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1.  Workshop on Use of Intravenous Immunoglobulin in Hand, Foot and Mouth Disease in Southeast Asia 
Emerging Infectious Diseases  2015;21(1):e140992.
A randomized, placebo-controlled clinical trial is needed to determine efficacy and safety of this treatment method.
The South East Asia Infectious Disease Clinical Research Network convened subject matter experts at a workshop to make consensus recommendations for study design of a clinical trial for use of intravenous immunoglobulin (IVIg) in severe hand, foot and mouth disease (HFMD). HFMD is a highly contagious emerging infection among children in the region, a small proportion of whom develop neurologic and cardiopulmonary complications with high case-fatality rates. The use of IVIg for treatment of severe disease is widespread and a part of local, national, and international guidelines, but no clinical evidence warrants the use of this drug, which is expensive and has potentially serious side effects. During a 2-day workshop in March 2014, a group of HFMD experts reviewed the current evidence related to use of IVIg in HFMD and discussed potential study design, feasibility, inclusion and exclusion criteria, sample size, primary and secondary endpoints, and subsidiary studies for a randomized, placebo-controlled trial.
doi:10.3201/eid2101.140992
PMCID: PMC4285270  PMID: 25531166
enterovirus; enterovirus 71; hand foot and mouth disease; intravenous immunoglobulin; Southeast Asia; workshop; IVIg
3.  Towards New Antifolates Targeting Eukaryotic Opportunistic Infections▿  
Eukaryotic Cell  2009;8(4):483-486.
Trimethoprim, an antifolate commonly prescribed in combination with sulfamethoxazole, potently inhibits several prokaryotic species of dihydrofolate reductase (DHFR). However, several eukaryotic pathogenic organisms are resistant to trimethoprim, preventing its effective use as a therapeutic for those infections. We have been building a program to reengineer trimethoprim to more potently and selectively inhibit eukaryotic species of DHFR as a viable strategy for new drug discovery targeting several opportunistic pathogens. We have developed a series of compounds that exhibit potent and selective inhibition of DHFR from the parasitic protozoa Cryptosporidium and Toxoplasma as well as the fungus Candida glabrata. A comparison of the structures of DHFR from the fungal species Candida glabrata and Pneumocystis suggests that the compounds may also potently inhibit Pneumocystis DHFR.
doi:10.1128/EC.00298-08
PMCID: PMC2669212  PMID: 19168759
5.  Engineering of a Human Vaginal Lactobacillus Strain for Surface Expression of Two-Domain CD4 Molecules▿  
Applied and Environmental Microbiology  2008;74(15):4626-4635.
Women are at significant risk of heterosexually transmitted human immunodeficiency virus (HIV) infection, with the mucosal epithelium of the cervix and vagina serving as a major portal of entry. The cervicovaginal mucosa naturally harbors dynamic microflora composed predominantly of lactobacilli, which may be genetically modified to serve as a more efficient protective barrier against the heterosexual transmission of HIV. We selected a vaginal strain of Lactobacillus, L. jensenii 1153, for genetic modification to display surface-anchored anti-HIV proteins. Genomic sequencing analyses revealed that L. jensenii 1153 encodes several unique high-molecular-weight cell wall-anchored proteins with a C-terminal cell wall sorting LPQTG motif. In this report, we employed these proteins to express a surface-anchored two-domain CD4 (2D CD4) molecule in L. jensenii 1153. Our studies indicated that the C-terminal cell wall sorting signal LPQTG motif alone is insufficient to drive the surface expression of heterologous proteins, and the display of surface-anchored 2D CD4 molecules required native sequences of a defined length upstream of the unique C-terminal LPQTG cell wall sorting signal and the positively charged C terminus in a Lactobacillus-based expression system. The modified L. jensenii strain displayed 2D CD4 molecules that were uniformly distributed on bacterial surfaces. The surface-anchored 2D CD4 molecule was recognized by a conformation-dependent anti-CD4 antibody, suggesting that the expressed proteins adopted a native conformation. The establishment of this Lactobacillus-based surface expression system, with potential broad applicability, represents a major step toward developing an inexpensive yet durable approach to topical microbicides for the mitigation of heterosexual transmission of HIV and other mucosally transmitted viral pathogens.
doi:10.1128/AEM.00104-08
PMCID: PMC2504410  PMID: 18539799
6.  Diffusion-Weighted Magnetic Resonance Imaging as a Cancer Biomarker: Consensus and Recommendations 
Neoplasia (New York, N.Y.)  2009;11(2):102-125.
On May 3, 2008, a National Cancer Institute (NCI)-sponsored open consensus conference was held in Toronto, Ontario, Canada, during the 2008 International Society for Magnetic Resonance in Medicine Meeting. Approximately 100 experts and stakeholders summarized the current understanding of diffusion-weighted magnetic resonance imaging (DW-MRI) and reached consensus on the use of DW-MRI as a cancer imaging biomarker. DW-MRI should be tested as an imaging biomarker in the context of well-defined clinical trials, by adding DW-MRI to existing NCI-sponsored trials, particularly those with tissue sampling or survival indicators. Where possible, DW-MRI measurements should be compared with histologic indices including cellularity and tissue response. There is a need for tissue equivalent diffusivity phantoms; meanwhile, simple fluid-filled phantoms should be used. Monoexponential assessments of apparent diffusion coefficient values should use two b values (> 100 and between 500 and 1000 mm2/sec depending on the application). Free breathing with multiple acquisitions is superior to complex gating techniques. Baseline patient reproducibility studies should be part of study designs. Both region of interest and histogram analysis of apparent diffusion coefficient measurements should be obtained. Standards for measurement, analysis, and display are needed. Annotated data from validation studies (along with outcome measures) should be made publicly available. Magnetic resonance imaging vendors should be engaged in this process. The NCI should establish a task force of experts (physicists, radiologists, and oncologists) to plan, organize technical aspects, and conduct pilot trials. The American College of Radiology Imaging Network infrastructure may be suitable for these purposes. There is an extraordinary opportunity for DW-MRI to evolve into a clinically valuable imaging tool, potentially important for drug development.
PMCID: PMC2631136  PMID: 19186405
7.  Engineering Human Vaginal Lactobacillus for Surface Expression of Two-Domain CD4 
Applied and environmental microbiology  2008;74(15):4626-4635.
Women are at significant risk of heterosexually transmitted HIV infection, with the mucosal epithelium of the cervix and vaginal serving as a major portal of entry. The cervico-vaginal mucosa naturally harbors dynamic microflora composed predominantly of lactobacilli, which may be genetically modified to serve as a more efficient protective barrier against heterosexual transmission of HIV. We selected a vaginal strain of Lactobacillus, L. jensenii 1153, for genetic modification to display surface-anchored anti-HIV proteins. Genomic sequencing analyses revealed that the L. jensenii 1153 encodes several unique high-molecular-weight cell wall anchored proteins with a C-terminal cell wall sorting LPQTG motif. In this report, we employed these proteins to express a surface-anchored two-domain CD4 (2D CD4) in L. jensenii 1153. Our studies indicated that the C-terminal cell wall sorting signal LPQTG motif alone is insufficient to drive surface expression of heterologous proteins, and display of surface-anchored 2D CD4 required native sequences of a defined length upstream of the unique C-terminal LPQTG cell wall sorting signal and the positively charged C-terminus in a Lactobacillus-based expression system. The modified L. jensenii displayed 2D CD4 molecules that were uniformly distributed on the bacterial surfaces. The surface-anchored 2D CD4 was recognized by a conformation dependent anti-CD4 antibody, suggesting that the expressed proteins adopted a native conformation. Establishment of this Lactobacillus-based surface expression system, with potential broad applicability, represents a major step toward developing an inexpensive, yet durable approach to topical microbicides for mitigation of heterosexual transmission of HIV and other mucosally transmitted viral pathogens.
doi:10.1128/AEM.00104-08
PMCID: PMC2504410  PMID: 18539799
8.  Predict, prevent and personalize: Genomic and proteomic approaches to cardiovascular medicine 
The Canadian Journal of Cardiology  2007;23(Suppl A):28A-33A.
Genomic and proteomic approaches to cardiovascular medicine promise to revolutionize our understanding of disease initiation and progression. This improved appreciation of pathophysiology may be translated into avenues of clinical utility. Gene-based presymptomatic prediction of illness, finer diagnostic subclassifications and improved risk assessment tools will permit earlier and more targeted intervention. Pharmacogenetics will guide our therapeutic decisions and monitor response to therapy. Personalized medicine will require the integration of clinical information, stable and dynamic genomics, and molecular phenotyping. Bioinformatics will be crucial in translating these data into useful applications, leading to improved diagnosis, prediction, prognostication and treatment. The present paper reviews the potential contributions of genomic and proteomic approaches in developing a more personalized approach to cardiovascular medicine.
PMCID: PMC2787001  PMID: 17668085
Biomarkers; Genes; Personalized medicine; Proteins
9.  Global Transcriptome Analysis of the Heat Shock Response of Shewanella oneidensis† ‡  
Journal of Bacteriology  2004;186(22):7796-7803.
Shewanella oneidensis is an important model organism for bioremediation studies because of its diverse respiratory capabilities. However, the genetic basis and regulatory mechanisms underlying the ability of S. oneidensis to survive and adapt to various environmentally relevant stresses is poorly understood. To define this organism's molecular response to elevated growth temperatures, temporal gene expression profiles were examined in cells subjected to heat stress by using whole-genome DNA microarrays for S. oneidensis. Approximately 15% (n = 711) of the total predicted S. oneidensis genes (n = 4,648) represented on the microarray were significantly up- or downregulated (P < 0.05) over a 25-min period after shift to the heat shock temperature. As expected, the majority of the genes that showed homology to known chaperones and heat shock proteins in other organisms were highly induced. In addition, a number of predicted genes, including those encoding enzymes in glycolysis and the pentose cycle, serine proteases, transcriptional regulators (MerR, LysR, and TetR families), histidine kinases, and hypothetical proteins were induced. Genes encoding membrane proteins were differentially expressed, suggesting that cells possibly alter their membrane composition or structure in response to variations in growth temperature. A substantial number of the genes encoding ribosomal proteins displayed downregulated coexpression patterns in response to heat stress, as did genes encoding prophage and flagellar proteins. Finally, a putative regulatory site with high conservation to the Escherichia coli σ32-binding consensus sequence was identified upstream of a number of heat-inducible genes.
doi:10.1128/JB.186.22.7796-7803.2004
PMCID: PMC524878  PMID: 15516594
10.  Department of Defense Era of Hope Meeting, Orlando, Florida, USA, 25–28 September 2002 
Breast Cancer Research  2002;5(1):53-56.
The Era of Hope meeting addressed with a multidisciplinary approach the most critical issues in breast carcinogenesis. The issues that we summarize here include: a) the use of rodent models for the study of mammary gland development and breast tumorigenesis; b) the effects of stroma on mammary epithelial differentiation and malignant transformation; c) a further characterization of the interactions between steroid and growth factor receptors; d) the improvement of technologies for early detection of breast tumors and the establishment of their progression; and e) the development of vaccines as potential new therapies against specific tumor markers.
PMCID: PMC154137  PMID: 12559047
animal models; breast cancer; imaging; mammary gland development; stromal–epithelial interactions
11.  Structural genomics: a new era for pharmaceutical research 
Genome Biology  2002;3(2):reports4004.1-reports4004.3.
A report on the 15th Annual Center for Advanced Biotechnology and Medicine Symposium on structural genomics in pharmaceutical design, Princeton, USA, 24-25 October 2001.
PMCID: PMC139010  PMID: 11864367

Results 1-11 (11)