Feasibility Study of Single-Photon Emission Computed Tomography with Iodine-123 Labeled Metaiodobenzylguanidine for Preclinical Evaluation of Labetalol as a ß-Adrenergic Receptor Blocker.

Among clinically used radiopharmaceuticals, iodine-123 labeled metaiodobenzylguanidine ([123I]mIBG) serves for diagnosing neuroendocrine tumors and obtaining images of myocardial sympathetic innervation. mIBG, a structural analogue of norepinephrine (NE), a neurotransmitter acting in peripheral and central nerves, follows a pathway similar to NE, transmitting signals through the NE transporter (NET) located at synaptic terminals. It moves through the body without decomposing, enabling noninvasive image evaluation. In this study, we aimed to quantify [123I]mIBG uptake in the adrenal glands using small animal single-photon emission computed tomography/computed tomography (SPECT/CT) images post [123I]mIBG administration. We investigated the possibility of assessing the effectiveness of ß-adrenergic receptor blockers by quantifying SPECT/CT images and biodistribution results to determine the degree of [123I]mIBG uptake in the adrenal glands treated with labetalol, a known ß-adrenergic receptor blocker. Upon intravenous administration of [123I]mIBG to mice, SPECT/CT images were acquired over time to confirm the in vivo distribution pattern, revealing a clear uptake in the adrenal glands. Labetalol inhibited the uptake of [123I]mIBG in cell lines expressing NET. A decrease in [123I]mIBG uptake in the adrenal glands was observed in the labetalol-treated group compared with the normal group through SPECT/CT imaging and biodistribution studies. These results demonstrate that SPECT/CT imaging with [123I]mIBG could be applicable for evaluating the preclinical efficacy of new antihypertensive drug candidates such as labetalol, a ß-adrenergic receptor blocker.

A Novel Tactile Sensing System Utilizing Magnetorheological Structures for Dynamic Contraction and Relaxation Motions.

It is well known that the rheological properties of magnetorheological (MR) material change under a magnetic field. So far, most works on MR materials have been oriented toward actuating characteristics instead of sensing functions. In this work, to realize dynamic tactile motion, a spherical MR structure was designed as a sensor, incorporating a magnetic circuit core to provide maximum dynamic motion. After manufacturing a prototype (sample), a sinusoidal magnetic field of varying exciting frequency and magnitude was applied to the sample, and the dynamic contraction and relaxation motion depending on the exciting magnetic field was observed. Among the test results, when 10% deformation occurred, the instantaneous force generated was from 2.8 N to 8.8 N, and the force when relaxed was from 1.2 N to 3.5 N. It is also shown that the repulsive force within this range can be implemented using an acceptable input current. The special tactile sensing structure proposed in this work can be used as a sensor to measure the field-dependent viscoelastic properties of human tissues such as stomach, liver, and overall body. In addition, it could be usefully applied to robot surgery, because it can mimic the dynamic motions of various human organs under various surgical conditions.

Half-Bridge Silicon Strain Gauges with Arc-Shaped Piezoresistors.

Half-bridge silicon strain gauges are widely used in the fabrication of diaphragm-type high-pressure sensors, but in some applications, they suffer from low output sensitivity because of mounting position constraints. Through a special design and fabrication approach, a new half-bridge silicon strain gauge comprising one arc gauge responding to tangential strain and another linear gauge measuring radial strain was developed using Silicon-on-Glass (SiOG) substrate technology. The tangential gauge consists of grid patterns, such as the reciprocating arc of silicon piezoresistors on a thin glass substrate. When two half-bridges are connected to form a full bridge with arc-shaped gauges that respond to tangential strain, they have the advantage of providing much higher output sensitivity than a conventional half-bridge. Pressure sensors tested under pressure ranging from 0 to 50 bar at five different temperatures indicate a linear output with a typical sensitivity of approximately 16 mV/V/bar, a maximum zero shift of 0.05% FS, and a span shift of 0.03% FS. The higher output level of pressure sensing gauges will provide greater signal strength, thus maintaining a better signal-to-noise ratio than conventional pressure sensors. The offset and span shift curves are quite linear across the operating temperature range, giving the end user the advantage of using very simple algorithms for temperature compensation of offset and span shift.

Intracellular energy production and distribution in hypoxia.

The hydrolysis of ATP is the primary source of metabolic energy for eukaryotic cells. Under physiological conditions, cells generally produce more than sufficient levels of ATP to fuel the active biological processes necessary to maintain homeostasis. However, mechanisms underpinning the distribution of ATP to subcellular microenvironments with high local demand remain poorly understood. Intracellular distribution of ATP in normal physiological conditions has been proposed to rely on passive diffusion across concentration gradients generated by ATP producing systems such as the mitochondria and the glycolytic pathway. However, subcellular microenvironments can develop with ATP deficiency due to increases in local ATP consumption. Alternatively, ATP production can be reduced during bioenergetic stress during hypoxia. Mammalian cells therefore need to have the capacity to alter their metabolism and energy distribution strategies to compensate for local ATP deficits while also controlling ATP production. It is highly likely that satisfying the bioenergetic requirements of the cell involves the regulated distribution of ATP producing systems to areas of high ATP demand within the cell. Recently, the distribution (both spatially and temporally) of ATP-producing systems has become an area of intense investigation. Here, we review what is known (and unknown) about intracellular energy production and distribution and explore potential mechanisms through which this targeted distribution can be altered in hypoxia, with the aim of stimulating investigation in this important, yet poorly understood field of research.

A Cylindrical Grip Type of Tactile Device Using Magneto-Responsive Materials Integrated with Surgical Robot Console: Design and Analysis.

This paper proposes a cylindrical grip type of tactile device that is effectively integrated to a surgical robot console so that a surgeon can easily touch and feel the same stiffness as the operating organs. This is possible since the yield stress (or stiffness) of magnetic-responsive materials can be tuned or controlled by the magnetic field intensity. The proposed tactile device consists of two main parts: a magnetorheological elastomer (MRE) layer and a magnetorheological fluid (MRF) core. The grip shape of the device to be positioned on the handle part of the master of the surgical robot is configured and its operating principle is discussed. Then, a couple of equations to calculate the stiffness from the gripping force and the field-dependent yield stress of MRF are derived and integrated using the finite element analysis (FEA) model. After simulating the stiffness of the proposed tactile device as a function of the magnetic field intensity (or current), the stiffnesses of various human organs, including the liver and heart, are calculated from known data of an elastic modulus. It is demonstrated from comparative data between calculated stiffness from human tissues and simulated stiffness from FEA that the proposed tactile device can generate sufficient stiffness with a low current level to recognize various human organs which are significantly required in the surgical robot system.

Three-dimensional Angiogenesis Assay System using Co-culture Spheroids Formed by Endothelial Colony Forming Cells and Mesenchymal Stem Cells.

Studies in the field of angiogenesis have been aggressively growing in the last few decades with the recognition that angiogenesis is a hallmark of more than 50 different pathological conditions, such as rheumatoid arthritis, oculopathy, cardiovascular diseases, and tumor metastasis. During angiogenesis drug development, it is crucial to use in vitro assay systems with appropriate cell types and proper conditions to reflect the physiologic angiogenesis process. To overcome limitations of current in vitro angiogenesis assay systems using mainly endothelial cells, we developed a 3-dimensional (3D) co-culture spheroid sprouting assay system. Co-culture spheroids were produced by two human vascular cell precursors, endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs) with a ratio of 5 to 1. ECFCs+MSCs spheroids were embedded into type I collagen matrix to mimic the in vivo extracellular environment. A real-time cell recorder was utilized to continuously observe the progression of angiogenic sprouting from spheroids for 24 h. Live cell fluorescent labeling technique was also applied to tract the localization of each cell type during sprout formation. Angiogenic potential was quantified by counting the number of sprouts and measuring the cumulative length of sprouts generated from the individual spheroids. Five randomly-selected spheroids were analyzed per experimental group. Comparison experiments demonstrated that ECFCs+MSCs spheroids showed greater sprout number and cumulative sprout length compared with ECFCs-only spheroids. Bevacizumab, an FDA-approved angiogenesis inhibitor, was tested with the newly-developed co-culture spheroid assay system to verify its potential to screen anti-angiogenic drugs. The IC50 value for ECFCs+MSCs spheroids compared to the ECFCs-only spheroids was closer to the effective plasma concentration of bevacizumab obtained from the xenograft tumor mouse model. The present study suggests that the 3D ECFCs+MSCs spheroid angiogenesis assay system is relevant to physiologic angiogenesis, and can predict an effective plasma concentration in advance of animal experiments.

Auranofin, an Anti-rheumatic Gold Drug, Aggravates the Radiation-Induced Acute Intestinal Injury in Mice.

Pelvic and abdominal radiotherapy plays an important role in eradication of malignant cells; however, it also results in slight intestinal injury. The apoptosis of cells in the intestinal epithelium is a primary pathological factor that initiates radiation-induced intestinal injury. Auranofin, a gold-containing triethylphosphine, was approved for the treatment of rheumatoid arthritis, and its therapeutic application has been expanded to a number of other diseases, such as parasitic infections, neurodegenerative disorders, AIDS, and bacterial infections. Recently, a treatment strategy combining the use of auranofin and ionizing radiation aimed at increasing the radiosensitivity of cancer cells was proposed for improving the control of local cancers. In this study, we evaluated the effect of auranofin on the radiosensitivity of intestinal epithelial cells. The treatment with a combination of 1 µM auranofin and 5 Gy ionizing radiation showed clear additive effects on caspase 3 cleavage and apoptotic DNA fragmentation in IEC-6 cells, and auranofin administration significantly aggravated the radiation-induced intestinal injury in mice. Auranofin treatment also resulted in the activation of the unfolded protein response and in the inhibition of thioredoxin reductase, which is a key component of the cellular antioxidant system. Pre-treatment with N-acetyl cysteine, a well-known scavenger of reactive oxygen species, but not with a chemical chaperone, which inhibits endoplasmic reticulum stress and the ensuing unfolded protein response, significantly reduced the radiosensitizing effects of auranofin in the IEC-6 cells. In addition, transfection of IEC-6 cells with a small interfering RNA targeted against thioredoxin reductase significantly enhanced the radiosensitivity of these cells. These results suggest that auranofin-induced radiosensitization of intestinal epithelial cells is mediated through oxidative stress caused by the deregulation of thioredoxin redox system, and auranofin treatment can be an independent risk factor for the development of acute pelvic radiation disease.

Quadrilateral Micro-Hole Array Machining on Invar Thin Film: Wet Etching and Electrochemical Fusion Machining.

Ultra-precision products which contain a micro-hole array have recently shown remarkable demand growth in many fields, especially in the semiconductor and display industries. Photoresist etching and electrochemical machining are widely known as precision methods for machining micro-holes with no residual stress and lower surface roughness on the fabricated products. The Invar shadow masks used for organic light-emitting diodes (OLEDs) contain numerous micro-holes and are currently machined by a photoresist etching method. However, this method has several problems, such as uncontrollable hole machining accuracy, non-etched areas, and overcutting. To solve these problems, a machining method that combines photoresist etching and electrochemical machining can be applied. In this study, negative photoresist with a quadrilateral hole array pattern was dry coated onto 30-µm-thick Invar thin film, and then exposure and development were carried out. After that, photoresist single-side wet etching and a fusion method of wet etching-electrochemical machining were used to machine micro-holes on the Invar. The hole machining geometry, surface quality, and overcutting characteristics of the methods were studied. Wet etching and electrochemical fusion machining can improve the accuracy and surface quality. The overcutting phenomenon can also be controlled by the fusion machining. Experimental results show that the proposed method is promising for the fabrication of Invar film shadow masks.

[18F]FET PET is a useful tool for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic glioblastoma mouse model.

O-2-18F-fluoroethyl-l-tyrosine ([18F]FET) has been widely used for glioblastomas (GBM) in clinical practice, although evaluation of its applicability in non-clinical research is still lacking. The objective of this study was to examine the value of [18F]FET for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic mouse model of GBM. Human U87MG cells were implanted into nude mice and then bevacizumab, a representative anti-angiogenic drug, was administered. We monitored the effect of anti-angiogenic agents using multiple imaging modalities, including bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT). Among these imaging methods analyzed, only [18F]FET uptake showed a statistically significant decrease in the treatment group compared to the control group (P=0.02 and P=0.03 at 5 and 20 mg/kg, respectively). This indicates that [18F]FET PET is a sensitive method to monitor the response of GBM bearing mice to anti-angiogenic drug. Moreover, [18F]FET uptake was confirmed to be a significant parameter for predicting the prognosis of anti-angiogenic drug (P=0.041 and P=0.007, on Days 7 and 12, respectively, on Pearson's correlation; P=0.048 and P=0.030, on Days 7 and 12, respectively, on Cox regression analysis). However, results of BLI or MRI were not significantly associated with survival time. In conclusion, this study suggests that [18F]FET PET imaging is a pertinent imaging modality for sensitive monitoring and accurate prediction of treatment response to anti-angiogenic agents in an orthotopic model of GBM.

Chemical chaperones reduce ionizing radiation-induced endoplasmic reticulum stress and cell death in IEC-6 cells.

Radiotherapy, which is one of the most effective approaches to the treatment of various cancers, plays an important role in malignant cell eradication in the pelvic area and abdomen. However, it also generates some degree of intestinal injury. Apoptosis in the intestinal epithelium is the primary pathological factor that initiates radiation-induced intestinal injury, but the mechanism by which ionizing radiation (IR) induces apoptosis in the intestinal epithelium is not clearly understood. Recently, IR has been shown to induce endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) signaling pathway in intestinal epithelial cells. However, the consequences of the IR-induced activation of the UPR signaling pathway on radiosensitivity in intestinal epithelial cells remain to be determined. In this study, we investigated the role of ER stress responses in IR-induced intestinal epithelial cell death. We show that chemical ER stress inducers, such as tunicamycin or thapsigargin, enhanced IR-induced caspase 3 activation and DNA fragmentation in intestinal epithelial cells. Knockdown of Xbp1 or Atf6 with small interfering RNA inhibited IR-induced caspase 3 activation. Treatment with chemical chaperones prevented ER stress and subsequent apoptosis in IR-exposed intestinal epithelial cells. Our results suggest a pro-apoptotic role of ER stress in IR-exposed intestinal epithelial cells. Furthermore, inhibiting ER stress may be an effective strategy to prevent IR-induced intestinal injury.

Intraarterial mechanical thrombectomy for the treatment of postoperative cerebral infarction: a case report.

Perioperative ischemic stroke is an uncommon event associated with significant morbidity and mortality. The complexity of the surgical procedure and surgery induced hypercoagulable status also influence the incidence of stroke. The management of stroke involves a decision regarding the quickest suitable revascularization method. Endovascular mechanical thrombectomy, such as intra-arterial mechanical thrombectomy (IAMT), can restore vascular patency of the vessels, providing an alternative or synergistic method to restore blood flow. Although, there are no recommended treatment guidelines, IAMT is eligible to be a treatment of choice for perioperative ischemic stroke. We experienced a case of a patient who demonstrated hemiplegia and aphasia, the early symptom of acute ischemic stroke, in the post-anesthesia care unit and performed IAMT successfully. Thus we report the case with a review of the relevant literature.

Inhibition of STAT3 reverses drug resistance acquired in temozolomide-resistant human glioma cells.

The alkylating agent temozolomide (TMZ) is an effective drug used for the treatment of malignant gliomas. However, tumor relapse combined with the development of drug resistance remains a significant problem. To clarify the mechanism of the resistance of glioma cells to TMZ chemotherapy, TMZ-resistant glioma cell lines (TR cells) were generated using U373 and U251 human glioma cells, and TMZ-resistance was confirmed via viability and apoptosis assays. The TMZ-resistance of TR cells was not associated with the TMZ-resistance molecule O(6)-methylguanine-DNA-methyltransferase. Notably, the expression level of signal transducers and activators of transcription 3 (STAT3) and serine 727-phosphorylated STAT3 (pSTAT3-Ser727) was highly increased in TR cells, while that of 705-phosphorylated STAT3 (pSTAT3-Tyr705) was decreased. The inhibition of STAT3 expression by small interfering RNA enhanced TR cell TMZ sensitivity. These results suggest that STAT3 contributes to TMZ-resistance in gliomas and is a potential target for the reversal of TMZ-resistance in patients with a recurrent glioma.

Metronomic treatment of temozolomide increases anti-angiogenicity accompanied by down-regulated O(6)-methylguanine-DNA methyltransferase expression in endothelial cells.

Metronomic chemotherapy is a continuous low-dose administration of chemotherapeutic agents to minimize toxicity and target tumor-associated endothelial cells. This therapy is beneficial to anti-angiogenic efficacy which is linked to the inhibition of tumor growth. In the present study, we compared the anti-angiogenicity of temozolomide in human umbilical vein endothelial cells (HUVECs) between conventional and metronomic treatment. Metronomic treatment of temozolomide (TMZ) (6.25 and 12.5 µM) showed increased inhibition of the proliferation of HUVECs compared to an equivalent conventional treatment of TMZ. The differential effects between conventional and metronomic treatment of TMZ were also noted in cell migration and angiogenic tube formation. Notably, the expression level of O(6)-methylguanine-DNA methyltransferase (MGMT) was markedly reduced in the HUVECs treated with metronomic TMZ (12.5 and 25 µM) compared to cells treated with conventional treatment of TMZ. Accordingly, HUVECs treated with metronomic treatment of TMZ were more sensitive to TMZ treatment. Taken together, metronomic chemotherapy with TMZ enhances the inhibition of angiogenesis accompanied by the down-regulation of MGMT expression in endothelial cells when compared to conventional chemotherapy.

Anthropometric analysis of waist-to-hip ratio in Asian women.

BACKGROUND: The universally accepted attractive female figure has a waist-to-hip ratio (WHR) of 0.7 or 0.68 (WHR of the Venus de Milo). Using WHR and other parameters, the authors attempted to investigate chronologic changes in perceptions of the attractive female figure in Korean society, differences between Asian and Western societies in this respect, and changes in attractiveness with respect to body mass index (BMI) and age in the general female Korean population. METHODS: The authors analyzed the anthropometric measurements of 227 Miss Korea winners between 1971 and 2007, 60 candidates of the 2007 Miss Korea contest, 36 candidates of the 2007 Miss France contest, and 1785 normal women in the general population. RESULTS: In the Miss Korea winners' group, the WHR tended toward 0.7. The WHR of the 2007 Miss Korea candidates was statistically smaller than the WHR of the 2007 Miss France candidates. The WHR of normal women was statistically larger than WHR of the 2000s Miss Korea winners. In all age groups of normal women, subjects with a low BMI were not significantly different from the 2000s Miss Koreas in terms of waist circumference, but they had a relatively larger hip circumference. Moreover, subjects with a normal BMI had waist circumferences that were similar to those of the 2000s Miss Koreas but relatively larger hip circumferences, and subjects with high BMI had larger waist and hip circumferences than the 2000s Miss Koreas. CONCLUSION: The perceived attractive female figure in Asia has moved toward the universally accepted ideal WHR. However, there were still some differences between Asian and Western societies in the concept of ideal body figure. Also, a significant difference in body contour was observed between normal women and the ideal figure. This is because hip volume decreases and waist volume increases with age, although waist and hip volumes increase with BMI.