Metabolic remodeling is now widely regarded as a hallmark of cancer, but it is not clear whether individual metabolic strategies are frequently exploited by many tumours. Here we compare messenger RNA profiles of 1,454 metabolic enzymes across 1,981 tumours spanning 19 cancer types to identify enzymes that are consistently differentially expressed. Our meta-analysis recovers established targets of some of the most widely used chemotherapeutics, including dihydrofolate reductase, thymidylate synthase and ribonucleotide reductase, while also spotlighting new enzymes, such as the mitochondrial proline biosynthetic enzyme PYCR1. The highest scoring pathway is mitochondrial one-carbon metabolism and is centred on MTHFD2. MTHFD2 RNA and protein are markedly elevated in many cancers and correlated with poor survival in breast cancer. MTHFD2 is expressed in the developing embryo, but is absent in most healthy adult tissues, even those that are proliferating. Our study highlights the importance of mitochondrial compartmentalization of one-carbon metabolism in cancer and raises important therapeutic hypotheses.
Delay in the initiation of RT is associated with an increase [corrected] in LRR in breast cancer and head and neck cancer. Delays in starting RT should be as short as reasonably achievable.
Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-IC ytomegalovirus (CMV) (human herpesvirus 5 [HHV-5], a betaherpesvirus) is one of the most common etiological agents of chronic viral infection in humans, with primary infection developing in the majority of people at relatively young ages and lasting for life (1). Although acute CMV infection is mostly asymptomatic in healthy individuals, debilitating and even fatal complications arise in those with weakened immune systems, including pregnant women, infants, transplant recipients, and HIV patients. Remarkably, a recent analysis of monozygotic twin pairs revealed that CMV infection was the primary factor driving nonheritable diversity in the immune system (2). Consistent with the dramatic impact of CMV on the host immune system, infection has been associated with multiple chronic inflammatory conditions, including high blood pressure, heart disease/atherosclerosis, cancer, and aging-related immunodeficiencies (3, 4). Despite the clinical importance of human CMV (HCMV), there is currently no vaccine, and antiviral drugs are relatively toxic and cannot restrict viral persistence/latency.Both mouse CMV (MCMV) and HCMV contain a linear double-stranded DNA (dsDNA) genome of ϳ230 kb encoding hundreds of viral open reading frames (ORFs) (5, 6). CMV harbors an arsenal of immunoregulatory genes that allow the virus to evade or dampen host immune defenses. However, despite these numerous strategies, the virus still induces significant levels of type I interferon (IFN-I) from infected cells both in vitro and in vivo. We have previously shown that MCMV induces a biphasic IFN-I response in vivo, with the first wave of IFN-I being completely independent of Toll-like receptor (TLR), Nalp3, and MAVS and emanating from virally infected stromal cells during the first 12 h (7,8). This "first burst" of IFN-I is followed by a later wave produced at 36 to 44 h by plasmacytoid dendritic cells (DCs) (pDCs) and conventional DCs (cDCs) in response to viral particles released from the infected stroma (7,(9)(10)(11). It is the first wave of IFN-I that is critical to limit viral spread in the peripheral organs (7), while the second pDC-derived wave is mostly dispensable for restricting MCMV replication levels (12). Despite our previous work showing that lymphotoxin (LT) signaling is required to promote an optimal first-phase IFN-I response to MCMV in vivo (7,8,11,13,14), the specific innate sensing pathway required for this initial production has remained uncharacterized, although
Background: Persistent Staphylococcus aureus bacteremia (pSAB) is an emerging problem among hospitalized patients. We studied key clinical characteristics and outcomes associated with pSAB to better define the epidemiological features of this increasingly recognized clinical entity.Methods: A retrospective case-control study of patients hospitalized with SAB between January 1, 2001, and September 30, 2004, was conducted to compare the clinical characteristics, management, and outcomes of patients with pSAB (Ͼ7 days of bacteremia) with those of a cohort of patients with nonpersistent SAB (Ͻ 3 days of bacteremia). Patients with 4 to 6 days of bacteremia were excluded from the analysis. To detect a potential association between reduced susceptibility to vancomycin and persistent methicillin-resistant SAB, vancomycin susceptibilities were confirmed using standard dilution methods.Results: Eighty-four patients with pSAB and 152 patients with nonpersistent SAB were included in the analysis. Methicillin resistance (odds ratio [OR], 5.22; 95% confidence interval [CI], 2.63-10.38), intravascular catheter or other foreign body use (OR, 2.37; 95% CI, 1.11-3.96), chronic renal failure (OR, 2.08; 95% CI, 1.09-3.96), more than 2 sites of infection (OR, 3.31; 95% CI, 1.17-9.38), and infective endocarditis (OR, 10.30; 95% CI, 2.98-35.64) were independently associated with pSAB. The mean time to device removal was significantly longer in patients with pSAB than in patients with nonpersistent SAB (4.94 vs 1.64 days; P Ͻ.01). There was no evidence of reduced vancomycin susceptibility among persistent methicillin-resistant S aureus isolates. Clinical outcomes were significantly worse among patients with pSAB.Conclusions: Many hospitalized patients may be at risk for pSAB. Aggressive attempts to minimize the risk of complications and poor outcomes associated with pSAB, such as early device removal, should be encouraged.
The use of PRT varied across the dispersed population in Ontario and was influenced by factors unrelated to the patient's needs. An effort should be made to reduce barriers to access for disadvantaged groups.
Pregnancy is associated with changes in host susceptibility to infections and inflammatory disease. We hypothesize that metabolic enzyme trafficking affects maternal neutrophil activation. Specifically, immunofluorescence microscopy has shown that glucose-6-phosphate dehydrogenase (G-6-PDase), the rate-controlling step of the hexose monophosphate shunt (HMS), is located near the cell periphery in control neutrophils but is found near the microtubule-organizing centers in cells from pregnant women. Cytochemical studies confirmed that the distribution of the G-6-PDase antigen is coincident with functional G-6-PDase activity. Metabolic oscillations within activated pregnancy neutrophils are higher in amplitude, though lower in frequency, than activated control neutrophils, suggesting limited HMS activity. Analysis of radioisotope-labeled carbon flux from glucose to CO2 indicates that the HMS is intact in leukocytes from pregnant women, but its level is not enhanced by cell stimulation. Using extracellular fluorescent markers, activated pregnancy neutrophils were found to release reactive oxygen metabolites (ROMs) at a lower rate than activated control neutrophils. However, basal levels of ROM production in polarized pregnancy neutrophils were greater than in control neutrophils. Microtubule-disrupting agents reversed the observed changes in G-6-PDase trafficking, metabolic oscillations, and ROM production by maternal neutrophils. G-6-PDase trafficking appears to be one mechanism regulating ROM production by maternal neutrophils
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