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PURPOSE: Multiple sclerosis (MS) is a neuro-inflammatory disease affecting the central nervous system (CNS), where the immune system targets and damages the protective myelin sheath surrounding nerve fibers, inhibiting axonal signal transmission. Demyelinating optic neuritis (ON), a common MS symptom, involves optic nerve damage. We've developed NeuroVEP, a portable, wireless diagnostic system that delivers visual stimuli through a smartphone in a headset and measures evoked potentials at the visual cortex from the scalp using custom electroencephalography electrodes. METHODS: Subject vision is evaluated using a short 2.5-min full-field visual evoked potentials (ffVEP) test, followed by a 12.5-min multifocal VEP (mfVEP) test. The ffVEP evaluates the integrity of the visual pathway by analyzing the P100 component from each eye, while the mfVEP evaluates 36 individual regions of the visual field for abnormalities. Extensive signal processing, feature extraction methods, and machine learning algorithms were explored for analyzing the mfVEPs. Key metrics from patients' ffVEP results were statistically evaluated against data collected from a group of subjects with normal vision. Custom visual stimuli with simulated defects were used to validate the mfVEP results which yielded 91% accuracy of classification. RESULTS: 20 subjects, 10 controls and 10 with MS and/or ON were tested with the NeuroVEP device and a standard-of-care (SOC) VEP testing device which delivers only ffVEP stimuli. In 91% of the cases, the ffVEP results agreed between NeuroVEP and SOC device. Where available, the NeuroVEP mfVEP results were in good agreement with Humphrey Automated Perimetry visual field analysis. The lesion locations deduced from the mfVEP data were consistent with Magnetic Resonance Imaging and Optical Coherence Tomography findings. CONCLUSION: This pilot study indicates that NeuroVEP has the potential to be a reliable, portable, and objective diagnostic device for electrophysiology and visual field analysis for neuro-visual disorders.
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Potenciais Evocados Visuais , Esclerose Múltipla , Neurite Óptica , Humanos , Potenciais Evocados Visuais/fisiologia , Neurite Óptica/diagnóstico , Neurite Óptica/fisiopatologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/fisiopatologia , Feminino , Masculino , Adulto , Campos Visuais/fisiologia , Córtex Visual/fisiopatologia , Eletroencefalografia/instrumentação , Pessoa de Meia-Idade , Projetos Piloto , Estimulação LuminosaRESUMO
A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.
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Mapeamento Encefálico/métodos , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Angiografia Cerebral/métodos , Nanopartículas de Magnetita , Animais , Volume Sanguíneo/fisiologia , Determinação do Volume Sanguíneo/métodos , Circulação Cerebrovascular/fisiologia , Compostos Férricos , Imageamento por Ressonância Magnética/métodos , Ratos , Ratos Sprague-DawleyRESUMO
Encapsulating bacteria within constrained microenvironments can promote the manifestation of specialized behaviors. Using double-emulsion droplet-generating microfluidic synthesis, live Bacillus subtilis bacteria were encapsulated in a semi-permeable membrane composed of poly(ethylene glycol)-b-poly(D,L-lactic acid) (mPEG-PDLLA). This polymer membrane was sufficiently permeable to permit exponential bacterial growth, metabolite-induced gene expression, and rapid biofilm growth. The biodegradable microparticles retained structural integrity for several days and could be successfully degraded with time or sustained bacterial activity. Microencapsulated B. subtilis successfully captured and contained sodium selenite added outside the polymersomes, converting the selenite into elemental selenium nanoparticles that were selectively retained inside the polymer membrane. This remediation of selenium using polymersomes has high potential for reducing the toxicity of environmental selenium contamination, as well as allowing selenium to be harvested from areas not amenable to conventional waste or water treatment.
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Bacillus subtilis/metabolismo , Composição de Medicamentos/métodos , Selênio/metabolismo , Plásticos Biodegradáveis , Biodegradação AmbientalRESUMO
More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.
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Ouro/efeitos adversos , Nanopartículas Metálicas/efeitos adversos , Neoplasias/radioterapia , Neovascularização Patológica/tratamento farmacológico , Linhagem Celular Tumoral , Endotélio/efeitos dos fármacos , Endotélio/patologia , Endotélio/efeitos da radiação , Ouro/química , Humanos , Nanopartículas Metálicas/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neovascularização Patológica/patologia , Neovascularização Patológica/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Radioterapia Guiada por ImagemRESUMO
PURPOSE: Conventional MRI using contrast agents is semiquantitative because it is inherently sensitive to extravoxular susceptibility artifacts, field inhomogeneity, partial voluming, perivascular effects, and motion/flow artifacts. Herein we demonstrate a quantitative contrast-enhanced MRI technique using ultrashort time-to-echo pulse sequences for measuring clinically relevant concentrations of ferumoxytol, a superparamagnetic iron oxide nanoparticle contrast agent with high sensitivity and precision in vitro and in vivo. METHODS: The method achieves robust, reproducible results by using rapid signal acquisition at ultrashort time-to-echo (UTE) to produce positive contrast images with pure T1 weighting and little T2* decay. The spoiled gradient echo equation is used to transform UTE intensities directly into concentration using experimentally determined relaxivity constants and image acquisition parameters. RESULTS: A multiparametric optimization of acquisition parameters revealed an optimal zone capable of producing high-fidelity measurements. Clinically relevant intravascular concentrations of ferumoxytol were measured longitudinally in mice with high sensitivity and precision (â¼7.1% error). MRI measurements were independently validated by elemental iron analysis of sequential blood draws. Automated segmentation of ferumoxytol concentration yielded high quality three-dimensional images for visualization of perfusion. CONCLUSIONS: This ability to longitudinally quantify blood pool CA concentration is unique to quantitative UTE contrast-enhanced (QUTE-CE) MRI and makes QUTE-CE MRI competitive with nuclear imaging.
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Algoritmos , Óxido Ferroso-Férrico/administração & dosagem , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética/métodos , Processamento de Sinais Assistido por Computador , Imagem Corporal Total/métodos , Animais , Meios de Contraste/administração & dosagem , Relação Dose-Resposta a Droga , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Contemporary high-density electroencephalographic systems (hd-EEG) comprising up to 256 electrodes have inter-electrode separations of 2-4 cm. Because electric currents of the brain are believed to strongly diffuse before reaching the scalp surface, higher-density electrode coverage is often deemed unnecessary. We used an ultra-dense electroencephalography (ud-EEG) sensor array to reveal strong potential variation at 1cm scale and discovered that it reflects functional brain activity. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for brain-response classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications.
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Algoritmos , Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Eletroencefalografia/métodos , Adulto , Eletrodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Processamento de Sinais Assistido por Computador , Adulto JovemRESUMO
The clinical application of gene silencing mediated by small interfering RNA (siRNA) has been limited by the lack of efficient and safe carriers. Phospholipid modification of low molecular weight polyethylenimine (PEI 1.8 kDa) dramatically increased its gene down-regulation capacity while keeping cytotoxicity levels low. The silencing efficacy was highly dependent on the nature of the lipid grafted to PEI and the polymer/siRNA ratio employed. Phosphoethanolamine (DOPE and DPPE) and phosphocholine (PC) conjugation did not change the physicochemical properties and siRNA binding capacity of PEI complexes but had a large impact on their transfection and ability to down-regulate Green Fluorescent Protein (GFP) expression (60%, 30% and 5% decrease of GFP expression respectively). We found that the micelle-forming structure of DOPE and DPPE-PEI dramatically changed PEI's interaction with cell membranes and played a key role in promoting PEI 1.8 kDa transfection, completely ineffective in the absence of the lipid modification. FROM THE CLINICAL EDITOR: While siRNA-based gene silencing methods could have numerous clinical applications, efficient delivery remains a major challenge. This team reports that DOPE-PEI and DPPE-PEI based micelle-forming nanostructures may be able to provide an efficient vector for siRNA transfection.
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Lipídeos/química , Nanopartículas/química , Fosfolipídeos/química , Polietilenoimina/química , Interferência de RNA , Animais , Linhagem Celular , Membrana Celular/metabolismo , Portadores de Fármacos/química , Etanolaminas/química , Proteínas de Fluorescência Verde/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Micelas , Peso Molecular , Nanomedicina , Fosforilcolina/química , RNA Interferente Pequeno/químicaRESUMO
Background: Ferumoxytol (Ferahame, AMAG Pharmaceuticals, Waltham, MA) is increasingly used off-label as an MR contrast agent due to its relaxivity and safety profiles. However, its potent T2∗ relaxivity limits achievable T1-weighted positive contrast and leads to artifacts in standard MRI protocols. Optimization of protocols for ferumoxytol deployment is necessary to realize its potential. Methods: We present first-in-human clinical results of the Quantitative Ultrashort Time-to-Echo Contrast Enhanced (QUTE-CE) MRA technique using the superparamagnetic iron oxide nanoparticle agent ferumoxytol for vascular imaging of the head/brain in 15 subjects at 3.0T. The QUTE-CE MRA method was implemented on a 3T scanner using a stack-of-spirals 3D Ultrashort Time-to-Echo sequence. Time-of-flight MRA and standard TE T1-weighted (T1w) images were also collected. For comparison, gadolinium-enhanced blood pool phase images were obtained retrospectively from clinical practice. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and intraluminal signal heterogeneity (ISH) were assessed and compared across approaches with Welch's two-sided t-test. Results: Fifteen volunteers (54 ± 17 years old, 9 women) participated. QUTE-CE MRA provided high-contrast snapshots of the arterial and venous networks with lower intraluminal heterogeneity. QUTE-CE demonstrated significantly higher SNR (1707 ± 226), blood-tissue CNR (1447 ± 189), and lower ISH (0.091 ± 0.031) compared to ferumoxytol T1-weighted (551 ± 171; 319 ± 144; 0.186 ± 0.066, respectively) and time-of-flight (343 ± 104; 269 ± 82; 0.190 ± 0.016, respectively), with p < 0.001 in each comparison. The high CNR increased the depth of vessel visualization. Vessel lumina were captured with lower heterogeneity. Conclusion: Quantitative Ultrashort Time-to-Echo Contrast-Enhanced MR angiography provides approximately 5-fold superior contrast with fewer artifacts compared to other contrast-enhanced vascular imaging techniques using ferumoxytol or gadolinium, and to noncontrast time-of-flight MR angiography, for clinical vascular imaging. This trial is registered with NCT03266848.
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This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources. HeLa cell cultures incubated with and without AuNP were irradiated with an I-125 seed plaque designed to produce a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at low-dose rates ranging from 2.1 to 4.5cGy/h. Residual γH2AX was measured 24h after irradiation and used to compare radiation damage to the cells with and without AuNP. The data demonstrate that the biological effect when irradiating in the presence of 0.2mg/ml concentration of AuNP is about 70%-130% greater than without AuNP. Meanwhile, without radiation, the AuNP showed minimal effect on the cancer cells. These findings provide in vitro evidence that AuNP may be employed as radiosensitizers during continuous LDR brachytherapy. FROM THE CLINICAL EDITOR: In this basic science paper, the application of gold nanoparticles as radiosensitizing agents for low dose rate gamma radiation therapy is discussed, demonstrating efficacy in cell culture models.
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Braquiterapia , Ouro/química , Radioisótopos do Iodo/administração & dosagem , Nanopartículas Metálicas , Relação Dose-Resposta à Radiação , Raios gama , Células HeLa , HumanosRESUMO
Detection of ultrasmall masses such as proteins and pathogens has been made possible as a result of advancements in nanotechnology. Development of label-free and highly sensitive biosensors has enabled the transduction of molecular recognition into detectable physical quantities. Microcantilever (MC)-based systems have played a widespread role in developing such biosensors. One of the most important drawbacks of all of the available biosensors is that they all come at a very high cost. Moreover, there are certain limitations in the measurement equipments attached to the biosensors which are mostly optical measurement systems. A unique self-sensing detection technique is proposed in this paper in order to address most of the limitations of the current measurement systems. A self-sensing bridge is used to excite piezoelectric MC-based sensor functioning in dynamic mode, which simultaneously measures the system's response through the self-induced voltage generated in the piezoelectric material. As a result, the need for bulky, expensive read-out equipment is eliminated. A comprehensive mathematical model is presented for the proposed self-sensing detection platform using distributed-parameters system modeling. An adaptation strategy is then implemented in the second part in order to compensate for the time-variation of piezoelectric properties which dynamically improves the behavior of the system. Finally, results are reported from an extensive experimental investigation carried out to prove the capability of the proposed platform. Experimental results verified the proposed mathematical modeling presented in the first part of the study with accuracy of 97.48%. Implementing the adaptation strategy increased the accuracy to 99.82%. These results proved the measurement capability of the proposed self-sensing strategy. It enables development of a cost-effective, sensitive and miniaturized mass sensing platform.
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Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Eletricidade , Modelos Teóricos , Tamanho da Partícula , Proteínas/análise , Adsorção , Simulação por Computador , Análise de Fourier , Vibração , Óxido de Zinco/químicaRESUMO
Purpose: Multiple Sclerosis (MS) is a neuro-inflammatory disease of the Central Nervous System (CNS) in which the body's immune system attacks and destroys myelin sheath that protects nerve fibers and causes disruption in axonal signal transmission. Demyelinating Optic Neuritis (ON) is often a manifestation of MS and involves inflammation of the optic nerve. ON can cause vision loss, pain and discomfort in the eyes, and difficulties in color perception.In this study, we developed NeuroVEP, a portable, wireless diagnostic system that delivers visual stimuli through a smartphone in a headset and measures evoked potentials at the visual cortex from near the O1, Oz, O2, O9 and O10 locations on the scalp (extended 10-20 system) using custom electroencephalography (EEG) electrodes. Methods: Each test session is constituted by a short 2.5-minute full-field visual evoked potentials (ffVEP) test, followed by a 12.5-minute multifocal VEP (mfVEP) test. The ffVEP test evaluates the integrity of the visual pathway by analyzing the P1 (also known as P100) component of responses from each eye, while the mfVEP test evaluates 36 individual regions of the visual field for abnormalities. Extensive signal processing, feature extraction methods, and machine learning algorithms were explored for analyzing the mfVEP responses. The results of the ffVEP test for patients were evaluated against normative data collected from a group of subjects with normal vision. Custom visual stimuli with simulated defects were used to validate the mfVEP results which yielded 91% accuracy of classification. Results: 20 subjects, 10 controls and 10 with MS and/or ON were tested with the NeuroVEP device and a standard-of-care (SOC) VEP testing device which delivers only ffVEP stimuli. In 91% of the cases, the ffVEP results agreed between NeuroVEP and SOC device. Where available, the NeuroVEP mfVEP results were in good agreement with Humphrey Automated Perimetry visual field analysis. The lesion locations deduced from the mfVEP data were consistent with Magnetic Resonance Imaging (MRI) and Optical Coherence Tomography (OCT) findings. Conclusion: This pilot study indicates that NeuroVEP has the potential to be a reliable, portable, and objective diagnostic device for electrophysiology and visual field analysis for neuro-visual disorders.
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Background: Ovarian cancer has long been known to be the deadliest cancer associated with the female reproductive system. More than 15% of ovarian cancer patients have a defective BRCA-mediated homologous recombination repair pathway that can be therapeutically targeted with PARP inhibitors (PARPi), such as Talazoparib (TLZ). The expansion of TLZ clinical approval beyond breast cancer has been hindered due to the highly potent systemic side effects resembling chemotherapeutics. Here we report the development of a novel TLZ-loaded PLGA implant (InCeT-TLZ) that sustainedly releases TLZ directly into the peritoneal (i.p.) cavity to treat patient-mimicking BRCA-mutated metastatic ovarian cancer (mOC). Methods: InCeT-TLZ was fabricated by dissolving TLZ and PLGA in chloroform, followed by extrusion and evaporation. Drug loading and release were confirmed by HPLC. The in vivo therapeutic efficacy of InCeT-TLZ was carried out in a murine Brca2-/-p53R172H/-Pten-/- genetically engineered peritoneally mOC model. Mice with tumors were divided into four groups: PBS i.p. injection, empty implant i.p. implantation, TLZ i.p. injection, and InCeT-TLZ i.p. implantation. Body weight was recorded three times weekly as an indicator of treatment tolerance and efficacy. Mice were sacrificed when the body weight increased by 50% of the initial weight. Results: Biodegradable InCeT-TLZ administered intraperitoneally releases 66 µg of TLZ over 25 days. In vivo experimentation shows doubled survival in the InCeT-TLZ treated group compared to control, and no significant signs of toxicity were visible histologically in the surrounding peritoneal organs, indicating that the sustained and local delivery of TLZ greatly maximized therapeutic efficacy and minimized severe clinical side effects. The treated animals eventually developed resistance to PARPi therapy and were sacrificed. To explore treatments to overcome resistance, in vitro studies with TLZ sensitive and resistant ascites-derived murine cell lines were carried out and demonstrated that ATR inhibitor and PI3K inhibitor could be used in combination with the InCeT-TLZ to overcome acquired PARPi resistance. Conclusion: Compared to intraperitoneal PARPi injection, the InCeT-TLZ better inhibits tumor growth, delays the ascites formation, and prolongs the overall survival of treated mice, which could be a promising therapy option that benefits thousands of women diagnosed with ovarian cancer.
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Background: Despite medicinal advances, cancer is still a big problem requiring better diagnostic and treatment tools. Magnetic nanoparticle (MNP)-based nanosystems for multiple-purpose applications were developed for these unmet needs. Methods: This study fabricated novel trifunctional MNPs of Fe3O4@PLA-PEG for drug release, MRI and magnetic fluid hyperthermia. Result: The MNPs provided a significant loading of curcumin (â¼11%) with controllable release ability, a high specific absorption rate of 82.2 W/g and significantly increased transverse relaxivity (r2 = 364.75 mM-1 s-1). The in vivo study confirmed that the MNPs enhanced MRI contrast in tumor observation and low-field magnetic fluid hyperthermia could effectively reduce the tumor size in mice bearing sarcoma 180. Conclusion: The nanocarrier has potential for drug release, cancer treatment monitoring and therapy.
In this study, the authors designed and fabricated novel magnetic trifunctional nanoparticles of Fe3O4@PLA-PEG. The 8.5 nm Fe3O4 core was covered with the polymeric matrix of PLA-PEG to encapsulate an anticancer agent of curcumin at a content of about 11%. Curcumin release from the nanoparticles (NPs) could be controlled by applying a remote alternating magnetic field. The NPs enhanced MRI contrast, which allowed the authors to better distinguish the tumor and surroundings in MR images, which would help monitor treatment. The heat that NPs generated when applied to a field at low intensity could effectively reduce the tumor size in mice bearing sarcoma 180. The nanocarrier, therefore, has potential for cancer treatment monitoring and drug release conjuvant with magnetic hyperthermia therapy.
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Curcumina , Hipertermia Induzida , Nanopartículas de Magnetita , Neoplasias , Animais , Camundongos , Curcumina/farmacologia , Curcumina/uso terapêutico , Nanopartículas de Magnetita/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Imageamento por Ressonância Magnética , Poliésteres , Linhagem Celular TumoralRESUMO
Cancer is the second biggest cause of death in children in the US. With the development of chemotherapy, there has been a substantial increase in the overall survival rate in the last 30 years. However, the overall mortality rate in children with cancer remains 25%, and many survivors experience a decline in overall quality of life and long-term adverse effects caused by treatments. Although cancer cells share common characteristics, pediatric cancers are different from adult cancers in their prevalence, mutation load, and drug response. Therefore, there is an urgent unmet need to develop therapeutic approaches specifically designed for children with cancer. Nanotechnology can potentially overcome the deficiencies of conventional methods of administering chemotherapy and ultimately improve clinical outcomes. The nanoparticle-based drug delivery systems can decrease the toxicity of therapy, provide a sustained or controlled drug release, improve the pharmacokinetic properties of loading contents, and achieve a targeted drug delivery with achievable modifications. Furthermore, therapeutic approaches based on combining nanoformulated drugs with novel immunotherapeutic agents are emerging. In this review, we discussed the recently developed nanotechnology-based strategies for treating blood and solid pediatric cancers.
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Nanoencapsulated drug delivery to solid tumors is a promising approach to overcome pharmacokinetic limitations of therapeutic drugs. However, encapsulation leads to complex drug biodistribution and delivery making analysis of delivery efficacy challenging. As proxies, nanocarrier accumulation or total tumor drug uptake in the tumor are used to evaluate delivery. Yet, these measurements fail to assess delivery of active, released drug to the target, and thus it commonly remains unknown if drug-target occupancy has been achieved. Here, we develop an approach to evaluate the delivery of encapsulated drug to the target, where residual drug target vacancy is measured using a fluorescent drug analog. In vitro measurements reveal that burst release governs drug delivery independent of nanoparticle uptake, and highlight limitations of evaluating nanoencapsulated drug delivery in these models. In vivo, however, our approach captures successful nanoencapsulated delivery, finding that tumor stromal cells drive nanoparticle accumulation and mediate drug delivery to adjacent cancer cells. These results, and generalizable approach, provide a critical advance to evaluate delivery of encapsulated drug to the drug target - the central objective of nanotherapeutics.
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BACKGROUND: Delayed Dark-Adapted vision Recovery (DAR) is a biomarker for Age-related Macular Degeneration (AMD), however its measurement is burdensome for patients and examiners. METHODS: In this study, we developed a portable, wireless and user-friendly system that employs a headset with a smartphone to deliver controlled photo-bleach and monocular pattern reversal stimuli, while using custom electroencephalography (EEG) electrodes and electronics in order to measure Dark-Adapted Visual Evoked Potentials (DAVEP) objectively and separately at the peripheral and central visual field. This is achieved in one comfortable 20-minute session, without requiring subject reporting. DAVEP responses post photo-bleach for up to 15 minutes were measured concurrently from both eyes in 12 AMD-patients, 1 degenerative myopia patient, and 8 controls who had no diagnosed macular vision loss. RESULTS: Robust positive polarity DAVEP responses were observed at 200-500 ms from stimulus onset to scotopic stimuli that have been seldom reported and analyzed previously. The amplitude recovery of the DAVEP response was significantly delayed in AMD patients as compared to controls. We developed DAVEP1 scores, a simple metric for DAR, which classified 90% of subject eyes correctly, indicating the presence of AMD in at least one eye of all pre-confirmed subjects with this diagnosis. CONCLUSION: We developed a user-friendly, portable VEP system and DAVEP1 metric, which show a high potential to identify DAR-deficits in AMD-patients. This novel technology could aid in early diagnosis of AMD.
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Mutations in BRCA genes are the leading cause of hereditary breast cancer. Current options to prevent cancer in these high-risk patients, such as anti-estrogen drugs and radical mastectomy, are limited by lack of efficacy, undesirable toxicities, or physical and emotional challenges. We have previously shown that PARP inhibitors can significantly delay tumor development in BRCA1-deficient mice. Here, we fabricated the PARP inhibitor talazoparib (TLZ) into spacer implants (InCeT-TLZ) for localized and sustained delivery. We hypothesized that this novel formulation will provide an effective chemopreventive strategy with minimal toxicity. TLZ was released gradually over 30 days as implants degraded. InCeT-TLZ significantly decreased proliferation and increased DNA damage in the mammary glands of BRCA1-deficient mice. Notably, the number of mice that developed hyperplasia in the mammary glands was significantly lower with InCeT-TLZ treatment compared to the control group. Meanwhile, InCeT-TLZ was also better tolerated than oral TLZ, without loss of body weight or anemia. This study provides proof of concept for a novel and safe chemopreventive strategy using localized delivery of a PARP inhibitor for high-risk individuals. Future studies will directly evaluate the effects of InCeT-TLZ for preventing tumor development.
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Proteína BRCA1/deficiência , Hiperplasia/metabolismo , Hiperplasia/prevenção & controle , Glândulas Mamárias Animais/efeitos dos fármacos , Ftalazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Animais , Antineoplásicos/farmacologia , Proteína BRCA1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Feminino , Glândulas Mamárias Animais/metabolismo , Camundongos , Mutação/efeitos dos fármacosRESUMO
Demand for undergraduate research experiences typically outstrips the available laboratory positions, which could have been exacerbated during the remote work conditions imposed by the SARS-CoV-2/COVID-19 pandemic. This report presents a collection of examples of how undergraduates have been engaged in research under pandemic work restrictions. Examples include a range of projects related to fluid dynamics, cancer biology, nanomedicine, circadian clocks, metabolic disease, catalysis, and environmental remediation. Adaptations were made that included partnerships between remote and in-person research students and students taking on more data analysis and literature surveys, as well as data mining, computational, and informatics projects. In many cases, these projects engaged students who otherwise would have worked in traditional bench research, as some previously had. Several examples of beneficial experiences are reported, such as the additional time spent studying the literature, which gave students a heightened sense of project ownership, and more opportunities to integrate feedback into writing and research. Additionally, the more intentional and regular communication necessitated by remote work proved beneficial for all team members. Finally, online seminars and conferences have made participation possible for many more students, especially those at predominantly undergraduate institutions. Participants aim to adopt these beneficial practices in our research groups even after pandemic restrictions end.