Complement regulatory protein CD46 promotes bladder cancer metastasis through activation of MMP9.

CD46, a transmembrane protein known for protecting cells from complement­mediated damage, is frequently dysregulated in various types of cancer. Its overexpression in bladder cancers safeguards the cancer cells against both complement and antibody­mediated cytotoxicity. The present study explored a new role of CD46 in facilitating cancer cell invasion and metastasis, examining its regulatory effect on matrix metalloproteases (MMPs) and their effect on the metastatic capability of bladder cancer cells. Specifically, CD46 alteration positively influenced MMP9 expression, but not MMP2, in several bladder cancer cell lines. Furthermore, CD46 overexpression triggered phosphorylation of p38 MAPK and protein kinase B (AKT), leading to enhanced activator protein 1 (AP­1) activity via c­Jun upregulation. The inhibition of p38 or AKT pathways attenuated the CD46­induced MMP9 and AP­1 upregulation, indicating that the promotion of MMP9 by CD46 involved activating both p38 MAPK and AKT. Functionally, the upregulation of MMP9 by CD46 translated to increased migratory and invasive capabilities of bladder cancer cells, as well as enhanced in vivo metastasis. Overall, the present study revealed a novel role for CD46 as a metastasis promoter through MMP9 activation in bladder cancers and highlighted the regulatory mechanism of CD46­mediated MMP9 promotion via p38 MAPK and AKT activation.

From Diagnosis to Treatment: Recent Advances in Patient-Friendly Biosensors and Implantable Devices.

Patient-friendly medical diagnostics and treatments have been receiving a great deal of interest due to their rapid and cost-effective health care applications with minimized risk of infection, which has the potential to replace conventional hospital-based medical procedures. In particular, the integration of recently developed materials into health care devices allows the rapid development of point-of-care (POC) sensing platforms and implantable devices with special functionalities. In this review, the recent advances in biosensors for patient-friendly diagnosis and implantable devices for patient-friendly treatment are discussed. Comprehensive analysis of portable and wearable biosensing platforms for patient-friendly health monitoring and disease diagnosis is provided, including topics such as materials selection, device structure and integration, and biomarker detection strategies. Moreover, specific challenges related to each biological fluid for wearable biosensor-based POC applications are presented. Also, advances in implantable devices, including recent materials development and wireless communication strategies, are discussed. Furthermore, various patient-friendly surgical and treatment approaches are reviewed, such as minimally invasive insertion and mounting, in vivo electrical and optical modulations, and post-operation health monitoring. Finally, the challenges and future perspectives toward the development of the patient-friendly diagnosis and treatment are provided.

Parallel Signal Processing of a Wireless Pressure-Sensing Platform Combined with Machine-Learning-Based Cognition, Inspired by the Human Somatosensory System.

Inspired by the human somatosensory system, pressure applied to multiple pressure sensors is received in parallel and combined into a representative signal pattern, which is subsequently processed using machine learning. The pressure signals are combined using a wireless system, where each sensor is assigned a specific resonant frequency on the reflection coefficient (S11 ) spectrum, and the applied pressure changes the magnitude of the S11 pole with minimal frequency shift. This allows the differentiation and identification of the pressure applied to each sensor. The pressure sensor consists of polypyrrole-coated microstructured poly(dimethylsiloxane) placed on top of electrodes, operating as a capacitive sensor. The high dielectric constant of polypyrrole enables relatively high pressure-sensing performance. The coils are vertically stacked to enable the reader to receive the signals from all of the sensors simultaneously at a single location, analogous to the junction between neighboring primary neurons to a secondary neuron. Here, the stacking order is important to minimize the interference between the coils. Furthermore, convolutional neural network (CNN)-based machine learning is utilized to predict the applied pressure of each sensor from unforeseen S11 spectra. With increasing training, the prediction accuracy improves (with mean squared error of 0.12), analogous to humans' cognitive learning ability.

Electronic Skin: Recent Progress and Future Prospects for Skin-Attachable Devices for Health Monitoring, Robotics, and Prosthetics.

Recent progress in electronic skin or e-skin research is broadly reviewed, focusing on technologies needed in three main applications: skin-attachable electronics, robotics, and prosthetics. First, since e-skin will be exposed to prolonged stresses of various kinds and needs to be conformally adhered to irregularly shaped surfaces, materials with intrinsic stretchability and self-healing properties are of great importance. Second, tactile sensing capability such as the detection of pressure, strain, slip, force vector, and temperature are important for health monitoring in skin attachable devices, and to enable object manipulation and detection of surrounding environment for robotics and prosthetics. For skin attachable devices, chemical and electrophysiological sensing and wireless signal communication are of high significance to fully gauge the state of health of users and to ensure user comfort. For robotics and prosthetics, large-area integration on 3D surfaces in a facile and scalable manner is critical. Furthermore, new signal processing strategies using neuromorphic devices are needed to efficiently process tactile information in a parallel and low power manner. For prosthetics, neural interfacing electrodes are of high importance. These topics are discussed, focusing on progress, current challenges, and future prospects.

Microstructured Porous Pyramid-Based Ultrahigh Sensitive Pressure Sensor Insensitive to Strain and Temperature.

An ultrahigh sensitive capacitive pressure sensor based on a porous pyramid dielectric layer (PPDL) is reported. Compared to that of the conventional pyramid dielectric layer, the sensitivity was drastically increased to 44.5 kPa-1 in the pressure range <100 Pa, an unprecedented sensitivity for capacitive pressure sensors. The enhanced sensitivity is attributed to a lower compressive modulus and larger change in an effective dielectric constant under pressure. By placing the pressure sensors on islands of hard elastomer embedded in a soft elastomer substrate, the sensors exhibited insensitivity to strain. The pressure sensors were also nonresponsive to temperature. Finally, a contact resistance-based pressure sensor is also demonstrated by chemically grafting PPDL with a conductive polymer, which also showed drastically enhanced sensitivity.

Highly Ordered 3D Microstructure-Based Electronic Skin Capable of Differentiating Pressure, Temperature, and Proximity.

Electronic skin are devices that mimic the functionalities of human skin, which require high sensitivity, large dynamic range, high spatial uniformity, low-cost and large-area processability, and the capacity to differentiate various external inputs. We herein introduce a versatile droplet-based microfluidic-assisted emulsion self-assembly process to generate three-dimensional microstructure-based high-performance capacitive and piezoresistive pressure sensors for electronic skin applications. Our technique can generate uniformly sized micropores that are self-assembled in an orderly close-packed manner over a large area, which results in high spatial uniformity. The size of the micropores can easily be tuned from 100 to 500 µm, through which sensitivity and dynamic range were controlled as high as 0.86 kPa-1 and up to 100 kPa. Our device can be printed on curvilinear surfaces and be molded into various shapes. We furthermore demonstrate that by simultaneously utilizing capacitive and piezoresistive pressure sensors, we can distinguish between pressure and temperature, or between pressure and proximity. These demonstrations make our process and sensors highly useful for a wide variety of electronic skin applications.

Zinc Inhibits Expression of Androgen Receptor to Suppress Growth of Prostate Cancer Cells.

The prostate gland contains a high level of intracellular zinc, which is dramatically diminished during prostate cancer (PCa) development. Owing to the unclear role of zinc in this process, therapeutic applications using zinc are limited. This study aimed to clarify the role of zinc and its underlying mechanism in the growth of PCa. ZnCl2 suppressed the proliferation of androgen receptor (AR)-retaining PCa cells, whereas it did not affect AR-deficient PCa cells. In LNCaP and TRAMP-C2 cells, zinc downregulated the expression of AR in a dose- and time-dependent fashion. Zinc-mediated AR suppression accordingly inhibited the androgen-mediated transactivation and expression of the androgen target, prostate specific antigen (PSA). This phenomenon resulted from facilitated protein degradation, not transcriptional control. In studies using mice bearing TRAMP-C2 subcutaneous tumors, the intraperitoneal injection of zinc significantly reduced tumor size. Analyses of both xenograft tumors and normal prostates showed reduced expression of AR and increased cell death. Considering the significant loss of intracellular zinc and the dominant growth-modulating role of AR during PCa development, loss of zinc may be a critical step in the transformation of normal cells to cancer cells. This study provides the underlying mechanism by which zinc functions as a PCa suppressor, and forms the foundation for developing zinc-mediated therapeutics for PCa.

Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer.

CD46 is generally overexpressed in many human cancers, representing a prime target for CD46-binding adenoviruses (Ads). This could help to overcome low anti-tumoral activity by coxsackie-adenoviral receptor (CAR)-targeting cancer gene therapy viruses. However, because of scarce side-by-side information about CAR and CD46 expression levels in cancer cells, mixed observations of cancer therapeutic efficacy have been observed. This study evaluated Ad-mediated therapeutic efficacy using either CAR-targeting Ad5 or CD46-targeting Ad5/35 fiber chimera in bladder cancer cell lines. Compared with normal urothelia, bladder cancer tissue generally overexpressed both CAR and CD46. While CAR expression was not correlated with disease progression, CD46 expression was inversely correlated with tumor grade, stage, and risk grade. In bladder cancer cell lines, expression levels of CD46 and CAR were highly correlated with Ad5/35- and Ad5-mediated gene transduction and cytotoxicity, respectively. In a human EJ bladder cancer xenograft mouse model, with either overexpressed or suppressed CD46 expression levels, Ad5/35-tk followed by ganciclovir (GCV) treatment significantly affected tumor growth, whereas Ad5-tk/GCV had only minimal effects. Overall, our findings suggest that bladder cancer cells overexpress both CAR and CD46, and that adenoviral cancer gene therapy targeting CD46 represents a more suitable therapy option than a CAR-targeting therapy, especially in patients with low risk bladder cancers.

Pressure Insensitive Strain Sensor with Facile Solution-Based Process for Tactile Sensing Applications.

Tactile sensors that can mechanically decouple, and therefore differentiate, various tactile inputs are highly important to properly mimic the sensing capabilities of human skin. Herein, we present an all-solution processable pressure insensitive strain sensor that utilizes the difference in structural change upon the application of pressure and tensile strain. Under the application of strain, microcracks occur within the multiwalled carbon nanotube (MWCNT) network, inducing a large change in resistance with gauge factor of ∼56 at 70% strain. On the other hand, under the application of pressure to as high as 140 kPa, negligible change in resistance is observed, which can be attributed to the pressure working primarily to close the pores, and hence minimally changing the MWCNT network conformation. Our sensor can easily be coated onto irregularly shaped three-dimensional objects (e.g., robotic hand) via spray coating, or be attached to human joints, to detect bending motion. Furthermore, our sensor can differentiate between shear stress and normal pressure, and the local strain can be spatially mapped without the use of patterned electrode array using electrical impedance tomography. These demonstrations make our sensor highly useful and important for the future development of high performance tactile sensors.

Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers.

CD46 is a complement inhibitor membrane cofactor which also acts as a receptor for various microbes, including species B adenoviruses (Ads). While most Ad gene therapy vectors are derived from species C and infect cells through coxsackie-adenovirus receptor (CAR), CAR expression is downregulated in many cancer cells, resulting inefficient Ad-based therapeutics. Despite a limited knowledge on the expression status of many cancer cells, an increasing number of cancer gene therapy studies include fiber-modified Ad vectors redirected to the more ubiquitously expressed CD46. Since our finding from tumor microarray indicate that CD46 was overexpressed in cancers of the prostate and colon, fiber chimeric Ad5/35 vectors that have infection tropism for CD46 were employed to demonstrate its efficacy in colorectal cancers (CRC). CD46-overexpressed cells showed a significantly higher response to Ad5/35-GFP and to Ad5/35-tk/GCV. While CRC cells express variable levels of CD46, CD46 expression was positively correlated with Ad5/35-mediated GFP fluorescence and accordingly its cell killing. Injection of Ad5/35-tk/GCV caused much greater tumor-suppression in mice bearing CD46-overexpressed cancer xenograft compared to mock group. Analysis of CRC samples revealed that patients with positive CD46 expression had a higher survival rate (p=0.031), carried tumors that were well-differentiated, but less invasive and metastatic, and with a low T stage (all p<0.05). Taken together, our study demonstrated that species B-based adenoviral gene therapy is a suitable approach for generally CD46-overexpressed CRC but would require careful consideration preceding CD46 analysis and categorizing CRC patients.

Cloning of the xylose reductase gene of Candida milleri.

The entire nucleotide sequence of the xylose reductase (XR) gene in Candida milleri CBS8195 sourdough yeast was determined by degenerate polymerase chain reaction (PCR) and genome walking. The sequence analysis revealed an open-reading frame of 981 bp that encoded 326 amino acids with a predicted molecular mass of 36.7 kDa. The deduced amino acid sequence of XR of C. milleri was 64.7% homologous to that of Kluyveromyces lactis. The cloned XR gene was expressed in Saccharomyces cerevisiae, and the resulting recombinant S. cerevisiae strain produced xylitol from xylose, indicating that the C. milleri XR introduced into S. cerevisiae is functional. An enzymatic activity assay and semiquantitative reverse transcription-PCR revealed that the expression of CmXR was induced by xylose.