Potential Risk of Choline Alfoscerate on Isoflurane-Induced Toxicity in Primary Human Astrocytes.

Objective: Isoflurane, a widely used common inhalational anesthetic agent, can induce brain toxicity. The challenge lies in protecting neurologically compromised patients from neurotoxic anesthetics. Choline alfoscerate (L-α-Glycerophosphorylcholine, α-GPC) is recognized for its neuroprotective properties against oxidative stress and inflammation, but its optimal therapeutic window and indications are still under investigation. This study explores the impact of α-GPC on human astrocytes, the most abundant cells in the brain that protect against oxidative stress, under isoflurane exposure. Methods: This study was designed to examine changes in factors related to isoflurane-induced toxicity following α-GPC administration. Primary human astrocytes were pretreated with varying doses of α-GPC (ranging from 0.1 to 10.0 µM) for 24 hours prior to 2.5% isoflurane exposure. In vitro analysis of cell morphology, water-soluble tetrazolium salt-1 assay, quantitative real-time polymerase chain reaction, proteome profiler array, and transcriptome sequencing were conducted. Results: A significant morphological damage to human astrocytes was observed in the group that had been pretreated with 10.0 mM of α-GPC and exposed to 2.5% isoflurane. A decrease in cell viability was identified in the group pretreated with 10.0 µM of α-GPC and exposed to 2.5% isoflurane compared to the group exposed only to 2.5% isoflurane. Quantitative real-time polymerase chain reaction revealed that mRNA expression of heme-oxygenase 1 and hypoxia-inducible factor-1α, which were reduced by isoflurane, was further suppressed by 10.0 µM α-GPC pretreatment. The proteome profiler array demonstrated that α-GPC pretreatment influenced a variety of factors associated with apoptosis induced by oxidative stress. Additionally, transcriptome sequencing identified pathways significantly related to changes in isoflurane-induced toxicity caused by α-GPC pretreatment. Conclusion: The findings suggest that α-GPC pretreatment could potentially enhance the vulnerability of primary human astrocytes to isoflurane-induced toxicity by diminishing the expression of antioxidant factors, potentially leading to amplified cell damage.

Penetrative and Sustained Drug Delivery Using Injectable Hydrogel Nanocomposites for Postsurgical Brain Tumor Treatment.

Postsurgical treatment of glioblastoma multiforme (GBM) by systemic chemotherapy and radiotherapy is often inefficient. Tumor cells infiltrating deeply into the brain parenchyma are significant obstacles to the eradication of GBM. Here, we present a potential solution to this challenge by introducing an injectable thermoresponsive hydrogel nanocomposite. As a liquid solution that contains drug-loaded micelles and water-dispersible ferrimagnetic iron oxide nanocubes (wFIONs), the hydrogel nanocomposite is injected into the resected tumor site after surgery. It promptly gelates at body temperature to serve as a soft, deep intracortical drug reservoir. The drug-loaded micelles target residual GBM cells and deliver drugs with a minimum premature release. Alternating magnetic fields accelerate diffusion through heat generation from wFIONs, enabling penetrative drug delivery. Significantly suppressed tumor growth and improved survival rates are demonstrated in an orthotopic mouse GBM model. Our system proves the potential of the hydrogel nanocomposite platform for postsurgical GBM treatment.

Multiparametric magnetic resonance imaging features of a canine glioblastoma model.

PURPOSE: To assess glioblastoma multiforme (GBM) formation with similar imaging characteristics to human GBM using multiparametric magnetic resonance imaging (MRI) in an orthotopic xenograft canine GBM model. MATERIALS AND METHODS: The canine GBM cell line J3T1 was subcutaneously injected into 6-week-old female BALB/c nude mice to obtain tumour fragments. Tumour fragments were implanted into adult male mongrel dog brains through surgery. Multiparametric MRI was performed with conventional MRI, diffusion-weighted imaging, and dynamic susceptibility contrast-enhanced perfusion-weighted imaging at one week and two weeks after surgery in a total of 15 surgical success cases. The presence of tumour cells, the necrotic area fraction, and the microvessel density (MVD) of the tumour on the histologic specimen were assessed. Tumour volume, diffusion, and perfusion parameters were compared at each time point using Wilcoxon signed-rank tests, and the differences between tumour and normal parenchyma were compared using unpaired t-tests. Spearman correlation analysis was performed between the imaging and histologic parameters. RESULTS: All animals showed a peripheral enhancing lesion on MRI and confirmed the presence of a tumour through histologic analysis (92.3%). The normalized perfusion values did not show significant decreases through at least 2 weeks after the surgery (P > 0.05). There was greater cerebral blood volume and flow in the GBM than in the normal-appearing white matter (1.46 ± 0.25 vs. 1.13 ± 0.16 and 1.30 ± 0.22 vs. 1.02 ± 0.14; P < 0.001 and P < 0.001, respectively). The MVD in the histologic specimens was correlated with the cerebral blood volume in the GBM tissue (r = 0.850, P = 0.004). CONCLUSION: Our results suggest that the canine GBM model showed perfusion imaging characteristics similar to those of humans, and it might have potential as a model to assess novel technical developments for GBM treatment.

Localized Delivery of Theranostic Nanoparticles and High-Energy Photons using Microneedles-on-Bioelectronics.

The low delivery efficiency of light-responsive theranostic nanoparticles (NPs) to target tumor sites, particularly to brain tumors due to the blood-brain barrier, has been a critical issue in NP-based cancer treatments. Furthermore, high-energy photons that can effectively activate theranostic NPs are hardly delivered to the target region due to the strong scattering of such photons while penetrating surrounding tissues. Here, a localized delivery method of theranostic NPs and high-energy photons to the target tumor using microneedles-on-bioelectronics is presented. Two types of microneedles and flexible bioelectronics are integrated and mounted on the edge of surgical forceps. Bioresorbable microneedles containing theranostic NPs deliver the NPs into target tumors (e.g., glioblastoma, pituitary adenoma). Magnetic resonance imaging can locate the NPs. Then, light-guiding/spreading microneedles deliver high-energy photons from bioelectronics to the NPs. The high-energy photons activate the NPs to treat tumor tissues by photodynamic therapy and chemotherapy. The controlled thermal actuation by the bioelectronics accelerates the diffusion of chemo-drugs. The proposed method is demonstrated with mouse tumor models in vivo.

Decreased APE-1 by Nitroxoline Enhances Therapeutic Effect in a Temozolomide-resistant Glioblastoma: Correlation with Diffusion Weighted Imaging.

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor survival rates. The current standard treatment includes chemotherapy with temozolomide (TMZ), but acquisition of resistance is a persistent clinical problem limiting the successful treatment of GBM. The purpose of our study was to investigate therapeutic effects of nitroxoline (NTX) against TMZ-resistant GBM in vitro and in vivo in TMZ-resistant GBM-bearing mouse model, which was correlated with diffusion-weighted imaging (DWI). For in vitro study, we used TMZ-resistant GBM cell lines and evaluated therapeutic effects of NTX by clonogenic and migration assays. Quantitative RT-PCR was used to investigate the expression level of TMZ-resistant genes after NTX treatment. For in vivo study, we performed 9.4 T MR imaging to obtain T2WI for tumor volume measurement and DWI for assessment of apparent diffusion coefficient (ADC) changes by NTX in TMZ-resistant GBM mice (n = 8). Moreover, we performed regression analysis for the relationship between ADC and histological findings, which reflects the changes in cellularity and apurinic/apyrimidinic endonuclease-1 (APE-1) expression. We observed the recovery of TMZ-induced morphological changes, a reduced number of colonies and a decreased rate of migration capacity in TMZ-resistant cells after NTX treatment. The expression of APE-1 was significantly decreased in TMZ-resistant cells after NTX treatment compared with those without treatment. In an in vivo study, NTX reduced tumor growth in TMZ-resistant GBM mice (P = 0.0122). Moreover, ADC was increased in the NTX-treated TMZ-resistant GBM mice compared to the control group (P = 0.0079), which was prior to a tumor volume decrease. The cellularity and APE-1 expression by histology were negatively correlated with the ADC value, which in turn resulted in longer survival in NTX group. The decreased expression of APE-1 by NTX leads to therapeutic effects and is inversely correlated with ADC in TMZ-resistant GBM. Therefore, NTX is suggested as potential therapeutic candidate against TMZ-resistant GBM.

Flexible, sticky, and biodegradable wireless device for drug delivery to brain tumors.

Implantation of biodegradable wafers near the brain surgery site to deliver anti-cancer agents which target residual tumor cells by bypassing the blood-brain barrier has been a promising method for brain tumor treatment. However, further improvement in the prognosis is still necessary. We herein present novel materials and device technologies for drug delivery to brain tumors, i.e., a flexible, sticky, and biodegradable drug-loaded patch integrated with wireless electronics for controlled intracranial drug delivery through mild-thermic actuation. The flexible and bifacially-designed sticky/hydrophobic device allows conformal adhesion on the brain surgery site and provides spatially-controlled and temporarily-extended drug delivery to brain tumors while minimizing unintended drug leakage to the cerebrospinal fluid. Biodegradation of the entire device minimizes potential neurological side-effects. Application of the device to the mouse model confirms tumor volume suppression and improved survival rate. Demonstration in a large animal model (canine model) exhibited its potential for human application.

Increased Antiangiogenic Effect by Blocking CCL2-dependent Macrophages in a Rodent Glioblastoma Model: Correlation Study with Dynamic Susceptibility Contrast Perfusion MRI.

When glioblastoma multiforme (GBM) is treated with anti-vascular endothelial growth factor (VEGF) agents, it commonly exhibits tumor progression due to the development of resistance, which results in a dismal survival rate. GBM tumors contain a large number of monocytes/macrophages, which have been shown to be resistant to the effects of bevacizumab. It has been reported that tumor-associated macrophages (TAMs) promote resistance to bevacizumab treatment. Therefore, it is important to target TAMs in the GBM microenvironment. TAMs, which depend on chemokine ligand 2 (CCL2) for differentiation and survival, induce the expression of proangiogenic factors such as VEGF. Dynamic susceptibility contrast (DSC)-MR imaging is an advanced technique that provides information on tumor blood volume and can potentially predict the response to several treatments, including anti-angiogenic agents such as bevacizumab, in human GBM. In this study, we used a CCL2 inhibitor, mNOX-E36, to suppress the recruitment of TAMs in a CCL2-expressing rat GBM model and investigated the effect of combination therapy with bevacizumab using DSC-MR imaging. We demonstrated that the inhibition of CCL2 blocked macrophage recruitment and angiogenesis, which resulted in decreased tumor volume and blood volume in CCL2-expressing GBM in a rat model. Our results provide direct evidence that CCL2 expression can increase the resistance to bevacizumab, which can be assessed noninvasively with the DSC-MR imaging technique. This study shows that the suppression of CCL2 can play an important role in increasing the efficacy of anti-angiogenic treatment in GBM by inhibiting the recruitment of CCL2-dependent macrophages.

Assessment of Early Therapeutic Response to Nitroxoline in Temozolomide-Resistant Glioblastoma by Amide Proton Transfer Imaging: A Preliminary Comparative Study with Diffusion-weighted Imaging.

Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. In this preliminary study, the purpose was to evaluate the feasibility of APT imaging in monitoring the early therapeutic response to nitroxoline (NTX) in a temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) mouse model, which was compared with diffusion-weighted imaging (DWI). Here, we prepared TMZ-resistant GBM mouse model (n = 12), which were treated with 100 mg/kg/day of NTX (n = 4) or TMZ (n = 4), or saline (n = 4) for 7 days for the evaluation of short-term treatment by using APT imaging and DWI sequentially. The APT signal intensities and apparent diffusion coefficient (ADC) values were calculated and compared before and after treatment. Moreover, immunohistological analysis was also employed for the correlation between APT imaging and histopathology. The association between the APT value and Ki-67 labeling index was evaluated by using simple linear regression analysis. The short-term NTX treatment resulted in significant decrease in APT value as compared to untreated and TMZ group, in which APT signals were increased. However, we did not observe significantly increased mean ADC value following short-term NTX treatment. The Ki-67 labeling index shows a correlation with APT value. APT imaging could show the earlier response to NTX treatment as compared to ADC values in a TMZ-resistant mouse model. We believe that APT imaging can be a useful imaging biomarker for the early therapeutic evaluation in GBM patients.

Modified Rat Hepatocellular Carcinoma Models Overexpressing Vascular Endothelial Growth Factor.

PURPOSE: To compare tumor vascularity in 4 types of rat hepatocellular carcinoma (HCC) models: N1S1, vascular endothelial growth factor (VEGF)-transfected N1S1 (VEGF-N1S1), McA-RH7777, and VEGF-transfected McA-RH7777 (VEGF-McA-RH777) tumors. MATERIALS AND METHODS: The N1S1 and McA-RH7777 cell lines were transfected with expression vectors containing cDNA for rat VEGF. Eighty-eight male Sprague-Dawley rats (weight range, 400-450 g) were randomly divided into 4 groups (ie, 22 rats per model), and 4 types of tumor models were created by using the N1S1, VEGF-N1S1, McA-RH7777, and VEGF-McA-RH777 cell lines. Tumor vascularity was evaluated by perfusion computed tomography (CT), enzyme-linked immunosorbent assay of VEGF, CD34 staining, angiography, and Lipiodol transarterial embolization. Intergroup discrepancies were evaluated by Kruskal-Wallis test. RESULTS: Arterial perfusion (P < .001), portal perfusion (P = .015), total perfusion (P < .001), tumor VEGF level (P = .002), and microvessel density (MVD; P = .007) were significantly different among groups. VEGF-McA-RH7777 tumors showed the greatest arterial perfusion (46.7 mL/min/100 mL ± 15.5), total perfusion (60.7 mL/min/100 mL ± 21.8), tumor VEGF level (3,376.7 pg/mL ± 145.8), and MVD (34.5‰ ± 7.5). Whereas most tumors in the N1S1, VEGF-N1S1, and McA-RH7777 groups showed hypovascular staining on angiography and minimal Lipiodol uptake after embolization, 5 of 6 VEGF-McA-RH7777 tumors (83.3%) presented hypervascular tumor staining and moderate to compact Lipiodol uptake. CONCLUSIONS: McA-RH7777 tumors were more hypervascular than N1S1 tumors, and tumor vascularity was enhanced further by VEGF transfection. Therefore, the VEGF-McA-RH7777 tumor is recommended to mimic hypervascular human HCC in rats.

Radiogenomics Profiling for Glioblastoma-related Immune Cells Reveals CD49d Expression Correlation with MRI parameters and Prognosis.

Although there have been a plethora of radiogenomics studies related to glioblastoma (GBM), most of them only used genomic information from tumor cells. In this study, we used radiogenomics profiling to identify MRI-associated immune cell markers in GBM, which was also correlated with prognosis. Expression levels of immune cell markers were correlated with quantitative MRI parameters in a total of 60 GBM patients. Fourteen immune cell markers (i.e., CD11b, CD68, CSF1R, CD163, CD33, CD123, CD83, CD63, CD49d and CD117 for myeloid cells, and CD4, CD3e, CD25 and CD8 for lymphoid cells) were selected for RNA-level analysis using quantitative RT-PCR. For MRI analysis, quantitative MRI parameters from FLAIR, contrast-enhanced (CE) T1WI, dynamic susceptibility contrast perfusion MRI and diffusion-weighted images were used. In addition, PFS associated with interesting mRNA data was performed by Kaplan-Meier survival analysis. CD163, which marks tumor associated microglia/macrophages (TAMs), showed the highest expression level in GBM patients. CD68 (TAMs), CSF1R (TAMs), CD33 (myeloid-derived suppressor cell) and CD4 (helper T cell, regulatory T cell) levels were highly positively correlated with nCBV values, while CD3e (helper T cell, cytotoxic T cell) and CD49d showed a significantly negative correlation with apparent diffusion coefficient (ADC) values. Moreover, regardless of any other molecular characteristics, CD49d was revealed as one independent factor for PFS of GBM patients by Cox proportional-hazards regression analysis (P = 0.0002). CD49d expression level CD49d correlated with ADC can be considered as a candidate biomarker to predict progression of GBM patients.

BCAT1 is a New MR Imaging-related Biomarker for Prognosis Prediction in IDH1-wildtype Glioblastoma Patients.

Isocitrate dehydrogenase 1 (IDH1)-wildtype glioblastoma (GBM) has found to be accompanied with increased expression of branched-chain amino acid trasaminase1 (BCAT1), which is associated with tumor growth and disease progression. In this retrospective study, quantitative RT-PCR, immunohistochemistry, and western blot were performed with GBM patient tissues to evaluate the BCAT1 level. Quantitative MR imaging parameters were evaluated from DSC perfusion imaging, DWI, contrast-enhanced T1WI and FLAIR imaging using a 3T MR scanner. The level of BCAT1 was significantly higher in IDH1-wildtype patients than in IDH1-mutant patients obtained in immunohistochemistry and western blot. The BCAT1 level was significantly correlated with the mean and 95th percentile-normalized CBV as well as the mean ADC based on FLAIR images. In addition, the 95th percentile-normalized CBV from CE T1WI also had a significant correlation with the BCAT1 level. Moreover, the median PFS in patients with BCAT1 expression <100 was longer than in those with BCAT1 expression ≥100. Taken together, we found that a high BCAT1 level is correlated with high CBV and a low ADC value as well as the poor prognosis of BCAT1 expression is related to the aggressive nature of GBM.

Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma.

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is now a widely-used modality for glioblastoma (GBM) treatment. However, intratumoral heterogeneity of fluorescence intensity may reflect different onco-metabolic programs. Here, we investigated the metabolic mechanism underlying the heterogeneity of 5-ALA fluorescence in GBM. Using an in-house developed fluorescence quantification system for tumor tissues, we collected 3 types of GBM tissues on the basis of their fluorescence intensity, which was characterized as strong, weak, and none. Expression profiling by RNA-sequencing revealed 77 genes with a proportional relationship and 509 genes with an inverse relationship between gene expression and fluorescence intensity. Functional analysis and in vitro experiments confirmed glutaminase 2 (GLS2) as a key gene associated with the fluorescence heterogeneity. Subsequent metabolite profiling discovered that insufficient NADPH due to GLS2 underexpression was responsible for the delayed metabolism of 5-ALA and accumulation of protoporphyrin IX (PpIX) in the high fluorescence area. The expression level of GLS2 and related NADPH production capacity is associated with the regional heterogeneity of 5-ALA fluorescence in GBM.

Continuous O2-Evolving MnFe2O4 Nanoparticle-Anchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer.

Therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O2 concentration. Herein, we design biocompatible manganese ferrite nanoparticle-anchored mesoporous silica nanoparticles (MFMSNs) to overcome hypoxia, consequently enhancing the therapeutic efficiency of PDT. By exploiting the continuous O2-evolving property of MnFe2O4 nanoparticles through the Fenton reaction, MFMSNs relieve hypoxic condition using a small amount of nanoparticles and improve therapeutic outcomes of PDT for tumors in vivo. In addition, MFMSNs exhibit T2 contrast effect in magnetic resonance imaging (MRI), allowing in vivo tracking of MFMSNs. These findings demonstrate great potential of MFMSNs for theranostic agents in cancer therapy.

Multifunctional nanoparticles as a tissue adhesive and an injectable marker for image-guided procedures.

Tissue adhesives have emerged as an alternative to sutures and staples for wound closure and reconnection of injured tissues after surgery or trauma. Owing to their convenience and effectiveness, these adhesives have received growing attention particularly in minimally invasive procedures. For safe and accurate applications, tissue adhesives should be detectable via clinical imaging modalities and be highly biocompatible for intracorporeal procedures. However, few adhesives meet all these requirements. Herein, we show that biocompatible tantalum oxide/silica core/shell nanoparticles (TSNs) exhibit not only high contrast effects for real-time imaging but also strong adhesive properties. Furthermore, the biocompatible TSNs cause much less cellular toxicity and less inflammation than a clinically used, imageable tissue adhesive (that is, a mixture of cyanoacrylate and Lipiodol). Because of their multifunctional imaging and adhesive property, the TSNs are successfully applied as a hemostatic adhesive for minimally invasive procedures and as an immobilized marker for image-guided procedures.

Sorafenib and 2,3,5-triiodobenzoic acid-loaded imageable microspheres for transarterial embolization of a liver tumor.

Sorafenib (SOF; an angiogenesis inhibitor) and 2,3,5-triiodobenzoic acid (TIBA; a contrast agent for computed tomography imaging)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres (MSs) were fabricated. Embolization, drug delivery, and tracing the distribution of MSs for liver cancer therapy were accomplished with the developed MSs after their intra-arterial (IA) administration. SOF/TIBA/PLGA MSs with 24.8-28.5 µm mean diameters were prepared, and the sustained release of SOF from MSs was observed. Lower systemic exposure (represented as the area under the curve [AUC]) and maximum drug concentration in plasma (Cmax) values of the SOF/TIBA/PLGA MSs group (IA administration, 1 mg/kg) in the results of the pharmacokinetic study imply alleviated unwanted systemic effects (e.g., hand and foot syndrome), compared to the SOF solution group (oral administration, 10 mg/kg). In a rat hepatoma model, the increase of microvessel density (MVD) following arterial embolization (i.e., reactive angiogenesis) was partially limited by SOF/TIBA/PLGA MSs. This resulted in the SOF/TIBA/PLGA MSs group (IA administration, single dosing, 1 mg/kg) showing a smaller tumor size increase and viable tumor portion compared to the TIBA/PLGA MSs group. These findings suggest that a developed SOF/TIBA/PLGA MS can be a promising therapeutic system for liver cancer using a transarterial embolization strategy.

Wearable/disposable sweat-based glucose monitoring device with multistage transdermal drug delivery module.

Electrochemical analysis of sweat using soft bioelectronics on human skin provides a new route for noninvasive glucose monitoring without painful blood collection. However, sweat-based glucose sensing still faces many challenges, such as difficulty in sweat collection, activity variation of glucose oxidase due to lactic acid secretion and ambient temperature changes, and delamination of the enzyme when exposed to mechanical friction and skin deformation. Precise point-of-care therapy in response to the measured glucose levels is still very challenging. We present a wearable/disposable sweat-based glucose monitoring device integrated with a feedback transdermal drug delivery module. Careful multilayer patch design and miniaturization of sensors increase the efficiency of the sweat collection and sensing process. Multimodal glucose sensing, as well as its real-time correction based on pH, temperature, and humidity measurements, maximizes the accuracy of the sensing. The minimal layout design of the same sensors also enables a strip-type disposable device. Drugs for the feedback transdermal therapy are loaded on two different temperature-responsive phase change nanoparticles. These nanoparticles are embedded in hyaluronic acid hydrogel microneedles, which are additionally coated with phase change materials. This enables multistage, spatially patterned, and precisely controlled drug release in response to the patient's glucose level. The system provides a novel closed-loop solution for the noninvasive sweat-based management of diabetes mellitus.

Assessment of bevacizumab resistance increased by expression of BCAT1 in IDH1 wild-type glioblastoma: application of DSC perfusion MR imaging.

BCAT1 (branched-chain amino acid trasaminase1) expression is necessary for the progression of IDH1 wild-type (WT) glioblastoma multiforme (GBM), which is known to be associated with aggressive tumors. The purpose of our study is to investigate the bevacizumab resistance increased by the expression of BCAT1 in IDH1 WT GBM in a rat model, which was evaluated using DSC perfusion MRI. BCAT1 sh#1 inhibits cell proliferation and limits cell migration potential in vitro. In vivo MRI showed that the increase in both tumor volume and nCBV after bevacizumab treatment in IDH1 WT tumors was significantly higher compared with BCAT1 sh#1tumors. In a histological analysis, more micro-vessel reformation by bevacizumab resistance was observed in IDH1 WT tumors than BCAT1 sh#1 tumors. These findings indicate that BCAT1 expression in IDH1 WT GBM increases resistance to bevacizumab treatment, which could be assessed by DSC perfusion MRI, and that nCBV can be a surrogate imaging biomarker for the prediction of antiangiogenic treatment in GBM.

Metabolomic analysis of percutaneous fine-needle aspiration specimens of thyroid nodules: Potential application for the preoperative diagnosis of thyroid cancer.

Thyroid nodules are a very common problem. Since malignant thyroid nodules should be treated surgically, preoperative diagnosis of thyroid cancer is very crucial. Cytopathologic analysis of percutaneous fine-needle aspiration (FNA) specimens is the current gold standard for diagnosing thyroid nodules. However, this method has led to high rates of inconclusive results. Metabolomics has emerged as a useful tool in medical fields and shown great potential in diagnosing various cancers. Here, we evaluated the potential of nuclear magnetic resonance (NMR) analysis of percutaneous FNA specimens for preoperative diagnosis of thyroid cancer. We analyzed metabolome of FNA samples of papillary thyroid carcinoma (n = 35) and benign follicular nodule (n = 69) using a proton NMR spectrometer. The metabolomic profiles showed a considerable discrimination between benign and malignant nodules. Receiver operating characteristic (ROC) curve analysis indicated that seven metabolites could serve as discriminators (area under ROC curve value, 0.64-0.85). These findings demonstrated that NMR analysis of percutaneous FNA specimens of thyroid nodules can be potentially useful in the accurate and rapid preoperative diagnosis of thyroid cancer.

Electromechanical cardioplasty using a wrapped elasto-conductive epicardial mesh.

Heart failure remains a major public health concern with a 5-year mortality rate higher than that of most cancers. Myocardial disease in heart failure is frequently accompanied by impairment of the specialized electrical conduction system and myocardium. We introduce an epicardial mesh made of electrically conductive and mechanically elastic material, to resemble the innate cardiac tissue and confer cardiac conduction system function, to enable electromechanical cardioplasty. Our epicardium-like substrate mechanically integrated with the heart and acted as a structural element of cardiac chambers. The epicardial device was designed with elastic properties nearly identical to the epicardial tissue itself and was able to detect electrical signals reliably on the moving rat heart without impeding diastolic function 8 weeks after induced myocardial infarction. Synchronized electrical stimulation over the ventricles by the epicardial mesh with the high conductivity of 11,210 S/cm shortened total ventricular activation time, reduced inherent wall stress, and improved several measures of systolic function including increases of 51% in fractional shortening, ~90% in radial strain, and 42% in contractility. The epicardial mesh was also capable of delivering an electrical shock to terminate a ventricular tachyarrhythmia in rodents. Electromechanical cardioplasty using an epicardial mesh is a new pathway toward reconstruction of the cardiac tissue and its specialized functions.

A graphene-based electrochemical device with thermoresponsive microneedles for diabetes monitoring and therapy.

Owing to its high carrier mobility, conductivity, flexibility and optical transparency, graphene is a versatile material in micro- and macroelectronics. However, the low density of electrochemically active defects in graphene synthesized by chemical vapour deposition limits its application in biosensing. Here, we show that graphene doped with gold and combined with a gold mesh has improved electrochemical activity over bare graphene, sufficient to form a wearable patch for sweat-based diabetes monitoring and feedback therapy. The stretchable device features a serpentine bilayer of gold mesh and gold-doped graphene that forms an efficient electrochemical interface for the stable transfer of electrical signals. The patch consists of a heater, temperature, humidity, glucose and pH sensors and polymeric microneedles that can be thermally activated to deliver drugs transcutaneously. We show that the patch can be thermally actuated to deliver Metformin and reduce blood glucose levels in diabetic mice.