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Featured researches published by David R. Vera.


Proceedings of the National Academy of Sciences of the United States of America | 2009

mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome

David B. Shackelford; Debbie S. Vasquez; Jacqueline Corbeil; Shulin Wu; Mathias Leblanc; Chin-Lee Wu; David R. Vera; Reuben J. Shaw

Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/ STK11 serine/threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies. Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice. Consistent with a central role for mTORC1 in these tumors, rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1+/− mice. However, the key targets of mTORC1 in LKB1-deficient tumors remain unknown. We demonstrate here that these polyps, and LKB1- and AMPK-deficient mouse embryonic fibroblasts, show dramatic up-regulation of the HIF-1α transcription factor and its downstream transcriptional targets in an rapamycin-suppressible manner. The HIF-1α targets hexokinase II and Glut1 are up-regulated in these polyps, and using FDG-PET, we demonstrate that LKB1+/− mice show increased glucose utilization in focal regions of their GI tract corresponding to these gastrointestinal hamartomas. Importantly, we demonstrate that polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1α, and GLUT1 levels. Furthermore, like HIF-1α and its target genes, the FDG-PET signal in the GI tract of these mice is abolished by rapamycin treatment. These findings suggest a number of therapeutic modalities for the treatment and detection of hamartomas in PJS patients, and potential for the screening and treatment of the 30% of sporadic human lung cancers bearing LKB1 mutations.


Annals of Surgical Oncology | 2003

Lymphoseek: a molecular radiopharmaceutical for sentinel node detection.

Anne M. Wallace; Carl K. Hoh; David R. Vera; Denise Darrah; Gery Schulteis

Background: Lymphoseek is a new radiopharmaceutical that accumulates in lymphatic tissue by binding to a receptor that resides on the surface of macrophage cells. We conducted a phase I clinical trial in which Lymphoseek was compared with filtered [99mTc]sulfur colloid (fTcSC) for sentinel node detection in patients with breast cancer.Methods: Twelve women (42–71 years) with breast cancer were randomly assigned to a 3-hour imaging protocol with peritumoral/subdermal injections (.5 mCi) of either Lymphoseek (1 nmol; molecular weight, 28 kDa; diameter, .007 μm) or .2 μm of fTcSC. Serial images were acquired for 180 minutes. Sentinel nodes, excised within 4.2 to 7.3 hours of administration, were assayed in a dose calibrator.Results: The receptor-binding agent, Lymphoseek, exhibited a significantly (P = .0025) faster injection site clearance (rate, .255 ± .147/hour; fTcSC rate, .014 ± .018/hour); the mean Lymphoseek clearance half-time was 2.72 ± 1.57 hours compared with 49.5 ± 38.5 hours for fTcSC. The primary sentinel node uptake of Lymphoseek (range, .02%–1.12%; mean, .55% ± .43%) and fTcSC (range, .00%–1.93%; mean, .65% ± .63%) did not differ (P = .75). Lymphoseek exhibited a lower mean number of sentinel nodes per study (n = 1.3) than fTcSC (n = 1.7) and a higher concordance with Lymphazurin.Conclusions: The molecular receptor-binding agent Lymphoseek demonstrated faster injection site clearance and equivalent primary sentinel node uptake when compared with fTcSC.


World Journal of Surgery | 2002

Predictors of Successful Hepatic Resection: Prognostic Usefulness of Hepatic Asialoglycoprotein Receptor Analysis

Norihiro Kokudo; David R. Vera; Keiichiro Tada; Mitsuru Koizumi; Makoto Seki; Toshiki Matsubara; Hirotoshi Ohta; Toshiharu Yamaguchi; Takashi Takahashi; Toshifusa Nakajima; Tetsuichiro Muto

To test the clinical usefulness of hepatic asialogycoprotein receptor analysis in liver surgery, we have conducted univariate and multivariate analysis for the detection of cirrhotic patients and prediction of morbidity after hepatic resection. Liver scintigraphy using technetium 99m-labeled asialoglycoprotein analog (TcGSA), ICG test, and CT hepatic volumetry were undertaken in 158 surgical patients including 111 who underwent hepatic resection. Hepatic functional parameters including Child-Pugh score, indocyanine green retention at 15 minutes (ICG-R15), clearance index (HH15), receptor index (LHL15), receptor concentration ([R]0), total hepatic receptor amount (R0) and hepatic parenchymal volume (HPV) were compared among patients with normal, cirrhotic, and non-cirrhotic damaged liver. Preoperative hepatic functional parameters, resected parenchymal fraction (RPf), operative blood loss, and total receptor amount of the remnant liver (R0-remnant) were compared between patients with and without signs of postoperative liver failure. All parameters but HPV were significantly different among patients with normal, cirrhotic, and noncirrhotic damaged liver. The multivariate analysis selected two significant (p<0.05) parameters, [R]0 and Child-Pugh score for the detection of liver cirrhosis. Of the 111 patients who underwent resection, 14 developed transient signs of postoperative liver failure. Of the parameters tested, presence of liver cirrhosis, LHL15, R0, intraoperative blood loss, and R0-remnant were significantly different between patients with and without signs of postoperative liver failure (p<0.05). The multivariate logistic regression analysis selected only R0-remnant as a significant (p=0.022) parameter for the prediction of liver failure. The morbidity rate in patients with R0-remnant under 0.05 µmoles was 100%, and the rate decreased in inverse proportion to R0-remnant. in conclusion, combining the ASGP-R concentration ([R]0) and the Child-Pugh score best detected liver cirrhosis in surgical candidates. Cirrhotic patients and patients with a low R0-remnant are at higher risk for postoperative liver failure. The present study confirms the usefulness of hepatic asialogycoprotein receptor analysis in liver surgery.RésuméAfin de tester l’utilité clinique de l’analyse des récepteurs asialogycoprotéiniques (RAGP) en chirurgie hépatique, nous avons mené une étude mono et multivariée pour détecter les patients cirrhotiques et pouvoir savoir si elle pouvait prédire la morbidité après résection hépatique. On a exploré 158 patients chirurgicaux, dont 111 qui ont eu une résection hépatique, par une scintigraphie à l’analogue d’asialoglycoprotéine marqué au technetium-99m (TcGSA), le test de rétention du vert d’indigocyanine (ICG), et la volumétrie hépatique par tomodensitométrie. Pour les patients ayant un foie normal, cirrhotique et non-cirrhotique, on a comparé les paramètres fonctionnels hépatiques comprenant le score de Child-Pugh, la rétention d’ICG à 15 minutes (ICG-R15), l’indexe de clairance (HH15), l’indexe de récepteur (LHL15), la concentration en récepteur ([R]0), la quantité totale de récepteur hépatique (RO) et le volume parenchymateux hépatique (VPH). Les paramètres préopératoires hépatiques fonctionnels, la fraction de parenchyme réséquée (RPf), les pertes sanguines opératoires, et la quantité totale de récepteurs RAGP dans le foie restant (R0-remnant) ont été comparés entre les patients avec et sans insuffisance hépatique postopératoire. Tous les paramètres sauf le VPH ont différé de façon significative entre les patients à foie normal, cirrhotique et non-cirrhotique. En analyse multivariée deux facteurs sont restés significatifs (p<0.05) pour la détection de cirrhose hépatique, la [R]0 et le score de Child-Pugh. Parmi les 111 cas réséqués, 14 ont développé des signes transitoires d’insuffisance hépatique postopératoire. Parmi les paramètres testés, la présence de cirrhose hépatique, de LHL15, de [R]0, les pertes sanguines et le facteur «R0-remnant» différaient de façon significative entre les patients avec ou sans signes d’insuffisance hépatique postopératoire (p<0.05). L’analyse multivariée par régression logistique a retrouvé que le moignon R0 (p=0.022) était prédictif de l’insuffisance hépatique. Le taux de morbidité chez les patients ayant un R0-remnant en dessous des 0.05 µmoles a été de 100% et ce taux a diminué en sens inverse par rapport au taux R0-remnant. En conclusion, la meilleure prédiction de cirrhose hépatique chez les candidats à la chirurgie est fournie par la combinaison de concentrations en RAGP, le ([R]0) et le score de Child-Pugh. Les patients cirrhotiques et les patients ayant un taux R0-remnant bas sont à haut risque d’insuffisance hépatique postopératoire. Cette étude confirme l’utilité de l’analyse des RAGP hépatiques dans la chirurgie hépatique.ResumenPara comprobar la utilidad del análisis del receptor de la asialoglicoproteína hepática en cirugía de hígado, realizamos una serie de análisis uni y multivariantes para su detección en pacientes cirróticos, así como para evaluar su capacidad pronóstica por lo que a la morbilidad, tras resección hepática, se refiere. En 158 paciente quirúrgicos incluidos 111 sometidos a resección hepática se realizaron las siguientes pruebas: escintigrafía con tecnecio 99 marcado con un análago de asialoglicoproteína (TcGSA), test de ICG y volumetría hepática mediante tomografía axial computarizada (CT). Se compararon, entre pacientes con hígado normal, cirrótico y patológico por causas no cirróticas, los siguientes parámetros funcionales hepáticos: Valoración Child-Pugh, retención a los 15 minutos de ICG (ÏCG-R15), índice de aclaramiento (HH15), índice receptor (LHL15), concentración de receptor ([R]0), cantidad de recepción hepática total [R0] y volumen del parénquima hepático (HPV). Entre pacientes con y sin signos de fracaso hepático postoperatorio se compararon los siguiente parámetros: Función hepática preoperatoria, fracción parenquimatosa resecada (RPf), hemorragia y cantidad total de receptores en el remanente hepático (R0-remanent). Todos los parámetros, excepto el HPV, fueron significativamente diferentes entre pacientes con hígado normal, cirrótico y lesión hepática no cirrótica. El análisis multivariante seleccionó dos, muy significativos (p<0.05) para el diagnóstico de cirrosis: [R]0 y la valoración de Child-Pugh. 14, de los 111 casos con resección hepática, desarrollaron síndrome transitorio de fracaso hepático postoperatorio. De los parámetros estudiados: la cirrosis, LHL15, R0, hemorragia intraoperatoria y remanente R0, mostraron diferencias significativas (p<0.05) entre pacientes con o sin signos de fracaso hepático postoperatorio. El análisis de regresión logística multivariable demostró que el parámetro pronóstico más significativo de fracaso hepático es el remanente-R0 (p=0.022). La tasa de morbilidad en pacientes con un remanente-R0 inferior a 0.05 µmoles fue del 100%, disminuyendo en sentido inverso al tamaño del remanente-R0. Conclusión: las pruebas más eficaces para detectar la cirrosis hepática en posibles candidatos a tratamiento quirúrgico son: la ASGP-R concentración ([R]0) y la clasificación de Child-Pugh. Enfermos cirróticos y con un pequeño remanente-R0 son los que conllevan un mayor riesgo de fracaso hepático postoperatorio. El presente estudio confirma la utilidad, en cirugía hepática, del análisis del receptor hepático de asialoglicoproteína.


Nuclear Medicine and Biology | 2003

Clinical application of TcGSA

Norihiro Kokudo; David R. Vera; Masatoshi Makuuchi

Asialoglycoprotein receptor (ASGP-R) is a hepatic cell surface receptor specific for galactose-terminated glycoprotein. The (99m)Tc-labeled asialoglycoprotein analog, TcGSA (galactosyl-human serum albumin-diethylenetriamine-pentaacetic acid) has been applied to human hepatic receptor imaging. This method is unique and provides information that is totally independent of the ICG test or Child-Turcotte Score. However, simple parameters, HH15 or LHL15 are no better than conventional Child-Turcotte Score. Parameters obtained from kinetic modeling were useful in detecting liver cirrhosis or postoperative liver failure. They provide quantitative data on functioning liver mass. Considering the moderate cost and widespread availability of gamma cameras, a TcGSA test should be performed on patients whose liver function are not adequately estimated by an ICG test or a Child-Turcotte score.


Bioconjugate Chemistry | 2010

Fast 18F Labeling of a Near-Infrared Fluorophore Enables Positron Emission Tomography and Optical Imaging of Sentinel Lymph Nodes

Richard Ting; Todd A. Aguilera; Jessica L. Crisp; David J. Hall; William C. Eckelman; David R. Vera; Roger Y. Tsien

We combine a novel boronate trap for F− with a near-infrared fluorophore into a single molecule. Attachment to targeting ligands enables localization by positron emission tomography (PET) and near-infrared fluorescence (NIRF). Our first application of this generic tag is to label Lymphoseek (tilmanocept), an agent designed for receptor-specific sentinel lymph node (SLN) mapping. The new conjugate incorporates 18F− in a single, aqueous step, targets mouse SLN rapidly (1 h) with reduced distal lymph node accumulation, permits PET or scintigraphic imaging of SLN, and enables NIRF-guided excision and histological verification even after 18F decay. This embodiment is superior to current SLN mapping agents such as nontargeted [99mTc]sulfur colloids and Isosulfan Blue, as well as the phase III targeted ligand [99mTc]SPECT Lymphoseek counterpart, species that are visible by SPECT or visible absorbance separately. Facile incorporation of 18F into a NIRF probe should promote many synergistic PET and NIRF combinations.


American Journal of Physiology-renal Physiology | 2009

β1-Integrin is required for kidney collecting duct morphogenesis and maintenance of renal function

Wei Wu; Shinji Kitamura; David M. Truong; Timo Rieg; Volker Vallon; Hiroyuki Sakurai; Kevin T. Bush; David R. Vera; Robert S. Ross; Sanjay K. Nigam

Deletion of integrin-beta1 (Itgb1) in the kidney collecting system led to progressive renal dysfunction and polyuria. The defect in the concentrating ability of the kidney was concomitant with decreased medullary collecting duct expression of aquaporin-2 and arginine vasopressin receptor 2, while histological examination revealed hypoplastic renal medullary collecting ducts characterized by increased apoptosis, ectasia and cyst formation. In addition, a range of defects from small kidneys with cysts and dilated tubules to bilateral renal agenesis was observed. This was likely due to altered growth and branching morphogenesis of the ureteric bud (the progenitor tissue of the renal collecting system), despite the apparent ability of the ureteric bud-derived cells to induce differentiation of the metanephric mesenchyme. These data not only support a role for Itgb1 in the development of the renal collecting system but also raise the possibility that Itgb1 links morphogenesis to terminal differentiation and ultimately collecting duct function and/or maintenance.


IEEE Transactions on Biomedical Engineering | 1985

Identifiability Analysis of an In Vivo Receptor-Binding Radiopharmacokinetic System

David R. Vera; Kenneth A. Krohn; Paul O. Scheibe; Robert C. Stadalnik

A five-state, nonlinear model describing the pharmacokinetics of a receptor-binding radiopharmaceutical is presented. Local parameter identifiability analysis was performed preexperimentally to investigate the chemical and observational conditions required for adequate estimates of hepatic blood flow, receptor-ligand affinity, and receptor population. The ability to estimate the above parameters from externally observed kinetic data depended upon receptor-ligand affinity, the molar dose of the radiopharmaceutical, the number and coupling of the observers, and independent knowledge of the coupling coefficients or ligand-receptor affinity.


Nuclear Medicine and Biology | 2003

Preclinical studies of [99mTc]DTPA-mannosyl-dextran☆☆

Carl K. Hoh; Anne M. Wallace; David R. Vera

We report the preclinical testing of a synthetic receptor-binding macromolecule, [(99m)Tc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, K(D) = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration, and perivascular irritation studies in rabbits following intra-muscular administration at 100 and 1000 times the scaled human dose. Biodistribution studies in rabbits at 15 m, 1 h, and 3 h indicated that [(99m)Tc]DTPA-mannosyl-dextran cleared the hind foot pad with a biological half-life of 2.21 +/- 0.27 h. Other than mild hepatocyte hypertrophy in rabbits, no abnormalities in toxicology or pathology were found. Intravenous administration had no effect on survival, any clinical observations, electrocardiograms, or blood pressures. Intramuscular injection had no effect on survival, clinical observations, injection site observations, or injection site histopathology. The estimated absorbed radiation dose to the affected breast was 0.15 mGy/MBq and the effective dose was 1.06 x 10(-2) mSv/MBq. This preclinical study demonstrates that [(99m)Tc]DTPA-mannosyl-dextran has no toxicities and has an acceptable biodistribution and radiation dose.


Nuclear Medicine and Biology | 2001

[99mTc]MAG3-mannosyl-dextran: a receptor-binding radiopharmaceutical for sentinel node detection

David R. Vera; Anne M. Wallace; Carl K. Hoh

Technetium-99m-labeled benzoyl-mercaptoacetylglycylglycyl-glycine-mannosyl-dextran ([(99m)Tc]MAG(3)-mannosyl-dextran) is a receptor-binding radiotracer that binds to mannose-binding protein, a receptor expressed by recticuloendothelial tissue. This agent is composed of a 10.5-kilodalton molecule of dextran and multiple units of mannose, and benzoyl-mercaptoacetylglycylglycyl-glycine (BzMAG(3)). The tetraflorophenol-activated ester of BzMAG(3) and the imidate of thiomannose were used to covalently attach BzMAG(3) and mannose to an amino-terminated conjugate of dextran. This yielded a 19-kilodalton macromolecule consisting of 3 BzMAG(3) and 21 mannose units per dextran. Dynamic light scattering was used to measure a mean diameter of 5.5 nanometers for BzMAG(3)-mannosyl-dextran and 0.28 microns for filtered Tc-99m sulfur colloid. A preliminary sentinel node detection study employing right fore and hind footpad injections of [(99m)Tc]MAG(3)-mannosyl-dextran and left fore and hind footpad injections of filtered Tc-99m sulfur colloid demonstrated greater sentinel lymph node uptake by the receptor-binding agent.


Academic Radiology | 1995

A molecular receptor-binding contrast agent for magnetic resonance imaging of the liver.

David R. Vera; Michael H. Buonocore; Erik R. Wisner; Richard W. Katzberg; Robert C. Stadalnik

RATIONALE AND OBJECTIVES A gadolinium complex of polydiethylenetriamine pentaacetic acid polyneogalactosyl polylysine (Gd-DTPA-gal-PL) was developed and tested as a paramagnetic contrast agent for magnetic resonance (MR) imaging of the liver. The agent was designed for receptor-mediated uptake by the asialoglycoprotein receptor (ASGP-R), which is unique to hepatocytes and exhibits high specificity for galactose-terminated glycoconjugates. METHODS Polylysine was alkylated with a mixed anhydride of diethylenetriamine pentaacetic acid. This product was complexed with gadolinium and N-alkylated with 3-oxopropyl-1-thio-beta-D-galactopyranoside. With this reaction sequence, we prepared a gadolinium complex consisting of 2284 galactose groups and 858 chelators per polylysine having 2136 amino groups. Hepatic enhancement was tested by MR imaging of nine rats with liver-implanted mammary adenocarcinoma before and after injection of 20 x 10(-9) mol/kg Gd-DTPA858-gal2284-PL2136. The conjugate was labeled with technetium-99m and tested (1.5 x 10(-10) mol/kg) for hepatic specificity via nuclear imaging. RESULTS Mean hepatic enhancement was 86% within 10 min and remained constant for 25 min. Hepatic relative intensity exceeded preinjection intensities by at least four times the standard deviation of the preinjection values (p < .01). The tumors, which are devoid of ASGP-R, did not exhibit significant enhancement (p > .1). The liver accumulated 90% of the technetium-99m-labeled conjugate. CONCLUSION A molecular paramagnetic ligand to the asialoglycoprotein receptor has been developed for hepatocyte-specific MR contrast enhancement.

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Carl K. Hoh

University of California

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Zhengtao Qin

University of California

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David J. Hall

University of California

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Robert F. Mattrey

University of Texas Southwestern Medical Center

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William C. Eckelman

National Institutes of Health

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