Should Informed Consent for Cancer Treatment Include a Discussion about Hospital Outcome Disparities?

Background to the debate: Several studies have found disparities in the outcome of medical procedures across different hospitals—better outcomes have been associated with higher procedure volume. An Institute of Medicine workshop found such a “volume–outcome relationship” for two types of cancer surgery: resection of the pancreas and esophagus (http://www.iom.edu/?id=31508). This debate examines whether physicians have an ethical obligation to inform patients of hospital outcome disparities for these cancers.     

Competing endogenous RNA database

A given mRNA can be regulated by interactions with miRNAs and in turn the availability of these miRNAs can be regulated by their interactions with alternate mRNAs. The concept of regulation of a given mRNA by alternate mRNA (competing endogenous mRNA) by virtue of interactions with miRNAs through shared miRNA response elements is poised to become a fundamental genetic regulatory mechanism. The molecular basis of the mRNA-mRNA cross talks is via miRNA response elements, which can be predicted based on both molecular interaction and evolutionary conservation. By examining the co-occurrence of miRNA response elements in the mRNAs on a genome-wide basis we predict competing endogenous RNA for specific mRNAs targeted by miRNAs. Comparison of the mRNAs predicted to regulate PTEN with recently published work, indicate that the results presented within the competing endogenous RNA database (ceRDB) have biological relevance.

Availability

http://www.oncomir.umn.edu/cefinder/     

SPPS: a sequence-based method for predicting probability of protein-protein interaction partners

Background

The molecular network sustained by different types of interactions among proteins is widely manifested as the fundamental driving force of cellular operations. Many biological functions are determined by the crosstalk between proteins rather than by the characteristics of their individual components. Thus, the searches for protein partners in global networks are imperative when attempting to address the principles of biology.

Results

We have developed a web-based tool “Sequence-based Protein Partners Search” (SPPS) to explore interacting partners of proteins, by searching over a large repertoire of proteins across many species. SPPS provides a database containing more than 60,000 protein sequences with annotations and a protein-partner search engine in two modes (Single Query and Multiple Query). Two interacting proteins of human FBXO6 protein have been found using the service in the study. In addition, users can refine potential protein partner hits by using annotations and possible interactive network in the SPPS web server.

Conclusions

SPPS provides a new type of tool to facilitate the identification of direct or indirect protein partners which may guide scientists on the investigation of new signaling pathways. The SPPS server is available to the public at http://mdl.shsmu.edu.cn/SPPS/.     

MycoProtease-DB: Useful resource for Mycobacterium tuberculosis complex and nontuberculous mycobacterial proteases

MycoProtease-DB is an online MS SQL and CGI-PERL driven relational database that domiciles protease information of Mycobacterium tuberculosis (MTB) complex and Nontuberculous Mycobacteria (NTM), whose complete genome sequence is available. Our effort is to provide comprehensive information on proteases of 5 strains of Mycobacterium tuberculosis (H₃₇Rv, H₃₇Ra, CDC1551, F11 and KZN 1435), 3 strains of Mycobacterium bovis (AF2122/97, BCG Pasteur 1173P2 and BCG Tokyo 172) and 4 strains of NTM (Mycobacterium avium 104, Mycobacterium smegmatis MC2 155, Mycobacterium avium paratuberculosis K-10 and Nocardia farcinica IFM 10152) at gene, protein and structural level. MycoProtease-DB currently hosts 1324 proteases, which include 906 proteases from MTB complex with 237distinct proteases & 418 from NTM with 404 distinct proteases. Flexible database design and easy expandability & retrieval of information are the main features of MycoProtease-DB. All the data were validated with various online resources and published literatures for reliable serving as comprehensive resources of various Mycobacterial proteases.

Availability

The Database is publicly available at http://www.bicjbtdrc-mgims.in/MycoProtease-DB/     

Sequence Maneuverer: tool for sequence extraction from genomes

The availability of genomic sequences of many organisms has opened new challenges in many aspects particularly in terms of genome analysis. Sequence extraction is a vital step and many tools have been developed to solve this issue. These tools are available publically but have limitations with reference to the sequence extraction, length of the sequence to be extracted, organism specificity and lack of user friendly interface. We have developed a java based software package having three modules which can be used independently or sequentially. The tool efficiently extracts sequences from large datasets with few simple steps. It can efficiently extract multiple sequences of any desired length from a genome of any organism. The results are crosschecked by published data.

Availability

URL 1: http://ww3.comsats.edu.pk/bio/ResearchProjects.aspxURL 2: http://ww3.comsats.edu.pk/bio/SequenceManeuverer.aspx     

Open Labware: 3-D Printing Your Own Lab Equipment

The introduction of affordable, consumer-oriented 3-D printers is a milestone in the current “maker movement,” which has been heralded as the next industrial revolution. Combined with free and open sharing of detailed design blueprints and accessible development tools, rapid prototypes of complex products can now be assembled in one’s own garage—a game-changer reminiscent of the early days of personal computing. At the same time, 3-D printing has also allowed the scientific and engineering community to build the “little things” that help a lab get up and running much faster and easier than ever before.Applications of 3-D printing technologies (Fig. 1A, Box 1) have become as diverse as the types of materials that can be used for printing. Replacement parts at the International Space Station may be printed in orbit from durable plastics or metals, while back on Earth the food industry is starting to explore the same basic technology to fold strings of chocolate into custom-shaped confectionary. Also, consumer-oriented laser-cutting technology makes it very easy to cut raw materials such as sheets of plywood, acrylic, or aluminum into complex shapes within seconds. The range of possibilities comes to light when those mechanical parts are combined with off-the-shelf electronics, low-cost microcontrollers like Arduino boards [1], and single-board computers such as a Beagleboard [2] or a Raspberry Pi [3]. After an initial investment of typically less than a thousand dollars (e.g., to set-up a 3-D printer), the only other materials needed to build virtually anything include a few hundred grams of plastic (approximately US$30/kg), cables, and basic electronic components [4,5].Open in a separate windowFig 1Examples of open 3-D printed laboratory tools. A ₁, Components for laboratory tools, such as the base for a micromanipulator [18] shown here, can be rapidly prototyped using 3-D printing. A _2, The printed parts can be easily combined with an off-the-shelf continuous rotation servo-motor (bottom) to motorize the main axis. B ₁, A 3-D printable micropipette [8], designed in OpenSCAD [19], shown in full (left) and cross-section (right). B ₂, The pipette consists of the printed parts (blue), two biro fillings with the spring, an off-the-shelf piece of tubing to fit the tip, and one screw used as a spacer. B ₃, Assembly is complete with a laboratory glove or balloon spanned between the two main printed parts and sealed with tape to create an airtight bottom chamber continuous with the pipette tip. Accuracy is ±2–10 μl depending on printer precision, and total capacity of the system is easily adjusted using two variables listed in the source code, or accessed via the “Customizer” plugin on the thingiverse link [8]. See also the first table.

Box 1. Glossary

Open source

A collective license that defines terms of free availability and redistribution of published source material. Terms include free and unrestricted distribution, as well as full access to source code/blueprints/circuit board designs and derived works. For details, see http://opensource.org.

Maker movement

Technology-oriented extension of the traditional “Do-it-Yourself (DIY)” movement, typically denoting specific pursuits in electronics, CNC (computer numerical control) tools such as mills and laser cutters, as well as 3-D printing and related technologies.

3-D printing

Technology to generate three-dimensional objects from raw materials based on computer models. Most consumer-oriented 3-D printers print in plastic by locally melting a strand of raw material at the tip (“hot-end”) and “drawing” a 3-D object in layers. Plastic materials include Acrylnitrile butadiene styrene (ABS) and Polylactic acid (PLA). Many variations of 3-D printers exist, including those based on laser-polymerization or fusion of resins or powdered raw materials (e.g., metal or ceramic printers).

Arduino boards

Inexpensive and consumer-oriented microcontroller boards built around simple processors. These boards offer a variety of interfaces (serial ports, I2C and CAN bus, etc.), μs-timers, and multiple general-purpose input-output (GPIO) pins suitable for running simple, time-precise programs to control custom-built electronics.

Single board computers

Inexpensive single-board computers capable of running a mature operating system with graphical-user interface, such as Linux. Like microcontroller boards, they offer a variety of hardware interfaces and GPIO pins to control custom-built electronics.It therefore comes as no surprise that these technologies are also routinely used by research scientists and, especially, educators aiming to customize existing lab equipment or even build sophisticated lab equipment from scratch for a mere fraction of what commercial alternatives cost [6]. Designs for such “Open Labware” include simple mechanical adaptors [7], micropipettes (Fig. 1B) [8], and an egg-whisk–based centrifuge [9] as well as more sophisticated equipment such as an extracellular amplifier for neurophysiological experiments [10], a thermocycler for PCR [11], or a two-photon microscope [12]. At the same time, conceptually related approaches are also being pursued in chemistry [13–15] and material sciences [16,17]. See also

SALMONELLABASE - An online database of druggable targets of Salmonella species

Salmonellosis is one of the most common and widely distributed food borne diseases caused by Salmonella serovars. The emergence of multi drug resistant strains has become a threatening public health problem and targeting unique effectors of this pathogen can be considered as a powerful strategy for drug design. SalmonellaBase is an online web portal serving as an integrated source of information about Salmonella serovars with the data required for the structural and functional studies and the analysis of druggable targets in Salmonella. We have identified several target proteins, which helps in the pathogenicity of the organism and predicted their structures. The database will have the information on completely sequenced genomes of Salmonella species with the complete set of protein sequences of the respective strains, determined structures, predicted protein structures and biochemical pathways of the respective strains. In addition, we have provided information about name and source of the protein, Uniprot and Protein Data Bank codes and literature information. Furthermore, SalmonellaBase is linked to related databases and other resources. We have set up a web interface with different search and display options so that users have the ability to get the data in several ways. SalmonellaBase is a freely available database.

Availability

http://www.salmonellabase.com/     

Enhancing protein-vitamin binding residues prediction by multiple heterogeneous subspace SVMs ensemble

Background

Vitamins are typical ligands that play critical roles in various metabolic processes. The accurate identification of the vitamin-binding residues solely based on a protein sequence is of significant importance for the functional annotation of proteins, especially in the post-genomic era, when large volumes of protein sequences are accumulating quickly without being functionally annotated.

Results

In this paper, a new predictor called TargetVita is designed and implemented for predicting protein-vitamin binding residues using protein sequences. In TargetVita, features derived from the position-specific scoring matrix (PSSM), predicted protein secondary structure, and vitamin binding propensity are combined to form the original feature space; then, several feature subspaces are selected by performing different feature selection methods. Finally, based on the selected feature subspaces, heterogeneous SVMs are trained and then ensembled for performing prediction.

Conclusions

The experimental results obtained with four separate vitamin-binding benchmark datasets demonstrate that the proposed TargetVita is superior to the state-of-the-art vitamin-specific predictor, and an average improvement of 10% in terms of the Matthews correlation coefficient (MCC) was achieved over independent validation tests. The TargetVita web server and the datasets used are freely available for academic use at http://csbio.njust.edu.cn/bioinf/TargetVita or http://www.csbio.sjtu.edu.cn/bioinf/TargetVita.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-297) contains supplementary material, which is available to authorized users.     

MULTBLAST: A web application for multiple BLAST searches

Basic Local Alignment Search Tool, (BLAST) allows the comparison of a query sequence/s to a database of sequences and identifies those sequences that are similar to the query above a user-defined threshold. We have developed a user friendly web application, MULTBLAST that runs a series of BLAST searches on a user-supplied list of proteins against one or more target protein or nucleotide databases. The application pre-processes the data, launches each individual BLAST search on the University of Nevada, Reno''s-TimeLogic DeCypher® system (available from Active Motif, Inc.) and retrieves and combines all the results into a simple, easy to read output file. The output file presents the list of the query proteins, followed by the BLAST results for the matching sequences from each target database in consecutive columns. This format is especially useful for either comparing the results from the different target databases, or analyzing the results while keeping the identification of each target database separate.

Availability

The application is available at the URLhttp://blastpipe.biochem.unr.edu/     

SoyProDB: A database for the identification of soybean seed proteins

Soybean continues to serve as a rich and inexpensive source of protein for humans and animals. A substantial amount of information has been reported on the genotypic variation and beneficial genetic manipulation of soybeans. For better understanding of the consequences of genetic manipulation, elucidation of soybean protein composition is necessary, because of its direct relationship to phenotype. We have conducted studies to determine the composition of storage, allergen and anti-nutritional proteins in cultivated soybean using a combined proteomics approach. Two-dimensional polyacrylamide gel electrophoresis (2DPAGE) was implemented for the separation of proteins along with matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and liquid chromatography mass spectrometry (LC-MS/MS) for the identification of proteins. Our analysis resulted in the identification of several proteins, and a web based database named soybean protein database (SoyProDB) was subsequently built to house and allow scientists to search the data. This database will be useful to scientists who wish to genetically alter soybean with higher quality storage proteins, and also helpful for consumers to get a greater understanding about proteins that compose soy products available in the market. The database is freely accessible.

Availability

http://bioinformatics.towson.edu/Soybean_Seed_Proteins_2D_Gel_DB/Home.aspx     

A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect in Caenorhabditis elegans

The Prp43 DExD/H-box protein is required for progression of the biochemically distinct pre-messenger RNA and ribosomal RNA (rRNA) maturation pathways. In Saccharomyces cerevisiae, the Spp382/Ntr1, Sqs1/Pfa1, and Pxr1/Gno1 proteins are implicated as cofactors necessary for Prp43 helicase activation during spliceosome dissociation (Spp382) and rRNA processing (Sqs1 and Pxr1). While otherwise dissimilar in primary sequence, these Prp43-binding proteins each contain a short glycine-rich G-patch motif required for function and thought to act in protein or nucleic acid recognition. Here yeast two-hybrid, domain-swap, and site-directed mutagenesis approaches are used to investigate G-patch domain activity and portability. Our results reveal that the Spp382, Sqs1, and Pxr1 G-patches differ in Prp43 two-hybrid response and in the ability to reconstitute the Spp382 and Pxr1 RNA processing factors. G-patch protein reconstitution did not correlate with the apparent strength of the Prp43 two-hybrid response, suggesting that this domain has function beyond that of a Prp43 tether. Indeed, while critical for Pxr1 activity, the Pxr1 G-patch appears to contribute little to the yeast two-hybrid interaction. Conversely, deletion of the primary Prp43 binding site within Pxr1 (amino acids 102–149) does not impede rRNA processing but affects small nucleolar RNA (snoRNA) biogenesis, resulting in the accumulation of slightly extended forms of select snoRNAs, a phenotype unexpectedly shared by the prp43 loss-of-function mutant. These and related observations reveal differences in how the Spp382, Sqs1, and Pxr1 proteins interact with Prp43 and provide evidence linking G-patch identity with pathway-specific DExD/H-box helicase activity.     

Functional group and substructure searching as a tool in metabolomics

Background

A direct link between the names and structures of compounds and the functional groups contained within them is important, not only because biochemists frequently rely on literature that uses a free-text format to describe functional groups, but also because metabolic models depend upon the connections between enzymes and substrates being known and appropriately stored in databases.

Methodology

We have developed a database named “Biochemical Substructure Search Catalogue” (BiSSCat), which contains 489 functional groups, >200,000 compounds and >1,000,000 different computationally constructed substructures, to allow identification of chemical compounds of biological interest.

Conclusions

This database and its associated web-based search program (http://bisscat.org/) can be used to find compounds containing selected combinations of substructures and functional groups. It can be used to determine possible additional substrates for known enzymes and for putative enzymes found in genome projects. Its applications to enzyme inhibitor design are also discussed.     

In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile

Background

Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX.

Methods and Findings

We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial “up-front” in vivo MTX treatment (1 g/m²) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1–18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02).

Conclusions

Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL.Trial registrations: Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00137111","term_id":"NCT00137111"}}NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D).     

VMD DisRg: New User-Friendly Implement for calculation distance and radius of gyration in VMD program

Molecular dynamic simulation is a practical and powerful technique for analysis of protein structure. Several programs have been developed to facilitate the mentioned investigation, under them the visual molecular dynamic or VMD is the most frequently used programs. One of the beneficial properties of the VMD is its ability to be extendable by designing new plug-in. We introduce here a new facility of the VMD for distance analysis and radius of gyration of biopolymers such as protein and DNA.

Availability

The database is available for free at http://trc.ajums.ac.ir/HomePage.aspx/?TabID/=12618/&Site/=trc.ajums.ac/&Lang/=fa-IR     

VSDK: Virtual screening of small molecules using AutoDock Vina on Windows platform

Screening of ligand molecules to target proteins using computer-aided docking is a critical step in rational drug discovery. Based on this circumstance, we attempted to develop a virtual screening application system, named VSDK Virtual Screening by Docking, which can function under the Windows platform. This is a user-friendly, flexible, and versatile tool which can be used by users who are familiar with Windows OS. The virtual screening performance was tested for an arbitrarily-selected receptor, FGFR tyrosine kinase (pdb code: 1agw), by using ligands downloaded from ZINC database with its grid size of x,y,z = 30,30,30 and run number of 10. It took 90 minutes for 100 molecules for this virtual screening. VSDK is freely available at the designated URL, and a simplified manual can be downloaded from VSDK home page. This tool will have a more challenging scope and achievement as the computer speed and accuracy are increased and secured in the future.

Availability

The database is available for free at http://www.pharm.kobegakuin.ac.jp/˜akaho/english_top.html