The macrofilaricidal efficacy of repeated doses of ivermectin for the treatment of river blindness

Background: Mass drug administration (MDA) with ivermectin is the cornerstone of efforts to eliminate human onchocerciasis by 2020 or 2025. The feasibility of elimination crucially depends on the effects of multiple ivermectin doses on Onchocerca volvulus. A single ivermectin (standard) dose clears the skin-dwelling microfilarial progeny of adult worms (macrofilariae) and temporarily impedes the release of such progeny by female macrofilariae, but a macrofilaricidal effect has been deemed minimal. Multiple doses of ivermectin may cumulatively and permanently reduce the fertility and shorten the lifespan of adult females. However, rigorous quantification of these effects necessitates interrogating longitudinal data on macrofilariae with suitably powerful analytical techniques. Methods: Using a novel mathematical modeling approach, we analyzed, at an individual participant level, longitudinal data on viability and fertility of female worms from the single most comprehensive multiple-dose clinical trial of ivermectin, comparing 3-monthly with annual treatments administered for 3 years in Cameroon

Head and Neck Cancer Tumor Segmentation Using Support Vector Machine in Dynamic Contrast-Enhanced MRI

Objective. We aimed to propose an automatic method based on Support Vector Machine (SVM) and Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) to segment the tumor lesions of head and neck cancer (HNC). Materials and Methods. 120 DCE-MRI samples were collected. Five curve features and two principal components of the normalized time-intensity curve (TIC) in 80 samples were calculated as the dataset in training three SVM classifiers. The other 40 samples were used as the testing dataset. The area overlap measure (AOM) and the corresponding ratio (CR) and percent match (PM) were calculated to evaluate the segmentation performance. The training and testing procedure was repeated for 10 times, and the average performance was calculated and compared with similar studies. Results. Our method has achieved higher accuracy compared to the previous results in literature in HNC segmentation. The average AOM with the testing dataset was 0.76 ± 0.08, and the mean CR and PM were 79 ± 9% and 86 ± 8%, respectively. Conclusion. With improved segmentation performance, our proposed method is of potential in clinical practice for HNC

Berberine Induces Caspase-Independent Cell Death in Colon Tumor Cells through Activation of Apoptosis-Inducing Factor

Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apcmin mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth

Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA

Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the “anti-Warburg” metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers

Cell cycle, motility and invasion: CDPK4 is a pleiotropic regulator across the lifecycle of parasites causing malaria

In Plasmodium, calcium-dependent protein kinase 4 (CDPK4) is essential for the process of male gametogenesis, where eight flagellated male gametes are produced from a single male gametocyte in ten minutes. This thesis characterised the molecular roles of CDPK4 during male gametogenesis and identified substrates of CDPK4 which mediate the respective molecular processes. CDPK4 mediates the initiation of DNA replication and promotes mitotic spindle formation through SOC1 and SOC2, and initiates axoneme motility through SOC3. A subsequent study uncovered a functional interaction network involving CDPK4, the cGMP-dependent protein kinase (PKG) and another CDPK of the same family, CDPK1, persevered in multiple life cycle stages. Upstream PKG mobilises intracellular calcium and subsequently activates CDPK4 and CDPK1, which mediate erythrocyte invasion and parasite motility in the mosquito gut. A substrate of CDPK4, SOC6 which mediates the aforementioned processes is equally involved in erythrocytic and mosquito stages

Pandemics, global supply chains and local labor demand: evidence from 100 million posted jobs in China

This paper studies how the COVID-19 pandemic has affected labor demand, using over 100 million posted jobs on one of the largest online platforms in China. Our data reveal that the number of newly posted jobs within the first 14 weeks after the Wuhan lockdown on January 23, 2020, was about 31% lower than that of comparable periods in 2018 and 2019. We show that, via the global supply chain, COVID-19 cases abroad and pandemic-control policies by foreign governments reduced new-job creation in China by 11.7%. We also find that firms most exposed to international trade outperformed other firms at the beginning of the pandemic but underperformed during the recovery as the virus spread throughout the world