Efficient Hydrogen-Dependent Carbon Dioxide Reduction by Escherichia coli

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Discovery of thalicthuberine as a novel antimitotic agent from nature that disrupts microtubule dynamics and induces apoptosis in prostate cancer cells

We report for the first time the mechanism of action of the natural product thalicthuberine (TH) in prostate and cervical cancer cells. TH induced a strong accumulation of LNCaP cells in mitosis, severe mitotic spindle defects, and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. However, unlike microtubule-binding drugs (vinblastine and paclitaxel), TH did not directly inhibit tubulin polymerization when tested in a cell-free system, whereas it reduced cellular microtubule polymer mass in LNCaP cells. This suggests that TH indirectly targets microtubule dynamics through inhibition of a critical regulator or tubulin-associated protein. Furthermore, TH is not a major substrate for P-glycoprotein (Pgp), which is responsible for multidrug resistance in numerous cancers, providing a rationale to further study TH in cancers with Pgp-mediated treatment resistance. The identification of TH's molecular target in future studies will be of great value to the development of TH as potential treatment of multidrug-resistant tumors.     

The disaccharide anthracycline MEN 10755 binds human serum albumin to a non-classical drug binding site

The interaction of the novel disaccharide anthracycline MEN 10755 with human serum albumin (HSA) was investigated by visible absorption and fluorescence spectroscopies and by ultrafiltration. Notably, MEN 10755 binds serum albumin far stronger than doxorubicin. Albumin binding results into a drastic quenching of the intrinsic fluorescence of MEN 10755; a binding constant of 1.1 x 10(5) was determined from fluorescence data. To localize the HSA binding site of MEN 10755 competition experiments were carried out with ligands that are selective for the different drug binding sites of the protein. No relevant competition effects were seen in the case of warfarin, diazepam and hemin, known ligands of sites I, II and III, respectively. Modest effects were observed following addition of palmitic acid that targets the several fatty acid binding sites of the protein. In contrast, extensive displacement of the bound anthracycline was achieved upon addition of ethacrinic acid. On the basis of these results, it is proposed that MEN 10755 binds serum albumin tightly to a non-canonical surface binding site for which it competes specifically with ethacrinic acid.     

Multiparameter analysis of naevi and primary melanomas identifies a subset of naevi with elevated markers of transformation

Here we have carried out a multiparameter analysis using a panel of 28 immunohistochemical markers to identify markers of transformation from benign and dysplastic naevus to primary melanoma in three separate cohorts totalling 279 lesions. We have identified a set of eight markers that distinguish naevi from melanoma. None of markers or parameters assessed differentiated benign from dysplastic naevi. Indeed, the naevi clustered tightly in terms of their immunostaining patterns whereas primary melanomas showed more diverse staining patterns. A small subset of histopathologically benign lesions had elevated levels of multiple markers associated with melanoma, suggesting that these represent naevi with an increased potential for transformation to melanoma.     

S-100 immunoreactive interdigitating cells in normal and in Down's syndrome human thymuses.

The present research deals with the localization of the interdigitating cells (IDCs) in normal and in Down's human thymuses. Eight thymic biopsy samples of normal children from 16 months to 10 1/2 years and six samples of Down's children from 2 months to 6 1/2 years were stained by the indirect immuno-peroxidase method using an anti-S-100 protein serum. IDCs are localized in the medullary zones, always numerous in all the Down's thymuses and in an age-related decreasing number in normal thymuses. The interrelationships between the physiological and pathological role of IDCs in inducing self-tolerance and T-cell activation and the numerical distribution in normal and in Down's human thymuses are discussed.     

Multiple splicing variants of cdc25B regulate G2/M progression.

Progression through G2 phase into mitosis is regulated by the activation of the mitotic cyclin/cdk complexes, which are in turn activated cdc25B and cdc25C phosphatases. Here we report that alternate splicing produces at least five variants of cdc25B, although only cdc25B2 and cdc25B3 are detectable as proteins. Analysis of these two variants shows that cdc25B2 is expressed at lower levels relative to cdc25B3 in all cell lines tested, and the expression of both increased markedly during G2 and mitosis. Overexpression of the catalytically inactive version of either cdc25B variant produced a G2 arrest implicating both in regulating G2/M progression.     

Differential inhibition by acetazolamide on carbonic anhydrase distribution in the quail kidney: a proposal for a membrane-bound isoenzyme

Summary The effects of different concentrations of acetazolamide, a specific carbonic anhydrase inhibitor, have been investigated in the quail kidney. The histochemical patterns, interpreted by means of quantitative analyses proved that 0.1 m acetazolamide inhibited the enzyme activity in all the reactive tubular segments except for distal tubules. At this site, the reaction product disappeared from the cytoplasm but strong positivity persisted at the apical surface. The luminal staining was still present at higher inhibitor concentrations up to 0.8 m acetazolamide. Under histophotometric analyses, the residual reactivity proved to be nearly the same at the increasing inhibitor concentrations assayed. The validity of the results was checked by similar investigations in other control tissues.On the basis of the properties known for carbonic anhydrase in mammalian kidney, we conclude that the luminal membrane staining in the quail distal tubules might be due to a carbonic anhydrase isoenzyme that is similar, both in affinity for acetazolamide and in intracellular localization, to the membrane-bound enzyme purified from mammalian proximal convoluted tubules.     

Renal carbonic anhydrase in the quail Coturnix coturnix japonica: I. Activity and distribution in male and female metanephros

Summary Carbonic anhydrase activity was studied in the quail metanephros by means of histochemical, histophotometrical and biochemical methods. Male and female samples were examined separately in order to show sex-related differences in enzyme activity and localization. The staining patterns revealed differential distribution of reaction product in the different, tubular segments. The initial portion of proximal tubules showed positivity on the brush border in female kidneys only.Extra situ investigations provided further evidence of sexual dimorphism resulting in higher values of enzyme activity for female than for male kidneys.In both sexes, marked staining was detected at the distal tubule level where histophotometric analysis confirmed the highest amount of reaction product. Moreover, the intracellular staining distribution at this site proved to be similar to that observed for mammalian proximal convoluted tubules.In the collecting ducts, a mosaic-like pattern was found with respect to both carbonic anhydrase staining and metachromatic properties.The functional significance of the presence of enzyme in the different renal tubules is discussed by comparison with the mammalian kidney. A model is proposed whereby the distal tubules represent the main sites of urinary acidification and bicarbonate reabsorption.     

Controlling soil-transmitted helminthiasis in pre-school-age children through preventive chemotherapy

Pre-school age children account for 10%-20% of the 2 billion people worldwide who are infected with soil-transmitted helminths (STHs): Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), and Ancylostoma duodenale/Necator americanus (hookworms). Through a systematic review of the published literature and using information collated at World Health Organization headquarters, this paper summarizes the available evidence to support the recommendation that pre-school children should be included in regular deworming programmes. The first section describes the burden of STH disease in this age group, followed by a summary of how infection impacts iron status, growth, vitamin A status, and cognitive development and how STHs may exacerbate other high mortality infections. The second section explores the safety of the drugs themselves, given alone or co-administered, drug efficacy, and the importance of safe administration. The third section provides country-based evidence to demonstrate improved health outcomes after STH treatment. The final section provides country experiences in scaling up coverage of pre-school children by using other large scale public health interventions, including vitamin A programmes, immunization campaigns, and Child Health days. The paper concludes with a number of open research questions and a summary of some of the operational challenges that still need to be addressed.     

Triple co-administration of ivermectin, albendazole and praziquantel in zanzibar: a safety study

Background

Public health interventions based on distribution of anthelminthic drugs against lymphatic filariasis (LF), onchocerciasis, soil-transmitted helminthiasis (STH) and schistosomiasis have been implemented separately to date. A better use of available resources might be facilitated by a more coordinated approach to control such infections, including the possibility of co-administering the three recommended anthelminthic drugs through a single, large-scale intervention.

Methodology/Principal Findings

Ivermectin, albendazole and praziquantel were co-administered to 5,055 children and adults living in areas endemic for LF, STH and schistosomiasis in Zanzibar, United Republic of Tanzania, during a pilot intervention aimed at elucidating and quantifying possible side-effects. Subsequently, these drugs were co-administered to about 700,000 individuals during a countrywide intervention targeting a large part of the total population of Zanzibar. Passive and active surveillance measures carried out during both interventions showed that side-effects attributable to the three drugs given at the same time were mild and self-limiting events.

Conclusions/Significance

Our data suggest that co-administration of ivermectin, albendazole and praziquantel is safe in areas where lymphatic filariasis, soil-transmitted helminthiasis and schistosomiasis are co-endemic and where several rounds of treatment with one or two drugs have been implemented in the past. Passive surveillance measures, however, should be continued and detection, management and reporting of possible side-effects should be considered a key component of any health intervention administering drugs.