Are Biomphalaria snails resistant to Schistosoma mansoni?

Among Biomphalaria glabrata/Schistosoma mansoni snail-trematode combinations, it appears that some parasites succeed whilst others fail to infect snails. Snails that become infected are termed susceptible hosts. Those which are not infected are traditionally determined as 'resistant'. Here the concept of B. glabrata resistance to S. mansoni is re-examined in the light of additional observations. It is suggested that, in B. glabrata/S. mansoni, compatibility is tested independently for each individual miracidium and host, and that the success or failure of an infection does not depend on the snail susceptibility/resistance status, but on the 'matched' or 'mismatched' status of the host and parasite phenotypes.     

Intracellular distribution of tamoxifen in resistant human breast adenocarcinoma cells using tamoxifen–eosin association

A tamoxifen-resistant cell line (MCF7TAM) was established from tamoxifen-sensitive MCF-7 human breast cancer cells expressing estrogen receptors. Though the resistant cell line grows in the presence of tamoxifen, estrogen receptors continue to be expressed at similar levels as in the parental cell line. However, estrogen receptors appeared to be altered in the resistant cell line since important discrepancies are observed between results obtained with ligand binding assays and immunoenzymatic assays, tending to show modifications of estrogen receptor ligand binding capacity. The intracellular distribution of tamoxifen in sensitive and resistant cell lines was investigated using fluorescence of eosin–tamoxifen ionic association. Fluorescence emission spectra of eosin, tamoxifen and eosin–tamoxifen complex (ex = 480 nm) were analyzed and the maximal fluorescence intensity found for the complex (em = 540 nm) was four times higher than that of eosin alone, while tamoxifen alone did not emit any fluorescence in this spectral range. In MCF-7 cells, tamoxifen was found to be mainly located surrounding the nucleus, although nuclear fluorescence intensity was significantly lower. No highly fluorescent granules were observed in the resistant cell lines as opposed to sensitive cells. Improvement of this fluorescence microscopy methodology could appear of interest, taking into account the complexity of tamoxifen resistance molecular pathways.     

Are mesenchymal stromal cells from children resistant to apoptosis?

Objectives:  Mesenchymal stromal cells (MSC) represent a novel cellular candidate in the field of transplantation and tissue regeneration. Their clinical application requires their in vitro expansion. The aim of this study was to assess the effect of conditions that would favour apoptosis, and of long-term expansion, on the characteristics of MSC from children.
Materials and methods:  Bone marrow mononuclear cells were cultured for 10 passages (P1–P10). Expression of CD105, CD146, CD95 and apoptosis by 7-amino-actinomycin D staining were evaluated. CFU-F and cell doubling time (DT) were assessed in every passage. Cell-cycle study was performed at P2 and P6.
Results:  CFU-F decreased from 38 ± 3.7 at P2 to 9.6 ± 3.2 per 10 MSC/cm² at P10 and DT increased from 1.93 ± 0.1 (P2) to 6.1 ± 2.45 days (P10). A low percentage of apoptotic (dead) cells was detected at P2 and this did not change until P10. Cells at P2 were at G₀/G₁ phase, but in advanced passages more cells were in an active state. Induction of apoptosis (addition of anti-Fas agonist antibody) using standard culture conditions, showed a minor effect on MSC survival. Serum deprivation of MSC (up to 72 h) revealed no substantial apoptotic effect while cells retained their tri-lineage differentiation capacity.
Conclusions:  We conclude that MSC from children retain their functional characteristics throughout serial passages and remain stable under conditions that usually cause apoptosis. These features render MSC, especially those of early passages, optimal candidates for use in clinical applications.     

Are plant communities on the Canary Islands resistant to plant invasion?

Oceanic islands are renowned for their unique flora and high levels of endemism. Native island plants, however, are imperilled by non-native species that can become invasive by outcompeting natives. The threat of native island assemblages generally increases with isolation and the number of endemics featured, but also with human-associated disturbance and land use. Based on this, the Canary Island native plant systems should be highly threatened by invasives, similar to other oceanic islands globally. However, Canarian native plant systems are only weakly infiltrated and are rarely directly threatened by invasive plants. Further, highly disturbed areas, usually among the first colonized by invasives on islands, are recolonized here by natives. Based on this, we postulate four hypotheses (climatic filter, well-preservation status, human legacy and permanent colonization) for explaining this unusual behaviour of plant systems on the Canary Islands, providing an opportunity to understand the drivers and processes behind invasion into plant communities on islands.     

Are hERG channel blockers also phospholipidosis inducers?

Both pharmacophore models of the human ether-à-go-go-related gene (hERG) channel blockers and phospholipidosis (PLD) inducers contain a hydrophobic moiety and a hydrophilic motif/positively charged center, so it is interesting to investigate the overlap between the ligand chemical spaces of both targets. We have assayed over 4000 non-redundant drug-like compounds for both their hERG inhibitory activity and PLD inducing potential in a quantitative high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compounds identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compounds were positively charged. Among the 48 compounds that induced PLD without inhibiting hERG channel, 24 compounds (50.0%) carried steroidal structures. According to our results, hERG channel blockers and PLD inducers share a large chemical space. In addition, a positively charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker.     

Multidrug resistant to extensively drug resistant tuberculosis: What is next?

Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to at least rifampicin and isoniazid among the first line anti tubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second line anti tubercular drugs i.e. amikacin, kanamycin and/or capreomycin. Mismanagement of tuberculosis paves the way to drug resistant tuberculosis. Emergence of XDR-TB is reported world wide. Reported prevalence rates of XDR-TB of total MDR cases are; 6.6% overall worldwide, 6.5% in industrialized countries, 13.6% in Russia and Eastern Europe, 1.5% in Asia, 0.6% in Africa and Middle East and 15.4% in Republic of Korea. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory, co-morbitidy of HIV and tuberculosis, new anti-TB drug regimens, better diagnostic tests, international standards for second line drugs (SLD)-susceptibility testing, invention of newer antitubercular molecules and vaccines and knowing the real magnitude of XDR-TB are some of the important issues to be addressed for effective prevention and management of XDR-TB.     

ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells

Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca²⁺ signaling leading to tumor progression. The K⁺/Cl⁻ co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn²⁺ upregulated K⁺/Cl⁻ co-transport activity, measured using NH₄⁺ as a surrogate to K⁺ while monitoring intracellular pH. Upregulation of NH₄⁺ transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca²⁺ signaling but not in MCF-7 cells lacking this response. The NH₄⁺ transport was Na⁺-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn²⁺-dependent K⁺/Cl⁻ co-transport, suggesting that KCC3 is mediating upregulated NH₄⁺ transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn²⁺-dependent scratch closure. Thus, a novel link between KCC3 and Zn²⁺, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.     

Are traits that experience reinforcement also under sexual selection?

Where closely related species occur in sympatry, reinforcement may result in the evolution of traits involved in species recognition that are at the same time used for within-species mate choice. Drosophila serrata lives in forested habitat on the east coast of Australia, and over the northern half of its distribution it coexists with a closely related species, Drosophila birchii. Here we show that the strength of reinforcing selection in natural populations is sufficient to generate reproductive character displacement along a 36-km transect across the contact between sympatric and allopatric populations of D. serrata. The sympatric and allopatric populations display genetically based differences in male cuticular hydrocarbons (CHCs), while female CHCs changed with latitude across the contact. The directional changes observed in male CHCs between sympatric and allopatric regions were the same changes that were generated by experimental sympatry in the laboratory, providing direct evidence that the changes across the contact zone are due to the presence of D. birchii. We show that sympatric and allopatric females differ in preference for male CHCs and that females from allopatric populations prefer allopatric-like male CHCs over sympatric-like CHCs. Male attractiveness within D. serrata may therefore be compromised by reinforcing selection, preventing the spread of sympatric-like blends to the area of allopatry.     

Will tuberculosis become resistant to all antibiotics?

The discovery of high prevalences of antibiotic resistance in some pathogens, in some parts of the world, has provoked fears of a widespread loss of drug efficacy. Here, we use a mathematical model to investigate the evolution of resistance to four major anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol and streptomycin) in 47 sites around the world. The model provides a new method of estimating the relative risk of treatment failure for patients carrying drug-resistant strains and the proportion of patients who develop resistance after failing treatment. Using estimates of these two quantities together with other published data, we reconstructed the epidemic spread of isoniazid resistance over the past 50 years. The predicted median prevalence of resistance among new cases today was 7.0% (range 0.9-64.3%), close to the 6.3% (range 0-28.1%) observed. Predicted and observed prevalences of resistance to isoniazid plus rifampicin (multidrug-resistant or MDR-TB) after 30 years of combined drug use were also similar, 0.9% (0.1-5.9%) and 1.0% (range 0-14.1%), respectively. With current data, and under prevailing treatment practices, it appears that MDR-TB will remain a localized problem, rather than becoming a global obstacle to tuberculosis control. To substantiate this result, further measurements are needed of the relative fitness of drug-resistant strains.     

Are estrogen receptor content in breast cancer and effects of tamoxifen on sex hormone-binding globulin markers for individual estrogen sensitivity?

Individual women differ with respect to their sensitivity to estrogen and serum levels of sex hormone-binding globulin (SHBG) may reflect the individual response. We found a significant correlation between estrogen receptor (ER) concentrations in breast cancer tissue and SHBG levels during tamoxifen treatment. Estrogen sensitivity may be a general characteristic common to various organs and different between individual women.     

Suppression of long non-coding RNA CCAT2 improves tamoxifen-resistant breast cancer cells’ response to tamoxifen

Breast cancer is one of the most common cancers in women worldwide. Tamoxifen (TAM) provided a successful treatment for ER-positive (ER+) breast cancer for many years. However, ER+ patients with metastatic diseases respond poorly to TAM therapy and many initial responders eventually relapse. Emerging evidence indicates that long non-coding RNAs (lncRNAs) may have a critical role in the regulation of cellular processes such as cancer progression and metastasis, though the function of lncRNAs in TAM-resistance is still unclear. To investigate the role of CCAT2 in the development of resistance to TAM treatment of breast cancer, we established TAM-resistant models in MCF-7 and T47D cells. The present study demonstrates that TAM-resistant cells show a higher level of CCAT2 expression compared with TAM-sensitive cells. Biologically, CCAT2 knockdown could inhibit proliferation and induce apoptosis in TAM-resistant cells exposed to TAM. Furthermore, knockdown of CCAT2 improves the sensitivity to TAM in TAM-resistant cells. Overall, the study results provide a novel therapeutic approach for TAM-resistant patients through depleting CCAT2 expression.     

Why is Deinococcus radiodurans so resistant to ionizing radiation?

When exponential-phase cultures of Deinococcus radiodurans are exposed to a 5000-Gray dose of gamma radiation, individual cells suffer massive DNA damage. Despite this insult to their genetic integrity, these cells survive without loss of viability or evidence of mutation, repairing the damage by as-yet-poorly-understood mechanisms.     

Are aromatase inhibitors superior to antiestrogens?

Aromatase inhibitors (AIs) have been in use to treat metastatic breast cancer for over 25 years. Recently potent and specific AIs have been introduced, which, because of their low toxicity profile, are being used in the adjuvant and neoadjuvant situation and also for the prevention of breast cancer. The two non-steroidal AIs, anastrozole and letrozole, and the steroidal AI, exemestane, have all shown superiority to tamoxifen as first-line treatment for advanced breast cancer. Interestingly, the oestrogen receptor downregulator, fulvestrant, was shown to be equivalent to anastrozole when compared as second-line therapy after the failure of tamoxifen. The first adjuvant AI trial began in 1996 and recruited over 9000 patients (ATAC trial). Anastrozole was compared with tamoxifen and a combination of the two drugs. There were no significant differences between tamoxifen and the combination. However, anastrozole showed about a 20% improvement in disease-free survival in ER+ disease compared with the other treatments. An overall survival analysis will be reported later this year. Two trials have compared 5 years of tamoxifen with 2–3 years of tamoxifen, followed by 2–3 years of AI (one trial (ITA) used anastrozole and another (intergroup) exemestane). Both trials show a disease-free advantage for the switch to AI. In another study (MA17) 5 years of tamoxifen was followed by a randomisation to letrozole or placebo and showed a significant disease-free advantage to the AI. Both letrozole and anastrozole show superiority to tamoxifen when used as a neoadjuvant therapy. Anastrozole significantly reduced contralateral breast cancer compared with tamoxifen, and this has led to two prevention trials: one in women at risk comparing anastrozole with placebo and the other after excision of DCIS comparing anastrozole with tamoxifen (IBIS II). The NCI Canada has also just initiated a trial of exemestane for prevention. Nearly all data available indicate that AIs are superior to tamoxifen. The important question is whether survival is improved when they are used as adjuvant therapy?