Vitamin B6 in acute encephalopathy with biphasic seizures and late reduced diffusion

BackgroundThe initial presentation of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is indistinguishable from that of complex febrile seizures (FS), which poses a great diagnostic challenge for clinicians. Excitotoxicity is speculated to be the pathogenesis of AESD. Vitamin B6 (VB6) is essential for the biosynthesis of gamma-aminobutyric acid, an inhibitory neurotransmitter. The aim of this study is to investigate our hypothesis that VB6 deficiency in the brain may play a role in AESD.MethodsWe obtained cerebrospinal fluid (CSF) samples from pediatric patients with AESD after early seizures and those with FS. We measured pyridoxal 5′-phosphate (PLP) and pyridoxal (PL) concentrations in the CSF samples using high-performance liquid chromatography with fluorescence detection.ResultsThe subjects were 5 patients with AESD and 17 patients with FS. Age did not differ significantly between AESD and FS. In AESD, CSF PLP concentration was marginally lower (p = 0.0999) and the PLP-to-PL ratio was significantly (p = 0.0417) reduced compared to those in FS.ConclusionsAlthough it is impossible to conclude that low PLP concentration and PLP-to-PL ratio are causative of AESD, this may be a risk factor for developing AESD. When combined with other markers, this finding may be useful in distinguishing AESD from FS upon initial presentation.     

Targeted therapy in gastric cancer:Personalizing cancer treatment based on patient genome

Gastric cancer is the second leading cause of cancerrelated deaths worldwide.Conventional cytotoxic chemotherapy has limited efficacy for metastatic gastric cancer,with an overall survival of approximately ten months.Recent advances in high-throughput technologies have enabled the implementation of personalized cancer therapy for high-risk patients.The use of such high-throughput technologies,including microarray and next generation sequencing,have promoted the discovery of novel targets that offer new treatment strategies for patients lacking other therapeutic options.Many molecular pathways are currently under investigation as therapeutic targets in gastric cancer,including those related to the epidermal growth factor receptor family,the mesenchymal-epithelial transition factor axis,and the phosphatidylinositol 3-kinase-AKTmammalian target of rapamycin factors.Advances in molecular diagnostic tools further support the discovery of new molecular targets.Limitations exist,however;not all patients can be tested for biomarkers,and numerous challenges hamper implementation of targeted therapy in clinical settings.Indeed,the scale of tumor genomic profiling is rapidly outpacing our ability to appropriately synthesize all the information in order to optimally refine patient care.Therefore,clinicians must continue to educate themselves regarding new tools and frameworks,and to utilize multidisciplinary team science,comprised of oncologists,geneticists,pathologists,biologists and bioinformaticians,to successfully implement this genomic approach therapeutically.     

Pre-clinical use of isogenic cell lines and tumours in vitro and in vivo for predictive biomarker discovery; impact of KRAS and PI3KCA mutation status on MEK inhibitor activity is model dependent

Studies to identify predictive biomarkers can be carried out in isogenic cancer cell lines, which enable interrogation of the effect of a specific mutation. We assessed the effects of four drugs, the PI3K–mammalian target of rapamycin inhibitor dactolisib, the PI3K inhibitor pictrelisib, and the MEK (MAPK/ERK Kinase) inhibitors PD 0325901 and selumetinib, in isogenic DLD1 parental, KRAS^+/−, KRAS^G13D/−, PIK3CA^+/− and PIK3CA^E545K/− colorectal carcinoma cell lines. Importantly, we found substantial differences in the growth of these cells and in their drug sensitivity depending on whether they were studied under 2D (standard tissue culture on plastic) or 3D (in vitro soft agar and in vivo xenograft) conditions. DLD1 KRAS^+/− and DLD1 PIK3CA^+/− cells were more sensitive to MEK inhibitors than parental, DLD1 KRAS^G13D/− and DLD1 PIK3CA^E545K/− cells under 2D conditions, whereas DLD1 KRAS^G13D/− and DLD1 PIK3CA^E545K/− xenografts were sensitive to 10 mg/kg daily ×14 PD 0325901 in vivo (p ≤ 0.02) but tumours derived from parental DLD1 cells were not. These findings indicate that KRAS and PIK3CA mutations can influence the response of DLD1 colorectal cancer cell lines to MEK and PI3K inhibitors, but that the effect is dependent on the experimental model used to assess drug sensitivity.     

Elevated TRIM23 expression predicts poor prognosis in Chinese gastric cancer

The gene TRIM23 (tripartite motif containing 23) is a member of the tripartite motif (TRIM) family whose expression putatively participates in many pathophysiological processes. Nonetheless, the role of TRIM23 in gastric cancer (GC) remains uncertain. Our study evaluated the expression of TRIM23 in GC tissues and cell lines, and investigated an association between TRIM23 and survival. In the present study, our results demonstrated that TRIM23 mRNA and protein were frequently over-expressed in GC cell lines and GC tissues. High level of TRIM23 protein correlated with tumor size, tumor-node-metastasis (TNM) stage, depth of invasion, lymph node metastasis (LNM), tumor differentiation, and nerve invasion. Compared with the low TRIM23 protein group, the high TRIM23 protein group was significantly associated with worse prognosis of GC patients. Consistently, the KM-plot database suggested that high TRIM23 mRNA expression was also linked to a poor prognosis in GC patients both in positive and negative subgroups of human epidermal growth factor receptor 2 (HER2). But in the HER2 positive subgroup, the advantages of the low TRIM23 expression on overall survival were much more statistically significant. The univariate analysis indicated that TRIM23 expression correlated with overall survival. The multivariate analysis showed that independent factors of prognosis in GC were lymph node metastasis, vascular invasion, and depth of invasion. In summary, TRIM23 may be associated with progression of GC, and may be considered a therapeutic target for GC patients.     

The current status of heart failure diagnostic biomarkers

Heart failure (HF) affects approximately 23 million individuals worldwide and this number is increasing, due to an aging and growing population. Early detection of HF is crucial in the management of this debilitating disease. Current diagnostic methods for HF rely heavily on clinical imaging techniques and blood analysis, which makes them less than ideal for population-based screening purposes. Studies focusing on developing novel biomarkers for HF have utilized various techniques and biological fluids, including urine and saliva. Promising results from these studies imply that these body fluids can be used in evaluating the clinical manifestation of HF and will one day be integrated into a clinical workflow and facilitate HF management.     

Model selection based on combined penalties for biomarker identification

The growing role of targeted medicine has led to an increased focus on the development of actionable biomarkers. Current penalized selection methods that are used to identify biomarker panels for classification in high-dimensional data, however, often result in highly complex panels that need careful pruning for practical use. In the framework of regularization methods, a penalty that is a weighted sum of the L₁ and L₀ norm has been proposed to account for the complexity of the resulting model. In practice, the limitation of this penalty is that the objective function is non-convex, non-smooth, the optimization is computationally intensive and the application to high-dimensional settings is challenging. In this paper, we propose a stepwise forward variable selection method which combines the L₀ with L₁ or L₂ norms. The penalized likelihood criterion that is used in the stepwise selection procedure results in more parsimonious models, keeping only the most relevant features. Simulation results and a real application show that our approach exhibits a comparable performance with common selection methods with respect to the prediction performance while minimizing the number of variables in the selected model resulting in a more parsimonious model as desired.     

Anti-sRAGE autoimmunity in obesity: Downturn after bariatric surgery is independent of previous diabetic status

AimMorbid obesity increases the risk of cardiovascular disease (CVD). The receptor for advanced glycation end-products (RAGE) is implicated in proinflammatory processes that underlie CVD. Its soluble form (sRAGE) has been proposed as a vascular biomarker. Recently, anti-sRAGE autoantibodies were described and found to be increased in diseases where RAGE is overexpressed. This study aimed to investigate serum levels of anti-sRAGE autoantibodies in morbidly obese patients.MethodsAfter exclusion based on specific criteria, 150 subjects (50 normoglycemics, 50 glucose-intolerants and 50 diabetics) were randomly recruited from a cohort of 750 obese patients (ABOS). Serum sRAGE and anti-sRAGE autoantibodies were measured before bariatric surgery. Sixty-nine patients were followed for up to 1 year after gastric bypass, and their levels of sRAGE and anti-sRAGE autoantibodies measured. The control group consisted of healthy blood donors.ResultsCompared with controls, baseline levels of sRAGE and anti-sRAGE autoantibodies were significantly higher in all obese patients independently of glucose regulation (P < 0.001). At 1 year after gastric bypass, sRAGE and anti-sRAGE were decreased (P < 0.001). The decrease in anti-sRAGE autoantibodies was correlated with an increase in high-density lipoprotein (HDL; P = 0.02).ConclusionIndependently of previous diabetic status, morbid obesity increases sRAGE and anti-sRAGE levels. Weight loss after gastric bypass is followed by a decrease in both titres. The decrease in anti-sRAGE correlates with an increase in HDL.