Conservation of receptor antagonist anti-tumor activity by epidermal growth factor receptor antibody expressed in transgenic corn seed

Recombinant protein production in plants such as corn is a promising means to generate high product yields at low comparable production cost. The anti-EGFR monoclonal antibody C225, cetuximab, is a well-characterized receptor antagonist antibody recently approved for the treatment of refractory colorectal cancer. We initiated a study to test and compare the functional activity of glycosylated and aglycosylated C225 produced in stable transgenic corn seed. Both corn antibodies were shown to be functionally indistinguishable from mammalian-derived C225 in demonstrating high-affinity binding to the EGF receptor, blocking of ligand-dependent signaling, and inhibiting cell proliferation. In addition, consistent with cetuximab, both corn antibodies possessed strong anti-tumor activity in vivo. Acute dose primate pharmacokinetic studies, however, revealed a marked increase in clearance for the glycosylated corn antibody, while the aglycosylated antibody possessed in vivo kinetics similar to cetuximab. This experimentation established that corn-derived receptor blocking monoclonal antibodies possess comparable efficacy to mammalian cell culture-derived antibody, and offer a cost effective alternative to large-scale mammalian cell culture production.     

Alternative Healthy Eating Index-2010 and Incident Non-Communicable Diseases: Findings from a 15-Year Follow Up of Women from the 1973–78 Cohort of the Australian Longitudinal Study on Women’s Health

Non-communicable diseases (NCDs) and multimorbidity (≥two chronic conditions), are increasing globally. Diet is a risk factor for some NCDs. We aimed to investigate the association between diet quality (DQ) and incident NCDs. Participants were from the Australian Longitudinal Study on Women’s Health 1973–78 cohort with no NCD and completed dietary data at survey 3 (2003, aged 25–30 years) who responded to at least one survey between survey 4 (2006) and survey 8 (2018). DQ was measured by the Alternative Healthy Eating Index-2010 (AHEI-2010). Outcomes included coronary heart disease (CHD), hypertension (HT), asthma, cancer (excluding skin cancer), diabetes mellitus (DM), depression and/or anxiety, multimorbidity, and all-cause mortality. Repeated cross-sectional multivariate logistic regressions were performed to investigate the association between baseline DQ and NCDs over 15 years. The AHEI-2010 mean (±sd) for participants (n = 8017) was 51.6 ± 11.0 (range: 19–91). There was an inverse association between AHEI-2010 and incident asthma at survey 4 (OR_Q5–Q1: 0.75, 95% CI: 0.57, 0.99). Baseline DQ did not predict the occurrence of any NCDs or multimorbidity between the ages of 25–45 years. Further well-planned, large prospective studies conducted in young women are needed to explore dietary risk factors before the establishment of NCDs.     

Association of Lifetime Exposure to Glyphosate and Aminomethylphosphonic Acid (AMPA) with Liver Inflammation and Metabolic Syndrome at Young Adulthood: Findings from the CHAMACOS Study

Background: The prevalence of liver disorders and metabolic syndrome has increased among youth. Glyphosate, the most widely used herbicide worldwide, could contribute to the development of these conditions.Objective: We aimed to assess whether lifetime exposure to glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), is associated with elevated liver transaminases and metabolic syndrome among young adults.Methods: We conducted a prospective cohort study (n=480 mother–child dyads) and a nested case–control study (n=60 cases with elevated liver transaminases and 91 controls) using data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). We measured glyphosate and AMPA concentrations in urine samples collected during pregnancy and at child ages 5, 14, and 18 y from cases and controls. We calculated glyphosate residue concentrations: [glyphosate +(1.5×AMPA)]. We estimated the amount of agricultural-use glyphosate applied within a 1-km radius of every residence from pregnancy to age 5 y for the full cohort using California Pesticide Use Reporting data. We assessed liver transaminases and metabolic syndrome at 18 y of age.Results: Urinary AMPA at age 5 y was associated with elevated transaminases [relative risk (RR) per 2-fold increase=1.27, 95% confidence interval (CI): 1.06, 1.53] and metabolic syndrome (RR=2.07, 95% CI: 1.38, 3.11). Urinary AMPA and glyphosate residues at age 14 y were associated with metabolic syndrome [RR=1.80 (95% CI: 1.10, 2.93) and RR=1.88 (95% CI: 1.03, 3.42), respectively]. Overall, a 2-fold increase in urinary AMPA during childhood was associated with a 14% and a 55% increased risk of elevated liver transaminases and metabolic syndrome, respectively. Living near agricultural glyphosate applications during early childhood (birth to 5 y of age) was also associated with metabolic syndrome at age 18 y in the case–control group (RR=1.53, 95% CI: 1.16, 2.02).Discussion: Childhood exposure to glyphosate and AMPA may increase risk of liver and cardiometabolic disorders in early adulthood, which could lead to more serious diseases later in life. https://doi.org/10.1289/{"type":"entrez-protein","attrs":{"text":"EHP11721","term_id":"372011122","term_text":"EHP11721"}}EHP11721     

Tau protein kinases: Involvement in Alzheimer's disease

Tau phosphorylation is regulated by a balance between tau kinase and phosphatase activities. Disruption of this equilibrium was suggested to be at the origin of abnormal tau phosphorylation and thereby might contribute to tau aggregation. Thus, understanding the regulation modes of tau phosphorylation is of high interest in determining the possible causes at the origin of the formation of tau aggregates in order to elaborate protection strategies to cope with these lesions in Alzheimer's disease. Among the possible and specific interventions that reverse tau phosphorylation is the inhibition of certain tau kinases. Here, we extensively reviewed tau protein kinases, their physiological roles and regulation, their involvement in tau phosphorylation and their relevance to AD. We also reviewed the most common inhibitory compounds acting on each tau kinase.     

Clinical and mutational characteristics of spinal muscular atrophy with respiratory distress type 1 in the Netherlands

Spinal muscular atrophy with respiratory distress type 1 is an autosomal recessive disorder with early respiratory difficulties, distal muscle weakness, and contractures leading to foot deformities as the most striking clinical symptoms. Mutations of the gene encoding the immunoglobulin heavy chain μ-binding protein 2, mapped on chromosome 11q13, are the cause of the disease. We present the clinical and mutational characteristics of ten patients in the Netherlands who showed considerable clinical variability; they carried six novel mutations, including a deletion of exon 2. However, there were no clear phenotype–genotype correlations.     

Single variable domain antibody as a versatile building block for the construction of IgG-like bispecific antibodies

Bispecific antibodies (BsAb) have been traditionally utilized to redirect cytotoxic effector cells and agents to kill tumor cells expressing the target antigens. Recently a new concept is emerging to develop BsAb that simultaneously block the functions of two tumor-associated targets, eg., growth factor receptors, for enhanced antitumor efficacies. Broad clinical applications of BsAb have been, and still are, significantly hampered by the difficulty in producing the materials in sufficient quantity and quality by traditional approaches. Here we describe a recombinant approach for the production of an Fc domain-containing, IgG-like tetravalent BsAb, using a single variable domain (sVD) antibody as a versatile building block. In this method, a sVD of a defined specificity is genetically fused to either the N-terminus of the light chain or the C-terminus of the heavy chain of a functional IgG antibody of a different specificity. A model BsAb was constructed using a sVD to mouse platelet derived growth factor receptor alpha and a conventional IgG antibody to mouse platelet derived growth factor receptor beta. The BsAb were expressed in mammalian cells and purified to homogeneity by a one-step Protein A affinity chromatography. Further, the BsAb retained the antigen binding specificity and the receptor neutralizing activity of both of its parent antibodies. Importantly, the BsAb inhibited the activation of both its target receptors in tumor cells stimulated by both platelet derived growth factor AA and BB, whereas the parent monospecific antibody only inhibited the activation of a single receptor stimulated by its cognate ligand. This format of BsAb should be readily applicable to the production of other BsAb recognizing any pairs of antigens.     

Risk factors for postoperative seizures in patients with chronic subdural haematomas

Neurosurgical Review - Postoperative seizures are a frequently occurring yet not well-understood complication in patients undergoing surgical treatment of chronic subdural haematomas (cSDHs)....