Convection enhanced delivery for treating brain tumors and selected neurological disorders: symposium review

In 2003 the Cleveland Clinic Brain Tumor Institute sponsored a symposium to mark the progress being made in what was then a new approach to treating brain tumors—convection enhanced delivery (CED) [Vogelbaum MA (2005) J NeuroOncol 73(1):57–69]. A second symposium was held in February, 2006, to review new accomplishments and identify promising avenues of research in this evolving but still novel therapy. Among the general subjects covered by a host of international experts in their respective fields were advances in CED technology, new clinical applications of the technology, advances in CED-related imaging procedures, reviews of current or proposed trials, new drugs and the status of projects moving from lab to clinical practice. Specific subjects included the design of new catheters, the development of mathematic models for planning, novel therapeutics for CED treatment of stroke, spinal cord degenerative disease and epilepsy, liposome-based agents administered via CED, ultra-sound driven CED, monitoring the in vivo effects of intratumoral paclitaxel and other topics. Each speaker’s presentation has been abstracted along with relevant references.     

HYPOTHALAMIC DIGOXIN,HEMISPHERIC CHEMICAL DOMINANCE,AND MESENTERIC ARTERY OCCLUSION

The role of the isoprenoid pathway in vascular thrombosis, especially mesenteric artery occlusion and its relation to hemispheric dominance, was assessed in this study. The following parameters were measured in patients with mesenteric artery occlusion and individuals with right hemispheric, left hemispheric, and bihemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition. In patients with mesenteric artery occlusion there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, low ubiquinone, and elevated free radical levels. The RBC membrane Na+-K+ ATPase activity and serum magnesium were decreased. There was also an increase in tryptophan catabolites and reduction in tyrosine catabolites in the serum. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these patients. The biochemical patterns obtained in mesenteric artery occlusion is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with mesenteric artery occlusion were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Mesenteric artery occlusion occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function. Hemispheric chemical dominance may thus control the risk for developing vascular thrombosis in individuals     

Investigation into modification of mass transfer kinetics by acrolein in a renal biochip

In this study we present a method for investigating the effect of acrolein, a nephrotoxic and urotoxic metabolite of the anticancerous prodrugs ifosfamide and cyclophosphamide, in a blood-renal barrier biochip. The real time monitoring of mass transfers of caffeine, vitamin B12 and albumin in the biochip was performed thanks to an in vitro dialysis method. The diffusion coefficients of the solutes and their dialysance from the apical to the basolateral compartments were found to be molecular weight and cell-membrane dependent, thus demonstrating the cell-barrier functionality. The toxicity induced by the acrolein led to modifications to mass transfer properties which appeared to be acrolein dose, time and solute molecular weight dependent. Solute mass transfer across the cell layer increased with acrolein concentrations. The sensitivity of this analysis method contributes to identify the mass transfer properties and to monitor the modification to the renal parameter when submitted to toxic cell compounds. The results provide the foundation for exploring kidney behavior in response to drugs thanks to a blood-tissue barrier model using a technique based on in vitro dialysis and real time analysis.     

Chronic lead intoxication affects glial and neural systems and induces hypoactivity in adult rat

Lead is an environmental toxin and its effects are principally manifested in the brain. Glial and neuronal changes have been described during development following chronic or acute lead intoxication, however, little is known about the effects of chronic lead intoxication in adults. In this study we evaluated immunohistochemically the glial and dopaminergic systems in adult male Wistar rats. 0.5% (v/v) lead acetate in drinking water was administrated chronically over a 3-month period. Hypertrophic immunoreactive astrocytes were observed in the frontal cortex and other brain structures of the treated animals. Analysis of the astroglial features showed increased number of astrocyte cell bodies and processes in treated rats, an increase confirmed by Western blot. Particular distribution of glial fibrillary acidic protein immunoreactivity was observed within the blood vessel walls in which dense immunoreactive glial processes emanate from astrocytes. Glial changes in the frontal cortex were concomitant with reduced tyrosine hydroxylase immunoreactive neuronal processes, which seem to occur as a consequence of significantly reduced dopaminergic neurons within the nucleus of origin in the substantia nigra. These glial and neuronal changes following lead intoxication may affect animal behavior as evidenced by reduced locomotor activity in an open field test. These findings demonstrate that chronic lead exposure induces astroglial changes, which may compromise neuronal function and consequently animal behavior.     

Huangqin decoction regulates autophagy to intervene with intestinal acute graft-versus-host disease in mice北大核心

BACKGROUND: How to use traditional Chinese medicine to intervene the imbalance of autophagy after intestinal mucosal barrier injury, so as to ultimately intervene the occurrence of gastrointestinal acute graft-versus-host disease, is an urgent problem to be solved after hematopoietic stem cell transplantation. OBJECTIVE: To verify the precise mechanism by which Huangqin Decoction interferes with acute intestinal graft-versus-host disease. METHODS: CB6F1 mice were randomly divided into normal control group, model control group, low-dose Huangqin Decoction group, medium-does Huangqin Decoction group and high-does Huangqin Decoction group, with 16 mice per group. CB6F1 mice in the model control group, low-dose Huangqin Decoction group, medium-does Huangqin Decoction group and high-does Huangqin Decoction group were infused with mononuclear cell suspension (bone marrow cell 8×107 + spleen cell 8×107) obtained from Balb/c mice via caudal vein within 4 hours after60Co whole body irradiation (radiation dose was 8 Gy). Different concentrations of Huangqin Decoction were given by gavage on the same day after modeling. The rats in the model control group and the normal control group were given the same volume of normal saline by gavage for 15 days. Eight hours after the last gavage, the small intestine tissues of six mice in each group were collected. PCR and western blot assay were used to detect the expression levels of LC3II/I, Beclin1 and P62. The pathological grading of small intestinal mucosa was scored by hematoxylin-eosin staining. The autophagic vesicle structure of small intestinal mucosal epithelial cells was observed by transmission electron microscope. The remaining 10 rats in each group (except the normal control group) were used to observe the clinical grading of acute graft-versus-host disease and record the survival time. RESULTS AND CONCLUSION: (1) After the application of Huangqin Decoction, the survival time of mice was significantly prolonged; the clinical acute graft-versus-host disease score was significantly decreased, and the pathological grading score of small intestinal mucosa was significantly decreased. The score of medium-does Huangqin Decoction group and high-does Huangqin Decoction group was significantly lower than that of model control group, but there was no significant difference between medium-does Huangqin Decoction group and high-does Huangqin Decoction group. (2) The LC3II/I and Beclin1 expression was significantly lower in the model control group than that in the normal control group (P < 0.01), and P62 expression was significantly higher than that in the normal control group (P < 0.01). Huangqin Decoction could promote the recovery of LC3II/I and Beclin1 levels and downregulate p62 levels (P < 0.01). (3) Under transmission electron microscope, the number of autophagic vesicles in the treatment group was significantly higher than that in the model control group, accompanied by the recovery of important organelles such as mitochondria. (4) The results confirm that by interfering autophagy related proteins, Huangqin Decoction can promote the recovery of autophagy in acute graft-versus-host disease, protect intestinal mucosal barrier and reduce intestinal rejection after transplantation and has promise as a new treatment for acute graft-versus-host disease. © 2022, Publishing House of Chinese Journal of Tissue Engineering Research. All rights reserved.     

Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma

Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the “immunologically privileged” CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity.     

In vivo assessment of macrophage CNS infiltration during disruption of the blood�Cbrain barrier with focused ultrasound: a magnetic resonance imaging study

Focused ultrasound has been discovered to locally and reversibly increase permeability of the blood–brain barrier (BBB). However, inappropriate sonication of the BBB may cause complications, such as hemorrhage and brain tissue damage. Tissue damage may be controlled by selecting optimal sonication parameters. In this study, we sought to investigate the feasibility of labeling cells with superparamagnetic iron oxide particles to assess the inflammatory response during focused-ultrasound-induced BBB opening. We show that infiltration of phagocytes does not occur using optimal parameters of sonication. Taken together, the results of our study support the usefulness and safety of focused-ultrasound-induced BBB opening for enhancing drug delivery to the brain. These findings may have implications for the optimization of sonication parameters.     

Intestinal epithelial cells in inflammatory bowel diseases

The pathogenesis of inflammatory bowel diseases (IBDs) seems to involve a primary defect in one or more of the elements responsible for the maintenance of intestinal homeostasis and oral tolerance. The most important element is represented by the intestinal barrier, a complex system formed mostly by intestinal epithelial cells (IECs). IECs have an active role in producing mucus and regulating its composition; they provide a physical barrier capable of controlling antigen traff ic through the intestinal muco...