MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate.

Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of ASCL1, NEUROD1, POU2F3, or YAP1. Here, we use mouse and human models with a time-series single-cell transcriptome analysis to reveal that MYC drives dynamic evolution of SCLC subtypes. In neuroendocrine cells, MYC activates Notch to dedifferentiate tumor cells, promoting a temporal shift in SCLC from ASCL1+ to NEUROD1+ to YAP1+ states. MYC alternatively promotes POU2F3+ tumors from a distinct cell type. Human SCLC exhibits intratumoral subtype heterogeneity, suggesting that this dynamic evolution occurs in patient tumors. These findings suggest that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis.

Ergosterol synthesis is essential for cellular growth and viability of the budding yeast Saccharomyces cerevisiae, and intracellular sterol distribution and homeostasis are therefore highly regulated in this species. Erg25 is an iron-containing C4-methyl sterol oxidase that contributes to the conversion of 4,4-dimethylzymosterol to zymosterol, a precursor of ergosterol. The ERG29 gene encodes an endoplasmic reticulum (ER)-associated protein, and here we identified a role for Erg29 in the methyl sterol oxidase step of ergosterol synthesis. ERG29 deletion resulted in lethality in respiring cells, but respiration-incompetent (Rho- or Rho0) cells survived, suggesting that Erg29 loss leads to accumulation of oxidized sterol metabolites that affect cell viability. Down-regulation of ERG29 expression in Δerg29 cells indeed led to accumulation of methyl sterol metabolites, resulting in increased mitochondrial oxidants and a decreased ability of mitochondria to synthesize iron-sulfur (Fe-S) clusters due to reduced levels of Yfh1, the mammalian frataxin homolog, which is involved in mitochondrial iron metabolism. Using a high-copy genomic library, we identified suppressor genes that permitted growth of Δerg29 cells on respiratory substrates, and these included genes encoding the mitochondrial proteins Yfh1, Mmt1, Mmt2, and Pet20, which reversed all phenotypes associated with loss of ERG29 Of note, loss of Erg25 also resulted in accumulation of methyl sterol metabolites and also increased mitochondrial oxidants and degradation of Yfh1. We propose that accumulation of toxic intermediates of the methyl sterol oxidase reaction increases mitochondrial oxidants, which affect Yfh1 protein stability. These results indicate an interaction between sterols generated by ER proteins and mitochondrial iron metabolism.

Towards precision medicine in sepsis: a position paper from the European Society of Clinical Microbiology and Infectious Diseases.

BACKGROUND: Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored. AIMS: To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research. SOURCES: A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed. CONTENT: The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1). IMPLICATIONS: A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways.

LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells.

Endosomal sorting complexes required for transport III (ESCRT-III) proteins have been implicated in sealing the nuclear envelope in mammals, spindle pole body dynamics in fission yeast, and surveillance of defective nuclear pore complexes in budding yeast. Here, we report that Lem2p (LEM2), a member of the LEM (Lap2-Emerin-Man1) family of inner nuclear membrane proteins, and the ESCRT-II/ESCRT-III hybrid protein Cmp7p (CHMP7), work together to recruit additional ESCRT-III proteins to holes in the nuclear membrane. In Schizosaccharomyces pombe, deletion of the ATPase vps4 leads to severe defects in nuclear morphology and integrity. These phenotypes are suppressed by loss-of-function mutations that arise spontaneously in lem2 or cmp7, implying that these proteins may function upstream in the same pathway. Building on these genetic interactions, we explored the role of LEM2 during nuclear envelope reformation in human cells. We found that CHMP7 and LEM2 enrich at the same region of the chromatin disk periphery during this window of cell division and that CHMP7 can bind directly to the C-terminal domain of LEM2 in vitro. We further found that, during nuclear envelope formation, recruitment of the ESCRT factors CHMP7, CHMP2A, and IST1/CHMP8 all depend on LEM2 in human cells. We conclude that Lem2p/LEM2 is a conserved nuclear site-specific adaptor that recruits Cmp7p/CHMP7 and downstream ESCRT factors to the nuclear envelope.

Genetic factors affecting dental caries risk.

This article reviews the literature on genetic aspects of dental caries and provides a framework for the rapidly changing disease model of caries. The scope is genetic aspects of various dental factors affecting dental caries. The PubMed database was searched for articles with keywords 'caries', 'genetics', 'taste', 'diet' and 'twins'. This was followed by extensive handsearching using reference lists from relevant articles. The post-genomic era will present many opportunities for improvement in oral health care but will also present a multitude of challenges. We can conclude from the literature that genes have a role to play in dental caries; however, both environmental and genetic factors have been implicated in the aetiology of caries. Additional studies will have to be conducted to replicate the findings in a different population. Identification of genetic risk factors will help screen and identify susceptible patients to better understand the contribution of genes in caries aetiopathogenesis. Information derived from these diverse studies will provide new tools to target individuals and/or populations for a more efficient and effective implementation of newer preventive measures and diagnostic and novel therapeutic approaches in the management of this disease.

Endothelial barrier dysfunction in septic shock.

The endothelium provides an essential and selective membrane barrier that regulates the movement of water, solutes, gases, macromolecules and the cellular elements of the blood from the tissue compartment in health and disease. Its structure and continuous function is essential for life for all vertebrate organisms. Recent evidence indicates that the endothelial surface does not have a passive role in systemic inflammatory states such as septic shock. In fact, endothelial cells are in dynamic equilibrium with a myriad of inflammatory mediators and elements of the innate immune and coagulation systems to orchestrate the host response in sepsis. The barrier function of the endothelial surface is almost uniformly impaired in septic shock, and it is likely that this contributes to adverse outcomes. In this review, we will highlight recent advances in the understanding of the signalling events that regulate endothelial function and molecular events that induce endothelial dysfunction in sepsis. Endothelial barrier repair strategies as a treatment for sepsis include modulation of C5a, high-mobility group box 1 and VEGF receptor 2; stimulation of angiopoietin-1, sphingosine 1 phosphate receptor 1 and Slit; and a number of other innovative approaches.

Minimally invasive clinical approach in indirect pulp therapy and healing of deep carious lesions.

Indirect pulp treatment is a conservative vital pulp procedure performed in deep carious lesion approximating the pulp, but without signs or symptoms of pulp degeneration. Removing the carious biomass along with sealing the residual caries from extrinsic substrate and oral bacteria makes residual caries after the first excavation less active. This allows time for pulpo dentinal complex to form tertiary dentine so that at the second excavation, there is less likelihood of pulpal exposure. It has also been suggested that by changing the cavity environment from an active lesion into a more slowly progressing lesion, will be accompanied by more regular tubular tertiary dentin formation. The success of this approach has been demonstrated by various randomized controlled studies comparing conventional treatment of such lesions with stepwise excavation. These results are echoed at clinical, radiographic, macroscopic, microscopic and ultrastructural level during follow up visits. This study reviews promising concepts and rationale of minimally invasive indirect pulp therapy technique where conventional wisdom of caries removal is challenged

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012

Objective: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. Design: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. Methods: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Results: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7­9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO 2/FiO 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO 2/FI O 2<150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5­10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). Conclusions: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

Identification of FRA1 and FRA2 as genes involved in regulating the yeast iron regulon in response to decreased mitochondrial iron-sulfur cluster synthesis.

The nature of the connection between mitochondrial Fe-S cluster synthesis and the iron-sensitive transcription factor Aft1 in regulating the expression of the iron transport system in Saccharomyces cerevisiae is not known. Using a genetic screen, we identified two novel cytosolic proteins, Fra1 and Fra2, that are part of a complex that interprets the signal derived from mitochondrial Fe-S synthesis. We found that mutations in FRA1 (YLL029W) and FRA2 (YGL220W) led to an increase in transcription of the iron regulon. In cells incubated in high iron medium, deletion of either FRA gene results in the translocation of the low iron-sensing transcription factor Aft1 into the nucleus, where it occupies the FET3 promoter. Deletion of either FRA gene has the same effect on transcription as deletion of both genes and is not additive with activation of the iron regulon due to loss of mitochondrial Fe-S cluster synthesis. These observations suggest that the FRA proteins are in the same signal transduction pathway as Fe-S cluster synthesis. We show that Fra1 and Fra2 interact in the cytosol in an iron-independent fashion. The Fra1-Fra2 complex binds to Grx3 and Grx4, two cytosolic monothiol glutaredoxins, in an iron-independent fashion. These results show that the Fra-Grx complex is an intermediate between the production of mitochondrial Fe-S clusters and transcription of the iron regulon.

Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.

Transcription of the yeast iron regulon does not respond directly to iron but rather to iron-sulfur cluster biosynthesis.

Saccharomyces cerevisiae responds to iron deprivation by increased transcription of the iron regulon, including the high affinity cell-surface transport system encoded by FET3 and FTR1. Here we demonstrate that transcription of these genes does not respond directly to cytosolic iron but rather to the mitochondrial utilization of iron for the synthesis of iron-sulfur (Fe-S) clusters. We took advantage of a mutant form of an iron-dependent enzyme in the sterol pathway (Erg25-2p) to assess cytosolic iron levels. We showed that disruption of mitochondrial Fe-S biosynthesis, which results in excessive mitochondrial iron accumulation, leads to transcription of the iron transport system independent of the cytosolic iron level. There is an inverse correlation between the activity of the mitochondrial Fe-S-containing enzyme aconitase and the induction of FET3. Regulation of transcription by Fe-S biosynthesis represents a mechanism by which cellular iron acquisition is integrated with mitochondrial iron metabolism.

Genetic analysis of iron citrate toxicity in yeast: implications for mammalian iron homeostasis.

Deletion of the yeast homologue of frataxin, YFH1, results in mitochondrial iron accumulation and respiratory deficiency (petite formation). We used a genetic screen to identify mutants that modify iron-associated defects in respiratory activity in Deltayfh1 cells. A deletion in the peroxisomal citrate synthase CIT2 in Deltayfh1 cells decreased the rate of petite formation. Conversely, overexpression of CIT2 in Deltayfh1 cells increased the rate of respiratory loss. Citrate toxicity in Deltayfh1 cells was dependent on iron but was independent of mitochondrial respiration. Citrate toxicity was not restricted to iron-laden mitochondria but also occurred when iron accumulated in cytosol because of impaired vacuolar iron storage. These results suggest that high levels of citrate may promote iron-mediated tissue damage.

Inhibition of Fe-S cluster biosynthesis decreases mitochondrial iron export: evidence that Yfh1p affects Fe-S cluster synthesis.

Decreased expression of Yfh1p in the budding yeast, Saccharomyces cerevisiae, and the orthologous human gene frataxin results in respiratory deficiency and mitochondrial iron accumulation. The absence of Yfh1p decreases mitochondrial iron export. We demonstrate that decreased expression of Nfs1p, the yeast cysteine desulfurase that plays a central role in Fe-S cluster synthesis, also results in mitochondrial iron accumulation due to decreased export of mitochondrial iron. In the absence of Yfh1p, activity of Fe-S-containing enzymes (aconitase, succinate dehydrogenase) is decreased, whereas the activity of a non-Fe-S-containing enzyme (malate dehydrogenase) is unaffected. Aconitase protein was abundant even though the activity of aconitase was decreased in both aerobic and anaerobic conditions. These results demonstrate a direct role of Yfh1p in the formation of Fe-S clusters and indicate that mitochondrial iron export requires Fe-S cluster biosynthesis.

Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial.

CONTEXT: Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients. OBJECTIVE: To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock. DESIGN AND SETTING: Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000. PATIENTS: A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin). MAIN OUTCOME MEASURE: All-cause mortality 28 days after initiation of study medication. RESULTS: Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001). CONCLUSIONS: High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.

Lipopolyamines as a therapeutic strategy in experimental Gram-negative bacterial sepsis.

Lipopolyamines are a class of polycationic amphiphilic compounds that have been shown to bind with high affinity to polyanionic macromolecules, including both DNA and bacterial lipopoly-saccharide (LPS). One of these compounds, termed DOSPER (1,3-di-oleoyloxy-2-(6-carboxyl-spermyl)- propylamide), is non-cytotoxic and has been shown to inhibit LPS-mediated cytokine release and lethality in endotoxin challenge models. In the study reported here, the activity of DOSPER was tested in neutropenic rats with invasive Gram-negative bacteremia caused by Pseudomonas aeruginosa. DOSPER alone was ineffective (0/8) at influencing mortality, but provided a significant survival advantage if administered in combination with a bactericidal antibiotic, ceftazidime (10/12; P<0.05). Ceftazidime alone was partially protective (6/12) while the control group had no survivors (0/8). DOSPER administration markedly reduced circulating endotoxin levels (P<0.01) and interleukin-6 levels (P<0.05) but had no significant effect on bacteremia and bacterial concentrations of P. aeruginosa in liver or spleen tissue. Lipopolyamines may be potentially valuable as a therapeutic adjunct in treatment of Gram-negative bacterial sepsis.

Release of urokinase plasminogen activator receptor during urosepsis and endotoxemia.

BACKGROUND: The urokinase receptor (uPAR; CD87) is a multifunctional molecule involved in fibrinolysis, in proteolysis, in renal tubular functions, and in migration and adhesion of inflammatory cells to the site of infection. METHODS: To gain insight into systemic and local release of uPAR and into its regulation during urosepsis, which is one of the leading causes of chronic renal failure, uPAR was measured in urine and plasma of healthy human controls (N = 20), patients with culture-proven urosepsis (N = 30), and healthy human volunteers intravenously injected with endotoxin (N = 7). RESULTS: Patients had elevated uPAR levels in both plasma and urine. Three hours after endotoxin challenge in volunteers, there was also a significant increase of uPAR in plasma and in urine. The urine/plasma ratio for uPAR was highly elevated during urosepsis and experimental endotoxemia, suggesting local production in the kidney. Accordingly, damaged tubuli strongly expressed uPAR during pyelonephritis. Moreover, tubular epithelial cells produced uPAR in vitro, and this secretion was strongly up-regulated after stimulation with interleukin-1 beta or tumor necrosis factor-alpha. CONCLUSIONS: We found that uPAR is released systemically and in the urinary tract during urosepsis and experimental endotoxemia. This systemic and renal production of uPAR during pyelonephritis may play a central role in eliminating the infection and protecting renal function.