led to the clinical use of a natural fluorophore called protoporphyrin IX (PpIX) for image-guided surgical resection of high-grade brain tumors (glioblastomas). However, traditional fluorescence imaging methods have only limited detection sensitivity and identification accuracy and are unable to detect low-grade or diffuse infiltrating gliomas (DIGs). Here we report a low-cost hand-held spectroscopic device that is capable of ultrasensitive detection of protoporphyrin IX fluorescence in vivo, together with intraoperative spectroscopic data obtained from both animal xenografts and human brain tumor specimens. The results indicate that intraoperative spectroscopy is at least 3 orders of magnitude more sensitive than the current surgical microscopes, allowing ultrasensitive detection of as few as 1000 tumor cells. For detection specificity, intraoperative spectroscopy allows the differentiation of brain tumor cells from normal brain cells with a contrast signal ratio over 100. In vivo animal studies reveal that protoporphyrin IX fluorescence is strongly correlated with both MRI and histological staining, confirming that the fluorescence signals are highly specific to tumor cells. Furthermore, ex vivo spectroscopic studies of excised brain tissues demonstrate that the hand-held spectroscopic device is capable of detecting diffuse tumor margins with low fluorescence contrast that are not detectable with current systems in the operating room. These results open new opportunities for intraoperative detection and fluorescence-guided resection of microscopic and low-grade glioma brain tumors with invasive or diffusive margins.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Monitorização Intraoperatória , Cirurgia Assistida por Computador , Animais , Linhagem Celular Tumoral , Fluorescência , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Camundongos , Camundongos Nus , Espectrofotometria
14.
J Urol ; 195(3): 748-55, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26541080

RESUMO

PURPOSE: Margin status can often be difficult to assess intraoperatively, particularly during partial nephrectomy given the time constraints related to renal hilar clamping. We hypothesized that a targeted molecular imaging approach could be used during surgery to identify tumor margins and confirm disease clearance. MATERIALS AND METHODS: EC17, a novel tracer targeting FRα, was used in murine models of renal cell carcinoma to identify positive margins after surgery. Positive margins were detected due to elevated tumor-to-background ratios of the tumor compared to surrounding normal tissues. We performed a pilot study in 4 patients using EC17 preoperatively with intraoperative imaging during the operation. RESULTS: FRα was highly expressed in 65% of clear cell renal cell carcinomas harvested from the operating room. In the murine model intraoperative imaging of renal cell carcinoma revealed a mean ± SD tumor-to-background ratio of 8.2 ± 1.1 in the RCC10, 11.2 ± 1.1 in the 786-0 and 4.3 ± 1.1 in the UMRC2 cell line. Compared to visual inspection intraoperative imaging of the surgical resection bed identified residual disease in 24% more animals. In the human pilot study targeted molecular imaging identified 2 of 4 renal cell carcinomas and had no false-positive results. In these 2 cases the tumor-to-background ratio was 3.7 and 4.6, respectively. In each case we confirmed disease clearance and tumor fluorescence did not correlate with nodule size or tumor grade. CONCLUSIONS: To our knowledge this is the first demonstration in humans of identifying renal cell carcinoma during surgery using a targeted molecular contrast agent. This approach may lead to a superior method of identifying malignancy and tumor borders in the intraoperative setting.


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/cirurgia , Cuidados Intraoperatórios , Neoplasias Renais/diagnóstico , Neoplasias Renais/cirurgia , Técnicas de Diagnóstico Molecular/métodos , Imagem Molecular , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Nefrectomia , Projetos Piloto
15.
Annu Rev Phys Chem ; 66: 521-47, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25622189

RESUMO

Nanomedicine is an interdisciplinary field of research at the interface of science, engineering, and medicine, with broad clinical applications ranging from molecular imaging to medical diagnostics, targeted therapy, and image-guided surgery. Despite major advances during the past 20 years, there are still major fundamental and technical barriers that need to be understood and overcome. In particular, the complex behaviors of nanoparticles under physiological conditions are poorly understood, and detailed kinetic and thermodynamic principles are still not available to guide the rational design and development of nanoparticle agents. Here we discuss the interactions of nanoparticles with proteins, cells, tissues, and organs from a quantitative physical chemistry point of view. We also discuss insights and strategies on how to minimize nonspecific protein binding, how to design multistage and activatable nanostructures for improved drug delivery, and how to use the enhanced permeability and retention effect to deliver imaging agents for image-guided cancer surgery.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Imagem Molecular/métodos , Nanomedicina/métodos , Nanopartículas/metabolismo , Animais , Membrana Celular/metabolismo , Humanos , Nanopartículas/análise , Nanotecnologia/métodos , Neoplasias/diagnóstico , Proteínas/metabolismo , Cirurgia Assistida por Computador/métodos
16.
J Surg Oncol ; 113(5): 508-14, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26843131

RESUMO

BACKGROUND AND OBJECTIVES: Current methods of intraoperative breast cancer margin assessment are labor intensive, not fully reliable, and time consuming; therefore novel strategies are necessary. We hypothesized that near infrared (NIR) intraoperative molecular imaging using systemic indocyanine green (ICG) would be helpful in discerning tumor margins. METHODS: A mammary cancer cell line, 4T1, was used to establish tumors in mouse flanks (n = 60). Tumors were excised 24 hr after intravenous ICG. Assessment of residual tumor in the wound bed was performed using a combination of NIR imaging and traditional method (by visual inspection and palpation) versus traditional method alone. Next we performed a clinical trial to evaluate the role of NIR imaging after systemic ICG for the margin assessment of 12 patients undergoing breast-conserving surgery. RESULTS: Traditional margin assessment identified 30% of positive margins while NIR imaging identified 90% of positive margins. In our clinical trial, all tumors were detected by NIR imaging and there was fluorescent evidence of residual tumor in the tumor bed in 6 of the 12 patients. None of these patients had positive margins on pathology. CONCLUSIONS: Systemic ICG reliably accumulates in breast cancers in murine models as well as human breast cancer. While NIR imaging is helpful for detection of retained tumor margins in our animal model, intraoperative imaging for precise margin detection will need further refinement before clinical value can be obtained. J. Surg. Oncol. 2016;113:508-514. © 2016 Wiley Periodicals, Inc.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Corantes , Verde de Indocianina , Margens de Excisão , Espectroscopia de Luz Próxima ao Infravermelho , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Cuidados Intraoperatórios , Mastectomia Segmentar , Camundongos , Pessoa de Meia-Idade , Imagem Molecular , Neoplasia Residual , Projetos Piloto
17.
Ann Surg ; 262(4): 602-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26366539

RESUMO

BACKGROUND: With increasing use of chest computed tomography scans, indeterminate pulmonary nodules are frequently detected as an incidental finding and present a diagnostic challenge. Tissue biopsy followed by histological review and immunohistochemistry is the gold standard to obtain a diagnosis and the most common malignant finding is a primary lung adenocarcinoma. Our objective was to determine whether an intraoperative optical biopsy (molecular imaging) may provide an alternative approach for determining if a pulmonary nodule is a primary lung adenocarcinoma. METHODS: Before surgery, 30 patients with an indeterminate pulmonary nodule were intravenously administered a folate receptor-targeted fluorescent contrast agent specific for primary lung adenocarcinomas. During surgery, the nodule was removed and the presence of fluorescence (optical biopsy) was assessed in the operating room to determine if the nodule was a primary pulmonary adenocarcinoma. Standard-of-care frozen section and immunohistochemical staining on permanent sections were then performed as the gold standard to validate the results of the optical biopsy. RESULTS: Optical biopsies identified 19 of 19 (100%) primary pulmonary adenocarcinomas. There were no false positive or false negative diagnoses. An optical biopsy required 2.4 minutes compared to 26.5 minutes for frozen section (P < 0.001) and it proved more accurate than frozen section in diagnosing lung adenocarcinomas. CONCLUSIONS: An optical biopsy has excellent positive predictive value for intraoperative diagnosis of primary lung adenocarcinomas. With refinement, this technology may prove to be an important supplement to standard pathology for examining close surgical margins, identifying lymph node involvement, and determining whether suspicious nodules are malignant.


Assuntos
Adenocarcinoma/patologia , Neoplasias Pulmonares/patologia , Pulmão/patologia , Imagem Óptica/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Adulto , Idoso , Biópsia , Feminino , Fluoresceína-5-Isotiocianato , Ácido Fólico , Secções Congeladas , Humanos , Período Intraoperatório , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Tomografia Computadorizada por Raios X
18.
Mol Imaging ; 132014.
Artigo em Inglês | MEDLINE | ID: mdl-25442640

RESUMO

Surgical biopsy of potential tumor recurrence is a common challenge facing oncologists, surgeons, and cancer patients. Imaging modalities have limited ability to accurately detect recurrent cancer in fields affected by previous surgery, chemotherapy, or radiation. However, definitive tissue diagnosis is often needed to initiate treatment and to direct therapy. We sought to determine if a targeted fluorescent intraoperative molecular imaging technique could be applied in a clinical setting to assist a surgical biopsy in a "hostile" field. We describe the use of a folate-fluorescein conjugate to direct the biopsy of a suspected recurrent lung adenocarcinoma invading the mediastinum that had been previously treated with chemoradiation. We found that intraoperative imaging allowed the identification of small viable tumor deposits that were otherwise indistinguishable from scar and necrosis. Our operative observations were confirmed by histology, fluorescence microscopy, and immunohistochemistry. Our results demonstrate one possible application and clinical value of intraoperative molecular imaging.


Assuntos
Adenocarcinoma/cirurgia , Meios de Contraste , Receptor 1 de Folato/metabolismo , Ácido Fólico , Neoplasias Pulmonares/cirurgia , Imagem Molecular/métodos , Recidiva Local de Neoplasia/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Meios de Contraste/química , Fluoresceína/química , Ácido Fólico/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mediastino/patologia , Pessoa de Meia-Idade , Monitorização Intraoperatória
19.
J Biomed Opt ; 29(7): 076005, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39045222

RESUMO

Significance: Single-chip imaging devices featuring vertically stacked photodiodes and pixelated spectral filters are advancing multi-dye imaging methods for cancer surgeries, though this innovation comes with a compromise in spatial resolution. To mitigate this drawback, we developed a deep convolutional neural network (CNN) aimed at demosaicing the color and near-infrared (NIR) channels, with its performance validated on both pre-clinical and clinical datasets. Aim: We introduce an optimized deep CNN designed for demosaicing both color and NIR images obtained using a hexachromatic imaging sensor. Approach: A residual CNN was fine-tuned and trained on a dataset of color images and subsequently assessed on a series of dual-channel, color, and NIR images to demonstrate its enhanced performance compared with traditional bilinear interpolation. Results: Our optimized CNN for demosaicing color and NIR images achieves a reduction in the mean square error by 37% for color and 40% for NIR, respectively, and enhances the structural dissimilarity index by 37% across both imaging modalities in pre-clinical data. In clinical datasets, the network improves the mean square error by 35% in color images and 42% in NIR images while enhancing the structural dissimilarity index by 39% in both imaging modalities. Conclusions: We showcase enhancements in image resolution for both color and NIR modalities through the use of an optimized CNN tailored for a hexachromatic image sensor. With the ongoing advancements in graphics card computational power, our approach delivers significant improvements in resolution that are feasible for real-time execution in surgical environments.


Assuntos
Redes Neurais de Computação , Humanos , Processamento de Imagem Assistida por Computador/métodos , Cor , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Imagem Óptica/instrumentação
20.
Chem Sci ; 15(8): 2954-2962, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38404390

RESUMO

Materials with two or more fluorescence features under different excitation sources have great potential in optical applications, but luminous materials with three emission characteristics have been largely undeveloped. Here, we report a novel zero-dimensional (0D) organic-inorganic hybrid ((C2H5)4N)2ZrCl6 perovskite with multiple emissions. The zirconium-based perovskite exhibits a red emission around 620 nm, a green emission at 527 nm, and a blue emission around 500 nm. The red and green emissions come from self-trapped excitons (STEs) and the d-d transitions of Zr(iv), respectively, which are caused by distortion of the [ZrCl6]2- octahedra. The blue emission is caused by thermally activated delayed fluorescence (TADF), which is similar to that of Cs2ZrCl6. The absolute photoluminescence quantum yield (PLQY) of the red and blue double emission is up to 83% and the PLQY of the green emission is 27%. With different combinations of ((C2H5)4N)2ZrCl6 samples, we achieve a variety of applications, including a two-color luminescent anti-counterfeiting device, a white light-emitting diode (WLED) with a color rendering index (CRI) of 95 and information encryption with different excitations. We also synthesize other hybrid zirconium perovskites with tri-luminescence through a similar method. Our work provides a potential set of excitation-dependent luminescent materials and is expected to expand the basic research and practical applications of multi-luminescence materials.

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