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Semiconducting polymers with oligoethylene glycol sidechains have attracted strong research interest for organic electrochemical transistor (OECT) applications. However, key molecular design rules for high-performance OECTs via efficient mixed electronic/ionic charge transport are still unclear. Herein, we synthesize and characterize new glycolated copolymers (gDPP-TTT and gDPP-TTVTT) with diketopyrrolopyrrole (DPP) acceptor and thiophene-based (TTT or TTVTT) donor units for accumulation mode OECTs, where a long-alkyl-group (C12 ) attached to DPP unit acts as a spacer distancing the oligoethylene glycol from the polymer backbone. gDPP-TTVTT shows the highest OECT transconductance (61.9 S cm-1 ) and high operational stability, compared to gDPP-TTT and their alkylated counterparts. Surprisingly, gDPP-TTVTT also shows high electronic charge mobility in field-effect transistor, suggesting efficient ion injection/diffusion without hindering its efficient electronic charge transport. The elongated donor unit (TTVTT) facilitates the hole polaron formation more localized to the donor unit, leading to faster and easier polaron formation with less impact on polymer structure during OECT operation, as opposed to the TTT unit. This is supported by molecular dynamics (MD) simulation. We conclude that these simultaneously high electronic and ionic charge transport properties are achieved due to the long-alkyl-group spacer in amphipathic sidechains, providing an important molecular design rule for glycolated copolymers. This article is protected by copyright. All rights reserved.

The portability of physiological monitoring has necessitated the biocompatibility of components used in circuitry local to biological environments. A key component in processing circuitry is the linear amplifier. Amplifier circuit topologies utilize transistors, and recent advances in bioelectronics have focused on organic electrochemical transistors (OECTs). OECTs have shown the capability to transduce physiological signals at high signal-to-noise ratios. In this study high-performance interdigitated electrode OECTs are implemented in a common source linear amplifier topology. Under the constraints of OECT operation, stable circuit component parameters are found, and OECT geometries are varied to determine the best amplifier performance. An equation is formulated which approximates transistor behavior in the linear, nonlinear, and saturation regimes. This equation is used to simulate the amplifier response of the circuits with the best performing OECT geometries. The amplifier figures of merit, including distortion characterizations, are then calculated using physical and simulation measurements. Based on the figures of merit, prerecorded electrophysiological signals from spreading depolarizations, electrocorticography, and electromyography fasciculations are inputted into an OECT linear amplifier. Using frequency filtering, the primary features of events in the bioelectric signals are resolved and amplified, demonstrating the capability of OECT amplifiers in bioelectronics.

Biological environments use ions in charge transport for information transmission. The properties of mixed electronic and ionic conductivity in organic materials make them ideal candidates to transduce physiological information into electronically processable signals. A device proven to be highly successful in measuring such information is the organic electrochemical transistor (OECT). Previous electrophysiological measurements performed using OECTs show superior signal‐to‐noise ratios than electrodes at low frequencies. Subsequent development has significantly improved critical performance parameters such as transconductance and response time. Here, interdigitated‐electrode OECTs are fabricated on flexible substrates, with one such state‐of‐the‐art device achieving a peak transconductance of 139 mS with a 138 µs response time. The devices are implemented into an array with interconnects suitable for micro‐electrocorticographic application and eight architecture variations are compared. The two best‐performing arrays are subject to the full electrophysiological spectrum using prerecorded signals. With frequency filtering, kHz‐scale frequencies with 10 µV‐scale voltages are resolved. This is supported by a novel quantification of the noise, which compares the gate voltage input and drain current output. These results demonstrate that high‐performance OECTs can resolve the full electrophysiological spectrum and suggest that superior signal‐to‐noise ratios could be achieved in high frequency measurements of multiunit activity.

(U-Th)/He thermochronology is a well-established dating technique used to understand the temperature-time histories of rocks in a wide range of geologic settings. The technique is presently restricted to rocks that contain specific accessory minerals, such as apatite or zircon. Marine carbonates and shales typically lack these accessory phases in quantities and sizes practical for (U-Th)/He dating and thus present a challenge for application of the method. Here, we explore the utility of biogenic apatite from conodonts as a (U-Th)/He thermochronometer at a well-studied calibration site located in eastern Nevada and southwestern Utah. We performed (U-Th)/He thermochronometry, laser ablation inductively coupled plasma mass spectrometry, X-ray micro-computed tomography, and scanning electron microscopy (SEM) on specimens with conodont color alteration indices (CAI) of 1.5–3, extracted from carbonate rocks in the footwalls of low-angle normal faults in the Mormon Mountains, Tule Spring Hills, and Beaver Dam Mountains. Conodont (U-Th)/He (CHe) dates have high scatter; dates are commonly reproducible to 20% of sample means but can deviate up to 150%. All CAI 1.5–2.5 conodonts produce CHe dates younger than 240 Ma, consistent with thermal resetting of samples; however, most CAI 3 conodonts give ages 2–6× older than Mississippian and Permian deposition. Average U, Th, and rare earth element (REE) concentrations depend on porosity and permeability differences between albid and hyaline conodont tissue and range from We propose that microstructural changes associated with increasing CAI influence CHe dates. Parent isotope loss occurs during the post-cooling stage, either in the outcrop or in the laboratory. Our hypothesis is that the double-buffered formic acid procedure for dissolving dolomitized carbonates may accelerate this loss in thermally altered, higher CAI conodonts.

Uncontrolled growth in a confined space generates mechanical compressive stress within tumors, but little is known about how such stress affects tumor cell behavior. Here we show that compressive stress stimulates migration of mammary carcinoma cells. The enhanced migration is accomplished by a subset of “leader cells” that extend filopodia at the leading edge of the cell sheet. Formation of these leader cells is dependent on cell microorganization and is enhanced by compressive stress. Accompanied by fibronectin deposition and stronger cell–matrix adhesion, the transition to leader-cell phenotype results in stabilization of persistent actomyosin-independent cell extensions and coordinated migration. Our results suggest that compressive stress accumulated during tumor growth can enable coordinated migration of cancer cells by stimulating formation of leader cells and enhancing cell–substrate adhesion. This novel mechanism represents a potential target for the prevention of cancer cell migration and invasion.

Not all tumor vessels are equal. Tumor-associated vasculature includes immature vessels, regressing vessels, transport vessels undergoing arteriogenesis and peritumor vessels influenced by tumor growth factors. Current techniques for analyzing tumor blood flow do not discriminate between vessel subtypes and only measure average changes from a population of dissimilar vessels. We developed methodologies for simultaneously quantifying blood flow (velocity, flux, hematocrit and shear rate) in extended networks at single-capillary resolution in vivo. Our approach relies on deconvolution of signals produced by labeled red blood cells as they move relative to the scanning laser of a confocal or multiphoton microscope and provides fully resolved three-dimensional flow profiles within vessel networks. Using this methodology, we show that blood velocity profiles are asymmetric near intussusceptive tissue structures in tumors in mice. Furthermore, we show that subpopulations of vessels, classified by functional parameters, exist in and around a tumor and in normal brain tissue.

Background: Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). However, the survival benefit is usually short-lived as tumors escape anti-VEGF therapies. Here we tested the hypothesis that Platelet Derived Growth Factor-C (PDGF-C), an isoform of the PDGF family, affects GBM progression independent of VEGF pathway and hinders anti-VEGF therapy. Principal Findings: We first showed that PDGF-C is present in human GBMs. Then, we overexpressed or downregulated PDGF-C in a human GBM cell line, U87MG, and grew them in cranial windows in nude mice to assess vessel structure and function using intravital microscopy. PDGF-C overexpressing tumors had smaller vessel diameters and lower vascular permeability compared to the parental or siRNA-transfected tumors. Furthermore, vessels in PDGF-C overexpressing tumors had more extensive coverage with NG2 positive perivascular cells and a thicker collagen IV basement membrane than the controls. Treatment with DC101, an anti-VEGFR-2 antibody, induced decreases in vessel density in the parental tumors, but had no effect on the PDGF-C overexpressing tumors. Conclusion: These results suggest that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization.

Tissue engineering requires formation of a de novo stable vascular network. Because of their ability to proliferate, differentiate into endothelial cells, and form new vessels, blood-derived endothelial progenitor cells (EPCs) are attractive source of cells for use in engineering blood vessels. However, the durability and function of EPC-derived vessels implanted in vivo are unclear. To this end, we directly compared formation and functions of tissue-engineered blood vessels generated by peripheral blood– and umbilical cord blood–derived EPCs in a model of in vivo vasculogenesis. We found that adult peripheral blood EPCs form blood vessels that are unstable and regress within 3 weeks. In contrast, umbilical cord blood EPCs form normal-functioning blood vessels that last for more than 4 months. These vessels exhibit normal blood flow, perm-selectivity to macromolecules, and induction of leukocyte-endothelial interactions in response to cytokine activation similar to normal vessels. Thus, umbilical cord blood EPCs hold great therapeutic potential, and their use should be pursued for vascular engineering.

Normalization of tumor vasculature is an emerging strategy to improve cytotoxic therapies. Here we show that eliminating nitric oxide (NO) production from tumor cells via neuronal NO synthase silencing or inhibition establishes perivascular gradients of NO in human glioma xenografts in mice and normalizes the tumor vasculature, resulting in improved tumor oxygenation and response to radiation treatment. Creation of perivascular NO gradients may be an effective strategy for normalizing abnormal vasculature.

This paper presents methods to model complex vasculature in three-dimensional (3-D) images using cylindroidal superellipsoids, along with robust estimation and detection algorithms for automated image analysis. This model offers an explicit, low-order parameterization, enabling joint estimation of boundary, centerlines, and local pose. It provides a geometric framework for directed vessel traversal, and extraction of topological information like branch point locations and connectivity. M-estimators provide robust region-based statistics that are used to drive the superellipsoid toward a vessel boundary. A robust likelihood ratio test is used to differentiate between noise, artifacts, and other complex unmodeled structures, thereby verifying the model estimate. The proposed methodology behaves well across scale-space, shows a high degree of insensitivity to adjacent structures and implicitly handles branching. When evaluated on synthetic imagery mimicking specific structural complexities in tumor microvasculature, it consistently produces ubvoxel accuracy estimates of centerlines and widths in the presence of closely-adjacent vessels, branch points, and noise. An edit-based validation demonstrated a precision level of 96.6% at a recall level of 95.4%. Overall, it is robust enough for large-scale application.

This paper presents automated methods for robust modeling and analysis of 3-D tumor microvasculature. Our methodology uses a cylindroidal superellipsoid to model localized segments of vasculature. The proposed vessel model has an explicit, low-order parameterization, allowing for joint estimation of boundary and centerline information, thereby approximating the medial axis. Further, this explicit parameterization provides a geometric framework for traversing vessels in a directed manner. Topological information like branch point location and connectivity is provided as a side effect. The proposed methodology behaves quite well across scalespace, shows a high degree of insensitivity to adjacent structures and implicitly handles branching. Exemplar results are presented from a pre-clinical study of tumor microvasculature in mice.

This paper presents model-based information-theoretic methods to quantify the complexity of tumor microvasculature, taking into account shape, textural, and structural irregularities. The proposed techniques are completely automated, and are applicable to optical slices (3-D) or projection images (2-D). Improvements upon the prior literature include: (i) measuring local (vessel segment) as well as global (entire image) vascular complexity without requiring explicit segmentation or tracing; (ii) focusing on the vessel boundaries in the complexity estimate; and (iii) added robustness to image artifacts common to tumor microvasculature images. Vessels are modeled using a family of super-Gaussian functions that are based on the superquadric modeling primitive common in computer vision. The superquadric generalizes a simple ellipsoid by including shape parameters that allow it to approximate a cylinder with elliptical cross-sections (generalized cylinder). The super-Gaussian is obtained by composing a superquadric with an exponential function giving a form that is similar to a standard Gaussian function but with the ability to produce level sets that approximate generalized cylinders. Importantly, the super-Gaussian is continuous and differentiable so it can be fit to image data using robust non-linear regression. This fitting enables quantification of the intrinsic complexity of vessel data vis-a-vis the super-Gaussian model within a minimum message length (MML) framework. The resulting measures are expressed in units of information (bits). Synthetic and real-data examples are provided to illustrate the proposed measures.

Extended abstract of a paper presented at Microscopy and Microanalysis 2004 in Savannah, Georgia, USA, August 1–5, 2004.

Uncontrolled cell proliferation of a solid tumor in a confined space not only creates oxidative stress (hypoxia), but also generates mechanical compressive stress, which can influence the tumor cells and modify their interactions with neighboring cells and the extracellular matrix. Little is known about how such compressive stress affects cancer progression. Here we show, for the first time, that externally-applied compressive stress results in faster migration of mammary carcinoma cells. Compression induces migration of mammary carcinoma cells in a coordinated sheet, initiated by “leader cells” - single cells at the leading edge of the sheet, extending long filopodia. The formation of leader cells is dependent on the geometry of association with neighboring cells, but the frequency of leader-cell formation - and sheet migration speed - is increased by applying compression perpendicular to the sheet. Accompanied by redistribution of fibronectin deposition, applied compression enhances cell-matrix adhesion and stabilizes cell distension independent of actomyosin contractile machinery. Our results suggest that mechanical stress accumulated during tumor growth is sufficient to enhance cell-substrate adhesion and stimulate cancer cell migration. This mechanism opens the door to a new class of targets for blocking mechanical stress pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4811.

Synthetic luteinizing hormone-releasing hormone was given to six patients (3 men and 3 women) with active acromegaly. All three men had rapid increases in growth hormone, as well as luteinizing and follicle-stimulating hormones. This represents further evidence that the pituitary gland remains under hypothalamic control in some cases of acromegaly.