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author:("yoph, Arjun G")
1.  Diffuse correlation spectroscopy for non-invasive, micro-vascular cerebral blood flow measurement 
NeuroImage  2013;85(0 1):51-63.
Diffuse correlation spectroscopy (DCS) uses the temporal fluctuations of near-infrared (NIR) light to measure cerebral blood flow (CBF) non-invasively. Here, we provide a brief history of DCS applications in brain with an emphasis on the underlying physical ideas, common instrumentation and validation. Then we describe recent clinical research that employs DCS-measured CBF as a biomarker of patient well-being, and as an indicator of hemodynamic and metabolic response to functional stimuli.
doi:10.1016/j.neuroimage.2013.06.017
PMCID: PMC3991554  PMID: 23770408
diffuse correlation spectroscopy; cerebral blood flow; functional neuroimaging; diffuse optics; near-infrared spectroscopy; cerebral metabolic rate of oxygen extraction; ischemic stroke; neurocritical care; neonatalogy
2.  Diffuse optical monitoring of hemodynamic changes in piglet brain with closed head injury 
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)
3.  Time-to-Surgery and Pre-operative Cerebral Hemodynamics Predict Post-operative White Matter Injury in Neonates with Hypoplastic Left Heart Syndrome 
Objective
Hypoxic-ischemic white mater brain injury commonly occurs in neonates with hypoplastic left heart syndrome (HLHS). Approximately half of the HLHS survivors exhibit neurobehavioral symptoms believed to be associated with this injury, though the exact timing of the injury is not known.
Methods
Neonates with HLHS were recruited for pre- and post-operative monitoring of cerebral oxygen saturation (ScO2), cerebral oxygen extraction fraction (OEF), and cerebral blood flow (CBF) using two non-invasive optical-based techniques, namely diffuse optical spectroscopy and diffuse correlation spectroscopy. Anatomical magnetic resonance imaging (MRI) scans were performed prior to and approximately one week after surgery in order to quantify the extent and timing of the acquired white matter injury. Risk factors for developing new or worsened white matter injury were assessed using uni- and multi-variate logistic regression.
Results
Thirty-seven neonates with HLHS were studied. In a univariate analysis, neonates who developed a large volume of new, or worsened, postoperative white matter injury had a significantly longer time-to-surgery (p=0.0003). In a multivariate model, longer time between birth and surgery (i.e., time-to-surgery), delayed sternal closure, and higher pre-operative CBF were predictors of post-operative white matter injury. Additionally, longer time-to-surgery and higher pre-operative CBF on morning of surgery were correlated with lower ScO2 (p=0.03 and p=0.05) and higher OEF (p=0.05 and p=0.05).
Conclusions
Longer time-to-surgery is associated with new post-operative white matter injury in otherwise healthy neonates with HLHS. The results suggest that earlier Norwood palliation may decrease the likelihood of acquiring postoperative white matter injury.
doi:10.1016/j.jtcvs.2014.05.081
PMCID: PMC4254035  PMID: 25109755
5.  Diffuse correlation spectroscopy for measurement of cerebral blood flow: future prospects 
Neurophotonics  2014;1(1):011009.
Abstract.
Diffuse correlation spectroscopy (DCS) is an emerging optical modality used to measure cortical cerebral blood flow. This outlook presents a brief overview of the technology, summarizing the advantages and limitations of the method, and describing its recent applications to animal, adult, and infant cohorts. At last, the paper highlights future applications where DCS may play a pivotal role individualizing patient management and enhancing our understanding of neurovascular coupling, activation, and brain development.
doi:10.1117/1.NPh.1.1.011009
PMCID: PMC4292799  PMID: 25593978
cerebral blood flow; biomedical optics; spectroscopy; medical imaging
6.  Continuous Optical Monitoring of Cerebral Hemodynamics during Head-of-Bed Manipulation in Brain-Injured Adults 
Neurocritical care  2014;20(3):443-453.
Introduction
Head-of-bed manipulation is commonly performed in the neurocritical care unit to optimize cerebral blood flow (CBF), but its effects on CBF are rarely measured. This pilot study employs a novel, non-invasive instrument combining two techniques, diffuse correlation spectroscopy (DCS) for measurement of CBF and near-infrared spectroscopy (NIRS) for measurement of cerebral oxy- and deoxy-hemoglobin concentrations, to monitor patients during head-of-bed lowering.
Methods
Ten brain-injured patients and ten control subjects were monitored continuously with DCS and NIRS while the head-of-bed was positioned first at 30° and then at 0°. Relative CBF (rCBF) and concurrent changes in oxy- (ΔHbO2), deoxy- (ΔHb), and total-hemoglobin concentrations (ΔTHC) from left/right frontal cortices were monitored for 5 minutes at each position. Patient and control response differences were assessed.
Results
rCBF, ΔHbO2, and ΔTHC responses to head lowering differed significantly between brain-injured patients and healthy controls (P<0.02). For patients, rCBF changes were heterogeneous, with no net change observed in the group average (0.3% ± 28.2%, P=0.938). rCBF increased in controls (18.6% ± 9.4%, P<0.001). ΔHbO2, ΔHb, and ΔTHC increased with head lowering in both groups, but to a larger degree in brain-injured patients. rCBF correlated moderately with changes in cerebral perfusion pressure (R=0.40, P<0.001), but not intracranial pressure.
Conclusion
DCS/NIRS detected differences in CBF and oxygenation responses of brain-injured patients versus controls during head-of-bed manipulation. This pilot study supports the feasibility of continuous bedside measurement of cerebrovascular hemodynamics with DCS/NIRS and provides the rationale for further investigation in larger cohorts.
doi:10.1007/s12028-013-9849-7
PMCID: PMC3883971  PMID: 23653267
Diffuse correlation spectroscopy; Near-infrared spectroscopy; Diffuse optical spectroscopy; Head-of-bed; Cerebral blood flow; Neurocritical care; Cerebral hemodynamics
7.  Macroscopic optical physiological parameters correlate with microscopic proliferation and vessel area breast cancer signatures 
Introduction
Non-invasive diffuse optical tomography (DOT) and diffuse correlation spectroscopy (DCS) can detect and characterize breast cancer and predict tumor responses to neoadjuvant chemotherapy, even in patients with radiographically dense breasts. However, the relationship between measured optical parameters and pathological biomarker information needs to be further studied to connect information from optics to traditional clinical cancer biology. Thus we investigate how optically measured physiological parameters in malignant tumors such as oxy-, deoxy-hemoglobin concentration, tissue blood oxygenation, and metabolic rate of oxygen correlate with microscopic histopathological biomarkers from the same malignant tumors, e.g., Ki67 proliferation markers, CD34 stained vasculature markers and nuclear morphology.
Methods
In this pilot study, we investigate correlations of macroscopic physiological parameters of malignant tumors measured by diffuse optical technologies with microscopic histopathological biomarkers of the same tumors, i.e., the Ki67 proliferation marker, the CD34 stained vascular properties marker, and nuclear morphology.
Results
The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01). In a subset of the Ki67-negative group (defined by the 15 % threshold), an inverse correlation between Ki67 expression level and mammary metabolic rate of oxygen was observed (R = −0.95, p-value: 0.014). Further, CD34 stained mean-vessel-area in tumor is positively correlated with tumor-to-normal total-hemoglobin and oxy-hemoglobin concentration. Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments.
Conclusions
Collectively, the pilot data are consistent with the notion that increased blood is supplied to breast cancers, and it also suggests that less conversion of oxy- to deoxy-hemoglobin occurs in more proliferative cancers. Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0578-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0578-z
PMCID: PMC4487833  PMID: 26013572
8.  Optical Bedside Monitoring of Cerebral Blood Flow in Acute Ischemic Stroke Patients during Head of Bed Manipulation 
Background and Purpose
A primary goal of acute ischemic stroke (AIS) management is to maximize perfusion in the affected region and surrounding ischemic penumbra. However, interventions to maximize perfusion, such as flat head-of-bed (HOB) positioning, are currently prescribed empirically. Bedside monitoring of cerebral blood flow (CBF) allows the effects of interventions such as flat HOB to be monitored, and may ultimately be used to guide clinical management.
Methods
Cerebral perfusion was measured during head of bed (HOB) manipulations in 17 patients with unilateral acute ischemic stroke affecting large cortical territories in the anterior circulation. Simultaneous measurements of frontal CBF and arterial flow velocity were performed with diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound, respectively. Results were analyzed in the context of available clinical data and a previous study.
Results
Frontal CBF, averaged over the patient cohort, decreased by 17% (p=0.034) and 15% (p=0.011) in the ipsilesional and contralesional hemispheres, respectively, when HOB was changed from flat to 30°. Significant (cohort-averaged) changes in blood velocity were not observed. Individually, varying responses to HOB manipulation were observed, including paradoxical increases in CBF with increasing HOB angle. Clinical features, stroke volume, and distance to the optical probe could not explain this paradoxical response.
Conclusions
A lower HOB angle results in an increase in cortical CBF without a significant change in arterial flow velocity in AIS, but there is variability across patients in this response. Bedside CBF monitoring with DCS provides a potential means to individualize interventions designed to optimize CBF in AIS.
doi:10.1161/STROKEAHA.113.004116
PMCID: PMC4006296  PMID: 24652308
stroke; perfusion; near-infrared spectroscopy; cerebral hemodynamics; head-of-bed manipulation
9.  Blood Flow Reduction in Breast Tissue due to Mammographic Compression 
Academic radiology  2014;21(2):151-161.
Rationale and objectives
This study measures hemodynamic properties such as blood flow and hemoglobin concentration and oxygenation in the healthy human breast under a wide range of compressive loads. Because many breast-imaging technologies derive contrast from the deformed breast, these load-dependent vascular responses affect contrast agent–enhanced and hemoglobin-based breast imaging.
Methods
Diffuse optical and diffuse correlation spectroscopies were used to measure the concentrations of oxygenated and deoxygenated hemoglobin, lipid, water, and microvascular blood flow during axial breast compression in the parallel-plate transmission geometry.
Results
Significant reductions (P < .01) in total hemoglobin concentration (~30%), blood oxygenation (~20%), and blood flow (~87%) were observed under applied pressures (forces) of up to 30 kPa (120 N) in 15 subjects. Lipid and water concentrations changed <10%.
Conclusions
Imaging protocols based on injected contrast agents should account for variation in tissue blood flow due to mammographic compression. Similarly, imaging techniques that depend on endogenous blood contrasts will be affected by breast compression during imaging.
doi:10.1016/j.acra.2013.10.009
PMCID: PMC4393946  PMID: 24439328
Mammographic compression; breast cancer; blood flow; breast imaging; diffuse optics
10.  Cerebral oxygen metabolism in neonates with congenital heart disease quantified by MRI and optics 
Neonatal congenital heart disease (CHD) is associated with altered cerebral hemodynamics and increased risk of brain injury. Two novel noninvasive techniques, magnetic resonance imaging (MRI) and diffuse optical and correlation spectroscopies (diffuse optical spectroscopy (DOS), diffuse correlation spectroscopy (DCS)), were employed to quantify cerebral blood flow (CBF) and oxygen metabolism (CMRO2) of 32 anesthetized CHD neonates at rest and during hypercapnia. Cerebral venous oxygen saturation (SvO2) and CBF were measured simultaneously with MRI in the superior sagittal sinus, yielding global oxygen extraction fraction (OEF) and global CMRO2 in physiologic units. In addition, microvascular tissue oxygenation (StO2) and indices of microvascular CBF (BFI) and CMRO2 (CMRO2i) in the frontal cortex were determined by DOS/DCS. Median resting-state MRI-measured OEF, CBF, and CMRO2 were 0.38, 9.7 mL/minute per 100 g and 0.52 mL O2/minute per 100 g, respectively. These CBF and CMRO2 values are lower than literature reports for healthy term neonates (which are sparse and quantified using different methods) and resemble values reported for premature infants. Comparison of MRI measurements of global SvO2, CBF, and CMRO2 with corresponding local DOS/DCS measurements demonstrated strong linear correlations (R2=0.69, 0.67, 0.67; P<0.001), permitting calibration of DOS/DCS indices. The results suggest that MRI and optics offer new tools to evaluate cerebral hemodynamics and metabolism in CHD neonates.
doi:10.1038/jcbfm.2013.214
PMCID: PMC3948119  PMID: 24326385
cerebral blood flow; cerebral hemodynamics; diffuse optics; MRI; near-infrared spectroscopy; neonatal ischemia
11.  The Challenge of Connecting the Dots in the B.R.A.I.N 
Neuron  2013;80(2):10.1016/j.neuron.2013.09.008.
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts, and discuss likely technological deliverables and neuroscience progress.
doi:10.1016/j.neuron.2013.09.008
PMCID: PMC3864648  PMID: 24139032
12.  Noninvasive Optical Quantification of Cerebral Venous Oxygen Saturation in Humans 
Academic radiology  2014;21(2):162-167.
Rationale and Objectives
Cerebral oxygen extraction, defined as the difference between arterial and venous oxygen saturations (SaO2 and SvO2), is a critical parameter for managing intensive care patients at risk for neurological collapse. Although quantification of SaO2 is easily performed with pulse oximetry or moderately invasive arterial blood draws in peripheral vessels, cerebral SvO2 is frequently not monitored because of the invasiveness and risk associated with obtaining jugular bulb or super vena cava (SVC) blood samples.
Materials and Methods
In this study, near-infrared spectroscopy (NIRS) was used to noninvasively measure cerebral SvO2 in anesthetized and mechanically ventilated pediatric patients (n = 10). To quantify SvO2, the NIRS signal component that fluctuates at the respiration frequency is isolated. This respiratory component is dominated by the venous portion of the interrogated vasculature. The NIRS measurements of SvO2 were validated against the clinical gold standard: invasively measured oxygen saturations from SVC blood samples. This technique was also applied in healthy volunteers (n = 5) without mechanical ventilation to illustrate its potential for use in healthy populations with natural airways.
Results
Ten pediatric patients with pulmonary hypertension were studied. In these patients, SvO2 in the SVC exhibited good agreement with NIRS-measured SvO2 (R2 = 0.80, P = .001, slope = 1.16 ± 0.48). Furthermore, in the healthy adult volunteers, mean (standard deviation) NIRS-measured SvO2 was 79.4 (6.8)%. This value is in good agreement with the expected average central venous saturation reported in literature.
Conclusion
Respiration frequency-selected NIRS can noninvasively quantify cerebral SvO2. This bedside technique can be used to help assess brain health in neurologically unstable patients.
doi:10.1016/j.acra.2013.10.013
PMCID: PMC4126245  PMID: 24439329
Near-infrared spectroscopy; cerebral venous oxygenation; pediatrics; validation; noninvasive
13.  Towards non-invasive characterization of breast cancer and cancer metabolism with diffuse optics 
PET clinics  2013;8(3):10.1016/j.cpet.2013.04.004.
We review recent developments in diffuse optical imaging and monitoring of breast cancer, i.e. optical mammography. Optical mammography permits non-invasive, safe and frequent measurement of tissue hemodynamics oxygen metabolism and components (lipids, water, etc.), the development of new compound indices indicative of the risk and malignancy, and holds potential for frequent non-invasive longitudinal monitoring of therapy progression.
doi:10.1016/j.cpet.2013.04.004
PMCID: PMC3826963  PMID: 24244206
Diffuse Optical Tomography; Diffuse Optical Spectroscopy; Metabolic Imaging; Blood Flow; Breast Cancer; Neo-adjuvant chemotherapy
14.  Optically Measured Microvascular Blood Flow Contrast of Malignant Breast Tumors 
PLoS ONE  2014;9(6):e99683.
Microvascular blood flow contrast is an important hemodynamic and metabolic parameter with potential to enhance in vivo breast cancer detection and therapy monitoring. Here we report on non-invasive line-scan measurements of malignant breast tumors with a hand-held optical probe in the remission geometry. The probe employs diffuse correlation spectroscopy (DCS), a near-infrared optical method that quantifies deep tissue microvascular blood flow. Tumor-to-normal perfusion ratios are derived from thirty-two human subjects. Mean (95% confidence interval) tumor-to-normal ratio using surrounding normal tissue was 2.25 (1.92–2.63); tumor-to-normal ratio using normal tissues at the corresponding tumor location in the contralateral breast was 2.27 (1.94–2.66), and using normal tissue in the contralateral breast was 2.27 (1.90–2.70). Thus, the mean tumor-to-normal ratios were significantly different from unity irrespective of the normal tissue chosen, implying that tumors have significantly higher blood flow than normal tissues. Therefore, the study demonstrates existence of breast cancer contrast in blood flow measured by DCS. The new, optically accessible cancer contrast holds potential for cancer detection and therapy monitoring applications, and it is likely to be especially useful when combined with diffuse optical spectroscopy/tomography.
doi:10.1371/journal.pone.0099683
PMCID: PMC4072684  PMID: 24967878
15.  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
16.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
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

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