PLoS Articles
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UNC-authored articles published by the Public Library of Science (PLoS)
Works (2112)
1821. Prenatal care and child growth and schooling in four low- and medium-income countries
- Title Tesim:
- Prenatal care and child growth and schooling in four low- and medium-income countries
- Creator:
- Sachdev, Harshpal S., Da Silveira, Mariangela Freitas, Behrman, Jere R., Adair, Linda S., Borja, Judith B., Bhargava, Santosh K., Richter, Linda M., Stein, Aryeh D., Horta, Bernardo L., Martorell, Reynaldo, Norris, Shane A., and Liu, Xiaoying
- Date of publication:
- 2017
- Abstract Tesim:
- The effectiveness of prenatal care for improving birth and subsequent child outcomes in low-income countries remains controversial, with much of the evidence to date coming from high-income countries and focused on early-life outcomes. We examined associations between prenatal care visits and birth weight, height-for-age at 24 months and attained schooling in four low- and middle-income countries.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Nutrition
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/ftyn-xp35
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pone.0171299, PMCID: PMC5291430, Onescience id: ef47282ce44fad5512cfa93c131a62333a15e3c9, and PMID: 28158229
- ISSN:
- 1932-6203
- Journal Issue:
- 2
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Humans, Income, Male, Developing Countries, Schools, Pregnancy, Patient Acceptance of Health Care, Child Development, Child, Female, Education, and Prenatal Care
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Pediatrics and Clinical Epidemiology; Sitaram Bhartia Institute of Science and Research, Postgraduation Program in Epidemiology; Faculty of Medicine; Federal University of Pelotas, Population Studies Center; University of Pennsylvania, USC-Office of Population Studies Foundation; Inc.; Department of Nutrition and Dietetics; University of San Carlos, Department of Pediatrics; S.L. Jain Hospital, University of the Witwatersrand; DST-NRF Centre of Excellence in Human Development, Medical Research Council Developmental Pathways to Health Research Unit; University of the Witwatersrand, and Hubert Department of Global Health; Rollins School of Public Health; Emory University
- Page Start:
- e0171299
- Person:
- Sachdev, Harshpal S., Da Silveira, Mariangela Freitas, Behrman, Jere R., Adair, Linda S., Borja, Judith B., Bhargava, Santosh K., Richter, Linda M., Stein, Aryeh D., Horta, Bernardo L., Martorell, Reynaldo, Norris, Shane A., and Liu, Xiaoying
- Rights Statement Label:
- In Copyright
- Source:
- 9880vx17r
1822. Predictors of Student Productivity in Biomedical Graduate School Applications
- Title Tesim:
- Predictors of Student Productivity in Biomedical Graduate School Applications
- Creator:
- O'Connell, Anna B., Hall, Joshua D., and Cook, Jeanette G.
- Date of publication:
- 2017
- Abstract Tesim:
- Many US biomedical PhD programs receive more applications for admissions than they can accept each year, necessitating a selective admissions process. Typical selection criteria include standardized test scores, undergraduate grade point average, letters of recommendation, a resume and/or personal statement highlighting relevant research or professional experience, and feedback from interviews with training faculty. Admissions decisions are often founded on assumptions that these application components correlate with research success in graduate school, but these assumptions have not been rigorously tested. We sought to determine if any application components were predictive of student productivity measured by first-author student publications and time to degree completion. We collected productivity metrics for graduate students who entered the umbrella first-year biomedical PhD program at the University of North Carolina at Chapel Hill from 2008–2010 and analyzed components of their admissions applications. We found no correlations of test scores, grades, amount of previous research experience, or faculty interview ratings with high or low productivity among those applicants who were admitted and chose to matriculate at UNC. In contrast, ratings from recommendation letter writers were significantly stronger for students who published multiple first-author papers in graduate school than for those who published no first-author papers during the same timeframe. We conclude that the most commonly used standardized test (the general GRE) is a particularly ineffective predictive tool, but that qualitative assessments by previous mentors are more likely to identify students who will succeed in biomedical graduate research. Based on these results, we conclude that admissions committees should avoid over-reliance on any single component of the application and de-emphasize metrics that are minimally predictive of student productivity. We recommend continual tracking of desired training outcomes combined with retrospective analysis of admissions practices to guide both application requirements and holistic application review.
- Resource type:
- Article
- Affiliation Label Tesim:
- School of Medicine
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/mc31-h989
- Identifier:
- PMCID: PMC5226343, Publisher DOI: https://doi.org/10.1371/journal.pone.0169121, PMID: 28076439, and Onescience id: ec3e3e2b82275dca7ef412fbfeb2f76a24514c5c
- ISSN:
- 1932-6203
- Journal Issue:
- 1
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Male, North Carolina, Female, Retrospective Studies, Education, Graduate, Biomedical Research, Students, School Admission Criteria, Health Occupations, Schools, Young Adult, Humans, Adult, and Educational Measurement
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Biochemistry and Biophysics
- Page Start:
- e0169121
- Person:
- O'Connell, Anna B., Hall, Joshua D., and Cook, Jeanette G.
- Rights Statement Label:
- In Copyright
- Source:
- 9z903491z
1823. Pharmacokinetics and toxicity of subcutaneous administration of carboplatin in poloxamer 407 in a rodent model pilot study
- Title Tesim:
- Pharmacokinetics and toxicity of subcutaneous administration of carboplatin in poloxamer 407 in a rodent model pilot study
- Creator:
- Zamboni, William C., Griffith, Emily, Linder, Keith E., Roberts, Brittney V., Risselada, Marije, Davidson, Gigi, and Messenger, Kristen M.
- Date of publication:
- 2017
- Abstract Tesim:
- The objectives of this study were to assess the pharmacokinetics and safety of subcutaneously delivered carboplatin in poloxamer 407 in rats. Carboplatin (5mg/rat) in 0.5ml poloxamer 407 (1.0 ml total volume) was administered subcutaneously in a right subcutaneous perineal incision in all 12 treatment rats. Three control rats received 1.0 ml of poloxamer 407. Total platinum was measured in plasma q24hrs from 0 to 168hrs. Protein-unbound platinum was measured in plasma at 168hrs. After sacrifice on day 7, total platinum was determined in wound bed muscle. Platinum concentrations in all samples were measured by ICP-MS. Wounds were visually assessed daily for 7 days. Perineal tissues (full wound bed including muscle, subcutis, skin) were assessed histologically and scored. Total platinum was detectable in plasma from 24 to 168 hrs. Total plasma platinum AUC and Cmax were 9,165.3 ng/mL•h and 129.4 ng/mL. Day 7 total platinum concentration in muscle was approximately 10-fold higher than total plasma platinum concentration. No unbound platinum was detected in plasma samples at 168 hours. No wound healing complications were detected at any time point, nor was tissue necrosis observed histologically. The results of this study suggest that subcutaneous carboplatin in poloxamer 407 can be used in vivo providing direct tissue exposure to carboplatin without significant local effects or systemic absorption and without wound healing complications.
- Resource type:
- Article
- Affiliation Label Tesim:
- Eshelman School of Pharmacy
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/ae7k-b903
- Identifier:
- PMID: 28982137, Onescience id: 9b5eb29fe71f1831b9ed694d6119681fa2c48b76, PMCID: PMC5642013, and Publisher DOI: https://doi.org/10.1371/journal.pone.0186018
- ISSN:
- 1932-6203
- Journal Issue:
- 10
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Female, Area Under Curve, Animals, Poloxamer, Rats, Injections, Subcutaneous, Antineoplastic Agents, Rats, Sprague-Dawley, Carboplatin, and Pilot Projects
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Clinical Sciences; College of Veterinary Medicine; North Carolina State University, Department of Statistics; College of Agriculture and Life Sciences; North Carolina State University, Department of Population Health and Pathobiology; College of Veterinary Medicine; North Carolina State University, Department of Veterinary Clinical Sciences; College of Veterinary Medicine; Purdue University, CPS; College of Veterinary Medicine; North Carolina State University, and Department of Molecular Biomedical Sciences; College of Veterinary Medicine; North Carolina State University
- Page Start:
- e0186018
- Person:
- Zamboni, William C., Griffith, Emily, Linder, Keith E., Roberts, Brittney V., Risselada, Marije, Davidson, Gigi, and Messenger, Kristen M.
- Rights Statement Label:
- In Copyright
- Source:
- 4q77fx42m
1824. Patterns of Contraceptive Adoption, Continuation, and Switching after Delivery among Malawian Women
- Title Tesim:
- Patterns of Contraceptive Adoption, Continuation, and Switching after Delivery among Malawian Women
- Creator:
- Stuart, Gretchen S., Mwale, Mwawi, Kopp, Dawn M., Rosenberg, Nora E., Bonongwe, Phylos, Miller, William C., Hosseinipour, Mina C., and Tang, Jennifer H.
- Date of publication:
- 2017
- Abstract Tesim:
- Women who report use of postpartum family planning may not continue their initial method or use it consistently. Understanding the patterns of method uptake, discontinuation, and switching among women after delivery is important to promote uptake and continuation of effective methods of contraception. This is a secondary analysis of 634 Malawian women enrolled into a prospective cohort study after delivery. They completed baseline surveys upon enrollment and follow-up telephone surveys 3, 6, and 12 months post-delivery. Women were included in this analysis if they had completed at least the 3- and 6-month post-delivery surveys. Descriptive statistics were used to assess contraceptive method mix and patterns of switching, whereas Pearson’s χ2 tests were used for bivariable analyses to compare characteristics of women who continued and discontinued their initial post-delivery contraceptive method. Among the 479 women included in this analysis, the use of abstinence/traditional methods decreased and the use of long-acting and permanent methods (LAPM) increased over time. Almost half (47%) discontinued the contraceptive method reported at 3-months post-delivery; women using injectables or LAPM at 3-months post-delivery were significantly more likely to continue their method than those using non-modern methods (p<0.001). Of the 216 women who switched methods, 82% switched to a more or equally effective method. The change in contraceptive method mix and high rate of contraceptive switching in the first 12 months postpartum highlights a need to assist women in accessing effective contraceptives soon after delivery.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Obstetrics and Gynecology and UNC Project-Malawi
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/nv44-kj47
- Identifier:
- PMID: 28107404, Onescience id: f5c0f7f500eef0b8cf3149a65547b5dd991c5441, Publisher DOI: https://doi.org/10.1371/journal.pone.0170284, and PMCID: PMC5249175
- ISSN:
- 1932-6203
- Journal Issue:
- 1
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Postpartum Period, Adult, Contraceptive Agents, Adolescent, Young Adult, Humans, Pregnancy, Female, and Malawi
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Bwaila Hospital; Lilongwe District Health Office, Department of Obstetrics and Gynecology, Department of Epidemiology, Malawi College of Medicine; Department of Obstetrics and Gynaecology, Division of Epidemiology; College of Public Health; Ohio State University, and Department of Medicine
- Page Start:
- e0170284
- Person:
- Stuart, Gretchen S., Mwale, Mwawi, Kopp, Dawn M., Rosenberg, Nora E., Bonongwe, Phylos, Miller, William C., Hosseinipour, Mina C., and Tang, Jennifer H.
- Rights Statement Label:
- In Copyright
- Source:
- gq67jw981
1825. Optimizing ultrasound molecular imaging of secreted frizzled related protein 2 expression in angiosarcoma
- Title Tesim:
- Optimizing ultrasound molecular imaging of secreted frizzled related protein 2 expression in angiosarcoma
- Creator:
- Klauber-DeMore, Nancy, Tsuruta, James K., Schaub, Nicholas P., Rojas, Juan D., Streeter, Jason, and Dayton, Paul
- Date of publication:
- 2017
- Abstract Tesim:
- Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. Previously, we showed ultrasound molecular imaging with SFRP2-targeted contrast increased average video pixel intensity (VI) of angiosarcoma vessels by 2.2 ± 0.6 VI versus streptavidin contrast. We hypothesized that redesigning our contrast agents would increase imaging performance. Improved molecular imaging reagents were created by combining NeutrAvidin™-functionalized microbubbles with biotinylated SFRP2 or IgY control antibodies. When angiosarcoma tumors in nude mice reached 8 mm, time-intensity, antibody loading, and microbubble dose experiments optimized molecular imaging. 10 minutes after injection, the control-subtracted time-intensity curve (TIC) for SFRP2-targeted contrast reached a maximum, after subtracting the contribution of free-flowing contrast. SFRP2 antibody-targeted VI was greater when contrast was formulated with 10-fold molar excess of maleimide-activated NeutrAvidin™ versus 3-fold (4.5 ± 0.18 vs. 0.32 ± 0.15, VI ± SEM, 5 x 106 dose, p < 0.001). Tumor vasculature returned greater average video pixel intensity using 5 x 107 versus 5 x 106 microbubbles (21.2 ± 2.5 vs. 4.5 ± 0.18, p = 0.0011). Specificity for tumor vasculature was confirmed by low VI for SFRP2-targeted, and control contrast in peri-tumoral vasculature (3.2 ± 0.52 vs. 1.6 ± 0.71, p = 0.92). After optimization, average video pixel intensity of tumor vasculature was 14.2 ± 3.0 VI units higher with SFRP2-targeted contrast versus IgY-targeted control (22.1 ± 2.5 vs. 7.9 ± 1.6, p < 0.001). After log decompression, 14.2 ΔVI was equal to ~70% higher signal, in arbitray acoustic units (AU), for SFRP2 versus IgY. This provided ~18- fold higher acoustic signal enhancement than provided previously by 2.2 ΔVI. Basing our targeted contrast on NeutrAvidin™-functionalized microbubbles, using IgY antibodies for our control contrast, and optimizing our imaging protocol significantly increased the SFRP2-specific signal returned from angiosarcoma vasculature, and may provide new opportunities for targeted molecular imaging.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Pediatrics, Department of Surgery, and Division of Molecular Pharmaceutics
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/t9vy-ze74
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pone.0174281, PMID: 28333964, Onescience id: b0ebbba1eb2768f7d78e2d0c7a6a9b2485ee5d48, and PMCID: PMC5363853
- ISSN:
- 1932-6203
- Journal Issue:
- 3
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Biochemistry, Diagnostic Medicine, Developmental Biology, Biology and Life Sciences, Physiology, Optimization, Research and Analysis Methods, Angiosarcoma, Bioacoustics, Radiology and Imaging, Medicine, Imaging Techniques, Sarcomas, Acoustic Signals, Science, Physics, Cardiovascular Physiology, Diagnostic Radiology, Q, Cancers and Neoplasms, Mathematics, Physical Sciences, Basic Cancer Research, Angiogenesis, R, Medicine an, Lipids, Research Article, Ultrasound Imaging, Tumor Physiology, Oncology, Tumor Angiogenesis, and Acoustics
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Engineering Science; Loyola University Chicago, Department of Surgery; Medical College of South Carolina, and Joint Department of Biomedical Engineering; North Carolina State University; University of North Carolina at Chapel Hill
- Page Start:
- e0174281
- Person:
- Klauber-DeMore, Nancy, Tsuruta, James K., Schaub, Nicholas P., Rojas, Juan D., Streeter, Jason, and Dayton, Paul
- Rights Statement Label:
- In Copyright
- Source:
- jm214v49f
1826. Novel application of the published kinase inhibitor set to identify therapeutic targets and pathways in triple negative breast cancer subtypes
- Title Tesim:
- Novel application of the published kinase inhibitor set to identify therapeutic targets and pathways in triple negative breast cancer subtypes
- Creator:
- Phamduy, Theresa B., Collins-Burow, Bridgette, Chrisey, Douglas B., Matossian, Margarite D., Wells, Carrow, Hoang, Van T., Elliott, Steven, Drewry, David H., Burow, Matthew E., Zuercher, William J., and Burks, Hope E.
- Date of publication:
- 2017
- Abstract Tesim:
- Triple negative breast cancers (TNBCs) have high recurrence and metastasis rates. Acquisition of a mesenchymal morphology and phenotype in addition to driving migration is a consequential process that promotes metastasis. Although some kinases are known to regulate a mesenchymal phenotype, the role for a substantial portion of the human kinome remains uncharacterized. Here we evaluated the Published Kinase Inhibitor Set (PKIS) and screened a panel of TNBC cell lines to evaluate the compounds’ effects on a mesenchymal phenotype. Our screen identified 36 hits representative of twelve kinase inhibitor chemotypes based on reversal of the mesenchymal cell morphology, which was then prioritized to twelve compounds based on gene expression and migratory behavior analyses. We selected the most active compound and confirmed mesenchymal reversal on transcript and protein levels with qRT-PCR and Western Blot. Finally, we utilized a kinase array to identify candidate kinases responsible for the EMT reversal. This investigation shows the novel application to identify previously unrecognized kinase pathways and targets in acquisition of a mesenchymal TNBC phenotype that warrant further investigation. Future studies will examine specific roles of the kinases in mechanisms responsible for acquisition of the mesenchymal and/or migratory phenotype.
- Resource type:
- Article
- Affiliation Label Tesim:
- Eshelman School of Pharmacy
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/2kr8-5z68
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pone.0177802, PMCID: PMC5542472, Onescience id: 57a1a68dae0948c730f3f33724eef2e789cafc02, and PMID: 28771473
- ISSN:
- 1932-6203
- Journal Issue:
- 8
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Cancers and Neoplasms, Enzymology, Breast Tumors, Phenotypes, Developmental Biology, Genetics, Molecular Biology Techniques, Cancer Treatment, Molecular Biology, Biotechnology, Biology and Life Sciences, Research and Analysis Methods, Molecular Biology Assays and Analysis Techniques, Chemistry, Research Article, Oncology, Cell Motility, Library Screening, Cell Migration, Chemical Compounds, Kinase Inhibitors, Organic Chemistry, Breast Cancer, and Physical Sciences
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Physics; Tulane University and Department of Medicine: Section of Hematology and Oncology; Tulane University
- Page Start:
- e0177802
- Person:
- Phamduy, Theresa B., Collins-Burow, Bridgette, Chrisey, Douglas B., Matossian, Margarite D., Wells, Carrow, Hoang, Van T., Elliott, Steven, Drewry, David H., Burow, Matthew E., Zuercher, William J., and Burks, Hope E.
- Rights Statement Label:
- In Copyright
- Source:
- b2774156x
1827. No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival
- Title Tesim:
- No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival
- Creator:
- Berwick, Marianne, Kanetsky, Peter A., Lee, Ji-Hyun, Lee, Jeffrey E., Thomas, Nancy E., Orlow, Irene, Fang, Shenying, and Luo, Li
- Date of publication:
- 2017
- Abstract Tesim:
- The prognostic improvement attributed to genetic markers over current prognostic system has not been well studied for melanoma. The goal of this study is to evaluate the added prognostic value of Vitamin D Pathway (VitD) SNPs to currently known clinical and demographic factors such as age, sex, Breslow thickness, mitosis and ulceration (CDF). We utilized two large independent well-characterized melanoma studies: the Genes, Environment, and Melanoma (GEM) and MD Anderson studies, and performed variable selection of VitD pathway SNPs and CDF using Random Survival Forest (RSF) method in addition to Cox proportional hazards models. The Harrell’s C-index was used to compare the performance of model predictability. The population-based GEM study enrolled 3,578 incident cases of cutaneous melanoma (CM), and the hospital-based MD Anderson study consisted of 1,804 CM patients. Including both VitD SNPs and CDF yielded C-index of 0.85, which provided slight but not significant improvement by CDF alone (C-index = 0.83) in the GEM study. Similar results were observed in the independent MD Anderson study (C-index = 0.84 and 0.83, respectively). The Cox model identified no significant associations after adjusting for multiplicity. Our results do not support clinically significant prognostic improvements attributable to VitD pathway SNPs over current prognostic system for melanoma survival.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Dermatology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/a1pr-rs08
- Identifier:
- PMID: 28323902, Publisher DOI: https://doi.org/10.1371/journal.pone.0174234, Onescience id: 3ab0261aa59f828d004c220164b63339cb6c83c6, and PMCID: PMC5360355
- ISSN:
- 1932-6203
- Journal Issue:
- 3
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Middle Aged, Vitamin D Deficiency, Proportional Hazards Models, Male, Melanoma, Cutaneous Malignant, Biomarkers, Tumor, Prognosis, Skin Neoplasms, Receptors, Calcitriol, Polymorphism, Single Nucleotide, Melanoma, Female, Humans, and Vitamin D
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Internal Medicine; University of New Mexico, University of New Mexico Comprehensive Cancer Center, Department of Cancer Epidemiology; H. Lee Moffitt Cancer Center Annd Research Institute, Department of Surgical Oncology; University of Texas MD Anderson Cancer Center, and Department of Epidemiology and Biostatistics; Epidemiology Service; Memorial Sloan Kettering Cancer Center
- Page Start:
- e0174234
- Person:
- Berwick, Marianne, Kanetsky, Peter A., Lee, Ji-Hyun, Lee, Jeffrey E., Thomas, Nancy E., Orlow, Irene, Fang, Shenying, and Luo, Li
- Rights Statement Label:
- In Copyright
- Source:
- hx11xm60f
1828. NNKTT120, an anti-iNKT cell monoclonal antibody, produces rapid and sustained iNKT cell depletion in adults with sickle cell disease
- Title Tesim:
- NNKTT120, an anti-iNKT cell monoclonal antibody, produces rapid and sustained iNKT cell depletion in adults with sickle cell disease
- Creator:
- Ataga, Kenneth I., Schaub, Robert, Majerus, Elaine, Mashal, Robert, Nathan, David G., Vichinsky, Elliot P., and Field, Joshua J.
- Date of publication:
- 2017
- Abstract Tesim:
- Invariant NKT (iNKT) cells can be activated to stimulate a broad inflammatory response. In murine models of sickle cell disease (SCD), interruption of iNKT cell activity prevents tissue injury from vaso-occlusion. NKTT120 is an anti-iNKT cell monoclonal antibody that has the potential to rapidly and specifically deplete iNKT cells and, potentially, prevent vaso-occlusion. We conducted an open-label, multi-center, single-ascending-dose study of NKTT120 to determine its pharmacokinetics, pharmacodynamics and safety in steady-state patients with SCD. Doses were escalated in a 3+3 study design over a range from 0.001 mg/kg to 1.0 mg/kg. Twenty-one adults with SCD were administered NKTT120 as part of 7 dose cohorts. Plasma levels of NKTT120 predictably increased with higher doses. Median half-life of NKTT120 was 263 hours. All subjects in the higher dose cohorts (0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg) demonstrated decreased iNKT cells below the lower limit of quantification within 6 hours after infusion, the earliest time point at which they were measured. In those subjects who received the two highest doses of NKTT120 (0.3, 1 mg/kg), iNKT cells were not detectable in the peripheral blood for a range of 2 to 5 months. There were no serious adverse events in the study deemed to be related to NKTT120. In adults with SCD, NKTT120 produced rapid, specific and sustained iNKT cell depletion without any infusional toxicity or attributed serious adverse events. The next step is a trial to determine NKTT120’s ability to decrease rate of vaso-occlusive pain episodes.
- Resource type:
- Article
- Affiliation Label Tesim:
- University of North Carolina at Chapel Hill
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/vfrm-mn40
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pone.0171067, PMID: 28152086, PMCID: PMC5289534, and Onescience id: 22a480dbcee0c2f523a18a70ce42b8e5d1b4b98d
- ISSN:
- 1932-6203
- Journal Issue:
- 2
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Immune System, Immune Physiology, Animal Cells, Morbidity, Pharmacokinetics, Blood Cells, Pharmacodynamics, Body Fluids, Health Statistics, Clinical Research Design, Pharmacology, Health Care, Hematology, Immune Cells, T Cells, Cellular Types, Blood, Physiology, Adverse Events, Biology and Life Sciences, Immunology, Cytokines, Cell Biology, Medicine and Health Sciences, Anatomy, and White Blood Cells
- Language Label:
- English
- ORCID:
- Other Affiliation:
- NKT Therapeutics, Department of Medicine; Washington University in St. Louis, Harvard Medical School, Dana-Farber Cancer Institute, Boston Children's Hospital, Oakland Children's Hospital, Department of Medicine; Medical College of Wisconsin, and Blood Center of Wisconsin; Medical Sciences Institute
- Page Start:
- e0171067
- Person:
- Ataga, Kenneth I., Schaub, Robert, Majerus, Elaine, Mashal, Robert, Nathan, David G., Vichinsky, Elliot P., and Field, Joshua J.
- Rights Statement Label:
- In Copyright
- Source:
- r781wn25g
1829. Nearest shrunken centroids via alternative genewise shrinkages
- Title Tesim:
- Nearest shrunken centroids via alternative genewise shrinkages
- Creator:
- Choi, Byeong Yeob, Lee, Jae Won, and Bair, Eric
- Date of publication:
- 2017
- Abstract Tesim:
- Nearest shrunken centroids (NSC) is a popular classification method for microarray data. NSC calculates centroids for each class and “shrinks” the centroids toward 0 using soft thresholding. Future observations are then assigned to the class with the minimum distance between the observation and the (shrunken) centroid. Under certain conditions the soft shrinkage used by NSC is equivalent to a LASSO penalty. However, this penalty can produce biased estimates when the true coefficients are large. In addition, NSC ignores the fact that multiple measures of the same gene are likely to be related to one another. We consider several alternative genewise shrinkage methods to address the aforementioned shortcomings of NSC. Three alternative penalties were considered: the smoothly clipped absolute deviation (SCAD), the adaptive LASSO (ADA), and the minimax concave penalty (MCP). We also showed that NSC can be performed in a genewise manner. Classification methods were derived for each alternative shrinkage method or alternative genewise penalty, and the performance of each new classification method was compared with that of conventional NSC on several simulated and real microarray data sets. Moreover, we applied the geometric mean approach for the alternative penalty functions. In general the alternative (genewise) penalties required fewer genes than NSC. The geometric mean of the class-specific prediction accuracies was improved, as well as the overall predictive accuracy in some cases. These results indicate that these alternative penalties should be considered when using NSC.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Biostatistics
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/7k2j-hz18
- Identifier:
- PMID: 28199352, Publisher DOI: https://doi.org/10.1371/journal.pone.0171068, Onescience id: 95513a3f566f48a323821b0408a94aa389bbc4cf, and PMCID: PMC5310887
- ISSN:
- 1932-6203
- Journal Issue:
- 2
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Algorithms, Oligonucleotide Array Sequence Analysis, Breast Neoplasms, Computer Simulation, Central Nervous System Diseases, Female, and Humans
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Epidemiology and Biostatistics; University of Texas; Health Science Center, Department of Statistics; Korea University, and Department of Endodontics
- Page Start:
- e0171068
- Person:
- Choi, Byeong Yeob, Lee, Jae Won, and Bair, Eric
- Rights Statement Label:
- In Copyright
- Source:
- 8336h6993
1830. Multi-scale model of drug induced adaptive resistance of Gram-negative bacteria to polymyxin B
- Title Tesim:
- Multi-scale model of drug induced adaptive resistance of Gram-negative bacteria to polymyxin B
- Creator:
- Krzyzanski, Wojciech and Rao, Gauri G.
- Date of publication:
- 2017
- Abstract Tesim:
- The purpose of this report is to apply multi-scale modeling using the theory of physiologically structured populations (PSP) to develop a mathematical model for antimicrobial resistance based on a heterogeneous distribution of receptors and affinities among bacterial cells. The theory has been tested on data obtained from an in vitro static time-kill infection model analyzing the pharmacodynamics of polymyxin B against Gram-negative bacteria. The drug binding parameter KD (dissociation equilibrium constant) is assumed to vary between the bacterial cells. The PSP model describes the time course of the density distribution of KD upon exposure to cytotoxic drug concentrations. The drug increases the hazard of cell death as a function of receptor occupancy. The initial distribution of KD is described by the Weibull function. Time-kill data were used for model qualification. In vitro static time-kill experiments to evaluate the rate and extent of killing due to polymyxin B against two Klebsiella pneumoniae clinical isolates with differing susceptibilities to polymyxin B were performed over 48 h. The time-kill kinetics data of bacterial load cfu (colony forming units)/mL was used for model qualification. The resistant bacterial population is determined by the balance between growth rate and hazard of cell death controlled by polymyxin B concentrations. There exists a critical KD value below which cells continue to grow. Estimates of shape parameters for distributions of KD yielded unimodal distributions with the modes at 0 nM and the right tails containing approximately 25% of the bacteria. Our findings support a hypothesis that resistance of Klebsiella pneumoniae to polymyxin B can be at least partially attributed to a drug-induced selection of a subpopulation due to heterogeneity of polymyxin B receptor binding in the bacterial population.
- Resource type:
- Article
- Affiliation Label Tesim:
- Division of Pharmacotherapy and Experimental Therapeutics
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/hazp-7g29
- Identifier:
- Onescience id: 23d1c92074c46acc60e6cd16196428993c4e65f6, PMID: 28334005, PMCID: PMC5363806, and Publisher DOI: https://doi.org/10.1371/journal.pone.0171834
- ISSN:
- 1932-6203
- Journal Issue:
- 3
- Journal Title:
- PloS One
- Journal Volume:
- 12
- Keyword:
- Kinetics, Cell Death, Klebsiella pneumoniae, Anti-Bacterial Agents, Microbial Sensitivity Tests, Gram-Negative Bacteria, Drug Resistance, Bacterial, and Polymyxin B
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Pharmaceutical Sciences; School of Pharmacy Practice and Pharmaceutical Sciences; University at Buffalo
- Page Start:
- e0171834
- Person:
- Krzyzanski, Wojciech and Rao, Gauri G.
- Rights Statement Label:
- In Copyright
- Source:
- bz60d2389
Collection Details
- Total items
-
2112
- Size
-
unknown
- Date created
-
February 2, 2022