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Background Q fever is a neglected zoonosis caused by the bacterium Coxiella burnetii . The knowledge of the epidemiology of Q fever in Kenya is limited with no attention to control and prevention programs. The purpose of this review is to understand the situation of Q fever in human and animal populations in Kenya in the past 60 years, and help identify future research priorities for the country. Methods Databases were searched for national and international scientific studies or reports on Q fever. We included studies and reports published between 1950 and 2015 if they reported on Q fever prevalence, incidence, and infection control programs in Kenya. Data were extracted with respect to studies on prevalence of Coxiella infections, study design, study region, the study populations involved, and sorted according to the year of the study. Results We identified 15 studies and reports which qualified for data extraction. Human seroprevalence studies revealed evidence of C. burnetii infections ranging from 3 to 35.8 % in all regions in which surveys were made and two Q fever outbreak episodes. Coxiella burnetii infections found in cattle 7.4–51.1 %, sheep 6.7–20 %, camels 20–46 %, and goats 20–46 % revealed variation based on ecoregions and the year of study. Farming and lack of protective clothing were associated with increased seropositivity among humans. However, high quality data is lacking on Q fever awareness, underlying cultural-economic factors influencing C. burnetii infection, and how the pathogen cycles may be embedded in livestock production and management systems in the economically and ecologically different Kenyan regions. We found no studies on national disease incidence estimates or disease surveillance and control efforts. Conclusion Coxiella burnetii infections are common in human and in a wide range of animal populations but are still unrecognized and underestimated thus presenting a significant human and animal health threat in Kenya. The factors influencing pathogen transmission, persistence and spread are poorly understood. Integrated disease surveillance and prevention/control programs are needed in Kenya.

Background Brucellosis is a debilitating zoonotic disease affecting humans and animals. A comprehensive, evidence-based assessment of literature and officially available data on animal and human brucellosis for Kenya are missing. The aim of the current review is to provide frequency estimates of brucellosis in humans, animals and risk factors for human infection, and help to understand the current situation in Kenya. Methods A total of accessible 36 national and international publications on brucellosis from 1916 to 2016 were reviewed to estimate the frequency of brucellosis in humans and animals, and strength of associations between potential risk factors and seropositivity in humans in Kenya. Results The conducted studies revealed only few and fragmented evidence of the disease spatial and temporal distribution in an epidemiological context. Bacteriological evidence revealed the presence of Brucella (B.) abortus and B. melitensis in cattle and human patients, whilst B. suis was isolated from wild rodents only. Similar evidence for Brucella spp infection in small ruminants and other animal species is unavailable. The early and most recent serological studies revealed that animal brucellosis is widespread in all animal production systems. The animal infection pressure in these systems has remained strong due to mixing of large numbers of animals from different geographical regions, movement of livestock in search of pasture, communal sharing of grazing land, and the concentration of animals around water points. Human cases are more likely seen in groups occupationally or domestically exposed to livestock or practicing risky social-cultural activities such as consumption of raw blood and dairy products, and slaughtering of animals within the homesteads. Many brucellosis patients are misdiagnosed and probably mistreated due to lack of reliable laboratory diagnostic support resulting to adverse health outcomes of the patients and routine disease underreporting. We found no studies of disease incidence estimates or disease control efforts. Conclusion The risk for re-emergence and transmission of brucellosis is evident as a result of the co-existence of animal husbandry activities and social-cultural activities that promote brucellosis transmission. Well-designed countrywide, evidence-based, and multidisciplinary studies of brucellosis at the human/livestock/wildlife interface are needed. These could help to generate reliable frequency and potential impact estimates, to identify Brucella reservoirs, and to propose control strategies of proven efficacy.

Live, attenuated viral vectors that express HIV-1 antigens are being investigated as an approach to generating durable immune responses against HIV-1 in humans. We recently developed a replication-competent, highly attenuated Ad26 vector that expresses mosaic HIV-1 Env (rcAd26.MOS1.HIV-Env, \"rcAd26\"). Here we present the results of a first-in-human, placebo-controlled clinical trial to test the safety, immunogenicity and mucosal shedding of rcAd26 given orally. Healthy adults were randomly assigned to receive a single oral dose of vaccine or placebo at 5:1 ratio in a dosage escalation of 10^8 to 10^11 rcAd26 VP (nominal doses) at University of Rochester Medical Center, Rochester, NY, USA. Participants were isolated and monitored for reactogenicity for 10 days post-vaccination, and adverse events were recorded up to day 112. Rectal and oropharyngeal secretions were evaluated for shedding of the vaccine. Humoral and cellular immune responses were measured. Household contacts were monitored for secondary vaccine transmission. We enrolled 22 participants and 11 household contacts between February 7 and June 24, 2015. 18 participants received one dose of HIV-1 vaccine and 4 participants received placebo. The vaccine caused only mild to moderate adverse events. No vaccine-related SAEs were observed. No infectious rcAd26 viral particles were detected in rectal or oropharyngeal secretions from any participant. Env-specific ELISA and ELISPOT responses were undetectable. No household contacts developed vaccine-induced HIV-1 seropositivity or vaccine-associated illness. The highly attenuated rcAd26.MOS1.HIV-Env vaccine was well tolerated up to 10^11 VP in healthy, HIV-1-uninfected adults, though the single dose was poorly immunogenic suggesting the replicative capacity of the vector was too attenuated. There was no evidence of shedding of infectious virus or secondary vaccine transmission following the isolation period. These data suggest the use of less attenuated viral vectors in future studies of live, oral HIV-1 vaccines. ClinicalTrials.gov NCT02366013.

Direct analysis of circulating tumor cells (CTCs) can inform on molecular mechanisms underlying systemic spread. Here we investigated promoter methylation of three genes regulating epithelial-to-mesenchymal transition (EMT), a key mechanism enabling epithelial tumor cells to disseminate and metastasize. For this, we developed a single-cell protocol based on agarose-embedded bisulfite treatment, which allows investigating DNA methylation of multiple loci via a multiplex PCR (multiplexed-scAEBS). We established our assay for the simultaneous analysis of three EMT-associated genes miR-200c/141, miR-200b/a/429 and CDH1 in single cells. The assay was validated in solitary cells of GM14667, MDA-MB-231 and MCF-7 cell lines, achieving a DNA amplification efficiency of 70% with methylation patterns identical to the respective bulk DNA. Then we applied multiplexed-scAEBS to 159 single CTCs from 11 patients with metastatic breast and six with metastatic castration-resistant prostate cancer, isolated via CellSearch (EpCAM pos /CK pos /CD45 neg /DAPI pos ) and subsequent FACS sorting. In contrast to CD45 pos white blood cells isolated and processed by the identical approach, we observed in the isolated CTCs methylation patterns resembling more those of epithelial-like cells. Methylation at the promoter of microRNA-200 family was significantly higher in prostate CTCs. Data from our single-cell analysis revealed an epigenetic heterogeneity among CTCs and indicates tumor-specific active epigenetic regulation of EMT-associated genes during blood-borne dissemination.

Background Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. Methods and results In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-x L and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. Conclusions We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK + ALCL patients.

Background Q fever in Kenya is poorly reported and its surveillance is highly neglected. Standard empiric treatment for febrile patients admitted to hospitals is antimalarials or penicillin-based antibiotics, which have no activity against Coxiella burnetii . This study aimed to assess the seroprevalence and the predisposing risk factors for Q fever infection in febrile patients from a pastoralist population, and derive a model for clinical prediction of febrile patients with acute Q fever. Methods Epidemiological and clinical data were obtained from 1067 patients from Northeastern Kenya and their sera tested for IgG antibodies against Coxiella burnetii antigens by enzyme-linked-immunosorbent assay (ELISA), indirect immunofluorescence assay (IFA) and quantitative real-time PCR (qPCR). Logit models were built for risk factor analysis, and diagnostic prediction score generated and validated in two separate cohorts of patients. Results Overall 204 (19.1 %, 95 % CI: 16.8–21.6) sera were positive for IgG antibodies against phase I and/or phase II antigens or Coxiella burnetii IS1111 by qPCR. Acute Q fever was established in 173 (16.2 %, 95 % CI: 14.1–18.7) patients. Q fever was not suspected by the treating clinicians in any of those patients, instead working diagnosis was fever of unknown origin or common tropical fevers. Exposure to cattle (adjusted odds ratio [aOR]: 2.09, 95 % CI: 1.73–5.98), goats (aOR: 3.74, 95 % CI: 2.52–9.40), and animal slaughter (aOR: 1.78, 95 % CI: 1.09–2.91) were significant risk factors. Consumption of unpasteurized cattle milk (aOR: 2.49, 95 % CI: 1.48–4.21) and locally fermented milk products (aOR: 1.66, 95 % CI: 1.19–4.37) were dietary factors associated with seropositivity. Based on regression coefficients, we calculated a diagnostic score with a sensitivity 93.1 % and specificity 76.1 % at cut off value of 2.90: fever >14 days (+3.6), abdominal pain (+0.8), respiratory tract infection (+1.0) and diarrhoea (−1.1). Conclusion Q fever is common in febrile Kenyan patients but underappreciated as a cause of community-acquired febrile illness. The utility of Q fever score and screening patients for the risky social-economic and dietary practices can provide a valuable tool to clinicians in identifying patients to strongly consider for detailed Q fever investigation and follow up on admission, and making therapeutic decisions.

The actin binding protein CapG modulates cell motility by interacting with the cytoskeleton. CapG is associated with tumor progression in different nongynecologic tumor entities and overexpression in breast cancer cell lines correlates with a more invasive phenotype in vitro. Here, we report a significant CapG overexpression in 18/47 (38%) of ovarian carcinomas (OC) analyzed by qRealTime-PCR analyses. Functional analyses in OC cell lines through siRNA mediated CapG knockdown and CapG overexpression showed CapG-dependent cell migration and invasiveness. A single nucleotide polymorphism rs6886 inside the CapG gene was identified, affecting a CapG phosphorylation site and thus potentially modifying CapG function. The minor allele frequency (MAF) of SNP rs6886 (c.1004A/G) was higher and the homozygous (A/A, His335) genotype was significantly more prevalent in patients with fallopian tube carcinomas (50%) as in controls (10%). With OC being one of the most lethal cancer diseases, the detection of novel biomarkers such as CapG could reveal new diagnostic and therapeutic targets. Moreover, in-depth analyses of SNP rs6886 related to FTC and OC will contribute to a better understanding of carcinogenesis and progression of OC.

Aims/hypothesis Excessive ectopic lipid deposition contributes to impaired insulin action in peripheral tissues and is considered an important link between obesity and type 2 diabetes mellitus. Acetyl-CoA carboxylase 2 (ACC2) is a key regulatory enzyme controlling skeletal muscle mitochondrial fatty acid oxidation; inhibition of ACC2 results in enhanced oxidation of lipids. Several mouse models lacking functional ACC2 have been reported in the literature. However, the phenotypes of the different models are inconclusive with respect to glucose homeostasis and protection from diet-induced obesity. Methods Here, we studied the effects of pharmacological inhibition of ACC2 using as a selective inhibitor the S enantiomer of compound 9c ([ S ]-9c). Selectivity was confirmed in biochemical assays using purified human ACC1 and ACC2. Results ( S )-9c significantly increased fatty acid oxidation in isolated extensor digitorum longus muscle from different mouse models (EC 50 226 nmol/l). Accordingly, short-term treatment of mice with ( S )-9c decreased malonyl-CoA levels in skeletal muscle and concomitantly reduced intramyocellular lipid levels. Treatment of db / db mice for 70 days with ( S )-9c (10 and 30 mg/kg, by oral gavage) resulted in improved oral glucose tolerance (AUC −36%, p  < 0.05), enhanced skeletal muscle 2-deoxy-2-[ 18 F]fluoro- d -glucose (FDG) uptake, as well as lowered prandial glucose (−31%, p  < 0.01) and HbA 1c (−0.7%, p  < 0.05). Body weight, liver triacylglycerol, plasma insulin and pancreatic insulin content were unaffected by the treatment. Conclusions/interpretation In conclusion, the ACC2-selective inhibitor ( S )-9c revealed glucose-lowering effects in a mouse model of diabetes mellitus.

Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFR[beta]. Blocking PDGFR[beta] kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. In a transgenic mouse model that mimics PDGFR[beta]-driven human ALCL in vivo, we identify PDGFR[beta] as a driver of aggressive tumor growth. Mechanistically, PDGFR[beta] induces the pro-survival factor Bcl-x.sub.L and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. We therefore propose PDGFR[beta] as a novel biomarker and introduce PDGFR[beta]-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFR[beta] or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK.sup.+ ALCL patients.

The sensitivity and specificity of three commercially available complement fixation test (CFT) antigens from c.c.pro (c.c.pro), Central Veterinary Institute of Wageningen UR (CIDC) and the United States Department of Agriculture (USDA) were comparatively evaluated by testing 410 sera collected from glanders-endemic and non-endemic areas (200 true-negative randomly collected sera and 210 sera collected from experimentally immunised animals (12 rabbits, 19 horses), clinically positive (135) and culture-positive (44) horses, donkeys and mules). Immunoblotting (IB) was used as the gold standard test. Highest sensitivity was shown for the CIDC antigen (100 per cent) followed by the c.c.pro antigen (99.39 per cent). However, the USDA antigen showed substantially less (p<0.05) sensitivity (62.19 per cent). Highest specificity was found for the USDA antigen (100 per cent) followed by the CIDC (97.5 per cent) and c.c.pro antigen (96.5 per cent). Positive and negative predictive values (assumed glanders prevalence of <0.1 per cent) for each antigen were calculated to be 95.88 and 99.48 (c.c.pro), 97.04 and 100 (CIDC), 100 and 76.33 per cent (USDA), respectively. Almost perfect agreement (0.96) was found between CFT using either c.c.pro or CIDC and IB.