Serum biomarker-based early detection of pancreatic ductal adenocarcinomas with ensemble learning.

BACKGROUND: Earlier detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes, as it is mostly detected at advanced stages which are associated with poor survival. Developing non-invasive blood tests for early detection would be an important breakthrough. METHODS: The primary objective of the work presented here is to use a dataset that is prospectively collected, to quantify a set of cancer-associated proteins and construct multi-marker models with the capacity to predict PDAC years before diagnosis. The data used is part of a nested case-control study within the UK Collaborative Trial of Ovarian Cancer Screening and is comprised of 218 samples, collected from a total of 143 post-menopausal women who were diagnosed with pancreatic cancer within 70 months after sample collection, and 249 matched non-cancer controls. We develop a stacked ensemble modelling technique to achieve robustness in predictions and, therefore, improve performance in newly collected datasets. RESULTS: Here we show that with ensemble learning we can predict PDAC status with an AUC of 0.91 (95% CI 0.75-1.0), sensitivity of 92% (95% CI 0.54-1.0) at 90% specificity, up to 1 year prior to diagnosis, and at an AUC of 0.85 (95% CI 0.74-0.93) up to 2 years prior to diagnosis (sensitivity of 61%, 95% CI 0.17-0.83, at 90% specificity). CONCLUSIONS: The ensemble modelling strategy explored here outperforms considerably biomarker combinations cited in the literature. Further developments in the selection of classifiers balancing performance and heterogeneity should further enhance the predictive capacity of the method.

Pancreatic cancers are most frequently detected at an advanced stage. This limits treatment options and contributes to the dismal survival rates currently recorded. The development of new tests that could improve detection of early-stage disease is fundamental to improve outcomes. Here, we use advanced data analysis techniques to devise an early detection test for pancreatic cancer. We use data on markers in the blood from people enrolled on a screening trial. Our test correctly identifies as positive for pancreatic cancer 91% of the time up to 1 year prior to diagnosis, and 78% of the time up to 2 years prior to diagnosis. These results surpass previously reported tests and should encourage further evaluation of the test in different populations, to see whether it should be adopted in the clinic.

LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer's disease brains.

Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2. Thus, siRNA loss of KLC1 or mutation of the WD motif disrupts axonal transport of LMTK2. We also show that LMTK2 facilitates the formation of a complex containing KLC1 and p35 and that siRNA loss of LMTK2 disrupts axonal transport of both p35 and cdk5. Finally, we show that LMTK2 levels are reduced in Alzheimer's disease brains. Damage to axonal transport and altered cdk5/p35 are pathogenic features of Alzheimer's disease. Thus, LMTK2 binds to KLC1 to direct axonal transport of p35 and its loss may contribute to Alzheimer's disease.

Arctigenin reduces neuronal responses in the somatosensory cortex via the inhibition of non-NMDA glutamate receptors.

Lignans are biologically active phenolic compounds related to lignin, produced in different plants. Arctigenin, a dibenzylbutyrolactone-type lignan, has been used as a neuroprotective agent for the treatment of encephalitis. Previous studies of cultured rat cerebral cortical neurones raised the possibility that arctigenin inhibits kainate-induced excitotoxicity. The aims of the present study were: 1) to analyse the effect of arctigenin on normal synaptic activity in ex vivo brain slices, 2) to determine its receptor binding properties and test the effect of arctigenin on AMPA/kainate receptor activation and 3) to establish its effects on neuronal activity in vivo. Arctigenin inhibited glutamatergic transmission and reduced the evoked field responses. The inhibitory effect of arctigenin on the evoked field responses proved to be substantially dose dependent. Our results indicate that arctigenin exerts its effects under physiological conditions and not only on hyper-excited neurons. Furthermore, arctigenin can cross the blood-brain barrier and in the brain it interacts with kainate sensitive ionotropic glutamate receptors. These results indicate that arctigenin is a potentially useful new pharmacological tool for the inhibition of glutamate-evoked responses in the central nervous system in vivo.

Lipid-soluble nutrient status of healthy Omani school children before and after intervention with oily fish meal or re-esterified triacylglycerol fish oil.

OBJECTIVES: Over the past two decades, the Omani diet has changed considerably to resemble a high calorie and a low nutrient density Western diet. We investigated the fat soluble nutrient status of children before and after intervention with fish diet or fish oil. METHODS: Children ages 9 and 10 y (n = 314) were recruited from three randomly selected schools. The schools were assigned to a fish, fish oil, or control group and the children were given a lightly grilled oily fish, a re-esterified triacylglycerol fish oil capsule, or no fish for 12 wk. RESULTS: Plasma vitamin A, beta carotene, vitamin E concentrations, and vitamin E/total lipid ratio at baseline were 2.7 ± 0.85 µmol/L, 0.68 ± 0.48 µmol/L, 21.1 ± 4.8 µmol/L, and 5.0 ± 0.81 µmol/mmol, respectively, and none of the children were deficient. They were severely deficient (<27.5 nmol/L; 10.5% boys and 28.5% girls), deficient (27.5-44.9 nmol/L; 47.6% boys and 49.4% girls) or insufficient (50-74.9 nmol/L; 34.6% boys and 21.5% girls) in vitamin D; only 7.3% boys and 0.6% girls had optimal status (≥75 nmol/L). Parathyroid hormone (5.0 ± 1.7 versus 5.8 ± 2.1 pmol/L; P < 0.0001) and alkaline phosphatase (225.2 ± 66.6 versus 247.8 ± 73.7 U/L; P < 0.01) levels were lower in boys. Postintervention, the fish oil (54.1 ± 17.5 nmol/L; P < 0.001) and fish (49.2 ± 17.4 nmol/L; P < 0.05) groups had elevated levels of vitamin D compared with the controls (42.3 ± 17.5 nmol/L). CONCLUSIONS: Vitamin D deficiency is prevalent in Omani school children, but it can be mitigated with omega-3 fatty acid supplementation. Vitamin D plays a crucial role in skeletal and extraskeletal systems. Hence, there is a need for a child-focused program of food fortification and outdoor activities to alleviate the problem.