Inflammatory monocytes have been shown to play key roles in cancer metastasis through promotion of tumor cell extravasation, growth, and angiogenesis. Monocyte recruitment to metastases is mediated ...primarily via the CCL2-CCR2 chemotactic axis. Thus, disruption of this axis represents an attractive therapeutic target for the treatment of metastatic disease. Losartan, a type I angiotensin II receptor (AT1R) antagonist, has been previously shown to have immunomodulatory actions involving monocyte and macrophage activity. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, we investigated the effects of losartan and its primary metabolite on CCL2-mediated monocyte recruitment and CCR2 receptor function using mouse tumor models and in vitro human monocyte cultures. We show, in this study, that losartan and its metabolite potently inhibit monocyte recruitment through the noncompetitive inhibition of CCL2-induced ERK1/2 activation, independent of AT1R activity. Studies in experimental metastasis models demonstrated that losartan treatment significantly reduced the metastatic burden in mice, an effect associated with a significant decrease in CD11b
/Ly6C
-recruited monocytes in the lungs. Collectively, these results indicate that losartan can exert antimetastatic activity by inhibiting CCR2 signaling and suppressing monocyte recruitment and therefore suggest that losartan (and potentially other AT1R blocker drugs) could be repurposed for use in cancer immunotherapy.
We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSCs) for the formation of signaling complexes, including NFκB, p38MAPK and JNK, that are involved in ...the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSCs that are key contributors to multiple myeloma bone disease (MMBD), and demonstrated that the ZZ domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, which inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study, we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2's capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of tumor necrosis factor alpha (TNFα), an osteoblast (OB) differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.
Many chemical substances of natural or anthropogenic origin are suspected or known to be endocrine disruptors, which can influence the endocrine system of life. This observation has led to increased ...interest on the part of the public and the media, as well as to a steep rise of research activities in the scientific community. New papers and results are presented so fast that it is impossible to give a complete review of this emerging research field. Therefore, this paper tries to give insight into some topics of the great scope of endocrine disruptors in the environment. To get a general idea of the biochemical and biological background, some parts of the endocrine systems of mammalians and nonmammalians are explained. The sections that follow describe important mechanisms of endocrine disruption such as interactions with hormone receptors. Test strategies for anthropogenic chemicals on various organisms are critically reviewed with respect to their problems and gaps concerning endocrine disruptors. The main emphasis of the paper is on the chemical substances suspected or known to be endocrine disruptors. To get a better comprehension of their behavior in the environment, physicochemical data such as water solubility or K
, as well as information about their use and/or function are reviewed and compared. The main routes of exposure for most chemicals are shortly described, and data about concentrations in the environment (soil/sediment, water) are detailed.
In order to evaluate an indoor airflow, which may cause the spread of viruses, it is effective to measure the speed and direction of the airflow using several accurately evaluated anemometers. ...However, since calibration of anemometers is a time-consuming task, so the authors developed a compact wind tunnel that can evaluate the accuracy of anemometers in a short amount of time. The design concept and performance of the wind tunnel are described by several indices, including averaging time, settling time, spatial distribution, and blockage effect. These results demonstrate the capability of the wind tunnel to evaluate several anemometers in a short measurement time with sufficiently high precision.
The condition of mtDNA in hair shafts preserved in a museum was examined using 30 study skins of masked palm civets, Paguma larvata (Viverridae), collected between 1924 and 2011. Comparisons of ...extracts from fresh and burnt alum-fixed hair shafts showed that burnt alum, which is commonly used in taxidermy, had no harmful effect on the amount of total DNA and lengths of the mtDNA fragments. Burnt alum-fixed hair shafts had a tendency to develop a small degree of melanin hindering PCR amplification compared with fresh hair shafts, although that observation was not supported statistically (Wilcoxon signed-rank test, Z = -0.183, P = 0.855). However, the amount of total DNA decreased after preparation of specimen in an exponential relation (regression of log DNA amount with year, regression analysis, F = 7.065, P = 0.013). Nevertheless, the oldest specimen, collected in 1924, yielded 1341.5 ng of DNA per 100 hair shafts, which was sufficient for PCR amplification. In addition, the mtDNA fragment length and amount of melanin in the hair shaft were not significantly correlated with the passage of time after preparation (F = 0.244, P = 0.625 for mtDNA fragment length; F = 0.039, P = 0.845 for the amount of melanin). Therefore, hair shafts prepared and preserved by chemical treatment in museums are good sources of mtDNA and useful for genetic analysis.
A total of 62 skulls from two herds of melon‐headed whales stranded on Japanese coasts were examined. Although the species originally had around 22 teeth in each tooth row, older specimens ...(30–35 years old) possessed only an average of 9.2 teeth on each side of the upper jaw. Significant shortening of the root caused the tooth loss observed in this species. In addition, we observed the following trends with respect to the pattern of tooth loss: (1) teeth are lost from the posterior to the anterior part of the tooth row, (2) the loss of teeth in the upper jaw precedes that in the lower jaw, and (3) tooth count decreases with age. The above‐mentioned tendencies were found in both herds. Bony tissues at the alveoli seem to push out the teeth: the bottom of the tooth socket rises both during the root‐shortening process and after the tooth falls out. There were no signs of accidental tooth loss such as resorption of alveolar bones due to gingival disease or injuries on alveolar bones by physical impacts. Therefore, the postnatal tooth count decrease is considered an ontogenetic event of this species. The ontogenetic decrease in tooth count coincides with the tendency of evolutionary tooth number reduction in odontocetes at two particular points, the secondary reduction from polyodontia and the more progressed decrease in teeth in the upper jaw than in the lower jaw. Therefore, the evolutionary tooth count reduction seems to be repeated in the lifetime of the melon‐headed whale.
A total of 62 skulls from two herds of melon‐headed whales stranded on Japanese coasts were examined. Although they originally have around 22 teeth in each tooth row, older specimens (30–35 years old) possessed only an average of 9.2 teeth on each side of the upper jaw. The ontogenetic decrease in tooth count coincides with the tendency of evolutionary tooth number reduction in odontocetes at two particular points, the secondary reduction from polyodontia and the more progressed decrease in teeth in the upper jaw than in the lower jaw. Therefore, the evolutionary tooth count reduction seems to be repeated in the lifetime of the melon‐headed whale.
National governments introduced residue limits and guideline levels for pesticide residues in water when policies were implemented to minimize the contamination of ground and surface waters. ...Initially, the main attention was given to drinking water.
Regulatory limits for pesticide residues in waters should have the following characteristics: definition of the type of water, definition of the residue, a suitable analytical method for the residues, and explanation for the basis for each limit.
Limits may be derived by applying a safety factor to a no-effect-level, or from levels occurring when good practices are followed and also passing a safety assessment, or from the detection limit of an analytical method, or directly by legislative decision.
The basis for limits and guideline values issued by WHO, Australia, the United States, New Zealand, Japan, Canada, European Union, and Taiwan is described, and examples of the limits are provided. Limits have been most commonly developed for drinking water, but values have also been proposed for environmental waters, effluent waters, irrigation waters, and livestock drinking waters. The contamination of ground water is of concern because it may be used as drinking water and act as a source of contamination for surface waters. Most commonly, drinking water standards have been applied to ground water.
The same terminology may have different meanings in different systems. For example, guideline value (GV) in WHO means a value calculated from a toxicology parameter, whereas in Australia, a GV is at or about the analytical limit of determination or a maximum level that might occur if good practices are followed. In New Zealand, the GV is the concentration where aesthetic significance is influenced.The Australian health value (HV) is conceptually the same as the WHO GV. The New Zealand maximum acceptable value (MAV) and the Canadian maximum acceptable concentration (MAC) are also conceptually the same as the WHO GV.
Each of the possible ways of defining the residues has its merits. A residue limit in water expressed as the sum of parent and toxicologically relevant transformation products makes sense where it is derived from the acceptable daily intake (ADI). For monitoring purposes, where it is best to keep the residue definition as simple as possible for the sake of practical enforcement and economy, theparent or a marker residue is preferable. It is also possible for parent and degradation products (hydrolysis and photolysis products and metabolites) to become physically separated as the water moves through soil strata, which suggests that separate limits should be set for parent and important degradation products.
The Commission has made 12 recommendations for regulatory limits for pesticide residues in water. The recommendations will act as a checklist for authorities introducing or revising limits or guidelines for pesticide residues in water.
Although leprosy is curable with drug treatment, the identification of biomarkers of infection, disease progression and treatment efficacy would greatly help to reduce the overall prevalence of the ...disease. Reliable biomarkers would also reduce the incidence of grade-2 disability by ensuring that those who are most at risk are diagnosed and treated early or offered repeated treatments in the case of relapse. In this study, we examined the reactivity of sera from lepromatous and tuberculoid leprosy patients (LPs) against a panel of 12 recombinant Mycobacterium leprae proteins and found that six proteins were strongly recognised by multibacillary (MB) patients, while only three were consistently recognised by paucibacillary patients. To better understand the dynamics of patient antibody responses during and after drug therapy, we measured antibody titres to four recombinant proteins, phenolic glycolipid-I and lipoarabinomannan at baseline and up to two years after diagnosis to investigate the temporal changes in the antibody titres. Reactivity patterns to individual antigens and decreases in antibody titres were patient-specific. Antibody titres to proteins declined more rapidly vs. those to carbohydrate and glycolipid antigens. Compared to baseline values, increases in antibody titres were observed during reactional episodes in one individual. Additionally, antibody responses against a subset of antigens that provided a good prognostic indicator of disease progression were analysed in 51 household contacts of MB index cases for up to two years. Although the majority of these contacts showed no change or exhibited decreases in antibody titres, seven individuals developed higher titres towards one or more of these antigens and one individual with progressively higher titres was diagnosed with borderline lepromatous leprosy 19 months after enrolment. The results of this study indicate that antibody titres to specific M. leprae antigens can be used to monitor treatment efficacy in LPs and assess disease progression in those most at risk for developing this disease.
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