Guihua Zhai - Academia.edu (original) (raw)
Papers by Guihua Zhai
The online version of this article, along with updated information and services, is located on the
Schizophrenia Research, 2003
affected but-also in the unaffected DS group. This leads to the conclusion that ventricular shape... more affected but-also in the unaffected DS group. This leads to the conclusion that ventricular shape change might reflect vulnerability for schizophrenia and hence be a marker for a neurodevelopmental aspect of the illness. Both statistical tests applied to volumes did not show any differences between MZ and DS groups, suggesting that shape analysis is more sensitive to subtle structural changes than volumetry.
Journal of magnetic resonance imaging : JMRI, Jan 20, 2015
To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease ind... more To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X-ray radiation in head and neck cancer mouse models using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Mice bearing SCC1 (or OSC19) tumor xenografts were treated with anti-EMMPRIN antibody, radiation, cisplatin, or anti-EMMPRIN antibody plus cisplatin (or radiation) for a week (n = 4-5 per group). DCE-MRI was carried out on a 9.4T small animal MR scanner on days 0, 3, and 7, and K(trans) values were averaged in a 0.5-mm-thick peripheral tumor region. Ki67 and CD31 staining were implemented for all tumors after imaging. The K(trans) changes of SCC1 and OSC19 tumors treated with anti-EMMPRIN antibody for 3 days were -18 ± 8% and 4 ± 7%, respectively, which were significantly lower than those of control groups (39 ± 5% and 45 ± 7%; P = 0.0025 and 0.0220, respectively). When cisplatin was added, those were -42 ± 9% and -44 ± 9%, re...
International journal of body composition research, 2013
Adipocyte cell size varies among individuals and importantly, is inversely correlated with insuli... more Adipocyte cell size varies among individuals and importantly, is inversely correlated with insulin sensitivity, and modifiable by weight loss or pharmaceutical agents. However, there are no non-invasive, in vivo methods for adipocyte cell size determination. Here we apply Chemical-Shift Water-Fat MRI to in vivo measures of subcutaneous (inguinal) and visceral (gonadal) white adipose tissue (WAT) to determine whether the fat-signal fraction (FF) is a sensitive indicator of adipocyte cell size. C57BL/6J male mice (8 weeks old) were singly housed and fed a low-fat diet, high-fat diet or very high-fat diet (n = 16 or 15/group) for 8 weeks. Food intake, body weight and composition were measured; CS-MRI was performed on a 9.4 Tesla Bruker magnet with respiratory gating and anesthesia. Histology was acquired for gonadal WAT; both gonadal and inguinal WAT were fixed with osmium tetroxide and then measured through Image J for cell size. Mice fed with higher fat content diets gained significa...
Cancer biology & therapy, 2014
TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect f... more TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect for triple negative breast cancer (TNBC) in preclinical models. Tamoxifen, the standard of care for ERα-positive breast cancer, induces apoptosis via ERβ, which commonly presents in TNBC cells. The current study investigates the combination effects of TRA-8 and tamoxifen for TNBC. In vitro assays were implemented with two ERβ-positive TNBC cell lines, SUM159 and 2LMP, and in vivo therapy studies were followed using orthotopic breast tumor mouse models. IC50 of tamoxifen for SUM159 and 2LMP were 29 μM and 38 μM, respectively. Synergy between TRA-8 (0-1000 ng/mL) and tamoxifen (20 μM) was observed for both the cell lines. Tamoxifen (400 mg/kg diet) markedly suppressed the growth of SUM159 tumors for 6 weeks after therapy initiation, but it did not induce antitumor effect for 2LMP tumors. TRA-8 (0.1 mg, weekly, i.p.) successfully arrested the growth of both SUM159 and 2LMP tumors during ther...
Stroke, 2007
Background and Purpose— Stroke-prone spontaneous hypertensive rats (SHRsp) fed a high-salt diet d... more Background and Purpose— Stroke-prone spontaneous hypertensive rats (SHRsp) fed a high-salt diet develop malignant hypertension, blood–brain barrier breakdown, and spontaneous intracerebral hemorrhage (ICH). The precise spatial and temporal relationship between these events has not been well-delineated. Methods— Ten SHRsp male rats, fed a high-salt diet, were imaged weekly using MRI, starting at 12 weeks of age. T1-weighted (with and without Gd), T2-weighted, and T2* sequences were acquired. Permeability maps were calculated. Results— Seven SHRsp rats had spontaneous ICH develop before death. Five of the 7 rats had focally increased vascular permeability at the site of the ICH; 3 of these rats had vascular permeability 1 to 2 weeks before spontaneous ICH. Conclusions— Salt-loaded SHRsp rats have increased vascular permeability up to 2 weeks before ICH, predicting hemorrhage both in space and time. These results suggest that hypertensive ICH is preceded by focal vasculopathy detectabl...
Radiology, 2003
Abbreviations: ADC ϭ apparent diffusion coefficient DW ϭ diffusion weighted FA ϭ fractional aniso... more Abbreviations: ADC ϭ apparent diffusion coefficient DW ϭ diffusion weighted FA ϭ fractional anisotropy GM ϭ gray matter MP-RAGE ϭ magnetization-prepared rapid gradient echo ROI ϭ region of interest WM ϭ white matter 1 From the Departments of Biomedical Engineering (G.
Psychiatry Research: Neuroimaging, 2004
While it has been hypothesized that brain development is abnormal in schizophrenia and other neur... more While it has been hypothesized that brain development is abnormal in schizophrenia and other neurodevelopmental disorders, there have been few attempts to study very early brain development in children. Twenty unsedated healthy newborns underwent 3 Tesla magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI). The left ventricle was significantly larger than the right; females had significantly larger ventricles than males. Fractional anisotropy (FA) increased significantly with gestational age in the genu and splenium of the corpus callosum. It is feasible to study brain development in unsedated newborns using 3 T MRI.
Journal of Magnetic Resonance Imaging, 2013
Purpose-To determine differences in fat-signal fraction (FF) from chemical-shift-encoded water-fa... more Purpose-To determine differences in fat-signal fraction (FF) from chemical-shift-encoded water-fat MRI of interscapular BAT in mice housed at different ambient temperatures (T a). Materials and Methods-C57BL/6J male mice (8 weeks old) were singly housed at 16°C, 23°C or 30°C (n=16/group) for 4 weeks. Measures included food intake, body weight (both measured weekly) and body composition (at baseline, 2 and 4 weeks post-thermal exposure); chemical-shift-encoded water-fat MRI was performed on a 9.4 Tesla Bruker magnet with respiratory gating and anesthesia at 4 weeks post-thermal exposure. Results-A significant inverse relationship between food intake and T a was evidenced (p < 0.0001). Lean mass was similar between groups, while total fat mass was significantly different between groups ([mean±SE]: 30°C=5.10±0.19 g; 23°C=4.18±0.16 g; 16°C=3.48±0.54 g; p < 0.0001). Mean BAT-FF was positively related to T a (means: 30°C=79.4%; 23°C=61.8%; 16°C=50.9%; p < 0.0001). Conclusion-These cross-sectional results demonstrate that MRI measurement of FF within the interscapular BAT in mice reflects recent functional status of the tissue, with a lower T a leading to a significantly reduced BAT-FF, indicative of the tissue's involvement in thermogenesis.
Journal of Magnetic Resonance Imaging, 2013
Purpose-To assess the early response of triple-negative breast-cancer (TNBC) following TRA-8 and ... more Purpose-To assess the early response of triple-negative breast-cancer (TNBC) following TRA-8 and carboplatin therapy using DWI and MRS in 2LMP and SUM159 mouse models. Materials and Methods-Four groups (n = 5/group) of each model were untreated or treated with carboplatin, TRA-8, and combination, respectively. DWI and MRS were applied on 0, 3, and 7 days after therapy initiation, and all tumors were collected thereafter for terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. The changes in intratumoral apparent diffusion coefficient (ADC) and fat-water ratios (FWRs) were compared with tumor volume changes and apoptotic cell densities. Results-Mean ADC values of 2LMP and SUM159 tumors significantly increased 4 ± 4% and 37 ± 11% during 7 days of combination therapy, respectively, as compared to control groups (P < 0.05). Similarly, mean FWRs of 2LMP and SUM159 tumors significantly increased 102 ± 30% and 126 ± 52%, respectively, for 7 days of combined treatment (P < 0.05). The changes of the mean ADC values for 3 days (or FWRs for 7 days) were linearly proportional to either the mean volume changes or apoptotic cell densities in both models. Conclusion-DWI and MRS assessed the early tumor response to TRA-8 and carboplatin in TNBC mouse models.
Journal of Cerebral Blood Flow & Metabolism, 2005
Increases of vascular extravasations of MR contrast agent have been implicated to be predictive o... more Increases of vascular extravasations of MR contrast agent have been implicated to be predictive of hemorrhagic transformation in acute stroke patients. However, systemic studies are lacking. In this study, we aim to determine how the increased vascular extravasations of MR contrast agent can be used to predict the presence of subsequent hemorrhages in Stroke-prone spontaneous hypertensive rats (SHRsp). SHRsp rats (n=12), fed a high-salt low-protein diet after weaning, were imaged weekly on a 3 T SIEMENS Allegra head-only scanner beginning at 12 week of age and continuing for five weeks. Three sequences were used to acquire images, including a T2-weighted, a T2*-weighted, and a turboFLASH sequence. The acquired T2-weighted images provided anatomical data as well as an indication of brain edema. T2*-weighted images allowed assessment of hemorrhage and were acquired using a 3D gradient echo sequence (TE=25 ms). To obtain estimates of vascular permeability, the Look-Locker (L-L) technique employing the T-one by multiple read-out pulses (TOMROP) sequence (1) was used for pixel-by-pixel estimates of T1. The TOMROP sequence was repeated 10 times post-contrast. Finally, the PATLAK approach was utilized with the images acquired using the TOMROP sequence for obtaining permeability maps for each rat (2). All 12 rats developed asymmetric T2 hyperintensities by 14 weeks of age; 5 rats developed 7 regions of intracerebral hemorrhage (detected by T2*) at later time-points. Four hemorrhages were located within the striatum; three were located in the cortex. All rats that developed spontaneous hemorrhages demonstrated concurrent or prior vascular permeability (determined by Gd as described above) at the site of the hemorrhage. In 4 of the 7 hemorrhages, evidence of vascular permeability was found prior to the detection of hemorrhage, preceding it by up to 2 weeks. The remaining three temporally coincided with the hemorrhage. The temporal evolution of vascular permeability, T2 and T2* images of a representative rats are shown in Fig. 1. It is immediately evident that the presence of vascular leak precedes the hemorrhage by one week. Although blood-brain-barrier (BBB) breakdown, cerebral edema, and hemorrhage have been well-described in this model, the spatial and temporal relationship between these events has not been well-delineated. Although increased vascular permeability did not precede 3 of 7 hemorrhages but rather appeared concurrently, we believe that this may be due to the poor temporal resolution of our imaging scheme. These data suggest that hypertensive intracerebral hemorrhage is preceded by focal vasculopathy resulting in breakdown of the BBB.
Breast Cancer Research and Treatment, 2011
The purpose is to evaluate sensitivity of basal-like breast cancer to treatment with anti-DR5 alo... more The purpose is to evaluate sensitivity of basal-like breast cancer to treatment with anti-DR5 alone and in combination with chemotherapy. Cytotoxicity of TRA-8 anti-DR5 alone and in combination with doxorubicin or paclitaxel was examined. The role of a DR5-associated molecule (DDX3) in the regulation of apoptosis by recruitment of cIAP1 to the DR5/DDX3 complex was studied. SUM159 and 2LMP orthotopic xenografts were treated with TRA-8 alone and in combination with Abraxane or doxorubicin, and tumor growth inhibition determined. Diffusionweighted magnetic resonance imaging was used to monitor early tumor response. The majority (12/15) of basal-like cell lines were very sensitive to TRA-8-induced cytotoxicity (IC 50 values of 1.0-49 ng/ml). In contrast, 8/11 luminal or HER2-positive cell lines were resistant (IC 50 > 1,000 ng/ml). Enhanced killing of basal-like cell lines was produced by combination treatment with TRA-8 and doxorubicin. Majority of basal cell lines expressed lower levels of DR5-associated DDX3 and cIAP1 than luminal and HER2-positive cell lines. TRA-8 inhibited growth of basal xenografts and produced 20% complete 2LMP tumor regressions. TRA-8 and chemotherapy produced greater 2LMP growth inhibition than either alone. An increase in apparent diffusion coefficient in 2LMP tumors was measured in a week of therapy with TRA-8 and Abraxane. Basallike cell lines were more sensitive to TRA-8-mediated cytotoxicity than HER2-over-expressing and luminal cell lines, and chemotherapy enhanced cytotoxicity. High sensitivity of basal cells to TRA-8 correlated with low expression of DR5/DDX3/cIAP1 complex. Treatment with TRA-8 and chemotherapy may be an effective therapy for basal-like breast cancer.
Anti-Cancer Drugs, 2011
The objective of this study was to evaluate extracelluar matrix metalloproteinase (EMMPRIN) as a ... more The objective of this study was to evaluate extracelluar matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic-cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3-7, while MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1-3 (residual tumor model) and at 21 days after cell implantation for groups 4-7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2-1.0 mg) twice weekly for 2-3 weeks, while the other groups served as the control. In residual tumor model, tumor growth of anti-EMMPRIN treated group was successfully arrested for 21 days (15±4 mm 3), significantly lower than that of EMMPRIN knockdown group (80±15 mm 3 ; p=0.001) or control group (240±41 mm 3 ; p<0.001). In established tumor model, anti-EMMPRIN therapy lowered tumor-volume increase about 40% compared with control regardless of dose amount. Ki67-expressed cell densities of group 5 was 939±150 mm −2 , significantly lower than that of group 4 (1709±145 mm −2 ; p=0.006). Microvessel density of group 5 (30±6 mm −2) was also significantly lower than that of group 4 (53±5 mm −2 ; p=0.014), while the microvessel size of group 5 (191±22 μm 2) was significantly larger than that of group 4 (113±26 μm 2 ; p=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer, and support its clinical translation.
Molecular Imaging and Biology, 2011
Purpose-To evaluate by sequential 18 F-FDG PET/CT imaging the therapeutic response to a novel mon... more Purpose-To evaluate by sequential 18 F-FDG PET/CT imaging the therapeutic response to a novel monoclonal antibody targeting human EMMPRIN (extracellular matrix metalloproteinase inducer) in combination with gemcitabine in a pancreatic-tumor xenograft murine model. Procedures-Four groups of SCID mice bearing orthotopic pancreatic tumor xenografts were injected with PBS, gemcitabine (120mg/kg BW), anti-EMMPRIN antibody (0.2mg), or combination, respectively twice weekly for 2 weeks, while 18 F-FDG PET/CT imaging was performed weekly for 3 weeks. Changes in mean standardized uptake value (SUV mean) of 18 F-FDG and volume of tumors were determined. Results-The tumor SUV mean change in the group receiving combination therapy was significantly lower than those of the other groups. Tumor-volume changes of groups treated with anti-EMMPRIN monotherapy or combined therapy were significantly lower than that of the control group. Conclusions-These data provide support for clinical studies of anti-EMMPRIN therapy with gemcitabine for pancreatic cancer treatment.
The online version of this article, along with updated information and services, is located on the
Schizophrenia Research, 2003
affected but-also in the unaffected DS group. This leads to the conclusion that ventricular shape... more affected but-also in the unaffected DS group. This leads to the conclusion that ventricular shape change might reflect vulnerability for schizophrenia and hence be a marker for a neurodevelopmental aspect of the illness. Both statistical tests applied to volumes did not show any differences between MZ and DS groups, suggesting that shape analysis is more sensitive to subtle structural changes than volumetry.
Journal of magnetic resonance imaging : JMRI, Jan 20, 2015
To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease ind... more To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X-ray radiation in head and neck cancer mouse models using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Mice bearing SCC1 (or OSC19) tumor xenografts were treated with anti-EMMPRIN antibody, radiation, cisplatin, or anti-EMMPRIN antibody plus cisplatin (or radiation) for a week (n = 4-5 per group). DCE-MRI was carried out on a 9.4T small animal MR scanner on days 0, 3, and 7, and K(trans) values were averaged in a 0.5-mm-thick peripheral tumor region. Ki67 and CD31 staining were implemented for all tumors after imaging. The K(trans) changes of SCC1 and OSC19 tumors treated with anti-EMMPRIN antibody for 3 days were -18 ± 8% and 4 ± 7%, respectively, which were significantly lower than those of control groups (39 ± 5% and 45 ± 7%; P = 0.0025 and 0.0220, respectively). When cisplatin was added, those were -42 ± 9% and -44 ± 9%, re...
International journal of body composition research, 2013
Adipocyte cell size varies among individuals and importantly, is inversely correlated with insuli... more Adipocyte cell size varies among individuals and importantly, is inversely correlated with insulin sensitivity, and modifiable by weight loss or pharmaceutical agents. However, there are no non-invasive, in vivo methods for adipocyte cell size determination. Here we apply Chemical-Shift Water-Fat MRI to in vivo measures of subcutaneous (inguinal) and visceral (gonadal) white adipose tissue (WAT) to determine whether the fat-signal fraction (FF) is a sensitive indicator of adipocyte cell size. C57BL/6J male mice (8 weeks old) were singly housed and fed a low-fat diet, high-fat diet or very high-fat diet (n = 16 or 15/group) for 8 weeks. Food intake, body weight and composition were measured; CS-MRI was performed on a 9.4 Tesla Bruker magnet with respiratory gating and anesthesia. Histology was acquired for gonadal WAT; both gonadal and inguinal WAT were fixed with osmium tetroxide and then measured through Image J for cell size. Mice fed with higher fat content diets gained significa...
Cancer biology & therapy, 2014
TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect f... more TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect for triple negative breast cancer (TNBC) in preclinical models. Tamoxifen, the standard of care for ERα-positive breast cancer, induces apoptosis via ERβ, which commonly presents in TNBC cells. The current study investigates the combination effects of TRA-8 and tamoxifen for TNBC. In vitro assays were implemented with two ERβ-positive TNBC cell lines, SUM159 and 2LMP, and in vivo therapy studies were followed using orthotopic breast tumor mouse models. IC50 of tamoxifen for SUM159 and 2LMP were 29 μM and 38 μM, respectively. Synergy between TRA-8 (0-1000 ng/mL) and tamoxifen (20 μM) was observed for both the cell lines. Tamoxifen (400 mg/kg diet) markedly suppressed the growth of SUM159 tumors for 6 weeks after therapy initiation, but it did not induce antitumor effect for 2LMP tumors. TRA-8 (0.1 mg, weekly, i.p.) successfully arrested the growth of both SUM159 and 2LMP tumors during ther...
Stroke, 2007
Background and Purpose— Stroke-prone spontaneous hypertensive rats (SHRsp) fed a high-salt diet d... more Background and Purpose— Stroke-prone spontaneous hypertensive rats (SHRsp) fed a high-salt diet develop malignant hypertension, blood–brain barrier breakdown, and spontaneous intracerebral hemorrhage (ICH). The precise spatial and temporal relationship between these events has not been well-delineated. Methods— Ten SHRsp male rats, fed a high-salt diet, were imaged weekly using MRI, starting at 12 weeks of age. T1-weighted (with and without Gd), T2-weighted, and T2* sequences were acquired. Permeability maps were calculated. Results— Seven SHRsp rats had spontaneous ICH develop before death. Five of the 7 rats had focally increased vascular permeability at the site of the ICH; 3 of these rats had vascular permeability 1 to 2 weeks before spontaneous ICH. Conclusions— Salt-loaded SHRsp rats have increased vascular permeability up to 2 weeks before ICH, predicting hemorrhage both in space and time. These results suggest that hypertensive ICH is preceded by focal vasculopathy detectabl...
Radiology, 2003
Abbreviations: ADC ϭ apparent diffusion coefficient DW ϭ diffusion weighted FA ϭ fractional aniso... more Abbreviations: ADC ϭ apparent diffusion coefficient DW ϭ diffusion weighted FA ϭ fractional anisotropy GM ϭ gray matter MP-RAGE ϭ magnetization-prepared rapid gradient echo ROI ϭ region of interest WM ϭ white matter 1 From the Departments of Biomedical Engineering (G.
Psychiatry Research: Neuroimaging, 2004
While it has been hypothesized that brain development is abnormal in schizophrenia and other neur... more While it has been hypothesized that brain development is abnormal in schizophrenia and other neurodevelopmental disorders, there have been few attempts to study very early brain development in children. Twenty unsedated healthy newborns underwent 3 Tesla magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI). The left ventricle was significantly larger than the right; females had significantly larger ventricles than males. Fractional anisotropy (FA) increased significantly with gestational age in the genu and splenium of the corpus callosum. It is feasible to study brain development in unsedated newborns using 3 T MRI.
Journal of Magnetic Resonance Imaging, 2013
Purpose-To determine differences in fat-signal fraction (FF) from chemical-shift-encoded water-fa... more Purpose-To determine differences in fat-signal fraction (FF) from chemical-shift-encoded water-fat MRI of interscapular BAT in mice housed at different ambient temperatures (T a). Materials and Methods-C57BL/6J male mice (8 weeks old) were singly housed at 16°C, 23°C or 30°C (n=16/group) for 4 weeks. Measures included food intake, body weight (both measured weekly) and body composition (at baseline, 2 and 4 weeks post-thermal exposure); chemical-shift-encoded water-fat MRI was performed on a 9.4 Tesla Bruker magnet with respiratory gating and anesthesia at 4 weeks post-thermal exposure. Results-A significant inverse relationship between food intake and T a was evidenced (p < 0.0001). Lean mass was similar between groups, while total fat mass was significantly different between groups ([mean±SE]: 30°C=5.10±0.19 g; 23°C=4.18±0.16 g; 16°C=3.48±0.54 g; p < 0.0001). Mean BAT-FF was positively related to T a (means: 30°C=79.4%; 23°C=61.8%; 16°C=50.9%; p < 0.0001). Conclusion-These cross-sectional results demonstrate that MRI measurement of FF within the interscapular BAT in mice reflects recent functional status of the tissue, with a lower T a leading to a significantly reduced BAT-FF, indicative of the tissue's involvement in thermogenesis.
Journal of Magnetic Resonance Imaging, 2013
Purpose-To assess the early response of triple-negative breast-cancer (TNBC) following TRA-8 and ... more Purpose-To assess the early response of triple-negative breast-cancer (TNBC) following TRA-8 and carboplatin therapy using DWI and MRS in 2LMP and SUM159 mouse models. Materials and Methods-Four groups (n = 5/group) of each model were untreated or treated with carboplatin, TRA-8, and combination, respectively. DWI and MRS were applied on 0, 3, and 7 days after therapy initiation, and all tumors were collected thereafter for terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. The changes in intratumoral apparent diffusion coefficient (ADC) and fat-water ratios (FWRs) were compared with tumor volume changes and apoptotic cell densities. Results-Mean ADC values of 2LMP and SUM159 tumors significantly increased 4 ± 4% and 37 ± 11% during 7 days of combination therapy, respectively, as compared to control groups (P < 0.05). Similarly, mean FWRs of 2LMP and SUM159 tumors significantly increased 102 ± 30% and 126 ± 52%, respectively, for 7 days of combined treatment (P < 0.05). The changes of the mean ADC values for 3 days (or FWRs for 7 days) were linearly proportional to either the mean volume changes or apoptotic cell densities in both models. Conclusion-DWI and MRS assessed the early tumor response to TRA-8 and carboplatin in TNBC mouse models.
Journal of Cerebral Blood Flow & Metabolism, 2005
Increases of vascular extravasations of MR contrast agent have been implicated to be predictive o... more Increases of vascular extravasations of MR contrast agent have been implicated to be predictive of hemorrhagic transformation in acute stroke patients. However, systemic studies are lacking. In this study, we aim to determine how the increased vascular extravasations of MR contrast agent can be used to predict the presence of subsequent hemorrhages in Stroke-prone spontaneous hypertensive rats (SHRsp). SHRsp rats (n=12), fed a high-salt low-protein diet after weaning, were imaged weekly on a 3 T SIEMENS Allegra head-only scanner beginning at 12 week of age and continuing for five weeks. Three sequences were used to acquire images, including a T2-weighted, a T2*-weighted, and a turboFLASH sequence. The acquired T2-weighted images provided anatomical data as well as an indication of brain edema. T2*-weighted images allowed assessment of hemorrhage and were acquired using a 3D gradient echo sequence (TE=25 ms). To obtain estimates of vascular permeability, the Look-Locker (L-L) technique employing the T-one by multiple read-out pulses (TOMROP) sequence (1) was used for pixel-by-pixel estimates of T1. The TOMROP sequence was repeated 10 times post-contrast. Finally, the PATLAK approach was utilized with the images acquired using the TOMROP sequence for obtaining permeability maps for each rat (2). All 12 rats developed asymmetric T2 hyperintensities by 14 weeks of age; 5 rats developed 7 regions of intracerebral hemorrhage (detected by T2*) at later time-points. Four hemorrhages were located within the striatum; three were located in the cortex. All rats that developed spontaneous hemorrhages demonstrated concurrent or prior vascular permeability (determined by Gd as described above) at the site of the hemorrhage. In 4 of the 7 hemorrhages, evidence of vascular permeability was found prior to the detection of hemorrhage, preceding it by up to 2 weeks. The remaining three temporally coincided with the hemorrhage. The temporal evolution of vascular permeability, T2 and T2* images of a representative rats are shown in Fig. 1. It is immediately evident that the presence of vascular leak precedes the hemorrhage by one week. Although blood-brain-barrier (BBB) breakdown, cerebral edema, and hemorrhage have been well-described in this model, the spatial and temporal relationship between these events has not been well-delineated. Although increased vascular permeability did not precede 3 of 7 hemorrhages but rather appeared concurrently, we believe that this may be due to the poor temporal resolution of our imaging scheme. These data suggest that hypertensive intracerebral hemorrhage is preceded by focal vasculopathy resulting in breakdown of the BBB.
Breast Cancer Research and Treatment, 2011
The purpose is to evaluate sensitivity of basal-like breast cancer to treatment with anti-DR5 alo... more The purpose is to evaluate sensitivity of basal-like breast cancer to treatment with anti-DR5 alone and in combination with chemotherapy. Cytotoxicity of TRA-8 anti-DR5 alone and in combination with doxorubicin or paclitaxel was examined. The role of a DR5-associated molecule (DDX3) in the regulation of apoptosis by recruitment of cIAP1 to the DR5/DDX3 complex was studied. SUM159 and 2LMP orthotopic xenografts were treated with TRA-8 alone and in combination with Abraxane or doxorubicin, and tumor growth inhibition determined. Diffusionweighted magnetic resonance imaging was used to monitor early tumor response. The majority (12/15) of basal-like cell lines were very sensitive to TRA-8-induced cytotoxicity (IC 50 values of 1.0-49 ng/ml). In contrast, 8/11 luminal or HER2-positive cell lines were resistant (IC 50 > 1,000 ng/ml). Enhanced killing of basal-like cell lines was produced by combination treatment with TRA-8 and doxorubicin. Majority of basal cell lines expressed lower levels of DR5-associated DDX3 and cIAP1 than luminal and HER2-positive cell lines. TRA-8 inhibited growth of basal xenografts and produced 20% complete 2LMP tumor regressions. TRA-8 and chemotherapy produced greater 2LMP growth inhibition than either alone. An increase in apparent diffusion coefficient in 2LMP tumors was measured in a week of therapy with TRA-8 and Abraxane. Basallike cell lines were more sensitive to TRA-8-mediated cytotoxicity than HER2-over-expressing and luminal cell lines, and chemotherapy enhanced cytotoxicity. High sensitivity of basal cells to TRA-8 correlated with low expression of DR5/DDX3/cIAP1 complex. Treatment with TRA-8 and chemotherapy may be an effective therapy for basal-like breast cancer.
Anti-Cancer Drugs, 2011
The objective of this study was to evaluate extracelluar matrix metalloproteinase (EMMPRIN) as a ... more The objective of this study was to evaluate extracelluar matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic-cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3-7, while MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1-3 (residual tumor model) and at 21 days after cell implantation for groups 4-7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2-1.0 mg) twice weekly for 2-3 weeks, while the other groups served as the control. In residual tumor model, tumor growth of anti-EMMPRIN treated group was successfully arrested for 21 days (15±4 mm 3), significantly lower than that of EMMPRIN knockdown group (80±15 mm 3 ; p=0.001) or control group (240±41 mm 3 ; p<0.001). In established tumor model, anti-EMMPRIN therapy lowered tumor-volume increase about 40% compared with control regardless of dose amount. Ki67-expressed cell densities of group 5 was 939±150 mm −2 , significantly lower than that of group 4 (1709±145 mm −2 ; p=0.006). Microvessel density of group 5 (30±6 mm −2) was also significantly lower than that of group 4 (53±5 mm −2 ; p=0.014), while the microvessel size of group 5 (191±22 μm 2) was significantly larger than that of group 4 (113±26 μm 2 ; p=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer, and support its clinical translation.
Molecular Imaging and Biology, 2011
Purpose-To evaluate by sequential 18 F-FDG PET/CT imaging the therapeutic response to a novel mon... more Purpose-To evaluate by sequential 18 F-FDG PET/CT imaging the therapeutic response to a novel monoclonal antibody targeting human EMMPRIN (extracellular matrix metalloproteinase inducer) in combination with gemcitabine in a pancreatic-tumor xenograft murine model. Procedures-Four groups of SCID mice bearing orthotopic pancreatic tumor xenografts were injected with PBS, gemcitabine (120mg/kg BW), anti-EMMPRIN antibody (0.2mg), or combination, respectively twice weekly for 2 weeks, while 18 F-FDG PET/CT imaging was performed weekly for 3 weeks. Changes in mean standardized uptake value (SUV mean) of 18 F-FDG and volume of tumors were determined. Results-The tumor SUV mean change in the group receiving combination therapy was significantly lower than those of the other groups. Tumor-volume changes of groups treated with anti-EMMPRIN monotherapy or combined therapy were significantly lower than that of the control group. Conclusions-These data provide support for clinical studies of anti-EMMPRIN therapy with gemcitabine for pancreatic cancer treatment.