Compatible co-administration of BioThrax® vaccine and ciprofloxacin-Results of a randomized open-label drug-vaccine interaction trial.

The recommended treatment for post-exposure prophylaxis (PEP) following known/suspected exposure to involves immunization with anthrax vaccine adsorbed (AVA, i.e., BioThrax® vaccine) and a course of antimicrobial therapy.

Animal-to-Human Dose Translation of ANTHRASIL for Treatment of Inhalational Anthrax in Healthy Adults, Obese Adults, and Pediatric Subjects.

Anthrax Immune Globulin Intravenous (AIGIV [ANTHRASIL]), was developed for the treatment of toxemia associated with inhalational anthrax. It is a plasma product collected from individuals vaccinated with anthrax vaccine and contains antitoxin IgG antibodies against Bacillus anthracis protective antigen. A pharmacokinetic (PK) and exposure-response model was constructed to assess the PKs of AIGIV in anthrax-free and anthrax-exposed rabbits, non-human primates and anthrax-free humans, as well as the relationship between AIGIV exposure and survival from anthrax, based on available preclinical/clinical studies.

Results of a Double-Blind, Randomized, Placebo-Controlled Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Anti-Zika Virus Immunoglobulin.

Zika virus (ZIKV) is transmitted primarily through infected Aedes aegypti or Aedes albopictus mosquitoes. ZIKV infection during pregnancy was linked to adverse fetal/infant outcomes, including microcephaly, brain anomalies, ocular disorders, intrauterine growth restriction, and other congenital malformations. Human anti-Zika virus immunoglobulin (ZIKV-Ig) is being developed for prophylaxis of ZIKV in at-risk populations, including women of childbearing potential and pregnant women.

Mitogen- and stress-activated protein kinases 1 and 2 are required for maximal trefoil factor 1 induction.

Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2), activated downstream of the ERK- and p38-mitogen-activated protein kinase pathways are involved in cell survival, proliferation and differentiation. Following mitogenic or stress stimuli, they mediate the nucleosomal response, which includes phosphorylation of histone H3 at serine 10 (H3S10ph) coupled with transcriptional activation of immediate-early genes. While MSK1 and MSK2 are closely related, their relative roles may vary with cellular context and/or stimuli.

Activation and function of immediate-early genes in the nervous system.

Immediate-early genes have important roles in processes such as brain development, learning, and responses to drug abuse. Further, immediate-early genes play an essential role in cellular responses that contribute to long-term neuronal plasticity. Neuronal plasticity is a characteristic of the nervous system that is not limited to the first stages of brain development but persists in adulthood and seems to be an inherent feature of everyday brain function.

Role of MSK1 in the malignant phenotype of Ras-transformed mouse fibroblasts.

Activated by the RAS-MAPK signaling pathway, MSK1 is recruited to immediate-early gene (IEG) regulatory regions, where it phosphorylates histone H3 at Ser-10 or Ser-28. Chromatin remodelers and modifiers are then recruited by 14-3-3 proteins, readers of phosphoserine marks, leading to the occupancy of IEG promoters by the initiation-engaged form of RNA polymerase II and the onset of transcription. In this study, we show that this mechanism of IEG induction, initially elucidated in parental 10T1/2 murine fibroblast cells, applies to metastatic Hras1-transformed Ciras-3 cells.

Current understanding and importance of histone phosphorylation in regulating chromatin biology.

The core histones H2A, H2B, H3 and H4, undergo various post-translational modifications, such as acetylation, methylation and phosphorylation. Core histone phosphorylation has roles in several biological responses, including transcription, mitosis, DNA repair and apoptosis. Histone phosphorylation may disrupt chromatin structure and/or provide a 'code' for the recruitment or occlusion of non-histone chromosomal proteins to chromatin.

Promoter chromatin remodeling of immediate-early genes is mediated through H3 phosphorylation at either serine 28 or 10 by the MSK1 multi-protein complex.

Upon activation of the ERK and p38 MAPK pathways, the MSK1/2-mediated nucleosomal response, including H3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early (IE) gene transcription. The outcome of this response, varying with the stimuli and cellular contexts, ranges from neoplastic transformation to neuronal synaptic plasticity. Here, we used sequential co-immunoprecipitation assays and sequential chromatin immunoprecipitation (ChIP) assays on mouse fibroblast 10T1/2 and MSK1 knockdown 10T1/2 cells to show that H3 serine 28 and 10 phosphorylation leads to promoter remodeling.

H3 phosphorylation: dual role in mitosis and interphase.

Chromatin condensation and subsequent decondensation are processes required for proper execution of various cellular events. During mitosis, chromatin compaction is at its highest, whereas relaxation of chromatin is necessary for DNA replication, repair, recombination, and gene transcription. Since histone proteins are directly complexed with DNA in the form of a nucleosome, great emphasis is put on deciphering histone post-translational modifications that control the chromatin condensation state.

Chromatin organization and nuclear microenvironments in cancer cells.

Nuclear morphometric descriptors such as nuclear size, shape, DNA content and chromatin organization are used by pathologists as diagnostic markers for cancer. However, our knowledge of events resulting in changes in nuclear shape and chromatin organization in cancer cells is limited. Nuclear matrix proteins, which include lamins, transcription factors (Sp1) and histone modifying enzymes (histone deacetylases), and histone modifications (histone H3 phosphorylation) have roles in organizing chromatin in the interphase nucleus, regulating gene expression programs and determining nuclear shape.

Abnormalities of chromatin in tumor cells.

Nuclear morphometric descriptors such as nuclear size, shape, DNA content and chromatin organization are used by pathologists as diagnostic markers for cancer. Tumorigenesis involves a series of poorly understood morphological changes that lead to the development of hyperplasia, dysplasia, in situ carcinoma, invasive carcinoma, and in many instances finally metastatic carcinoma. Nuclei from different stages of disease progression exhibit changes in shape and the reorganization of chromatin, which appears to correlate with malignancy.

The Ras-MAPK signal transduction pathway, cancer and chromatin remodeling.

Stimulation of the Ras-mitogen-activated protein kinase (MAPK) signal transduction pathway results in a multitude of events including expression of the immediate-early genes, c-fos and c-myc. Downstream targets of this stimulated pathway are the mitogen- and stress-activated protein kinases (MSK) 1 and 2, which are histone H3 kinases. In chromatin immunoprecipitation assays, it has been shown that the mitogen-induced phosphorylated H3 is associated with the immediate-early genes and that MSK1/2 activity and H3 phosphorylation have roles in chromatin remodeling and transcription of these genes.

Histone modifications as a platform for cancer therapy.

Tumorigenesis and metastasis are a progression of events resulting from alterations in the processing of the genetic information. These alterations result from stable genetic changes (mutations) involving tumor suppressor genes and oncogenes (e.g.

Mitogen- and stress-activated protein kinase 1 activity and histone h3 phosphorylation in oncogene-transformed mouse fibroblasts.

Activation of the Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-ERK signal transduction pathway or the SAPK2/p38 pathway results in the activation of mitogen- and stress-activated protein kinase 1 (MSK1). This activation of MSK1 leads to a rapid phosphorylation of histone H3 at Ser(10). Previously, we had demonstrated that Ser(10) phosphorylated H3 was elevated in Ciras-3 (c-Ha-ras-transformed 10T12) mouse fibroblasts and that H3 phosphatase activity was similar in Ciras-3 and 10T12 cells.