Reduced disease severity following therapeutic treatment with angiotensin 1-7 in a mouse model of multiple sclerosis

Multiple Sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by autoimmune and neurodegenerative pathologies for which there is no cure and no defined etiology. Although several, modestly effective, disease modifying drugs are available to treat MS, there are presently no treatments that offer neuroprotection and prevent clinical progression. Therapies are needed that control immune homeostasis, prevent disease progression, and stimulate regeneration in the CNS. Components of the renin-angiotensin-system (RAS) have recently been identified as chemical mediators in the CNS and in neurological disease. Here we show the beneficial effect of therapeutic treatment with the Mas receptor agonist and metabolite of the protective arm of RAS, angiotensin 1-7 (A(1-7)), in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Therapeutic treatment with A(1-7) caused a dose-dependent reduction both in clinical disease severity and progression, and was dependent on Mas receptor activation. Further analysis of the most optimal dose of A(1-7) treatment revealed that the reductions in clinical disease course were associated with decreased immune infiltration and demyelination, axonal loss and oxidative stress in the spinal cord. In addition A(1-7) treatment was also associated with increases in circulating alternatively activated monocytes/macrophages.Department of Defense, USC Clinical and Translational Science Institute, National Multiple Sclerosis Society12 month embargo; available online 25 February 2019.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]

Theory of d-density wave viewed from a vertex model and its implications

The thermal disordering of the $d$-density wave, proposed to be the origin of the pseudogap state of high temperature superconductors, is suggested to be the same as that of the statistical mechanical model known as the 6-vertex model. The low temperature phase consists of a staggered order parameter of circulating currents, while the disordered high temperature phase is a power-law phase with no order. A special feature of this transition is the complete lack of an observable specific heat anomaly at the transition. There is also a transition at a even higher temperature at which the magnitude of the order parameter collapses. These results are due to classical thermal fluctuations and are entirely unrelated to a quantum critical point in the ground state. The quantum mechanical ground state can be explored by incorporating processes that causes transitions between the vertices, allowing us to discuss quantum phase transition in the ground state as well as the effect of quantum criticality at a finite temperature as distinct from the power-law fluctuations in the classical regime. A generalization of the model on a triangular lattice that leads to a 20-vertex model may shed light on the Wigner glass picture of the metal-insulator transition in two-dimensional electron gas. The power-law ordered high temperature phase may be generic to a class of constrained systems and its relation to recent advances in the quantum dimer models is noted.Comment: RevTex4, 10 pages, 11 figure

Gene-specific repair of Pt/DNA lesions and induction of apoptosis by the oral platinum drug JM216 in three human ovarian carcinoma cell lines sensitive and resistant to cisplatin

JM216, an oral platinum drug entering into phase III clinical trial, exhibited comparable cytotoxicity to cisplatin in three human ovarian carcinoma cell lines: the sensitive (CH1), acquired resistant (CH1cisR) and intrinsically resistant (SKOV-3). Platinum accumulation and binding to DNA were similar in each of the three cell lines at equimolar doses, indicating that the resistant cell lines could tolerate higher intracellular platinum levels and platinum bound to DNA at IC50 concentrations of drug. Comparison with cisplatin demonstrated that intracellular platinum levels were marginally higher with JM216, but that platinum binding to DNA was similar for the two drugs in each of the cell lines. Each of the cell lines exhibited an ability to repair JM216 induced platinum/DNA lesions in the N-ras gene (gene-specific repair) at equitoxic concentrations of drug. However, this occurred to a greater extent in the two resistant cell lines such that by 24 h the CH1cisR and SKOV-3 had removed 72% and 67% respectively compared with approximately 32% for the CH1. Reduced gene-specific repair capacity in CH1 cells was also seen following incubation with 25 μM (or 5 μM – 2 × IC50) cisplatin, whereas the CH1cisR and SKOV-3 cell lines were repair proficient. JM216 induced apoptosis in the three cell lines following a 2h incubation with 2 × the IC50 of drug. Fluorescent microscopy of cells stained with propidium iodide showed that the detached cell population displayed typical apoptotic nuclei. Furthermore, field inversion gel electrophoresis demonstrated the presence of DNA fragments approximately 23–50 kb in size, indicative of apoptosis, in the detached cells. JM216 induced an S phase slow down in each of the three cell lines accompanied by a G2 block in the CH1 pair. Incubation with this concentration of JM216 also resulted in the induction of p53 in the CH1 and CH1cisR. These studies suggest that the relative sensitivity of the CH1 cell line to cisplatin and JM216 is at least partly attributable to a deficiency in gene-specific repair. The oral platinum drug, JM216, exerts its cytotoxic effects through the induction of apoptosis following a slow-down in S phase in both the sensitive and resistant lines. © 1999 Cancer Research Campaig

Breast cancer therapy for BRCA1 carriers: moving towards platinum standard?

Recently Byrski et al. reported the first-ever breast cancer (BC) study, which specifically selected BRCA1-carriers for the neoadjuvant treatment and used monotherapy by cisplatin instead of conventional schemes. Although the TNM staging of the recruited patients was apparently more favorable than in most of published neoadjuvant trials, the results of Byrski et al. clearly outperform any historical data. Indeed, 9 of 10 BRCA1-associated BC demonstrated complete pathological response to the cisplatin treatment, i.e. these women have good chances to be ultimately cured from the cancer disease. High sensitivity of BRCA1-related tumors to platinating agents has been discussed for years, but it took almost a decade to translate convincing laboratory findings into first clinical observations. With increasing stratification of tumor disease entities for molecular subtypes and rapidly growing armamentarium of cancer drugs, it is getting technically and ethically impossible to subject all promising treatment options to the large randomized prospective clinical trials. Therefore, alternative approaches for initial drugs evaluation are highly required, and one of the choices is to extract maximum benefit from already available collections of biological material and medical charts. For example, many thousands of BC patients around the world have already been subjected to second- or third-line therapy with platinum agents, but the association between BRCA status and response to the treatment has not been systematically evaluated in these women. While potential biases of retrospective studies are widely acknowledged, it is frequently ignored that the use of archival collections may provide preliminary answers for long-standing questions within days instead of years. However, even elegantly-designed, small-sized, hypothesis-generating retrospective studies may require multicenter efforts and somewhat cumbersome logistics, that may explain the surprising lack of historical data on the platinum-based treatment of BC in BRCA1 carriers

Radiofrequency ablation of ventricular tachycardia in Anderson–Fabry disease : a case series

Background Cardiac involvement in Anderson–Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited. Case summary We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure. Discussion RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease

Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal–organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.National Cancer Institute (U.S.) (CA034992

Cardiac stereotactic ablative radiotherapy for control of refractory ventricular tachycardia: initial UK multicentre experience

Background: Options for patients with ventricular tachycardia (VT) refractory to antiarrhythmic drugs and/or catheter ablation remain limited. Stereotactic radiotherapy has been described as a novel treatment option. Methods: Seven patients with recurrent refractory VT, deemed high risk for either first time or redo invasive catheter ablation, were treated across three UK centres with non-invasive cardiac stereotactic ablative radiotherapy (SABR). Prior catheter ablation data and non-invasive mapping were combined with cross-sectional imaging to generate radiotherapy plans with aim to deliver a single 25 Gy treatment. Shared planning and treatment guidelines and prospective peer review were used. Results: Acute suppression of VT was seen in all seven patients. For five patients with at least 6 months follow-up, overall reduction in VT burden was 85%. No high-grade radiotherapy treatment-related side effects were documented. Three deaths (two early, one late) occurred due to heart failure. Conclusions: Cardiac SABR showed reasonable VT suppression in a high-risk population where conventional treatment had failed