Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Syngap1 regulates experience-dependent cortical ensemble plasticity by promoting in vivo excitatory synapse strengthening

A significant proportion of autism risk genes regulate synapse function, including plasticity, which is believed to contribute to behavioral abnormalities. However, it remains unclear how impaired synapse plasticity contributes to network-level processes linked to adaptive behaviors, such as experience-dependent ensemble plasticity. We found that Syngap1, a major autism risk gene, promoted measures of experience-dependent excitatory synapse strengthening in the mouse cortex, including spike-timing–dependent glutamatergic synaptic potentiation and presynaptic bouton formation. Synaptic depression and bouton elimination were normal in Syngap1 mice. Within cortical networks, Syngap1 promoted experience-dependent increases in somatic neural activity in weakly active neurons. In contrast, plastic changes to highly active neurons from the same ensemble that paradoxically weaken with experience were unaffected. Thus, experience-dependent excitatory synapse strengthening mediated by Syngap1 shapes neuron-specific plasticity within cortical ensembles. We propose that other genes regulate neuron-specific weakening within ensembles, and together, these processes function to redistribute activity within cortical networks during experience.

Autism risk genes converge on several neurobiological functions, including the regulation of synapse biology (1–3). Synapse processes directly controlled by autism spectrum disorder (ASD) risk genes include de novo synapse formation, synapse maturation, and activity-driven changes in synapse function (i.e., synapse plasticity). Synapse plasticity, especially in cortical excitatory neurons, is a process enabling neural circuits to store new information, which is essential for experience-dependent modifications of behavior to promote survival (4, 5). Thus, risk genes are thought to contribute to ASD etiology by disrupting how neural circuits change in response to novel experiences, which in turn contributes to maladaptive behaviors. However, the study of risk gene biology and their relationship to neural plasticity is largely restricted to reduced biological preparations that focus on isolated changes to a small subset of synapses. Therefore, it is unclear how risk gene–driven regulation of synapse plasticity contributes to changes in neural dynamics within intact functional networks known to drive adaptive behaviors.Neuronal ensembles, or groups of coactivated neurons, are thought to be the direct neural substrate of cognitive processes and behavior (6). In cortex, ensemble plasticity is a multidimensional process that reflects the distribution of distinct cellular plasticity mechanisms across individual neuronal components within the assembly. For example, neurons within the same sensory-evoked cortical ensemble can undergo either increases or decreases in activity in response to the same sensory experience (7–9). While this general phenomenon has been observed in multiple contexts, it is unclear how neurons within the same functional network can have opposing changes to enduring neuronal activity in response to the same sensory experience. One way that this may occur is through the simultaneous activation of distinct forms of experience-dependent plasticity that are differentially distributed throughout neurons that comprise a functional network. Indeed, sensory experience drives the induction of Hebbian-type synaptic plasticity that can strengthen or weaken excitatory synaptic input onto sensory-responsive neurons (10). Experience-dependent circuit plasticity is not limited to changes in excitatory synaptic strength. Robust changes to the function and connectivity of GABAergic interneurons within cortical microcircuits also occurs in response to novel experience, which in turn regulates the output of pyramidal neurons (11–13). Moreover, intrinsic changes to neuronal excitability have also been observed, and in combination with changes to GABAergic function, these collective processes are thought to maintain a set firing rate within networks even as activity is redistributed among individual neurons (8, 14, 15).We propose that experience induces heterogenous changes in activity within neurons of a cortical assembly through cellular processes controlled, at least in part, by genetic mechanisms linked to ASD risk. This hypothesis originates from the clear overrepresentation of ASD risk genes that regulate the neurobiology of synapses and synapse plasticity (1–3). However, because of the multidimensional nature of cortical network plasticity, one cannot infer how a gene influences experience-dependent changes in distributed network dynamics when the function of the gene has only been studied in isolated subcellular structures, such as synapses. It is therefore important to study major ASD risk genes in the context of intact functional networks. Doing so will help to elucidate how their influence over molecular and cellular functions contribute to intermediate network-level processes more directly linked to behaviors, such as cortical ensemble plasticity.In this study, we investigated how a major ASD risk gene, SYNGAP1/Syngap1 (HUMAN/mouse–mouse only from now on), regulates specific aspects of cellular plasticity in vivo and how this process shapes experience-dependent ensemble plasticity with sensory-responsive cortical networks. The Syngap1 gene, which is a major autism risk factor (16), is a robust regulator of various forms of long-term potentiation (LTP) (17), a cellular model of Hebbian plasticity. It regulates LTP through control of excitatory synapse structure and function by gating NMDA receptor-dependent regulation of AMPA receptor trafficking and dendritic spine size (18–20). The role of Syngap1 in regulating synapse plasticity has been observed by various researchers across distinct neuronal subtypes in a variety of in vitro and ex vivo preparations (21–24). Based on this past work in reduced preparations, we hypothesized that Syngap1 regulates experience-dependent ensemble plasticity by promoting the strengthening of excitatory synapses within functional cortical networks. We found that Syngap1 was required for spike-timing-dependent (STD) synaptic potentiation and experience-mediated synapse bouton formation in layer (L) 2/3 of somatosensory cortex (SSC) but not synaptic depression or synapse bouton elimination. Syngap1 heterozygosity in mice disrupted experience-dependent potentiation of neuronal activity within a subpopulation of L2/3 SSC neurons. Syngap1 loss of function had no effect on plasticity of neurons within the same ensemble that weakens with experience. These findings indicate that disruptions to synapse-level strengthening mechanisms in Syngap1 mice contribute to imbalanced cortical ensemble plasticity driven by novel sensory experience. We propose that a key function of Syngap1 is to promote complex network-level plasticity through the strengthening of excitatory connections within cortical circuits.     

Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer

BackgroundThe immunoglobulin G1 (IgG₁) monoclonal antibody (MoAb) Cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumours. IgG₁ may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by Fc gamma receptor (FcγR) polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus Cetuximab.Patients and methodsTumour tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester, United Kingdom). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays.ResultsDCR was significantly higher in KRAS wild-type tumours (61% versus 39%, p = 0.049). In epidermal growth factor receptor (EGFR) downstream-mutated mCRC patients, those harbouring an FcγRIIa H/H genotype had a higher DCR than alternative genotypes (67% versus 33%, p = 0.017). By multivariate analysis, FcγRIIa-131H/H remained significantly correlated with DCR (p = 0.008).ConclusionFcγR polymorphisms may play a role in the clinical efficacy of Cetuximab in EGFR downstream mutated mCRC patients. Further research into Cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted.     

Trends in prostate cancer survival in Spain: results from population-based cancer registries

Introduction

The aim of this study is to analyse the evolution of the survival of patients diagnosed with prostate cancer during the period 1995?C2003.

Material and methods

This is a population survival study of incident cases of prostate cancer in four Spanish areas: Basque Country, Girona, Murcia and Navarra. We calculated the relative survival (RS) at 5 years and its 95% confidence intervals using a cohort analysis and adjusted for age. To assess the trend in survival between the periods (1995?C1999 and 2000?C2003) a Poisson regression model was used, adjusting for age, region and period, obtaining the relative risk of death.

Results

The number of patients diagnosed during the 1995?C1999 period was 6493 and 8331 in the period 2000?C03. The RS at 5 years adjusted for age increased significantly, from 75.3% (95% CI 73.3?C77.2) in the period 1995?C99 to 85% (95% CI 83.4?C86.4) in the period 2000?C03.

Conclusion

In Spain the survival of patients with prostate cancer has increased significantly from 1999 to 2003, probably due to the advancement in diagnosis produced by the opportunistic screening of prostate-specific antigen (PSA). Differences in the dissemination and use of the PSA level could explain the observed geographic differences in the increase of survival. It would be necessary to carry out studies to quantify the produced overdiagnosis by screening with PSA in prostate cancer.     

Cancer incidence in Gipuzkoa, Spain (1998-2002), and time trends from 1986

OBJECTIVES: To determine the cancer incidence in Gipuzkoa (Spain) from 1998 to 2002 and describe time trends since 1986. METHODS: The annual incidence of cancer in Gipuzkoa from 1998 to 2002 was estimated as a rate per 100,000 inhabitants. Incidence trends for the period 1986-2002 were studied for all cancers and for the main cancer sites using Poisson regression and Joinpoint regression for prostate tumours. RESULTS: On average, one in 3 men and one in 5 women would probably be diagnosed with cancer at some time during their life (0-74 years). Among men, prostate surpassed lung as the most frequent cancer site. Among women, breast cancer represented approximately 30% of all cases of cancer (excluding non-melanoma skin cancers). There was an annual increase in the incidence of cancer of 1.5% (95% CI, 1.1-1.8) in men and 0.9% (95% CI, 0.5-1.3) in women. The incidence of prostate cancer in men increased over the study period, and especially between 1996 and 1999, with an annual increase of 34.7% (95% CI, 5.9-71.5). The incidence of lung cancer in women presented an annual increase of 5.2% (95% CI, 3.4-7.1). In contrast, the incidence of stomach cancer decreased during the study period. CONCLUSIONS: Cancer incidence in Gipuzkoa increased during the study period. This increase was particularly marked in lung cancer and skin melanoma, for which preventive strategies are fundamental.