A new immunosuppressant, FTY720, in canine kidney transplantation: effect of single-drug, induction and combination treatments

Three different types of treatment were conducted to clarify the properties of a novel immunomodulator, FTY720, in canine kidney allograft models. Survival, biochemical and hematological tests, pharmacokinetics, and histopathology of grafts and extra-renal organs were analyzed. Accompanying a remarkable reduction in circulating lymphocytes, single-drug treatment of FTY720, ranging from 0.05 to 10 mg/kg, exhibited significant prolongation of graft survival without a dose-dependent effect. Short-course induction with FTY720 at 5 mg/kg per day exhibited similar anti-rejection effects as did single-drug treatment but no advantage in rescuing ongoing rejection. In combination with cyclosporine (CsA; 5 mg/kg) or tacrolimus (FK; 0.5 mg/kg), FTY720 had an additive effect. Trough blood concentrations of FTY720 were linearly correlated with dose. No animal showed critical adverse effects at any point. FTY720 holds promise as a candidate in a new category of drugs that can be combined with conventional agents for induction and maintenance immunosuppression in clinical organ transplantation.     

Incidence and computed tomography findings of lenvatinib-induced pancreatobiliary inflammation: A single-center,retrospective study

In this single-center retrospective study, we intended to evaluate the frequencies and characteristics of computed tomography findings of pancreatobiliary inflammation (PBI) in patients treated with lenvatinib and the relationship of these findings with treatment-planning changes.We included 78 patients (mean ± standard deviation, 69.8 ± 9.4 years, range: 39–84 years, 62 men) with hepatocellular carcinoma (n = 62) or thyroid carcinoma (n = 16) who received lenvatinib (June 2016–September 2020). Two radiologists interpreted the posttreatment computed tomography images and assessed the radiological findings of PBI (symptomatic pancreatitis, cholecystitis, or cholangitis). The PBI effect on treatment was statistically evaluated.PBI (pancreatitis, n = 1; cholecystitis, n = 7; and cholangitis, n = 2) was diagnosed in 11.5% (9/78) of the patients at a median of 35 days after treatment initiation; 6 of 9 patients discontinued treatment because of PBI. Three cases of cholecystitis and 1 of cholangitis were accompanied by gallstones, while the other 5 were acalculous. The treatment duration was significantly shorter in patients with PBI than in those without (median: 44 days vs. 201 days, P = .02). Overall, 9 of 69 patients without PBI showed asymptomatic gallbladder subserosal edema.Lenvatinib-induced PBI developed in 11.5% of patients, leading to a significantly shorter treatment duration. Approximately 55.6% of the PBI cases were acalculous. The recognition of this phenomenon would aid physicians during treatment planning in the future.     

Pro‐angiogenic TIE‐2‐expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma

Sorafenib, a multi‐kinase inhibitor, inhibits tumor angiogenesis and is the first‐line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE‐2‐expressing monocytes (TEMs) to predict the response in sorafenib‐treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51–48.16, p = 0.015] and Child‐Pugh class (HR = 5.59, 95% CI = 1.06–29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib‐treated patients with advanced HCC.     

Serum retinol of Chadian nomadic pastoralist women in relation to their livestocks' milk retinol and beta-carotene content

Human serum retinol and livestock milk retinol levels were assessed as part of a study on the health status of Chadian nomadic pastoralists and their livestock in close partnership between Chadian public health and livestock institutions. Of the examined women (n = 99), 43% were moderately retinol-deficient (0.35 mol/L < x < 0.7 mol/L 95% CI; 33-54%), and 17% severely retinol-deficient (< 0.35 mol/L 95% CI; 10-26%). None of the interviewed women (n = 87) reported the consumption of fruit, and only two of fresh vegetables were reported consumed in the past 24 hours. Milk is the almost exclusive source of vitamin A for these populations. Goats (n = 6) had the highest average milk retinol level (329 +/- 84 micrograms/kg [mean +/- SEM]), followed by cattle (n = 25; 247 +/- 32 micrograms/kg), and camels (n = 12; 120 +/- 18 micrograms/kg). Milk retinol levels did not differ between the rainy and dry seasons. Human serum retinol depends significantly on livestock milk retinol levels (partial slope 0.23; 95% CI: 0.008-0.47). Our study supports the use of goat and cow milk as an important source of vitamin A in pastoral nomadic settings. However, the levels still require to be complemented further by promoting green leafy vegetables, fruits, and supplements.     

A novel method to quantify calcium response pattern and oscillation using fura2 and acridine orange

To study calcium imaging data of cell populations that have various response patterns in peak amplitude and frequency of calcium oscillation in response to stimulation, comprehensive characterization based on statistical analysis of each response is important. In cultures of cells that are flat and in contact with each other, it is difficult to distinguish individual cells in calcium imaging data. We have developed a novel method to determine areas corresponding to individual cells in calcium imaging data. Rat neonatal cerebral astrocytes were filled with the calcium indicator Fura2, stained with acridine orange, and illuminated with UV light. The cell nuclei were clearly visualized. In addition, the images of these nuclei were useful for analyzing concentration-dependent alteration of calcium oscillation of cultured astrocytes in response to glutamate. This novel method may be useful for studying factors affecting calcium response patterns of cultured cell populations, including culture conditions, stimulus paradigms, and synthetic compounds.     

A scoping review of evaluations of and recommendations for default uncertainty factors in human health risk assessment

Uncertainty factors (UFs) are used to account for uncertainties and variability when setting exposure limits or guidance values. Starting from a proposal of a single UF of 100 to extrapolate from an animal NOAEL to a human acceptable exposure, the aspects of uncertainty and number of UFs have diversified and today there are several risk assessment guidelines that contain schemes of default UFs of varying complexity. In the present work, we scoped the scientific literature on default UFs to map developments regarding recommendations and evaluations of these. We identified 91 publications making recommendations for one or several UFs and 55 publications evaluating UFs without making explicit recommendations about numerical values; these were published between 1954 and 2021. The 2000s was the decade with the largest number of publications, interspecies differences and intraspecies variability being the most frequent topics. The academic sector has been the most active (76 out of 146 publications). Authors from the private sector more often presented UF recommendations, but differences between sectors regarding size of recommendations were not statistically significant. The empirical underpinning of the reviewed recommendations ranges from four to 462 chemicals, that is, relatively low numbers compared with the range of chemicals these default UFs are expected to cover. The recommended UFs have remained remarkably constant, with merely a slight decrease over time. Although chemical specific UFs are preferable, the widespread use of default UFs warrants further attention regarding their empirical and normative basis.     

Molecular pathological analysis on the mechanism of liver carcinogenesis in dicyclanil-treated mice

To investigate the mechanism of hepatocarcinogenesis due to dicyclanil (DC), an insect growth regulator for sheep, histopathological and molecular biological analyses were performed in the liver of male ICR mice fed on a diet containing 1500 ppm of DC for 2 weeks (Experiment I; Exp. I). In gene expression analyses using a large-scale cDNA microarray and RT-PCR, fluctuations of expressions of metabolism-/oxidation-/reduction-related genes, such as CYP1A, aldehyde dehydrogenase family 1 subfamily A1 (Aldh1a1), and thioredoxin reductase 1 (Txnrd1), were predominantly observed in the liver of the DC-treated group. In Experiment II (Exp. II), small-scale and metabolism/oxidative stress-specific cDNA microarray, real-time RT-PCR, and measurement of NF-kappaB protein were performed in the mice liver using a two-stage hepatocarcinogenesis model, in which the male ICR mice were fed on a diet containing 1500 ppm of DC for 7 weeks after a single injection of dimethylnitrosamine (DMN). These mice were subjected to two-thirds partial hepatectomy (PH) at week 3. During histopathological examinations, a remarkable increase in gamma-glutamyltransferase-positive cells was observed in the DMN+DC+PH group. During the microarray and PCR analyses, the metabolism and oxidative stress-related genes, such as Cyp1a, P450 oxidoreductase (Por), and thioredoxin reductase 1 (Txnrd1); a few DNA damage/repair genes, such as 8-oxoguanine DNA-glycosylase 1 (Ogg1); and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a), were fluctuated in this group, together with a slight increase in the concentration of activated NF-kappaB. These results suggest that DNA damages due to oxidative stress may be involved in the mechanism of DC-induced hepatocarcinogenesis in mice.     

Possible involvement of oxidative stress in dicyclanil-induced hepatocarcinogenesis in mice

Our previous study suggested the possibilities that dicyclanil (DC), a nongenotoxic carcinogen, produces oxidative stress in the liver of the two-stage hepatocarcinogenesis model of mice and the stress induced probably causes secondary oxidative DNA damage. However, clear evidences demonstrating the relationship between DC-induced hepatocarcinogenesis, oxidative stress, and oxidative DNA damage have not been obtained. To clarify the relationship, further investigations were performed in the liver of the partially hepatectomized (PH) mice maintained on diet containing 1,500 ppm of DC for 13 and 26 weeks after intraperitoneal injection of dimethylnitrosamine (DMN). Significant increases in mRNA expressions of some metabolism- and oxidative stress-related genes with a formation of γ-glutamyltranspeptidase (GGT) positive foci were observed in the DMN + DC + PH group by the treatment of DC for 13 and 26 weeks. The levels of 8-hydroxy-deoxyguanosine (8-OHdG) in the liver DNA also significantly increased in mice of the DMN + DC + PH group at weeks 13 and 26 and mice given DC alone for 26 weeks. The in vitro measurement of reactive oxygen species (ROS) generation from the mouse liver microsomes showed a significant increase of ROS production in the presence of DC. These results suggest that DC induces oxidative stress which is probably derived from its metabolic pathway, partly, and support our previous speculation that oxidative stress plays one of the important roles in the DC-induced hepatocarcinogenesis in mice.