Weiser J.R.,Cornell University |
Zawaneh P.N.,Cornell University |
Zawaneh P.N.,Millennium: The Takeda Oncology Company |
Putnam D.,Cornell University
Biomacromolecules | Year: 2011
The synthesis of new polymeric biomaterials using biocompatible building blocks is important for the advancement of the biomedical field. We report the synthesis of statistically random poly(carbonate-ester)s derived from lactic acid and dihydroxyacetone by ring-opening polymerization. The monomer mole feed ratio and initiator concentration were adjusted to create various copolymer ratios and molecular weights. A dimethoxy acetal protecting group was used to stabilize the dihydroxyacetone and was removed using elemental iodine and acetone at reflux to produce the final poly(lactide-co-dihydroxyacetone) copolymers. The characteristics of the copolymers in their protected and deprotected forms were characterized by 1H NMR, 13C NMR, GPC, TGA, and DSC. Hydrolytic degradation of the deprotected copolymers was tracked over an 8-week time frame. The results show that faster degradation occurred with increased carbonate content in the copolymer backbone. The degradation pattern of the copolymers was visualized using SEM and revealed a trend toward surface erosion as the primary mode of degradation. © 2011 American Chemical Society.
Lovchik J.A.,University of New Mexico |
Drysdale M.,University of New Mexico |
Drysdale M.,Millennium: The Takeda Oncology Company |
Koehler T.M.,University of Texas Health Science Center at Houston |
And 3 more authors.
Infection and Immunity | Year: 2012
The development of therapeutics against biothreats requires that we understand the pathogenesis of the disease in relevant animal models. The rabbit model of inhalational anthrax is an important tool in the assessment of potential therapeutics against Bacillus anthracis. We investigated the roles of B. anthracis capsule and toxins in the pathogenesis of inhalational anthrax in rabbits by comparing infection with the Ames strain versus isogenic mutants with deletions of the genes for the capsule operon (capBCADE), lethal factor (lef), edema factor (cya), or protective antigen (pagA). The absence of capsule or protective antigen (PA) resulted in complete avirulence, while the presence of either edema toxin or lethal toxin plus capsule resulted in lethality. The absence of toxin did not influence the ability of B. anthracis to traffic to draining lymph nodes, but systemic dissemination required the presence of at least one of the toxins. Histopathology studies demonstrated minimal differences among lethal wildtype and single toxin mutant strains. When rabbits were coinfected with the Ames strain and the PA-mutant strain, the toxin produced by the Ames strain was not able to promote dissemination of the PA-mutant, suggesting that toxigenic action occurs in close proximity to secreting bacteria. Taken together, these findings suggest that a major role for toxins in the pathogenesis of anthrax is to enable the organism to overcome innate host effector mechanisms locally and that much of the damage during the later stages of infection is due to the interactions of the host with the massive bacterial burden. © 2012, American Society for Microbiology.
Kothari K.,University of Minnesota |
Kothari K.,Millennium: The Takeda Oncology Company |
Ragoonanan V.,University of Minnesota |
Ragoonanan V.,DuPont Company |
Suryanarayanan R.,University of Minnesota
Molecular Pharmaceutics | Year: 2015
We investigated the influence of drug-polymer hydrogen bonding interactions on molecular mobility and the physical stability in solid dispersions of nifedipine with each of the polymers polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS), and poly(acrylic acid) (PAA). The drug-polymer interactions were monitored by FT-IR spectroscopy, the molecular mobility was characterized using broadband dielectric spectroscopy, and the crystallization kinetics was evaluated by powder X-ray diffractometry. The strength of drug-polymer hydrogen bonding, the structural relaxation time, and the crystallization kinetics were rank ordered as PVP > HPMCAS > PAA. At a fixed polymer concentration, the fraction of the drug bonded to the polymer was the highest with PVP. Addition of 20% w/w polymer resulted in ∼65-fold increase in the relaxation time in the PVP dispersion and only ∼5-fold increase in HPMCAS dispersion. In the PAA dispersions, there was no evidence of drug-polymer interactions and the polymer addition did not influence the relaxation time. Thus, the strongest drug-polymer hydrogen bonding interactions in PVP solid dispersions translated to the longest structural relaxation times and the highest resistance to drug crystallization. © 2014 American Chemical Society.
Blair D.,Chestnut Hill College |
Blair D.,Millennium: The Takeda Oncology Company |
Dufort F.J.,Chestnut Hill College |
Chiles T.C.,Chestnut Hill College
Biochemical Journal | Year: 2012
Signals derived from the BCR (B-cell antigen receptor) control survival, development and antigenic responses. One mechanism by which BCR signals may mediate these responses is by regulating cell metabolism. Indeed, the bioenergetic demands of naïve B-cells increase following BCR engagement and are characterized by a metabolic switch to aerobic glycolysis; however, the signalling pathways involved in this metabolic reprogramming are poorly defined. The PKC (protein kinase C) family plays an integral role in B-cell survival and antigenic responses. Using pharmacological inhibition and mice deficient in PKCβ, we demonstrate an essential role of PKCβ in BCR-induced glycolysis in B-cells. In contrast, mice deficient in PKCδ exhibit glycolytic rates comparable with those of wild-type B-cells following BCR cross-linking. The induction of several glycolytic genes following BCR engagement is impaired in PKCβ-deficient B-cells. Moreover, blocking glycolysis results in decreased survival of B-cells despite BCR engagement. The results establish a definitive role for PKCβ in themetabolic switch to glycolysis following BCR engagement of naïve B-cells. © The Authors Journal compilation © 2012 Biochemical Society.
Huang S.-C.,Millennium: The Takeda Oncology Company |
Korlipara V.L.,St. John's University
Expert Opinion on Therapeutic Patents | Year: 2010
Importance of the field: Substance P is involved in mediating a number of biological effects such as emesis, pain, inflammation, bronchoconstriction, antitumor activity, and regulation of gastrointestinal and CNS function by binding to the neurokinin-1 (NK1) receptor. Antagonists of this receptor have the potential to be useful in the treatment of various disease conditions. Areas covered in this review: More than 300 patents have been filed by nearly 20 companies and 2 academic institutions in the past 2 decades. This review provides an overview of the patenting activity in the NK1 antagonist field over the last 20 years. What the reader will gain: Chemically diverse non-peptide NK1 receptor antagonists have been identified since the discovery of CP-96,345 by Pfizer in 1991. Representative examples of patented ligands and their biological activities are presented in a company-wise approach. Take home message: The NK1 receptor research has led to the clinical introduction of aprepitant in 2003 and its water soluble injectable form, fosaprepitant dimeglumine, in 2009 by Merck for the prevention of postoperative nausea and vomiting and for inhibiting chemotherapy-induced nausea and vomiting. In addition, maropitant citrate received approval in 2007 for veterinary use. © Informa UK Ltd.
Hu M.,Millennium: The Takeda Oncology Company |
Zhou T.,Sanofi S.A.
Journal of Biopharmaceutical Statistics | Year: 2011
Intravascular ultrasound (IVUS) is a clinical imaging procedure used to assess drug effects on the progression of coronary atherosclerosis in clinical trials. It is an invasive medical procedure of measuring coronary artery atheroma (plaque) volume, and leads to high missing rates (often over 30%). This paper uses an IVUS Phase II clinical trial data to explore the missing mechanism of IVUS endpoint, the percent atheroma volume (PAV). We proposed a moving-window method to examine the relationship between continuous covariates such as lipid endpoint and the probability of missing IVUS values, which provides a general approach for missing mechanism exploration. The moving-window method is more intuitive and provides a fuller picture about the relationship. In the example, some covariates such as lipid measures also have high missing rates after 12 months because of compliance issues probably caused by fatigue of blood drawing. We found that if the method of last observation carried forward (LOCF) is used to impute the lipid endpoints, it leads to biologically unexplainable results. Using the multiple imputation approach for the missing covariates results in a more reasonable conclusion about the IVUS missing mechanism. Age, race, and baseline PAV are identified as key potential contributors to the probability of missing IVUS endpoint. This finding can be used to reduce missing values in future IVUS trials by setting up appropriate inclusion and exclusion criteria at the trial design stages. Copyright © Taylor & Francis Group, LLC.
Neel N.F.,University of North Carolina at Chapel Hill |
Stratford J.K.,University of North Carolina at Chapel Hill |
Shinde V.,Millennium: The Takeda Oncology Company |
Ecsedy J.A.,Millennium: The Takeda Oncology Company |
And 3 more authors.
Molecular Cancer Therapeutics | Year: 2014
The high prevalence of KRAS mutations and importance of the RalGEF-Ral pathway downstream of activated K-ras in pancreatic ductal adenocarcinoma (PDAC emphasize the importance of identifying novel methods by which to therapeutically target these pathways. It was recently demonstrated that phosphorylation of RalA S194 by Aurora A kinase (AAK) is critical for PDAC tumorigenesis. We sought to evaluate the AAKselective inhibitor MLN8237 as a potential indirect anti-RalA-targeted therapy for PDAC. We used a sitespecific phospho-S194 RalA antibody and determined that RalA S194 phosphorylation levels were elevated in a subset of PDAC cell lines and human tumors relative to unmatched normal controls. Effects of MLN8237 on anchorage-independent growth in PDAC cell lines and growth of patient-derived xenografts (PDX) were variable, with a subset of cell lines and PDX showing sensitivity. Surprisingly, RalA S194 phosphorylation levels in PDAC cell lines or PDX tumors did not correlate with MLN8237 responsiveness. However, we identified Ki67 as a possible early predictive biomarker for response to MLN8237 in PDAC. These results indicate that MLN8237 treatmentmaybe effective for a subset of patients with PDAC independent of RalA S194 phosphorylation. Ki67 may be an effective pharmacodynamic biomarker to identify response early in the course of treatment. © 2013 American Association for Cancer Research.
News Article | October 13, 2014
Millennium: The Takeda Oncology Company combines the innovative science of a leading American biopharmaceutical company with the global assets – both intellectual and fiscal – of Japan's largest pharmaceutical company. Our mission is to deliver extraordinary medicines to patients with cancer worldwide through our science, innovation, and passion. Millennium Pharmaceuticals, Inc., was established in 1993 as a genomics company applying world-class recombinant technology to the discovery and development of innovative new therapies in a broad spectrum of diseases. In May, 2008, Millennium was acquired by Takeda Pharmaceutical Company Limited. Millennium brings a strong oncology commercial presence and holds responsibility for the promotion of VELCADE within the United States. The commercial team at Millennium offers services including full scale reimbursement assistance, patient advocacy, liaisons with global medical affairs as well as health system and oncology based specialists.
News Article | December 14, 2012
—The last of the year’s major medical conferences, the American Society of Hematology annual meeting in Atlanta, was held this week (Dec. 8-11), and several biotechs reported promising clinical data results. Ariad Pharmaceuticals (NASDAQ: ARIA), in Cambridge, MA, said on Monday that 56 percent of 444 chronic myeloid leukemia patients treated with its drug ponatinib, all of whom had been heavily pretreated with other medicines, had a major response after one year, with minimal side effects. Ariad’s stock has been climbing all week as a result, from $22.07 last Friday to $23.88 this Thursday. —Celgene (NASDAQ:CELG), based in Summit, NJ, also announced good results at ASH for pomalidomide, its multiple myeloma drug scheduled for a decision from the FDA by Feb. 10. Patients who were given the drug and steroids lived a median of 3.6 months without their disease progressing, twice as long as those given steroids alone. And Cambridge, MA-based Millennium: The Takeda Oncology Company, reported that the oral version of Velcade, its top-selling multiple myeloma drug, proved safe and effective in an early stage clinical trial, and so warrants further study. —Arsenal Medical of Watertown, MA, said on Monday that it won a $15.5 million contract from the Defense Advanced Research Projects Agency to continue developing its foam-based product to control abdominal bleeding in soldiers injured on the battlefield. The foam is meant to be injected into the abdominal cavity, where it can control bleeding for at least an hour, Arsenal says. —Polaris Ventures Partners in Waltham, MA, and Arch Ventures Partners got a nice Christmas present on Tuesday when Amgen (NASDAQ: AMGN) announced it will buy deCode Genetics of Iceland for $415 million. As my colleague Luke Timmerman reported, the two VC firms paid $14 million less than three years ago to acquire deCode’s assets out of bankruptcy.