Cross Cancer Institute
Cross Cancer Institute
Preto J.,Cross Cancer Institute
Chaos | Year: 2016
Almost five decades ago, [H. Fröhlich, "Long-range coherence and energy storage in biological systems," Int. J. Quantum Chem. 2(5), 641-649 (1968), H. Fröhlich, "The biological effects of microwaves and related questions," Adv. Electron. Electron Phys. 53, 85-152 (1980)] reported, on a theoretical basis, that the excitation of quantum modes of vibration in contact with a thermal reservoir may lead to steady states, where under high enough rate of energy supply, only specific low-frequency modes of vibration are strongly excited. This nonlinear phenomenon was predicted to occur in biomolecular systems, which are known to exhibit complex vibrational spectral properties, especially in the terahertz frequency domain. However, since the effects of terahertz or lower-frequency modes are mainly classical at physiological temperatures, there are serious doubts that Fröhlich's quantum description can be applied to predict such a coherent behavior in a biological environment, as suggested by the author. In addition, a quantum formalism makes the phenomenon hard to investigate using realistic molecular dynamics simulations (MD) as they are usually based on the classical principles. In the current paper, we provide a general classical Hamiltonian description of a nonlinear open system composed of many degrees of freedom (biomolecular structure) excited by an external energy source. It is shown that a coherent behaviour similar to Fröhlich's effect is to be expected in the classical case for a given range of parameter values. Thus, the supplied energy is not completely thermalized but stored in a highly ordered fashion. The connection between our Hamiltonian description, carried out in the space of normal modes, and a more standard treatment in the physical space is emphasized in order to facilitate the prediction of the effect from MD simulations. It is shown how such a coherent phenomenon may induce long-range resonance effects that could be of critical importance at the biomolecular level. The present work is motivated by recent experimental evidences of long-lived excited low-frequency modes in protein structures, which were reported as a consequence of the Fröhlich's effect. © 2016 Author(s).
Preto J.,Cross Cancer Institute
Journal of Biological Physics | Year: 2017
Fröhlich’s model equations describing phonon condensation in open systems of biological relevance are reinvestigated within a semi-classical statistical framework. The main assumptions needed to deduce Fröhlich’s rate equations are identified and it is shown how they lead us to write an appropriate form for the corresponding master equation. It is shown how solutions of the master equation can be numerically computed and can highlight typical features of the condensation effect. Our approach provides much more information compared to the existing ones as it allows to investigate the time evolution of the probability density function instead of following single averaged quantities. The current work is also motivated, on the one hand, by recent experimental evidences of long-lived excited modes in the protein structure of hen-egg white lysozyme, which were reported as a consequence of the condensation effect, and, on the other hand, by a growing interest in investigating long-range effects of electromagnetic origin and their influence on the dynamics of biochemical reactions. © 2017 Springer Science+Business Media Dordrecht
News Article | November 29, 2016
Heart medication taken in combination with chemotherapy reduces the risk of serious cardiovascular damage in patients with early-stage breast cancer, according to results from a new landmark clinical trial. Existing research has shown some cancer therapies such as Herceptin greatly improve survival rates for early-stage breast cancer, but come with a fivefold risk of heart failure -- a devastating condition as life-threatening as the cancer itself. A new five-year study, led by researchers at the University of Alberta and Alberta Health Services and funded by the Canadian Institutes of Health Research (CIHR) and Alberta Cancer Foundation, shows that two kinds of heart medications, beta blockers and ACE inhibitors, effectively prevent a drop in heart function from cancer treatment. "We think this is practice-changing," said Edith Pituskin, co-investigator of the MANTICORE trial. "This will improve the safety of the cancer treatment that we provide." Pituskin, an assistant professor in the Faculty of Nursing and Faculty of Medicine & Dentistry at the U of A, published their findings Nov. 28 in the Journal of Clinical Oncology. In the double-blind trial, 100 patients from Alberta and Manitoba with early-stage breast cancer were selected at random to receive either a beta blocker, ACE inhibitor or placebo for one year. Beta blockers and ACE inhibitors are drugs used to treat several conditions, including heart failure. Cardiac MRI images taken over a two-year period showed that patients who received the beta blockers showed fewer signs of heart weakening than the placebo group. The ACE inhibitor drug also had heart protection effects. Study lead Ian Paterson, a cardiologist at the Mazankowski Alberta Heart Institute and associate professor with the U of A's Department of Medicine, said these medications not only safeguard against damage to the heart, but may improve breast cancer survival rates by limiting interruptions to chemotherapy treatment. Any time a patient shows signs of heart weakening, he said, chemotherapy is stopped immediately, sometimes for a month or two months until heart function returns to normal. "We are aiming for two outcomes for these patients--we're hoping to prevent heart failure and we're hoping for them to receive all the chemotherapy that they are meant to get, when they are supposed to get it--to improve their odds of remission and survival." Patients with heart failure often experience fatigue, shortness of breath or even death, making it "an equally devastating disease with worse prognosis than breast cancer," Paterson said. Brenda Skanes has a history of cardiovascular problems in her family--her mom died of a stroke and her dad had a heart attack. She was eager to join the trial, both for her own health and the health of other breast cancer survivors. "I met survivors through my journey who experienced heart complications caused by Herceptin. If they had access to this, maybe they wouldn't have those conditions now," she said. "Me participating, it's for the other survivors who are just going into treatment." With two daughters of her own and a mother who lost her fight with colon cancer, study participant Debbie Cameron says she'd do anything to ensure prevent others from going through similar upheaval. "My daughters are always in the back of my mind and the what ifs--if they're diagnosed, what would make their treatment safer, better," Cameron said. "Anything I could do to make this easier for anybody else or give some insight to treatment down the road was, to me, a very easy decision." Pituskin said the study team, which also includes collaborators from the AHS Clinical Trials Unit at the Cross Cancer Institute and the University of Manitoba, represents a strong mix of research disciplines, particularly the oncology and cardiology groups. She said the results would not have been possible without funding support from CIHR and the Alberta Cancer Foundation. "Local people in Alberta supported a study that not only Albertans benefited from, but will change, again, the way care is delivered around the world." The results are expected to have a direct impact on clinical practice guidelines in Canada and beyond. "Every day in Canada, around 68 women are diagnosed with breast cancer. This discovery holds real promise for improving these women's quality of life and health outcomes," said Stephen Robbins, scientific director of CIHR's Cancer Research Institute. "We couldn't be more pleased with this return on our investment," said Myka Osinchuk, CEO of the Alberta Cancer Foundation. "This clinical research will improve treatment and make life better not only for Albertans facing cancer, but also for those around the world." Paterson said the research team is also investigating how to prevent heart complications in patients with other cancers, noting several other therapies have been linked to heart complications.
Parliament M.B.,Cross Cancer Institute |
Murray D.,Cross Cancer Institute
Seminars in Radiation Oncology | Year: 2010
Radiation therapy is a key modality in the treatment of cancer. Substantial progress has been made in unraveling the molecular events which underpin the responses of malignant and surrounding normal tissues to ionizing radiation. An understanding of the genes involved in processes such as DNA double-strand break repair, DNA damage response, cell-cycle control, apoptosis, cellular antioxidant defenses, and cytokine production, has evolved toward examination of how genetic variants, most often, single nucleotide polymorphisms (SNPs), may influence interindividual radioresponse. Experimental approaches, such as candidate SNP-association studies, genome-wide association studies, and massively parallel sequencing are being proposed to address these questions. We present a focused review of the evidence supporting an association between SNPs in DNA repair genes and radioresponse in normal tissues and tumors. Although preliminary results indicate possible associations, there are methodological weaknesses in many of the studies, and independent validation of SNPs as biomarkers of radioresponse in much larger cohorts will likely require research cooperation through international consortia. © 2010 Elsevier Inc.
Makis W.,Cross Cancer Institute
Clinical Nuclear Medicine | Year: 2015
ABSTRACT: A 62-year-old man was diagnosed with a moderately differentiated gastric adenocarcinoma in the proximal stomach. A staging F-FDG PET/CT showed an intensely FDG-avid gastric mass, as well as a mildly FDG-avid misty nodular mesentery. After 3 cycles of neoadjuvant chemotherapy, a follow-up PET/CT showed partial response of the gastric primary, with increase in the size of nodules in the mesentery and increased FDG uptake, raising concern of secondary malignancy. Biopsy of the mesentery revealed xanthogranulomatous inflammation, consistent with sclerosing mesenteritis. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Meza-Junco J.,Cross Cancer Institute |
Sawyer M.B.,Cross Cancer Institute
Biologics: Targets and Therapy | Year: 2012
Gastric cancer (GC) is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling. © 2012 Meza-Junco and Sawyer, publisher and licensee Dove Medical Press Ltd.
Noonan K.L.,BC Cancer Agency |
North S.,Cross Cancer Institute |
Bitting R.L.,Duke University |
Armstrong A.J.,Duke University |
And 2 more authors.
Annals of Oncology | Year: 2013
Background: Abiraterone acetate and enzalutamide both improve outcomes in patients with metastatic castrationresistant prostate cancer (mCRPC). Optimal sequencing for these agents and whether cross-resistance occurs is unknown. Methods: Multicentre review of patients with mCRPC treated with abiraterone acetate and prednisone after progressing on enzalutamide. Primary objective was to determine abiraterone acetate response. Results: Thirty patients identified from four North American centres. At abiraterone initiation, median age was 70 years (56-84 years); 70% had ECOG performance status of 0-1; all had prior docetaxel. Median prior enzalutamide treatment duration was 41 weeks (6-95 weeks), with 70% (21 of 30) having a ≥30% prostate-specific antigen (PSA) decline. Median abiraterone acetate treatment duration was 13 weeks (1-52). No objective radiographic responses were observed. Median abiraterone time to progression (PSA, objective or symptomatic) was 15.4 weeks [95% confidence interval (CI) 10.7-20.2]. Median overall survival was 50.1 weeks (95% CI 28.3-72.0). Three patients had a ≥30% PSA decline with abiraterone. Two of these patients had PSA progression as best response with prior enzalutamide. Conclusions: In this study of patients progressing after enzalutamide, treatment with abiraterone was associated with a modest response rate and brief duration of effect. Primary progression on enzalutamide may not preclude a response to abiraterone. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Xia Z.,Cross Cancer Institute
Current drug delivery | Year: 2013
3'-O-Retinoyl-5-fluoro-2'-deoxyuridine (RFUdR) is a putative dual-acting, mutually-masking (DAMM) prodrug for the treatment of cancer. As part of the proof of principle for the DAMM concept, the concentrations of RFUdR and its post-hydrolysis active metabolites, 5-fluoro-2'-deoxyuridine (FUdR) and all-trans-retinoic acid (RA), were determined in plasma and selected tissues following either bolus intravenous (i.v.; 12.5 μmol/kg) or oral (p.o.; 13.7 μmol/kg) doses of RFUdR to mice bearing EMT6 murine mammary tumors. The concentrations of RFUdR and its primary metabolites were measured by high-performance liquid chromatography. A three compartment model provided the best fit for plasma RFUdR after an i.v. bolus, whereas FUdR and RA data were best fit by a one compartment model. The terminal half-life of RFUdR in plasma was 9 hours. The AUC of RFUdR in tumor (3400 μmol/L.min) was estimated to be about 4- fold higher than its AUC in the plasma (809 ± 241 μmol/L.min). A short-duration, saturated elimination phase for RFUdR was observed in both liver and kidney following an i.v. bolus. Neither unchanged RFUdR nor RA was detected in urine. The high bioavailability (~90%) following oral dosing with RFUdR indicates that this DAMM prodrug may be suitable for oral dosing to deliver FUdR and RA for cancer chemotherapy.
Craddock T.J.A.,University of Alberta |
Tuszynski J.A.,University of Alberta |
Tuszynski J.A.,Cross Cancer Institute |
Hameroff S.,University of Arizona
PLoS Computational Biology | Year: 2012
Memory is attributed to strengthened synaptic connections among particular brain neurons, yet synaptic membrane components are transient, whereas memories can endure. This suggests synaptic information is encoded and 'hard-wired' elsewhere, e.g. at molecular levels within the post-synaptic neuron. In long-term potentiation (LTP), a cellular and molecular model for memory, post-synaptic calcium ion (Ca2+) flux activates the hexagonal Ca2+-calmodulin dependent kinase II (CaMKII), a dodacameric holoenzyme containing 2 hexagonal sets of 6 kinase domains. Each kinase domain can either phosphorylate substrate proteins, or not (i.e. encoding one bit). Thus each set of extended CaMKII kinases can potentially encode synaptic Ca2+ information via phosphorylation as ordered arrays of binary 'bits'. Candidate sites for CaMKII phosphorylation-encoded molecular memory include microtubules (MTs), cylindrical organelles whose surfaces represent a regular lattice with a pattern of hexagonal polymers of the protein tubulin. Using molecular mechanics modeling and electrostatic profiling, we find that spatial dimensions and geometry of the extended CaMKII kinase domains precisely match those of MT hexagonal lattices. This suggests sets of six CaMKII kinase domains phosphorylate hexagonal MT lattice neighborhoods collectively, e.g. conveying synaptic information as ordered arrays of six "bits", and thus "bytes", with 64 to 5,281 possible bit states per CaMKII-MT byte. Signaling and encoding in MTs and other cytoskeletal structures offer rapid, robust solid-state information processing which may reflect a general code for MT-based memory and information processing within neurons and other eukaryotic cells. © 2012 Craddock et al.
Sangha R.,Cross Cancer Institute |
Price J.,Cross Cancer Institute |
Butts C.A.,Cross Cancer Institute
Oncologist | Year: 2010
The cornerstone of treatment for early-stage non-small cell lung cancer (NSCLC) has long been surgical resection. Over the past few years, there has been a paradigm shift to provide adjuvant platinum-based chemotherapy for patients with completely resected stage II-IIIA NSCLC founded on large randomized clinical trials demonstrating longer overall survival with this treatment. Reassuringly, the National Cancer Institute of Canada Cancer Therapeutics Group JBR.10 trial recently reported a continued survival advantage for patients treated with adjuvant chemotherapy after >9 years of median follow-up. In contrast, the gains from using this approach for stage IB disease are less clear, although data from an unplanned subgroup analysis suggest benefit for patients with tumors >4 cm. Herein, we review the evidence supporting adjuvant therapy in early-stage NSCLC patients before discussing key mitigating factors in providing treatment, such as stage of disease and the impact of the new seventh edition of the tumor-node-metastasis classification system. Criteria such as patient age and performance status, as well as the value of appropriate chemotherapy selection, are highlighted as measures to help guide management. The role of postoperative radiotherapy and the future landscape of early-stage NSCLC research are also explored; namely, therapeutic strategies exploiting pharmacogenomic and gene-expression profiling, in an attempt to personalize care, and the integration of novel targeted therapies into adjuvant clinical trials. © AlphaMed Press.