William Plunkett, PhD, Oral History Interview, April 10, 2013

Major Topics Covered The Department of Developmental Therapeutics Memories of Emil J Freireich, MD The CLL Moon Shot Programhttps://openworks.mdanderson.org/mchv_interviewsessions/1186/thumbnail.jp

William Plunkett, PhD, Oral History Interview, March 25, 2013

Major Topics Covered Personal and educational background View of history of biomedical sciences; evolution of team science Research: nucleoside analogues; gemcitabine, fludarabine; mechanisms of cell death, DNA repair Research collaborations: with Pharma; importance of collegiality; inter-disciplinary discussions The CLL Moon Shot Programhttps://openworks.mdanderson.org/mchv_interviewsessions/1185/thumbnail.jp

Rumble Stripes: Opportunity to Improve Safety and Retroreflectivity

Painted rumble stripes can provide safety benefits as well as improved retroreflectivy and paint durability. This presentation covers specifications and construction techniques. A case study will describe the recent application of rumble stripes on US 231 between Crawfordsville and Lafayette, Indiana

UCN-01 (7-hydroxystaurosporine) inhibits DNA repair and increases cytotoxicity in normal lymphocytes and chronic lymphocytic leukemia lymphocytes.

Elevated DNA repair processes represent resistance mechanisms to the treatment of malignancies with alkylating agents. Recently, the cell cycle checkpoint abrogator, UCN-01, was reported to inhibit nucleotide excision repair in cell-free systems. We hypothesized that if UCN-01 was combined with DNA-damaging agents, UCN-01 might inhibit the damage repair processes, thereby enhancing cytotoxicity in quiescent cells. Here, we investigated the effect of UCN-01 on DNA repair and viability of quiescent normal lymphocytes and chronic lymphocytic leukemia lymphocytes treated with UV or the cyclophosphamide prodrug 4-hydroperoxycyclophosphamide (4-HC). DNA damage repair kinetics were determined as DNA single strand breaks by the alkaline single cell gel electrophoresis (comet) assay and by [3H]thymidine incorporation. Pretreatment with UCN-01 inhibited DNA repair initiated by UV or 4-HC in normal lymphocytes as well as chronic lymphocytic leukemia lymphocytes in a concentration-dependent manner at clinically relevant levels (50-300 nM). This inhibition was demonstrated by the decreases in incision capability, DNA resynthesis, and in rejoining, suggesting that UCN-01 inhibits the multiple sites of the repair processes. The higher UCN-01 concentration (300 nM) maximized the inhibitory effects and enhanced the UV- or 4-HC-induced cytotoxicity, as determined by annexin V binding or Hoechst 33342 staining. This enhancement was not obtained by the lower concentrations that incompletely inhibited the repair, suggesting the close association between the inhibition of the repair and the enhancement of the cytotoxicity. Our findings suggest that UCN-01 may be a good candidate for combination strategies of cancer treatment

Ultrafast Rydberg-state dissociation in oxygen: Identifying the role of multielectron excitations

We investigated the fragmentation dynamics of highly excited states of molecular oxygen using femtosecond transient photoelectron spectroscopy. An extreme ultraviolet (XUV) pulse populates the autoionizing Rydberg series converging to O-2(+) c(4)Sigma(-)(u), and a femtosecond near-infrared (IR) pulse was used to photoionize these states as they dissociate. Monitoring the differential photoelectron spectra as a function of time delay allowed us to obtain the relaxation lifetimes of these Rydberg states. We observed a photoelectron signal corresponding to the formation of a 4p excited atomic oxygen fragment, which is not an expected dissociation product of the (O-2(+) c(4)Sigma(-)(u))nl sigma(g) Rydberg series. Analysis of the time-dependent photoelectron spectra and photoionization calculations indicate that this fragment results from a previously unexplored (O-2(+) (4)Pi(g))4p repulsive state and that, contrary to expectations, this multielectron excitation pathway presents a substantial cross section. Our study demonstrates that two-color time-resolved differential photoelectron spectroscopy is an excellent tool to study the fragmentation dynamics of such multielectron excited states, which are not easily probed by other means.US Army Research Laboratory; U.S. Army Research Office [W911NF-14-1-0383]; National Science Foundation (NSF) [PHY-1505556]; U.S. Department of Energy (DOE), Office of Science, Basic Energy Sciences (BES) [DE-SC0018251]; US Department of Energy Chemical Sciences, Geosciences, and Biosciences Division [DE-AC02-05CH11231]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Inhibition of fludarabine metabolism by arabinosylcytosine during therapy

The active 5′-triphosphate of arabinosyl-2-fluoroadenine (F-ara-ATP) increases the anabolism of arabinosylcytosine (ara-C), whereas ara-C 5′-triphosphate inhibits the phosphorylation of arabinosyl-2-fluoroadenine (F-ara-A) in human leukemia cells in vitro. These interactions have a potential impact on drug scheduling. Clinical trials of relapsed leukemia in which fludarabine (F-ara-A 5′-monophosphate) and ara-C were given in sequence provided the opportunity to evaluate the effects of ara-C infusion on two sequelae: the pharmacokinetics of F-ara-A in plasma and that of F-ara-ATP in leukemia cells. First, F-ara-A pharmacokinetics were altered by ara-C infusion. This was visualized as a transient increase in F-ara-A plasma levels during the ara-C infusion that was given 4 h after fludarabine. The perturbation in F-ara-A plasma levels was dependent on the dose of ara-C. Second, peak F-ara-ATP concentrations were lower in leukemia cells of patients who received ara-C in addition to fludarabine as compared with those who received fludarabine alone. The terminal half-life of F-ara-A in plasma and the half-life of intracellular F-ara-ATP were reduced after the ara-C infusion in a concentration-dependent manner. Studies using purified deoxycytidine kinase support the conclusion that the increase in plasma levels of F-ara-A is in part the result of an effective competition by ara-C for phosphorylation by this enzyme, leading to a perturbation of the pharmacokinetics of intracellular F-ara-ATP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46924/1/280_2004_Article_BF00685547.pd

Communication Support Needs: a Review of the Literature.

Scotlandcaslpub2013pu

Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents

A Threat Assessment and Security Analysis of the Three Sports Facilities of Indiana University-Purdue University, Indianapolis NCAA Softball Fields, Carroll Stadium, and the IU Natatorium

This research report provides a security assessment of the Softball Fields, Carroll Stadium, and the Natatorium Complex at Indiana University-Purdue University Indianapolis (IUPUI). The purpose of this report is to prevent and mitigate harm to visitors and these facilities which resulting from human-made or natural disasters. Research is guided by the hypothesis that these facilities- due to their respective importance, locations, and attendance patterns are in harm’s way; and that certain strategies of prevention, protection, and mitigation coupled with effective preparedness, response, and recovery can lessen risk, improve security and provide A THREAT ASSESSMENT AND SECURITY ANALYSIS 5 added resilience. Further, “harm’s way” is considered to be either a natural disaster or a human-made disaster, accident, active provocation, or act of terrorism. Methods of analysis include applied research; predominantly utilizing qualitative data with some quantitative investigation. Results of this assessment illustrate that these venues possess numerous vulnerabilities to both natural and human-made threats that if exposed, could result in serious consequences. The two most likely natural hazards identified include straight-line winds and tornadoes. Further, the most likely human threats to these facilities arise from a potential terrorist vehicle attack (TVA) and an active shooter. This project also identifies a specific need for additional planning to prevent an IED or VBIED attack on the Natatorium. Common themes from the attached three case studies reveal that given theses vulnerabilities, the following safety and security adjustments are recommended: Surveillance equipment Metal detectors Security bollards or other temporary barriers Evacuation routes and shelter in place plans Special event security procedures Weather related technology and protocols Staff training for emergency situation