Showcasing Environmental Health and Safety Activities During the Coronavirus Disease 2019 Pandemic.

Introduction: Emergency preparedness is not a novel topic. What has been novel is the fast pace at which organizations, including academic institutions, have had to adapt to infectious disease outbreaks since 2000. Objective: The goal of this article is to highlight the various environmental health and safety (EHS) team activities during the coronavirus disease 2019 (COVID-19) pandemic to ensure that on-site personnel was safe, the research could be conducted, and critical business operations such as academics, laboratory animal care, environmental compliance, and routine healthcare functions could continue during the pandemic. Methods: The response framework is presented by discussing first the lessons learned in preparedness and emergency response during outbreaks that occurred since 2000, namely Influenza virus, Zika virus, and Ebola virus. Then, how the response to the COVID-19 pandemic was activated, and the effects of ramping down research and business activities. Results: Next, the contributions of each EHS unit are presented, namely, environmental, industrial hygiene and occupational safety, research safety and biosafety, radiation safety, supporting healthcare activities, disinfection, and communications and training. Discussion: Lastly, a few lessons learned are shared with the reader for moving toward normalcy.

The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition.

Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high 18F-FDG uptake and poor prognosis. This previously undescribed metabolic heterogeneity of NSCLC subtypes implicates significant potential for the development of diagnostic, prognostic and targeted therapeutic strategies for lung SqCC, a cancer for which existing therapeutic options are clinically insufficient.

NQO1 inhibits proteasome-mediated degradation of HIF-1α.

Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF-1α and inhibits the proteasome-mediated degradation of HIF-1α by preventing PHDs from interacting with HIF-1α. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1α expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1α stability in cancers.

Regulation of obesity and insulin resistance by hypoxia-inducible factors.

In obesity, dysregulated metabolism and aberrant expansion of adipose tissue lead to the development of tissue hypoxia that plays an important role in contributing to obesity-associated metabolic disorders. Recent studies utilizing adipocyte-specific hypoxia-inducible factor-α (HIF-α) gain- or loss-of-function animal models highlight the pivotal involvement of hypoxic responses in the pathogenesis of obesity-associated inflammation and insulin resistance. HIF-1α, a master transcription factor of oxygen homeostasis, induces inflammation and insulin resistance in obesity, whereas its isoform, HIF-2α, exerts opposing functions in these obesity-associated metabolic phenotypes. In this review, recent evidence elucidating functional implications of adipocyte HIFs in obesity and, more importantly, how these regulate obesity-associated inflammation, fibrosis, and insulin resistance will be discussed. Further, we propose that modulation of HIF-1 could be a potential novel therapeutic strategy for antidiabetic treatment.

Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1.

Wound healing is a complex multi-step process that requires spatial and temporal orchestration of cellular and non-cellular components. Hypoxia is one of the prominent microenvironmental factors in tissue injury and wound healing. Hypoxic responses, mainly mediated by a master transcription factor of oxygen homeostasis, hypoxia-inducible factor-1 (HIF-1), have been shown to be critically involved in virtually all processes of wound healing and remodeling. Yet, mechanisms underlying hypoxic regulation of wound healing are still poorly understood. Better understanding of how the wound healing process is regulated by the hypoxic microenvironment and HIF-1 signaling pathway will provide insight into the development of a novel therapeutic strategy for impaired wound healing conditions such as diabetic wound and fibrosis. In this review, we will discuss recent studies illuminating the roles of HIF-1 in physiologic and pathologic wound repair and further, the therapeutic potentials of HIF-1 stabilization or inhibition.