Efficacy of albendazole against the whipworm Trichuris trichiura - a randomised, controlled trial

Objectives and design. To test the efficacy of albendazole against the whipworm Trichuris trichiura for  school-based deworming in the south-western Cape, South Africa. Children infected with Trichuris were  randomised to 3 doses of albendazole (400; 800 or 1 200 mg), each repeated 4 times. The boy I girl ratio was 1. A group not infected With worms was treated with placebo, creating a negative control. Subjects and setting. Pupils at a primary school serving a wineproducing area approximately 90 km east of Cape Town.Outcome measures. Trichuris cure rates and reduction in the number of eggs/gin faeces, as well as the  infection dynamics of Trichuris and Ascaris during treatment with placebo.Results. Albendazole treatment was associated with Trichuris cure rates of 23% (400 mg), 56% (800  mg) and 67% (1 200 mg) after the final treatment. The corresponding reductions in the number of eggs/g of faeces were 96.8%, 99.3% and 99.7%. Environmental pollution by human faeces was confirmed because worm egg-negative children in the placebo group became egg-positive while the study was in progress.Conclusion. The 400 mg stat dose had a low Trichuris cure rate. To repeat the dose on 2 or 3 days would  increase cost, reduce compliance and complicate management. Albendazole cannot be used in deworming programmes in South Africa because it is a Schedule 4 prescription medicine. De-scheduling is needed urgently, particularly because of high efficacy against hookworm in KwaZulu-Natal and  neighbouring countries

Trihydrophobin 1 Phosphorylation by c-Src Regulates MAPK/ERK Signaling and Cell Migration

c-Src activates Ras-MAPK/ERK signaling pathway and regulates cell migration, while trihydrophobin 1 (TH1) inhibits MAPK/ERK activation and cell migration through interaction with A-Raf and PAK1 and inhibiting their kinase activities. Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1. Further study reveals that Tyr-6 phosphorylation of TH1 reduces its inhibition on MAPK/ERK signaling, enhances c-Src mediated cell migration. Moreover, induced tyrosine phosphorylation of TH1 has been found by EGF and estrogen treatments. Taken together, our findings demonstrate a novel mechanism for the comprehensive regulation of Ras/Raf/MEK/ERK signaling and cell migration involving tyrosine phosphorylation of TH1 by c-Src

Elevated c-Src is linked to altered cell–matrix adhesion rather than proliferation in KM12C human colorectal cancer cells

Elevated expression and/or activity of c-Src, the prototype of the Src family of protein tyrosine kinases, is associated with the development of human colon cancer. However, despite the known pleiotropic effects of these kinases in promoting (a) cell growth downstream of growth factor receptors, and (b) the dynamic regulation of integrin adhesions in fibroblast model systems, their precise role in epithelial cancer cells is unknown. Here we addressed whether elevated expression and activity of cellular Src alters cell proliferation and/or cell–matrix adhesion in cancer cells from the Fidler model of colorectal metastasis. Although elevated Src correlates with ability to metastasise to the liver after intrasplenic injection, we found that this was not linked to enhanced growth, either in vitro or in vivo as sub-cutaneous tumours. However, elevated Src was associated with enhanced attachment to extracellular matrix. In addition, adhesion to fibronectin, was suppressed by agents that inhibited Src activity, while enforced elevation of Src in non-metastatic cells was sufficient to stimulate adhesion to fibronectin and enhanced assembly of adhesion complexes, without influencing cell growth. Thus, we conclude that one role of elevated Src in human colon cancer cells is to modulate integrin-dependent cell–matrix attachment and formation of adhesion structures, which may, in turn, influence cell motility and integrin-dependent cellular responses

The influence of different helminth infection phenotypes on immune responses against HIV in co-infected adults in South Africa

<p>Abstract</p> <p>Background</p> <p>The convergent distribution of the Human Immunodeficiency Virus (HIV) and helminth infections has led to the suggestion that infection with helminths exacerbates the HIV epidemic in developing countries. In South Africa, it is estimated that 57% of the population lives in poverty and carries the highest burden of both HIV and helmith infections, however, the disease interactions are under-researched.</p> <p>Methods</p> <p>We employed both coproscopy and <it>Ascaris lumbricoides</it>-specific serum IgE to increase diagnostic sensitivity and to distinguish between different helminth infection phenotypes and their effects on immune responses in HIV co-infected individuals. Coproscopy was done by formol ether and Kato Katz methods. HIV positive and negative adults were stratified according to the presence or absence of <it>A. lumbricoides </it>and/or <it>Trichuris trichuria </it>eggs with or without elevated <it>Ascaris </it>IgE. Lymphocyte subsets were phenotyped by flow cytometry. Viral loads, serum total IgE and eosinophils were also analysed. Lymphocyte activation markers (CCR5, HLA-DR, CD25, CD38 and CD71) were determined. Non parametric statistics were used to describe differences in the variables between the subgroups.</p> <p>Results</p> <p>Helminth prevalence ranged between 40%-60%. Four distinct subgroups of were identified, and this included egg positive/high <it>Ascaris</it>-specific IgE (egg⁺IgE^hi), egg positive/low IgE (egg⁺IgE^lo), egg negative/high IgE (egg^-IgE^hi) and egg negative/low IgE (egg^-IgE^lo) individuals. The egg⁺IgE^hisubgroup displayed lymphocytopenia, eosinophilia, (low CD4⁺counts in HIV^-group), high viral load (in HIV⁺group), and an activated lymphocyte profile. High <it>Ascaris </it>IgE subgroups (egg⁺IgE^hiand egg^-IgE^hi) had eosinophilia, highest viral loads, and lower CD4⁺counts in the HIV^-group). Egg excretion and low IgE (egg⁺IgE^lo) status demonstrated a modified Th₂immune profile with a relatively competent response to HIV.</p> <p>Conclusions</p> <p>People with both helminth egg excretion and high <it>Ascaris</it>-IgE levels had dysregulated immune cells, high viral loads with more immune activation. A modified Th₂helminth response in individuals with egg positive stools and low <it>Ascaris </it>IgE showed a better HIV related immune profile. Future research on helminth-HIV co-infection should include parasite-specific IgE measurements in addition to coproscopy to delineate the different response phenotypes. Helminth infection affects the immune response to HIV in some individuals with high IgE and egg excretion in stool.</p

Attachment, infidelity, and loneliness in college students involved in a romantic relationship: the role of relationship satisfaction, morbidity and prayer for partner

This study examined the mediating effects of relationship satisfaction, prayer for a partner, and morbidity in the relationship between attachment and loneliness, infidelity and loneliness, and psychological morbidity and loneliness, in college students involved in a romantic relationship. Participants were students in an introductory course on family development. This study examined only students (n = 345) who were involved in a romantic relationship. The average age of participants was 19.46 (SD = 1.92) and 25 % were males. Short-form UCLA Loneliness Scale (ULS-8), (Hays and DiMatteo in J Pers Assess 51:69–81, doi:10.1207/s15327752jpa5101_6, 1987); Relationship Satisfaction Scale (Funk and Rogge in J Fam Psychol 21:572–583, doi:10.1037/0893-3200.21.4.572, 2007); Rotterdam Symptom Checklist (De Haes et al. in Measuring the quality of life of cancer patients with the Rotterdam Symptom Checklist (RSCL): a manual, Northern Centre for Healthcare Research, Groningen, 1996); Prayer for Partner Scale, (Fincham et al. in J Pers Soc Psychol 99:649–659, doi:10.1037/a0019628, 2010); Infidelity Scale, (Drigotas et al. in J Pers Soc Psychol 77:509–524, doi:10.1037/0022-3514.77.3.509, 1999); and the Experiences in Close Relationship Scale-short form (Wei et al. in J Couns Psychol 52(4):602–614, doi:10.1037/0022-0167.52.4.602, 2005). Results showed that relationship satisfaction mediated the relationship between avoidance attachment and loneliness and between infidelity and loneliness. Physical morbidity mediated the relationship between anxious attachment and psychological morbidity. Psychological morbidity mediated the relationship between anxious attachment and physical morbidity. The present results expand the literature on attachment by presenting evidence that anxious and avoidant partners experience loneliness differently. Implications for couple’s therapy are addressed. Future research should replicate these results with older samples and married couples.Acknowledgments This research was supported by Grant Number 90FE0022 from the United States Department of Health and Human Services awarded to the last author

Grb2 monomer-dimer equilibrium determines normal versus oncogenic function

The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression

A Knockout of the Tsg101 Gene Leads to Decreased Expression of ErbB Receptor Tyrosine Kinases and Induction of Autophagy Prior to Cell Death

The Tumor Susceptibility Gene 101 (Tsg101) encodes a multi-domain protein that mediates a variety of molecular and biological processes including the trafficking and lysosomal degradation of cell surface receptors. Conventional and conditional knockout models have demonstrated an essential requirement of this gene for cell cycle progression and cell viability, but the consequences of a complete ablation of Tsg101 on intracellular processes have not been examined to date. In this study, we employed mouse embryonic fibroblasts that carry two Tsg101 conditional knockout alleles to investigate the expression of ErbB receptor tyrosine kinases as well as stress-induced intracellular processes that are known to be associated with a defect in growth and cell survival. The conditional deletion of the Tsg101 gene in this well-controlled experimental model resulted in a significant reduction in the steady-state levels of the EGFR and ErbB2 but a stress-induced elevation in the phosphorylation of mitogen activated protein (MAP) kinases independent of growth factor stimulation. As part of an integrated stress response, Tsg101-deficient cells exhibited extensive remodeling of actin filaments and greatly enlarged lysosomes that were enriched with the autophagy-related protein LC3. The increase in the transcriptional activation and expression of LC3 and its association with Lamp1-positive lysosomes in a PI3K-dependent manner suggest that Tsg101 knockout cells utilize autophagy as a survival mechanism prior to their ultimate death. Collectively, this study shows that a knockout of the Tsg101 gene causes complex intracellular changes associated with stress response and cell death. These multifaceted alterations need to be recognized as they have an impact on defining particular functions for Tsg101 in processes such as signal transduction and lysosomal/endosomal trafficking

Role of Palladin Phosphorylation by Extracellular Signal-Regulated Kinase in Cell Migration

Phosphorylation of actin-binding proteins plays a pivotal role in the remodeling of the actin cytoskeleton to regulate cell migration. Palladin is an actin-binding protein that is phosphorylated by growth factor stimulation; however, the identity of the involved protein kinases remains elusive. In this study, we report that palladin is a novel substrate of extracellular signal-regulated kinase (ERK). Suppression of ERK activation by a chemical inhibitor reduced palladin phosphorylation, and expression of active MEK alone was sufficient for phosphorylation. In addition, an in vitro kinase assay demonstrated direct palladin phosphorylation by ERK. We found that Ser77 and Ser197 are essential residues for phosphorylation. Although the phosphorylation of these residues was not required for actin cytoskeletal organization, we found that expression of non-phosphorylated palladin enhanced cell migration. Finally, we show that phosphorylation inhibits the palladin association with Abl tyrosine kinase. Taken together, our results indicate that palladin phosphorylation by ERK has an anti-migratory function, possibly by modulating interactions with molecules that regulate cell migration

FAK/src-Family Dependent Activation of the Ste20-Like Kinase SLK Is Required for Microtubule-Dependent Focal Adhesion Turnover and Cell Migration

Cell migration involves a multitude of signals that converge on cytoskeletal reorganization, essential for development, immune responses and tissue repair. Using knockdown and dominant negative approaches, we show that the microtubule-associated Ste20-like kinase SLK is required for focal adhesion turnover and cell migration downstream of the FAK/c-src complex. Our results show that SLK co-localizes with paxillin, Rac1 and the microtubules at the leading edge of migrating cells and is activated by scratch wounding. SLK activation is dependent on FAK/c-src/MAPK signaling, whereas SLK recruitment to the leading edge is src-dependent but FAK independent. Our results show that SLK represents a novel focal adhesion disassembly signal

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

BackgroundHere, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer.MethodsWe examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs.ResultsConcentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC(50) values (IC(50) range: 0.001-11.3 micromol l(-1)). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73-1.11) or paclitaxel (mean CI values, range: 0.76-1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib.ConclusionsThese data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer