Chris Sander

Bio: Chris Sander is an academic researcher from Harvard University. The author has contributed to research in topics: Large Hadron Collider & Protein structure. The author has an hindex of 178, co-authored 713 publications receiving 233287 citations. Previous affiliations of Chris Sander include Purdue University & University of Leeds.

MatchMiner: An open source computational platform for real-time matching of cancer patients to precision medicine clinical trials using genomic and clinical criteria

Abstract: Background: Molecular profiling of cancers is now routine at many cancer centers, and the number of precision cancer medicine clinical trials, which are informed by profiling, is steadily rising. Additionally, these trials are becoming increasingly complex, often having multiple arms and many genomic eligibility criteria. Currently, it is a challenging for physicians to match patients to relevant clinical trials using the patient9s genomic profile, which can lead to missed opportunities. Automated matching against uniformly structured and encoded genomic eligibility criteria is essential to keep pace with the complex landscape of precision medicine clinical trials. Results: To meet these needs, we built and deployed an automated clinical trial matching platform called MatchMiner at the Dana-Farber Cancer Institute (DFCI). The platform has been integrated with Profile, DFCI9s enterprise genomic profiling project, which contains tumor profile data for >20,000 patients, and has been made available to physicians across the Institute. As no current standard exists for encoding clinical trial eligibility criteria, a new language called Clinical Trial Markup Language (CTML) was developed, and over 158 genomically-driven clinical trials were encoded using this language. The platform is open source and freely available for adoption by other institutions. Conclusion: MatchMiner is the first open platform developed to enable computational matching of patient-specific genomic profiles to precision cancer medicine clinical trials. Creating MatchMiner required developing clinical trial eligibility standards to support genome-driven matching and developing intuitive interfaces to support practical use-cases. Given the complexity of tumor profiling and the rapidly changing multi-site nature of genome-driven clinical trials, open source software is the most efficient, scalable, and economical option for matching cancer patients to clinical trials.

Identification of Guanine-Nucleotide Binding Proteins in Plants: Structural Analysis and Evolutionary Comparison of the Ras-Related Ypt-Gene Family from Zea Mays

Abstract: The development of plants is regulated by five types of hormones known as auxins, cytokinins, gibberellins, abscisic acid and ethylene (Phillips, 1971). Only little is known about the mechanisms of action of these hormones at the cellular and molecular level. Genetic analysis of mutants with increased resistance to growth inhibiting concentrations of hormones argues for the presence of receptor like functions in plants (King, 1988). Biochemical evidence suggests that the action of auxins may be mediated after binding to plasmalemma located receptors (for review see: Davies, 1988). However, our current picture on other elements in the plant cell, involved in the transmission of this signal to its final biological target, is only slowly emerging. Recent evidence strengthens the importance of the calcium signal in plant cells (Marme, 1983; Hepler & Wayne, 1985). Transient changes in cytoplasmic calcium levels coupled to external stimuli such as light and phytohormones can modulate numerous developmental responses (Hepler & Wayne, 1985).

Measurement of hadronic event shapes in high-p T multijet final states at √{s } = 13 TeV with the ATLAS detector

Abstract: A measurement of event-shape variables in proton-proton collisions at large momentum transfer is presented using data collected at s = 13 TeV with the ATLAS detector at the Large Hadron Collider. Six event-shape variables calculated using hadronic jets are studied in inclusive multijet events using data corresponding to an integrated luminosity of 139 fb−1. Measurements are performed in bins of jet multiplicity and in different ranges of the scalar sum of the transverse momenta of the two leading jets, reaching scales beyond 2 TeV. These measurements are compared with predictions from Monte Carlo event generators containing leading-order or next-to-leading order matrix elements matched to parton showers simulated to leading-logarithm accuracy. At low jet multiplicities, shape discrepancies between the measurements and the Monte Carlo predictions are observed. At high jet multiplicities, the shapes are better described but discrepancies in the normalisation are observed. [Figure not available: see fulltext.]

Search for dark matter produced in association with a single top quark in $\sqrt{s}=13$ TeV $pp$ collisions with the ATLAS detector

Abstract: This paper presents a search for dark matter in the context of a two-Higgs-doublet model together with an additional pseudoscalar mediator, $a$, which decays into the dark-matter particles. Processes where the pseudoscalar mediator is produced in association with a single top quark in the 2HDM+$a$ model are explored for the first time at the LHC. Several final states which include either one or two charged leptons (electrons or muons) and a significant amount of missing transverse momentum are considered. The analysis is based on proton-proton collision data collected with the ATLAS experiment at $\sqrt{s} = 13$ TeV during LHC Run2 (2015-2018), corresponding to an integrated luminosity of 139 fb$^{-1}$. No significant excess above the Standard Model predictions is found. The results are expressed as 95% confidence-level limits on the parameters of the signal models considered.

Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

Abstract: The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSIBLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.

Clustal w: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice

Abstract: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved for the alignment of divergent protein sequences. Firstly, individual weights are assigned to each sequence in a partial alignment in order to down-weight near-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitution matrices are varied at different alignment stages according to the divergence of the sequences to be aligned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regions encourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positions in early alignments where gaps have been opened receive locally reduced gap penalties to encourage the opening up of new gaps at these positions. These modifications are incorporated into a new program, CLUSTAL W which is freely available.

The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools.

Abstract: CLUSTAL X is a new windows interface for the widely-used progressive multiple sequence alignment program CLUSTAL W. The new system is easy to use, providing an integrated system for performing multiple sequence and profile alignments and analysing the results. CLUSTAL X displays the sequence alignment in a window on the screen. A versatile sequence colouring scheme allows the user to highlight conserved features in the alignment. Pull-down menus provide all the options required for traditional multiple sequence and profile alignment. New features include: the ability to cut-and-paste sequences to change the order of the alignment, selection of a subset of the sequences to be realigned, and selection of a sub-range of the alignment to be realigned and inserted back into the original alignment. Alignment quality analysis can be performed and low-scoring segments or exceptional residues can be highlighted. Quality analysis and realignment of selected residue ranges provide the user with a powerful tool to improve and refine difficult alignments and to trap errors in input sequences. CLUSTAL X has been compiled on SUN Solaris, IRIX5.3 on Silicon Graphics, Digital UNIX on DECstations, Microsoft Windows (32 bit) for PCs, Linux ELF for x86 PCs, and Macintosh PowerMac.

MUSCLE: multiple sequence alignment with high accuracy and high throughput

Abstract: We describe MUSCLE, a new computer program for creating multiple alignments of protein sequences. Elements of the algorithm include fast distance estimation using kmer counting, progressive alignment using a new profile function we call the logexpectation score, and refinement using treedependent restricted partitioning. The speed and accuracy of MUSCLE are compared with T-Coffee, MAFFT and CLUSTALW on four test sets of reference alignments: BAliBASE, SABmark, SMART and a new benchmark, PREFAB. MUSCLE achieves the highest, or joint highest, rank in accuracy on each of these sets. Without refinement, MUSCLE achieves average accuracy statistically indistinguishable from T-Coffee and MAFFT, and is the fastest of the tested methods for large numbers of sequences, aligning 5000 sequences of average length 350 in 7 min on a current desktop computer. The MUSCLE program, source code and PREFAB test data are freely available at http://www.drive5. com/muscle.

Gene Ontology: tool for the unification of biology

Abstract: Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.