bluuebunny/crossref_metadata_2025 huggingface dataset:
CONNECTING THE NONSINGULAR ORIGIN OF THE UNIVERSE, THE VACUUM STRUCTURE AND THE COSMOLOGICAL CONSTANT PROBLEM
Authors: GUENDELMAN EDUARDO I. , LABRAÑA PEDRO
Published: June 2013

We consider a nonsingular origin for the universe starting from an Einstein static universe, the so-called "emergent universe" scenario, in the framework of a theory which uses two volume elements [Formula: see text] and Φd4x, where Φ is a metric independent density, used as an additional measure of integration. Also curvature, curvature square terms and for scale invariance a dilaton field ϕ are considered in the action. The first-order formalism is applied. The integration of the equations of motion associated with the new measure gives rise to the spontaneous symmetry breaking (SSB) of scale invariance (SI). After SSB of SI, it is found that a nontrivial potential for the dilaton is generated. In the Einstein frame we also add a cosmological term that parametrizes the zero point fluctuations. The resulting effective potential for the dilaton contains two flat regions, for ϕ → ∞ relevant for the nonsingular origin of the universe, followed by an inflationary phase and ϕ → -∞, describing our present universe. The dynamics of the scalar field becomes nonlinear and these nonlinearities produce a nontrivial vacuum structure for the theory and are responsible for the stability of some of the emergent universe solutions, which exists for a parameter range of values of the vacuum energy in ϕ → -∞, which must be positive but not very big, avoiding the extreme fine tuning required to keep the vacuum energy density of the present universe small. The nontrivial vacuum structure is crucial to ensure the smooth transition from the emerging phase, to an inflationary phase and finally to the slowly accelerated universe now. Zero vacuum energy density for the present universe defines the threshold for the creation of the universe.
SURFACE MORPHOLOGY AND X-RAY DIFFRACTION ANALYSIS FOR SILICON NANOCRYSTAL-BASED HETEROSTRUCTURES
Authors: SALIM EVAN T.
Published: June 2013

In this work, we studied the effect of rapid thermal oxidation process on the structural and surface morphology of silicon nanocrystal-based heterostructures. PLD technique was employed in combination with rapid thermal oxidation process to form multilayers heterostructures. Results show the dependence of the surface roughness and structure on the oxidation temperature. Best surface morphology was achieved at 723 K oxidation temperature, at which, the X-ray diffraction result ensured the formation of the Cu 2 O phase at (111) and (002) diffraction plain with uniform porous surface.
NUMERICAL STUDY OF MIXED BIOCONVECTION IN POROUS MEDIA SATURATED WITH NANOFLUID CONTAINING OXYTACTIC MICROORGANISMS
Authors: BÉG O. ANWAR , PRASAD V. R. , VASU B.
Published: June 2013

A mathematical model has been developed for steady-state boundary layer flow of a nanofluid past an impermeable vertical flat wall in a porous medium saturated with a water-based dilute nanofluid containing oxytactic microorganisms. The nanoparticles were distributed sufficiently to permit bioconvection. The product of chemotaxis constant and maximum cell swimming speed was assumed invariant. Using appropriate transformations, the partial differential conservation equations were non-dimensionalised to yield a quartet of coupled, non-linear ordinary differential equations for momentum, energy, nanoparticle concentration and dimensionless motile microorganism density, with appropriate boundary conditions. The dominant parameters emerging in the normalised model included the bioconvection Lewis number, bioconvection Peclet number, Lewis number, buoyancy ratio parameter, Brownian motion parameter, thermophoresis parameter, local Darcy-Rayleigh number and the local Peclet number. An implicit numerical solution to the well-posed two-point non-linear boundary value problem is developed using the well-tested and highly efficient Keller box method. Computations are validated with the Nakamura tridiagonal implicit finite difference method, demonstrating excellent agreement. Nanoparticle concentration and temperature were found to be generally enhanced through the boundary layer with increasing bioconvection Lewis number, whereas dimensionless motile microorganism density was only increased closer to the wall. Temperature, nanoparticle concentration and dimensionless motile microorganism density were all greatly increased with a rise in Peclet number. Temperature and dimensionless motile microorganism density were reduced with increasing buoyancy parameter, whereas nanoparticle concentration was increased. The present study found applications in the fluid mechanical design of microbial fuel cell and bioconvection nanotechnological devices.
GLOBALIZATION AND SCIENCE EDUCATION
Authors: BENCZE J. LAWRENCE , CARTER LYN , CHIU MEI-HUNG , DUIT REINDERS , MARTIN SONYA , SIRY CHRISTINA , KRAJCIK JOSEPH , SHIN NAMSOO , CHOI KYUNGHEE , LEE HYUNJU , KIM SUNG-WON
Published: June 2013

Processes of globalization have played a major role in economic and cultural change worldwide. More recently, there is a growing literature on rethinking science education research and development from the perspective of globalization. This paper provides a critical overview of the state and future development of science education research from the perspective of globalization. Two facets are given major attention. First, the further development of science education as an international research domain is critically analyzed. It seems that there is a predominance of researchers stemming from countries in which English is the native language or at least a major working language. Second, the significance of rethinking the currently dominant variants of science instruction from the perspectives of economic and cultural globalization is given major attention. On the one hand, it is argued that processes concerning globalization of science education as a research domain need to take into account the richness of the different cultures of science education around the world. At the same time, it is essential to develop ways of science instruction that make students aware of the various advantages, challenges and problems of international economic and cultural globalization.
Distinguishing the effects of convective and diffusive O2 delivery on V̇o2 on-kinetics in skeletal muscle contracting at moderate intensity
Authors: Spires Jessica , Gladden L. Bruce , Grassi Bruno , Goodwin Matthew L. , Saidel Gerald M. , Lai Nicola
Published: June 2013

With current techniques, experimental measurements alone cannot characterize the effects of oxygen blood-tissue diffusion on muscle oxygen uptake (V̇o2) kinetics in contracting skeletal muscle. To complement experimental studies, a computational model is used to quantitatively distinguish the contributions of convective oxygen delivery, diffusion into cells, and oxygen utilization to V̇o2 kinetics. The model is validated using previously published experimental V̇o2 kinetics in response to slowed blood flow (Q) on-kinetics in canine muscle (τQ = 20 s, 46 s, and 64 s) [Goodwin ML, Hernández A, Lai N, Cabrera ME, Gladden LB. J Appl Physiol. 112:9–19, 2012]. Distinctive effects of permeability-surface area or diffusive conductance ( PS) and Q on V̇o2 kinetics are investigated. Model simulations quantify the relationship between PS and Q, as well as the effects of diffusion associated with PS and Q dynamics on the mean response time of V̇o2. The model indicates that PS and Q are linearly related and that PS increases more with Q when convective delivery is limited by slower Q dynamics. Simulations predict that neither oxygen convective nor diffusive delivery are limiting V̇o2 kinetics in the isolated canine gastrocnemius preparation under normal spontaneous conditions during transitions from rest to moderate (submaximal) energy demand, although both operate close to the tipping point.
Procollagen I-expressing renin cell precursors
Authors: Karger Christian , Kurtz Felix , Steppan Dominik , Schwarzensteiner Ilona , Machura Katharina , Angel Peter , Banas Bernhard , Risteli Juha , Kurtz Armin
Published: June 2013

Renin-expressing cells in the kidney normally appear as mural cells of developing preglomerular vessels and finally impose as granulated juxtaglomerular cells in adult kidneys. The differentiation of renin-expressing cells from the metanephric mesenchyme in general and the potential role of special precursor stages in particular is not well understood. Therefore, it was the aim of this study to search for renin cell precursors in the kidney. As an experimental model, we used kidneys of aldosterone synthase-deficient mice, which display a prominent compensatory overproduction of renin cells that are arranged in multilayered perivascular cell clusters. We found that the perivascular cell clusters contained two apparently distinct cell types, one staining positive for renin and another one staining positive for type I procollagen (PC1). It appeared as if PC1 and renin expression were inversely related at the cellular level. The proportion of renin-positive to PC1-positive cells in the clusters was inversely linked to the rate of salt intake, as was overall renin expression. Our findings suggest that the cells in the perivascular cell clusters can reversibly switch between PC1 and renin expression and that PC1-expressing cells might be precursors of renin cells. A few of those PC1-positive cells were found also in adult wild-type kidneys in the juxtaglomerular lacis cell area, in which renin expression can be induced on demand.
Regulation of BK-α expression in the distal nephron by aldosterone and urine pH
Authors: Wen Donghai , Cornelius Ryan J. , Yuan Yang , Sansom Steven C.
Published: June 2013

In the distal nephron, the large-conductance Ca-activated K (BK) channel, comprised of a pore-forming-α (BK-α) and the BK-β4 subunit, promotes K excretion when mice are maintained on a high-K alkaline diet (HK-alk). We examined whether BK-β4 and the acid-base status regulate apical membrane expression of BK-α in the cortical (CCD) and medullary collecting ducts (MCD) using immunohistochemical analysis (IHC) and Western blot. With the use of IHC, BK-α of mice on acontrol diet localized mostly cytoplasmically in intercalated cells (IC) of the CCD and in the perinuclear region of both principle cells (PC) and IC of the MCD. HK-alk wild-type mice (WT), but not BK-β4 knockout mice (β4KO), exhibited increased apical BK-α in both the CCD and MCD. When given a high-K acidic diet (HK-Cl), BK-α expression increased but remained cytoplasmic in the CCD and perinuclear in the MCD of both WT and β4KO. Western blot confirmed that total BK-α expression was enhanced by either HK-alk or HK-Cl but only increased in the plasma membrane with HK-alk. Compared with controls, mice drinking NaHCO3 water exhibited more apical BK-α and total cellular BK-β4. Spironolactone given to mice on HK-alk significantly reduced K secretion and decreased total cellular BK-α but did not affect cellular BK-β4 and apical BK-α. Experiments with MDCK-C11 cells indicated that BK-β4 stabilizes surface BK-α by inhibiting degradation through a lysosomal pathway. These data suggest that aldosterone mediates a high-K-induced increase in BK-α and urinary alkalinization increases BK-β4 expression, which promotes the apical localization of BK-α.
Renal and cardiovascular sensory receptors and blood pressure regulation
Authors: Pluznick Jennifer L.
Published: June 2013

Studies over the past decade have highlighted important roles played by sensory receptors outside of traditionally sensory tissues; for example, taste receptors participate in pH sensing in the cerebrospinal fluid, bitter taste receptors mediate bronchodilation and ciliary beating in the lung (Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JS, Liggett SB. Nat Med 16: 1299–1304, 2010; Shah AS, Ben-Shahar Y, Moninger TO, Kline JN, Welsh MJ. Science 325: 1131–1134, 2009), and olfactory receptors play roles in both sperm chemotaxis and muscle cell migration (Griffin CA, Kafadar KA, Pavlath GK. Cell 17: 649–661, 2009). More recently, several studies have shown that sensory receptors also play important roles in the regulation of blood pressure. This review will focus on several recent studies examining the roles that sensory receptors play in blood pressure regulation, with an emphasis on three pathways: the adenylate cyclase 3 (AC3) pathway, the Gpr91-succinate signaling pathway, and the Olfr78/Gpr41 short-chain fatty acid signaling pathway. Together, these pathways demonstrate that sensory receptors play important roles in mediating blood pressure control and that blood pressure regulation is coupled to the metabolism of the host as well as the metabolism of the gut microbiota.
Regulation of urinary ACE2 in diabetic mice
Authors: Wysocki Jan , Garcia-Halpin Laura , Ye Minghao , Maier Christoph , Sowers Kurt , Burns Kevin D. , Batlle Daniel
Published: June 2013

Angiotensin-converting enzyme-2 (ACE2) enhances the degradation of ANG II and its expression is altered in diabetic kidneys, but the regulation of this enzyme in the urine is unknown. Urinary ACE2 was studied in the db/db model of type 2 diabetes and stretozotocin (STZ)-induced type 1 diabetes during several physiological and pharmacological interventions. ACE2 activity in db/db mice was increased in the serum and to a much greater extent in the urine compared with db/m controls. Neither a specific ANG II blocker, telmisartan, nor an ACE inhibitor, captopril, altered the levels of urinary ACE2 in db/db or db/m control mice. High-salt diet (8%) increased whereas low-salt diet (0.1%) decreased urinary ACE2 activity in the urine of db/db mice. In STZ mice, urinary ACE2 was also increased, and insulin decreased it partly but significantly after several weeks of administration. The increase in urinary ACE2 activity in db/db mice reflected an increase in enzymatically active protein with two bands identified of molecular size at 110 and 75 kDa and was associated with an increase in kidney cortex ACE2 protein at 110 kDa but not at 75 kDa. ACE2 activity was increased in isolated tubular preparations but not in glomeruli from db/db mice. Administration of soluble recombinant ACE2 to db/m and db/db mice resulted in a marked increase in serum ACE2 activity, but no gain in ACE2 activity was detectable in the urine, further demonstrating that urinary ACE2 is of kidney origin. Increased urinary ACE2 was associated with more efficient degradation of exogenous ANG II (10−9 M) in urine from db/db compared with that from db/m mice. Urinary ACE2 could be a potential biomarker of increased metabolism of ANG II in diabetic kidney disease.
Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury
Authors: Huen Sarah C. , Moeckel Gilbert W. , Cantley Lloyd G.
Published: June 2013

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.
A model of calcium transport along the rat nephron
Authors: Tournus Magali , Seguin Nicolas , Perthame Benoît , Thomas S. Randall , Edwards Aurélie
Published: June 2013

We developed a mathematical model of calcium (Ca2+) transport along the rat nephron to investigate the factors that promote hypercalciuria. The model is an extension of the flat medullary model of Hervy and Thomas ( Am J Physiol Renal Physiol 284: F65–F81, 2003). It explicitly represents all the nephron segments beyond the proximal tubules and distinguishes between superficial and deep nephrons. It solves dynamic conservation equations to determine NaCl, urea, and Ca2+concentration profiles in tubules, vasa recta, and the interstitium. Calcium is known to be reabsorbed passively in the thick ascending limbs and actively in the distal convoluted (DCT) and connecting (CNT) tubules. Our model predicts that the passive diffusion of Ca2+from the vasa recta and loops of Henle generates a significant axial Ca2+concentration gradient in the medullary interstitium. In the base case, the urinary Ca2+concentration and fractional excretion are predicted as 2.7 mM and 0.32%, respectively. Urinary Ca2+excretion is found to be strongly modulated by water and NaCl reabsorption along the nephron. Our simulations also suggest that Ca2+molar flow and concentration profiles differ significantly between superficial and deep nephrons, such that the latter deliver less Ca2+to the collecting duct. Finally, our results suggest that the DCT and CNT can act to counteract upstream variations in Ca2+transport but not always sufficiently to prevent hypercalciuria.
Effects of spectral and temporal disruption on cortical encoding of gerbil vocalizations
Authors: Ter-Mikaelian Maria , Semple Malcolm N. , Sanes Dan H.
Published: June 2013

Animal communication sounds contain spectrotemporal fluctuations that provide powerful cues for detection and discrimination. Human perception of speech is influenced both by spectral and temporal acoustic features but is most critically dependent on envelope information. To investigate the neural coding principles underlying the perception of communication sounds, we explored the effect of disrupting the spectral or temporal content of five different gerbil call types on neural responses in the awake gerbil's primary auditory cortex (AI). The vocalizations were impoverished spectrally by reduction to 4 or 16 channels of band-passed noise. For this acoustic manipulation, an average firing rate of the neuron did not carry sufficient information to distinguish between call types. In contrast, the discharge patterns of individual AI neurons reliably categorized vocalizations composed of only four spectral bands with the appropriate natural token. The pooled responses of small populations of AI cells classified spectrally disrupted and natural calls with an accuracy that paralleled human performance on an analogous speech task. To assess whether discharge pattern was robust to temporal perturbations of an individual call, vocalizations were disrupted by time-reversing segments of variable duration. For this acoustic manipulation, cortical neurons were relatively insensitive to short reversal lengths. Consistent with human perception of speech, these results indicate that the stable representation of communication sounds in AI is more dependent on sensitivity to slow temporal envelopes than on spectral detail.
Modular control of varied locomotor tasks in children with incomplete spinal cord injuries
Authors: Fox Emily J. , Tester Nicole J. , Kautz Steven A. , Howland Dena R. , Clark David J. , Garvan Cyndi , Behrman Andrea L.
Published: June 2013

A module is a functional unit of the nervous system that specifies functionally relevant patterns of muscle activation. In adults, four to five modules account for muscle activation during walking. Neurological injury alters modular control and is associated with walking impairments. The effect of neurological injury on modular control in children is unknown and may differ from adults due to their immature and developing nervous systems. We examined modular control of locomotor tasks in children with incomplete spinal cord injuries (ISCIs) and control children. Five controls (8.6 ± 2.7 yr of age) and five children with ISCIs (8.6 ± 3.7 yr of age performed treadmill walking, overground walking, pedaling, supine lower extremity flexion/extension, stair climbing, and crawling. Electromyograms (EMGs) were recorded in bilateral leg muscles. Nonnegative matrix factorization was applied, and the minimum number of modules required to achieve 90% of the “variance accounted for” (VAF) was calculated. On average, 3.5 modules explained muscle activation in the controls, whereas 2.4 modules were required in the children with ISCIs. To determine if control is similar across tasks, the module weightings identified from treadmill walking were used to reconstruct the EMGs from each of the other tasks. This resulted in VAF values exceeding 86% for each child and each locomotor task. Our results suggest that 1) modularity is constrained in children with ISCIs and 2) for each child, similar neural control mechanisms are used across locomotor tasks. These findings suggest that interventions that activate the neuromuscular system to enhance walking also may influence the control of other locomotor tasks.
Event-related desynchronization reflects downregulation of intracortical inhibition in human primary motor cortex
Authors: Takemi Mitsuaki , Masakado Yoshihisa , Liu Meigen , Ushiba Junichi
Published: June 2013

There is increasing interest in electroencephalogram (EEG)-based brain-computer interface (BCI) as a tool for rehabilitation of upper limb motor functions in hemiplegic stroke patients. This type of BCI often exploits mu and beta oscillations in EEG recorded over the sensorimotor areas, and their event-related desynchronization (ERD) following motor imagery is believed to represent increased sensorimotor cortex excitability. However, it remains unclear whether the sensorimotor cortex excitability is actually correlated with ERD. Thus we assessed the association of ERD with primary motor cortex (M1) excitability during motor imagery of right wrist movement. M1 excitability was tested by motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) with transcranial magnetic stimulation (TMS). Twenty healthy participants were recruited. The participants performed 7 s of rest followed by 5 s of motor imagery and received online visual feedback of the ERD magnitude of the contralateral hand M1 while performing the motor imagery task. TMS was applied to the right hand M1 when ERD exceeded predetermined thresholds during motor imagery. MEP amplitudes, SICI, and ICF were recorded from the agonist muscle of the imagined hand movement. Results showed that the large ERD during wrist motor imagery was associated with significantly increased MEP amplitudes and reduced SICI but no significant changes in ICF. Thus ERD magnitude during wrist motor imagery represents M1 excitability. This study provides electrophysiological evidence that a motor imagery task involving ERD may induce changes in corticospinal excitability similar to changes accompanying actual movements.
Stimulation of Cellular Proliferation by Hepatitis B Virus X Protein
Authors: Madden Charles R. , Slagle Betty L.
Published: June 2013

Chronic infection with the hepatitis B virus (HBV) is a known risk factor in the development of human hepatocellular carcinoma (HCC). The HBV‐encoded X protein, HBx, has been investigated for properties that may explain its cancer cofactor role in transgenic mouse lines. We discuss here recent data showing that HBx is able to induce hepatocellular proliferation in vitro and in vivo. This property of HBx is predicted to sensitize hepatocytes to other HCC cofactors, including exposure to carcinogens and to other hepatitis viruses. Cellular proliferation is intimately linked to the mechanism(s) by which most tumor‐associated viruses transform virus‐infected cells. The HBx alteration of the cell cycle provides an additional mechanism by which chronic HBV infection may contribute to HCC.
Association of Epstein‐Barr Virus with Human Mammary Carcinoma. Pros and Cons
Authors: Touitou Robert , Bonnet-Duquenoy Mathide , Joab Irène
Published: June 2013

The Epstein‐Barr virus (EBV) is associated with the development of different malignancies. In the last few years, EBV has been detected in a subset of breast tumors. The EBV genome was detected by PCR and Southern‐blot analysis and identification of the infected cells was determined using different in situ methods. EBV has detected more frequently in steroid hormone receptors negative tumors, in high histological SBR grade tumors and furthermore, the EBV genome was also observed in metastatic lymph nodes, along with EBV detection in the primary tumor. Opposing results are discussed.
Emerging Ultrasound Technologies for Early Markers of Disease
Authors: Feleppa Ernest J. , Alam S. Kaisar , Deng Cheri X.
Published: June 2013

Ultrasound has been a popular clinical imaging modality for decades. It is well established as a means of displaying the macroscopic anatomy of soft‐tissue structures. While conventional ultrasound methodologies (i.e., B‐mode and Doppler methods) are well proven and continue to advance technically on a daily basis, e.g. by extending into higher frequencies and taking advantage of harmonic phenomena in tissues, fundamentally new ultrasound technologies also are emerging and offer exciting promise for making significant improvements in the clinical imaging of disease. These emerging methods include spectrum analysis, elasticity imaging, contrast‐agent methods, and advanced flow detection and measurement techniques. Each provides independent information and, used alone, each can provide powerful new imaging capabilities; combined with each other, their capabilities may be even greater in many applications; and all in principle can be used in concert with other imaging modalities to offer the possibility of further improvements in disease detection, evaluation, and monitoring.
Endoscopic Microscopy
Authors: Sokolov Konstantin , Sung Kung-Bin , Collier Tom , Clark Anne , Arifler Dizem , Lacy Alicia , Descour Michael , Richards-Kortum Rebecca
Published: June 2013

In vivo endoscopic optical microscopy provides a tool to assess tissue architecture and morphology with contrast and resolution similar to that provided by standard histopathology – without need for physical tissue removal. In this article, we focus on optical imaging technologies that have the potential to dramatically improve the detection, prevention, and therapy of epithelial cancers. Epithelial pre‐cancers and cancers are associated with a variety of morphologic, architectural, and molecular changes, which currently can be assessed only through invasive, painful biopsy. Optical imaging is ideally suited to detecting cancer‐related alterations because it can detect biochemical and morphologic alterations with sub‐cellular resolution throughout the entire epithelial thickness. Optical techniques can be implemented non‐invasively, in real time, and at low cost to survey the tissue surface at risk. Our manuscript focuses primarily on modalities that currently are the most developed: reflectance confocal microscopy (RCM) and optical coherence tomography (OCT). However, recent advances in fluorescence‐based endoscopic microscopy also are reviewed briefly. We discuss the basic principles of these emerging technologies and their current and potential applications in early cancer detection. We also present research activities focused on development of exogenous contrast agents that can enhance the morphological features important for cancer detection and that have the potential to allow vital molecular imaging of cancer‐related biomarkers. In conclusion, we discuss future improvements to the technology needed to develop robust clinical devices.
Assessment of Normal Variability in Peripheral Blood Gene Expression
Authors: Campbell Catherine , Vernon Suzanne D. , Karem Kevin L. , Nisenbaum Rosane , Unger Elizabeth R.
Published: June 2013

Peripheral blood is representative of many systemic processes and is an ideal sample for expression profiling of diseases that have no known or accessible lesion. Peripheral blood is a complex mixture of cell types and some differences in peripheral blood gene expression may reflect the timing of sample collection rather than an underlying disease process. For this reason, it is important to assess study design factors that may cause variability in gene expression not related to what is being analyzed. Variation in the gene expression of circulating peripheral blood mononuclear cells (PBMCs) from three healthy volunteers sampled three times one day each week for one month was examined for 1,176 genes printed on filter arrays. Less than 1% of the genes showed any variation in expression that was related to the time of collection, and none of the changes were noted in more than one individual. These results suggest that observed variation was due to experimental variability.
Novel Approaches to Identification of Biomarkers for Detection of Early Stage Cancer
Authors: Kiviat Nancy B. , Critchlow Cathy W.
Published: June 2013

Implementation of routine cancer screening accompanied by treatment of early stage disease is paramount to realizing reductions in cancer mortality rates. While morphologic assessment of relevant cells has traditionally been used to identify individuals with cancer, this approach is not feasible to identify cancers at inaccessible sites, such as the ovary or pancreas. For these and many other cancers, cancer mortality remains high, as sensitive and specific screening assays to detect in‐situ or early stage disease are as yet unavailable. Identification of novel markers for early identification of cancer is an established priority of the National Cancer Institute. The rapid expansion of genomic‐based technologies developed over the last decade, and the development of sensitive and specific blood‐based assays for the detection of molecular changes associated with cancer, begin to offer the means for achieving this goal. Below, we review current approaches used in the effort to identify biomarkers appropriate for early cancer detection.
Nanotechnology: Emerging Developments and Early Detection of Cancer. A Two‐Day Workshop Sponsored by the National Cancer Institute and the National Institute of Standards and Technology, August 30–31 2001, on the National Institute of Standards and Technology Campus, Gaithersburg, MD, USA
Authors: Zullo Steven J. , Srivastava Sudhir , Looney J. Patrick , Barker Peter E.
Published: June 2013

A recent meeting jointly sponsored by the National Cancer Institute (NCI) and National Institute of Standards and Technology (NIST) brought together researchers active in nanotechnology and cancer molecular biology to discuss and evaluate the interface between disciplines. Emerging areas where nanotechnologies may impact cancer prevention and early cancer detection were elaborated by key researchers who catalyzed interdisciplinary dialogue aimed at fostering cross‐discipline communications and future collaboration.
Intravital Fluorescence Facilitates Measurement of Multiple Physiologic Functions and Gene Expression in Tumors of Live Animals
Authors: Dewhirst Mark W. , Shan S. , Cao Yiting , Moeller Benjamin , Yuan Fan , Li Chuan-Yuan
Published: June 2013

The purpose of this report is to present an overview of the use of fluorescence imaging in vivo, with particular emphasis on oncology. It is important to note, however, that many of the methods described herein have been applied to the study of non‐malignant tissues as well. Modern medicine and biology research has benefited greatly from an ever‐expanding assortment of fluorescent markers and labels. These markers and labels have allowed investigators to observe the behavior and properties of cell and molecular entities of interest in the context of complicated biological systems such as a mammalian cell or a whole mouse. Methods developed to image fluorescence in whole mice have been valuable in studying patterns of tumor growth and metastases. Alternatively, more detailed information and a wide variety of endpoints can be obtained using “intravital” preparations. This review focuses on use of fluorescence imaging for intravital preparations. For detail on fluorescence imaging of whole animals, refer to reviews on this subject [1,2]. For oncologic applications, studies have focused primarily on window chamber preparations that allow for real‐time visualization of tumor growth, vascularity, vascular responses to stimulation, vascular permeability, vascular orientation, flow instability, and the like. These endpoints have been used to show that there are functional differences between tumor and normal tissues with respect to these functions under baseline conditions and after therapeutic manipulation. Examples of some of these differences are provided in this review as a means to illustrate how they can be used.
Mechanical Spectral Signatures of Malignant Disease? A Small‐Sample, Comparative Study of Continuum vs. Nano‐Biomechanical Data Analyses
Authors: Liu Jun , Ferrari Mauro
Published: June 2013

Thin sections from human breast biopsies were employed to perform a differential analysis of the ultrasound spectral responses from invasive ductal carcinoma and normal tissue. A non‐destructive testing methodology was employed, yielding the reflection coefficients as function of frequency in the clinical ultrasound range. The spectral responses were simulated both in the context of continuum and nano‐biomechanics, with the objective of quantifying the physical properties that determine the differences in the spectral signature of normal vs. malignant tissue. The properties that were employed for the theoretical reconstruction of the spectra were: the density, the continuum and the nanomechanical elastic constants, and the nanomechanical theory internodal distance. The latter is a measure of the depth‐of‐penetration of mechanical actions between contiguous tissue elements. Together with vectorial descriptors of the tissue spatial arrangement, the internodal distance variable affords the quantitative incorporation of tissue architectural data in the theoretical model.

In this paper, the validity of the nanomechanical approach to tissue characterization is discussed, and its potential extensions to biomolecular marker‐based cancer diagnostics and therapeutics are considered.
p53 and erbB‐2 Are Not Associated in Matched Cases of Primary and Metastatic Ovarian Carcinomas
Authors: Rodríguez-Burford Cristina , Chhieng David C. , Stockard Cecil R. , Kleinberg Marc J. , Barnes Mack N. , Partridge Edward E. , Weiss Heidi L. , Grizzle William E.
Published: June 2013

Ovarian cancer has a high mortality rate largely due to the limited number of ovarian carcinomas detected at an early stage. Understanding the molecular changes occurring during the progression of ovarian carcinoma would aid in the development of therapies that may inhibit or target metastasis. Primary and metastatic lesions from 54 and 40 patients with advanced ovarian carcinoma, respectively (including matched primary and metastatic lesions from 30 patients) were evaluated for nuclear accumulation of p53 (clone BP53‐12‐1) and cytoplasmic and membranous immunostaining of p185 erbB‐2 (clone 3B5) by immunohistochemistry. No differences in the immunostaining of p53 and p185erbB‐2 (cytoplasm or membrane) were observed between primary and metastatic lesions of the matched cases. Similarly, no differences in the proportion of positive cases of p53 between primary and metastatic lesions of the matched cases was observed. Thus, novel therapies that target p53 or p185erbB‐2 can utilize specimens from either primary or metastatic lesions to characterize these targets prior to therapy. Spearman correlations between p53 and p185erbB‐2 (cytoplasm or membrane) immunohistochemistry scores were insignificant for the matched cases, all primary lesions, and all metastatic lesions. Also, no significant associations occurred between nuclear accumulation of p53 (positive versus negative) and phenotypic expression of p185erbB‐2 (cytoplasm or membrane) immunostaining scores for the matched cases, all primary lesions, and all metastatic lesions. Thus, the nuclear accumulation of p53 and immunostaining of p185erbB‐2 in the cytoplasm or on the cellular membranes are independent.
Development of Proteomic Patterns for Detecting Lung Cancer
Authors: Xiao Xueyuan , Liu Danhui , Tang Ying , Guo Fuzheng , Xia Liang , Liu Jin , He Dacheng
Published: June 2013

Lung cancer is at present the number one cause of cancer death and no biomarker is available to detect early lung cancer in serum samples so far. The objective of this study is to find specific biomarkers for detection of lung cancer using Surface Enhanced Laser Desorption/Ionization (SELDI) technology. In this study, serum samples from 30 lung cancer patients and 51 age‐and sex‐matched healthy were analyzed by SELDI based ProteinChip reader, PBSII‐C. The spectra were generated on WCX2 chips and protein peaks clustering and classification analyses were performed utilizing Biomarker Wizard and Biomarker Patterns software packages, respectively. Three protein peaks were automatically chosen for the system training and the development of a decision classification tree. The constructed model was then used to test an independent set of masked serum samples from 15 lung cancer patients and 31 healthy individuals. The analysis yielded a sensitivity of 93.3%, and a specificity of 96.7%. These results suggest that the serum is a capable resource for detection of specific lung cancer biomarkers. SELDI technique combined with an artificial intelligence classification algorithm can both facilitate the discovery of better biomarkers for lung cancer and provide a useful tool for molecular diagnosis in future.
Identification of HNPCC by Molecular Analysis of Colorectal and Endometrial Tumors
Authors: Vasen H. F. A. , Hendriks Y. , de Jong A. E. , van Puijenbroek M. , Tops C. , Bröcker-Vriends A. H. J. T. , Wijnen J. Th. , Morreau H.
Published: June 2013

Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is a dominantly inherited syndrome characterized by the development of colorectal cancer, endometrial cancer and other cancers and the presence of microsatellite instability (MSI) in tumors. The Bethesda guidelines have been proposed for the identification of families suspected of HNPCC that require further molecular analysis. We have evaluated the yield of MSI‐analysis in a large series of Dutch families suspected of HNPCC. We also analysed whether the loss of mismatch repair (MMR) protein detected by immunohistochemistry (IHC) of colorectal cancer (CRC) and endometrial cancer correlated with the presence of MSI and/or a MMR gene mutation. The results showed that the Bethesda criteria with a few modifications are appropriate to identify families eligible for genetic testing. In addition, we found that MSI and IHC‐analysis of CRC using antibodies against MLH1, MSH2, MSH6 and PMS2 proteins are equally effective for identifying carriers of the known MMR gene defects. However, as long as the role of other putative MMR genes in hereditary CRC has not been elucidated, IHC‐analysis cannot completely replace MSI. For this reason, we prefer MSI‐analysis as first step in families suspected of HNPCC. On the other hand, in families fulfilling the revised Amsterdam criteria in which the probability of detecting a mutation is relatively high, we would recommend IHC as first diagnostic step because the result might predict the specific underlying MMR gene mutation. MSI or IHC‐analysis of endometrial cancer alone was found to be less sensitive compared with these tests performed in colorectal cancer. Therefore, probably the best approach in the analysis of this cancer is to perform both techniques. The identification of HNPCC is important as it makes it possible to target effective preventative measures. Our studies showed that MSI and IHC analysis of colorectal and endometrial cancer, are reliable cost‐effective tools that can be used to identify patients with HNPCC.
In Vivo Measurement of Phosphorous Markers of Disease
Authors: Arias-Mendoza Fernando , Brown Truman R.
Published: June 2013

Phosphorus Magnetic Resonance Spectroscopy (31P‐MRS) has been utilized to study energy, carbohydrate, and phospholipid metabolism in vitro and in vivo in live tissues non‐invasively. Despite its lack of sensitivity, its application has extended to in situ human tissues and organs since proper signal localization was devised. Follow‐up of phosphocreatine in neuromuscular diseases and schizophrenia and follow‐up of phospholipid‐related molecules in tumors are described here to demonstrate the value of 31P‐MRS as an imaging technique to determine in vivo markers of disease and in the diagnosis, prognosis, and follow‐up of human diseases.
Magnetic Resonance Spectroscopic Imaging of Tumor Metabolic Markers for Cancer Diagnosis, Metabolic Phenotyping, and Characterization of Tumor Microenvironment
Authors: He Qiuhong , Xu Ray Z. , Shkarin Pavel , Pizzorno Giuseppe , Lee-French Carol H. , Rothman Douglas L. , Shungu Dikoma C. , Shim Hyunsuk
Published: June 2013

Cancer cells display heterogeneous genetic characteristics, depending on the tumor dynamic microenvironment. Abnormal tumor vasculature and poor tissue oxygenation generate a fraction of hypoxic tumor cells that have selective advantages in metastasis and invasion and often resist chemo‐ and radiation therapies. The genetic alterations acquired by tumors modify their biochemical pathways, which results in abnormal tumor metabolism. An elevation in glycolysis known as the “Warburg effect” and changes in lipid synthesis and oxidation occur. Magnetic resonance spectroscopy (MRS) has been used to study tumor metabolism in preclinical animal models and in clinical research on human breast, brain, and prostate cancers. This technique can identify specific genetic and metabolic changes that occur in malignant tumors. Therefore, the metabolic markers, detectable by MRS, not only provide information on biochemical changes but also define different metabolic tumor phenotypes. When combined with the contrast‐enhanced Magnetic Resonance Imaging (MRI), which has a high sensitivity for cancer diagnosis, in vivo magnetic resonance spectroscopic imaging (MRSI) improves the diagnostic specificity of malignant human cancers and is becoming an important clinical tool for cancer management and care. This article reviews the MRSI techniques as molecular imaging methods to detect and quantify metabolic changes in various tumor tissue types, especially in extracranial tumor tissues that contain high concentrations of fat. MRI/MRSI methods have been used to characterize tumor microenvironments in terms of blood volume and vessel permeability. Measurements of tissue oxygenation and glycolytic rates by MRS also are described to illustrate the capability of the MR technology in probing molecular information non‐invasively in tumor tissues and its important potential for studying molecular mechanisms of human cancers in physiological conditions.
Ultrasound‐Mediated Biophotonic Imaging: A Review of Acousto‐Optical Tomography and Photo‐Acoustic Tomography
Authors: Wang Lihong V.
Published: June 2013

This article reviews two types of ultrasound‐mediated biophotonic imaging–acousto‐optical tomography (AOT, also called ultrasound‐modulated optical tomography) and photo‐acoustic tomography (PAT, also called opto‐acoustic or thermo‐acoustic tomography)–both of which are based on non‐ionizing optical and ultrasonic waves. The goal of these technologies is to combine the contrast advantage of the optical properties and the resolution advantage of ultrasound. In these two technologies, the imaging contrast is based primarily on the optical properties of biological tissues, and the imaging resolution is based primarily on the ultrasonic waves that either are provided externally or produced internally, within the biological tissues. In fact, ultrasonic mediation overcomes both the resolution disadvantage of pure optical imaging in thick tissues and the contrast and speckle disadvantages of pure ultrasonic imaging. In our discussion of AOT, the relationship between modulation depth and acoustic amplitude is clarified. Potential clinical applications of ultrasound‐mediated biophotonic imaging include early cancer detection, functional imaging, and molecular imaging.
Evaluation on the Use of β‐Lactamase and Aminoglycoside Modifying Enzyme Gene Sequences as Markers for the Early Detection of Antibiotic Resistance Profile of Pseudomonas aeruginosa
Authors: Doss Victor A. , Parvathi S. , Raju B. Appala , Devi N. Abitha
Published: June 2013

Pseudomonas aeruginosa is one of the major causes of infections including the hospital acquired (Nosocomial) infections. Detection of them and their antibiotic resistance profile by conventional method takes about three days. Recently, DNA based diagnostic methods are being used for the identification of the pathogens. Hence we have tested a rapid and sensitive method using DNA sequences as markers for detecting the presence of three genes coding for the enzymes that inactivate the two most commonly used Anti‐pseudomonadal drugs such as β‐lactam antibiotics (Penicillin, and its derivatives) and Aminoglycosides such as Gentamicin, Tobramycin, Amikacin, Streptomycin. The internal region of these genes were used for designing and synthesizing primers and these primers were used in Polymerase Chain Reaction (PCR) to screen for the presence of these genes in the clinical isolates and to label them non‐radioactively with Biotin. They in turn were used to detect the presence of the antibiotic resistance genes in the clinical isolates by hybridization. The specificity (ratio of positive results obtained in both methods and the sensitivity (the minimum amount of sample DNA and the labeled probe required for the tests) were evaluated.
The Matrix Metalloproteinase‐3 (MMP‐3) 5A/6A Promoter Polymorphism Is Not Associated with Ischaemic Heart Disease: Analysis Employing a Family Based Approach
Authors: McGlinchey Paul G. , Spence Mark S. , Patterson Chris C. , Allen Adrian R. , Murphy Gillian , Fogarty Damian , Evans Alun , McKeown Pascal P.
Published: June 2013

Matrix metalloproteinase‐3 (MMP‐3) has been proposed as an important mediator of the atherosclerotic process. The possible role of the functional ‐1612 5A/6A polymorphism of the MMP‐3 gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well‐defined Irish population using two recently described family based tests of association. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped. Using the combined transmission disequilibrium test (TDT)/sib‐TDT and the pedigree disequilibrium test (PDT), no association between the MMP‐3 ‐1612 5A/6A polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the MMP‐3 ‐1612 5A/6A polymorphism is not associated with IHD.