Multi-Target Prediction: A Unifying View on Problems and Methods

Multi-target prediction (MTP) is concerned with the simultaneous prediction of multiple target variables of diverse type. Due to its enormous application potential, it has developed into an active and rapidly expanding research field that combines several subfields of machine learning, including multivariate regression, multi-label classification, multi-task learning, dyadic prediction, zero-shot learning, network inference, and matrix completion. In this paper, we present a unifying view on MTP problems and methods. First, we formally discuss commonalities and differences between existing MTP problems. To this end, we introduce a general framework that covers the above subfields as special cases. As a second contribution, we provide a structured overview of MTP methods. This is accomplished by identifying a number of key properties, which distinguish such methods and determine their suitability for different types of problems. Finally, we also discuss a few challenges for future research

A G-quadruplex aptamer based impedimetric sensor for free lysine and arginine.

This paper describes a label free sensor for the sensitive detection of certain, basic primary amino acids containing free ethyl and methyl amino acids. The control of interfacial electron transfer of a G-quadruplex DNA aptamer, using a Fe(CN)63–/4− redox probe responds rapidly to variations in arginine and lysine concentrations, but not to histidine, using non-labelled, impedance spectroscopy (EIS) detection. Two binding aptamer binding regimes were observed. At the low concentration range (0–0.15 μg/mL), selectivity between lysine and arginine was apparent with limits of detection at approximately 0.5 pMand 1.6 pM respectively. At higher levels of concentrations, 0.15–10 μg/mL, selectivity was limited. The aptamer was immobilised on gold substrates ensuring optimal probe density which was monitored by Atomic Force Microscopy. Initial studies indicate that the relative change in charge transfer resistance (Rct) values can be used as a parameter for monitoring free lysine to arginine ratios and free total lysine and arginine for direct detection of total lysine and arginine in food samples (milk, egg white and yoghurt) in Tris/HCl buffer, demonstrating its potential in many applications

Finding RNA structure in the unstructured RBPome

Background RNA-binding proteins (RBPs) play vital roles in many processes in the cell. Different RBPs bind RNA with different sequence and structure specificities. While sequence specificities for a large set of 205 RBPs have been reported through the RNAcompete compendium, structure specificities are known for only a small fraction. The main limitation lies in the design of the RNAcompete technology, which tests RBP binding against unstructured RNA probes, making it difficult to infer structural preferences from these data. We recently developed RCK, an algorithm to infer sequence and structural binding models from RNAcompete data. The set of binding models enables, for the first time, a large-scale assessment of RNA structure in the RBPome. Results We re-validate and uncover the role of RNA structure in the RPBome through novel analysis of the largest-scale dataset to date. First, we show that RNA structure exists in presumably unstructured RNA probes and that its variability is correlated with RNA-binding. Second, we examine the structural binding preferences of RBPs and discover an overall preference to bind RNA loops. Third, we significantly improve protein-binding prediction using RNA structure, both in vitro and in vivo. Lastly, we demonstrate that RNA structural binding preferences can be inferred for new proteins from solely their amino acid content. Conclusions By counter-intuitively demonstrating through our analysis that we can predict both the RNA structure of and RBP binding to these putatively unstructured RNAs, we transform a compendium of RNA-binding proteins into a valuable resource for structure-based binding models. We uncover the important role RNA structure plays in protein-RNA interaction for hundreds of RNA-binding proteins

Abstract LB-A24: Molecular alteration of SMAD4 in hindgut-derived colorectal tumors identifies a distinct subset of patients and is associated with worse recurrence-free survival

Abstract This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Friday, November 6. Citation Format: Jesse Joshua Smith, Lik Hang Lee, Xi Chen, Chao Wu, Raphael Pelossof, Garrett M. Nash, Larissa R. Temple, Jose G. Guillem, Martin R. Weiser, Philip B. Paty, Jinru Shia, Julio Garcia-Aguilar, Charles L. Sawyers. Molecular alteration of SMAD4 in hindgut-derived colorectal tumors identifies a distinct subset of patients and is associated with worse recurrence-free survival. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A24.</jats:p

KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy

BackgroundThe response of rectal cancers to neoadjuvant chemoradiation (CRT) is variable, but tools to predict response remain lacking. We evaluated whether KRAS and TP53 mutations are associated with pathologic complete response (pCR) and lymph node metastasis after adjusting for neoadjuvant regimen.MethodsRetrospective analysis of 229 pretreatment biopsies from patients with stage II/III rectal cancer was performed. All patients received CRT. Patients received 0-8 cycles of FOLFOX either before or after CRT, but prior to surgical excision. A subset was analyzed to assess concordance between mutation calls by Sanger Sequencing and a next-generation assay.ResultsA total of 96 tumors (42&nbsp;%) had KRAS mutation, 150 had TP53 mutation (66&nbsp;%), and 59 (26&nbsp;%) had both. Following neoadjuvant therapy, 59 patients (26&nbsp;%) achieved pCR. Of 133 KRAS wild-type tumors, 45 (34&nbsp;%) had pCR, compared with 14 of 96 (15&nbsp;%) KRAS mutant tumors (p&nbsp;=&nbsp;.001). KRAS mutation remained independently associated with a lower pCR rate on multivariable analysis after adjusting for clinical stage, CRT-to-surgery interval and cycles of FOLFOX (OR 0.34; 95&nbsp;% CI 0.17-0.66, p&nbsp;&lt;&nbsp;.01). Of 29 patients with KRAS G12V or G13D, only 2 (7&nbsp;%) achieved pCR. Tumors with both KRAS and TP53 mutation were associated with lymph node metastasis. The concordance between platforms was high for KRAS (40 of 43, 93&nbsp;%).ConclusionsKRAS mutation is independently associated with a lower pCR rate in locally advanced rectal cancer after adjusting for variations in neoadjuvant regimen. Genomic data can potentially be used to select patients for "watch and wait" strategies

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial.

BackgroundAdding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response.ObjectiveThe purpose of this study was to analyze disease-free and overall survival.DesignThis was a nonrandomized phase II trial.SettingsThe study was conducted at multiple institutions.PatientsFour sequential study groups with stage II or III rectal cancer were included.InterventionAll of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6.Main outcome measuresThe trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study.ResultsOf 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, &lt;0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03).LimitationsThe trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients.ConclusionsAdding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739