Harvey Hensley - Academia.edu (original) (raw)
Papers by Harvey Hensley
Oncogene, 2021
The Hedgehog (Hh) pathway plays an indispensable role in bone development and genetic activation ... more The Hedgehog (Hh) pathway plays an indispensable role in bone development and genetic activation of the pathway results in medulloblastoma (MB), the most common malignant brain tumor in children. Inhibitors of Hh pathway (such as vismodegib and sonedigib), which are used to treat MB, cause irreversible defects in bone growth in young children. Cholesterol is required for the activation of the Hh pathway, and statins, inhibitors of cholesterol biosynthesis, suppress MB growth by repressing Hh signaling in tumor cells. Here, we investigate the role of cholesterol biosynthesis in the proliferation and Hh signaling in chondrocytes, and examine the bone development in mice after statin treatment. Statins significantly inhibited MB growth in young mice, but caused no defects in bone development. Conditional deletion of NADP steroid dehydrogenase-like (NSDHL), an enzyme necessary for cholesterol biosynthesis, suppressed cholesterol synthesis in chondrocytes, and disrupted the growth plate in mouse femur and tibia, indicating the important function of intracellular cholesterol in bone development. Hh pathway activation and the proliferation of chondrocytes were inhibited by statin treatment in vitro; however, statins did not impair bone growth in vivo due to insufficient penetration into the bone. Our studies reveal a critical role of cholesterol in bone development, and support the utilization of statins for treatment of MB as well as other Hh pathway-associated malignancies.
Medical Physics, 2014
Purpose:Magnetic resonance spectroscopic (MRS) imaging may provide important bio‐markers to disti... more Purpose:Magnetic resonance spectroscopic (MRS) imaging may provide important bio‐markers to distinguish normal/cancerous prostate tissue. While MRS imaging requires a high uniform magnetic field, the ability of a clinical 1.5T MRI to achieve a comparable MRS signal is of interest for radiation treatment planning/assessment. This study is to evaluate the MRS imaging of a 1.5T clinical MRI for prostate cancers by comparing with a small animal 7T MRS scanner.Methods:A tumor model was developed by implanting LNCaP tumor cells in nude mice prostates. Tumor was monitored 3 weeks after implantation using MRI, and MRS imaging was performed on the tumor area when the tumor reached around 1cm in diameter. The 1.5T GE clinical MR scanner and the 7T Bruker small animal MR scanner were used for each mouse. MR spectrums acquired with these scanners were analyzed and compared. The signals of Choline and Citrate were considered.Results:The prostate tumor MR spectrum under the 1.5T clinical MRI show...
We have measured magnetic field distortion of the order parameter and the longitudinal resonance ... more We have measured magnetic field distortion of the order parameter and the longitudinal resonance frequency of superfluid ^3He-B using pulsed nuclear magnetic resonance. There are three aspects of this work on the non-linear spin dynamics of the superfluid. First we generalized Leggett's equations for the case of large magnetic fields, sufficiently large to distort the order parameter. Second we numerically
Physical Review Letters, 1996
Physica B: Condensed Matter, 1994
Pulsed NMR experiments have been performed on monodomain U2D2 solid 3He in high magnetic fields. ... more Pulsed NMR experiments have been performed on monodomain U2D2 solid 3He in high magnetic fields. It was found that the frequency of the free induction signal changed with time, and in some cases a negative frequency shift as large as 20 kHz from the Larmor frequency was observed. The precession frequency immediately following the rf pulse agreed with Namaizawa's theory,
Physica B: Condensed Matter, 1994
We have performed pulsed NMR experiments in superfluid 3He-B under conditions of high H0 and H1 h... more We have performed pulsed NMR experiments in superfluid 3He-B under conditions of high H0 and H1 homogeneity in order to study non-linear spin dynamics. We made extensive measurements near the ``magic'' tipping angle in order to measure its temperature dependence. We report the discovery of new effects, including a small negative frequency shift at tipping angles close to, but slightly
Physica B: Condensed Matter, 1994
H 2 (pc)I is known to have highly anisotropic electronic and structural properties. Electrical co... more H 2 (pc)I is known to have highly anisotropic electronic and structural properties. Electrical conductivity and magnetoresistance measurements have been performed on high purity H 2 (pc)I single crystals ranging from room temperature to 20 mK in magnetic fields up to 5.5 tesla. We have ...
Magnetic Resonance in Medicine, 2000
This article presents a microscopic MR technique for imaging small mammalian fetuses in utero and... more This article presents a microscopic MR technique for imaging small mammalian fetuses in utero and in vivo which can be used as a tool for studying normal and abnormal development in small animal fetal models, for targeting in utero intervention in such models, and for following development serially. This new method is applied to a rat model of congenital diaphragmatic hernia (CDH). Pregnant Sprague-Dawley rats were fed nitrofen at 9.5 days postcoitus to induce CDH in the fetuses. The dams were imaged to identify fetuses with CDH for targeted in utero intervention, which consisted of fetal tracheal ligation. Following tracheal ligation, the fetuses were followed serially with our MR technique. For MR imaging, the dam was anesthetized with intramuscular ketamine and intraperitoneal pentobarbital. In utero imaging was performed on a 4 Tesla MRI system using a multislice, fast spin echo sequence with a long TR and short effective TE. These results were validated by examining individual fetuses postmortem using high-resolution MR and anatomic dissection. The in utero, in vivo MR technique is highly accurate for diagnosing CDH and following the effects of surgical intervention, and shows promise as a tool for the study of embryogenesis in small animal models. Magn Reson Med 44:331-335, 2000.
Journal of Low Temperature Physics, 1993
We present pulsed NMR measurements of the low temperature (˜0.003 K) magnetic susceptibility of n... more We present pulsed NMR measurements of the low temperature (˜0.003 K) magnetic susceptibility of normal liquid3He as a function of pressure. Our results agree well with the extrapolation from 0.035 K of the data of Ramm et al. We calculate new values for the Fermi liquid parameter F0a using the heat capacity data of Greywall.
Journal of Low Temperature Physics, 1989
An acoustic technique has been developed that permits high-resolution velocity measurements to be... more An acoustic technique has been developed that permits high-resolution velocity measurements to be performed in liquids and gases under circumstances where the acoustic attenuation may become very large. This cavity resonance method has been demonstrated in cavities with lengths as small as 150 µm at acoustic frequencies up to 151 MHz. The acoustic path length is continuously adjusted by a
We report on nuclear magnetic resonance studies of normal and superfluid ^3He. The normal fluid w... more We report on nuclear magnetic resonance studies of normal and superfluid ^3He. The normal fluid work extended previous measurements of the susceptibility from 30 mK to 3 mK, in order to more accurately determine the limiting value of the susceptibility. We took all the data in a single pressure sweep, from 26 to 0.5 bar. We use these values of
Journal of Virology, 2009
Although much is known about lymphocytic choriomeningitis virus (LCMV) infection and the subseque... more Although much is known about lymphocytic choriomeningitis virus (LCMV) infection and the subsequent immune response in its natural murine host, some crucial aspects of LCMV-mediated pathogenesis remain undefined, including the underlying basis of the characteristic central nervous system disease that occurs following intracerebral (i.c.) challenge. We show that the classic seizures and paresis that occur following i.c. infection of adult, immunocompetent mice with LCMV are accompanied by anatomical and histological changes that are consistent with brain herniation, likely of the uncal subtype, as a causative basis for disease and precipitous death. Both by water weight determinations and by magnetic resonance imaging of infected brain tissues, edema was detected only at the terminal stages of disease, likely caused by the leakage of cerebrospinal fluid from the ventricles into the parenchyma. Furthermore, death was accompanied by unilateral pupillary dilation, which is indicative of...
Carcinogenesis, 2016
The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic ... more The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic inflammation. Natural compounds represent an enormous source of new anti-inflammatory and anticancer agents. We previously showed that the styryl lactone goniothalamin (GTN) has promising antiproliferative and anti-inflammatory activities. Because inflammation is a major driver of colorectal cancer (CRC), we therefore evaluated the therapeutic and preventive potentials of GTN in colitis, colitis-associated cancer (CAC) and spontaneous CRC. First, in a simplistic model of inflammation in vitro, GTN was able to inhibit cytokine production in bone marrow-derived macrophages induced by lipopolysaccharide. Next, in dextran sulfate sodium (DSS) induced-colitis model, mice treated with GTN displayed restored tissue architecture, increased cell proliferation in the colonic crypts and reduced epithelial damage. Moreover, colon tissue from GTN-treated mice had significantly less expression of the inflammatory genes interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), S100A9, interleukin 23A (IL-23A), IL-22 and IL-17A. In the azoxymethane/DSS model of CAC, GTN reduced tumor multiplicity, load and size. Additionally, GTN suppressed production of IL-6, IL-17 and TNF-α in tumor tissue, as well as abrogated stromal immune cell activation and nuclear translocation of NF-κB. Finally, in a tamoxifen inducible model of sporadic CRC, GTN-treated mice had significantly fewer tumors and decreased levels of IL-17A, IL-6, S100A9 and TNF-α protein within the tumors. These results suggest that GTN possesses anti-inflammatory and antitumor activities and represents a preventive and therapeutic agent modulating the inflammatory environment in the colon during colitis as well as CAC and CRC development.
Revue des Maladies Respiratoires, 2013
Introduction.-Certaines mutations de l'EGFR sont prédictives de réponse aux inhibiteurs de tyrosi... more Introduction.-Certaines mutations de l'EGFR sont prédictives de réponse aux inhibiteurs de tyrosine-kinase de l'EGFR (ITK-EGFR) mais in fine tous les patients progressent. Des mécanismes de résistance ont été décrits et la notion d'hétérogénéité tumorale émerge. L'objectif de ce travail est l'étude de l'hétérogénéité tumorale des altérations géniques les plus fréquentes dans le cancer bronchique et son rôle dans les résistances aux ITK-EGFR. Patients et méthodes.-Vingt patients avec mutations synchrones de KRAS et EGFR ont été sélectionnés. Ces mutations ont été vérifiées sur tous les blocs et sections disponibles par PCR et séquençage. Les mutations d'EGFR à la surface des blocs ont été étudiées par IHC. Des carottes biopsiques ont été réalisées en profondeur pour l'étude de l'hétérogénéité des mutations d'EGFR et KRAS. Le pourcentage des mutations d'EGFR et KRAS a été déterminé par PCR digitale. Sept patients avec mutation d'EGFR résistants aux ITK-EGFR ont été sélectionnés pour l'étude par PCR et séquençage des facteurs de résistance connus. Résultats.-Pour un même patient, les mutations d'EGFR et KRAS sont différentes dans chaque bloc ou section. Le marquage en IHC est hétérogène. L'analyse en profondeur des blocs retrouve une hétérogénéité, surtout pour KRAS. La PCR digitale montre pour chaque prélèvement un pourcentage de mutations de KRAS et EGFR. L'étude des patients résistants retrouve des mutations synchrones et une hétérogénéité de KRAS. Discussion.-L'hétérogénéité tumorale est ici démontrée dans un contexte clinique avec des techniques très sensibles applicables en routine. L'implication de ces résultats doit encore être étudiée.
International Journal of Radiation Oncology Biology Physics, 2006
18-20 MV. This study compared the risk of second primary malignancy in prostate cancer (CaP) pati... more 18-20 MV. This study compared the risk of second primary malignancy in prostate cancer (CaP) patients treated with combined neutron/photon irradiation (N/PRT), photon irradiation (PRT) alone, or prostatectomy (RP). Materials/Methods: All men treated with N/PRT or PRT for CaP at the Karmanos Cancer Institute between January 1991 and June 2003 were eligible for inclusion. Second malignancies were identified by linking patients with the Metropolitan Detroit Cancer Surveillance System database, a Surveillance, Epidemiology and End Results site. We identified CaP patients treated via RP for this same time period from MDCSS, and frequency matched a random sample to the PRT and N/PRT groups by race, 5-year age group, stage, grade, and diagnosis year. Second cancer risk was evaluated after excluding patients who had less than 2 years and 5 years follow up or were diagnosed with a second cancer within 2 or 5 years of original prostate cancer diagnosis. Results: At five years, the N/PRT therapy recipients were significantly less likely to have a second cancer than the PRT group (5.97% vs. 10.25% pϭ0.005). There was no difference in the second cancer risk when comparing N/PRT to RP (5.78% vs. 4.22% pϭ0.26) (TABLE). When compared to RP, patients treated with either form of irradiation had an increased risk of skin cancer 2 years post-treatment, and patients treated with photons alone had a higher risk of skin, lung, bronchus, colon, liver, and biliary cancers 5 years post-treatment. After stratifying by race, there were significantly more second cancers at 5 years in the PRT group in whites when compared to N/PRT (pϭ0.01) and when compared to RP (10.06% vs. 3.23% pϭ0.006). There was no significant difference in blacks. Overall there was a higher rate of second cancer in blacks treated with either form of radiation, but this was not statistically significant. Conclusions: At five years post-treatment, N/PRT for prostate cancer is associated with a lower risk of any second primary cancer in comparison to photon RT and had a comparable risk of second malignancy when compared to prostatectomy, regardless of race. Since there was an increased risk of developing cancers outside the treatment field for both forms of irradiation, other etiologies may play a role in second cancer risk.
PLOS ONE, 2019
Human achaete scute homolog 2 (HASH2) and its murine ortholog MASH2 are potential targets for col... more Human achaete scute homolog 2 (HASH2) and its murine ortholog MASH2 are potential targets for colorectal cancer immunotherapy. We assessed immunogenicity and antitumor potential of recombinant MASH2 protein combined with AS15 immunostimulant (recMASH2+ AS15) in CB6F1 and Apc +/Min-FCCC mice. CB6F1 mice received 4 injections of recMASH2+ AS15 or AS15 alone before challenge with TC1-MASH2 tumor cells (Tumor Challenge). Apc +/Min-FCCC mice received 9 injections of recMASH2+AS15 or vehicle (phosphate buffer saline [PBS] or AS15 alone), before (two independent Prophylactic Studies) or after (Immunotherapy) colon adenomas were detectable by colonoscopy. CB6F1 mice immunized with recMASH2+AS15 had a significantly smaller mean tumor size and improved survival rate compared to controls (104 mm 2 vs. 197 mm 2 [p = 0.009] and 67% vs. 7% [p = 0.001], respectively). In Prophylactic Study 1, the mean number of colon adenomas was significantly lower in Apc +/Min-FCCC mice receiving recMASH2+AS15 compared to PBS (1.8 [95% confidence interval 1.0-3.3] vs. 5.2 [3.7-7.4], p = 0.003). Fewer microadenomas were observed in recMASH2+AS15 groups compared to PBS in both Prophylactic Studies (Study 1: mean 0.4
The Journal of clinical investigation, Jan 13, 2018
ONC201 is a first-in-class, orally active anti-tumor agent that upregulates cytotoxic TRAIL pathw... more ONC201 is a first-in-class, orally active anti-tumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in the first-in-human trial where patients were dosed every 3 weeks. We hypothesized that dose-intensification of ONC201 may impact anti-tumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell-death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observe accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors, and NK-cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice with GFP-expressing NK-cells demonstrate GFP(+)-NK cell infiltration of syngeneic MC38 colorectal t...
Gut, Jul 9, 2017
The response of subjects to preventive intervention is heterogeneous. The goal of this study was ... more The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc+/Min-FCCC mice with known tumour-bearing status at treatment initiation. Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both. The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline...
Cancer Research, 2017
Non-small cell lung cancer (NSCLC) has a low survival rate, with metastasis contributing to the v... more Non-small cell lung cancer (NSCLC) has a low survival rate, with metastasis contributing to the vast majority of deaths. The NEDD9 (HEF1/Cas-L) protein has been reported to be elevated in expression and to promote metastasis in a large subset of lung cancers and in other malignancies. NEDD9 functions as a scaffold for multiple critical effectors in integrin/FAK/SRC and receptor tyrosine kinase signaling cascades, as well as for the mitotic kinase Aurora-A, with overexpression thought to sustain signaling by these pro-oncogenic proteins. Previous studies demonstrated depletion of NEDD9 by RNAi reduced the growth and invasion of established lung cell lines and tumors, based on cell culture and xenograft assays. We have now investigated the consequences of a null genotype for Nedd9 from the earliest stages of tumor formation, crossing Nedd9 null mice to a 129S/Sv-Krastm3Tyj/Trp53tm1Brn (KP) model in which Kras mutation is induced specifically in lung tissue by inhalation of adenovirus ...
Oncogene, 2021
The Hedgehog (Hh) pathway plays an indispensable role in bone development and genetic activation ... more The Hedgehog (Hh) pathway plays an indispensable role in bone development and genetic activation of the pathway results in medulloblastoma (MB), the most common malignant brain tumor in children. Inhibitors of Hh pathway (such as vismodegib and sonedigib), which are used to treat MB, cause irreversible defects in bone growth in young children. Cholesterol is required for the activation of the Hh pathway, and statins, inhibitors of cholesterol biosynthesis, suppress MB growth by repressing Hh signaling in tumor cells. Here, we investigate the role of cholesterol biosynthesis in the proliferation and Hh signaling in chondrocytes, and examine the bone development in mice after statin treatment. Statins significantly inhibited MB growth in young mice, but caused no defects in bone development. Conditional deletion of NADP steroid dehydrogenase-like (NSDHL), an enzyme necessary for cholesterol biosynthesis, suppressed cholesterol synthesis in chondrocytes, and disrupted the growth plate in mouse femur and tibia, indicating the important function of intracellular cholesterol in bone development. Hh pathway activation and the proliferation of chondrocytes were inhibited by statin treatment in vitro; however, statins did not impair bone growth in vivo due to insufficient penetration into the bone. Our studies reveal a critical role of cholesterol in bone development, and support the utilization of statins for treatment of MB as well as other Hh pathway-associated malignancies.
Medical Physics, 2014
Purpose:Magnetic resonance spectroscopic (MRS) imaging may provide important bio‐markers to disti... more Purpose:Magnetic resonance spectroscopic (MRS) imaging may provide important bio‐markers to distinguish normal/cancerous prostate tissue. While MRS imaging requires a high uniform magnetic field, the ability of a clinical 1.5T MRI to achieve a comparable MRS signal is of interest for radiation treatment planning/assessment. This study is to evaluate the MRS imaging of a 1.5T clinical MRI for prostate cancers by comparing with a small animal 7T MRS scanner.Methods:A tumor model was developed by implanting LNCaP tumor cells in nude mice prostates. Tumor was monitored 3 weeks after implantation using MRI, and MRS imaging was performed on the tumor area when the tumor reached around 1cm in diameter. The 1.5T GE clinical MR scanner and the 7T Bruker small animal MR scanner were used for each mouse. MR spectrums acquired with these scanners were analyzed and compared. The signals of Choline and Citrate were considered.Results:The prostate tumor MR spectrum under the 1.5T clinical MRI show...
We have measured magnetic field distortion of the order parameter and the longitudinal resonance ... more We have measured magnetic field distortion of the order parameter and the longitudinal resonance frequency of superfluid ^3He-B using pulsed nuclear magnetic resonance. There are three aspects of this work on the non-linear spin dynamics of the superfluid. First we generalized Leggett's equations for the case of large magnetic fields, sufficiently large to distort the order parameter. Second we numerically
Physical Review Letters, 1996
Physica B: Condensed Matter, 1994
Pulsed NMR experiments have been performed on monodomain U2D2 solid 3He in high magnetic fields. ... more Pulsed NMR experiments have been performed on monodomain U2D2 solid 3He in high magnetic fields. It was found that the frequency of the free induction signal changed with time, and in some cases a negative frequency shift as large as 20 kHz from the Larmor frequency was observed. The precession frequency immediately following the rf pulse agreed with Namaizawa's theory,
Physica B: Condensed Matter, 1994
We have performed pulsed NMR experiments in superfluid 3He-B under conditions of high H0 and H1 h... more We have performed pulsed NMR experiments in superfluid 3He-B under conditions of high H0 and H1 homogeneity in order to study non-linear spin dynamics. We made extensive measurements near the ``magic'' tipping angle in order to measure its temperature dependence. We report the discovery of new effects, including a small negative frequency shift at tipping angles close to, but slightly
Physica B: Condensed Matter, 1994
H 2 (pc)I is known to have highly anisotropic electronic and structural properties. Electrical co... more H 2 (pc)I is known to have highly anisotropic electronic and structural properties. Electrical conductivity and magnetoresistance measurements have been performed on high purity H 2 (pc)I single crystals ranging from room temperature to 20 mK in magnetic fields up to 5.5 tesla. We have ...
Magnetic Resonance in Medicine, 2000
This article presents a microscopic MR technique for imaging small mammalian fetuses in utero and... more This article presents a microscopic MR technique for imaging small mammalian fetuses in utero and in vivo which can be used as a tool for studying normal and abnormal development in small animal fetal models, for targeting in utero intervention in such models, and for following development serially. This new method is applied to a rat model of congenital diaphragmatic hernia (CDH). Pregnant Sprague-Dawley rats were fed nitrofen at 9.5 days postcoitus to induce CDH in the fetuses. The dams were imaged to identify fetuses with CDH for targeted in utero intervention, which consisted of fetal tracheal ligation. Following tracheal ligation, the fetuses were followed serially with our MR technique. For MR imaging, the dam was anesthetized with intramuscular ketamine and intraperitoneal pentobarbital. In utero imaging was performed on a 4 Tesla MRI system using a multislice, fast spin echo sequence with a long TR and short effective TE. These results were validated by examining individual fetuses postmortem using high-resolution MR and anatomic dissection. The in utero, in vivo MR technique is highly accurate for diagnosing CDH and following the effects of surgical intervention, and shows promise as a tool for the study of embryogenesis in small animal models. Magn Reson Med 44:331-335, 2000.
Journal of Low Temperature Physics, 1993
We present pulsed NMR measurements of the low temperature (˜0.003 K) magnetic susceptibility of n... more We present pulsed NMR measurements of the low temperature (˜0.003 K) magnetic susceptibility of normal liquid3He as a function of pressure. Our results agree well with the extrapolation from 0.035 K of the data of Ramm et al. We calculate new values for the Fermi liquid parameter F0a using the heat capacity data of Greywall.
Journal of Low Temperature Physics, 1989
An acoustic technique has been developed that permits high-resolution velocity measurements to be... more An acoustic technique has been developed that permits high-resolution velocity measurements to be performed in liquids and gases under circumstances where the acoustic attenuation may become very large. This cavity resonance method has been demonstrated in cavities with lengths as small as 150 µm at acoustic frequencies up to 151 MHz. The acoustic path length is continuously adjusted by a
We report on nuclear magnetic resonance studies of normal and superfluid ^3He. The normal fluid w... more We report on nuclear magnetic resonance studies of normal and superfluid ^3He. The normal fluid work extended previous measurements of the susceptibility from 30 mK to 3 mK, in order to more accurately determine the limiting value of the susceptibility. We took all the data in a single pressure sweep, from 26 to 0.5 bar. We use these values of
Journal of Virology, 2009
Although much is known about lymphocytic choriomeningitis virus (LCMV) infection and the subseque... more Although much is known about lymphocytic choriomeningitis virus (LCMV) infection and the subsequent immune response in its natural murine host, some crucial aspects of LCMV-mediated pathogenesis remain undefined, including the underlying basis of the characteristic central nervous system disease that occurs following intracerebral (i.c.) challenge. We show that the classic seizures and paresis that occur following i.c. infection of adult, immunocompetent mice with LCMV are accompanied by anatomical and histological changes that are consistent with brain herniation, likely of the uncal subtype, as a causative basis for disease and precipitous death. Both by water weight determinations and by magnetic resonance imaging of infected brain tissues, edema was detected only at the terminal stages of disease, likely caused by the leakage of cerebrospinal fluid from the ventricles into the parenchyma. Furthermore, death was accompanied by unilateral pupillary dilation, which is indicative of...
Carcinogenesis, 2016
The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic ... more The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic inflammation. Natural compounds represent an enormous source of new anti-inflammatory and anticancer agents. We previously showed that the styryl lactone goniothalamin (GTN) has promising antiproliferative and anti-inflammatory activities. Because inflammation is a major driver of colorectal cancer (CRC), we therefore evaluated the therapeutic and preventive potentials of GTN in colitis, colitis-associated cancer (CAC) and spontaneous CRC. First, in a simplistic model of inflammation in vitro, GTN was able to inhibit cytokine production in bone marrow-derived macrophages induced by lipopolysaccharide. Next, in dextran sulfate sodium (DSS) induced-colitis model, mice treated with GTN displayed restored tissue architecture, increased cell proliferation in the colonic crypts and reduced epithelial damage. Moreover, colon tissue from GTN-treated mice had significantly less expression of the inflammatory genes interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), S100A9, interleukin 23A (IL-23A), IL-22 and IL-17A. In the azoxymethane/DSS model of CAC, GTN reduced tumor multiplicity, load and size. Additionally, GTN suppressed production of IL-6, IL-17 and TNF-α in tumor tissue, as well as abrogated stromal immune cell activation and nuclear translocation of NF-κB. Finally, in a tamoxifen inducible model of sporadic CRC, GTN-treated mice had significantly fewer tumors and decreased levels of IL-17A, IL-6, S100A9 and TNF-α protein within the tumors. These results suggest that GTN possesses anti-inflammatory and antitumor activities and represents a preventive and therapeutic agent modulating the inflammatory environment in the colon during colitis as well as CAC and CRC development.
Revue des Maladies Respiratoires, 2013
Introduction.-Certaines mutations de l'EGFR sont prédictives de réponse aux inhibiteurs de tyrosi... more Introduction.-Certaines mutations de l'EGFR sont prédictives de réponse aux inhibiteurs de tyrosine-kinase de l'EGFR (ITK-EGFR) mais in fine tous les patients progressent. Des mécanismes de résistance ont été décrits et la notion d'hétérogénéité tumorale émerge. L'objectif de ce travail est l'étude de l'hétérogénéité tumorale des altérations géniques les plus fréquentes dans le cancer bronchique et son rôle dans les résistances aux ITK-EGFR. Patients et méthodes.-Vingt patients avec mutations synchrones de KRAS et EGFR ont été sélectionnés. Ces mutations ont été vérifiées sur tous les blocs et sections disponibles par PCR et séquençage. Les mutations d'EGFR à la surface des blocs ont été étudiées par IHC. Des carottes biopsiques ont été réalisées en profondeur pour l'étude de l'hétérogénéité des mutations d'EGFR et KRAS. Le pourcentage des mutations d'EGFR et KRAS a été déterminé par PCR digitale. Sept patients avec mutation d'EGFR résistants aux ITK-EGFR ont été sélectionnés pour l'étude par PCR et séquençage des facteurs de résistance connus. Résultats.-Pour un même patient, les mutations d'EGFR et KRAS sont différentes dans chaque bloc ou section. Le marquage en IHC est hétérogène. L'analyse en profondeur des blocs retrouve une hétérogénéité, surtout pour KRAS. La PCR digitale montre pour chaque prélèvement un pourcentage de mutations de KRAS et EGFR. L'étude des patients résistants retrouve des mutations synchrones et une hétérogénéité de KRAS. Discussion.-L'hétérogénéité tumorale est ici démontrée dans un contexte clinique avec des techniques très sensibles applicables en routine. L'implication de ces résultats doit encore être étudiée.
International Journal of Radiation Oncology Biology Physics, 2006
18-20 MV. This study compared the risk of second primary malignancy in prostate cancer (CaP) pati... more 18-20 MV. This study compared the risk of second primary malignancy in prostate cancer (CaP) patients treated with combined neutron/photon irradiation (N/PRT), photon irradiation (PRT) alone, or prostatectomy (RP). Materials/Methods: All men treated with N/PRT or PRT for CaP at the Karmanos Cancer Institute between January 1991 and June 2003 were eligible for inclusion. Second malignancies were identified by linking patients with the Metropolitan Detroit Cancer Surveillance System database, a Surveillance, Epidemiology and End Results site. We identified CaP patients treated via RP for this same time period from MDCSS, and frequency matched a random sample to the PRT and N/PRT groups by race, 5-year age group, stage, grade, and diagnosis year. Second cancer risk was evaluated after excluding patients who had less than 2 years and 5 years follow up or were diagnosed with a second cancer within 2 or 5 years of original prostate cancer diagnosis. Results: At five years, the N/PRT therapy recipients were significantly less likely to have a second cancer than the PRT group (5.97% vs. 10.25% pϭ0.005). There was no difference in the second cancer risk when comparing N/PRT to RP (5.78% vs. 4.22% pϭ0.26) (TABLE). When compared to RP, patients treated with either form of irradiation had an increased risk of skin cancer 2 years post-treatment, and patients treated with photons alone had a higher risk of skin, lung, bronchus, colon, liver, and biliary cancers 5 years post-treatment. After stratifying by race, there were significantly more second cancers at 5 years in the PRT group in whites when compared to N/PRT (pϭ0.01) and when compared to RP (10.06% vs. 3.23% pϭ0.006). There was no significant difference in blacks. Overall there was a higher rate of second cancer in blacks treated with either form of radiation, but this was not statistically significant. Conclusions: At five years post-treatment, N/PRT for prostate cancer is associated with a lower risk of any second primary cancer in comparison to photon RT and had a comparable risk of second malignancy when compared to prostatectomy, regardless of race. Since there was an increased risk of developing cancers outside the treatment field for both forms of irradiation, other etiologies may play a role in second cancer risk.
PLOS ONE, 2019
Human achaete scute homolog 2 (HASH2) and its murine ortholog MASH2 are potential targets for col... more Human achaete scute homolog 2 (HASH2) and its murine ortholog MASH2 are potential targets for colorectal cancer immunotherapy. We assessed immunogenicity and antitumor potential of recombinant MASH2 protein combined with AS15 immunostimulant (recMASH2+ AS15) in CB6F1 and Apc +/Min-FCCC mice. CB6F1 mice received 4 injections of recMASH2+ AS15 or AS15 alone before challenge with TC1-MASH2 tumor cells (Tumor Challenge). Apc +/Min-FCCC mice received 9 injections of recMASH2+AS15 or vehicle (phosphate buffer saline [PBS] or AS15 alone), before (two independent Prophylactic Studies) or after (Immunotherapy) colon adenomas were detectable by colonoscopy. CB6F1 mice immunized with recMASH2+AS15 had a significantly smaller mean tumor size and improved survival rate compared to controls (104 mm 2 vs. 197 mm 2 [p = 0.009] and 67% vs. 7% [p = 0.001], respectively). In Prophylactic Study 1, the mean number of colon adenomas was significantly lower in Apc +/Min-FCCC mice receiving recMASH2+AS15 compared to PBS (1.8 [95% confidence interval 1.0-3.3] vs. 5.2 [3.7-7.4], p = 0.003). Fewer microadenomas were observed in recMASH2+AS15 groups compared to PBS in both Prophylactic Studies (Study 1: mean 0.4
The Journal of clinical investigation, Jan 13, 2018
ONC201 is a first-in-class, orally active anti-tumor agent that upregulates cytotoxic TRAIL pathw... more ONC201 is a first-in-class, orally active anti-tumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in the first-in-human trial where patients were dosed every 3 weeks. We hypothesized that dose-intensification of ONC201 may impact anti-tumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell-death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observe accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors, and NK-cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice with GFP-expressing NK-cells demonstrate GFP(+)-NK cell infiltration of syngeneic MC38 colorectal t...
Gut, Jul 9, 2017
The response of subjects to preventive intervention is heterogeneous. The goal of this study was ... more The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc+/Min-FCCC mice with known tumour-bearing status at treatment initiation. Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both. The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline...
Cancer Research, 2017
Non-small cell lung cancer (NSCLC) has a low survival rate, with metastasis contributing to the v... more Non-small cell lung cancer (NSCLC) has a low survival rate, with metastasis contributing to the vast majority of deaths. The NEDD9 (HEF1/Cas-L) protein has been reported to be elevated in expression and to promote metastasis in a large subset of lung cancers and in other malignancies. NEDD9 functions as a scaffold for multiple critical effectors in integrin/FAK/SRC and receptor tyrosine kinase signaling cascades, as well as for the mitotic kinase Aurora-A, with overexpression thought to sustain signaling by these pro-oncogenic proteins. Previous studies demonstrated depletion of NEDD9 by RNAi reduced the growth and invasion of established lung cell lines and tumors, based on cell culture and xenograft assays. We have now investigated the consequences of a null genotype for Nedd9 from the earliest stages of tumor formation, crossing Nedd9 null mice to a 129S/Sv-Krastm3Tyj/Trp53tm1Brn (KP) model in which Kras mutation is induced specifically in lung tissue by inhalation of adenovirus ...