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A critical hallmark of cancer cells is their ability to evade programmed apoptotic cell death. Consequently, resistance to anti-cancer therapeutics is a hurdle often observed in the clinic. Ferroptosis, a non-apoptotic form of cell death distinguished by toxic lipid peroxidation and iron accumulation, has garnered substantial attention as an alternative therapeutic strategy to selectively destroy tumours. Although there is a plethora of research outlining the molecular mechanisms of ferroptosis, these findings are yet to be translated into clinical compounds inducing ferroptosis. In this perspective, we elaborate on how ferroptosis can be leveraged in the clinic. We discuss a therapeutic window for compounds inducing ferroptosis, the subset of tumour types that are most sensitive to ferroptosis, conventional therapeutics that induce ferroptosis, and potential strategies for lowering the threshold for ferroptosis.

The prevalence and dire implications of mutations in the tumour suppressor, p53, highlight its appeal as a chemotherapeutic target. We recently showed that impairing cellular antioxidant systems via inhibition of SLC7A11, a component of the system x c − cystine-glutamate antiporter, enhances sensitivity to mutant-p53 targeted therapy, APR-246. We investigated whether this synergy extends to other genes, such as those encoding enzymes of the pentose phosphate pathway (PPP). TKT, one of the major enzymes of the PPP, is allegedly regulated by NRF2, which is in turn impaired by accumulated mutant-p53 protein. Therefore, we investigated the relationship between mutant-p53, TKT and sensitivity to APR-246. We found that mutant-p53 does not alter expression of TKT, nor is TKT modulated directly by NRF2, suggesting a more complex mechanism at play. Furthermore, we found that in p53null cells, knockdown of TKT increased sensitivity to APR-246, whilst TKT overexpression conferred resistance to the drug. However, neither permutation elicited any effect on cells overexpressing mutant-p53 protein, despite mediating oxidative stress levels in a similar fashion to that in p53-null cells. In sum, this study has unveiled TKT expression as a determinant for sensitivity to APR-246 in p53-null cells.

Severe tricuspid regurgitation remains largely undertreated given limited treatment options. Transcatheter tricuspid valve interventions have emerged as a promising therapy for these patients, and the TRISCEND II pivotal trial is the first randomized controlled trial to evaluate transcatheter tricuspid valve replacement (TTVR). The TRISCEND II pivotal trial studies the transcatheter EVOQUE (Edwards Lifesciences, Irvine, California) tricuspid valve replacement system using a United States Food and Drug Administration Breakthrough Device Designation—a program intended to provide timely access to medical devices by speeding up development, assessment, and review. The TRISCEND II trial is a prospective, multicenter trial that randomizes patients with symptomatic severe tricuspid regurgitation to treatment with either TTVR in conjunction with optimal medical therapy or optimal medical therapy alone. The trial's novel 2-phase design evaluates 30-day safety and 6-month effectiveness end points for the first 150 patients in the initial phase and a 1-year safety and effectiveness end point for the full cohort of 400 patients in the second phase. The TRISCEND II trial's 2-phase trial design provided an opportunity for early review and led to the first commercial approval of a TTVR system. In conclusion, the design of the TRISCEND II trial will likely inform future transcatheter tricuspid device trials.

ABSTRACT Purpose APR-246 (Eprenetapopt) is in clinical development with a focus on haematological malignancies and is marketed as a mutant-p53 reactivation therapy. Currently, the detection of at least one TP53 mutation is an inclusion criterion for patient selection into most clinical trials. Preliminary results from our phase Ib/II clinical trial investigating APR-246 combined with combination chemotherapy (cisplatin and 5-Fluorouracil) in metastatic oesophageal cancer, together with previous pre-clinical studies, indicate that TP53 mutation status alone may not be a sufficient biomarker for response to APR-246. This study aimed to identify a robust biomarker for response to APR-246. Methods Correlation analysis of the PRIMA-1 activity (lead compound to APR-246) with mutational status, gene expression, protein expression and metabolite abundance across over 800 cancer cell lines was performed. Functional validation and a boutique siRNA screen of over 750 redox-related genes were also conducted. Results TP53 mutation status was not predictive of response to APR-246. The expression of SLC7A11, the cystine/glutamate transporter, was identified as a superior determinant of response to APR-246. Genetic regulators of SLC7A11, including ATF4, MDM2, wild-type p53 and c-Myc were confirmed to also regulate cancer cell sensitivity to APR-246. Conclusions SLC7A11 expression is the major determinant of sensitivity to APR-246 and should be utilised as a predictive biomarker in future clinical investigation of APR-246. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵* Lead contact * Declaration: The authors disclose that there are no conflicts of interest in the work that contributed towards this manuscript.

We use a sample of 1338 spectroscopically confirmed and photometrically classified Type Ia Supernovae (SNe Ia), sourced from the CSP, CfA, SDSS-II, and SNLS supernova samples, to examine the relationships between SNe Ia and the galaxies that host them. Our results provide confirmation with improved statistical significance that SNe Ia, after standardization, are on average more luminous in massive hosts (significance \\(\\rm > 5 \\sigma\\)), and decline more rapidly in massive hosts (significance \\(\\rm > 9\\sigma\\)) and in hosts with low specific star formation rates (significance \\(\\rm > 8\\sigma\\)). We study the variation of these relationships with redshift and detect no evolution. We split SNe Ia into pairs of subsets that are based on the properties of the hosts, and fit cosmological models to each subset. Including both systematic and statistical uncertainties, we do not find any significant shift in the best-fit cosmological parameters between the subsets. Among different SN Ia subsets, we find that SNe Ia in hosts with high specific star formation rates have the least intrinsic scatter (\\(\\rm \\sigma_{int}=0.08\\pm0.01\\)) in luminosity after standardization.

The SkyMapper 1.3 m telescope at Siding Spring Observatory has now begun regular operations. Alongside the Southern Sky Survey, a comprehensive digital survey of the entire southern sky, SkyMapper will carry out a search for supernovae and other transients. The search strategy, covering a total footprint area of ~2000 deg2 with a cadence of \\(\\leq 5\\) days, is optimised for discovery and follow-up of low-redshift type Ia supernovae to constrain cosmic expansion and peculiar velocities. We describe the search operations and infrastructure, including a parallelised software pipeline to discover variable objects in difference imaging; simulations of the performance of the survey over its lifetime; public access to discovered transients; and some first results from the Science Verification data.

ABSTRACT The mechanisms by which cells respond and adapt to oxidative stress are largely unknown but are key to developing a rationale for cancer therapies that target antioxidant pathways. APR-246 is a mutant-p53 targeted therapeutic currently under clinical investigation in myeloid dysplastic syndrome (MDS) and acute myeloid leukemia1. Whilst the mechanism of action of APR-246 is thought to be reactivation of wild-type p53 activity through covalent modification of cysteine residues in the core domain of mutant-p53 protein2,3, here we report that the anti-neoplastic capacity of APR-246 lies predominantly in the conjugation of free cysteine. Genome-wide CRISPR perturbation screening, metabolite profiling and proteomics in response to APR-246 treatment in mutant-p53 cancer cells highlighted the role of GSH and mitochondrial metabolism in determining APR-246 efficacy. APR-246 sensitivity was increased through loss of key enzymes in mitochondrial one-carbon metabolism, SHMT2 and MTHFD1L, due to diminished glycine supply for de novo GSH synthesis. Critically, we show that APR-246 induces iron-dependent, apoptotic machinery-independent cell death, ferroptosis. Whole-cell proteomics analyses indicated an upregulation of proteins involved in iron-sulfur cluster biogenesis (eg. FDX1). GSH, acetyl-CoA and NADH levels were also depleted in APR-246 treated cells. Importantly, we found that APR-246 inhibits iron-sulfur cluster biogenesis in the mitochondria of cancer cells through cysteine conjugation. This work not only details novel determinants of APR-246 activity in cancer cells, but also provides a clinical roadmap for targeting antioxidant pathways in tumours - beyond targeting mutant-p53 tumours. Figure1 Figure1 * Download figure * Open in new tab Competing Interest Statement The authors have declared no competing interest. Footnotes * Declaration: The authors disclose that there are no conflicts of interest in the work that contributed towards this manuscript.

Presently a \\({>}3\\sigma\\) tension exists between values of the Hubble constant \\(H_0\\) derived from analysis of fluctuations in the Cosmic Microwave Background by Planck, and local measurements of the expansion using calibrators of type Ia supernovae (SNe Ia). We perform a blinded reanalysis of Riess et al. 2011 to measure \\(H_0\\) from low-redshift SNe Ia, calibrated by Cepheid variables and geometric distances including to NGC 4258. This paper is a demonstration of techniques to be applied to the Riess et at. 2016 data. Our end-to-end analysis starts from available CfA3 and LOSS photometry, providing an independent validation of Riess et al. 2011. We obscure the value of \\(H_0\\) throughout our analysis and the first stage of the referee process, because calibration of SNe Ia requires a series of often subtle choices, and the potential for results to be affected by human bias is significant. Our analysis departs from that of Riess et al. 2011 by incorporating the covariance matrix method adopted in SNLS and JLA to quantify SN Ia systematics, and by including a simultaneous fit of all SN Ia and Cepheid data. We find \\(H_0 = 72.5 \\pm 3.1\\) (stat) \\(\\pm 0.77\\) (sys) km s\\(^{-1}\\) Mpc\\(^{-1}\\) with a three-galaxy (NGC 4258+LMC+MW) anchor. The relative uncertainties are 4.3% statistical, 1.1% systematic, and 4.4% total, larger than in Riess et al. 2011 (3.3% total) and the Efstathiou 2014 reanalysis (3.4% total). Our error budget for \\(H_0\\) is dominated by statistical errors due to the small size of the supernova sample, whilst the systematic contribution is dominated by variation in the Cepheid fits, and for the SNe Ia, uncertainties in the host galaxy mass dependence and Malmquist bias.

This paper presents the first major data release and survey description for the ANU WiFeS SuperNovA Program (AWSNAP). AWSNAP is an ongoing supernova spectroscopy campaign utilising the Wide Field Spectrograph (WiFeS) on the Australian National University (ANU) 2.3m telescope. The first and primary data release of this program (AWSNAP-DR1) releases 357 spectra of 175 unique objects collected over 82 equivalent full nights of observing from July 2012 to August 2015. These spectra have been made publicly available via the WISeREP supernova spectroscopy repository. We analyse the AWSNAP sample of Type Ia supernova spectra, including measurements of narrow sodium absorption features afforded by the high spectral resolution of the WiFeS instrument. In some cases we were able to use the integral-field nature of the WiFeS instrument to measure the rotation velocity of the SN host galaxy near the SN location in order to obtain precision sodium absorption velocities. We also present an extensive time series of SN 2012dn, including a near-nebular spectrum which both confirms its \"super-Chandrasekhar\" status and enables measurement of the sub-solar host metallicity at the SN site.

We present the discovery of a z=0.65 low-ionization broad absorption line (LoBAL) quasar in a post-starburst galaxy in data from the Dark Energy Survey (DES) and spectroscopy from the Australian Dark Energy Survey (OzDES). LoBAL quasars are a minority of all BALs, and rarer still is that this object also exhibits broad FeII (an FeLoBAL) and Balmer absorption. This is the first BAL quasar that has signatures of recently truncated star formation, which we estimate ended about 40 Myr ago. The characteristic signatures of an FeLoBAL require high column densities, which could be explained by the emergence of a young quasar from an early, dust-enshrouded phase, or by clouds compressed by a blast wave. The age of the starburst component is comparable to estimates of the lifetime of quasars, so if we assume the quasar activity is related to the truncation of the star formation, this object is better explained by the blast wave scenario.