Pharmacogenomics and cancer stem cells: a changing landscape?

Pharmacogenomics in oncology holds the promise to personalize cancer therapy. However, its clinical application is still limited to a few genes, and, in the large majority of cancers, the correlation between genotype and clinical outcome has been disappointing. One possible explanation is that current pharmacogenomic studies do not take into account the emerging role of cancer stem cells (CSCs) in drug sensitivity and resistance. CSCs are a subpopulation of cells driven by specific signal-transduction pathways, but genetic variants affecting their activity are generally neglected in current pharmacogenomic studies. Moreover, in several malignancies, CSCs represent a rare sub-population; therefore, whole tumor profiling might mask CSC gene expression patterns. This article reviews current evidence on CSC chemoresistance and shows how common genetic variations in CSC-related genes may predict individual response to anti-cancer agents. Furthermore, we provide insights into the design of pharmacogenomic studies to address the clinical usefulness of CSC genetic profiling

Relationship between admission serum C-reactive protein and short term outcome following acute ischaemic stroke at a tertiary health institution in Nigeria

Background: There is evidence of an association between mediators of inflammation, particularly C-reactive protein (CRP), and outcome of acute ischaemic stroke. This provides a potential opportunity for interventions aimed at improving outcome. There is sparse data exploring the role of inflammatory markers such as CRP and stroke outcome in Africans. The study objective was to determine the association between admission serum CRP levels and short-term outcome in the Nigerian patient presenting with acute ischaemic stroke.Materials and Methods: Consecutive patients hospitalized for first-ever acute ischaemic stroke at the Lagos University Teaching Hospital, Lagos, Nigeria, were prospectively enrolled between October 2007 and June 2008. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Serum CRP was determined on samples obtained within 7 days of stroke onset. All stroke patients were followed up till day 30 post-stroke. Outcome measures were 30 day Glasgow outcome scale score and functional impairment on the modified Rankin Scale (mRS). An age- and gender-matched healthy control group had serum CRP determined at inclusion. Elevated CRP was defined as any level above the cutoff (mean +2 x standard deviation of CRP level of controls).Results: Eighty patients with acute ischaemic stroke (47 men and 33 women) and 40 controls (27 male and 13 female) (P = 0.47) were studied. Mean age in cases was 59.1 ± 15.0 years. Mean CRP was significantly higher in stroke cases than controls (17.7 ± 14.4 mg/L versus 1.1 ± 1.7 mg/L respectively) (P < 0.00001). The frequency of elevated CRP (>4.5 mg/L) was 76.3% in stroke (N = 61) and 5% (N = 2) in controls (P < 0.0001). The case fatality rate in stroke with elevated CRP (32.8%) was significantly higher than stroke with normal admission CRP (0%; P= 0.015). The association of higher admission CRP with fatality () was statistically significant (P < 0.0001). Amongst survivors, mean CRP levels were markedly higher in the patients with unfavorable motor outcome (moderate/severe disability; n = 22; 21.5 ± 11.1) compared to those with favorable outcome (mild disability; n = 38; 6.5 ± 6.2) (P < 0.00001). In multivariate regression analysis, only high NIHSS score (P = 0.004) and admission CRP (P = 0.008) were independently associated with case fatality.Conclusions: Elevated admission CRP and high NIHSS score are independent predictors of short-term case fatality and adverse functional outcome following acute ischaemic stroke in Nigerians.Key words: C-reactive protein, ischaemic stroke, outcom

Interaction between gemcitabine and topotecan in human non-small-cell lung cancer cells: effects on cell survival, cell cycle and pharmacogenetic profile

The pyrimidine analogue gemcitabine is an established effective agent in the treatment of non-small-cell lung cancer (NSCLC). The present study investigates whether gemcitabine would be synergistic with the topoisomerase I inhibitor topotecan against the NSCLC A549 and Calu-6 cells. Cells were treated with gemcitabine and topotecan for 1 h and the type of drug interaction was assessed using the combination index (CI). Cell cycle alterations were analysed by flow cytometry, while apoptosis was examined by the occurrence of DNA internucleosomal fragmentation, nuclear condensation and caspase-3 activation. Moreover, the possible involvement of the PI3K-Akt signalling pathway was investigated by the measurement of Akt phosphorylation. Finally, quantitative, real-time PCR (QRT-PCR) was used to study modulation of the gemcitabine-activating enzyme deoxycytidine kinase (dCK) and the cellular target enzyme ribonucleotide reductase (RR). In results, it was found that simultaneous and sequential topotecan → gemcitabine treatments were synergistic, while the reverse sequence was antagonistic in both cell lines. DNA fragmentation, nuclear condensation and enhanced caspase-3 activity demonstrated that the drug combination markedly increased apoptosis in comparison with either single agent, while cell cycle analysis showed that topotecan increased cells in S phase. Furthermore, topotecan treatment significantly decreased the amount of the activated form of Akt, and enhanced the expression of dCK (+155.0 and +115.3% in A549 and Calu-6 cells, respectively), potentially facilitating gemcitabine activity. In conclusion, these results indicate that the combination of gemcitabine and topotecan displays schedule-dependent activity in vitro against NSCLC cells. The gemcitabine → topotecan sequence is antagonistic while drug synergism is obtained with the simultaneous and the sequential topotecan → gemcitabine combinations, which are associated with induction of decreased Akt phosphorylation and increased dCK expression

Autoimmune hepatitis in 828 Brazilian children and adolescents: clinical and laboratory findings, histological profile, treatments, and outcomes

In this large clinical series of Brazilian children and adolescents, autoimmunehepatitis-1 was more frequent, and patients with autoimmune hepatitis-2 exhibited higherdisease remission rates with earlier response to treatment. Patients with autoimmune hepatitis-1 had a higher risk of death.sentation, laboratory findings, histological profile, treatments, and outcomes of children andadolescents with autoimmune hepatitis.Methods: The medical records of 828 children and adolescents with autoimmune hepatitiswere reviewed. A questionnaire was used to collect anonymous data on clinical presentation,biochemical and histological findings, and treatments.Results: Of all patients, 89.6% had autoimmune hepatitis-1 and 10.4% had autoimmunehepatitis-2. The female sex was predominant in both groups. The median age at symptomonset was 111.5 (6; 210) and 53.5 (8; 165) months in the patients with autoimmune hepatitis1 and autoimmune hepatitis-2, respectively. Acute clinical onset was observed in 56.1% and58.8% and insidious symptoms in 43.9% and 41.2% of the patients with autoimmune hepatitis-1and autoimmune hepatitis-2, respectively. The risk of hepatic failure was 1.6-fold higher forautoimmune hepatitis-2. Fulminant hepatic failure occurred in 3.6% and 10.6% of the patientswith autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively; the risk was 3.1-foldhigher for autoimmune hepatitis-2. The gamma globulin and immunoglobulin G levels were sig-nificantly higher in autoimmune hepatitis-1, while the immunoglobulin A and C3 levels werelower in autoimmune hepatitis-2. Cirrhosis was observed in 22.4% of the patients; biochem-ical remission was achieved in 76.2%. The actuarial survival rate was 93.0%. A total of 4.6%underwent liver transplantation, and 6.9% died (autoimmune hepatitis-1: 7.5%; autoimmunehepatitis-2: 2.4%).Conclusions: In this large clinical series of Brazilian children and adolescents, autoimmunehepatitis-1 was more frequent, and patients with autoimmune hepatitis-2 exhibited higherdisease remission rates with earlier response to treatment. Patients with autoimmune hepatitis-1 had a higher risk of death.info:eu-repo/semantics/publishedVersio

Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients

BACKGROUND: The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. METHODS: CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. RESULTS: Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. CONCLUSIONS: CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment

Videogame consumption: The apophatic dimension

This article applies psychological-sociological accounts of the ‘apophatic’, a form of negative thinking, to examples of gaming practices to conceptualise a new theory of videogame consumption. It challenges the prevailing notion that the games consumer is always a ‘cataphatic’ thinker – that is, an activistic, rational-pleasure seeker – and looks to the ‘sorrows’ of gaming to find evidence of its more undesirable nature. The term ‘apophatic’ is characterised as an attempt to de-value the rational value purportedly placed on gaming practices. ‘Griefing’ other players is a good example of this apophatic ethic, where players derive value from the subversion of serious play through the disruption and destruction of other players’ game worlds. The struggle with ‘failure’ is another. As such, the article concludes with a reflection on the almost unsayable nature of videogame consumption, and suggests that consumer value may be derived from its more negative, spiritual-like aspects

An Estimate of the Incidence and Prevalence of Stroke in Africa:A Systematic Review and Meta-Analysis

Background: Stroke is increasingly becoming a challenging public health issue in Africa, and the non-availability of data has limited research output and consequently the response to this burden. This study aimed to estimate the incidence and prevalence of stroke in Africa in 2009 towards improved policy response and management of the disease in the region. Methods: A systematic search of Medline, EMBASE and Global Health for original population-based or hospital-based studies on stroke was conducted. A random effect meta-analysis was conducted on crude stroke incidence and prevalence rates, and a meta-regression-like epidemiological model was applied on all data points. The fitted curve generated from the model was used to estimate incident cases of stroke and number of stroke survivors in Africa at midpoints of the United Nation population 5-year age groups for the year 2009. Results: The literature search yielded a total of 1227 studies. 19 studies from 10 African countries were selected. 483 thousand new stroke cases among people aged 15 years or more were estimated in Africa in 2009, equivalent to 81.2 (13.2– 94.9)/100,000 person years. A total of 1.89 million stroke survivors among people aged 15 years or more were estimated in Africa in 2009, with a prevalence of 317.3 (314.0–748.2)/100000 population. Comparable figures for the year 2013 based on the same rates would amount to 535 thousand (87.0–625.3) new stroke cases and 2.09 million (2.06–4.93) stroke survivors, suggesting an increase of 10.8% and 9.6% of incident stroke cases and stroke survivors respectively, attributable to population growth and ageing between 2009 and 2013. Conclusion: The findings of this review suggest the burden of stroke in Africa is high and still increasing. There is need for more research on stroke and other vascular risk factors towards instituting appropriate policy, and effective preventive and management measures

ICAR: endoscopic skull‐base surgery

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