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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.

The continued expansion of the underground economy is one of Canada's major problems. Using the definition of underground economy as unrecorded GDP, Statistics Canada placed the country's hidden economy at around 2% to 3% of GDP in 1990. However, if underground economy was defined as unreported taxable economic activity, this estimate would have been closer to 15%. Based on the latter definition, the hidden economy covers unreported rental and investment incomes, tips and childcare earnings, income from off-the-books employment, barter activities, proceeds from home-produced goods, and skimming by business owners. It also includes unregulated activities such as drug dealing, smuggling, illegal gambling and some construction activities. Canada's underground economy has been growing due to such factors as burdensome taxes, unemployment, self-employment, immigration and changing demographics. Measures for resolving this problem are suggested., GOVERNMENT AND BUSINESS CAN WORK TOGETHER TO KEEP THE UNDERGROUND ECONOMY IN CHECK Over the last decade and a half, there seems to have been a significant increase in the [...]

Managing a university is one of the most challenging management jobs, but it must be done well. Business leaders have an important role to play Increasingly business leaders serve in [...]

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 BRCA1/2and 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.

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.

ABSTRACTPseudomonas aeruginosautilizes a number of distinct pathways to secrete proteins that play various roles during infection. These include the type II secretion system, which is responsible for the secretion of the majority of exoproducts into the surrounding environment, including toxins and degradative enzymes. In contrast, the type III secretion system mediates the delivery of protein effectors directly into the cytoplasm of the host cell. Using tissue culture assays and a mouse acute-pneumonia model, we have determined the contribution of each of the type III effectors during infection. In strain PAK, ExoS is the major cytotoxin required for colonization and dissemination during infection. ExoT confers protection of tissue culture cells from type III-dependent lysis, while ExoY seemed to have little effect on cytotoxicity. ExoU is over 100-fold more cytotoxic than ExoS. The cytotoxicity of type II secretion was determined following deletion of the genes for the more toxic type III secretion system. The participation of these secretion systems during lifelong colonization of cystic fibrosis (CF) patients is unclear. By comparing clonal strains from the same patient isolated at the initial onset of P. aeruginosainfection and more than a decade later, after chronic colonization has been established, we show that initial strains are more cytotoxic than chronic strains that have evolved to reduce type III secretion. Constitutive expression of genes for the type III secretion system restored ExoS secretion but did not always reestablish cytotoxicity, suggesting that CF strains accumulate a number of mutations to reduce bacterial toxicity to the host.

Infections caused by the opportunistic pathogen Pseudomonas aeruginosa involve the interplay of several bacterial virulence factors. It has recently been established that the delivery of toxic effector proteins by the type III secretion system is an important virulence mechanism in several animal models. Furthermore, the expression of the type III secretion system and its effectors has been correlated with a poor clinical outcome during human infections. A novel cyclic AMP (cAMP) regulatory network that controls the expression of virulence factors, including the type III secretion system, was examined to determine its contribution to P. aeruginosa colonization and dissemination in a mouse pneumonia model. Mutants lacking the two genome-encoded adenylate cyclases, CyaA and CyaB, and the cAMP-dependent regulator Vfr were examined. Based on the enumeration of bacteria in lungs, livers, and spleens, as well as the assessment of mouse lung pathology, mutations in the cyaB and vfr genes resulted in a more significantly attenuated phenotype than mutations in cyaA. Moreover, in this model, expression of the type III secretion system was essential for lung colonization and pathology. Strains with mutations in the exsA gene, which encodes a type III regulatory protein, or pscC, which encodes an essential component of the secretion apparatus, were also significantly attenuated. Finally, we demonstrate that virulence can be restored in an adenylate cyclase mutant by the overexpression of exsA, which specifically restores expression of the type III secretion system in the absence of a functional cAMP-dependent regulatory network.

ABSTRACTInfections caused by the opportunistic pathogen Pseudomonas aeruginosainvolve the interplay of several bacterial virulence factors. It has recently been established that the delivery of toxic effector proteins by the type III secretion system is an important virulence mechanism in several animal models. Furthermore, the expression of the type III secretion system and its effectors has been correlated with a poor clinical outcome during human infections. A novel cyclic AMP (cAMP) regulatory network that controls the expression of virulence factors, including the type III secretion system, was examined to determine its contribution to P. aeruginosacolonization and dissemination in a mouse pneumonia model. Mutants lacking the two genome-encoded adenylate cyclases, CyaA and CyaB, and the cAMP-dependent regulator Vfr were examined. Based on the enumeration of bacteria in lungs, livers, and spleens, as well as the assessment of mouse lung pathology, mutations in the cyaBand vfrgenes resulted in a more significantly attenuated phenotype than mutations in cyaA. Moreover, in this model, expression of the type III secretion system was essential for lung colonization and pathology. Strains with mutations in the exsAgene, which encodes a type III regulatory protein, or pscC, which encodes an essential component of the secretion apparatus, were also significantly attenuated. Finally, we demonstrate that virulence can be restored in an adenylate cyclase mutant by the overexpression of exsA, which specifically restores expression of the type III secretion system in the absence of a functional cAMP-dependent regulatory network.

ABSTRACTMulti-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RETfusions; 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 RETrearrangements 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 RETrearrangements. 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 RETrearrangements with three different 5′ fusion partners (CCDC6, KIF5Band TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and downregulated by treatment with cabozantinib, opening up potentially new therapeutic avenues for the combinatorial targetin of RET fusion- driven lung cancers. The novel RET fusion-dependent preclinical models described here represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.

We hypothesized that professional football teams would perform better than anticipated during games occurring close to their circadian peak in performance.

Poly-sulfobetaine surface modification on a vascular catheter inhibits microbial adherence and thrombosis.