Search

Purpose: The use of receptor-targeted antibodies conjugated to photosensitizers is actively being explored to enhance treatment efficacy. To facilitate clinical testing, we evaluated cetuximab conjugated to IRDye700DX (IR700) in cynomolgus macaques.Procedures: Total IR700 and intact cetuximab-IR700 were measured in 51 tissues at 2 and 14 days after intravenous injection of 40 and 80 mg/kg cetuximab-IR700, respectively, and compared with an unlabeled cetuximab-dosed control group (two each per sex per time point per group).Results: The IR700 retrieved from all tissues at 2 and 14 days after dosing was estimated at 34.9 ± 1.8 and 2.53 ± 0.67% of the total dose, respectively. The tissues with the highest levels of intact cetuximab-IR700 at 2 days after dosing were the blood, lung, and skin. Formalin-fixed paraffin-embedded tissue sections at 2 days after dosing showed the highest IR700 signals in the axillary lymph node, mammary gland, and gall bladder.Conclusions: Both IR700 and intact cetuximab-IR700 biodistributions were consistent with known epidermal growth factor receptor (EGFR) expression, and changes between 2 and 14 days were consistent with rapid metabolism and excretion of the cetuximab-IR700. [ABSTRACT FROM AUTHOR]

The article highlights a study which analyzed nonneoplastic lesion data from cancer bioassays that made use of rats with Mycoplasma pulmonis disease. According to the authors, more than 76 percent of the rats used in the study were found to have bronchitis which is the signature lesion of M pulmonis. They assert that the findings support earlier claims that bioassays of aspartame, methanol and methyl tertiary butyl ether were compromised by M pulmonis disease and that the reported induction of lymphomas should not be considered in assessing cancer risks.

This study utilizes morphological and mechanistic endpoints to characterize the onset of bilateral atresia of the vas deferens in a recently derived cystic fibrosis (CF) rat model. Embryonic reproductive structures, including Wolffian (mesonephric) duct, Mullerian (paramesonephric) duct, mesonephric tubules, and gonad, were shown to mature normally through late embryogenesis, with involution of the vas deferens and/or epididymis typically occurring between birth and postnatal day 4 (P4), although timing and degree of atresia varied. No evidence of mucus obstruction, which is associated with pathology in other CF-affected tissues, was observed at any embryological or postnatal time point. Reduced epididymal coiling was noted post-partum and appeared to coincide with, or predate, loss of more distal vas deferens structure. Remarkably, α smooth muscle actin expression in cells surrounding duct epithelia was markedly diminished in CF animals by P2.5 when compared to wild type counterparts, indicating reduced muscle development. RNA-seq and immunohistochemical analysis of affected tissues showed disruption of developmental signaling by Wnt and related pathways. The findings have relevance to vas deferens loss in humans with CF, where timing of ductular damage is not well characterized and underlying mechanisms are not understood. If vas deferens atresia in humans begins in late gestation and continues through early postnatal life, emerging modulator therapies given perinatally might preserve and enhance integrity of the reproductive tract, which is otherwise absent or deficient in 97% of males with cystic fibrosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The authors recently assessed the likelihood that lifetime cancer bioassays of aspartame, methanol, and methyl tertiary butyl ether conducted with conventional (not specific pathogen free) Sprague-Dawley rats were compromised by Mycoplasma pulmonis disease. From the tumor data and other information, the authors concluded that the rats used in these bioassays likely had M pulmonis disease and that lesions of the disease were plausibly interpreted as lymphoma. Subsequently, they analyzed the nonneoplastic lesion data from these bioassays for occurrence of inflammatory lesions and found that 2,267 of 2,960 rats (76.6%) were reported to have bronchitis, the signature lesion of M pulmonis disease, and that 633 rats (21.4%) were reported to have otitis, another common lesion of the disease. Also, documentation is now available containing serologic evidence of mycoplasma infection in the rats. In contrast, the reports of 6 National Toxicology Program bioassays based on specific pathogen-free Sprague-Dawley rats listed no instances of bronchitis or otitis. These findings provide substantial additional evidence that the bioassays in question were compromised by M pulmonis disease. Therefore, the reported induction of lymphoma in these studies should not be considered in cancer risk assessments. The authors also found that inflammatory lesions were prevalent in lymph nodes, thymus, pleura, and brain. Finally, they found that of all 328 cases of lymphoimmunoblastic lymphoma affecting the lung (the primary form of lymphoma reported), 218 (66.5%) occurred within the first 104 weeks of the studies, showing that occurrence of such lesions was not due to appearance in rats surviving beyond that interval.

Six 3-month-old BALB/c Rag2-/- mice developed dyspnea 10 days after intravenous injection of wild type BALB/c CD45RB(high) lymphocytes to induce colitis as a model of inflammatory bowel disease. The lungs of all 6 mice were diffusely gray-purple and did not collapse completely. Microscopic findings were extensive coalescent patchy to diffuse alveolitis, characterized by macrophages and multinucleate giant cells, lymphocytes in alveolar lumina and septa, alveolar luminal of neutrophils, and alveolar proteinic material containing small black vesicular bodies characteristic of Pneumocystis sp. in methenamine silver stained sections. The morphologic diagnosis was diffuse granulomatous pneumonia with intra-alveolar organisms consistent with Pneumocystis sp., with an unusually aggressive inflammatory response related to the experimental procedure and possibly to the BALB/c genetic background.

An outbreak of mycoplasmosis caused by Mycoplasma alligatoris resulted in the death or euthanasia of 60 American alligators (Alligator mississippiensis) from a population of 74 captive bull alligators in Florida in 1995. The natural reservoir, routes of transmission, and host range of M. alligatoris are unknown. This study was undertaken to determine whether crocodilian species other than American alligators are susceptible to M. alligatoris. Six broad-nosed caimans (Caiman latirostris) and six Siamese crocodiles (Crocodylus siamensis) were experimentally inoculated with 10(6) colony forming units (CFU) of M. alligatoris instilled through the glottis. Two caimans and two crocodiles were used as negative controls. Six and four American alligators were used as positive and negative controls, respectively. Three of six (50%) inoculated caimans died within 10 wk postinoculation (PI) of severe mycoplasmosis. Gross necropsy, histopathologic, and culture results were similar for broad-nosed caimans and American alligators. None of the inoculated Siamese crocodiles developed mycoplasmosis, though M. alligatoris was isolated from the tonsils in three of six (50%) animals at necropsy. All the inoculated crocodilians that survived showed significant seroconversion by 6-8-wk PI (P < 0.05). The infective dose 50% (ID50) and lethal dose 50% (LD50) of M. alligatoris for the broad-nosed caiman are 10(6) CFU when instilled through the glottis, which is similar to that of the American alligator. Although the host range of M. alligatoris is not restricted to the American alligator, the organism does not appear to be pathogenic for Siamese crocodiles. Other species of crocodilians may be susceptible to infection with M. alligatoris, and this organism should be considered when the rapid onset of clinical signs of pneumonia, polyarthritis, pericarditis, and death occur.

The myxoma virus (MYX) serpin SERP1 is a secreted glycoprotein with anti-inflammatory activity that is required for full MYX virulence in vivo. The cowpox virus (CPV) serpin SPI-3 (vaccinia virus ORF K2L) is a nonsecreted glycoprotein that blocks cell-cell fusion, independent of serpin activity, and is not required for virulence of vaccinia virus or CPV in mice. Although SPI-3 has only 29% overall identity to SERP1, both serpins have arginine at the P1 position in the reactive center loop, and SPI-3 has a proteinase inhibitory profile strikingly similar to that of SERP1 [Turner, P. C., Baquero, M. T., Yuan, S., Thoennes, S. R., and Moyer, R. W. (2000) Virology 272, 267-280]. To determine whether SPI-3 and SERP1 were functionally equivalent, a CPV variant was constructed where the SPI-3 gene was deleted and replaced with the SERP1 gene regulated by the SPI-3 promoter. Cells infected with CPVDeltaSPI-3::SERP1 secrete SERP1 and show extensive fusion, suggesting that SERP1 is unable to functionally substitute for SPI-3 in fusion inhibition. In the reciprocal experiment, both copies of SERP1 were deleted from MYX and replaced with SPI-3 under the control of the SERP1 promoter. Cells infected with the MYXDeltaSERP1::SPI-3 recombinant unexpectedly secreted SPI-3, suggesting either that the cellular secretory pathway is enhanced by MYX or that CPV encodes a protein that prevents SPI-3 secretion. MYXDeltaSERP1::SPI-3 was as attenuated in rabbits as MYXDeltaSERP1::lacZ, indicating that SPI-3 cannot substitute for SERP1 in MYX pathogenesis., (Copyright 2000 Academic Press.)

Practitioners may be called on to treat rodents with respiratory diseases or to advise clients concerning the care of these rodents. Respiratory diseases of mice, rats, guinea pigs, and Syrian hamsters are well known because of the use of these species in research, whereas few or no reports of respiratory disease in rodents of other species exist. Features of the respiratory diseases of these four commonly encountered species are reviewed, including causes; clinical signs; diagnostic procedures; preventive measures; and, where appropriate, therapies.