Inhibition of rat yolk sac tumour growth in vivo by a monoclonal antibody to the retroviral molecule P15E

Summary A monoclonal mouse IgG2b antibody 19F8, directed towards a determinant on the retroviral transmembranous molecule p15E, binds selectively to certain rat tumours, including all tested yolk sac tumours, one rat colon carcinoma, one spontaneous kidney carcinoma and an adenovirus-type-9-induced rat breast tumour, as tested by antibody-dependent cellular cytotoxicity (ADCC) and immunohistochemistry. Groups of rats receiving yolk sac tumour F56 isografts intraperitoneally (i.p.) or subperitoneally (s.p.) were treated with this monoclonal antibody (mAb), 19F8, inoculated twice a week in doses of 100 µg. Parallel control groups received analogous inoculations of an isotype-matched monoclonal antibody. A significant growth inhibitory effect was observed with 19F8. In 5/10 rats isografted i.p., tumour outgrowth was completely inhibited and in the other 5 rats the outgrowth was delayed compared to the 10 rats in the control group, which all developed tumours. All rats of the control group developed large volumes of ascites, whereas the 5 rats in the therapy group with eventual tumour outgrowth had little or no ascites. In two experiments with rats carrying subperitoneal isografts and treated with the 19F8 mAb, tumour grew out in 4/5 and 5/10 rats, though growth was delayed compared to the control groups, in which 5/5 and 9/9 rats developed tumours. The tumours grew significantly more slowly in the therapy groups compared to the controls. All rats that developed tumours in the therapy groups showed an anti-idiotypic response against mAb 19F8. The single tumour-free rat in the first experiment and 1/5 tumour-free rats in the other showed no such response. The draining lymph node cells from the tumour-free animals showed a specific proliferative response to yolk sac tumour F56 cells in a mixed lymphocyte tumour cell culture (MLTC), and the MLTC-induced cells were cytotoxic to F56 but not to the natural-killer-sensitive rat T cell lymphoma G1—Tc1. The cytotoxic cell population was more than 90% CD4⁺. It is concluded that the two test systems for identification of the epitope of p15E detected by mAb 19F8 correlated well in detection of the epitope in the cells (immunohistochemistry) and at the cell surface (ADCC). It is also concluded that mAb 19F8 has a growth-inhibitory effect on yolk sac tumour F56 and that, as a result of the treatment, T cells with specificity for F56 are appearing in draining lymph nodes of tumour-free animals.     

Noradrenaline Metabolism in Neocortex and Hippocampus Following Transient Forebrain Ischemia in Rats: Relation to Development of Selective Neuronal Necrosis

Noradrenaline (NA) metabolism in the neocortex and hippocampus was examined in rats at 1, 24, and 48 h following 15 min of reversible forebrain ischemia. As assessed by the ratio of accumulated 3,4-dihydroxyphenylalanine (DOPA) to the tissue NA level after inhibition of DOPA decarboxylase, the NA turnover rates were markedly increased (120-148% above the control) at 1 h postischemia in both the neocortex and hippocampal formation (CA1 and CA3 plus dentate gyrus). The DOPA:NA ratio went back to control levels after longer postischemic survival times. The ratio between levels of the deaminated NA metabolite, 3,4-dihydroxyphenylethyleneglycol (DOPEG), and NA, which gives another measure of NA turnover rate, showed similar changes. In the neocortex and the CA3 plus dentate gyrus, the DOPEG:NA ratio was markedly increased (89-118%) 1 h after the ischemia, but this change had disappeared at 24 and 48 h. Thus, both the DOPA accumulation experiments and the NA and DOPEG measurements indicate that following transient forebrain ischemia, there is an increased NA turnover in the hippocampus and cortex only in the early recirculation period and not after longer postischemic survival times. The degree of neuronal necrosis in the CA1 region was examined light microscopically on celestine blue-acid fuchsin-stained sections at 24, 48, and 96 h following the ischemic insult. The neuronal damage in CA1 was sparse after 24 h of recovery, had increased markedly after 48 h, and was very pronounced at 96 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Whole inactivated SIV vaccine grown on human cells fails to protect against homologous SIV grown on simian cells

Several groups have reported protection against experimental SIV infection in macaques immunized with a whole inactivated virus vaccine. The aim of the current study was to investigate whether five macaques vaccinated with whole inactivated SIV and previously shown to be protected against challenge with two divergent strains of SIV grown on human cells could resist challenge with a subsequent homologous SIV grown on macaque cells. We show here that this same vaccine did not protect when the challenge virus was grown on primary cells of monkey origin.     

Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae – Identification of LYS228

Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).     

Alternative reproductive tactics are associated with sperm performance in invasive round goby from two different salinity environments

During male–male competition, evolution can favor alternative reproductive tactics. This often results in a dominant morph that holds a resource, such as a nest for egg laying, which competes with a smaller sneaker morph that reproduces by stealing fertilizations. The salinity environment can influence male growth rates, for example, via osmoregulatory costs, which in turn may influence the use of sneaker tactics for small males competing for mating opportunities. Salinity can also affect sperm directly; however, little is known of how salinity influences sneaker tactics through sperm performance. We sampled males of the invasive round goby (Neogobius melanostomus) from two environments, a freshwater river and a brackish estuary. This fish has two male morphs: nest‐holding dark males and non‐nest‐holding light males. We examined the role of water salinity of 0, 8, and 16 on sperm performance and found that for estuarine males, a salinity of 0 reduced sperm velocity compared to a salinity of 8 and 16. Riverine males had low velocity in all salinities. Sperm viability also decreased by over 30% in 0 salinity, compared to 8 and 16, for fish from both environments. Gobies produce ejaculate contents in specialized glands that could in theory shield sperm in an adverse environment. However, gland contents did not improve sperm performance in our tests. Body mass and age estimates indicate that riverine males invested more in somatic growth compared to estuarine males. Estuarine light morph males had a high enough gonadosomatic index to indicate sneaker tactics. We propose that when sperm performance is low, such as for the riverine males, sneaker tactics are ineffective and will be selected against or phenotypically suppressed. Instead, we interpret the increased investment in somatic growth found in riverine males as a life‐history decision that is advantageous when defending a nest in the next reproductive season.