Author
Shannon Smith
Other affiliations: J. Craig Venter Institute
Bio: Shannon Smith is an academic researcher from Harvard University. The author has contributed to research in topics: Gene & Fulvestrant. The author has an hindex of 8, co-authored 8 publications receiving 2930 citations. Previous affiliations of Shannon Smith include J. Craig Venter Institute.
Papers
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TL;DR: The genomic sequence of six strains representing the five major disease-causing serotypes of Streptococcus agalactiae, the main cause of neonatal infection in humans, was generated and Mathematical extrapolation of the data suggests that the gene reservoir available for inclusion in the S. agalactic pan-genome is vast and that unique genes will continue to be identified even after sequencing hundreds of genomes.
Abstract: The development of efficient and inexpensive genome sequencing methods has revolutionized the study of human bacterial pathogens and improved vaccine design. Unfortunately, the sequence of a single genome does not reflect how genetic variability drives pathogenesis within a bacterial species and also limits genome-wide screens for vaccine candidates or for antimicrobial targets. We have generated the genomic sequence of six strains representing the five major disease-causing serotypes of Streptococcus agalactiae, the main cause of neonatal infection in humans. Analysis of these genomes and those available in databases showed that the S. agalactiae species can be described by a pan-genome consisting of a core genome shared by all isolates, accounting for ≈80% of any single genome, plus a dispensable genome consisting of partially shared and strain-specific genes. Mathematical extrapolation of the data suggests that the gene reservoir available for inclusion in the S. agalactiae pan-genome is vast and that unique genes will continue to be identified even after sequencing hundreds of genomes.
2,092 citations
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TL;DR: Analysis identified proteins potentially involved in vacuole confinement of the Anaplasmataceae, a life cycle involving a hematophagous vector, vertebrate pathogenesis, human pathogenesis and lack of transovarial transmission, which provide significant insights into the biology of these obligate intracellular pathogens.
Abstract: Anaplasma (formerly Ehrlichia) phagocytophilum, Ehrlichia chaffeensis, and Neorickettsia (formerly Ehrlichia) sennetsu are intracellular vector-borne pathogens that cause human ehrlichiosis, an emerging infectious disease. We present the complete genome sequences of these organisms along with comparisons to other organisms in the Rickettsiales order. Ehrlichia spp. and Anaplasma spp. display a unique large expansion of immunodominant outer membrane proteins facilitating antigenic variation. All Rickettsiales have a diminished ability to synthesize amino acids compared to their closest free-living relatives. Unlike members of the Rickettsiaceae family, these pathogenic Anaplasmataceae are capable of making all major vitamins, cofactors, and nucleotides, which could confer a beneficial role in the invertebrate vector or the vertebrate host. Further analysis identified proteins potentially involved in vacuole confinement of the Anaplasmataceae, a life cycle involving a hematophagous vector, vertebrate pathogenesis, human pathogenesis, and lack of transovarial transmission. These discoveries provide significant insights into the biology of these obligate intracellular pathogens.
472 citations
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TL;DR: Findings suggest that a subset of lung cancers, lymphomas, and neuroblastomas that harbor genomic ALK alterations may be clinically responsive to pharmacologic ALK inhibition.
Abstract: Selective kinase inhibitors have had a substantial impact on the field of medical oncology. Whereas these agents can elicit dramatic clinical responses in some settings, their activity is generally limited to a subset of treated patients whose tumor cells harbor a specific genetic lesion. We have established an automated platform for examining the sensitivity to various molecularly targeted inhibitors across a large panel of human tumor-derived cell lines to identify additional genotype-correlated responses that may be clinically relevant. Among the inhibitors tested in a panel of 602 cell lines derived from a variety of human cancers, we found that a selective inhibitor of the anaplastic lymphoma kinase (ALK) potently suppressed growth of a small subset of tumor cells. This subset included lines derived from anaplastic large cell lymphomas, non-small-cell lung cancers, and neuroblastomas. ALK is a receptor tyrosine kinase that was first identified as part of a protein fusion derived from a chromosomal translocation detected in the majority of anaplastic large cell lymphoma patients, and has recently been implicated as an oncogene in a small fraction of non-small-cell lung cancers and neuroblastomas. Significantly, sensitivity in these cell lines was well correlated with specific ALK genomic rearrangements, including chromosomal translocations and gene amplification. Moreover, in such cell lines, ALK kinase inhibition can lead to potent suppression of downstream survival signaling and an apoptotic response. These findings suggest that a subset of lung cancers, lymphomas, and neuroblastomas that harbor genomic ALK alterations may be clinically responsive to pharmacologic ALK inhibition.
413 citations
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TL;DR: Nine candidate fumonisin regulatory genes and a number of genes that may play a role in plant-fungal interaction were identified and evidence for a previously unidentified gene (FUM20) in the FUM gene cluster was provided.
101 citations
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TL;DR: The results suggest that the T/F-sublines are derived from a common monoclonal progenitor that lost transcriptomal responsiveness to antiestrogens as a consequence of genetic abnormalities many population doublings ago, not from the antiestrogen-sensitive cells in the same culture during the exposure toAntiestrogens.
Abstract: Emergence of antiestrogen-resistant cells in MCF-7 cells during suppression of estrogen signaling is a widely accepted model of acquired breast cancer resistance to endocrine therapy. To obtain insight into the genomic basis of endocrine therapy resistance, we characterized MCF-7 monoclonal sublines that survived 21-day exposure to tamoxifen (T-series sublines) or fulvestrant (F-series sublines) and sublines unselected by drugs (U-series). All T/F-sublines were resistant to the cytocidal effects of both tamoxifen and fulvestrant. However, their responses to the cytostatic effects of fulvestrant varied greatly, and their remarkably diversified morphology showed no correlation with drug resistance. mRNA expression profiles of the U-sublines differed significantly from those of the T/F-sublines, whose transcriptomal responsiveness to fulvestrant was largely lost. A set of genes strongly expressed in the U-sublines successfully predicted metastasis-free survival of breast cancer patients. Most T/F-sublines shared highly homogeneous genomic DNA aberration patterns that were distinct from those of the U-sublines. Genomic DNA of the U-sublines harbored many aberrations that were not found in the T/F-sublines. These results suggest that the T/F-sublines are derived from a common monoclonal progenitor that lost transcriptomal responsiveness to antiestrogens as a consequence of genetic abnormalities many population doublings ago, not from the antiestrogen-sensitive cells in the same culture during the exposure to antiestrogens. Thus, the apparent acquisition of antiestrogen resistance by MCF-7 cells reflects selection of preexisting drug-resistant subpopulations without involving changes in individual cells. Our results suggest the importance of clonal selection in endocrine therapy resistance of breast cancer.
73 citations
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。
18,940 citations
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TL;DR: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients, and the drug resulted in grade 1 or 2 gastrointestinal side effects.
Abstract: Background Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non–small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. Methods After screening tumor samples from approximately 1500 patients with non–small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Results Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. Conclusions The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.)
4,091 citations
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TL;DR: The new NCBI's Prokaryotic Genome Annotation Pipeline (PGAP) relies less on sequence similarity when confident comparative data are available, while it relies more on statistical predictions in the absence of external evidence.
Abstract: Recent technological advances have opened unprecedented opportunities for large-scale sequencing and analysis of populations of pathogenic species in disease outbreaks, as well as for large-scale diversity studies aimed at expanding our knowledge across the whole domain of prokaryotes. To meet the challenge of timely interpretation of structure, function and meaning of this vast genetic information, a comprehensive approach to automatic genome annotation is critically needed. In collaboration with Georgia Tech, NCBI has developed a new approach to genome annotation that combines alignment based methods with methods of predicting protein-coding and RNA genes and other functional elements directly from sequence. A new gene finding tool, GeneMarkS+, uses the combined evidence of protein and RNA placement by homology as an initial map of annotation to generate and modify ab initio gene predictions across the whole genome. Thus, the new NCBI's Prokaryotic Genome Annotation Pipeline (PGAP) relies more on sequence similarity when confident comparative data are available, while it relies more on statistical predictions in the absence of external evidence. The pipeline provides a framework for generation and analysis of annotation on the full breadth of prokaryotic taxonomy. For additional information on PGAP see https://www.ncbi.nlm.nih.gov/genome/annotation_prok/ and the NCBI Handbook, https://www.ncbi.nlm.nih.gov/books/NBK174280/.
3,902 citations
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TL;DR: A new method to align two or more genomes that have undergone rearrangements due to recombination and substantial amounts of segmental gain and loss is described, demonstrating high accuracy in situations where genomes have undergone biologically feasible amounts of genome rearrangement, segmental loss and loss.
Abstract: Background
Multiple genome alignment remains a challenging problem. Effects of recombination including rearrangement, segmental duplication, gain, and loss can create a mosaic pattern of homology even among closely related organisms.
3,302 citations
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TL;DR: The basic biology of Wolbachia is reviewed, with emphasis on recent advances in the authors' understanding of these fascinating endosymbionts, which are found in arthropods and nematodes.
Abstract: Wolbachia are common intracellular bacteria that are found in arthropods and nematodes. These alphaproteobacteria endosymbionts are transmitted vertically through host eggs and alter host biology in diverse ways, including the induction of reproductive manipulations, such as feminization, parthenogenesis, male killing and sperm-egg incompatibility. They can also move horizontally across species boundaries, resulting in a widespread and global distribution in diverse invertebrate hosts. Here, we review the basic biology of Wolbachia, with emphasis on recent advances in our understanding of these fascinating endosymbionts.
2,333 citations