Targeting autophagy: a novel anticancer strategy with therapeutic implications for imatinib resistance

Autophagy is an ancient, intracellular degradative system which plays important roles in regulating protein homeostasis and which is essential for survival when cells are faced with metabolic stress. Increasing evidence suggests that autophagy also functions as a tumor suppressor mechanism that harnesses the growth and/or survival of cells as they transition towards a rapidly dividing malignant state. However, the impact of autophagy on cancer progression and on the efficacy of cancer therapeutics is controversial. In particular, although the induction of autophagy has been reported after treatment with a number of therapeutic agents, including imatinib, this response has variously been suggested to either impair or contribute to the effects of anticancer agents. More recent studies support the notion that autophagy compromises the efficacy of anticancer agents, where agents such as chloroquine (CQ) that impair autophagy augment the anticancer activity of histone deacetylase (HDAC) inhibitors and alkylating agents. Inhibition of autophagy is a particularly attractive strategy for the treatment of imatinib-refractory chronic myelogenous leukemia (CML) since a combination of CQ with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) compromises the survival of even BCR-ABL-T315I+ imatinib-resistant CML. Additional studies are clearly needed to establish the clinical utility of autophagy inhibitors and to identify patients most likely to benefit from this novel therapeutic approach

Geology of Cat Island, Bahamas: A Field Trip Guide

See other Smith authored Field Trip Guides of Gerace Research Centre

Pleistocene and Holocene Carbonate Environments on San Salvador Island, Bahamas: A Field Trip Guide

Although isolated and small in size, San Salvador Island is in many ways a unique place - an all carbonates setting on a small, tectonically stable platform, surrounded by deep oceanic waters, and an historical footnote as the widely accepted first landing site of Christopher Columbus in the New World in 1492. Columbus\u27 stay here was brief, and the major events of subsequent history largely have passed San Salvador by. This is not a tourist island; the natural beauty, floras, and faunas of the Bahamas are well preserved here. The overview theme of this series of field excursions on San Salvador will be interpretation of paleodepositional environments for the well-exposed Pleistocene and Holocene carbonate rocks that cap the island and recognition of modem analogues from the varied carbonate environments found on the island and its surrounding shelf. Questions of sea level history, diagenetic change, and the surficial processes operating on carbonate island terranes also will be considered. Our trip will begin with a low-attitude overflight to view features of the main Bahama platform enroute to San Salvador, which lies just beyond the eastern edge of the platform. The field trip leaders all have been working on San Salvador and elsewhere in the Bahamas for the past decade. We have experienced the good and the bad - a pleasant tropical climate, warm and alive marine waters, a generally unspoiled setting, and the friendly Bahamian people, along with sometimes fierce no-see-um attacks, sun-burnt skin, and unexpected soakings from tropical storms. Throughout, the experiences have been rewarding and the challenges of geologic interpretation great. We look forward to sharing some of our findings and experiences with you. Welcome to the Bahamas and San Salvador Island! See other Smith authored Field Trip Guides of Gerace Research Centre

Pressure-vessel-damage fluence reduction by low-leakage fuel management. [PWR]

As a result of neutron-induced radiation damage to the pressure vessel and of an increased concern that in a PWR transient the pressure vessel may be subjected to pressurized thermal shock (PTS), detailed analyses have been undertaken to determine the levels of neutron fluence accumulation at the pressure vessels of selected PWR's. In addition, various methods intended to limit vessel damage by reducing the vessel fluence have been investigated. This paper presents results of the fluence analysis and the evaluation of the low-leakage fuel management fluence reduction method. The calculations were performed with DOT-3.5 in an octant of the core/shield/vessel configuration using a 120 x 43 (r, theta) mesh structure

Intense hurricane activity over the past 1500 years at South Andros Island, the Bahamas

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in E. J., Donnelly, J. P., van Hengstum, P. J., Wiman, C., Sullivan, R. M., Winkler, T. S., d'Entremont, N. E., Toomey, M., & Albury, N. Intense hurricane activity over the past 1500 years at South Andros Island, the Bahamas. Paleoceanography and Paleoclimatology, 34(11), (2019): 1761-1783, doi:10.1029/2019PA003665.Hurricanes cause substantial loss of life and resources in coastal areas. Unfortunately, historical hurricane records are too short and incomplete to capture hurricane‐climate interactions on multi‐decadal and longer timescales. Coarse‐grained, hurricane‐induced deposits preserved in blue holes in the Caribbean can provide records of past hurricane activity extending back thousands of years. Here we present a high resolution record of intense hurricane events over the past 1500 years from a blue hole on South Andros Island on the Great Bahama Bank. This record is corroborated by shorter reconstructions from cores collected at two nearby blue holes. The record contains coarse‐grained event deposits attributable to known historical hurricane strikes within age uncertainties. Over the past 1500 years, South Andros shows evidence of four active periods of hurricane activity. None of these active intervals occurred in the past 163 years. We suggest that Intertropical Convergence Zone position modulates hurricane activity on the island based on a correlation with Cariaco Basin titanium concentrations. An anomalous gap in activity on South Andros Island in the early 13th century corresponds to a period of increased volcanism. The patterns of hurricane activity reconstructed from South Andros Island closely match those from the northeastern Gulf of Mexico but are anti‐phased with records from New England. We suggest that either changes in local environmental conditions (e.g., SSTs) or a northeastward shift in storm tracks can account for the increased activity in the western North Atlantic when the Gulf of Mexico and southeastern Caribbean are less active.This work was funded by the National Science Foundation Graduate Research Fellowship (to E.J.W.), National Science Foundation grant OCE‐1356708 (to J.P.D. and P.J.vH.), the Dalio Explore Foundation and the USGS Land Change Science Program (M.R.T.). We are grateful to members of WHOI Coastal Systems Group, in particular Stephanie Madsen, for their help in the processing core samples. We thank two anonymous reviewers, Matthew Lachniet, Marci Robinson (USGS) and Miriam Jones (USGS) for their helpful feedback on earlier versions of this manuscript. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government. The data are available on the National Climatic Data Center (http://www.ncdc.noaa.gov/dataaccess/paleoclimatology‐data) and WHOI Coastal Systems Group (https://web.whoi.edu/coastal‐group/) websites

Racism, anti-racist practice and social work: articulating the teaching and learning experiences of Black social workers

In the mid 1990s a Black practice teacher programme was established in Manchester and Merseyside with the primary aim to increase the number of Black practice teachers in social work organisations, and in turn provide a supportive and encouraging learning environment for Black student social workers whilst on placement. In the north‐west of England research has been undertaken, to establish the quality of the practice teaching and student learning taking place with Black practice teachers and students. This paper is an exploration of the ideas generated within the placement process that particularly focused on the discourse of racism and ant‐racist practice. Black students and practice teachers explain their understanding of racism and anti‐racist practice within social work. From the research, the paper will critique some of the ideas concerning anti‐racism. In particular, it will question whether anti‐racist social work practice needs to be re‐evaluated in the light of a context with new migrants, asylum seekers and refugees. It will concluded, by arguing that whilst the terms anti‐racism, Black and Minority Ethnic have resonance as a form of political strategic essentialism, it is important to develop more positive representations in the future

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

Substantia nigra echomorphology and motor cortex excitability

The aim of our study was to investigate the relation between substantia nigra (SN) echomorphology and indices of motor cortex excitability. Nigral hyperechogenicity in healthy individuals is thought to represent an SN abnormality or predisposition to Parkinson's disease (PD) and its prevalence is greater in the very old. Our study involved 20 old healthy subjects (aged 72-84 years) known to have normal (n = 10) or abnormal (n = 10) SN echomorphology. All were in good health with no overt neurological signs. SN morphology was assessed with transcranial sonography through the pre-auricular bone window. Motor cortical excitability and intracortical inhibition were assessed with transcranial magnetic stimulation (TMS) over the first dorsal interosseus motor area. Single stimuli were delivered during relaxation and voluntary contraction and paired stimuli were delivered during relaxation. Each cortical hemisphere was analysed separately. The response to single-pulse TMS (in motor cortex ipsilateral to the target SN) did not differ between groups. However, a significant difference between groups was observed in the paired pulse paradigm (conditioning stimulus intensity: 70% resting motor threshold; interstimulus interval: 2 ms). The conditioned motor evoked potential amplitude was significantly larger ipsilateral to the hyperechogenic SN than in controls (P = 0.014). Thus, healthy subjects with SN hyperechogenicity exhibit significantly less intracortical inhibition within the motor cortex than subjects with normal echomorphology. Decreased intracortical inhibition is also observed in PD patients. This study provides further evidence that SN hyperechogenicity in healthy individuals is associated with changes characteristic of PD supporting a role for this feature as a vulnerability marker or state marker for subtle nigral dopaminergic dysfunction

Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death

Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.These studies were supported by NIH grants R35 HL 161177 (to ACS), R01 HL 133864 (to ACS), R01 HL 128304 (to ACS), R41 HL15098 (to GS), R01 GM 122091 (to PHT), GM125944 (to FJS), R01 DK112854 (to FJS), R21 NS112787 (to MF), NS121706 (to YLW), EB023507 (to YLW), F31 HL149241 (to HMS), and F31 HL151173 (to JCG). Support was also provided by American Heart Association grants 19EIA34770095 (to ACS), AHA 18CDA34140024 (to YLW), and 19PRE34380152 (to NTC); the Spanish Ministry of Health (grant FIS PI17-01286); Junta de Andalucía BIO-177 and the FEDER Funding Program from the European Union and CIBERER (U729)-ISCIII (to PN); Department of Defense W81XWH1810070 (to YLW); and Vitalant. This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483.Peer reviewe