Antibody mediated CDCP1 degradation as mode of action for cancer targeted therapy

CUB-domain-containing-protein-1 (CDCP1) is an integral membrane protein whose expression is up-regulated in various cancer types. Although high CDCP1 expression has been correlated with poor prognosis in lung, breast, pancreas, and renal cancer, its functional role in tumor formation or progression is incompletely understood. So far it has remained unclear, whether CDCP1 is a useful target for antibody therapy of cancer and what could be a desired mode of action for a therapeutically useful antibody. To shed light on these questions, we have investigated the cellular effects of a therapeutic antibody candidate (RG7287). In focus formation assays, prolonged RG7287 treatment prevented the loss of contact inhibition caused by co-transformation of NIH3T3 cells with CDCP1 and Src. In a xenograft study, MCF7 cells stably overexpressing CDCP1 reached the predefined tumor volume faster than the parental MCF7 cells lacking endogenous CDCP1. This tumor growth advantage was abolished by RG7287 treatment. In vitro, RG7287 induced rapid tyrosine phosphorylation of CDCP1 by Src, which was accompanied by translocation of CDCP1 to a Triton X-100 insoluble fraction of the plasma membrane. Triggering these effects required bivalency of the antibody suggesting that it involves CDCP1 dimerization or clustering. However, this initial activation of CDCP1 was only transient and prolonged RG7287 treatment induced internalization and down-regulation of CDCP1 in different cancer cell lines. Antibody stimulated CDCP1 degradation required Src activity and was proteasome dependent. Also in three different xenograft models with endogenous CDCP1 expression RG7287 treatment resulted in significant tumor growth inhibition concomitant with substantially reduced CDCP1 levels as judged by immunohistochemistry and Western blotting. Thus, despite transiently activating CDCP1 signaling, the RG7287 antibody has a therapeutically useful mode of action.     

Retrograde leptomeningeal venous approach for dural arteriovenous fistulas at foramen magnum

A 72-year-old man presented with sudden right homonymous hemianopsia. Work-up imaging revealed a left occipital haematoma and an arteriovenous fistula supplied by the meningeal branches to the clivus from the left vertebral artery (VA) with a rostral venous reflux into cortical veins. A microcatheter was advanced through brainstem veins into the venous collector. A compliant balloon was placed in the left VA facing the origin of feeders. The balloon was inflated to protect the vertebrobasilar circulation from embolic migration. Onyx was injected by the transvenous catheter. Control angiogram revealed exclusion of the lesion.Informed consent was obtained from the patient.     

Effects of Mistletoe (Viscum Album L., Loranthaceae) Extracts on Arterial Blood Pressure in Rats Treated with Atropine Sulfate and Hexocycline

Acute effects of different extracts of mistletoe stem (Viscum album) were investigated on values of arterial blood pressure in Wistar rats. Arterial blood pressure was registered by direct method in the left carotid artery and the investigated extracts (total ethanol, ether and ethyl acetate) of mistletoe stem were administered into the right jugular vein. The total ethanol extract exhibited the best effect even on the lowest applied concentration (3.33 × 10^?5 mg kg^?1) and significantly decreased the blood pressure after applied concentration 1.00 × 10^?3 mg kg^?1. On the contrary, the ether and ethyl acetate extracts exhibited notable activity only by higher administered doses. Atropine as a nonselective blocker of muscarinic receptors reduced the hypotensive effects of ethanol extract of mistletoe. Hexocycline, a selective blocker of muscarine receptors, significantly raised blood pressure and decreased the hypotensive effect of ethanol extract of mistletoe on arterial blood pressure in rats.     

Antibiofilm Peptides Increase the Susceptibility of Carbapenemase-Producing Klebsiella pneumoniae Clinical Isolates to β-Lactam Antibiotics

Multidrug-resistant carbapenemase-producing Klebsiella pneumoniae (KpC) strains are becoming a common cause of infections in health care centers. Furthermore, Klebsiella can develop multicellular biofilms, which lead to elevated adaptive antibiotic resistance. Here, we describe the antimicrobial and antibiofilm activities of synthetic peptides DJK-5, DJK-6, and 1018 against five KpC isolates. Using static microplate assays, it was observed that the concentration required to prevent biofilm formation by these clinical isolates was below the MIC for planktonic cells. More-sophisticated flow cell experiments confirmed the antibiofilm activity of the peptides against 2-day-old biofilms of different KpC isolates, and in some cases, the peptides induced significant biofilm cell death. Clinically relevant combinations of DJK-6 and β-lactam antibiotics, including the carbapenem meropenem, also prevented planktonic growth and biofilm formation of KpC strain1825971. Interestingly, peptide DJK-6 was able to enhance, at least 16-fold, the ability of meropenem to eradicate preformed biofilms formed by this strain. Using peptide DJK-6 to potentiate the activity of β-lactams, including meropenem, represents a promising strategy to treat infections caused by KpC isolates.     

The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost

Neuroscientists have become used to a number of "facts" about the human brain: It has 100 billion neurons and 10- to 50-fold more glial cells; it is the largest-than-expected for its body among primates and mammals in general, and therefore the most cognitively able; it consumes an outstanding 20% of the total body energy budget despite representing only 2% of body mass because of an increased metabolic need of its neurons; and it is endowed with an overdeveloped cerebral cortex, the largest compared with brain size. These facts led to the widespread notion that the human brain is literally extraordinary: an outlier among mammalian brains, defying evolutionary rules that apply to other species, with a uniqueness seemingly necessary to justify the superior cognitive abilities of humans over mammals with even larger brains. These facts, with deep implications for neurophysiology and evolutionary biology, are not grounded on solid evidence or sound assumptions, however. Our recent development of a method that allows rapid and reliable quantification of the numbers of cells that compose the whole brain has provided a means to verify these facts. Here, I review this recent evidence and argue that, with 86 billion neurons and just as many nonneuronal cells, the human brain is a scaled-up primate brain in its cellular composition and metabolic cost, with a relatively enlarged cerebral cortex that does not have a relatively larger number of brain neurons yet is remarkable in its cognitive abilities and metabolism simply because of its extremely large number of neurons.     

Cellular composition characterizing postnatal development and maturation of the mouse brain and spinal cord

The process of development, maturation, and regression in the central nervous system (CNS) are genetically programmed and influenced by environment. Hitherto, most research efforts have focused on either the early development of the CNS or the late changes associated with aging, whereas an important period corresponding to adolescence has been overlooked. In this study, we searched for age-dependent changes in the number of cells that compose the CNS (divided into isocortex, hippocampus, olfactory bulb, cerebellum, ‘rest of the brain’, and spinal cord) and the pituitary gland in 4–40-week-old C57BL6 mice, using the isotropic fractionator method in combination with neuronal nuclear protein as a marker for neuronal cells. We found that all CNS structures, except for the isocortex, increased in mass in the period of 4–15 weeks. Over the same period, the absolute number of neurons significantly increased in the olfactory bulb and cerebellum while non-neuronal cell numbers increased in the ‘rest of the brain’ and isocortex. Along with the gain in body length and weight, the pituitary gland also increased in mass and cell number, the latter correlating well with changes of the brain and spinal cord mass. The majority of the age-dependent alterations (e.g., somatic parameters, relative brain mass, number of pituitary cells, and cellular composition of the cerebellum, isocortex, rest of the brain, and spinal cord) occur rapidly between the 4th and 11th postnatal weeks. This period includes murine adolescence, underscoring the significance of this stage in the postnatal development of the mouse CNS.     

Double-masked randomized clinical trial evaluating the effect of a triclosan/copolymer dentifrice on periodontal healing after one-stage full-mouth debridement

Background: This study evaluates the effect of triclosan/copolymer dentifrice on the 6‐month clinical response of patients with generalized severe chronic periodontitis (GSCP) treated with one‐stage, full‐mouth ultrasonic debridement (FMUD). Methods: Thirty patients diagnosed with GSCP (≥8 teeth presenting probing depth [PD] ≥5 mm and bleeding on probing [BOP]) were selected and randomly allocated to a control group (n = 15) subjected to FMUD and daily use of a placebo dentifrice or to a test group (n = 15) subjected to FMUD and daily use of a triclosan/copolymer dentifrice. Patients were analyzed for the following parameters: full‐mouth plaque index (FMPI), full‐mouth BOP score (FMBS), gingival recession, PD, and clinical attachment level (CAL). Patients were evaluated at 3 and 6 months by a calibrated and masked examiner. Results: Initially, the groups presented similar periodontal conditions, with no significant differences in any of the parameters evaluated (P >0.05). In both groups, improvements in all periodontal parameters (P <0.05) were seen at the completion of the experimental period. Additionally, the test group showed lower FMPI (3 months) and FMBS (3 and 6 months) than the control group (P <0.05). Moreover, the CAL gain was significantly greater in the test group, especially at initially deep pockets (PD ≤7 mm). Whereas in the control group the CAL gain in deep pockets was 2.7 ± 0.6 mm, in the test group the CAL gain was 3.6 ± 1.4 mm (P <0.05). Conclusion: Within the limits of the present study, the use of triclosan/copolymer dentifrice promoted additional clinical benefits in the treatment of GSCP treated by one‐stage FMUD.