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

ELR510444 Inhibits Tumor Growth and Angiogenesis by Abrogating HIF Activity and Disrupting Microtubules in Renal Cell Carcinoma

Background: Hypoxia-inducible factor (HIF) is an attractive therapeutic target for renal cell carcinoma (RCC) as its high expression due to the loss of von Hippel-Lindau (VHL) promotes RCC progression. Considering this, we hypothesized that ELR510444, a novel orally available small molecule inhibitor of HIF activity, would reduce angiogenesis and possess significant activity in RCC. The mechanism of action and therapeutic efficacy of ELR510444 were investigated in in vitro and in vivo models of RCC. Principal Findings: ELR510444 decreased HIF-1a and HIF-2a levels, reduced RCC cell viability and clonogenic survival, and induced apoptosis. VHL-deficient RCC cells were more sensitive to ELR510444-mediated apoptosis and restoration of VHL promoted drug resistance. Higher concentrations of ELR51044 promoted apoptosis independently of VHL status, possibly due to the microtubule destabilizing properties of this agent. ELR510444 significantly reduced tumor burden in the 786-O and A498 RCC xenograft models. These effects were associated with increased necrosis and apoptosis and inhibition of angiogenesis. Conclusions: ELR510444 is a promising new HIF inhibitor that reduced RCC cell viability, induced apoptosis, and diminished tumor burden in RCC xenograft models. ELR510444 also destabilized microtubules suggesting that it possesses vascula

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

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

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

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

Characterization of Polymorphic Microsatellites in the Giant Bulldog Ant, Myrmecia brevinoda and the Jumper Ant, M. pilosula

The ant genus Myrmecia Fabricius (Hymenoptera: Formicidae) is endemic to Australia and New Caledonia, and has retained many biological traits that are considered to be basal in the family Formicidae. Here, a set of 16 dinucleotide microsatellite loci were studied that are polymorphic in at least one of the two species of the genus: the giant bulldog ant, M. brevinoda Forel, and the jumper ant, M. pilosula Smith; 13 are novel loci and 3 are loci previously published for the genus Nothomyrmecia Clark (Hymenoptera: Formicidae). In M. brevinoda, the total of 12 polymorphic microsatellites yielded a total of 125 alleles, ranging from 3 to 18 with an average of 10.42 per locus; the observed and expected heterozygosities ranged from 0.4000 to 0.9000 and from 0.5413 to 0.9200, respectively. In M. pilosula, the 9 polymorphic loci yielded a total of 67 alleles, ranging from 3 to 12 with an average of 7.44 per locus; the observed and expected heterozygosities ranged from 0.5625 to 0.9375 and from 0.4863 to 0.8711, respectively. Five loci were polymorphic in both target species. In addition, 15 out of the 16 loci were successfully amplified in M. pyriformis. These informative microsatellite loci provide a powerful tool for investigating the population and colony genetic structure of M. brevinoda and M. pilosula, and may also be applicable to a range of congeners considering the relatively distant phylogenetic relatedness between M. pilosula and the other two species within the genus Myrmecia

Determinants of patient recruitment in a multicenter clinical trials group: trends, seasonality and the effect of large studies

BACKGROUND: We examined whether quarterly patient enrollment in a large multicenter clinical trials group could be modeled in terms of predictors including time parameters (such as long-term trends and seasonality), the effect of large trials and the number of new studies launched each quarter. We used the database of all clinical studies launched by the AIDS Clinical Trials Group (ACTG) between October 1986 and November 1999. Analyses were performed in two datasets: one included all studies and substudies (n = 475, total enrollment 69,992 patients) and the other included only main studies (n = 352, total enrollment 57,563 patients). RESULTS: Enrollment differed across different months of the year with peaks in spring and late fall. Enrollment accelerated over time (+27 patients per quarter for all studies and +16 patients per quarter for the main studies, p < 0.001) and was affected by the performance of large studies with target sample size > 1,000 (p < 0.001). These relationships remained significant in multivariate autoregressive modeling. A time series based on enrollment during the first 32 quarters could forecast adequately the remaining 21 quarters. CONCLUSIONS: The fate and popularity of large trials may determine the overall recruitment of multicenter groups. Modeling of enrollment rates may be used to comprehend long-term patterns and to perform future strategic planning

Being tolerated and being discriminated against:Links to psychological well-being through threatened social identity needs

We investigated whether and how the experience of being tolerated and of being discriminated against are associated with psychological well‐being in three correlational studies among three stigmatized groups in Turkey (LGBTI group members, people with disabilities, and ethnic Kurds, total N = 862). Perceived threat to social identity needs (esteem, meaning, belonging, efficacy, and continuity) was examined as a mediator in these associations. Structural equation models showed evidence for the detrimental role of both toleration and discrimination experiences on positive and negative psychological well‐being through higher levels of threatened social identity needs. A mini‐meta analysis showed small to moderate effect sizes and toleration was associated with lower positive well‐being through threatened needs among all three stigmatized groups