Changes in gray whale phenology and distribution related to prey variability and ocean biophysics in the northern Bering and eastern Chukchi seas.

Changes in gray whale (Eschrichtius robustus) phenology and distribution are related to observed and hypothesized prey availability, bottom water temperature, salinity, sea ice persistence, integrated water column and sediment chlorophyll a, and patterns of wind-driven biophysical forcing in the northern Bering and eastern Chukchi seas. This portion of the Pacific Arctic includes four Distributed Biological Observatory (DBO) sampling regions. In the Bering Strait area, passive acoustic data showed marked declines in gray whale calling activity coincident with unprecedented wintertime sea ice loss there in 2017-2019, although some whales were seen there during DBO cruises in those years.

Recommendations from a global cross-company data sharing initiative on the incorporation of recovery phase animals in safety assessment studies to support first-in-human clinical trials.

An international expert group which includes 30 organisations (pharmaceutical companies, contract research organisations, academic institutions and regulatory bodies) has shared data on the use of recovery animals in the assessment of pharmaceutical safety for early development. These data have been used as an evidence-base to make recommendations on the inclusion of recovery animals in toxicology studies to achieve scientific objectives, while reducing animal use. Recovery animals are used in pharmaceutical development to provide information on the potential for a toxic effect to translate into long-term human risk.

Valedictory address.

Janet Clarke was installed as President of the British Dental Association at last year's 2011 British Dental Conference and Exhibition held in Manchester. At this year's conference, also in Manchester, she gave the following valedictory address.

In vivo pharmacology and toxicology evaluation of polyethylene glycol-conjugated interferon beta-1a.

Human interferon (IFN) β has well established beneficial effects in treating relapsing forms of multiple sclerosis, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20-kDa polyethylene glycol (PEG)-conjugated IFN β-1a (PEG-IFN β-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. We present pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN β-1a in Rhesus monkeys in support of a phase 1 clinical trial.

Mechanisms of adverse drug reactions to biologics.

Biologics encompass a broad range of therapeutics that include proteins and other products derived from living systems. Although the multiplicity of target organs often seen with new chemical entities is generally not seen with biologics, they can produce significant adverse reactions. Examples include IL-12 and an anti-CD28 antibody that resulted in patient deaths and/or long stays in intensive care units.

Immunotoxicity profile of natalizumab.

Natalizumab is a monoclonal antibody to human alpha4 integrin indicated for treatment of multiple sclerosis and Crohn's disease that prevents extravasation of leukocytes into surrounding tissues and their involvement in inflammation. Because alpha4 integrins and their receptors are involved in hematopoiesis and immune cell trafficking, natalizumab may interfere with these processes. We evaluated the effects of natalizumab on immune function in monkeys using in vitro and in vivo studies.

Effects of natalizumab, an alpha4 integrin inhibitor, on the development of Hartley guinea pigs.

Background: Natalizumab is a humanized monoclonal immunoglobulin G4 antibody directed against the human alpha4 integrin subunit, disrupting interaction with its ligands. Natalizumab inhibits the interaction of alpha4 integrins with fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1, which are of potential importance in development. Two studies were undertaken to evaluate the effects of natalizumab on embryo/fetal development in guinea pigs.

Effects of natalizumab, an alpha4 integrin inhibitor, on fertility in male and female guinea pigs.

Background: Natalizumab is a humanized monoclonal immunoglobulin G4 antibody directed against the human alpha4 integrin subunit disrupting interaction with its ligands. As alpha4 integrins and/or their ligands appear to be involved in reproductive function, the effects of natalizumab on fertility in male and female guinea pigs were investigated.

Methods: Natalizumab was administered by bolus intravenous injection every other day at doses of 0, 3, 10, and 30 mg/kg.

Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 integrin inhibitor.

Background: Natalizumab is a humanized monoclonal IgG4 antibody to human alpha4 integrin that blocks the interaction of alpha4beta1 and alpha4beta7 integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because alpha4 integrins and their ligands are widely involved in mammalian development, lymphopoeisis, and hematopoiesis, natalizumab may interfere with these processes.

Methods: The effects of prenatal exposure to natalizumab on postnatal development were assessed in cynomolgus monkeys at doses of 0 and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70 or GD 20 to term.

Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an alpha4 integrin inhibitor.

Background: Natalizumab is a humanized monoclonal immunoglobulin G4 antibody to human alpha4 integrin that binds to the alpha4 subunit of alpha4beta1 and alpha4beta7 integrins, where it blocks the interaction of these integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because alpha4 integrins and their ligands appear to be involved in mammalian fetal development, it is possible that natalizumab may interfere with these processes.

Methods: The effects of natalizumab on fetal development were assessed in cynomolgus monkeys at doses of 0, 3, 10, and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70.

Duration of chronic toxicity studies for biotechnology-derived pharmaceuticals: is 6 months still appropriate?

For chronic use biotechnology-derived pharmaceuticals, toxicity studies of 6 months have generally been accepted for regulatory approval. This review assessed the data for 23 approved biotechnology-derived pharmaceuticals to determine whether the studies conducted were predictive of human safety and whether there is new data from approved products indicating that longer than 6 months is necessary. This assessment involved three approaches; whether new toxicities were identified at >6 months, similarity of findings between 6 months and shorter studies and predictivity of clinical adverse events.

Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab.

Dimerization is essential for activity of human epidermal growth factor receptors (HER1/EGFR, HER2/ErbB2, HER3/ErbB3, and ErbB4) and mediates intracellular signaling events leading to cancer cell proliferation, survival, and resistance to therapy. HER2 is the preferred dimerization partner. Activation of HER signaling pathways may be blocked by inhibition of dimer formation using a monoclonal antibody (MAb) directed against the dimerization domain of HER2.

Evaluation of a surrogate antibody for preclinical safety testing of an anti-CD11a monoclonal antibody.

Surrogate antibodies are a potential solution to the limited safety testing possible with humanized monoclonal antibodies with restricted species cross-reactivity. However, there are currently no defined criteria by which a potential surrogate antibody should be judged prior to its use in determining safety issues for the clinical agent. We propose that, potential surrogates should undergo rigorous evaluation to assess pharmacological and toxicological activities in comparison to the clinical agent.

The dental team--PCDs. Where are we now?

Professionals Complementary to Dentistry (PCDs) have varying roles within the dental team, from chairside assisting to the actual provision of clinical treatment. These tasks are closely proscribed at present, but this may change in the future. The modernization of dentistry, the introduction of registration for PCDs, the introduction of workforce development confederations responsible for funding and commissioning training of dentists and PCDs, and a workforce review looking at the whole dental team will all impact upon the working lives of dentists and their teams.