Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12.

Although chemokines are well established to function in immunity and endothelial cell activation and proliferation, a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 are critical in the development and progression of solid tumors. The effect of these chemokine receptors in tumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12). Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solid tumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrich the existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12-CXCR4 axis have emerged as additional or alternative agents for neo-adjuvant treatments and even many of them are in preclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in cancer progression, has questioned the potential of "selective blockade" of CXCR4 as cancer chemotherapeutics. Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3. Recent reports have documented that CXCR3 and their ligands are overexpressed in different solid tumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactions and crosstalk between these three chemokine receptors and their ligand mediated signaling cascades for the development of effective anti-cancer therapies. Emerging evidence also indicates that these receptors are differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting their direct role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signals mediated by this receptor trio via their shared ligands and their role in tumor growth and progression

From Rags to Riches: Assessing poverty and vulnerability in urban Nepal

Urbanisation brings with it rapid socio-economic change with volatile livelihoods and unstable ownership of assets. Yet, current measures of wealth are based predominantly on static livelihoods found in rural areas. We sought to assess the extent to which seven common measures of wealth appropriately capture vulnerability to poverty in urban areas. We then sought to develop a measure that captures the characteristics of one urban area in Nepal. We collected and analysed data from 1,180 households collected during a survey conducted between November 2017 and January 2018 and designed to be representative of the Kathmandu valley. A separate survey of a sub set of households was conducted using participatory qualitative methods in slum and non-slum neighbourhoods. A series of currently used indices of deprivation were calculated from questionnaire data. We used bivariate statistical methods to examine the association between each index and identify characteristics of poor and non-poor. Qualitative data was used to identify characteristics of poverty from the perspective of urban poor communities which were used to construct an Urban Poverty Index that combined asset and consumption focused context specific measures of poverty that could be proxied by easily measured indicators as assessed through multivariate modelling. We found a strong but not perfect association between each measure of poverty. There was disagreement when comparing the consumption and deprivation index on the classification of 19% of the sample. Choice of short-term monetary and longer-term capital approaches accounted for much of the difference. Those who reported migrating due to economic necessity were most likely to be categorised as poor. A combined index was developed to capture these dimension of poverty and understand urban vulnerability. A second version of the index was constructed that can be computed using a smaller range of variables to identify those in poverty. Current measures may hide important aspects of urban poverty. Those who migrate out of economic necessity are particularly vulnerable. A composite index of socioeconomic status helps to capture the complex nature of economic vulnerability

MANTRA: Improving Knowledge of Maternal Health, Neonatal Health, and Geohazards in Women in Rural Nepal Using a Mobile Serious Game

Serious games, conveying educational knowledge rather than merely entertainment, are a rapidly expanding research domain for cutting-edge educational technology. Digital interventions like serious games are great opportunities to overcome challenges in low-and-middle-income countries that limit access to health information, such as social barriers like low-literacy and gender. MANTRA: Increasing maternal and child health resilience before, during and after disasters using mobile technology in Nepal takes on these challenges with a novel digital health intervention; a serious mobile game aimed at vulnerable low-literacy female audiences in rural Nepal. The serious game teaches 28 learning objectives of danger signs in geohazards, maternal, and neonatal health to improve knowledge and self-assessment of common conditions and risks to inform healthcare-seeking behavior. Evaluations consisted of recruiting 35 end users to participate in a pre-test assessment, playing the game, post-test assessment, and focus groups to elicit qualitative feedback. Assessments analyzed knowledge gain in two ways; by learning objective with McNemar tests for each learning objective, and by participant scores with paired t-tests of overall scores and by module. Results of assessments of knowledge gain by learning objective (McNemar tests) indicate participants had sufficient prior knowledge to correctly interpret and respond to 26% of pictograms (coded AA), which is a desirable result although without the possibility of improvement through the intervention. The geohazard module had greatest impact as 16% of responses showed knowledge gain (coded BA). The two most successful learning objectives showing statistically significant positive change were evidence of rockfalls and small cracks in the ground (p = < 0.05). Assessment of knowledge gain by participant scores (paired t-tests) showed the 35 participants averaged a 7.7 point improvement (p < 0.001) in the assessment (28 learning objectives). Average change in knowledge of subdivided module scores (each module normalized to 100 points for comparison) was greatest in the geohazard module (9.5 points, p < 0.001), then maternal health (7.4 points, p = 0.0067), and neonatal health (6.0 points, p = 0.013). This evaluation demonstrated that carefully designed digital health interventions with pictograms co-authored by experts and users can teach complex health and geohazard situations. Significant knowledge gain was demonstrated for several learning objectives while those with non-significant or negative change will be re-designed to effectively convey information

Combination HIV prevention among MSM in South Africa: results from agent-based modeling

HIV prevention trials have demonstrated the effectiveness of a number of behavioral and biomedical interventions. HIV prevention packages are combinations of interventions and offer potential to significantly increase the effectiveness of any single intervention. Estimates of the effectiveness of prevention packages are important for guiding the development of prevention strategies and for characterizing effect sizes before embarking on large scale trials. Unfortunately, most research to date has focused on testing single interventions rather than HIV prevention packages. Here we report the results from agent-based modeling of the effectiveness of HIV prevention packages for men who have sex with men (MSM) in South Africa. We consider packages consisting of four components: antiretroviral therapy for HIV infected persons with CD4 count <350; PrEP for high risk uninfected persons; behavioral interventions to reduce rates of unprotected anal intercourse (UAI); and campaigns to increase HIV testing. We considered 163 HIV prevention packages corresponding to different intensity levels of the four components. We performed 2252 simulation runs of our agent-based model to evaluate those packages. We found that a four component package consisting of a 15% reduction in the rate of UAI, 50% PrEP coverage of high risk uninfected persons, 50% reduction in persons who never test for HIV, and 50% ART coverage over and above persons already receiving ART at baseline, could prevent 33.9% of infections over 5 years (95% confidence interval, 31.5, 36.3). The package components with the largest incremental prevention effects were UAI reduction and PrEP coverage. The impact of increased HIV testing was magnified in the presence of PrEP. We find that HIV prevention packages that include both behavioral and biomedical components can in combination prevent significant numbers of infections with levels of coverage, acceptance and adherence that are potentially achievable among MSM in South Africa