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author:("yoph, Arjun")
1.  Neurovascular coupling varies with level of global cerebral ischemia in a rat model 
In this study, cerebral blood flow, oxygenation, metabolic, and electrical functional responses to forepaw stimulation were monitored in rats at different levels of global cerebral ischemia from mild to severe. Laser speckle contrast imaging and optical imaging of intrinsic signals were used to measure changes in blood flow and oxygenation, respectively, along with a compartmental model to calculate changes in oxygen metabolism from these measured changes. To characterize the electrical response to functional stimulation, we measured somatosensory evoked potentials (SEPs). Global graded ischemia was induced through unilateral carotid artery occlusion, bilateral carotid artery occlusion, bilateral carotid and right subclavian artery (SCA) occlusion, or carotid and SCA occlusion with negative lower body pressure. We found that the amplitude of the functional metabolic response remained tightly coupled to the amplitude of the SEP at all levels of ischemia observed. However, as the level of ischemia became more severe, the flow response was more strongly attenuated than the electrical response, suggesting that global ischemia was associated with an uncoupling between the functional flow and electrical responses.
doi:10.1038/jcbfm.2012.137
PMCID: PMC3597370  PMID: 23032485
cerebral hemodynamics; evoked potentials; global ischemia; intrinsic optical imaging; neurovascular coupling
2.  Optical Monitoring and Detection of Spinal Cord Ischemia 
PLoS ONE  2013;8(12):e83370.
Spinal cord ischemia can lead to paralysis or paraparesis, but if detected early it may be amenable to treatment. Current methods use evoked potentials for detection of spinal cord ischemia, a decades old technology whose warning signs are indirect and significantly delayed from the onset of ischemia. Here we introduce and demonstrate a prototype fiber optic device that directly measures spinal cord blood flow and oxygenation. This technical advance in neurological monitoring promises a new standard of care for detection of spinal cord ischemia and the opportunity for early intervention. We demonstrate the probe in an adult Dorset sheep model. Both open and percutaneous approaches were evaluated during pharmacologic, physiological, and mechanical interventions designed to induce variations in spinal cord blood flow and oxygenation. The induced variations were rapidly and reproducibly detected, demonstrating direct measurement of spinal cord ischemia in real-time. In the future, this form of hemodynamic spinal cord diagnosis could significantly improve monitoring and management in a broad range of patients, including those undergoing thoracic and abdominal aortic revascularization, spine stabilization procedures for scoliosis and trauma, spinal cord tumor resection, and those requiring management of spinal cord injury in intensive care settings.
doi:10.1371/journal.pone.0083370
PMCID: PMC3865183  PMID: 24358279
3.  Optical malignancy parameters for monitoring progression of breast cancer neoadjuvant chemotherapy 
Biomedical Optics Express  2012;4(1):105-121.
We introduce and demonstrate use of a novel, diffuse optical tomography (DOT) based breast cancer signature for monitoring progression of neoadjuvant chemotherapy. This signature, called probability of malignancy, is obtained by statistical image analysis of total hemoglobin concentration, blood oxygen saturation, and scattering coefficient distributions in the breast tomograms of a training-set population with biopsy-confirmed breast cancers. A pilot clinical investigation adapts this statistical image analysis approach for chemotherapy monitoring of three patients. Though preliminary, the study shows how to use the malignancy parameter for separating responders from partial-responders and demonstrates the potential utility of the methodology compared to traditional DOT quantification schemes.
doi:10.1364/BOE.4.000105
PMCID: PMC3539198  PMID: 23304651
(170.3830) Mammography; (170.3880) Medical and biological imaging; (170.1610) Clinical applications; (170.6510) Spectroscopy, tissue diagnostics
4.  NON-INVASIVE MEASUREMENT OF DEEP TISSUE TEMPERATURE CHANGES CAUSED BY APOPTOSIS DURING BREAST CANCER NEOADJUVANT CHEMOTHERAPY: A CASE STUDY 
Treatment-induced apoptosis of cancer cells is one goal of cancer therapy. Interestingly, more heat is generated by mitochondria during apoptosis, especially the uncoupled apoptotic state,1,2 compared to the resting state. In this case study, we explore these thermal effects by longitudinally measuring temperature variations in a breast lesion of a pathological complete responder during neadjuvant chemotherapy (NAC). Diffuse Optical Spectroscopic Imaging (DOSI) was employed to derive absolute deep tissue temperature using subtle spectral features of the water peak at 975 nm.3 A significant temperature increase was observed in time windows during the anthracycline and cyclophosphamide (AC) regimen but in not paclitaxel and bevacizumab regimen. Hemoglobin concentration changes generally did not follow temperature, suggesting that the measured temperature increases were likely due to mitochondrial uncoupling rather than a direct vascular effect. A simultaneous increase of tissue oxygen saturation with temperature was also observed, suggesting that oxidative stress also contributes to apoptosis. Although preliminary, this study indicates that longitudinal DOSI tissue temperature monitoring provides information that can improve our understanding of the mechanisms of tissue response during NAC.
doi:10.1142/S1793545811001708
PMCID: PMC3296557  PMID: 22408653
5.  O2 Regulates Skeletal Muscle Progenitor Differentiation through Phosphatidylinositol 3-Kinase/AKT Signaling 
Molecular and Cellular Biology  2012;32(1):36-49.
Skeletal muscle stem/progenitor cells, which give rise to terminally differentiated muscle, represent potential therapies for skeletal muscle diseases. Delineating the factors regulating these precursors will facilitate their reliable application in human muscle repair. During embryonic development and adult regeneration, skeletal muscle progenitors reside in low-O2 environments before local blood vessels and differentiated muscle form. Prior studies established that low O2 levels (hypoxia) maintained muscle progenitors in an undifferentiated state in vitro, although it remained unclear if progenitor differentiation was coordinated with O2 availability in vivo. In addition, the molecular signals linking O2 to progenitor differentiation are incompletely understood. Here we show that the muscle differentiation program is repressed by hypoxia in vitro and ischemia in vivo. Surprisingly, hypoxia can significantly impair differentiation in the absence of hypoxia-inducible factors (HIFs), the primary developmental effectors of O2. In order to maintain the undifferentiated state, low O2 levels block the phosphatidylinositol 3-kinase/AKT pathway in a predominantly HIF1α-independent fashion. O2 deprivation affects AKT activity by reducing insulin-like growth factor I receptor sensitivity to growth factors. We conclude that AKT represents a key molecular link between O2 and skeletal muscle differentiation.
doi:10.1128/MCB.05857-11
PMCID: PMC3255700  PMID: 22006022
6.  Two-Photon Absorption Properties of Proquinoidal D-A-D and A-D-A Quadrupolar Chromophores 
The journal of physical chemistry. A  2011;115(22):5525-5539.
We report the synthesis, one- and two-photon absorption spectroscopy, fluorescence, and electrochemical properties of a series of quadrupolar molecules that feature proquinoidal π-aromatic acceptors. These quadrupolar molecules possess either donor-acceptor-donor (D–A–D) or acceptor-donor-acceptor (A–D–A) electronic motifs, and feature 4-N,N-dihexylaminophenyl, 4-dodecyloxyphenyl, 4-(N,N-dihexylamino)benzo[c][1,2,5]thiadiazolyl or 2,5-dioctyloxyphenyl electron donor moieties and benzo[c][1,2,5]thiadiazole (BTD) or 6,7-bis(3’,7’-dimethyloctyl)[1,2,5]thiadiazolo[3,4-g]quinoxaline (TDQ) electron acceptor units. These conjugated structures are highly emissive in nonpolar solvents and exhibit large spectral red-shifts of their respective lowest energy absorption bands relative to analogous reference compounds that incorporate phenylene components in place of BTD and TDQ moieties. BTD-based D-A-D and A-D-A chromophores exhibit increasing fluorescence emission red-shifts, and a concomitant decrease of the fluorescence quantum yield (Φf) with increasing solvent polarity; these data indicate that electronic excitation augments benzothiadiazole electron density via an internal charge transfer mechanism. The BTD- and TDQ-containing structures exhibit blue-shifted two-photon absorption (TPA) spectra relative to their corresponding one-photon absorption (OPA) spectra, and display high TPA cross-sections (>100 GM) within these spectral windows. D-A-D and A-D-A structures that feature more extensive conjugation within this series of compounds exhibit larger TPA cross-sections consistent with computational simulation. Factors governing TPA properties of these quadrupolar chromophores are discussed within the context of a three-state model.
doi:10.1021/jp2000738
PMCID: PMC3121192  PMID: 21568299
7.  Tumor Blood Flow Differs between Mouse Strains: Consequences for Vasoresponse to Photodynamic Therapy 
PLoS ONE  2012;7(5):e37322.
Fluctuations in tumor blood flow are common and attributed to factors such as vasomotion or local vascular structure, yet, because vessel structure and physiology are host-derived, animal strain of tumor propagation may further determine blood flow characteristics. In the present report, baseline and stress-altered tumor hemodynamics as a function of murine strain were studied using radiation-induced fibrosacomas (RIF) grown in C3H or nude mice. Fluctuations in tumor blood flow during one hour of baseline monitoring or during vascular stress induced by photodynamic therapy (PDT) were measured by diffuse correlation spectroscopy. Baseline monitoring revealed fluctuating tumor blood flow highly correlated with heart rate and with similar median periods (i.e., ∼9 and 14 min in C3H and nudes, respectively). However, tumor blood flow in C3H animals was more sensitive to physiologic or stress-induced perturbations. Specifically, PDT-induced vascular insults produced greater decreases in blood flow in the tumors of C3H versus nude mice; similarly, during baseline monitoring, fluctuations in blood flow were more regular and more prevalent within the tumors of C3H mice versus nude mice; finally, the vasoconstrictor L-NNA reduced tumor blood flow in C3H mice but did not affect tumor blood flow in nudes. Underlying differences in vascular structure, such as smaller tumor blood vessels in C3H versus nude animals, may contribute to strain-dependent variation in vascular function. These data thus identify clear effects of mouse strain on tumor hemodynamics with consequences to PDT and potentially other vascular-mediated therapies.
doi:10.1371/journal.pone.0037322
PMCID: PMC3356280  PMID: 22624014
8.  Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes 
The Journal of Clinical Investigation  2012;122(4):1427-1443.
Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2α (HIF-2α) is highly expressed in vascular ECs and, along with HIF-1α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2α regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2α expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2α–deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2α–dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2α–dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2α in ECs. These results indicate that HIF-1α and HIF-2α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.
doi:10.1172/JCI57322
PMCID: PMC3314446  PMID: 22426208
9.  Direct measurement of tissue blood flow and metabolism with diffuse optics 
Diffuse optics has proven useful for quantitative assessment of tissue oxy- and deoxyhaemoglobin concentrations and, more recently, for measurement of microvascular blood flow. In this paper, we focus on the flow monitoring technique: diffuse correlation spectroscopy (DCS). Representative clinical and pre-clinical studies from our laboratory illustrate the potential of DCS. Validation of DCS blood flow indices in human brain and muscle is presented. Comparison of DCS with arterial spin-labelled MRI, xenon-CT and Doppler ultrasound shows good agreement (0.50
doi:10.1098/rsta.2011.0232
PMCID: PMC3263785  PMID: 22006897
diffuse correlation spectroscopy; blood flow; cerebral blood flow; oxygen metabolism; brain; cancer
Journal of biomedical optics  2009;14(3):034015.
We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R = 0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.
doi:10.1117/1.3146814
PMCID: PMC3169814  PMID: 19566308
diffuse correlation spectroscopy (DCS); diffuse reflectance spectroscopy (DRS); cerebral hemodynamics; cerebral blood flow; traumatic brain injury; near—infrared spectroscopy (NIRS)
Head & Neck Oncology  2011;3:38.
While histopathology of excised tissue remains the gold standard for diagnosis, several new, non-invasive diagnostic techniques are being developed. They rely on physical and biochemical changes that precede and mirror malignant change within tissue. The basic principle involves simple optical techniques of tissue interrogation. Their accuracy, expressed as sensitivity and specificity, are reported in a number of studies suggests that they have a potential for cost effective, real-time, in situ diagnosis.
We review the Third Scientific Meeting of the Head and Neck Optical Diagnostics Society held in Congress Innsbruck, Innsbruck, Austria on the 11th May 2011. For the first time the HNODS Annual Scientific Meeting was held in association with the International Photodynamic Association (IPA) and the European Platform for Photodynamic Medicine (EPPM). The aim was to enhance the interdisciplinary aspects of optical diagnostics and other photodynamic applications. The meeting included 2 sections: oral communication sessions running in parallel to the IPA programme and poster presentation sessions combined with the IPA and EPPM posters sessions.
doi:10.1186/1758-3284-3-38
PMCID: PMC3180646  PMID: 21861912
Neurocritical care  2010;12(2):173-180.
Background
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Methods
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
Results
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
Conclusions
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
doi:10.1007/s12028-009-9305-x
PMCID: PMC2844468  PMID: 19908166
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care
The complete surgical removal of disease is a desirable outcome particularly in oncology. Unfortunately much disease is microscopic and difficult to detect causing a liability to recurrence and worsened overall prognosis with attendant costs in terms of morbidity and mortality. It is hoped that by advances in optical diagnostic technology we could better define our surgical margin and so increase the rate of truly negative margins on the one hand and on the other hand to take out only the necessary amount of tissue and leave more unaffected non-diseased areas so preserving function of vital structures. The task has not been easy but progress is being made as exemplified by the presentations at the 2nd Scientific Meeting of the Head and Neck Optical Diagnostics Society (HNODS) in San Francisco in January 2010. We review the salient advances in the field and propose further directions of investigation.
doi:10.1186/1758-3284-3-7
PMCID: PMC3048561  PMID: 21306627
Photodynamic therapy (PDT) can lead to the creation of heterogeneous, response-limiting hypoxia during illumination, which may be controlled in part through illumination fluence rate. In the present report we consider 1) regional differences in hypoxia, vascular response, and cell kill as a function of tumor depth and 2) the role of fluence rate as a mediator of depth-dependent regional intratumor heterogeneity. Intradermal RIF murine tumors were treated with Photofrin-PDT using surface illumination at an irradiance of 75 or 38 mW/cm2. Regional heterogeneity in tumor response was examined through comparison of effects in the surface vs. base of tumors, i.e. along a plane parallel to the skin surface and perpendicular to the incident illumination. 75 mW/cm2-PDT created significantly greater hypoxia in tumor bases relative to their surfaces. Increased hypoxia in the tumor base could not be attributed to regional differences in Photofrin concentration nor effects of fluence rate distribution on photochemical oxygen consumption, but significant depth-dependent heterogeneity in vascular responses and cytotoxic response were detected. At a lower fluence rate of 38 mW/cm2, no detectable regional differences in hypoxia or cytotoxic responses were apparent, and heterogeneity in vascular response was significantly less than that during 75 mW/cm2-PDT. This research suggests that the benefits of low-fluence-rate-PDT are mediated in part by a reduction in intratumor heterogeneity in hypoxic, vascular and cytotoxic responses.
doi:10.1039/b9pp00004f
PMCID: PMC2834171  PMID: 20024165
photodynamic therapy; fluence rate; hypoxia; EF3; blood flow
Biomedical Optics Express  2010;1(4):1173-1187.
Murine hindlimb ischemia is a useful model for investigation of the mechanisms of peripheral arterial disease and for understanding the role of endothelial cells and generic factors affecting vascular regeneration or angiogenesis. To date, important research with these models has explored tissue reperfusion following ischemia with Laser Doppler methods, methods which provide information about superficial (~mm) vascular regeneration. In this work, we employ diffuse correlation spectroscopy (DCS) and diffuse optical spectroscopy (DOS) in mice after hindlimb ischemia. We hypothesize that vascular re-growth is not uniform in tissue, and therefore, since diffuse optical methods are capable of probing deep tissues, that the diffuse optics approach will provide a more complete picture of the angiogenesis process throughout the whole depth profile of the limb. Besides increased depth penetration, the combined measurements of DCS and DOS enable all-optical, noninvasive, longitudinal monitoring of tissue perfusion and oxygenation that reveals the interplay between these hemodynamic parameters during angiogenesis. Control mice were found to reestablish 90% of perfusion and oxygen consumption during this period, but oxygen saturation in the limb only partially recovered to about 30% of its initial value. The vascular recovery of mice with endothelial cell-specific deletion of HIF-2α was found to be significantly impaired relative to control mice, indicating that HIF-2α is important for endothelial cell functions in angiogenesis. Comparison of DOS/DCS measurements to parallel measurements in the murine models using Laser Doppler Flowmetry reveal differences in the reperfusion achieved by superficial versus deep tissue during neoangiogenesis; findings from histological analysis of blood vessel development were further correlated with these differences. In general, the combination of DCS and DOS enables experimenters to obtain useful information about oxygenation, metabolism, and perfusion throughout the limb. The results establish diffuse optics as a practical noninvasive method to evaluate the role of transcription factors, such as the endothelial cell-specific HIF-2α, in genetic ally modified mice.
doi:10.1364/BOE.1.001173
PMCID: PMC3018079  PMID: 21258539
(170.3880) Medical and biological imaging; (170.1420) Biology; (170.3660) Light propagation in tissues; (170.5380) Physiology
Our group has already published the possible neuroprotective effect of contralateral forepaw stimulation in temporary focal ischemia in a study. However, the background is still unclear. In the present study we investigated the possible mechanism by monitoring focal ischemia with multispectral [laser speckle, imaging of intrinsic signals (OIS)] imaging. Sprague–Dawley rats were prepared using 1.2% isoflurane anesthesia. The middle cerebral artery was occluded by photothrombosis (4 mW) and the common carotid artery was ligated permanently. Physiological variables were constantly monitored during the experiment. A 6 × 6 mm area centered 3 mm posterior and 4 mm lateral to Bregma was thinned for laser speckle and OIS imaging. Nine circular regions of interests (0.3 mm in diameter) were evenly spaced on the speckle contrast image for the analysis of peri-infarct flow transients, blood flow, and metabolic changes. Both the sham (n = 7) and forepaw-stimulated animals (n = 7) underwent neurological examinations 24 h after ischemia at which point all animals were sacrificed and the infarct size was determined by triphenyltetrazolium chloride. The physiological variables were in normal range and the experimental protocol did not cause significant differences between groups. Both the neurological scores (sham: 3.6 ± 1.7, stimulated: 4.3 ± 1.4) and the infarct volume (sham: 124 ± 39 mm3, stimulated: 147 ± 47 mm3) did not show significant differences between groups. The forepaw stimulation did not increase the intra-ischemic flow neither over the penumbral or the peri-ischemic area. However, the hemoglobin transients related metabolic load (CMRO2) was significantly lower (p < 0.001) while the averaged number of hyperemic flow transients were significantly (p = 0.013) higher in the forepaw (sham: 3.5 ± 2.2, stimulated: 7.0 ± 2.3) stimulated animals.
doi:10.3389/fnene.2010.00019
PMCID: PMC2922941  PMID: 20725601
optical imaging; focal cerebral ischemia; forepaw stimulation; middle cerebral artery occlusion; photothrombosis; speckle contrast; OIS; flow transients
Journal of biomedical optics  2009;14(2):024020.
We have developed a novel parallel-plate diffuse optical tomography (DOT) system for three-dimensional in vivo imaging of human breast tumor based on large optical data sets. Images of oxy-, deoxy-, total-hemoglobin concentration, blood oxygen saturation, and tissue scattering were reconstructed. Tumor margins were derived using the optical data with guidance from radiology reports and Magnetic Resonance Imaging. Tumor-to-normal ratios of these endogenous physiological parameters and an optical index were computed for 51 biopsy-proven lesions from 47 subjects. Malignant cancers (N=41) showed statistically significant higher total hemoglobin, oxy-hemoglobin concentration, and scattering compared to normal tissue. Furthermore, malignant lesions exhibited a two-fold average increase in optical index. The influence of core biopsy on DOT results was also explored; the difference between the malignant group measured before core biopsy and the group measured more than one week after core biopsy was not significant. Benign tumors (N=10) did not exhibit statistical significance in the tumor-to-normal ratios of any parameter. Optical index and tumor-to-normal ratios of total hemoglobin, oxy-hemoglobin concentration, and scattering exhibited high area under the receiver operating characteristic curve values from 0.90 to 0.99, suggesting good discriminatory power. The data demonstrate that benign and malignant lesions can be distinguished by quantitative three-dimensional DOT.
doi:10.1117/1.3103325
PMCID: PMC2782703  PMID: 19405750
Breast Cancer; Diffuse Optical Tomography; Near Infrared Light; Photon Migration; Optical Mammography
After complete cerebral ischemia, the postischemic blood flow response to functional activation is severely attenuated for several hours. However, little is known about the spatial and temporal extent of the blood flow response in the acute postischemic period after incomplete cerebral ischemia. To investigate the relative cerebral blood flow (rCBF) response in the somatosensory cortex of rat to controlled vibrissae stimulation after transient incomplete ischemia (15-min bilateral common carotid artery occlusion + hypotension), we employed laser speckle imaging combined with statistical parametric mapping. We found that the ischemic insult had a significant impact on the baseline blood flow (P < 0.005) and the activation area in response to functional stimulation was significantly reduced after ischemia (P < 0.005). The maximum rCBF response in the activation area determined from the statistical analysis did not change significantly up to 3 h after ischemia (P > 0.1). However, the time when rCBF response reached its maximum was significantly delayed (P < 0.0001) from 2.4 ± 0.2 secs before ischemia to 3.6 ± 0.1 secs at 20 mins into reperfusion (P < 0.001); the delay was reduced gradually to 2.9 ± 0.2 secs after 3 h, which was still significantly greater than that observed before the insult (P = 0.04).
doi:10.1038/jcbfm.2008.21
PMCID: PMC2771551  PMID: 18382471
cerebral blood flow; cerebral ischemia; functional activation; functional recovery; laser speckle imaging; statistical parametric map
Optics express  2009;17(5):3884-3902.
“Diffuse correlation spectroscopy” (DCS) is a technology for non-invasive transcranial measurement of cerebral blood flow (CBF) that can be hybridized with “near-infrared spectroscopy” (NIRS). Taken together these methods hold potential for monitoring hemodynamics in stroke patients. We explore the utility of DCS and NIRS to measure effects of head-of-bed (HOB) positioning at 30°, 15°, 0°, −5° and 0° angles in patients with acute ischemic stroke affecting frontal cortex and in controls. HOB positioning significantly altered CBF, oxy-hemoglobin (HbO2) and total-hemoglobin (THC) concentrations. Moreover, the presence of an ipsilateral infarct was a significant effect for all parameters. Results are consistent with the notion of impaired CBF autoregulation in the infarcted hemisphere.
PMCID: PMC2724658  PMID: 19259230
Optics express  2009;17(15):12571-12581.
Four very low birth weight, very premature infants were monitored during a 12° postural elevation using diffuse correlation spectroscopy (DCS) to measure microvascular cerebral blood flow (CBF) and transcranial Doppler ultrasound (TCD) to measure macrovascular blood flow velocity in the middle cerebral artery. DCS data correlated significantly with peak systolic, end diastolic, and mean velocities measured by TCD (pA =0.036, 0.036, 0.047). Moreover, population averaged TCD and DCS data yielded no significant hemodynamic response to this postural change (p>0.05). We thus demonstrate feasibility of DCS in this population, we show correlation between absolute measures of blood flow from DCS and blood flow velocity from TCD, and we do not detect significant changes in CBF associated with a small postural change (12°) in these patients.
PMCID: PMC2723781  PMID: 19654660
PLoS ONE  2009;4(8):e6539.
Background
Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity.
Methodology/Principal Findings
Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1α and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O2 saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic.
Conclusions/Significance
EGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.
doi:10.1371/journal.pone.0006539
PMCID: PMC2716529  PMID: 19657384
Head & Neck Oncology  2009;1:25.
Review paper and Proceedings of the Inaugural Meeting of the Head and Neck Optical Diagnostics Society (HNODS) on March 14th 2009 at University College London.
The aim of our research must be to provide breakthrough translational research which can be applied clinically in the immediate rather than the near future. We are fortunate that this is indeed a possibility and may fundamentally change current clinical and surgical practice to improve our patients' lives.
doi:10.1186/1758-3284-1-25
PMCID: PMC2720388  PMID: 19594907
Medical physics  2008;35(2):446-455.
We acquire and compare three-dimensional tomographic breast images of three females with suspicious masses using diffuse optical tomography (DOT) and positron emission tomography (PET). Co-registration of DOT and PET images was facilitated by a mutual information maximization algorithm. We also compared DOT and whole-body PET images of 14 patients with breast abnormalities. Positive correlations were found between total hemoglobin concentration and tissue scattering measured by DOT, and fluorodeoxyglucose (18F-FDG) uptake. In light of these observations, we suggest potential benefits of combining both PET and DOT for characterization of breast lesions.
doi:10.1118/1.2826560
PMCID: PMC2471877  PMID: 18383664
diffuse optical tomography; positron emission tomography; breast cancer; near-infrared imaging; breast imaging; tumor metabolism; 18F fluorodeoxyglucose; hypoxia
Optics express  2008;16(7):5048-5060.
We use diffuse optical tomography to quantitatively reconstruct images of complex phantoms with millimeter sized features located centimeters deep within a highly-scattering medium. A non-contact instrument was employed to collect large data sets consisting of greater than 107 source-detector pairs. Images were reconstructed using a fast image reconstruction algorithm based on an analytic solution to the inverse scattering problem for diffuse light.
PMCID: PMC2471872  PMID: 18542605
Low density lipoproteins (LDLs) are naturally occurring nanoparticles that are biocompatible, biodegradable and non-immunogenic. Moreover, the size of LDL particle is precisely controlled (~22 nm) by its apoB-100 component, setting them apart from liposomes and lipid micelles. LDL particles have long been proposed as a nanocarrier for targeted delivery of diagnostics and therapeutics to LDL receptor (LDLR)-positive cancers. Here, we report the design and synthesis of a novel naphthalocyanine (Nc)-based photodynamic therapy (PDT) agent, SiNcBOA, and describe its efficient reconstitution into LDL core (100:1 payload). Possessing a near-infrared (NIR) absorption wavelength (>800 nm) and extremely high extinction coefficient (>105 M–1cm–1), SiNcBOA holds the promise of treating deeply seated tumors. Reconstituted LDL particles (r-Nc-LDL) maintain the size and shape of native LDL as determined by transmission electron microscopy, and also retain their LDLR-mediated uptake by cancer cells as demonstrated by confocal microscopy. Its preferential uptake by tumor vs normal tissue was confirmed in vivo by noninvasive optical imaging technique, demonstrating the feasibility of using this nanoparticle for NIR imaging-guided PDT of cancer.
PMCID: PMC2676824  PMID: 18203443
naphthalocyanine; lipoproteins; photodynamic therapy; near-infrared optical imaging; nanoparticle; drug delivery

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