Histopathological effects of cisplatin,doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats

Cisplatin, doxorubicin and fluorouracil (5-FU), drugs belonging to different chemical classes, have been extensively used for chemotherapy of various cancers. Despite extensive investigations into their hepatotoxicity, there is very limited information on their effects on the structure and ultra-structure of liver cells in vivo. Here, we demonstrate for the first time, the effects of these three anticancer drugs on rat liver toxicity using both light and electron microscopy. Light microscopic observations revealed that higher doses of cisplatin and doxorubicin caused massive hepatotoxicity compared to 5-FU treatment, including dissolution of hepatic cords, focal inflammation and necrotic tissues. Interestingly, low doses also exhibited abnormal changes, including periportal fibrosis, degeneration of hepatic cords and increased apoptosis. These changes were confirmed at ultrastructural level, including vesiculated rough endoplasmic reticulum and atrophied mitochondria with ill-differentiated cisternae, dense collection of macrophages and lymphocytes as well as fibrocytes with collagenous fibrils manifesting early sign of fibrosis, especially in response to cisplatin and doxorubicin -treatment. Our results provide in vivo evidence, at ultrastructural level, of direct hepatotoxicity caused by cisplatin, doxorubicin and 5-FU at both light and electron microscopi. These results can guide the design of appropriate treatment regimen to reduce the hepatotoxic effects of these anticancer drugs.     

Mutations in the INK4a/ARF melanoma susceptibility locus functionally impair p14ARF

The INK4a/ARF locus encodes two cell cycle regulatory proteins, the cyclin-dependent kinase inhibitor, p16(INK4a), and the p53 activator, p14(ARF). Germline mutations in this locus are associated with melanoma susceptibility in 20-40% of multiple case melanoma families. Many of these mutations specifically impair p16(INK4a), whereas mutations uniquely targeting p14(ARF) are rare. Nevertheless, the importance of p14(ARF) has not been excluded because more than 40% of INK4a/ARF alterations affect p16(INK4a) and p14(ARF). We now report that p14(ARF) is functionally impaired in melanoma kindreds carrying INK4a/ARF mutations. Of the seven INK4a/ARF mutations tested, three altered the subcellular distribution of p14(ARF) and diminished the ability of p14(ARF) to activate the p53 pathway. This work establishes the importance of p14(ARF) in melanoma predisposition.     

The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue

Introduction  

Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients share many similarities with transformed cancer cells, including spontaneous production of matrix metalloproteinases (MMPs). Altered or chronic activation of proto-oncogenic Ras family GTPases is thought to contribute to inflammation and joint destruction in RA, and abrogation of Ras family signaling is therapeutic in animal models of RA. Recently, expression and post-translational modification of Ras guanine nucleotide releasing factor 1 (RasGRF1) was found to contribute to spontaneous MMP production in melanoma cancer cells. Here, we examine the potential relationship between RasGRF1 expression and MMP production in RA, reactive arthritis, and inflammatory osteoarthritis synovial tissue and FLS.     

Interactions among stressors may be weak: Implications for management of freshwater macroinvertebrate communities

Aim

Ecological models that do not account for interactions among stressors, if interactions are important, could be inaccurate and lead to inefficient conservation strategies. Conversely, if interactions are not important (i.e., stressors operate largely independently), then actions concentrating on a stressor‐by‐stressor basis would be warranted. Here, we investigated whether interactions among multiple stressors affected widely used indices of freshwater macroinvertebrate biodiversity, which are sensitive to environmental change at management‐relevant scales (i.e., reaches and catchments).

Location

State of Victoria, south‐eastern Australia.

Methods

We used a 7,418‐sample dataset for stream macroinvertebrates from 2,165 sites distributed over 237,630 km² for 20 years. We calculated the interactive effects on stream macroinvertebrates of stressors operating at different scales, namely vegetation loss at the catchment and reach scales and hydrological change and salinization at the local scale. The importance of interactions among multiple stressors was assessed by comparing the cross‐validated predictive performance of models with and without multiple stressor interaction terms.

Results

Cross‐validated models explained 31%–63% of the variation in the macroinvertebrate responses. The most important stressors were catchment vegetation loss (the proportion of remaining native vegetation cover) and salinity. The inclusion of interaction terms did not increase cross‐validated predictive performance, which indicates that there was little evidence that interactions among stressors were important for explaining variation in commonly used freshwater macroinvertebrate condition indices.

Main conclusions

Interactions among vegetation, salinity and hydrological change stressors may not always be of importance for determining patterns of stream macroinvertebrate biodiversity, so that such interactions may not necessarily be critical considerations for catchment and reach scale management, at least if based on these or comparable condition indices. The mitigation of the impacts of vegetation loss, salinization and hydrological change stressors one‐by‐one probably is sufficient to guide conservation activities and might be advantageous if socio‐political contexts make it difficult to address interactions among stressors.

     

Molecular oncogenetics of metastasis

Metastasis is a complex non-stochastic process that is most likely the result of genetic and epigenetic interactions of a wide variety of genes. The search for a single gene which can encompass such a pleiotropic response as to account for the observed phenotypic characteristics of metastatic tumour populations has been unsuccessful. Particular studies involving gene transfection, subtractive hybridisation and cell fusion are beginning to identify specific genes which contribute to metastasis in some cell types. However, such analyses are complicated by the inherent genetic instability and phenotypic heterogeneity present in tumour populations. A more detailed understanding of the metastatic process may require an abandoning of current generalised approaches to metastasis in favour of concentrating on key components of the metastatic cascade such as adhesion and invasion.     

Global scale variation in the salinity sensitivity of riverine macroinvertebrates: eastern Australia, France, Israel and South Africa

Salinity is a key abiotic property of inland waters; it has a major influence on biotic communities and is affected by many natural and anthropogenic processes. Salinity of inland waters tends to increase with aridity, and biota of inland waters may have evolved greater salt tolerance in more arid regions. Here we compare the sensitivity of stream macroinvertebrate species to salinity from a relatively wet region in France (Lorraine and Brittany) to that in three relatively arid regions eastern Australia (Victoria, Queensland and Tasmania), South Africa (south-east of the Eastern Cape Province) and Israel using the identical experimental method in all locations. The species whose salinity tolerance was tested, were somewhat more salt tolerant in eastern Australia and South Africa than France, with those in Israel being intermediate. However, by far the greatest source of variation in species sensitivity was between taxonomic groups (Order and Class) and not between the regions. We used a bayesian statistical model to estimate the species sensitivity distributions (SSDs) for salinity in eastern Australia and France adjusting for the assemblages of species in these regions. The assemblage in France was slightly more salinity sensitive than that in eastern Australia. We therefore suggest that regional salinity sensitivity is therefore likely to depend most on the taxonomic composition of respective macroinvertebrate assemblages. On this basis it would be possible to screen rivers globally for risk from salinisation.     

Effects of different ionic compositions on survival and growth of <Emphasis Type="Italic">Physa acuta</Emphasis>

Most inland saline waters in southern Australia predominantly contain Na⁺ and Cl⁻ as major ions. The proportions of Ca²⁺, Mg²⁺, SO₄ ²⁻, HCO₃ ⁻ and CO₃ ²⁻ in these waters somewhat vary and might influence salinity tolerance of freshwater organisms. Here the salinity stress of five ionic compositions to the freshwater snail Physa acuta Draparnaud (Gastropoda: Physidae) was compared: commercial sea salt Ocean Nature (ON), synthetic Ocean Nature (ONS) and three saline water types that are common in southern Australia (ONS but without [1]: SO₄ ²⁻, HCO₃ ⁻ and CO₃ ²⁻, [2]: Ca²⁺, HCO₃ ⁻ and CO₃ ²⁻, [3]: Ca²⁺, Mg²⁺), Milli-Q water was used as a negative control. The 96-h LC₅₀ values for all treatments did not differ. However in prolonged sub-lethal exposures, results varied depending on the ionic composition. Growth was negative and shell strength reduced in treatments lacking Ca. Though the content of major cationic elements (Ca, Mg, Na and K) did not differ per unit dry weight of snail across the treatments, the total load of these elements per individual snail varied among treatments. Furthermore, at the sub-lethal salinities tested, 1 and 5 mS cm⁻¹, ionic compositions had more effect on the snail’s growth than salinity. The long-term effects on freshwater animals, especially taxa with calcium-based exoskeletons, from exposure to common saline water types with low calcium concentrations will likely be greater than from exposure to saline waters with an ionic composition similar to seawater.     

Retardation of leaf senescence by urea cytokinins in Raphanus sativus

Approximately 500 urea derivatives and related compounds were tested for ability to retard leaf senescence as measured by chlorophyll retention in radish (Raphanus sativus) leaf discs. Of the 90 compounds found to be active, some had activity at 10^?6 M of the same order as kinetin. There was a high correlation between ability to promote chlorophyll retention and initiation of cell division. Highly active compounds had a planar ring and a HNCONH bridge; substitution with a HNCSNH bridge reduced activity and all other tested arrangements of the bridge gave inactive compounds. Substitution of both amino hydrogen atoms on one or both sides of the bridge reduced or removed activity. Some N′-substituted phenyl ureas were highly active. Introduction of a N-phenyl ring to a N-phenyl urea increased activity except where one ring was substituted in the para position with chloro, bromo or iodo. The activities of symmetrical disubstituted ureas were generally less than the corresponding N-monosubstituted derivative. The results suggest that the receptor site for cytokinin activity is the same for senescence retadation and cell division initiation.