In this review, we discuss the interaction between cancer and markers of inflammation (such as levels of inflammatory cells and proteins) in the circulation, and the potential benefits of routinely monitoring these markers in peripheral blood measurement assays. Next, we discuss the prognostic value and limitations of using inflammatory markers such as neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios and C-reactive protein measurements. Furthermore, the review discusses the benefits of combining multiple types of measurements and longitudinal tracking to improve staging and prognosis prediction of patients with cancer, and the ability of novel in silico frameworks to leverage this high-dimensional data.

Platelets engage cues of pending vascular injury through coordinated adhesion, secretion and aggregation responses. These rapid, progressive changes in platelet form and function are orchestrated downstream of specific receptors on the platelet cell surface, and through intracellular signaling mechanisms that remain systematically undefined. This study brings together cell physiological and phosphoproteomics methods incorporating peptide tandem mass tag (TMT) labeling, sample multiplexing, synchronous precursor selection (SPS) and triple stage tandem mass spectrometry (MS3) to profile signaling mechanisms downstream of the immunotyrosine activation motif (ITAM) platelet collagen receptor GPVI. Altogether, >3,000 significant (FDR<0.05) phosphorylation events on >1,300 proteins were detected in initial and progressing conditions of GPVI-mediated platelet activation. With literature-guided causal inference tools, >300 site-specific signaling relations were mapped from phosphoproteomics data among key and emerging GPVI effectors (i.e., FcRg, Syk, PLCg2, PKCd, DAPP1). Through signaling validation studies and functional screening, other less-characterized targets were also considered within the context of GPVI/ITAM pathways, including Ras/MAPK axis proteins (i.e., KSR1, SOS1, STAT1, Hsp27). Networks highly regulated in GPVI/ITAM signaling out of context of curated knowledge were also illuminated, including a system of >40 Rab GTPases and associated regulatory proteins - where TAK1-mediated Rab7 S72 phosphorylation associated with endolysosomal maturation and GPVI-mediated platelet function. In addition to serving as a model for generating and testing hypotheses from omics datasets, this study puts forth a means to identify hemostatic effectors, biomarkers and therapeutic targets relevant to thrombosis, vascular inflammation and other platelet-associated disease states.

BackgroundAdequate knowledge of malaria prevention and control can help in reducing the growing burden of malaria among vulnerable groups, particularly pregnant women and children aged under 5 years living in malaria endemic settings. Similar studies have been conducted but with less focus on these vulnerable groups. This study assessed knowledge of malaria prevention and control among the pregnant women and non-pregnant mothers of children aged under 5 years in Ibadan, Oyo State, South West Nigeria.MethodsIn this cross sectional study, data on socio-demographic, clinical and knowledge on malaria prevention was collected using interviewer administered questionnaires from consenting study participants attending Adeoyo maternity hospital between May and November 2016. Data was described using percentages and compared across the two maternal groups in the study population. Knowledge scoring from collected data was computed using the variables on causes, symptoms and prevention of malaria and thereafter dichotomised. Multivariate analyses were used to assess the interactive effect of socio demographic and clinical characteristics with malaria knowledge. Level of statistical significance was set at p < 0.05.ResultsOf the 1373 women in the study, 59.6% (818) were pregnant women while 40.4% (555) were mothers of children aged under 5 years. The respondents mean age was 29 years ± 5.2. A considerable proportion of both the pregnant women (n = 494, 60.4%) and the non-pregnant mothers of children aged under 5 years (n = 254, 45.8%) did not have correct knowledge on malaria prevention measures based on our assessment threshold (p < 0.001). Having a tertiary level education was associated with better knowledge on malaria (4.20 ± 1.18, F = 16.80, p < 0.001). Multivariate analyses showed that marital status, educational attainment, gravidity, and HIV status were significantly associated with knowledge of malaria prevention and control.ConclusionThe findings indicate that socio-demographic factors such as marital and educational status greatly influence knowledge on malaria prevention and control measures. Key health stakeholders and authorities need to implement strategies and direct resources to improve the knowledge of mothers on malaria prevention and control. This would stem the tides of malaria related deaths among pregnant women and children aged under 5 years.

Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. However, the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression, thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and thromboxane A2. Platelet-colon cancer cell interactions potentiated the release of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally, in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy.

Platelets have been hypothesized to promote certain neoplastic malignancies, however, antiplatelet drugs are still not part of routine pharmacological cancer prevention and treatment protocols. Paracrine interactions between platelets and cancer cells have been implicated in potentiating the dissemination, survival within the circulation, and extravasation of cancer cells at distant sites of metastasis. Signals from platelets have also been suggested to confer epigenetic alterations including upregulating oncoproteins in circulating tumor cells, while secretion of potent growth factors may play roles in promoting mitogenesis, angiogenesis, and metastatic outgrowth. Thrombocytosis remains a marker of poor prognosis in patients with solid tumors. Experimental data suggest that lowering of platelet count may reduce tumor growth and metastases. Based on the mechanisms by which platelets could contribute to cancer growth and metastasis, it is conceivable that drugs reducing platelet count or platelet activation might attenuate cancer progression and improve outcomes. Herein we will review select pharmacological approaches that inhibit platelets and may affect cancer development and propagation. We begin by presenting an overview of clinical cancer prevention and outcome studies with low dose aspirin. We then review current nonclinical development of drugs targeted to platelet binding, activation and count as potential mitigating agents in cancer.

BackgroundSampling of saliva for diagnosing Plasmodium falciparum infections is a safe, non-invasive alternative to sampling of blood. However, the use of saliva presents a challenge because lower concentrations of parasite DNA are present in saliva compared to peripheral blood. Therefore, a sensitive method is needed for detection of parasite DNA in saliva. This study utilized two recently reported “ultra-sensitive” PCR assays based on detection of the P. falciparum mitochondrial cox3 gene and the multi-copy nuclear varATS gene. The ultra-sensitive assays have an advantage over standard 18S rRNA gene-based PCR assay as they target genes with higher copy numbers per parasite genome. Stored saliva DNA samples from 60 Cameroonian individuals with infections previously confirmed by 18S rRNA gene PCR in peripheral blood were tested with assays targeting the cox3 and varATS genes.ResultsOverall, the standard 18S rRNA gene-based PCR assay detected P. falciparum DNA in 62% of the stored saliva DNA samples, whereas 77 and 68% of the samples were positive with assays that target the cox3 and varATS genes, respectively. Interestingly, the ultra-sensitive assays detected more P. falciparum infections in stored saliva samples than were originally detected by thick-film microscopy (41/60 = 68%). When stratified by number of parasites in the blood, the cox3 assay successfully detected more than 90% of infections using saliva when individuals had > 1000 parasites/μl of peripheral blood, but sensitivity was reduced at submicroscopic parasitemia levels. Bands on electrophoresis gels were distinct for the cox3 assay, whereas faint or non-specific bands were sometimes observed for varATS and 18S rRNA that made interpretation of results difficult. Assays could be completed in 3.5 and 3 h for the cox3 and varATS assays, respectively, whereas the 18S rRNA gene assays required at least 7 h.ConclusionsThis study demonstrates that a PCR assay targeting the cox3 gene detected P. falciparum DNA in more saliva samples than primers for the 18S rRNA gene. Non-invasive collection of saliva in combination with the proposed cox3 primer-based PCR assay could potentially enhance routine testing of P. falciparum during disease surveillance, monitoring, and evaluation of interventions for malaria elimination.Electronic supplementary materialThe online version of this article (10.1186/s41182-018-0100-2) contains supplementary material, which is available to authorized users.

The discovery and utility of clinically relevant circulating biomarkers depend on standardized methods that minimize preanalytical errors. Despite growing interest in studying extracellular vesicles (EVs) and cell-free messenger RNA (cf-mRNA) as potential biomarkers, how blood processing and freeze/thaw impacts the profiles of these analytes in plasma was not thoroughly understood. We utilized flow cytometric analysis to examine the effect of differential centrifugation and a freeze/thaw cycle on EV profiles. Utilizing flow cytometry postacquisition analysis software (FCMpass) to calibrate light scattering and fluorescence, we revealed how differential centrifugation and post-freeze/thaw processing removes and retains EV subpopulations. Additionally, cf-mRNA levels measured by RT-qPCR profiles from a panel of housekeeping, platelet, and tissue-specific genes were preferentially affected by differential centrifugation and post-freeze/thaw processing. Critically, freezing plasma containing residual platelets yielded irreversible ex vivo generation of EV subpopulations and cf-mRNA transcripts, which were not removable by additional processing after freeze/thaw. Our findings suggest the importance of minimizing confounding variation attributed to plasma processing and platelet contamination.

Risk of malaria in infants can be influenced by prenatal factors. In this study, the potential for placental parasitemia at delivery in predicting susceptibility of infants to Plasmodium falciparum (Pf) infections was evaluated. Seventy-two newborns of mothers who were placental malaria negative (PM−) and of mothers who were PM+ with below (PM+ Lo) and above (PM + Hi) median placental parasitemia, were actively monitored during their first year of life. Median time to first PCR-detected Pf infection was shorter in PM + Lo infants (2.8 months) than in both PM− infants (4.0 months, p = 0.002) and PM + Hi infants (4.1 months, p = 0.01). Total number of new infections was also highest in the PM + Lo group. Only 24% of infants experienced clinical malaria episodes but these episodes occurred earlier in PM + Lo infants than in PM + Hi infants (p = 0.05). The adjusted hazard ratio (95% CI) of having Pf infection was 3.9 (1.8-8.4) and 1.5 (0.7-3.4) for infants in the PM + Lo and PM + Hi groups, respectively. Collectively, low placental parasitemia was associated with increased susceptibility to malaria during infancy. Therefore, malaria in pregnancy preventive regimens, such as sulfadoxine-pyremethamine, that reduce but do not eliminate placental Pf in areas of drug resistance may increase the risk of malaria in infants.When pregnant women become infected with the mosquito-borne parasite Plasmodium falciparum (Pf), parasitized erythrocytes adhere to placental villi and accumulate in the intervillous spaces (IVS), causing a condition referred to as placental malaria (PM) 1 . In addition to eliciting adverse pregnancy outcomes 2 , PM has been identified as a risk factor for early childhood morbidity and mortality. In general, infants born to PM-positive (PM+) mothers have a shorter time to first Pf infection 3,4 and first clinical episode of malaria 5,6 , a higher incidence of Pf infections early in life 7 , lower hemoglobin levels 8 , and higher risk of dying 9 compared to infants of PM-negative (PM−) mothers. However, the risk of malaria is not homogeneous among infants of PM+ mothers, since some PM+ infants have similar risk outcomes as PM− infants 3,5,9-11 . There is therefore a need to identify specific prenatal factors associated with increased susceptibility to malaria in infants whose mothers had PM.Factors thought to be important in modifying the susceptibility of infants to malaria include maternal gravidity and the timing of occurrence of malaria during pregnancy. For example, infants born to multigravid Tanzanian women had their first microscopically detected infection 12 weeks earlier than infants of primigravid women 3 . Likewise, Gabonese infants born to multigravidae were approximately twice as likely to experience clinical episodes of malaria during the first 30 months of life than infants born to primigravidae 5 . Concerning the timing of infection during pregnancy, when maternal Pf infections occurred within 3 months prior to delivery, Ugandan infants were at a higher risk of infection than when mothers...