Tag Archives: chemokine receptor

Gene expression analysis has also been used to identify

Gene expression analysis has also been used to identify signatures that may predict which patients are most likely to need or benefit from systemic chemotherapy. Smith et al. [63] reported a 20-gene signature that predicts for risk of occult nodal involvement at the time of cystectomy. In a validation cohort, the relative risk of nodal involvement in the defined high- and low-risk groups was 1.74 and 0.70, respectively. These findings are intriguing, though illustrate a common challenge of how best to define clinically meaningful thresholds often posed by the use of gene expression analysis for biomarker discovery. For example, what relative risk of nodal involvement should be acceptable to influence clinical recommendations? The answer to this and similar questions ultimately requires incorporation of gene expression data into prospective clinical trials before routine use could be expected.
Fortunately, efforts to develop clinical trials based on molecular profiling are underway. The Co-eXpression ExtrapolatioN (COXEN) algorithm is an interesting application of gene expression analysis to predict chemosensitivity in patients with chemokine receptor cancer [64]. This algorithm uses gene expression profiles generated from the U.S. National Cancer Institute\’s effort to screen more than 100,000 chemical compounds against a panel of 60 human tumor cell lines and matches profiles with clinical specimens to predict chemosensitivity. When this algorithm was applied to published bladder cancer gene expression sets, the COXEN score effectively predicted for chemotherapy response using multivariate analysis [65]. The algorithm serves as the basis for a planned cooperative group study to determine whether COXEN analysis of patient specimens can identify those most likely to respond to neoadjuvant cisplatin-based chemotherapy.
As the use of molecular profiling in bladder cancer increases, development of methodologies that can use routine clinical specimens will be critical. Most molecular profiling study results in bladder cancer have been derived from fresh frozen tissue; however, the use of formalin-fixed, paraffin embedded (FFPE) specimens is more practical for routine clinical use. As an example, the use of molecular inversion probe assays for identification of genomic changes and mutational profiling from FFPE specimens has recently been reported. Using this approach, Chekaluk and colleagues [66] identified 44 regions of chromosomal copy number changes and further examined 9 regions of amplification, based on the presumption that amplified genomic regions may be enriched for driver oncogenes. Using multiplex ligation-dependent probe assays for validation, the investigators identified the following genomic regions (and genes) as being most frequently amplified in primary bladder tumors: 1q23.3 (multiple genes), 6p22.3 (E2F3-SOX4), and 11q13.3 (CCND1). Rare amplification of 17q12 (ErbB2) was also noted. This work is notable for providing additional evidence of putative oncogenes that may be amenable to therapeutic targeting (CDK4 inhibitors for CCND1-amplified tumors and anti-her2 agents for ErbB2-amplified tumors) and also for describing a novel approach for performing genomic analysis on specimens derived from FFPE tissue.
Molecular concordance between primary tumors and metastatic lesions is not well defined in bladder cancer, though emerging data suggest discordance may be prevalent. Using molecular inversion probe assays on 30 primary tumors and 33 metastatic lesions (with 14 paired samples from the same patients), increased genomic copy number changes were noted in metastatic lesions compared with primary tumors (8.4% vs. 4.3%) [67]. Primary and metastatic site copy number gains were present in E2F3 (7% vs. 27%) and in CCND1 (7% vs. 18%) genes, respectively. ErbB2 amplifications were present in 7% of primary lesions and 12% of metastatic lesions, and the investigators noted in the paired specimens that 7 of 14 patients contained genomic aberrations in the metastatic lesion not found in the primary tumor. If confirmed with larger data sets, these findings have a striking potential to affect clinical management. In the future, patients with metastatic disease may conceivably need biopsies of multiple lesions to assess for molecular heterogeneity that could influence the optimal selection of targeted agents.

The prevalence of antibodies and the clinical signs recorded

The prevalence of chemokine receptor and the clinical signs recorded in calves demonstrates the ability of B. besnoiti to infect and even cause disease in animals younger than 6 months old, supporting the susceptibility of cattle to the disease regardless of age, as Alzieu et al. demonstrated before detecting tissue cysts in young calves from 4–5 months old (Alzieu et al., 2011). Supposing that the antibodies observed in our study were due to a transfer of maternal immunity (Shkap et al., 1994), we would expect that all calves born to B. besnoiti seropositive dams presented with antibodies. However, only half of the infected calves descended from seropositive cows, suggesting that the antibodies detected were consistent with recent infections. Consequently, these results indicate that maternal antibodies were not transferred to calves for a protective immune response against subsequent infections. Regarding putative routes of transmission to calves, Hornok et al. noted an unlikely transmission pathway via the colostrum, given the lack of B. besnoiti DNA excretion in the colostrums of seropositive cows (Hornok et al., 2015). Similarly, Frey et al. described the improbability of the vertical transmission of the disease, as previously reported by Nobel et al. (Nobel et al., 1981), due to the failure to detect the parasite in the upper tract of the reproductive organs of infected cows (Frey et al., 2013). Based on similar studies of bovine neosporosis (Schares et al., 1998; Davison et al., 1999), in which congenital transmission was observed in 94% of seropositive cows, considering transplacental or congenital disease transmission in our study seems unlikely since approximately 70% of seropositive infected dams had healthy offspring, and contrary, 10% of healthy females had infected offspring, which suggests postnatal transmission between dams and offspring through close contact during the suckling period. Evidence for this pathway could be observed in the regression models of the present study, which revealed that calf descendants of seropositive dams had double the probability of seroconversion than those born to seronegative cows. According to a recent study, for seropositive pregnant cattle, the immediate separation of the calves after the ingestion of colostrum and subsequent artificial feeding could be a successful strategy for preventing parasite transmission (Hornok et al., 2015). Additionally, the seroprevalence was higher in the spring than in the autumn-calving animals, which could be due to the slight difference of age between the calving time points (spring-calving animals were one month and a half older than autumn-calving animals, being 6.5 and 5.2months old, respectively). Therefore, among calves born in the spring, the supraforestal-grazing season, the increased activity of vector insects during the summer months or just the difference in age could increase the risk of infection, which would explain the increased seroprevalence detected in calves born in the autumn. Additionally, the antibody titres of animals born in the spring were slightly higher, consistent with the presence of calves with clinical disease. As in the adult herd, clinically affected calves had higher antibody titres (≥1/400).
Finally, a hypothesis about the origin of the outbreak on the farm was suggested. Based on the evidence observed in the research, the beginning of the outbreak could be attributed to cattle trading, specifically to the introduction of eight new cows into the herd in spring 2008 with a genetic improvement purpose. In fact, all of them showed clinical signs in the course of this research. Consequently, and considering all the results drawn from the study, we recommend a set of measures to avoid infection diffusion in herds. Disease control strategies in farms should be based on two main approaches. Farms should avoid the introduction of parasites into herds by rigorous controls as new animals arrive. Additionally, affected farms should avoid parasite transmission by focusing on visual observation of parasitic cysts in the scleral conjunctivae and serological analyses coupled with the progressive culling of infected animals and following management measures including the physical separation of infected and healthy cattle (even infected dams and their offspring) until the total eradication of seropositive animals is achieved.

Methods We searched seven databases Medline

2. Methods
We searched seven databases (Medline, CINALH, EMBASE, Web of Science, Sociological Abstracts, Soc Serv Abstracts, and Cochrane) that index literature published in the health and social sciences to identify articles for review, using different combinations of search terms related to routine immunization systems, urban health and populations, and immunization uptake, dropout, and schedule compliance (Table 1). We restricted searches to articles published in English from January 1990 to May 2013.
Table 1.
Literature search strategy.Keywords used or in combinationLiterature databases searchedImmunization, immunization, vaccinationMedline (PubMed and OVID search engines)UrbanEMBASEPeri-urbanWeb of ScienceSlum(s)Sociological AbstractsMaternal and child healthSoc Serv AbsIntervention(s)CINALHStrategy/strategiesCochrane Central Register of Controlled TrialsChallenge(s)CoverageDropoutUptakeComplianceDeterminant(s)Health service(s)Primary health service(s)Full-size tableTable optionsView in workspaceDownload as CSV
We included studies if they were peer-reviewed; assessed an intervention implemented to improve routine immunization coverage of childhood vaccines; set in an LMIC; and either explicitly focused on an area described by the authors as urban, peri-urban, or slum, or drew comparisons between these areas and rural areas. We excluded studies focusing on adult or adolescent vaccines, chemokine receptor efficacy trials, assessments of supplemental or outbreak response immunization activities (campaigns), or that did not include primary data collection (e.g., systematic reviews, expert opinions). We identified additional articles by searching the references of included articles and applying the same inclusion and exclusion criteria.
We developed a data extraction tool based on recommendations from the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [10] and used the PICO (Population, Intervention, Control/Comparator, and Outcome) format to frame our question and guide our extraction of information from articles. The PICO format has recently been recommended chemokine receptor by WHO to guide the development of evidence-based recommendations on vaccine-related issues [11]. We extracted the following information from each included article: study design and research methods, study subject characteristics, and reported measures of immunization uptake.
We analyzed each study by qualitatively summarizing the main themes regarding lessons learned and best practices for the intervention as documented by authors. We also summarized the reported vaccination outcomes; if ‘fully immunized’; or a similar outcome was reported, this outcome was reported in place of coverage or vaccination status of individuals for specific vaccines. If vaccination status or coverage with individual vaccines was reported, these were reported in place of risk ratios reported by the authors, in order to standardize the information collected on each study and directly compare changes in vaccination status or coverage across studies. In several reviewed studies for which the study design was a hybrid between a pre- and post-intervention trial and a randomized controlled trial (RCT), we reported the RCT-based outcomes. The intervention described by each study was classified into one of three categories, based on whether the intervention primarily addressed: (1) utilization (demand) of immunization services by beneficiaries (caretakers on behalf of children), (2) availability (supply) of immunization services by healthcare providers; or (3) both availability and utilization.