A prostate cancer vaccine comprising whole cells secreting IL-7, effective against subcutaneous challenge,requires local GM-CSF for intra-prostatic efficacy

A panel of cytokine-secreting RM-9 prostate cancer cells were tested as whole cell vaccines to determine their capacity to evoke an anti-prostate cancer immune response. In our model, vaccines secreting mGM-CSF or mIL-7 resulted in the highest increase in circulating T lymphocytes after vaccination, prolonged survival and, in a proportion of animals, tumor-free survival. Anti-tumor effects were more evident after a subcutaneous RM-9 challenge than after an intraprostatic challenge. However, when the RM-9/mGM-CSF cell line was used as intraprostatic tumor challenge, protection after RM-9/mIL-7 vaccination was restored.     

Using invasion theory to predict the fate of arbuscular mycorrhizal fungal inoculants

The agricultural use of commercial “biofertilizers” containing arbuscular mycorrhizal (AM) fungi, obligate symbionts that help plants take up nutrients, has resulted in the global introduction of AM fungi to non-native environments. Despite their growing use and evidence for endemism among AM fungi, the risk of AM fungi becoming invasive through “biofertilizer” application has not been studied in the context of general invasion theory. Understanding their dispersal by multiple vectors and in different environments is key to understanding how quickly they could spread. In this review, we consider the risk of invasion by commercial AM fungi in terms of a theoretical framework. We propose traits that make an isolate good for use as a commercial product, such competitiveness and high sporulation rate, may also increase invasiveness.     

Decreased frequency of cytomegalovirus (CMV)-specific CD4+ T lymphocytes in simian immunodeficiency virus-infected rhesus macaques: inverse relationship with CMV viremia

The frequency of cytomegalovirus (CMV)-specific CD4+ T lymphocytes was determined in CMV-seropositive rhesus macaques with or without simian immunodeficiency virus (SIV) infection by using the sensitive assays of intracellular cytokine staining and gamma interferon ELISPOT. Both techniques yielded 3- to 1,000-fold-higher frequencies of CMV-specific CD4+ T lymphocytes than traditional proliferative limiting dilution assays. The median frequency of CMV-specific CD4+ T lymphocytes in 23 CMV-seropositive SIV-negative macaques was 0.63% (range, 0.16 to 5.8%). The majority of CMV-specific CD4+ T lymphocytes were CD95(pos) and CD27(lo) but expressed variable levels of CD45RA. A significant reduction (P < 0.05) in the frequency of CMV-specific CD4+ T lymphocytes was observed in pathogenic SIV-infected macaques but not in macaques infected with live attenuated strains of SIV. CMV-specific CD4+ T lymphocytes were not detected in six of nine pathogenic SIV-infected rhesus macaques. CMV DNA was detected in the plasma of four of six of these macaques but in no animal with detectable CMV-specific CD4+ T lymphocytes. In pathogenic SIV-infected macaques, loss of CMV-specific CD4+ T lymphocytes was not predicted by the severity of CD4+ T lymphocytopenia. Neither was it predicted by the pre-SIV infection frequencies of CD45RA(neg) or CCR5(pos) CMV-specific CD4+ T lymphocytes. However, the magnitude of activation, as evidenced by the intensity of CD40L expression on CMV-specific CD4+ T lymphocytes pre-SIV infection, was three- to sevenfold greater in the two macaques that subsequently lost these cells after SIV infection than in the two macaques that retained CMV-specific CD4+ T lymphocytes post-SIV infection. Future longitudinal studies with these techniques will facilitate the study of CMV pathogenesis in AIDS.     

Do Price Subsidies on Artemisinin Combination Therapy for Malaria Increase Household Use?: Evidence from a Repeated Cross-Sectional Study in Remote Regions of Tanzania

Background

The Affordable Medicines Facility-malaria (AMFm) is a pilot program that uses price subsidies to increase access to Artemisinin Combination Therapies (ACTs), currently the most effective malaria treatment. Recent evidence suggests that availability and affordability of ACTs in retail sector drug shops (where many people treat malaria) has increased under the AMFm, but it is unclear whether household level ACT use has increased.

Methods and Findings

Household surveys were conducted in two remote regions of Tanzania (Mtwara and Rukwa) in three waves: March 2011, December 2011 and March 2012, corresponding to 3, 13 and 16 months into the AMFm implementation respectively. Information about suspected malaria episodes including treatment location and medications taken was collected. Respondents were also asked about antimalarial preferences and perceptions about the availability of these medications. Significant increases in ACT use, preference and perceived availability were found between Rounds 1 and 3 though not for all measures between Rounds 1 and 2. ACT use among suspected malaria episodes was 51.1% in March 2011 and increased by 10.9 percentage points by Round 3 (p = .017). The greatest increase was among retail sector patients, where ACT use increased from 31% in Round 1 to 49% in Round 2 (p = .037) and to 61% (p<.0001) by Round 3. The fraction of suspected malaria episodes treated in the retail sector increased from 30.2% in Round 1 to 46.7% in Round 3 (p = .0009), mostly due to a decrease in patients who sought no treatment at all. No significant changes in public sector treatment seeking were found.

Conclusions

The AMFm has led to significant increases in ACT use for suspected malaria, especially in the retail sector. No evidence is found supporting the concerns that the AMFm would crowd out public sector treatment or neglect patients in remote areas and from low SES groups.     

The high affinity K+ transporter AtHAK5 plays a physiological role in planta at very low K+ concentrations and provides a caesium uptake pathway in Arabidopsis

Caesium (Cs⁺) is a potentially toxic mineral element that isreleased into the environment and taken up by plants. AlthoughCs⁺ is chemically similar to potassium (K⁺), and much is knownabout K⁺ transport mechanisms, it is not clear through whichK⁺ transport mechanisms Cs⁺ is taken up by plant roots. In thisstudy, the role of AtHAK5 in high affinity K⁺ and Cs⁺ uptakewas characterized. It is demonstrated that AtHAK5 is localizedto the plasma membrane under conditions of K⁺ deprivation, whenit is expressed. Growth analysis showed that AtHAK5 plays arole during severe K⁺ deprivation. Under K⁺-deficient conditionsin the presence of Cs⁺, Arabidopsis seedlings lacking AtHAK5had increased inhibition of root growth and lower Cs⁺ accumulation,and significantly higher leaf chlorophyll concentrations thanwild type. These data indicate that, in addition to transportingK⁺ in planta, AtHAK5 also transports Cs⁺. Further experimentsshowed that AtHAK5 mediated Cs⁺ uptake into yeast cells andthat, although the K⁺ deficiency-induced expression of AtHAK5was inhibited by low concentrations of NH     

Cesium toxicity in Arabidopsis

Cesium (Cs) is chemically similar to potassium (K). However, although K is an essential element, Cs is toxic to plants. Two contrasting hypotheses to explain Cs toxicity have been proposed: (1) extracellular Cs+ prevents K+ uptake and, thereby, induces K starvation; and (2) intracellular Cs+ interacts with vital K(+)-binding sites in proteins, either competitively or noncompetitively, impairing their activities. We tested these hypotheses with Arabidopsis (Arabidopsis thaliana). Increasing the Cs concentration in the agar ([Cs](agar)) on which Arabidopsis were grown reduced shoot growth. Increasing the K concentration in the agar ([K](agar)) increased the [Cs](agar) at which Cs toxicity was observed. However, although increasing [Cs](agar) reduced shoot K concentration ([K](shoot)), the decrease in shoot growth appeared unrelated to [K](shoot) per se. Furthermore, the changes in gene expression in Cs-intoxicated plants differed from those of K-starved plants, suggesting that Cs intoxication was not perceived genetically solely as K starvation. In addition to reducing [K](shoot), increasing [Cs](agar) also increased shoot Cs concentration ([Cs](shoot)), but shoot growth appeared unrelated to [Cs](shoot) per se. The relationship between shoot growth and [Cs](shoot)/[K](shoot) suggested that, at a nontoxic [Cs](shoot), growth was determined by [K](shoot) but that the growth of Cs-intoxicated plants was related to the [Cs](shoot)/[K](shoot) quotient. This is consistent with Cs intoxication resulting from competition between K+ and Cs+ for K(+)-binding sites on essential proteins.     

My Hand or Yours? Markedly Different Sensitivity to Egocentric and Allocentric Views in the Hand Laterality Task

In the hand laterality task participants judge the handedness of visually presented stimuli--images of hands shown in a variety of postures and views--and indicate whether they perceive a right or left hand. The task engages kinaesthetic and sensorimotor processes and is considered a standard example of motor imagery. However, in this study we find that while motor imagery holds across egocentric views of the stimuli (where the hands are likely to be one's own), it does not appear to hold across allocentric views (where the hands are likely to be another person's). First, we find that psychophysical sensitivity, d', is clearly demarcated between egocentric and allocentric views, being high for the former and low for the latter. Secondly, using mixed effects methods to analyse the chronometric data, we find high positive correlation between response times across egocentric views, suggesting a common use of motor imagery across these views. Correlations are, however, considerably lower between egocentric and allocentric views, suggesting a switch from motor imagery across these perspectives. We relate these findings to research showing that the extrastriate body area discriminates egocentric ('self') and allocentric ('other') views of the human body and of body parts, including hands.     

Activation of c-MET induces a stem-like phenotype in human prostate cancer

Prostate cancer consists of secretory cells and a population of immature cells. The function of immature cells and their mutual relation with secretory cells are still poorly understood. Immature cells either have a hierarchical relation to secretory cells (stem cell model) or represent an inducible population emerging upon appropriate stimulation of differentiated cells. Hepatocyte Growth Factor (HGF) receptor c-MET is specifically expressed in immature prostate cells. Our objective is to determine the role of immature cells in prostate cancer by analysis of the HGF/c-MET pathway.Gene-expression profiling of DU145 prostate cancer cells stimulated with HGF revealed induction of a molecular signature associated with stem cells, characterized by up-regulation of CD49b, CD49f, CD44 and SOX9, and down-regulation of CD24 ('stem-like signature'). We confirmed the acquisition of a stem-like phenotype by quantitative PCR, FACS analysis and Western blotting. Further, HGF led to activation of the stem cell related Notch pathway by up-regulation of its ligands Jagged-1 and Delta-like 4. Small molecules SU11274 and PHA665752 targeting c-MET activity were both able to block the molecular and biologic effects of HGF. Knock-down of c-MET by shRNA infection resulted in significant reduction and delay of orthotopic tumour-formation in male NMRI mice. Immunohistochemical analysis in prostatectomies revealed significant enrichment of c-MET positive cells at the invasive front, and demonstrated co-expression of c-MET with stem-like markers CD49b and CD49f.In conclusion, activation of c-MET in prostate cancer cells induced a stem-like phenotype, indicating a dynamic relation between differentiated and stem-like cells in this malignancy. Its mediation of efficient tumour-formation in vivo and predominant receptor expression at the invasive front implicate that c-MET regulates tumour infiltration in surrounding tissues putatively by acquisition of a stem-like phenotype.