Browse Health
Pediatrician, Oncology Specialist (cancer), Pediatric Specialist
7 years of experience
Accepting new patients

Education ?

Medical School Score
Wayne State University (2003)
  • Currently 1 of 4 apples

Awards & Distinctions ?

Associations
American Board of Pediatrics
American Society of Hematology

Affiliations ?

Dr. Callaghan is affiliated with 3 hospitals.

Hospital Affilations

Score

Rankings

  • Detroit Receiving Hospital & University Health Center
    4201 Saint Antoine St, Detroit, MI 48201
    • Currently 3 of 4 crosses
    Top 50%
  • Children's Hospital of Michigan
    3901 Beaubien St, Detroit, MI 48201
  • Sinai-Grace Hospital
    6071 W Outer Dr, Detroit, MI 48235
  • Publications & Research

    Dr. Callaghan has contributed to 8 publications.
    Title Complementary Cell-based High-throughput Screens Identify Novel Modulators of the Unfolded Protein Response.
    Date January 2012
    Journal Journal of Biomolecular Screening
    Excerpt

    Despite advances toward understanding the prevention and treatment of many cancers, patients who suffer from oral squamous cell carcinoma (OSCC) confront a survival rate that has remained unimproved for more than 2 decades, indicating our ability to treat them pharmacologically has reached a plateau. In an ongoing effort to improve the clinical outlook for this disease, we previously reported that an essential component of the mechanism by which the proteasome inhibitor bortezomib (PS-341, Velcade) induced apoptosis in OSCC required the activation of a terminal unfolded protein response (UPR). Predicated on these studies, the authors hypothesized that high-throughput screening (HTS) of large diverse chemical libraries might identify more potent or selective small-molecule activators of the apoptotic arm of the UPR to control or kill OSCC. They have developed complementary cell-based assays using stably transfected CHO-K1 cell lines that individually assess the PERK/eIF2α/CHOP (apoptotic) or the IRE1/XBP1 (adaptive) UPR subpathways. An 66 K compound collection was screened at the University of Michigan Center for Chemical Genomics that included a unique library of prefractionated natural product extracts. The mycotoxin methoxycitrinin was isolated from a natural extract and found to selectively activate the CHOP-luciferase reporter at 80 µM. A series of citrinin derivatives was isolated from these extracts, including a unique congener that has not been previously described. In an effort to identify more potent compounds, the authors examined the ability of citrinin and the structurally related mycotoxins ochratoxin A and patulin to activate the UPR. Strikingly, it was found that patulin at 2.5 to 10 µM induced a terminal UPR in a panel of OSCC cells that was characterized by an increase in CHOP, GADD34, and ATF3 gene expression and XBP1 splicing. A luminescent caspase assay and the induction of several BH3-only genes indicated that patulin could induce apoptosis in OSCC cells. These data support the use of this complementary HTS strategy to identify novel modulators of UPR signaling and tumor cell death.

    Title Large-scale Analysis of Upr-mediated Apoptosis in Human Cells.
    Date May 2011
    Journal Methods in Enzymology
    Excerpt

    The historic distinction between academic- and industry-driven drug discovery, whereby academicians worked to identify therapeutic targets and pharmaceutical companies advanced probe discovery, has been blurred by an academic high-throughput chemical genomic revolution. It is now common for academic labs to use biochemical or cell-based high-throughput screening (HTS) to investigate the effects of thousands or even hundreds of thousands of chemical probes on one or more targets over a period of days or weeks. To support the efforts of individual investigators, many universities have established core facilities where screening can be performed collaboratively with large chemical libraries managed by highly trained HTS personnel and guided by the experience of computational, medicinal, and synthetic organic chemists. The identification of large numbers of promising hits from such screens has driven the need for independent labs to scale down secondary in vitro assays in the hit to lead identification process. In this chapter, we will describe the use of luminescent and quantitative reverse transcription real-time PCR (qRT-PCR) technologies that permit evaluation of the expression patterns of multiple unfolded protein response (UPR) and apoptosis-related genes, and simultaneously evaluate proliferation and cell death in 96- or 384-well format.

    Title Ethanol Lock Therapy for the Treatment of Catheter-related Infections in Haemophilia Patients.
    Date August 2010
    Journal Haemophilia : the Official Journal of the World Federation of Hemophilia
    Excerpt

    Central venous access devices (CVAD) are increasingly being used for optimal delivery of clotting factor concentrates in patients with haemophilia with poor peripheral venous access. The utility of CVAD is particularly well recognized in young patients starting factor prophylaxis and in patients with inhibitors undergoing immune tolerance induction (ITI). A catheter-related infection (CRI) remains the most common complication of CVAD in haemophilia patients and is the most frequent indication for its removal. Additionally, in some patients the infection results in significant morbidity and mortality and also contributes to failure of the ITI regimen. Ethanol-lock therapy (ELT) is a treatment modality that has been used to treat CRI in patients with indwelling catheters for home parenteral nutrition and chemotherapy. The aim of this study was to report the success in treating CRI in haemophilia patients using ELT. Three severe haemophilia A patients undergoing ITI regimen who developed CVAD infections resistant to conventional management with antibiotics were treated by ELT according to the institutional technique. All three patients responded well to ELT with clearance of the CVAD infection. There were no adverse side effects. To our knowledge, this is the first report of ELT in patients with haemophilia. The role of ELT needs to be investigated in larger studies for treatment of CRI in patients with bleeding disorders.

    Title Index of Suspicion.
    Date July 2010
    Journal Pediatrics in Review / American Academy of Pediatrics
    Title Upr Pathways Combine to Prevent Hepatic Steatosis Caused by Er Stress-mediated Suppression of Transcriptional Master Regulators.
    Date January 2009
    Journal Developmental Cell
    Excerpt

    The unfolded protein response (UPR) is linked to metabolic dysfunction, yet it is not known how endoplasmic reticulum (ER) disruption might influence metabolic pathways. Using a multilayered genetic approach, we find that mice with genetic ablations of either ER stress-sensing pathways (ATF6alpha, eIF2alpha, IRE1alpha) or of ER quality control (p58(IPK)) share a common dysregulated response to ER stress that includes the development of hepatic microvesicular steatosis. Rescue of ER protein processing capacity by the combined action of UPR pathways during stress prevents the suppression of a subset of metabolic transcription factors that regulate lipid homeostasis. This suppression occurs in part by unresolved ER stress perpetuating expression of the transcriptional repressor CHOP. As a consequence, metabolic gene expression networks are directly responsive to ER homeostasis. These results reveal an unanticipated direct link between ER homeostasis and the transcriptional regulation of metabolism, and suggest mechanisms by which ER stress might underlie fatty liver disease.

    Title Decreased Clearance of Von Willebrand Factor in a Patient with Type 2b Von Willebrand Disease Following Development of Immune Thrombocytopenia.
    Date August 2008
    Journal Pediatric Blood & Cancer
    Excerpt

    We report a case of concurrent type 2B von Willebrand disease (VWD) and immune thrombocytopenia (ITP). The patient had characteristic loss of von Willebrand factor (VWF) high molecular weight multimers (HMWM) but a normal platelet count in the initial 8 years after diagnosis of type 2B VWD. When he developed severe thrombocytopenia, however, both his VWD indices and VWF HMWM normalized. As his platelet count increased, he again lost the HMWM and his VWD indices decreased. These results suggest that the severe thrombocytopenia led to decreased clearance of VWF, especially the HMWM.

    Title Genotype-phenotype Correlation in Combined Deficiency of Factor V and Factor Viii.
    Date July 2008
    Journal Blood
    Excerpt

    Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (D89A and D122V) abolish MCFD2 binding to LMAN1. Measurement of platelet factor V (FV) levels in 7 F5F8D patients (4 with LMAN1 and 3 with MCFD2 mutations) demonstrated similar reductions to those observed for plasma FV. Combining the current data together with all previous published reports, we performed a genotype-phenotype analysis comparing patients with MCFD2 mutations with those with LMAN1 mutations. A previously unappreciated difference is observed between these 2 classes of patients in the distribution of plasma levels for FV and factor VIII (FVIII). Although there is considerable overlap, the mean levels of plasma FV and FVIII in patients with MCFD2 mutations are significantly lower than the corresponding levels in patients with LMAN1 mutations. No differences in distribution of factor levels are observed by sex. These data suggest that MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2.

    Title Electron Spin Resonance of Dna Irradiated with a Heavy-ion Beam ([16]o[8+]): Evidence for Damage to the Deoxyribose Phosphate Backbone.
    Date November 1996
    Journal Radiation Research
    Excerpt

    The free radicals produced from the irradiation of hydrated DNA with a heavy-ion beam have been investigated by ESR spectroscopy. The dominant free radical species formed after 60 MeV/nucleon (16)O(8+) ion-beam irradiations at low temperatures (77 K) are the same as those previously identified from studies using low-LET radiation, pyrimidine electron-gain radicals and purine electron-loss radicals; however, greater relative amounts of neutral carbon-centered radicals are found with the higher-LET radiation, and a new phosphorus-centered radical is identified. The fraction of neutral carbon radicals is also found to increase along the ion-beam track with the highest amounts found in the Bragg peak. The neutral carbon-centered radicals likely arise in part from the sugar moiety. The G values found for total trapped radicals at 77 K are significantly smaller for the (16)O(8+) ion beam than those found for low-LET radiation. The new phosphorus-centered radical species is identified by its large 31P parallel hyperfine coupling of about 780 G as a phosphoryl radical. This species is produced linearly with dose and is not found in significant amounts in DNA irradiated with low-LET radiation. The phosphoryl radical must be produced by the fragmentation of a P-O bond and suggests the possibility of a direct strand break. The yield of phosphoryl species is small (about 0.1% of all radicals); however, it clearly indicates that new mechanisms of damage which are not significant for low-LET radiation must be considered for high-LET radiation.

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