John Kurhanewicz

University of California, San Francisco, San Francisco, California, United States

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Publications (289)924.91 Total impact

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    ABSTRACT: \textit{In vivo} spin spin relaxation time ($T_2$) heterogeneity of hyperpolarized \textsuperscript{13}C urea in the rat kidney was investigated. Selective quenching of the vascular hyperpolarized \textsuperscript{13}C signal with a macromolecular relaxation agent revealed that a long-$T_2$ component of the \textsuperscript{13}C urea signal originated from the renal extravascular space, thus allowing the vascular and renal filtrate contrast agent pools of the \textsuperscript{13}C urea to be distinguished via multi-exponential analysis. The $T_2$ response to induced diuresis and antidiuresis was performed with two imaging agents: hyperpolarized \textsuperscript{13}C urea and a control agent hyperpolarized bis-1,1-(hydroxymethyl)-1-\textsuperscript{13}C-cyclopropane-$^2\textrm{H}_8$. Large $T_2$ increases in the inner-medullar and papilla were observed with the former agent and not the latter during antidiuresis suggesting that $T_2$ relaxometry may be used to monitor the inner-medullary urea transporter (UT)-A1 and UT-A3 mediated urea concentrating process. Two high resolution imaging techniques - multiple echo time averaging and ultra-long echo time sub-2 mm$^3$ resolution 3D imaging - were developed to exploit the particularly long relaxation times observed.
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    ABSTRACT: Objective: The goal of this study was to compare the perceived quality of 3-T axial T2-weighted high-resolution 2D and high-resolution 3D fast spin-echo (FSE) endorectal MR images of the prostate. Materials and methods: Six radiologists independently reviewed paired 3-T axial T2-weighted high-resolution 2D and 3D FSE endorectal MR images of the prostates of 85 men in two sessions. In the first session (n = 85), each reader selected his or her preferred images; in the second session (n = 28), they determined their confidence in tumor identification and compared the depiction of the prostatic anatomy, tumor conspicuity, and subjective intrinsic image quality of images. A meta-analysis using a random-effects model, logistic regression, and the paired Wilcoxon rank-sum test were used for statistical analyses. Results: Three readers preferred the 2D acquisition (67-89%), and the other three preferred the 3D images (70-80%). The option for one of the techniques was not associated with any of the predictor variables. The 2D FSE images were significantly sharper than 3D FSE (p < 0.001) and significantly more likely to exhibit other (nonmotion) artifacts (p = 0.002). No other statistically significant differences were found. Conclusion: Our results suggest that there are strong individual preferences for the 2D or 3D FSE MR images, but there was a wide variability among radiologists. There were differences in image quality (image sharpness and presence of artifacts not related to motion) but not in the sequences' ability to delineate the glandular anatomy and depict a cancerous tumor.
    American Journal of Roentgenology 10/2015; DOI:10.2214/AJR.14.14065 · 2.73 Impact Factor
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    ABSTRACT: N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), one of Good’s buffers, was applied to pH imaging using hyperpolarized 13C magnetic resonance spectroscopy. Rapid NMR and MRI-based pH measurements were obtained by exploiting the sensitive pH-dependence of its 13C chemical shift within the physiologic range.
    Chemical Communications 08/2015; 51(74). DOI:10.1039/C5CC05348J · 6.83 Impact Factor
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    ABSTRACT: We have developed a 3D cell/tissue culture bioreactor compatible with hyperpolarized (HP) 13C MR and interrogated HP [1-13C]lactate production and efflux in human renal cell carcinoma (RCC) cells. This platform is capable of resolving intracellular and extracellular HP lactate pools, allowing the kinetic measurement of lactate production and efflux in the context of cancer aggressiveness and response to therapy. HP 13C MR studies were performed on three immortalized human renal cell lines: HK2, a normal renal proximal tubule cell line from which a majority of RCCs arise, UMRC6, a cell line derived from a localized RCC, and UOK262, an aggressive and metastatic RCC. The intra- (Lacin) and extracellular (Lacex) HP lactate signals were robustly resolved in dynamic 13C spectra of the cell lines due to a very small but reproducible chemical shift difference (0.031 ± 0.0005 ppm). Following HP [1-13C]pyruvate delivery, the ratio of HP Lacin/Lacex was significantly lower for UOK262 cells compared with both UMRC6 and HK2 cells due to a significant (p < 0.05) increase in the Lacex pool size. Lacin/Lacex correlated with the MCT4 mRNA expression of the cell lines, and inhibition of MCT4 transport using DIDS resulted in a significant reduction in the HP Lacex pool size. The extension of these studies to living patient-derived RCC tissue slices using HP [1,2-13C2]pyruvate demonstrated a similarly split lactate doublet with a high Lacex pool fraction; in contrast, only a single NMR resonance is noted for HP [5-13C]glutamate, consistent with intracellular localization. These studies support the importance of lactate efflux as a biomarker of cancer aggressiveness and metastatic potential, and the utility of the MR compatible 3D cell/tissue culture bioreactor to study not only cellular metabolism but also transport. Additionally, this platform offers a sophisticated way to follow therapeutic interventions and screen novel therapies that target lactate export. Copyright
    NMR in Biomedicine 07/2015; 28(9). DOI:10.1002/nbm.3354 · 3.04 Impact Factor
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    ABSTRACT: Metabolic shifts in disease are of great interest for the development of novel therapeutics. In cancer treatment, these therapies exploit the metabolic phenotype associated with oncogenesis and cancer progression. One recent strategy involves the depletion of the cofactors needed to maintain the high rate of glycolysis seen with the Warburg effect. Specifically, blocking nicotinamide adenine dinucleotide (NAD) biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) inhibition depletes cancer cells of the NAD needed for glycolysis. To characterize this metabolic phenotype in vivo and describe changes in flux with treatment, non-invasive biomarkers are necessary. One such biomarker is hyperpolarized (HP) [1-(13) C] pyruvate, a clinically translatable probe that allows real-time assessment of metabolism. We therefore developed a cell perfusion system compatible with HP magnetic resonance (MR) and positron emission tomography (PET) to develop translatable biomarkers of response to NAMPT inhibition in reduced volume cell cultures. Using this platform, we observed a reduction in pyruvate flux through lactate dehydrogenase with NAMPT inhibition in prostate cancer cells, and showed that both HP lactate and 2-[(18) F] fluoro-2-deoxy-D-glucose (FDG) can be used as biomarkers for treatment response of such targeted agents. Moreover, we observed dynamic flux changes whereby HP pyruvate was re-routed to alanine, providing both positive and negative indicators of treatment response. This study demonstrated the feasibility of a MR/PET compatible bioreactor approach to efficiently explore cell and tissue metabolism, the understanding of which is critical for developing clinically translatable biomarkers of disease states and responses to therapeutics. Prostate 9999: 1-9, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    The Prostate 07/2015; 75(14). DOI:10.1002/pros.23036 · 3.57 Impact Factor
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    ABSTRACT: In this work, we present a new ultrafast method for acquiring dynamic 2D EXchange SpectroscopY (EXSY) within a single acquisition. This technique reconstructs two-dimensional EXSY spectra from one-dimensional spectra based on the phase accrual during echo times. The Ultrafast-EXSY acquisition overcomes long acquisition times typically needed to acquire 2D NMR data by utilizing sparsity and phase dependence to dramatically undersample in the indirect time dimension. This allows for the acquisition of the 2D spectrum within a single shot. We have validated this method in simulations and hyperpolarized enzyme assay experiments separating the dehydration of pyruvate and lactate-to-pyruvate conversion. In a renal cell carcinoma cell (RCC) line, bidirectional exchange was observed. This new technique revealed decreased conversion of lactate-to-pyruvate with high expression of monocarboxylate transporter 4 (MCT4), known to correlate with aggressive cancer phenotypes. We also showed feasibility of this technique in vivo in a RCC model where bidirectional exchange was observed for pyruvate-lactate, pyruvate-alanine, and pyruvate-hydrate and were resolved in time. Broadly, the technique is well suited to investigate the dynamics of multiple exchange pathways and applicable to hyperpolarized substrates where chemical exchange has shown great promise across a range of disciplines. Copyright © 2015 Elsevier Inc. All rights reserved.
    Journal of Magnetic Resonance 06/2015; 257. DOI:10.1016/j.jmr.2015.05.011 · 2.51 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate (13) C hyperpolarization of α-ketobutyrate (αKB), an endogenous molecular analog of pyruvate, and its in vivo enzymatic conversion via lactate dehydrogenase (LDH) using localized MR spectroscopy. Hyperpolarized (HP) (13) C MR experiments were conducted using [(13) C]αKB with rats in vivo and with isolated LDH enzyme in vitro, along with comparative experiments using [(13) C]pyruvate. Based on differences in the kinetics of its reaction with individual LDH isoforms, HP [(13) C]αKB was investigated as a novel MR probe, with added specificity for activity of LDHB-expressed H ("heart"-type) subunits of LDH (e.g., constituents of LDH-1 isoform). Comparable T1 and polarization values to pyruvate were attained (T1 = 52 s at 3 tesla [T], polarization = 10%, at C1 ). MR experiments showed rapid enzymatic conversion with substantially increased specificity. Formation of product HP [(13) C]α-hydroxybutyrate (αHB) from αKB in vivo was increased 2.7-fold in cardiac slabs relative to liver and kidney slabs. In vitro studies resulted in 5.0-fold higher product production from αKB with bovine heart LDH-1, as compared with pyruvate. HP [(13) C]αKB may be a useful MR probe of cardiac metabolism and other applications where the role of H subunits of LDH is significant (e.g., renal cortex and brain). Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 06/2015; DOI:10.1002/mrm.25716 · 3.57 Impact Factor
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    06/2015; 3(Suppl 1):O62. DOI:10.1186/2050-5736-3-S1-O62
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    ABSTRACT: Osteoarthritis (OA) is a common multifactorial and heterogeneous degenerative joint disease, and biochemical changes in cartilage matrix occur during the early stages of OA before morphological changes occur. Thus, it is desired to measure regional biochemical changes in the joint. High-resolution magic angle spinning (HRMAS) NMR spectroscopy is a powerful method of observing cartilaginous biochemical changes ex vivo, including the concentrations of alanine and N-acetyl, which are markers of collagen and total proteoglycan content, respectively. Previous studies have observed significant changes in chondrocyte metabolism of OA cartilage via the altered gene expression profiles of ACAN, COL2A1 and MMP13, which encode aggrecan, type II collagen and matrix metalloproteinase 13 (a protein crucial in the degradation of type II collagen), respectively. Employing HRMAS, this study aimed to elucidate potential relationships between N-acetyl and/or alanine and ACAN, COL2A1 and/or MMP13 expression profiles in OA cartilage. Thirty samples from the condyles of five subjects undergoing total knee arthroplasty to treat OA were collected. HRMAS spectra were obtained at 11.7 T for each sample. RNA was subsequently extracted to determine gene expression profiles. A significant negative correlation between N-acetyl metabolite and ACAN gene expression levels was observed; this provides further evidence of N-acetyl as a biomarker of cartilage degeneration. The alanine doublet was distinguished in the spectra of 15 of the 30 specimens of this study. Alanine can only be detected with HRMAS NMR spectroscopy when the collagen framework has been degraded such that alanine is sufficiently mobile to form a distinguished peak in the spectrum. Thus, HRMAS NMR spectroscopy may provide unique localized measurements of collagenous degeneration in OA cartilage. The identification of imaging markers that could provide a link between OA pathology and chondrocyte metabolism will facilitate the development of more sensitive diagnostic techniques and will improve methods of monitoring treatment for patients suffering from OA. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    NMR in Biomedicine 03/2015; 28(5). DOI:10.1002/nbm.3285 · 3.04 Impact Factor
  • J.E. Lee · C.J. Diederich · V.A. Salgaonkar · R. Bok · A.G. Taylor · J. Kurhanewicz ·
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    ABSTRACT: Real-time hyperpolarized (HP) 13C MR can be utilized during high-intensity focal ultrasound (HIFU) therapy to improve treatment delivery strategies, provide treatment verification, and thus reduce the need for more radical therapies for lowand intermediate-risk prostate cancers. The goal is to develop imaging biomarkers specific to thermal therapies of prostate cancer using HIFU, and to predict the success of thermal coagulation and identify tissues potentially sensitized to adjuvant treatment by sub-ablative hyperthermic heat doses. Mice with solid prostate tumors received HIFU treatment (5.6 MHz, 160W/cm2, 60 s), and the MR imaging follow-ups were performed on a wide-bore 14T microimaging system. 13C-labeled pyruvate and urea were used to monitor tumor metabolism and perfusion accordingly. After treatment, the ablated tumor tissue had a loss in metabolism and perfusion. In the regions receiving sub-ablative heat dose, a timedependent change in metabolism and perfusion was observed. The untreated regions behaved as a normal untreated TRAMP prostate tumor would. This promising preliminary study shows the potential of using 13C MR imaging as biomarkers of HIFU/thermal therapies.
  • Renuka Sriram · John Kurhanewicz · Daniel B. Vigneron ·
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    ABSTRACT: Imaging of hyperpolarized nuclei provides significant new insights into previously inaccessible aspects of disease biology. Many of the biomolecules crucial for understanding and monitoring metabolism are present in low concentration and are often beyond the detection threshold of traditional magnetic resonance spectroscopy and imaging. A solution is to improve sensitivity by a factor of 10 000 or more by temporarily redistributing the populations of nuclear spins in a magnetic field, a process termed hyperpolarization. Nuclei such as 13C in metabolically active biomolecules can be hyperpolarized, providing unprecedented gains in sensitivity for imaging biologic compounds. Although the first US National Cancer Institute-sponsored white paper describing the potential of this new molecular imaging technique was published only 3 years ago, over 60 biomolecules have been polarized and tested in preclinical studies. Moreover, a phase 1 clinical trial of hyperpolarized [1-13C]pyruvate in prostate cancer patients has demonstrated that this powerful technology can be translated to the clinic. This review is focused on the dissolution dynamic nuclear polarization (DNP)-based polarization technique and summarizes the acquisition techniques used for hyperpolarized 13C imaging, in vivo applications of some of the most promising hyperpolarized 13C labeled biomolecules, and its clinical translation.Keywords:hyperpolarized dissolution dynamic nuclear polarization (DNP);carbon-13 magnetic resonance imaging (MRI);13C magnetic resonance spectroscopic imaging (MRSI);pyruvate;lactate;metabolic imaging;molecular imaging
    eMagRes, 12/2014: pages 311-324; , ISBN: 9780470058213
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    ABSTRACT: To demonstrate simultaneous hyperpolarization and imaging of three (13) C-labeled perfusion MRI contrast agents with dissimilar molecular structures ([(13) C]urea, [(13) C]hydroxymethyl cyclopropane, and [(13) C]t-butanol) and correspondingly variable chemical shifts and physiological characteristics, and to exploit their varying diffusibility for simultaneous measurement of vascular permeability and perfusion in initial preclinical studies. Rapid and efficient dynamic multislice imaging was enabled by a novel pulse sequence incorporating balanced steady state free precession excitation and spectral-spatial readout by multiband frequency encoding, designed for the wide, regular spectral separation of these compounds. We exploited the varying bilayer permeability of these tracers to quantify vascular permeability and perfusion parameters simultaneously, using perfusion modeling methods that were investigated in simulations. "Tripolarized" perfusion MRI methods were applied to initial preclinical studies with differential conditions of vascular permeability, in normal mouse tissues and advanced transgenic mouse prostate tumors. Dynamic imaging revealed clear differences among the individual tracer distributions. Computed permeability maps demonstrated differential permeability of brain tissue among the tracers, and tumor perfusion and permeability were both elevated over values expected for normal tissues. Tripolarized perfusion MRI provides new molecular imaging measures for specifically monitoring permeability, perfusion, and transport simultaneously in vivo. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 12/2014; 72(6). DOI:10.1002/mrm.25071 · 3.57 Impact Factor
  • Robert Toth · Bryan Traughber · Rodney Ellis · John Kurhanewicz · Anant Madabhushi ·
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    ABSTRACT: External beam radiation treatment (EBRT) is a popular method for treating prostate cancer (CaP) involving destroying tumor cells with ionizing radiation. Following EBRT, biochemical failure has been linked with disease recurrence. However, there is a need for methods for evaluating early treatment related changes to allow for an early intervention in case of incomplete disease response. One method for looking at treatment evaluation is to detect changes in MRI markers on a voxel-by-voxel basis following treatment. Changes in MRI markers may be correlated with disease recurrence and complete or partial response. In order to facilitate voxel-by-voxel imaging related treatment changes, and also to evaluate morphologic changes in the gland post treatment, the pre- and post-radiated MRI must first be brought into spatial alignment via image registration. However, EBRT induces changes in the prostate volume and distortion to the internal anatomy of the prostate following radiation treatment. The internal substructures of the prostate, the central gland (CG) and peripheral zone (PZ), may respond to radiation differently, and their resulting shapes may change drastically. Biomechanical models of the prostate that have been previously proposed tend to focus on how external forces affect the surface of the prostate (not the internals), and assume that the prostate is a volume-preserving entity. In this work we present DoCD, a biomechanical model for automatically registering pre-, post-EBRT MRI with the aim of expressly modeling the (1) changes in volume, and (2) changes to the CG and PZ. DoCD was applied to a cohort of 30 patients and achieved a root mean square error of 2.994 mm, which was statistically significantly better a traditional biomechanical model which did not consider changes to the internal anatomy of the prostate (mean of 5.071 mm).
    Neurocomputing 11/2014; 144:3–12. DOI:10.1016/j.neucom.2014.01.058 · 2.08 Impact Factor

  • Molecular Cancer Research 11/2014; 12(11 Supplement):B37-B37. DOI:10.1158/1557-3125.MODORG-B37 · 4.38 Impact Factor
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    ABSTRACT: Oxidative stress has been proposed to be a unifying cause for diabetic nephropathy, and a target for novel therapies. Here we apply a new endogenous redox sensor, hyperpolarized (HP) (13)C dehydroascorbate (DHA), in conjunction with magnetic resonance imaging to noninvasively interrogate the renal redox capacity in a mouse diabetes model. The diabetic mice demonstrate early decrease in renal redox capacity, as shown by the lower in vivo HP (13)C DHA reduction to the antioxidant Vitamin C, prior to histological evidence of nephropathy. This correlates to lower tissue reduced glutathione (GSH) concentration and higher NADPH Oxidase 4 (Nox4) expression, consistent with increased superoxide generation and oxidative stress. Angiotensin converting enzyme inhibition restores the HP (13)C DHA reduction to Vitamin C with concomitant normalization of GSH concentration and Nox4 expression in the diabetic mice. HP (13)C DHA enables rapid in vivo assessment of altered redox capacity in diabetic renal injury and following successful treatment.
    Diabetes 09/2014; 64(2). DOI:10.2337/db13-1829 · 8.10 Impact Factor
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    ABSTRACT: PurposeHyperpolarized 13C magnetic resonance allows for the study of real-time metabolism in vivo, including significant hyperpolarized 13C lactate production in many tumors. Other studies have shown that aggressive and highly metastatic tumors rapidly transport lactate out of cells. Thus, the ability to not only measure the production of hyperpolarized 13C lactate but also understand its compartmentalization using diffusion-weighted MR will provide unique information for improved tumor characterization.Methods We used a bipolar, pulsed-gradient, double spin echo imaging sequence to rapidly generate diffusion-weighted images of hyperpolarized 13C metabolites. Our methodology included a simultaneously acquired B1 map to improve apparent diffusion coefficient (ADC) accuracy and a diffusion-compensated variable flip angle scheme to improve ADC precision.ResultsWe validated this sequence and methodology in hyperpolarized 13C phantoms. Next, we generated ADC maps of several hyperpolarized 13C metabolites in a normal rat, rat brain tumor, and prostate cancer mouse model using both preclinical and clinical trial-ready hardware.ConclusionADC maps of hyperpolarized 13C metabolites provide information about the localization of these molecules in the tissue microenvironment. The methodology presented here allows for further studies to investigate ADC changes due to disease state that may provide unique information about cancer aggressiveness and metastatic potential. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 09/2014; 74(3). DOI:10.1002/mrm.25422 · 3.57 Impact Factor
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    ABSTRACT: The purpose of this study is to determine if the severity of visually-assessed image distortion is less in prostate MR apparent diffusion coefficient (ADC) maps generated from a reduced-field-of-view (rFOV) diffusion-weighted-imaging (DWI) technique than from a conventional DWI sequence (CONV) and to determine if the rFOV ADC contrast between untreated tumors and healthy-appearing tissue within subjects is as high as or better than that of the CONV sequence. Fifty patients underwent a 3 T prostate MRI with phased-array and fluid-filled endorectal coils. CONV and rFOV sequences, utilizing a 2D, echo-planar, rectangularly-selective RF pulse, were acquired using b = 600, 0 s/mm2. Distortion was visually scored 0–4 by three independent observers. Distortion scores were significantly lower with the rFOV sequence (p < 0.012, Wilcoxon Signed-Rank Test, n = 50). The difference in distortion score did not differ significantly among observers (p = 0.99, Kruskal-Wallis Rank Sum Test). For seventeen untreated patients, regions of interest to calculate contrast were selected on radiologist-identified tumor regions and healthy-appearing contralateral tissue. The rFOV sequence afforded significantly higher ADC contrast between untreated tumor and healthy tissue (44.0% versus 35.9%, p < 0.0012, paired t-test, n = 17). The rFOV sequence yielded significantly decreased rectal susceptibility artifact and provided significantly higher contrast between tumor and healthy tissue.
    Magnetic Resonance Imaging 09/2014; 33(1). DOI:10.1016/j.mri.2014.08.040 · 2.09 Impact Factor
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    David M Wilson · John Kurhanewicz ·
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    ABSTRACT: Hyperpolarization using dissolution dynamic nuclear polarization has emerged as a versatile method to dramatically improve the MR signal of low-sensitivity nuclei. This technique facilitates the study of real-time metabolism in vitro and in vivo using (13)C-enriched substrates and has been applied to numerous models of human disease. In particular, several mechanisms underlying prostate cancer have been interrogated using hyperpolarized (13)C MR spectroscopy. This review highlights key metabolic shifts seen in prostate cancer, their study by hyperpolarized (13)C MR spectroscopy, and the development of new platforms for metabolic study.
    Journal of Nuclear Medicine 08/2014; 55(10). DOI:10.2967/jnumed.114.141705 · 6.16 Impact Factor
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    ABSTRACT: Purpose: To investigate the potential clinical utility of endorectal MRI-guided biopsy in patients with known or suspected prostate cancer. Materials and methods: We prospectively recruited 24 men with known or suspected prostate cancer in whom MRI-guided biopsy was clinically requested after multiparametric endorectal MRI showed one or more appropriate targets. One to six 18-gauge biopsy cores were obtained from each patient. Transrectal ultrasound guided biopsy results and post MRI-guided biopsy complications were also recorded. Results: MRI-guided biopsy was positive in 5 of 7 patients with suspected prostate cancer (including 2 of 4 with prior negative ultrasound-guided biopsies), in 8 of 12 with known untreated prostate cancer (including 5 where MRI-guided biopsy demonstrated a higher Gleason score than ultrasound guided biopsy results), and in 3 of 5 with treated cancer. MRI-guided biopsies had a significantly higher maximum percentage of cancer in positive cores when compared with ultrasound guided biopsy (mean of 37 ± 8% versus 13 ± 4%; P = 0.01). No serious postbiopsy complications occurred. Conclusion: Our preliminary experience suggests endorectal MRI-guided biopsy may safely contribute to the management of patients with known or suspected prostate cancer by making a new diagnosis of malignancy, upgrading previously diagnosed disease, or diagnosing local recurrence.
    Journal of Magnetic Resonance Imaging 08/2014; 40(2). DOI:10.1002/jmri.24383 · 3.21 Impact Factor
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    ABSTRACT: Organic cation transporter 1, OCT1 (SLC22A1), is the major hepatic uptake transporter for metformin, the most prescribed antidiabetic drug. However, its endogenous role is poorly understood. Here we show that similar to metformin treatment, loss of Oct1 caused an increase in the ratio of AMP to ATP, activated the energy sensor AMP-activated kinase (AMPK), and substantially reduced triglyceride (TG) levels in livers from healthy and leptin-deficient mice. Conversely, livers of human OCT1 transgenic mice fed high-fat diets were enlarged with high TG levels. Metabolomic and isotopic uptake methods identified thiamine as a principal endogenous substrate of OCT1. Thiamine deficiency enhanced the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase. Metformin and the biguanide analog, phenformin, competitively inhibited OCT1-mediated thiamine uptake. Acute administration of metformin to wild-type mice reduced intestinal accumulation of thiamine. These findings suggest that OCT1 plays a role in hepatic steatosis through modulation of energy status. The studies implicate OCT1 as well as metformin in thiamine disposition, suggesting an intriguing and parallel mechanism for metformin and its major hepatic transporter in metabolic function.
    Proceedings of the National Academy of Sciences 06/2014; 111(27). DOI:10.1073/pnas.1314939111 · 9.67 Impact Factor

Publication Stats

11k Citations
924.91 Total Impact Points


  • 1990-2015
    • University of California, San Francisco
      • • Department of Radiology and Biomedical Imaging
      • • Department of Radiation Oncology
      • • Department of Urology
      • • Department of Medicine
      • • Department of Pharmaceutical Chemistry
      San Francisco, California, United States
  • 2008-2014
    • University of California, Berkeley
      • Department of Bioengineering
      Berkeley, California, United States
  • 2011
    • University of Toronto
      • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
  • 2004
    • Stanford University
      • Department of Electrical Engineering
      Palo Alto, California, United States