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1.
PLoS One ; 11(9): e0162199, 2016.
Article in English | MEDLINE | ID: mdl-27611077

ABSTRACT

BACKGROUND: The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic. METHODS AND FINDINGS: In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD. CONCLUSIONS: Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201411000939962.


Subject(s)
Antiviral Agents/therapeutic use , Cytosine/analogs & derivatives , Ebolavirus/physiology , Hemorrhagic Fever, Ebola/drug therapy , Organophosphonates/therapeutic use , Adult , Antiviral Agents/pharmacology , Cytosine/pharmacology , Cytosine/therapeutic use , Ebolavirus/drug effects , Female , Hemorrhagic Fever, Ebola/virology , Humans , Liberia , Male , Middle Aged , Organophosphonates/pharmacology , Treatment Outcome , Young Adult
2.
PLoS Med ; 13(4): e1001997, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27093560

ABSTRACT

BACKGROUND: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. METHODS AND FINDINGS: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. CONCLUSIONS: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.


Subject(s)
Antiviral Agents/therapeutic use , Ebolavirus/genetics , Hemorrhagic Fever, Ebola/drug therapy , RNA, Small Interfering/therapeutic use , RNA, Viral/genetics , RNAi Therapeutics/methods , Adult , Aged , Aged, 80 and over , Ebolavirus/pathogenicity , Female , Hemorrhagic Fever, Ebola/diagnosis , Hemorrhagic Fever, Ebola/genetics , Hemorrhagic Fever, Ebola/mortality , Hemorrhagic Fever, Ebola/virology , Host-Pathogen Interactions , Humans , Infusions, Intravenous , Male , Middle Aged , Nanoparticles , RNA, Small Interfering/administration & dosage , RNA, Viral/blood , RNAi Therapeutics/adverse effects , Sierra Leone , Survival Analysis , Time Factors , Treatment Outcome , Viral Load/drug effects , Viral Load/genetics , Young Adult
3.
Comput Struct Biotechnol J ; 6: e201303007, 2013.
Article in English | MEDLINE | ID: mdl-24688715

ABSTRACT

OUR STUDIES REVEAL PREVIOUSLY UNIDENTIFIED ELECTRICAL PROPERTIES OF CHROMOSOMES: (1) chromosomes are amazingly similar in construction and function to electrical transformers; (2) chromosomes possess in their construction and function, components similar to those of electric generators, conductors, condensers, switches, and other components of electrical circuits; (3) chromosomes demonstrate in nano-scale level electromagnetic interactions, resonance, fusion and other phenomena similar to those described by equations in classical physics. These electrical properties and phenomena provide a possible explanation for unclear and poorly understood mechanisms in clinical genetics including: (a) electrically based mechanisms responsible for breaks, translocations, fusions, and other chromosomal abnormalities associated with cancer, intellectual disability, infertility, pregnancy loss, Down syndrome, and other genetic disorders; (b) electrically based mechanisms involved in crossing over, non-disjunction and other events during meiosis and mitosis; (c) mechanisms demonstrating heterochromatin to be electrically active and genetically important.

4.
Pediatr Dev Pathol ; 15(3): 249-53, 2012.
Article in English | MEDLINE | ID: mdl-22356457

ABSTRACT

The identification of recurrent chromosomal abnormalities in benign and malignant mesenchymal neoplasms has provided important pathogenetic insight as well as powerful diagnostic adjuncts. Nasal chondromesenchymal hamartoma (NCMH), an extremely rare benign tumor arising in the sinonasal tract of infants and children, has not been previously subjected to cytogenetic analysis. Histopathologically composed of mixed mesenchymal elements, NCMH exhibits a relatively wide differential diagnosis to include chondromyxoid fibroma, chondroblastoma, aneurysmal bone cyst, fibrous dysplasia, and osteochondromyxoma. An interesting association with pleuropulmonary blastoma has been reported in a small subset of NCMH patients. In the current study, cytogenetic analysis of a NCMH arising in an 11-year-old boy with a past medical history of pleuropulmonary blastoma revealed a novel 12;17 translocation, t(12;17)(q24.1;q21), as the sole anomaly.


Subject(s)
Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 17 , Hamartoma/complications , Hamartoma/genetics , Nose Diseases/complications , Nose Diseases/genetics , Pulmonary Blastoma/complications , Translocation, Genetic , Abnormal Karyotype , Cartilage/pathology , Child , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 17/genetics , Hamartoma/pathology , Humans , Male , Mesoderm/pathology , Nose Diseases/pathology , Pulmonary Blastoma/genetics
5.
Clin Cancer Res ; 16(2): 497-508, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-20068083

ABSTRACT

PURPOSE: Targeted therapeutics have significantly changed the outcome for patients diagnosed with cancer. Still, effective therapeutic intervention does not exist for many cancers and much remains to be done. The objective of this study was to identify novel genes that potentially regulate tumor growth, to target these gene products with monoclonal antibodies, and to examine the therapeutic potential of these antibodies. EXPERIMENTAL DESIGN: Using cDNA microarray analysis, we identified genes overexpressed in several solid malignancies. We generated a mouse monoclonal antibody, 19.2.1, and its humanized counterpart, PDL192, to one such target, TweakR (TWEAK receptor, Fn14, TNFRSF12A, CD266), and characterized the antitumor activities in vitro and in mouse xenograft models. RESULTS: Both 19.2.1 (mouse IgG2a) and PDL192 (human IgG1), like TWEAK, the natural ligand of TweakR, inhibited the growth of several TweakR-expressing cancer cell lines in anchorage-dependent and anchorage-independent assays in vitro. Both antibodies showed significant antitumor activity in multiple mouse xenograft models. PDL192 and 19.2.1 also induced antibody-dependent cellular cytotoxicity (ADCC) of cancer cell lines in vitro. A chimeric version of 19.2.1 containing the mouse IgG1 Fc region (19.2.1 x G1) exhibited significantly less ADCC than 19.2.1. However, 19.2. 1x G1 showed differential activity in vivo, with activity equivalent to 19.2.1 in one model, but significantly less efficacy than 19.2.1 in a second model. These results indicate that PDL192 and 19.2.1 mediate their antitumor effects by signaling through TweakR, resulting in reduced tumor cell proliferation, and by ADCC.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Cell Proliferation/drug effects , Neoplasms/pathology , Tumor Necrosis Factors/immunology , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cancer Vaccines/therapeutic use , Cytokine TWEAK , Dose-Response Relationship, Drug , Humans , Immunotherapy/methods , Mice , Mice, Inbred BALB C , NIH 3T3 Cells , Neoplasm Metastasis , Neoplasms/therapy , Signal Transduction/drug effects , Signal Transduction/physiology , Tumor Burden/drug effects , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
6.
J Exp Ther Oncol ; 5(4): 273-86, 2006.
Article in English | MEDLINE | ID: mdl-17024968

ABSTRACT

Integrin alpha5beta1, the principal fibronectin receptor, is an important survival factor, playing a key role in angiogenesis. Angiogenesis is critical for tumor growth, and anti-angiogenic therapies have met clinical success. To validate the therapeutic potential of an anti-alpha5beta1 strategy, we generated volociximab (M200) a chimeric human IgG4 version of the alpha5beta1 function-blocking murine antibody IIA1; and F200, the Fab derivative. Volociximab, F200 and IIA1 showed similar activity by ELISA (EC50= 0.2nM), Biacore (Kd= 0.1-0.4nM) and inhibition of fibronectin binding (IC50= 2-3nM). The inhibitory potential of alpha5beta1 antibodies was compared to HuMV833, an anti-VEGF antibody. Both volociximab and HuMV833 inhibited HUVEC proliferation (IC50 of volociximab = 0.2-0.5nM; IC50 of HuMV833 = 45nM). However, IIA1, volociximab and F200 were also potent inhibitors of an in vitro model of angiogenesis (HUVEC tube formation assay), unlike HuMV833. Additionally, volociximab inhibited in vitro tube formation induced by VEGF and/or bFGF, suggesting a mechanism of action independent of growth factor stimulus. In fact, inhibition of alpha5beta1 function by volociximab induced apoptosis of actively proliferating, but not resting, endothelial cells. Volociximab does not cross-react with rodent alpha5beta1, therefore in vivo validation of an anti-alpha5beta1 approach was conducted in a cynomolgus model of choroidal revascularization. Volociximab and F200 were potent inhibitors of neovessel formation in this model. These data demonstrate that volociximab has therapeutic potential in diseases in which new vessel formation is a component of the pathology.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies/therapeutic use , Drug Evaluation, Preclinical , Integrin alpha5beta1/immunology , Animals , Antibodies, Monoclonal, Murine-Derived , COS Cells , Chlorocebus aethiops , Extracellular Matrix/metabolism , Humans , Inhibitory Concentration 50 , Integrin alpha5beta1/chemistry , Kinetics , Macaca fascicularis , Macular Degeneration/drug therapy , Neovascularization, Pathologic , Rituximab
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