Search

Original citation: J Clin Invest. 2012;122(4):1427-1443. https://doi.org/10.1172/JCI57322. Citation for this corrigendum: J Clin Invest. 2024;134(8):e180863. https://doi.org/10.1172/JCI180863. The authors recently became aware that the image presented in Figure 4A for the [...]

Objectives We aim to establish daily risk estimates of the relationships between grass, tree and weed pollen and asthma health outcomes.Design Time series regression analysis of exposure and health outcomes using interaction by month to determine risk estimates all year round.Setting Metropolitan Adelaide, South Australia.Participants Health outcomes for asthma are based on 15 years of hospital admissions, 13 years emergency presentations and ambulance callouts. In adults (≥18 years), there were 10 381 hospitalisations, 26 098 emergency department (ED) presentations and 11 799 ambulance callouts and in children (0–17 years), 22 114, 39 813 and 3774, respectively.Outcome measures The cumulative effect of 7 day lags was calculated as the sum of the coefficients and reported as incidence rate ratio (IRR) related to an increase in 10 grains of pollen/m3.Results In relation to grass pollen, children and adults were disparate in their timing of health effects. Asthma outcomes in children were positively related to grass pollen in May, and for adults in October. Positive associations with weed pollen in children was seen from February to May across all health outcomes. For adults, weed pollen-related health outcomes were restricted to February. Adults were not affected by tree pollen, while children’s asthma morbidity was associated with tree pollen in August and September. In children, IRRs ranged from 1.14 (95% CI 1.06 to 1.21) for ED presentations for tree pollen in August to 1.98 (95% CI 1.06 to 3.72) for weed pollen in February. In adults, IRRs ranged from 1.28 (95% CI 1.01 to 1.62) for weed pollen in February to 1.31 (95% CI 1.08 to 1.57) for grass pollen in October.Conclusion Monthly risk assessment indicated that most pollen-related asthma health outcomes in children occur in the colder part of the year, while adults are affected in the warm season. The findings indicate a need for year-round pollen monitoring and related health campaigns to provide effective public health prevention.

Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here, we show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the inositol-requiring enzyme 1[alpha] (IRE1[alpha])/X-box binding protein 1 (XBP1) pathway through multiple molecular mechanisms in a variety of c- Myc- and N-Myc-dependent cancers. In particular, Myc-overexpressing cells require IRE1[alpha]/XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity. Pharmacological and genetic XBP1 inhibition induces Myc-dependent apoptosis, which is alleviated by exogenous unsaturated fatty acids. Of note, SCD1 inhibition phenocopies IRE1[alpha] RNase activity suppression in vivo. Furthermore, IRE1[alpha] inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc-overexpressing Burkitt's lymphoma, suggesting that inhibiting the IRE1[alpha]/XBP1 pathway is a useful general strategy for treatment of Myc- driven cancers., Introduction The Myc family of proto-oncogenes (MYC, MYCN, MYCL) encodes bHLHZ (basic helix-loop-helix leucine zipper) transcription factors, which regulate thousands of genes coordinating numerous cellular processes, including proliferation, differentiation, self-renewal, [...]

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer (1), is characterized by elevated glycogen levels and fat deposition (2). These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) (3) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours (4). However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation (5), suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo 1, SET domain containing 2 and BRCAl-associated protein-1, among others) (6-9), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) (10) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients (11). Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin (12), thereby inhibiting a potential Warburg effect (13,14). Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours (6,7,15)., We performed pan-metabolomic analysis on 20 primary human ccRCC tumours and matching normal kidney tissues. Levels of metabolites involved in glycolysis, gluconeogenesis and glucose-related sugar metabolism were highly elevated in [...]

Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2 α (HIF-2 α) is highly expressed in vascular ECs and, along with HIF-1 α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2 α regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2 α expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2 α - deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2 α -dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2 α -dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2 α in ECs. These results indicate that HIF-1 α and HIF-2 α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis., Introduction The therapeutic manipulation of angiogenesis holds great promise for treating diverse pathological conditions, including cancer, macular degeneration, atherosclerosis, and peripheral arterial disease (PAD) (1), (2). However, the ability to [...]

Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1α and HIF-2α, and overexpression of HIF-2α in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2α during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1α versus HIF-2α must be elucidated. We demonstrate here that mice lacking HIF-2α in myeloid cells ([Hif2a.sup.Δ/Δ] mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2α directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. [Hif2a.sup.Δ/Δ] mice displayed reduced TAM infiltration in independent murine hepatocellular and colitisassociated colon carcinoma models, and this was associated with reduced tumor cell proliferation and progression. Notably, HIF-2α modulated macrophage migration by regulating the expression of the cytokine receptor M-CSFR and the chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2α as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer., Introduction Macrophages are versatile hematopoietic cells that mediate a wide array of immune functions, e.g., initiating inflammatory responses, executing phagocytosis and bacterial killing, and facilitating adaptive immunity (1-3). The plasticity [...]

HIF transcription factors (HIF-1 and HIF-2) are central mediators of cellular adaptation to hypoxia. Because the resting partial pressure of oxygen is low in the intestinal lumen, epithelial cells are believed to be mildly hypoxic. Having recently established a link between HIF and the iron-regulatory hormone hepcidin, we hypothesized that HIFs, stabilized in the hypoxic intestinal epithelium, may also play critical roles in regulating intestinal iron absorption. To explore this idea, we first established that the mouse duodenum, the site of iron absorption in the intestine, is hypoxic and generated conditional knockout mice that lacked either Hif1a or Hif2a specifically in the intestinal epithelium. Using these mice, we found that HIF-1[alpha] was not necessary for iron absorption, whereas HIF-2[alpha] played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the gene encoding divalent metal transporter 1 (DMT1), the principal intestinal iron transporter. Specific deletion of Hif2a led to a decrease in serum and liver iron levels and a marked decrease in liver hepcidin expression, indicating the involvement of an induced systemic response to counteract the iron deficiency. This finding may provide a basis for the development of new strategies, specifically in targeting HIF-2[alpha], to improve iron homeostasis in patients with iron disorders., Introduction Iron is an essential nutrient and is critical for a multitude of biological processes at the cellular level (including catalyzing essential enzymatic reactions and electron transport) and at the [...]