Prospective Design of Anti-Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain.

Anti-transferrin receptor (TfR)-based bispecific antibodies have shown promise for boosting antibody uptake in the brain. Nevertheless, there are limited data on the molecular properties, including affinity required for successful development of TfR-based therapeutics. A complex nonmonotonic relationship exists between affinity of the anti-TfR arm and brain uptake at therapeutically relevant doses. However, the quantitative nature of this relationship and its translatability to humans is heretofore unexplored. Therefore, we developed a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model for bispecific anti-TfR/BACE1 antibodies that accounts for antibody-TfR interactions at the blood-brain barrier (BBB) as well as the pharmacodynamic (PD) effect of anti-BACE1 arm. The calibrated model correctly predicted the optimal anti-TfR affinity required to maximize brain exposure of therapeutic antibodies in the cynomolgus monkey and was scaled to predict the optimal affinity of anti-TfR bispecifics in humans. Thus, this model provides a framework for testing critical translational predictions for anti-TfR bispecific antibodies, including choice of candidate molecule for clinical development.

Architectural pattern, tissue and cellular morphology in livers of fishes: relationship to experimentally-induced neoplastic responses.

The teleost liver is one of the most sensitive organs to show alteration in biochemistry, physiology and structure following exposure to various types of environmental pollutants. Despite the importance of this organ to environmental toxicology and to ecotoxicology where biomarkers of exposure and of deleterious effect are found, the architectural pattern is not well known. This chapter reviews an architectural plan for teleost liver and compares that to the often cited mammalian pattern. Hepatic tubules composed principally of hepatocytes and biliary epithelial cells are in close proximity to lacunae which are of mesodermal origin. As is described, the tubule and lacunae concepts provide a means to better interpret morphologic alterations following exposure. These concepts are used to illustrate features of the chronic toxicity following exposure to proven carcinogens.

Invading and metastasizing cardiac hemangioendothelial neoplasms in a cohort of the fish Rivulus marmoratus: unusually high prevalence, histopathology, and possible etiologies.

An unusually high, unprecedented prevalence of cardiac hemangioendotheliomata, including hemangiomas, hemangioendotheliomas, and hemangioendotheliosarcomas, was found in a laboratory cohort of the small, teleost fish Rivulus marmoratus. The neoplasms occurred in 51 of 204 fish (25%) used in a carcinogenicity study of butylated hydroxyanisole fed in a lyophilized chicken liver diet for up to 9 months. The cardiac neoplasms occurred in approximately equal numbers of both control (fed lyophilized chicken liver but not exposed to butylated hydroxyanisole) and exposed (fed 0.8% butylated hydroxyanisole in chicken liver) fish. The neoplasms occurred in the bulbus arteriosus and ventricle (accompanied by an intense epicarditis), and in some cases, in the gills. At least one case of hemangioma was characterized by cavernous vessels in the bulbar wall. Hemangioendothelioma cases consisted of pleomorphic endothelial cells that formed continuous tracts and anastomosing, typical vascular channels of varying sizes. The hemangioendotheliosarcomas consisted of atypical, spindle, polygonal, or round endothelial cells that formed solid tumor masses that contained abnormal vessels with atypical endothelium tufting into their lumina. Some fish had neoplasm cases containing varying regions with mixtures of the above features. Incipient neoplasms occurred on/in the semilunar valves, and their cells appeared to invade the adjacent walls of the bulbus and/or the ventricle. The gill lesions represented possible metastatic neoplasms, probably formed by atypical endothelial cells that exfoliated from the edges of cardiac neoplasms into the lumina of the ventricle or bulbus and were then pumped to the arterioles of the gills via the ventral aorta. Fish examined from the original colony in the laboratory and from the wild had no neoplasms. Possible causes are discussed, and studies are under way in an attempt to determine the etiology of the neoplasm and to evaluate Rivulus marmoratus as a possible model organism for study of these types of cardiac neoplasms.

The genome of the tropical tree Theobroma cacao L.

2C values for angiosperms vary over 2500-fold and a positive correlation exists between C-value and latitude in herbaceous plants. Woody plants differ from herbaceous plants in chromosome size and C-value. In addition, tropical hardwoods have smaller chromosomes than other tropical plants and do not share the correlation of minimum generation time with genome size seen in herbaceous plants. Theobroma cacao is a tropical hardwood cultivated for its beans, which are used to make chocolate and cocoa butter. Its cytology is typical of the pantropical and subtropical family Sterculiaceae. Its small chromosomes, single secondary constriction, and lack of C-banding suggest a small genome. The genome size of T. cacao, measured by reassociation kinetics, is 2.01 x 10(8), which is small compared to both temperate and tropical plants previously studied. We also provide data on the melting point, base composition, and relative extent of methylation (at sites most commonly methylated in higher plants), of T. cacao DNA.

Spongiosis hepatis: chemical induction, pathogenesis, and possible neoplastic fate in a teleost fish model.

Spongiosis hepatis (SH), first reported as a distinct lesion associated with certain forms of hepatic neoplasia in rats, has also been induced with chemicals, in a predictable fashion, in small teleost fishes being studied as carcinogenesis research models. The sheepshead minnow (Cyprinodon variegatus), exposed to N-nitrosodiethylamine (DENA) in sea water, provided the model for this study. The fish developed SH and presented a spectrum of developmental or progressive stages of the lesion over a 140 week holding period following a 6 week exposure to / 57 mg/L DENA. The origin of SH in the fish model is homologous to that in the rat model, both species having the perisinusoidal cell (stellate cells of Ito) in the space of Disse as the cell of origin. Light (LM) and electron microscopy (EM) studies characterized the different pathogenetic stages of SH in liver of the sheepshead minnow and revealed a possible late transition of SH to putative polymorphic cell neoplasms. The possible preneoplastic or neoplastic nature of SH from its time of origin in chemically exposed fish to time of appearance of associated presumptive neoplasms is discussed. SH may be a bioindicator of exposure to certain chemicals in some vertebrate species, from fishes to mammals.

Pericyte of a teleost fish: ultrastructure, position, and role in neoplasia as revealed by a fish model.

The morphology and position of the pericyte, a periendothelial cell, is described for a teleost fish, Cyprinodon variegatus. This cell was found attached to the abluminal surfaces of capillaries, venules, and arterioles of the submucosa of the midgut of the fish. The cell was encompassed by a thin basal lamina, possessed numerous plasmalemmal vesicles, a "sole region" which contained thinner actin-like filaments and possibly thicker myosin-like filaments, and ranged in form from ovoid to stellate, with long cytoplasmic extensions that partially covered the endothelium of the associated microvessel. The pericyte of C. variegatus has been shown to give rise to hemangiopericytomas (experimentally induced with diethylnitrosamine) and possibly to pericytomas. The range of phenotypic expression of these pericyte-derived neoplasms is broad, and dependent upon the degree of differentiation of their constituent cells which range from clear cell pericytes to myofilamentous laden cells that resemble smooth muscle cells. In this regard and in regard to its normal ultrastructural morphology, and anatomical position, in relationship to microvasculature in this fish, the cell is very similar to other vertebrate pericytes. Limited evidence suggests that small fish species may be excellent study models for further elucidation of pericyte form, function, and role in disease.

N-nitrosodiethylamine-induced hepatocarcinogenesis in estuarine sheepshead minnow (Cyprinodon variegatus): neoplasms and related lesions compared with mammalian lesions.

Groups of estuarine sheepshead minnows (Cyprinodon variegatus) were exposed to approximately 57 mg N-nitrosodiethylamine [(DENA) CAS: 55-18-5]/liter for 5-6 weeks. Exposure was stopped and the fish were then transferred to clean, flowing seawater. Induced liver lesions were studied in periodic samples of fish taken during the next 140 weeks of holding. Lesions found following exposure were early altered basophilic and eosinophilic foci, oval cell hyperplasia, clear cell foci, neoplastic nodules, hepatocellular carcinomas, cholangiolar carcinomas, possible pericytomas originating in liver, hemangiopericytomas, spongiosis hepatis, and cholangiofibrosis. The relative prevalence of these lesions was given. Most of these lesions morphologically were compared to their counterpart lesions in the rat. Certain lesions in our fish such as hepatocellular carcinomas, cholangiolar carcinomas, pericytomas, hemangiopericytomas, spongiosis hepatis, and cholangiofibrosis have apparent similar cellular origins and morphogenesis to those lesions in rats and perhaps in other mammals. Spongiosis hepatis in the sheepshead minnow apparently arises from perisinusoidal cells and may be a neoplasm of this cell type. The general similarity of response to DENA in sheepshead minnows and rats suggests that this fish has promise as a model subject for studying some hepatocarcinogens and as a sentinel organism for detecting hepatocarcinogens in contaminated coastal waters.

Usefulness of Cyprinodon variegatus and Fundulus grandis in carcinogenicity testing: advantages and special problems.

Cyprinodon variegatus and Fundulus grandis, two species of cyprinodontid fishes studied extensively and used in toxicological and biological investigations, are compared as laboratory test animals. Their ecology, general biology, and suitability for various types of experimentation are examined. A laboratory system for exposure of these species at critical life stages (embryos, fry, juveniles) to suspect carcinogens is described. A discussion of the use, findings, and potential of these species in oncological studies and carcinogen assays is presented, particularly in regard to responses to 3 known or suspect carcinogens (trifluralin, benzidine, and aflatoxin). Finally, advantages and disadvantages or special problems in using the species as carcinogen test animals are reviewed.

The effect of thiopentone and fazadinium on intraocular pressure.

Intraocular pressure was measured in twenty-four patients using an applanation tonometer, after using thiopentone and fazadinium as induction agents. No significant rise in intraocular pressure above resting levels was noted before or after tracheal intubation, and it is suggested that this combination of induction agents should be satisfactory for general anaesthesia of a patient with a perforating eye injury who presents with a full stomach.

Correlation of mixed-function oxidase activity with ultrastructural changes in the liver of a marine fish.

Specimens of mullet (Mugil cephalus), a marine fish, were given single doses of 3-methylcholanthrene intraperitoneally and the activity of the microsomal mixed-function oxygenase system in the liver was measured by the metabolism of benzo(a)pyrene. The enzyme system was found to be inducible with concomitant ultrastructural changes in the hepatocytes. The specific activity and the metabolic profile approximate those of the rat.

Interaction of chemical pollutants and virus in a crustacean: a novel bioassay system.

A large group of shrimp, 23.3% of which had light patent Baculovirus infections, was divided equally into two groups. One group was exposed to the chemical stressor Aroclor 1254 (a polychlorinated biphenyl) at 0.7 ppb for 35 days in flowing seawater. The other group was maintained as a control group in flowing seawater. Viral prevalence in exposed shrimp samples increased with time at a significantly greater rate than did viral frequency in control shrimp. Viral prevalence in Aroclor-exposed shrimp survivors was 75% after 35 days, whereas in control shrimp, only 45.7% had patent viral infections. This finding suggests an interaction among chemical stressor (Aroclor 1254), host, and virus. The nature or mechanism of this interaction has not been defined, but the shrimp-virus system shows, promise for future bioassays of influence of low concentrations of pollutants on natural pathogenhost interactions.

Kepone-induced scoliosis and its histological consequences in fish.

Scoliosis in fish is caused by several diverse agents that possibly act on the central nervous system, neuromuscular junctions, or ionic metabolism. The organochlorine pesticide Kepone induces scoliosis in the sheepshead minnow. Some effects associated with Kepone-induced scoliosis in these fish are disruption of myotomal patterns, inter- and intramuscular hemorrhage, fractured centra of vertebrae, and death. The histological syndrome of Kepone poisoning in fish and the clinical syndrome in humans suggest that the nervous system is a primary target for Kepone and that scoliosis is a secondary effect of Kepone poisoning in fish.

Toxicity of Aroclor-R 1254 and its physiological activity in several estuarine organisms.

The occurrence of high concentrations of a PCB (Aroclor 1254) in the Pensacola estuary prompted field and laboratory studies by the Gulf Breeze Environmental Research Laboratory (EPA). Monitoring of the estuary indicates the chemical is present in all components--particularly in sediments and fishes. Residues appear to be diminishing in sediments. Toxicity tests show estuarine species sensitive at ppb concentrations in water, with a ciliate protozoan (Tetrahymena pyriformis W), (Fundulus similis), affected at or near 1.0 ppb. Tissue concentrations of Aroclor 1254 similar to those found in natural populations of shrimps from the contaminated estuary were successfully duplicated in laboratory experiments. Shrimps also concentrated the PCB from very low concentrations (0.04 ppb) in the water. Three estuarine species demonstrated pathologic changes at tissue and cellular level after chronic exposure to the chemical. Oysters (Crassostrea virginica) developed abnormal infiltration of leukocytes in the connective tissue, spot (Leiostomus xanthurus) developed fatty changes in their livers, and shrimp (Penaeus duorarum) developed crystalloids in hepatopancreatic nuclei.