Mesothelioma: identical routes to malignancy from asbestos and carbon nanotubes

Exposure of laboratory mice to carbon nanotubes mimics exposure to asbestos, from initial and chronic inflammation, through loss of the same tumour-suppressor pathways and eventual sporadic development of malignant mesothelioma. Fibres of a similar nature may pose significant health risks to humans

Investigating the therapeutic potential of NUAK1 for the treatment of colorectal cancer

No abstract available

PAI-1 is a Critical Upstream Regulator of the TGF-β1/EGF-Induced Invasive Phenotype in Mutant p53 Human Cutaneous Squamous Cell Carcinoma

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-β synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-β/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in acquisition of an invasive phenotype. TGF-β1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs) in human SCC. Among the most prominent is MMP-10 which is known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also up-regulated under these conditions and is an early event in progression of incipient epidermal SCC. A model is proposed in which TGF-β1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling mechanisms that maintain this elegant balance is critical to developing potential therapeutics for the treatment of human cutaneous malignancies

Is oxidative stress MYC’s Achilles heel?

No abstract available

PAI-1 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-β synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-β/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype. In one physiologically relevant model of human cutaneous SCC progression, TGF-β1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs), among the most prominent of which is MMP-10—an MMP known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC. One testable hypothesis proposes that TGF-β1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies

PAI-1: An Integrator of Cell Signaling and Migration

Cellular migration, over simple surfaces or through complex stromal barriers, requires coordination between detachment/re-adhesion cycles, involving structural components of the extracellular matrix and their surface-binding elements (integrins), and the precise regulation of the pericellular proteolytic microenvironment. It is now apparent that several proteases and protease inhibitors, most notably urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1), also interact with several cell surface receptors transducing intracellular signals that significantly affect both motile and proliferative programs. These events appear distinct from the original function of uPA/PAI-1 as modulators of the plasmin-based proteolytic cascade. The multifaceted interactions of PAI-1 with specific matrix components (i.e., vitronectin), the low-density lipoprotein receptor-related protein-1 (LRP1), and the uPA/uPA receptor complex have dramatic consequences on the migratory phenotype and may underlie the pathophysiologic sequalae of PAI-1 deficiency and overexpression. This paper focuses on the increasingly intricate role of PAI-1 as a major mechanistic determinant of the cellular migratory phenotype

Patterns of hepatitis B prevalence and seroconversion in hemodialysis units from three continents: The DOPPS

Patterns of hepatitis B prevalence and seroconversion in hemodialysis units from three continents: The DOPPS.BackgroundHepatitis B (HBV) historically has been a public health issue within hemodialysis units. This study estimates HBV prevalence and seroconversion rates across seven countries and investigates associations with facility level practice patterns.MethodsThe study sample was from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a cross-sectional, prospective, observational study of adult hemodialysis patients randomly selected from 308 dialysis facilities in France, Germany, Italy, Spain, the United Kingdom, Japan, and the United States. Logistic regression was used to model the odds ratio (OR) of HBV prevalence, and Cox regression was used to model time from entry into the study to HBV seroconversion.ResultsIn this sample, mean HBV facility prevalence was 3.0% with a median of 1.9%. The percentage of facilities with an HBV prevalence 0% to 5% was 78.5%. Adjusted HBV prevalence was higher in France, Germany, and Italy and lower in Japan and the United Kingdom. The majority of facilities (78.1%) had a seroconversion rate of 0 conversions per 100 patient-years. Presence of a protocol for HBV-infected patients was significantly associated with HBV seroconversion in the separate practice pattern model [risk ratio (RR) = 0.52, P = 0.03] and in the combined practice pattern model (RR = 0.44, P = 0.01).ConclusionThere are differences in HBV prevalence and rate of seroconversion both at the country and the hemodialysis facility level. Presence of a protocol for HBV-infected patients was strongly and significantly associated with decreased risk for seroconversion. The observed variation suggests opportunities for improved HBV outcomes with further definition of optimal practice patterns at the facility level

Depression as a predictor of mortality and hospitalization among hemodialysis patients in the United States and Europe

Depression as a predictor of mortality and hospitalization among hemodialysis patients in the United States and Europe.BackgroundDepression is not uncommon among patients with end-stage renal disease (ESRD) being treated by hemodialysis. We investigated whether risk of mortality and rate of hospitalization may be predicted from physician-diagnosed depression and patients' self-reports of depressive symptoms.MethodsData were analyzed from the Dialysis Outcomes and Practice Patterns Study (DOPPS) for randomly selected ESRD patients being treated by hemodialysis in the United States (142 facilities, 2855 patients) and five European countries (101 facilities, 2401 patients). The diagnosis of depression during the past year was abstracted from the medical records. In addition, the patients were asked to indicate how much of their time over the previous four weeks they had felt (1) “so down in the dumps that nothing could cheer you up” and (2) “downhearted and blue.” A response of “a good bit,”“most,” or “all” of the time were classified as depressed.ResultsThe prevalence of depression was nearly 20%. The relative risks of mortality and hospitalization among depressed (vs. non-depressed), adjusted for time on dialysis, age, race, socioeconomic status, comorbid indicators and country were, respectively: 1.23 and 1.11 for physician-diagnosed depression, 1.48 and 1.15 for the “so down in the dumps” question, and 1.35 and 1.11 for the “downhearted and blue” question (P < 0.05 for all six relative risks). These associations were not significantly different between US and European patients.ConclusionsSelf-reported depression by two simple questions was associated with increased risks of mortality and hospitalization for hemodialysis patients. Future research needs to assess whether early identification and treatment of depression may help to improve quality of life and survival in hemodialysis patients

Nonadherence in hemodialysis: Associations with mortality, hospitalization, and practice patterns in the DOPPS

Nonadherence in hemodialysis: Associations with mortality, hospitalization, and practice patterns in the DOPPS.BackgroundNonadherence among hemodialysis patients compromises dialysis delivery, which could influence patient morbidity and mortality. The Dialysis Outcomes and Practice Patterns Study (DOPPS) provides a unique opportunity to review this problem and its determinants on a global level.MethodsNonadherence was studied using data from the DOPPS, an international, observational, prospective hemodialysis study. Patients were considered nonadherent if they skipped one or more sessions per month, shortened one or more sessions by more than 10 minutes per month, had a serum potassium level openface>6.0mEq/L, a serum phosphate level openface>7.5mg/dL (>2.4mmol/L), or interdialytic weight gain (IDWG)>5.7% of body weight. Predictors of nonadherence were identified using logistic regression. Survival analysis used the Cox proportional hazards model adjusting for case-mix.ResultsSkipping treatment was associated with increased mortality [relative risk (RR) = 1.30, P = 0.01], as were excessive IDWG (RR = 1.12, P = 0.047) and high phosphate levels (RR = 1.17, P = 0.001). Skipping also was associated with increased hospitalization (RR = 1.13, P = 0.04), as were high phosphate levels (RR = 1.07, P = 0.05). Larger facility size (per 10 patients) was associated with higher odds ratios (OR) of skipping (OR = 1.03, P = 0.06), shortening (OR = 1.03, P = 0.05), and IDWG (OR = 1.02, P = 0.07). An increased percentage of highly trained staff hours was associated with lower OR of skipping (OR = 0.84 per 10%, P = 0.02); presence of a dietitian was associated with lower OR of excessive IDWG (OR = 0.75, P = 0.08).ConclusionNonadherence was associated with increased mortality risk (skipping treatment, excessive IDWG, and high phosphate) and with hospitalization risk (skipping, high phosphate). Certain patient/facility characteristics also were associated with nonadherence

Characterization of 3D PET systems for accurate quantification of myocardial blood flow

Three-dimensional (3D) mode imaging is the current standard for positron emission tomography-computed tomography (PET-CT) systems. Dynamic imaging for quantification of myocardial blood flow (MBF) with short-lived tracers, such as Rb-82- chloride (Rb-82), requires accuracy to be maintained over a wide range of isotope activities and scanner count-rates. We propose new performance standard measurements to characterize the dynamic range of PET systems for accurate quantitative imaging. Methods: 1100-3000 MBq of Rb-82 or N-13-ammonia was injected into the heart wall insert of an anthropomorphic torso phantom. A decaying isotope scan was performed over 5 half-lives on 9 different 3D PET-CT systems and 1 3D/twodimensional (2D) PET-only system. Dynamic images (28x15s) were reconstructed using iterative algorithms with all corrections enabled. Dynamic range was defined as the maximum activity in the myocardial wall with <10% bias, from which corresponding dead-time, count-rates and/or injected activity limits were established for each scanner. Scatter correction residual bias was estimated as the maximum cavity blood-tomyocardium activity ratio. Image quality was assessed via the coefficient of variation measuring non-uniformity of the left ventricle (LV) myocardium activity distribution. Results: Maximum recommended injected activity/body-weight, peak dead-time correction factor, count-rates and residual scatter bias for accurate cardiac MBF imaging were: 3-14 MBq/kg, 1.5-4.0, 22-64 Mcps singles and 4-14 Mcps prompt coincidence count-rates, and 2-10% on the investigated scanners. Non-uniformity of the myocardial activity distribution varied from 3-16%. Conclusion: Accurate dynamic imaging is possible on the 10 3D-PET systems if the maximum injected MBq/kg values are respected to limit peak dead-time losses during the bolus first-pass transit