500 dical Center Drive

Byron Center, MI, United States

500 dical Center Drive

Byron Center, MI, United States
SEARCH FILTERS
Time filter
Source Type

Hah H.J.,University of Michigan | Kim G.,University of Michigan | Lee Y.-E.K.,University of Michigan | Orringer D.A.,500 dical Center Drive | And 2 more authors.
Macromolecular Bioscience | Year: 2011

Methylene blue-conjugated polyacrylamide nanoparticles are prepared through a microemulsion polymerization, after conjugation of the dye with a monomer. The nanoparticles have a 50-60 nm diameter in solution. This conjugation method enables a large increase in loading of methylene blue per nanoparticle and also minimizes dye leaching out of the nanoparticle. Furthermore, the dye content can be controlled by variation of the dye amount, enabling a more refined control of the singlet oxygen production ability. The nanoparticles are coated with F3 peptides, which give specific targeting to selected tumor cells, 9L, MDA-MB-435, and F98, in vitro. In addition, MTT assays reveal that the nanoparticles have no dark toxicity but excellent PDT efficacy increasing with the nanoparticle dose and irradiation time. Methylene blue-conjugated polyacrylamide nanoparticles are prepared in a microemulsion. The conjugation method enabled both the minimization of dye leaching and the facile control of the dye loading that leads to refined control of the singlet oxygen production. The F3-targeted nanoparticles show excellent PDT efficacy but no dark toxicity in in vitro tests on several cancer cell lines. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Schneider B.J.,New York Medical College | Kalemkerian G.P.,University of Michigan | Kalemkerian G.P.,500 dical Center Drive | Bradley D.,Duke University | And 9 more authors.
Investigational New Drugs | Year: 2012

Introduction Vorinostat is an inhibitor of histone deacetylase 6, which acetylates tubulin and stabilizes microtubules. Since taxanes also stabilize microtubules, we hypothesized that the administration of vorinostat followed by docetaxel should result in synergistic cytotoxicity. We conducted a phase I trial to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in =30%of patients. Methods Eligible patients had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after =1 prior chemotherapy regimen not containing docetaxel, performance status of 0-2, and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle, with docetaxel given intravenously over 1 h on day 4. The time-to-event continuous reassessment method (TITE-CRM) guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m2, respectively. Pharmacokinetic studies were performed on days 1 and 4 of cycle 1. Results Twelve patients were enrolled: median age 65 years (range 49-74); 9 male, 3 female; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles administered was 2. Two patients were treated at DL -1, 4 at DL 0, 5 atDL 1 and 1 at DL 2. Five DLTs occurred in 5 patients: neutropenic fever/sepsis (2), anaphylactic reaction (1), myocardial infarction (1) and gastrointestinal bleed (1). Other toxicities included grade 3/4 neutropenia (4), peripheral neuropathy (1), and gastrointestinal bleed (n=1). The estimated probability of DLT for DL -1 was 0.32 (90% posterior probability interval [PI], 0.11 to 0.53) for DL 0, 0.38 (90% PI, 0.16 to 0.58) and for DL 1, 0.43 (90% PI, 0.23 to 0.64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions The combination of vorinostat and docetaxel was poorly tolerated with excessive DLTs that required early study termination. No responses were identified. Vorinostat and docetaxel pharmacokinetics were comparable to previous reports in the literature, without obvious drug-drug interactions. © Springer Science+Business Media, LLC 2010.


Rupp J.D.,University of Michigan | Flannagan C.A.C.,University of Michigan | Hoff C.N.,University of Michigan | Cunningham R.M.,University of Michigan | Cunningham R.M.,500 dical Center Drive
Accident Analysis and Prevention | Year: 2010

Older occupants in motor-vehicle crashes are more likely to experience injury than younger occupants. One possible reason for this is that increasing age is associated with increased prevalence of osteoporosis, which decreases bone strength. Crash-injury data were used with Bayes' Theorem to estimate the conditional probability of AIS 3+ skeletal injury given that an occupant is osteoporotic for the injury to the head, spine, thorax, lower extremities, and upper extremities. This requires the conditional probabilities of osteoporosis given AIS 3+ injury for each of the body regions, which were determined from analysis of the Crash Injury Research and Engineering Network database. It also requires information on probability of osteoporosis in the crashinvolved population and the probabilities of AIS 3+ skeletal injury to different body regions in crashes. The latter probabilities were obtained from the National Automotive Sampling System-Crashworthiness Data System (NASS-CDS) database. The former was obtained by modeling the probability of osteoporosis in the US populations using data from the 2006 National Health Examination Nutrition Survey and applying this model to the estimate of the crash-involved population in NASS-CDS. To attempt to account for the effects of age on injury outcome that are independent of osteoporosis, only data from occupants who were 60 years of age or older were used in all analyses. Results indicate that the only body region that experiences a statistically significant change in fracture injury risk with osteoporosis is the spine, for which osteoporosis increases the risk of AIS 3+ fracture by 3.28 times, or from 0.41% to 1.34% (p<0.0001). This finding suggests that the increase in AIS 3+ injury risk with age for non-spine injuries is likely influenced by factors other than osteoporosis. © 2010 Elsevier Ltd. All rights reserved.


Thomas M.M.,500 dical Center Drive | Zhang Y.,500 dical Center Drive | Mathew E.,University of Michigan | Kane K.T.,500 dical Center Drive | And 2 more authors.
BMC Cancer | Year: 2015

Background: Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer. Methods: To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis. Results: We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation. However, over time, loss of Notch inhibition allows PanIN formation and progression. Conclusions: Epithelial-specific Notch signaling is important for PanIN initiation. Our findings indicate that PanIN formation can only occur upon loss of epithelial Notch inhibition, thus supporting an essential role of this signaling pathway during pancreatic carcinogenesis. © 2014 Thomas et al.; licensee BioMed Central Ltd.


Swigris J.J.,Autoimmune Lung Center and Interstitial Lung Disease Program | Brown K.K.,Autoimmune Lung Center and Interstitial Lung Disease Program | Flaherty K.R.,500 dical Center Drive
Current Rheumatology Reviews | Year: 2010

The idiopathic interstitial pneumonias (IIP) are seven fibro-inflammatory interstitial lung diseases of unknown cause, grouped together because of potentially similar clinical features. Each of the seven has a distinct histologic pattern; however, these patterns are not specific to the IIP, and they provide a framework for defining interstitial lung disease (ILD) of known-cause, including ILD associated with underlying connective tissue disease (CTD). With the exception of respiratory bronchiolitis, the histologic patterns corresponding with the other six IIP can be found in association with CTD. Considering all CTD together, the pattern of non-specific interstitial pneumonia is most common. High-resolution computed tomography (HRCT) can hint at the histologic pattern, track changes over time, and assess response to therapy. The goal of this article is to review histologic patterns and HRCT findings of the IIP as they relate to CTD-associated ILD. © 2010 Bentham Science Publishers Ltd.


Reeves S.L.,University of Michigan | Brown D.L.,University of Michigan | Chervin R.D.,500 dical Center Drive | Morgenstern L.B.,University of Michigan | And 2 more authors.
Sleep Medicine | Year: 2014

Background: Ascertaining self-reported information about the risk for pre-stroke obstructive sleep apnea (OSA) in the acute stroke period is challenging as many stroke patients have deficits that hinder communication. We examined agreement between stroke patients without communication limitations and family members (proxy) in the pre-stroke risk for OSA. Methods: Patient-proxy pairs (n= 42) were interviewed independently as part of the Brain Attack Surveillance in Corpus Christi (BASIC) Project from May 2010 to April 2011. The Berlin questionnaire was used to measure a high risk for OSA defined as the presence of at least two of the following conditions: (1) snoring behaviors/witnessed apneas, (2) daytime sleepiness, and (3) hypertension or obesity. Patient-proxy agreement was assessed using a κ coefficient. Results: Forty-three percent of patients self-identified as being at high risk for sleep apnea, and 45% of proxies identified patients as high risk. Patient-proxy agreement for high risk for pre-stroke OSA was fair (κ = 0.28) with better agreement for spouses and children proxies (κ = 0.38) than for other family members. Agreement also was fair for most individual questions. Conclusions: Spouse and child proxy use of the Berlin questionnaire may be an option to assess a patient's pre-stroke likelihood of sleep apnea. Whereas prospective studies of incident stroke in patients with and without objectively confirmed sleep apnea would require formidable resources, our results suggest that an alternative strategy may involve proxy use of the Berlin questionnaire in a retrospective study design. © 2013 Elsevier B.V.


Pasca di Magliano M.,500 dical Center Drive
BMC cancer | Year: 2014

BACKGROUND: Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer.METHODS: To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis.RESULTS: We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation. However, over time, loss of Notch inhibition allows PanIN formation and progression.CONCLUSIONS: Epithelial-specific Notch signaling is important for PanIN initiation. Our findings indicate that PanIN formation can only occur upon loss of epithelial Notch inhibition, thus supporting an essential role of this signaling pathway during pancreatic carcinogenesis.


Goonewardena S.N.,University of Michigan | Goonewardena S.N.,500 dical Center Drive | Prevette L.E.,University of Michigan | Desai A.A.,University of Chicago
Current Atherosclerosis Reports | Year: 2010

Metabolites reflect the dynamic processes underlying cellular homeostasis. Recent advances in analytical chemistry and molecular biology have set the stage for metabolite profiling to help us understand complex molecular processes and physiology. Metabolomics is the comparative analysis of metabolite flux and how it relates to biological phenotypes. As an intermediate phenotype, metabolite signatures capture a unique aspect of cellular dynamics that is not typically interrogated, providing a distinct perspective on cellular homeostasis. To date, there have been only a few metabolomics studies investigating cardiovascular diseases. In this review, we explore the principles of metabolomics and how it can provide further insight into the mechanisms of cardiovascular physiology and ultimately lead to improved diagnostic and therapeutic options for patients with cardiovascular disease. © Springer Science+Business Media, LLC 2010.


PubMed | 500 dical Center Drive
Type: | Journal: BMC cancer | Year: 2014

Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer.To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis.We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation. However, over time, loss of Notch inhibition allows PanIN formation and progression.Epithelial-specific Notch signaling is important for PanIN initiation. Our findings indicate that PanIN formation can only occur upon loss of epithelial Notch inhibition, thus supporting an essential role of this signaling pathway during pancreatic carcinogenesis.


PubMed | University of Michigan, University of Washington and 500 dical Center Drive
Type: Journal Article | Journal: Sleep medicine | Year: 2014

Ascertaining self-reported information about the risk for pre-stroke obstructive sleep apnea (OSA) in the acute stroke period is challenging as many stroke patients have deficits that hinder communication. We examined agreement between stroke patients without communication limitations and family members (proxy) in the pre-stroke risk for OSA.Patient-proxy pairs (n=42) were interviewed independently as part of the Brain Attack Surveillance in Corpus Christi (BASIC) Project from May 2010 to April 2011. The Berlin questionnaire was used to measure a high risk for OSA defined as the presence of at least two of the following conditions: (1) snoring behaviors/witnessed apneas, (2) daytime sleepiness, and (3) hypertension or obesity. Patient-proxy agreement was assessed using a coefficient.Forty-three percent of patients self-identified as being at high risk for sleep apnea, and 45% of proxies identified patients as high risk. Patient-proxy agreement for high risk for pre-stroke OSA was fair (=0.28) with better agreement for spouses and children proxies (=0.38) than for other family members. Agreement also was fair for most individual questions.Spouse and child proxy use of the Berlin questionnaire may be an option to assess a patients pre-stroke likelihood of sleep apnea. Whereas prospective studies of incident stroke in patients with and without objectively confirmed sleep apnea would require formidable resources, our results suggest that an alternative strategy may involve proxy use of the Berlin questionnaire in a retrospective study design.

Loading 500 dical Center Drive collaborators
Loading 500 dical Center Drive collaborators