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  1. Article ; Online: Repurposing the FDA-approved anthelmintic pyrvinium pamoate for pancreatic cancer treatment

    Benjamin E Leiby / Charles Yeo / James Posey / Avinoam Nevler / Harish Lavu / T Yeo / Francesca M Ponzini / Christopher W Schultz / Shawnna Cannaday / Wilbur B Bowne / Jonathan R Brody

    BMJ Open, Vol 13, Iss

    study protocol for a phase I clinical trial in early-stage pancreatic ductal adenocarcinoma

    2023  Volume 10

    Abstract: Background Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we ... ...

    Abstract Background Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates.Methods and analysis In a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will be continued to a reach a maximum of 20 mg/kg orally for 3 days, if the previous two dosages (5 mg/kg and 10 mg/kg) were tolerated. Dose-limiting toxicity grade≥3 is used as the primary endpoint. The pharmacokinetic and pharmacodynamic (PK/PD) profile of PP and bioavailability in humans will be used as the secondary objective. Each participant will be monitored weekly for a total of 30 days from the final dose of PP for any side effects. The purpose of this clinical trial is to examine whether PP is safe and tolerable in patients with pancreatic cancer, as well as assess the drug’s PK/PD profile in plasma and fatty tissue. Potential implications include the utilisation of PP in a synergistic manner with chemotherapeutics for the treatment of pancreatic cancer.Ethics and dissemination This study was approved by the Thomas Jefferson Institutional Review Board. The protocol number for this study is 20F.041 (Version 3.1 as of 27 October 2021). The data collected and analysed from this study will be used to present at local and national conferences, as well as, written into peer-reviewed manuscript publications.Trial registration number ClinicalTrials.gov: NCT05055323.
    Keywords Medicine ; R
    Subject code 610
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher BMJ Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The diverse club

    M. A. Bertolero / B. T. T. Yeo / M. D’Esposito

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 11

    Abstract: Complex networks represent systems such as neural networks and air traffic as interconnected nodes that organize themselves into subsets. Here Bertolero et al. propose a subset which they call the diverse club, which offers an alternative to the commonly ...

    Abstract Complex networks represent systems such as neural networks and air traffic as interconnected nodes that organize themselves into subsets. Here Bertolero et al. propose a subset which they call the diverse club, which offers an alternative to the commonly used rich club.
    Keywords Science ; Q
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: The diverse club

    M. A. Bertolero / B. T. T. Yeo / M. D’Esposito

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 11

    Abstract: Complex networks represent systems such as neural networks and air traffic as interconnected nodes that organize themselves into subsets. Here Bertolero et al. propose a subset which they call the diverse club, which offers an alternative to the commonly ...

    Abstract Complex networks represent systems such as neural networks and air traffic as interconnected nodes that organize themselves into subsets. Here Bertolero et al. propose a subset which they call the diverse club, which offers an alternative to the commonly used rich club.
    Keywords Science ; Q
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Serratia marcescens in the neonatal intensive care unit

    Kee T. Yeo / Sophie Octavia / Kian Lim / Cui Lin / Raymond Lin / Koh C. Thoon / Nancy W.S. Tee / Chee F. Yung

    Journal of Infection and Public Health, Vol 13, Iss 7, Pp 1006-

    A cluster investigation using molecular methods

    2020  Volume 1011

    Abstract: Background: Serratia marcescens (S. marcescens) is associated with nosocomial infections with significant morbidity and mortality in the neonatal intensive care units (NICU). We describe the control of a multi-clonal S. marcescens infections outbreak in ... ...

    Abstract Background: Serratia marcescens (S. marcescens) is associated with nosocomial infections with significant morbidity and mortality in the neonatal intensive care units (NICU). We describe the control of a multi-clonal S. marcescens infections outbreak in our tertiary-level NICU and the application of molecular typing using repetitive element palindromic PCR (rep-PCR) and next generation sequencing (NGS) in the investigation. Methods: Outbreak investigation was performed where clinical, spatial and epidemiologic links were established. Screening of all infants in the NICU and the environment was performed. Rep-PCR and NGS methods were used to identify potential environmental sources of infections and clustering among cases. Results: Eleven cases were detected during the outbreak period: mean gestational age 27 weeks (range: 24–32), predominantly male (82%), mean age of infection 24 days (range: 6–51). Six infants were treated for conjunctivitis and one for bacteraemia. Identification of colonized infant via a point prevalence survey and cohorting of all infected/colonized patients were implemented. We performed environmental swabbing of surfaces, water outlets, chlorhexidine hand wash solutions and hand hygiene hand rubs. Both rep-PCR and NGS classified the 11 case isolates into 5 types. No point source was identified except for a single positive environmental isolate from a sink which was clonally distinct from the cases. Conclusion: Identification and cohorting of infected/colonized patient was important in the control of S. marcescens outbreak in the NICU. The utility of rep-PCR was comparable to NGS in providing molecular information to develop S. marcescens outbreak control strategies.
    Keywords Serratia marcescens ; Outbreak ; Rep-PCR ; Molecular epidemiology ; Single nucleotide polymorphism (SNP) ; Infectious and parasitic diseases ; RC109-216 ; Public aspects of medicine ; RA1-1270
    Subject code 630
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Inhibition of Oncogenic Transcription Factor REL by the Natural Product Derivative Calafianin Monomer 101 Induces Proliferation Arrest and Apoptosis in Human B-Lymphoma Cell Lines

    Alan T. Yeo / Spandan Chennamadhavuni / Adrian Whitty / John A. Porco / Thomas D. Gilmore

    Molecules, Vol 20, Iss 5, Pp 7474-

    2015  Volume 7494

    Abstract: Increased activity of transcription factor NF-κB has been implicated in many B-cell lymphomas. We investigated effects of synthetic compound calafianin monomer (CM101) on biochemical and biological properties of NF-κB. In human 293 cells, CM101 ... ...

    Abstract Increased activity of transcription factor NF-κB has been implicated in many B-cell lymphomas. We investigated effects of synthetic compound calafianin monomer (CM101) on biochemical and biological properties of NF-κB. In human 293 cells, CM101 selectively inhibited DNA binding by overexpressed NF-κB subunits REL (human c-Rel) and p65 as compared to NF-κB p50, and inhibition of REL and p65 DNA binding by CM101 required a conserved cysteine residue. CM101 also inhibited DNA binding by REL in human B-lymphoma cell lines, and the sensitivity of several B-lymphoma cell lines to CM101-induced proliferation arrest and apoptosis correlated with levels of cellular and nuclear REL. CM101 treatment induced both phosphorylation and decreased expression of anti-apoptotic protein Bcl-XL, a REL target gene product, in sensitive B-lymphoma cell lines. Ectopic expression of Bcl-XL protected SUDHL-2 B-lymphoma cells against CM101-induced apoptosis, and overexpression of a transforming mutant of REL decreased the sensitivity of BJAB B-lymphoma cells to CM101-induced apoptosis. Lipopolysaccharide-induced activation of NF-κB signaling upstream components occurred in RAW264.7 macrophages at CM101 concentrations that blocked NF-κB DNA binding. Direct inhibitors of REL may be useful for treating B-cell lymphomas in which REL is active, and may inhibit B-lymphoma cell growth at doses that do not affect some immune-related responses in normal cells.
    Keywords c-Rel ; REL ; NF-kappaB ; chemical inhibitor ; B-cell lymphoma ; calafianin ; natural product ; Organic chemistry ; QD241-441
    Language English
    Publishing date 2015-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: CRISPR/Cas9-based editing of a sensitive transcriptional regulatory element to achieve cell type-specific knockdown of the NEMO scaffold protein.

    Milad Babaei / Yuekun Liu / Shelly M Wuerzberger-Davis / Ethan Z McCaslin / Christopher J DiRusso / Alan T Yeo / Larisa Kagermazova / Shigeki Miyamoto / Thomas D Gilmore

    PLoS ONE, Vol 14, Iss 9, p e

    2019  Volume 0222588

    Abstract: The use of alternative promoters for the cell type-specific expression of a given mRNA/protein is a common cell strategy. NEMO is a scaffold protein required for canonical NF-κB signaling. Transcription of the NEMO gene is primarily controlled by two ... ...

    Abstract The use of alternative promoters for the cell type-specific expression of a given mRNA/protein is a common cell strategy. NEMO is a scaffold protein required for canonical NF-κB signaling. Transcription of the NEMO gene is primarily controlled by two promoters: one (promoter B) drives NEMO transcription in most cell types and the second (promoter D) is largely responsible for NEMO transcription in liver cells. Herein, we have used a CRISPR/Cas9-based approach to disrupt a core sequence element of promoter B, and this genetic editing essentially eliminates expression of NEMO mRNA and protein in 293T human kidney cells. By cell subcloning, we have isolated targeted 293T cell lines that express no detectable NEMO protein, have defined genomic alterations at promoter B, and do not support activation of canonical NF-κB signaling in response to treatment with tumor necrosis factor. Nevertheless, non-canonical NF-κB signaling is intact in these NEMO-deficient cells. Expression of ectopic wild-type NEMO, but not certain human NEMO disease mutants, in the edited cells restores downstream NF-κB signaling in response to tumor necrosis factor. Targeting of the promoter B element does not substantially reduce NEMO expression (from promoter D) in the human SNU-423 liver cancer cell line. Thus, we have created a strategy for selectively eliminating cell type-specific expression from an alternative promoter and have generated 293T cell lines with a functional knockout of NEMO. The implications of these findings for further studies and for therapeutic approaches to target canonical NF-κB signaling are discussed.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: The Effects of TLR Activation on T-Cell Development and Differentiation

    Bo Jin / Tao Sun / Xiao-Hong Yu / Ying-Xiang Yang / Anthony E. T. Yeo

    Clinical and Developmental Immunology, Vol

    2012  Volume 2012

    Abstract: Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are ... ...

    Abstract Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.
    Keywords Medicine ; R ; Internal medicine ; RC31-1245 ; Specialties of internal medicine ; RC581-951 ; Immunologic diseases. Allergy ; RC581-607
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine

    Hyun Jung Jun / Vicky A. Appleman / Hua-Jun Wu / Christopher M. Rose / Javier J. Pineda / Alan T. Yeo / Bethany Delcuze / Charlotte Lee / Aron Gyuris / Haihao Zhu / Steve Woolfenden / Agnieszka Bronisz / Ichiro Nakano / Ennio A. Chiocca / Roderick T. Bronson / Keith L. Ligon / Jann N. Sarkaria / Steve P. Gygi / Franziska Michor /
    Timothy J. Mitchison / Al Charest

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 13

    Abstract: Amplification of PDGFRα is a common alteration in glioblastoma. In this study, the authors develop a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFR and discover Stathmin1 as an important PDGFRα ... ...

    Abstract Amplification of PDGFRα is a common alteration in glioblastoma. In this study, the authors develop a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFR and discover Stathmin1 as an important PDGFRα regulated-protein involved in the response to vinstabline.
    Keywords Science ; Q
    Language English
    Publishing date 2018-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine

    Hyun Jung Jun / Vicky A. Appleman / Hua-Jun Wu / Christopher M. Rose / Javier J. Pineda / Alan T. Yeo / Bethany Delcuze / Charlotte Lee / Aron Gyuris / Haihao Zhu / Steve Woolfenden / Agnieszka Bronisz / Ichiro Nakano / Ennio A. Chiocca / Roderick T. Bronson / Keith L. Ligon / Jann N. Sarkaria / Steve P. Gygi / Franziska Michor /
    Timothy J. Mitchison / Al Charest

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 13

    Abstract: Amplification of PDGFRα is a common alteration in glioblastoma. In this study, the authors develop a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFR and discover Stathmin1 as an important PDGFRα ... ...

    Abstract Amplification of PDGFRα is a common alteration in glioblastoma. In this study, the authors develop a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFR and discover Stathmin1 as an important PDGFRα regulated-protein involved in the response to vinstabline.
    Keywords Science ; Q
    Language English
    Publishing date 2018-08-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Mimotope ELISA for detection of broad spectrum antibody against avian H5N1 influenza virus.

    Yingwei Chen / Wenxin Luo / Huijuan Song / Boyuan Yin / Jixian Tang / Yixin Chen / Mun Hon Ng / Anthony E T Yeo / Jun Zhang / Ningshao Xia

    PLoS ONE, Vol 6, Iss 9, p e

    2011  Volume 24144

    Abstract: BACKGROUND: We have raised a panel of broad spectrum neutralizing monoclonal antibodies against the highly pathogenic H5N1 avian influenza virus, which neutralize the infectivity of, and afford protection against infection by, most of the major genetic ... ...

    Abstract BACKGROUND: We have raised a panel of broad spectrum neutralizing monoclonal antibodies against the highly pathogenic H5N1 avian influenza virus, which neutralize the infectivity of, and afford protection against infection by, most of the major genetic groups of the virus evolved since 1997. Peptide mimics reactive with one of these broad spectrum H5N1 neutralizing antibodies, 8H5, were identified from random phage display libraries. METHOD: The amino acid residues of the most reactive 12mer peptide, p125 (DTPLTTAALRLV), were randomly substituted to improve its mimicry of the natural 8H5 epitope. RESULT: 133 reactive peptides with unique amino acid sequences were identified from 5 sub-libraries of p125. Four residues (2,4,5.9) of the parental peptide were preserved among all the derived peptides and probably essential for 8H5 binding. These are interspersed among four other residues (1,3,8,10), which exhibit restricted substitution and probably could contribute to binding, and another four (6,7,11,12) which could be randomly substituted and probably are not essential for binding. One peptide, V-1b, derived by substituting 5 of the latter residues is the most reactive and has a binding constant of 3.16×10(-9) M, which is 38 fold higher than the affinity of the parental p125. Immunoassay produced with this peptide is specifically reactive with 8H5 but not also the other related broad spectrum H5N1 avian influenza virus neutralizing antibodies. Serum samples from 29 chickens infected with H5N1 avian influenza virus gave a positive result by this assay and those from 12 uninfected animals gave a negative test result. CONCLUSION: The immunoassay produced with the 12 mer peptide,V1-b, is specific for the natural 8H5 epitope and can be used for detection of antibody against the broad spectrum neutralization site of H5N1 avian influenza virus.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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