Complement Inhibition Prevents Oncolytic Vaccinia Virus Neutralization in Immune Humans and Cynomolgus Macaques

Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement. In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors. Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques. CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity. Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts.     

Determinants of participation in prostate cancer screening: A simple analytical framework to account for healthy‐user bias

In Japan at present, fecal occult blood testing (FOBT) is recommended for cancer screening while routine population‐based prostate‐specific antigen (PSA) screening is not. In future it may be necessary to increase participation in the former and decrease it in the latter. Our objectives were to explore determinants of PSA‐screening participation while simultaneously taking into account factors associated with FOBT. Data were gathered from a cross‐sectional study conducted with random sampling of 6191 adults in Osaka city in 2011. Of 3244 subjects (return rate 52.4%), 936 men aged 40–64 years were analyzed using log‐binomial regression to explore factors related to PSA‐screening participation within 1 year. Only responders for cancer screening, defined as men who participated in either FOBT or PSA‐testing, were used as main study subjects. Men who were older (prevalence ratio [PR] [95% confidence interval (CI)] = 2.17 [1.43, 3.28] for 60–64 years compared with 40–49 years), had technical or junior college education (PR [95% CI] = 1.76 [1.19, 2.59] compared with men with high school or less) and followed doctors' recommendations (PR [95% CI] = 1.50 [1.00, 2.26]) were significantly more likely to have PSA‐screening after multiple variable adjustment among cancer‐screening responders. Attenuation in PR of hypothesized common factors was observed among cancer‐screening responders compared with the usual approach (among total subjects). Using the analytical framework to account for healthy‐user bias, we found three factors related to participation in PSA‐screening with attenuated association of common factors. This approach may provide a more sophisticated interpretation of participation in various screenings with different levels of recommendation.     

Estimation of the phantom scatter factor (Sp) of rectangular fields

This study proposes a method to accurately estimate the phantom scatter factor (Sp) of arbitrary rectangular fields. We measured output doses in water and air; these measured values were based on square fields and a limited number of symmetric rectangular fields using 4 MV and 10 MV X-rays of a Varian Clinac-iX. We calculated Sp from these measured values. Then, using these Sp values, we estimated equations of Sp on square fields consisting of the primary dose, Day's scatter, and forward scatter. This equation may be used to estimate the Sp value on a square field, but it cannot estimate the Sp value on a rectangular field. We investigated the calculation method for an equivalent square of a rectangular field. As a result, this study's calculation method for an equivalent square, the area ratio correction method, was more accurate than the conventional Bj?rngard's method. Therefore, when using the approximate equation of Sp on a square field and the equivalent square calculated by the area ratio correction method, a Sp value of an arbitrary rectangular field may be accurately estimated.     

Work-related allergy in medical doctors: atopy,exposure to domestic animals,eczema induced by common chemicals and membership of the surgical profession as potential risk factors

Purpose  

To investigate the risk factors associated with work-related allergy-like symptoms in medical doctors.     

Homozygous familial hypercholesterolemia in Japan

Fifty-one homozygous patients with familial hypercholesterolemia, including our six patients, are described in this paper. Twenty were men and 31 were women. Their ages ranged between two and 52 years, with a mean of 16.8 years. Six patients exceeded the third decade. The mean age at death in seven patients was 17 years. The serum cholesterol levels were between 508 and 1,108 mg/dl. The mean and standard deviation (SD) of serum cholesterol were 713 ± 142 mg/dl. The serum cholesterol levels in the 35 parents (obligate heterozygotes) were between 246 and 571 mg/dl, except in one patient in whom the serum cholesterol level (936 mg/dl) was suggestive of homozygous familial hypercholesterolemia, considering the serum cholesterol level (354 mg/dl) of her heterozygous husband. The mean and SD of serum cholesterol levels of the 34 heterozygote parents were 342 ± 79 mg/dl. The mean and SD of serum cholesterol in 119 normal subjects were 187 ± 30 mg/dl. Thus, trimodai distribution was evident in the serum cholesterol levels of normal subjects, the heterozygotes and the homozygotes in Japan. The frequency of parental consanguinity was at least 33 per cent. The frequencies of ischemic heart disease in the age groups 0–9, 10–19 and above 20 years were 25 per cent (four of 16 patients), 33 per cent (six of 18 patients) and 53 per cent (nine of 17 patients), respectively. The frequency of homozygotes in Japan was in close accordance with those of Western countries. Therefore, the treatment of hypercholesterolemia and prevention of premature coronary heart disease in familial hypercholesterolemic patients are very important problems in Japan as well as in the West.     

Effects of advanced glycation endproducts on the generation of macrophage-mediated oxidized low-density lipoprotein

Macrophages have a receptor that recognizes advanced glycation endproducts (AGE). In this study, we evaluated the effect of AGEs on the generation of macrophage-mediated oxidized low-density lipoprotein (LDL) by measuring the electrophoretic mobilities and lipid hydroperoxide (LHPO) levels of LDL. In the absence of the macrophage monolayer, the differences of the electrophoretic mobilities or LHPO levels of native (n) LDL did not differ significantly between control (c) bovine serum albumin (BSA) and those with AGE-BSA. In the presence of the macrophage monolayer, however, the difference was significant with higher levels after the incubation with AGE-BSA than with c-BSA. In the case of cLDL and glycated (g) LDL, the electrophoretic mobilities and LHPO levels of LDL after 20 h incubation with AGE-BSA in the presence of the macrophage monolayer were significantly higher than those with c-BSA. There were no significant differences, however between the electrophoretic mobilities and LHPO levels of cLDL and of gLDL. These results suggest that AGEs stimulate the generation of macrophage-mediated oxidized LDL, but do not directly stimulate the oxidative modification of gLDL.