Breast cancer detection of large size to DCIS by hypoxia and angiogenesis using NIRS.

This investigation aimed to test all tumor-bearing patients who undergo biopsy to see if angiogenesis and hypoxia can detect cancer. We used continuous-wave near-infrared spectroscopy (NIRS) to measure blood hemoglobin concentration to obtain blood volume or total hemoglobin [Hbtot] and oxygen saturation for the angiogenesis and hypoxic biomarkers. The contralateral breast was used as a reference to derive the difference from breast tumor as a difference in total hemoglobin Δ[HBtot] and a difference in deoxygenation Δ([Hb]-[HbO2]). A total of 91 invasive cancers, 26 DCIS, 45 fibroblastomas, 96 benign tumors excluding cysts, and 67 normal breasts were examined from four hospitals. In larger-size tumors, there is significantly higher deoxygenation in invasive and ductal carcinoma in situ (DCIS) than in that of benign tumors, but no significant difference was seen in smaller tumors of ≤ 1 cm. With the two parameters of high total hemoglobin and hypoxia score, the sensitivity and specificity of cancer detection were 60.3 % and 85.3 %, respectively. In summary, smaller-size tumors are difficult to detect with NIRS, whereas DCIS can be detected by the same total hemoglobin and hypoxic score in our study.

The use of muscle near-infrared spectroscopy in sport, health and medical sciences: recent developments.

Near-infrared spectroscopy (NIRS) has been shown to be one of the tools that can measure oxygenation in muscle and other tissues in vivo. This review paper highlights the progress, specifically in this decade, that has been made for evaluating skeletal muscle oxygenation and oxidative energy metabolism in sport, health and clinical sciences. Development of NIRS technologies has focused on improving quantification of the signal using multiple wavelengths to solve for absorption and scattering coefficients, multiple pathlengths to correct for the influence of superficial skin and fat, and time-resolved and phase-modulated light sources to determine optical pathlengths. In addition, advances in optical imaging with multiple source and detector pairs as well as portability using small wireless detectors have expanded the usefulness of the devices. NIRS measurements have provided information on oxidative metabolism in various athletes during localized exercise and whole-body exercise, as well as training-induced adaptations. Furthermore, NIRS technology has been used in the study of a number of chronic health conditions. Future developments of NIRS technology will include enhancing signal quantification. In addition, advances in NIRS imaging and portability promise to transform how measurements of oxygen utilization are obtained in the future.

Evaluation of bacteriochlorophyll-reconstituted low-density lipoprotein nanoparticles for photodynamic therapy efficacy in vivo.

AIM: To evaluate the novel nanoparticle reconstituted bacteriochlorin e6 bisoleate low-density lipoprotein (r-Bchl-BOA-LDL) for its efficacy as a photodynamic therapy agent delivery system in xenografts of human hepatoblastoma G2 (HepG2) tumors. MATERIALS & METHODS: Bchl-BOA was encapsulated in the nanoparticle low-density lipoprotein (LDL), a native particle whose receptor's overexpression is a cancer signature for a number of neoplasms. Evaluation of r-Bchl-BOA-LDL as a potential photosensitizer was performed using a tumor response and foot response assay. RESULTS & DISCUSSION: When compared with controls, tumor regrowth was significantly delayed at injected murine doses of 2 µmole/kg r-Bchl-BOA-LDL after illumination at fluences of 125, 150 or 175 J/cm(2). Foot response assays showed that although normal tissue toxicity accompanied the higher fluences it was significantly reduced at the lowest fluence tested. CONCLUSION: This research demonstrates that r-Bchl-BOA-LDL is an effective photosensitizer and a promising candidate for further investigation.

Heterogeneity of mitochondrial redox state in premalignant pancreas in a PTEN null transgenic mouse model.

Pancreas-specific deletion of PTEN in mice revealed progressive premalignant lesions such as ductal metaplasia with infrequent malignant transformation. In this study, we aimed at evaluating the mitochondrial redox state of the metaplastic pancreas in a pancreas-specific PTEN null transgenic mouse model. The two intrinsic fluorophores, reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) such as flavin adenine dinucleotide (FAD), in the respiratory chain in mitochondria are sensitive indicators of mitochondrial redox states and have been applied to the studies of mitochondrial function with energy-linked processes. The redox ratio, Fp/(Fp+NADH) provides a sensitive index of mitochondrial redox state. We have obtained optical images of the in vivo mitochondrial redox states of the snap frozen pancreases from pancreas-specific PTEN null mice (Pdx1-Cre;PTEN(lox/lox), N=3) and the controls (PTEN(lox/lox), N=3) using the redox scanner at low temperature. The results showed high spatial heterogeneity of mitochondrial redox state in the mutated pancreases with hot spots of much higher Fp redox ratios whereas the normal ones, were relatively homogenous. The cystic dilation regions in the metaplastic pancreases showed little to no NADH or Fp signal. Histological analysis confirmed no cells existed in these regions. It is the first time that the in vivo mitochondrial redox states of the metaplastic mouse pancreas were optically imaged. Our previous results on human melanoma and breast cancer mouse xenografts have shown that mitochondrial redox state quantitatively correlates with cancer metastatic potential. The more oxidative mitochondrial redox state (higher Fp redox ratio) corresponded to the higher metastatic potential of the tumors. As mitochondrial redox state imbalance is associated with abnormal mitochondrial function, and redox state mediates the generation of reactive oxygen species and many signal transduction pathways, this research may provide insights for studying basic biology and developing early diagnostic imaging biomarkers for pancreatic cancer.

IMAGING REDOX STATE HETEROGENEITY WITHIN INDIVIDUAL EMBRYONIC STEM CELL COLONIES.

Redox state mediates embryonic stem cell (ESC) differentiation and thus offers an important complementary approach to understanding the pluripotency of stem cells. NADH redox ratio (NADH/(Fp + NADH)), where NADH is the reduced form of nicotinamide adenine dinucleotide and Fp is the oxidized flavoproteins, has been established as a sensitive indicator of mitochondrial redox state. In this paper, we report our redox imaging data on the mitochondrial redox state of mouse ESC (mESC) colonies and the implications thereof. The low-temperature NADH/Fp redox scanner was employed to image mESC colonies grown on a feeder layer of gamma-irradiated mouse embryonic fibroblasts (MEFs) on glass cover slips. The result showed significant heterogeneity in the mitochondrial redox state within individual mESC colonies (size: ∼200-440 µm), exhibiting a core with a more reduced state than the periphery. This more reduced state positively correlates with the expression pattern of Oct4, a well-established marker of pluripotency. Our observation is the first to show the heterogeneity in the mitochondrial redox state within a mESC colony, suggesting that mitochondrial redox state should be further investigated as a potential new biomarker for the stemness of embryonic stem cells.

Quantitative mitochondrial redox imaging of breast cancer metastatic potential.

Predicting tumor metastatic potential remains a challenge in cancer research and clinical practice. Our goal was to identify novel biomarkers for differentiating human breast tumors with different metastatic potentials by imaging the in vivo mitochondrial redox states of tumor tissues. The more metastatic (aggressive) MDA-MB-231 and less metastatic (indolent) MCF-7 human breast cancer mouse xenografts were imaged with the low-temperature redox scanner to obtain multi-slice fluorescence images of reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp). The nominal concentrations of NADH and Fp in tissue were measured using reference standards and used to calculate the Fp redox ratio, Fp(NADH+Fp). We observed significant core-rim differences, with the core being more oxidized than the rim in all aggressive tumors but not in the indolent tumors. These results are consistent with our previous observations on human melanoma mouse xenografts, indicating that mitochondrial redox imaging potentially provides sensitive markers for distinguishing aggressive from indolent breast tumor xenografts. Mitochondrial redox imaging can be clinically implemented utilizing cryogenic biopsy specimens and is useful for drug development and for clinical diagnosis of breast cancer.

In vivo fluorometric assessment of cyclosporine on mitochondrial function during myocardial ischemia and reperfusion.

BACKGROUND: Cyclosporine A (CsA) limits myocardial reperfusion injury and preserves mitochondrial integrity, but its influence on mitochondrial function has not been described in vivo. Auto-fluorescence of mitochondrial nicotinamide adenine dinucleotide and flavin adenine dinucleotide correlate with mitochondrial dysfunction. We hypothesized that CsA limits mitochondrial dysfunction and that fluorometry can quantify this influence. METHODS: Seventeen rabbits were studied: untreated (UnT, n = 7), CsA preinfarction (CsAp, n = 6), and CsA on reperfusion (CsAr, n = 4). Animals underwent 30 minutes of myocardial ischemia and 3 hours reperfusion. Infarct size was determined by staining. Nicotinamide adenine dinucleotide and flavin adenine dinucleotide fluorescence was continually measured in the risk area. The redox ratio was calculated [flavin adenine dinucleotide(f)/(flavin adenine dinucleotide(f) + nicotinamide adenine dinucleotide(f))]. Electron microscopy evaluated mitochondria morphology. RESULTS: The infarct size by group was 39.1% +/- 1.7% in CsAp, 39.1% +/- 1.7% in CsAr, and 53.4% +/- 1.9% in UnT (p < 0.001). During ischemia, the CsAp group demonstrated less hypoxic reduction, with the redox ratio decreasing to 75.6% +/- 4.1% of baseline. The UnT and CsAr groups deceased to 67.1% +/- 4.0% and 67.2% +/- 3.6%, respectively (p < 0.005). During reperfusion the UnT group redox ratio increased to 1.59 +/- 0.04 times baseline. This increase was blunted in the CsAp (1.17 +/- 0.04, p = 0.026) and CsAr (1.35 +/- 0.02, p = 0.056) groups. Electron microscopy revealed reduced mitochondrial disruption in CsAp (19.7% +/- 7.6%) and CsAr (18.1% +/- 7.1%) rabbits compared with UnT (53.3% +/- 12.5%). CONCLUSIONS: Fluorometric spectroscopy can be used in vivo to quantitatively assess the time course of CsA's influence on the mitochondrial dysfunction associated with myocardial ischemia and reperfusion.

Comparisons of muscle oxygenation changes between arm and leg muscles during incremental rowing exercise with near-infrared spectroscopy.

Our purpose is to compare the changes in muscle oxygenation in the vastus lateralis (VL) and biceps brachii (BB) muscles simultaneously using near-infrared spectroscopy (NIRS) during incremental rowing exercise in eight rowers. Based on the BB and VL muscle oxygenation patterns, two points are used to characterize the muscle oxygenation kinetics in both the arm and the leg muscles. The first point is the breaking point (Bp), which refers to an accelerated fall in muscle oxygenation that correlates with the gas exchange threshold (GET). The second point is the leveling-off point (Lo), which suggests the upper limit of O(2) extraction. The GET occurred at 63.3+/-2.4% of maximal oxygen uptake (VO(2 max)). The Bp appeared at 45.0+/-3.8% and 55.6+/-2.4% VO(2 max) in the BB and VL, respectively. The Lo appeared at 63.6+/-4.1% and 86.6+/-1.0% VO(2 max) in these two muscles, respectively. Both the Bp and the Lo occurred earlier in BB compared with VL. These results suggest that arm muscles have lower oxidative capacity than leg muscles during rowing exercise. The rowers with higher exercise performances showed heavier workloads, as evaluated by Bp and Lo. The monitoring of muscle oxygenation by NIRS in arm and leg muscles during rowing could be a useful guide for evaluation and training.

Investigation of the prefrontal cortex in response to duration-variable anagram tasks using functional near-infrared spectroscopy.

We hypothesize that nonlinearity between short-term anagram tasks and corresponding hemodynamic responses can be observed by functional near-infrared spectroscopy (fNIRS) in the prefrontal cortex (PFC). The PFC of six human subjects in response to anagram tasks is investigated using multichannel fNIRS. Concentration changes of oxyhemoglobin and deoxyhemoglobin in the PFC are measured with variable anagram durations and at two difficulty levels (four- and six-letter anagrams). The durations to perform the selected anagram tasks range from several seconds to more than one minute. The dorsolateral PFC areas exhibit consistent and strong hemodynamic deactivation during and shortly after task execution. The superposition principle of a linear system is employed to investigate nonlinear hemodynamic features among three task duration subgroups: D1 = 2.0 sec, D2 = 4.0 sec, and D3 = 8.0 sec. Such analysis shows clear nonlinearity in hemodynamic responses on the PFC with task durations shorter than 4 sec. Our observation of significant deactivation in early hemodynamic responses in the PFC is consistent with multiple fNIRS studies and several reports given in the field of functional magnetic resonance imaging. A better understanding of nonlinearity in fNIRS signals will have potential for us to investigate brain adaptation and to extrapolate neuronal activities from hemodynamic signals.

Differentiation of benign and malignant breast tumors by in-vivo three-dimensional parallel-plate diffuse optical tomography.

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-, and total hemoglobin concentration as well as 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 twofold 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 1 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.

Quantitative magnetic resonance and optical imaging biomarkers of melanoma metastatic potential.

Noninvasive or minimally invasive prediction of tumor metastatic potential would facilitate individualized cancer management. Studies were performed on a panel of human melanoma xenografts that spanned the full range of metastatic potential measured by an in vivo lung colony assay and an in vitro membrane invasion culture system. Three imaging methods potentially transferable to the clinic [dynamic contrast-enhanced (DCE) MRI, T(1(rho))-MRI, and low-temperature fluorescence imaging (measurable on biopsy specimens)] distinguished between relatively less metastatic and more metastatic human melanoma xenografts in nude mice. DCE-MRI, analyzed with the shutter-speed relaxometric algorithm and using an arterial input function simultaneously measured in the left ventricle of the mouse heart, yielded a blood transfer rate constant, K(trans), that measures vascular perfusion/permeability. K(trans) was significantly higher in the core of the least metastatic melanoma (A375P) than in the core of the most metastatic melanoma (C8161). C8161 melanoma had more blood vascular structures but fewer functional blood vessels than A375P melanoma. The A375P melanoma exhibited mean T(1(rho)) values that were significantly higher than those of C8161 melanoma. Measurements of T(1) and T(2) relaxation times did not differ significantly between these 2 melanomas. The mitochondrial redox ratio, Fp/(Fp + NADH), where Fp and NADH are the fluorescences of oxidized flavoproteins and reduced pyridine nucleotides, respectively, varied linearly with the in vitro invasive potential of the 5 melanoma cell lines (A375P, A375M, A375P10, A375P5, and C8161). This study shows that a harsh microenvironment may promote melanoma metastasis and provides potential biomarkers of metastatic potential.

Quantifying acute myocardial injury using ratiometric fluorometry.

Early reperfusion is the best therapy for myocardial infarction (MI). Effectiveness, however, varies significantly between patients and has implications for long-term prognosis and treatment. A technique to assess the extent of myocardial salvage after reperfusion therapy would allow for high-risk patients to be identified in the early post-MI period. Mitochondrial dysfunction is associated with cell death following myocardial reperfusion and can be quantified by fluorometry. Therefore, we hypothesized that variations in the fluorescence of mitochondrial nicotinamide adenine dinucleotide (NADH) and flavoprotein (FP) can be used acutely to predict the degree of myocardial injury. Thirteen rabbits had coronary occlusion for 30 min followed by 3 h of reperfusion. To produce a spectrum of infarct sizes, six animals were infused cyclosporine A prior to ischemia. Using a specially designed fluorometric probe, NADH and FP fluorescence were measured in the ischemic area. Changes in NADH and FP fluorescence, as early as 15 min after reperfusion, correlated with postmortem assessment infarct size ( r = 0.695, p < 0.01). This correlation strengthened with time ( r = 0.827, p < 0.001 after 180 min). Clinical application of catheter-based myocardial fluorometry may provide a minimally invasive technique for assessing the early response to reperfusion therapy.

Noninvasive determination of exercise-induced vasodilation during bicycle exercise using near infrared spectroscopy.

BACKGROUND: The purpose of this study was to examine the changes in total hemoglobin (Delta[tHb]) response during bicycle exercise at various constant workloads using near infrared continuous wave spectroscopy (NIRcws) in humans. We hypothesized that the Delta[tHb] during exercise may progressively increase as a result of a dilation of the vascular bed and/or capillary recruitment at lower constant work rates. MATERIAL/METHODS: Seven healthy subjects performed bicycle exercise at 20, 40, 60, 80, and 100% of maximal work rates (Wmax) for 5 min. Muscle oxygenation change (Delta[Oxy]) and Delta[tHb] at the right vastus lateralis were monitored using a NIRcws device. Exercise-induced Delta[tHb] and Delta[Oxy] responses at each constant workload were evaluated as functional Delta[tHb] change (f-Delta[tHb]) and functional oxygenation change (f-Delta[Oxy]), respectively. Blood lactate concentration [La] was also evaluated after each exercise stage. RESULTS: At work rates 60%Wmax and below, after an initial decrease at the start of exercise, both Delta[tHb] and Delta[Oxy] showed progressive increases until the end of exercise. A significant positive correlation was found between f-Delta[tHb] and f-Delta[Oxy] (p<0.01). In addition, there was a significant negative relationship of [La] to f-Delta[tHb] during exercise (p<0.05). CONCLUSIONS: These results provide evidence that increased muscle oxygenation during bicycle exercise up to 60%Wmax may be caused by increased O2 supply due to exercise-induced blood volume expansion. Subsequently, the cessation of increase in f-Delta[tHb] at higher intensity exercise may lead to lower muscle tissue oxygenation and higher lactate accumulation.

Lipoprotein nanoplatform for targeted delivery of diagnostic and therapeutic agents.

Low-density lipoprotein (LDL) provides a highly versatile natural nanoplatform for delivery of optical and MRI contrast agents, photodynamic therapy agents and chemotherapeutic agents to normal and neoplastic cells that over express LDL receptors (LDLR). Extension to other lipoproteins ranging in diameter from approximately 5-10 nm (high density lipoprotein, HDL) to over a micron (chilomicrons) is feasible. Loading of contrast or therapeutic agents has been achieved by covalent attachment to protein side chains, intercalation into the phospholipid monolayer and extraction and reconstitution of the triglyceride/cholesterol ester core. Covalent attachment of folate to the lysine side chain amino groups was used to reroute the LDL from its natural receptor (LDLR) to folate receptors and could be utilized to target other receptors. A semi-synthetic nanoparticle has been constructed by coating magnetite iron oxide nanoparticles (MIONs) with carboxylated cholesterol and overlaying a monolayer ofphospholipid to which Apo A1, Apo E or synthetic amphoteric alpha-helical polypeptides were adsorbed for targeting HDL, LDL or folate receptors, respectively. These particles can be utilized for in situ loading of magnetite into cells for MRI monitored cell tracking or gene therapy.

Histological basis of MR/optical imaging of human melanoma mouse xenografts spanning a range of metastatic potentials.

Predicting tumor aggressiveness will greatly facilitate cancer treatment. We have previously reported investigations utilizing various MR/optical imaging methods to differentiate human melanoma mouse xenografts spanning a range of metastatic potentials. The purpose of this study was to explore the histological basis of the previously reported imaging findings. We obtained the cryogenic tumor sections of three types of human melanoma mouse xenografts with their metastatic potentials falling in the rank order A375P

MITOCHONDRIAL REDOX IMAGING FOR CANCER DIAGNOSTIC AND THERAPEUTIC STUDIES.

Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including cancer. The redox scanning method developed at the Chance laboratory about 30 years ago has allowed 3D high-resolution (~ 50 × 50 × 10 µm3) imaging of mitochondrial redox state in tissue on the basis of the fluorescence of NADH (reduced nicotinamide adenine dinucleotide) and Fp (oxidized flavoproteins including flavin adenine dinucleotide, i.e., FAD). In this review, we illustrate its basic principles, recent technical developments, and biomedical applications to cancer diagnostic and therapeutic studies in small animal models. Recently developed calibration procedures for the redox imaging using reference standards allow quantification of nominal NADH and Fp concentrations, and the concentration-based redox ratios, e.g., Fp/(Fp+NADH) and NADH/(Fp+NADH) in tissues. This calibration facilitates the comparison of redox imaging results acquired for different metabolic states at different times and/or with different instrumental settings. A redox imager using a CCD detector has been developed to acquire 3D images faster and with a higher in-plane resolution down to 10 µm. Ex vivo imaging and in vivo imaging of tissue mitochondrial redox status have been demonstrated with the CCD imager. Applications of tissue redox imaging in small animal cancer models include metabolic imaging of glioma and myc-induced mouse mammary tumors, predicting the metastatic potentials of human melanoma and breast cancer mouse xenografts, differentiating precancerous and normal tissues, and monitoring the tumor treatment response to photodynamic therapy. Possible future directions for the development of redox imaging are also discussed.

QUANTITATIVE REDOX SCANNING OF TISSUE SAMPLES USING A CALIBRATION PROCEDURE.

The fluorescence properties of reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) including flavin adenine dinucleotide (FAD) in the respiratory chain are sensitive indicators of intracellular metabolic states and have been applied to the studies of mitochondrial function with energy-linked processes. The redox scanner, a three-dimensional (3D) low temperature imager previously developed by Chance et al., measures the in vivo metabolic properties of tissue samples by acquiring fluorescence images of NADH and Fp. The redox ratios, i.e. Fp/(Fp+NADH) and NADH/(Fp+NADH), provided a sensitive index of the mitochondrial redox state and were determined based on relative signal intensity ratios. Here we report the further development of the redox scanning technique by using a calibration method to quantify the nominal concentration of the fluorophores in tissues. The redox scanner exhibited very good linear response in the range of NADH concentration between 165-1318µM and Fp between 90-720 µM using snap-frozen solution standards. Tissue samples such as human tumor mouse xenografts and various mouse organs were redox-scanned together with adjacent NADH and Fp standards of known concentration at liquid nitrogen temperature. The nominal NADH and Fp concentrations as well as the redox ratios in the tissue samples were quantified by normalizing the tissue NADH and Fp fluorescence signal to that of the snap-frozen solution standards. This calibration procedure allows comparing redox images obtained at different time, independent of instrument settings. The quantitative multi-slice redox images revealed heterogeneity in mitochondrial redox state in the tissues.

Lipoprotein nanoplatform for targeted delivery of diagnostic and therapeutic agents.

Low-density lipoprotein (LDL) provides a highly versatile natural nanoplatform for delivery of visible or near-infrared fluorescent optical and magnetic resonance imaging (MRI) contrast agents and photodynamic therapy and chemotherapeutic agents to normal and neoplastic cells that overexpress low-density lipoprotein receptors (LDLRs). Extension to other lipoproteins ranging in diameter from about 10 nm (high-density lipoprotein [HDL]) to over a micron (chylomicrons) is feasible. Loading of contrast or therapeutic agents onto or into these particles has been achieved by protein loading (covalent attachment to protein side chains), surface loading (intercalation into the phospholipid monolayer), and core loading (extraction and reconstitution of the triglyceride/cholesterol ester core). Core and surface loading of LDL have been used for delivery of optical imaging agents to tumor cells in vivo and in culture. Surface loading was used for delivery of gadolinium-bis-stearylamide contrast agents for in vivo MRI detection in tumor-bearing mice. Chlorin and phthalocyanine near-infrared photodynamic therapy agents (< or = 400/LDL) have been attached by core loading. Protein loading was used to reroute the LDL from its natural receptor (LDLR) to folate receptors and could be used to target other receptors. A semisynthetic nanoparticle has been constructed by coating magnetite iron oxide nanoparticles with carboxylated cholesterol and overlaying a monolayer of phospholipid to which apolipoprotein A1 or E was adsorbed for targeting HDL or adsorbing synthetic amphipathic helical peptides ltargeting LDL or folate receptors. These particles can be used for in situ loading of magnetite into cells for MRI-monitored cell tracking or gene expression.

Pharmacokinetic-rate images of indocyanine green for breast tumors using near-infrared optical methods.

In this paper, we develop a method of forming pharmacokinetic-rate images of indocyanine green (ICG) and apply our method to in vivo data obtained from three patients with breast tumors. To form pharmacokinetic-rate images, we first obtain a sequence of ICG concentration images using the differential diffuse optical tomography technique. We next employ a two-compartment model composed of plasma, and extracellular-extravascular space (EES), and estimate the pharmacokinetic rates and concentrations in each compartment using the extended Kalman filtering framework. The pharmacokinetic-rate images of the three patient show that the rates from the tumor region and outside the tumor region are statistically different. Additionally, the ICG concentrations in plasma, and the EES compartments are higher around the tumor region agreeing with the hypothesis that around the tumor region ICG may act as a diffusible extravascular flow in compromised capillary of cancer vessels. Our study indicates that the pharmacokinetic-rate images may provide superior information than single set of pharmacokinetic rates estimated from the entire breast tissue for breast cancer diagnosis.

Biomathematics in cancer detection: simulation of lipogenesis in cancer.

The usual mechanisms for biochemical events are steady-state systems without dynamic simulation. Our study is to simulate lipogenesis from the breakdown of glucose coupled with oxidative phosphorylation in mitochondria by using JSim (for Java Simulator) as software development environment, which enables non-linear differential equations to be used in a simulation giving a time course through a variety of non-steady-state conditions. Glycolysis and lipogenesis coupled with oxidative phosphorylation in mitochondria non-linear differential model is built in this paper. Simulation and discussion on lipogenesis by carbohydrate responsive element-binding protein (ChREBP) are given. Our model provides a potential way to analyze the experimental databank.