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Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%-20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated genome-wide association study loci. Mechanistic studies indicate that some RBPs are recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD, with implications for basic biology, genetic screening, and therapy stratification., Competing Interests: Declaration of interests G.B.M. consults with AstraZeneca, ImmunoMET, Ionis, Nuevolution, PDX bio, Signalchem, Symphogen, and Tarveda; has stock options with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda; sponsored research from AstraZeneca, Immunomet, Pfizer, Nanostring, and Tesaro; has received travel support from Chrysallis Bio; and has licensed technology to Nanostring and Myriad Genetics. B.F. is an employee of AstraZeneca. A.K.S.: Consulting (Merck, Astra Zeneca, ImmunoGen, Iylon, GSK, Kiyatec); shareholder (BioPath); patent licensed (EGFL6 antibody)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

All cells contain specialized signaling pathways that enable adaptation to specific molecular stressors. Yet, whether these pathways are centrally regulated in complex physiological stress states remains unclear. Using genome-scale fitness screening data, we quantified the stress phenotype of 739 cancer cell lines, each representing a unique combination of intrinsic tumor stresses. Integrating dependency and stress perturbation transcriptomic data, we illuminated a network of genes with vital functions spanning diverse stress contexts. Analyses for central regulators of this network nominated C16orf72/HAPSTR1, an evolutionarily ancient gene critical for the fitness of cells reliant on multiple stress response pathways. We found that HAPSTR1 plays a pleiotropic role in cellular stress signaling, functioning to titrate various specialized cell-autonomous and paracrine stress response programs. This function, while dispensable to unstressed cells and nematodes, is essential for resilience in the presence of stressors ranging from DNA damage to starvation and proteotoxicity. Mechanistically, diverse stresses induce HAPSTR1, which encodes a protein expressed as two equally abundant isoforms. Perfectly conserved residues in a domain shared between HAPSTR1 isoforms mediate oligomerization and binding to the ubiquitin ligase HUWE1. We show that HUWE1 is a required cofactor for HAPSTR1 to control stress signaling and that, in turn, HUWE1 feeds back to ubiquitinate and destabilize HAPSTR1. Altogether, we propose that HAPSTR1 is a central rheostat in a network of pathways responsible for cellular adaptability, the modulation of which may have broad utility in human disease.

Heat shock factor 1 (HSF1) is well known for its role in the heat shock response (HSR), where it drives a transcriptional program comprising heat shock protein (HSP) genes, and in tumorigenesis, where it drives a program comprising HSPs and many noncanonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no substantial role in the HSR, physically and functionally interacts with HSF1 across diverse types of cancer. HSF1 and HSF2 have notably similar chromatin occupancy and regulate a common set of genes that include both HSPs and noncanonical transcriptional targets with roles critical in supporting malignancy. Loss of either HSF1 or HSF2 results in a dysregulated response to nutrient stresses in vitro and reduced tumor progression in cancer cell line xenografts. Together, these findings establish HSF2 as a critical cofactor of HSF1 in driving a cancer cell transcriptional program to support the anabolic malignant state.

The COVID-19 pandemic created unprecedented strain on the personal protective equipment (PPE) supply chain. Given the dearth of PPE and consequences for transmission, GetMePPE Chicago (GMPC) developed a PPE allocation framework and system, distributing 886 900 units to 274 institutions from March 2020 to July 2021 to address PPE needs. As the pandemic evolved, GMPC made difficult decisions about (1) building reserve inventory (to balance present and future, potentially higher clinical acuity, needs), (2) donating to other states/out-of-state organizations, and (3) receiving donations from other states. In this case study, we detail both GMPC's experience in making these decisions and the ethical frameworks that guided these decisions. We also reflect on lessons learned and suggest which values may have been in conflict (eg, maximizing benefits vs duty to mission, defined in the context of PPE allocation) in each circumstance, which values were prioritized, and when that prioritization would change. Such guidance can promote a values-based approach to key issues concerning distribution of PPE and other scarce medical resources in response to the COVID-19 pandemic and related future pandemics.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper., Competing Interests: Competing interests R.S.S., I.O., Z.L., A.J.-W.L., T.H., M.V., Y.S., L.D., M.S.M., H.A.R., M.S., G.B., A.B.H., E.G., S.K., H.M., I.K., E.D.S., M.P.L.Q., J.Y., M. Laé, S.B.L. and L.S. report no potential competing interest. J.H. is a Scientific Editor at DMM but was not included in any aspect of the editorial handling of this article. C.A.P. has received consulting fees from Genentech/Roche and receives research funding from Kura Oncology for studies not related to this paper. M. Ladanyi has received advisory board compensation from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Takeda, Bayer and Paige.AI, and research support from LOXO Oncology, Helsinn Healthcare, Elevation Oncology and Merus. R.S. has received research grants from Merus, Helsinn Healthcare, LOXO Oncology and Elevation Oncology for studies unrelated to this paper., (© 2022. Published by The Company of Biologists Ltd.)

Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET-fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5' fusion partners ( CCDC6 , KIF5B and TRIM33 ). Notably, we identify MYC as a protein that is upregulated by RET expression and down-regulated by cabozantinib treatment, opening up potentially new therapeutic avenues for combinatorial targeting RET-fusion driven lung cancers. The novel RET fusion-dependent preclinical models described herein represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies., (© 2020. Published by The Company of Biologists Ltd.)

Objective: We hypothesized that professional football teams would perform better than anticipated during games occurring close to their circadian peak in performance., Design: We reviewed the past 40 years of evening and daytime professional football games between west coast and east coast United States teams. In order to account for known factors influencing football game outcomes we compared the results to the point spread which addresses all significant differences between opposing teams for sports betting purposes. One sample t-tests, Wilcoxon signed ranked tests, and linear regression were performed. Comparison to day game data was included as a control., Setting: Academic medical center., Participants: N/A., Interventions: N/A., Results: The results were strongly in favor of the west coast teams during evening games against east coast teams, with the west coast teams beating the point spread about twice as often (t = 3.95, P < 0.0001) as east coast teams. For similar daytime game match-ups, we observed no such advantage., Conclusions: Sleep and circadian physiology have profound effects on human function including the performance of elite athletes. Professional football players playing close to the circadian peak in performance demonstrate a significant athletic advantage over those who are playing at other times. Application of this knowledge is likely to enhance human performance.

Mast cells, platelets, and some macrophages are abundant sources of PGD(2) and its active metabolite 15-deoxy-Delta(12,14)-PGJ(2) (15-d-PGJ(2)). The lipid mediator 15-d-PGJ(2) regulates numerous processes, including adipogenesis, apoptosis, and inflammation. The 15-d-PGJ(2) has been shown to both inhibit as well as induce the production of inflammatory mediators such as TNF-alpha, IL-1beta, and cyclooxygenase, mostly occurring via a nuclear receptor called peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Data concerning the effects of 15-d-PGJ(2) on human T cells and immune regulation are sparse. IL-8, a cytokine with both chemotactic and angiogenic effects, is produced by T lymphocytes following activation. Whether 15-d-PGJ(2) can regulate the production of IL-8 in T cells in unknown. Interestingly, 15-d-PGJ(2) treatment of unstimulated T cells induces cell death. In contrast, in activated human T lymphocytes, 15-d-PGJ(2) does not kill them, but induces the synthesis of IL-8. In this study, we report that 15-d-PGJ(2) induced a significant increase in both IL-8 mRNA and protein from activated human T lymphocytes. The induction of IL-8 by 15-d-PGJ(2) did not occur through the nuclear receptor PPAR-gamma, as synthetic PPAR-gamma agonists did not mimic the IL-8-inducing effects of 15-d-PGJ(2). The mechanism of IL-8 induction was through a mitogen-activated protein kinase and NF-kappaB pathway, as inhibitors of both systems abrogated IL-8 protein induction. Therefore, 15-d-PGJ(2) can act as a potent proinflammatory mediator in activated T cells by inducing the production of IL-8. These findings show the complexity with which 15-d-PGJ(2) regulates T cells by possessing both pro- and anti-inflammatory properties depending on the activation state of the cell. The implications of this research also include that caution is warranted in assigning a solely anti-inflammatory role for 15-d-PGJ(2).