HUWE1 cooperates with RAS activation to control leukemia cell proliferation and human hematopoietic stem cells differentiation fate

Acute myeloid leukemia (AML) is a poor prognosis hematopoietic malignance characterized by abnormal proliferation and differentiation of hematopoietic stem cells (HSCs). Although advances in treatment have greatly improved survival rates in young patients, in the elderly population, ~70% of patients present poor prognosis. A pan-cancer analysis on the TCGA cohort showed that AML has the second higher HUWE1 expression in tumor samples among all cancer types. In addition, pathway enrichment analysis pointed to RAS signaling cascade as one of the most important pathways associated to HUWE1 expression in this particular AML cohort. In silico analysis for biological processes enrichment also revealed that HUWE1 expression is correlated with 13 genes involved in myeloid differentiation. Therefore, to understand the role of HUWE1 in human hematopoietic stem and progenitor cells (HSPC) we constitutively expressed KRASG12V oncogene concomitantly to HUWE1 knockdown in stromal co-cultures. The results showed that, in the context of KRASG12V, HUWE1 significantly reduces cell cumulative growth and changes myeloid differentiation profile of HSPCs. Overall, these observations suggest that HUWE1 might contribute to leukemic cell proliferation and impact myeloid differentiation of human HSCs, thus providing new venues for RAS-driven leukemia targeted therapy approach

Hypoadiponectinemia in Extremely Low Gestational Age Newborns with Severe Hyperglycemia – A Matched-Paired Analysis

BACKGROUND: Hyperglycemia is commonly observed in extremely low gestational age newborns (ELGANs) and is associated with both increased morbidity and mortality. The objective of this study was to examine the relationship between neonatal hyperglycemia and adiponectin levels in ELGANs. METHODOLOGY/PRINCIPAL FINDINGS: Ten preterm infants between 22+6/7 and 27+3/7 weeks' gestation with neonatal hyperglycemia (defined as pre-feeding blood glucose levels above 200mg/dl on two consecutive measurements with a maximum parenteral glucose infusion of 4 mg/kg*min(-1)) formed the case cohort of this study. To every single patient of this case cohort a patient with normal fasting ( = pre-feeding) blood glucose levels was matched in terms of gestational age and gender. Adiponectin ELISAs were performed both at onset of hyperglycemia and at term-equivalent age. In the case cohort 9/10 patients had to be treated with insulin for 1-26 days (range 0.01-0.4 IU/kg*h(-1)). Compared to matched-paired controls, significant hypoadiponectinemia was observed at onset of hyperglycemia in these affected patients (6.9 µg/ml versus 15.1 µg/ml, p = 0.009). At term equivalent age, normoglycemia without any insulin treatment was found in both groups. Moreover, adiponectin levels at that time were no longer significantly different (12.3 µg/ml versus 20.0 µg/ml; p = 0.051) possibly indicating a mechanistic relevance of this adipokine in regulating insulin sensitivity in ELGANs. CONCLUSIONS/SIGNIFICANCE: Decreased circulating adiponectin levels are correlated with hyperglycemia in ELGANs and may contribute to the pathogenesis of impaired glucose homeostasis in these infants. These findings suggest that adiponectin might be a potential future drug target for the potentially save treatment of hyperglycemia in pre-term infants

The efficacy of four-slice helical CT in evaluating pancreatic trauma: a single institution experience

<p>Abstract</p> <p>Study objective</p> <p>To assess the efficacy of computed tomography (CT) in evaluating patients with pancreatic trauma.</p> <p>Methods</p> <p>We undertook a retrospective review of all blunt trauma patients admitted to the Chi-Mei Medical Center from January 2004 to June 2006. Every patients underwent abdominal CT scan in emergency department and the CT scans were obtained with a four-slice helical CT. Diagnosis of a pancreatic injury in these patients was by surgical observation or by CT findings. Radiographic pancreatic injuries were classified as deep or superficial lesions. Deep lesions were defined as the hematomas or lacerations >50% thickness of the pancreas. Superficial lesions were described as the hematomas or lacerations <50% thickness of the pancreas; pancreatic edema; and focal fluid accumulation around the pancreas</p> <p>Results</p> <p>Nineteen patients with pancreatic trauma, fourteen males and five females, average age 40.6 ± 21.4 years, were included. Most patients (73.7%) with pancreatic trauma had associated organ injuries. CT was performed in all patients and laparotomy in 14 patients. CT was 78.9% sensitive in detecting pancreatic trauma. All deep pancreatic lesions revealed on CT required surgical treatment, and complication was discovered in two patients undergoing delayed surgery. Superficial lesions were managed conservatively.</p> <p>Conclusion</p> <p>Four-slice helical CT can detect most pancreatic trauma and provide practical therapeutic guidance. Delayed operation might result in complications and is associated with prolonged hospital stays.</p

Update on the Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Virus Infection

Chronic hepatitis B virus infection is an important cause of liver-related morbidity and mortality, with hepatocellular carcinoma being the most life-threatening complication. Because of the highly variable clinical course of the disease, enormous research efforts have been made with the aim of revealing the factors in the natural history that are relevant to hepatocarcinogenesis. These include epidemiological studies of predisposing risk groups, viral studies of mutations within the hepatitis B viral genome, and clinical correlation of these risk factors in predicting the likelihood of development of hepatocellular cancer in susceptible hosts. This update addresses these risks, with emphasis on the latest research relevant to hepatocarcinogenesis

Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women

Endometriosis is a disorder that affects 5% of the normal population but is present in up to 40% of women with pelvic pain and/or infertility. Recent evidence suggests that the endometrium of women with endometriosis exhibits progesterone insensitivity. One endometrial protein that fluctuates in response to progesterone is the estrogen receptor-alpha (ER alpha), being down-regulated at the time of peak progesterone secretion during the window of implantation. Here we demonstrate that the biomarker of uterine receptivity, beta 3 integrin subunit, is reduced or absent in some women with endometriosis and that such defects are accompanied by inappropriate over-expression of ER alpha during the mid-secretory phase. Using a well-differentiated endometrial cell line we showed that the beta 3 integrin protein is negatively regulated by estrogen and positively regulated by epidermal growth factor (EGF). By competing against estrogen with various selective estrogen receptor modulators (SERMs) and estrogen receptor agonists and antagonists, inhibition of expression of the beta 3 integrin by estrogen can be mitigated. In conclusion, we hypothesize that certain types of uterine receptivity defects may be caused by the loss of appropriate ER alpha down-regulation in the mid-secretory phase, leading to defects in uterine receptivity. Such changes might be effectively treated by timely administration of the appropriate anti-estrogens to artificially block ER alpha and restore normal patterns of gene expression. Such treatments will require further clinical studies

Lattice Boltzmann simulations of soft matter systems

This article concerns numerical simulations of the dynamics of particles immersed in a continuum solvent. As prototypical systems, we consider colloidal dispersions of spherical particles and solutions of uncharged polymers. After a brief explanation of the concept of hydrodynamic interactions, we give a general overview over the various simulation methods that have been developed to cope with the resulting computational problems. We then focus on the approach we have developed, which couples a system of particles to a lattice Boltzmann model representing the solvent degrees of freedom. The standard D3Q19 lattice Boltzmann model is derived and explained in depth, followed by a detailed discussion of complementary methods for the coupling of solvent and solute. Colloidal dispersions are best described in terms of extended particles with appropriate boundary conditions at the surfaces, while particles with internal degrees of freedom are easier to simulate as an arrangement of mass points with frictional coupling to the solvent. In both cases, particular care has been taken to simulate thermal fluctuations in a consistent way. The usefulness of this methodology is illustrated by studies from our own research, where the dynamics of colloidal and polymeric systems has been investigated in both equilibrium and nonequilibrium situations.Comment: Review article, submitted to Advances in Polymer Science. 16 figures, 76 page

Early blood glucose profile and neurodevelopmental outcome at two years in neonatal hypoxic-ischaemic encephalopathy

Background: To examine the blood glucose profile and the relationship between blood glucose levels and neurodevelopmental outcome in term infants with hypoxic-ischaemic encephalopathy. Methods: Blood glucose values within 72 hours of birth were collected from 52 term infants with hypoxic-ischaemic encephalopathy. Hypoglycaemia [ 150 mg/dL (8.3 mmol/L)] were correlated to neurodevelopmental outcome at 24 months of age. Results: Four fifths of the 468 blood samples were in the normoglycaemic range (392/468:83.8%). Of the remaining 76 samples, 51.3% were in the hypoglycaemic range and (48.7%) were hyperglycaemic. A quarter of the hypoglycaemic samples (28.2%:11/39) and a third of the hyperglycaemic samples (32.4%:12/37) were recorded within the first 30 minutes of life. Mean (SD) blood glucose values did not differ between infants with normal and abnormal outcomes [4.89(2.28) mmol/L and 5.02(2.35) mmol/L, p value = 0.15] respectively. In term infants with hypoxic-ischaemic encephalopathy, early hypoglycaemia (between 0-6 hours of life) was associated with adverse outcome at 24 months of age [OR = 5.8, CI = 1.04-32)]. On multivariate analysis to adjust for grade of HIE this association was not statistically significant. Late hypoglycaemia (6-72 hours of life) was not associated with abnormal outcome [OR = 0.22, CI (0.04-1.14)]. The occurrence of hyperglycaemia was not associated with adverse outcome. Conclusion: During the first 72 hours of life, blood glucose profile in infants with hypoxic-ischaemic encephalopathy varies widely despite a management protocol. Early hypoglycaemia (0-6 hours of life) was associated with severe HIE, and thereby; adverse outcome

Predictors of dizziness in older persons: a 10-year prospective cohort study in the community

BACKGROUND: The current diagnosis-oriented approach of dizziness does not suit older patients. Often, it is difficult to identify a single underlying cause, and when a diagnosis is made, therapeutic options may be limited. Identification of predictors of dizziness may provide new leads for the management of dizziness in older patients. The aim of the present study was to investigate long-term predictors of regular dizziness in older persons. METHODS: Population-based cohort study of 1,379 community-dwelling participants, aged ≥60 years, from the Longitudinal Aging Study Amsterdam (LASA). Regular dizziness was ascertained during face-to-face medical interviews during 7- and 10-year follow-up. We investigated 26 predictors at baseline from six domains: socio-demographic, medical history, medication, psychological, sensory, and balance/gait. We performed multivariate logistic regression analyses with presence of regular dizziness at 7- and 10-year follow-up as dependent variables. We assessed the performance of the models by calculating calibration and discrimination. RESULTS: Predictors of regular dizziness at 7-year follow-up were living alone, history of dizziness, history of osteo/rheumatoid arthritis, use of nitrates, presence of anxiety or depression, impaired vision, and impaired function of lower extremities. Predictors of regular dizziness at 10-year follow-up were history of dizziness and impaired function of lower extremities. Both models showed good calibration (Hosmer-Lemeshow P value of 0.36 and 0.31, respectively) and acceptable discrimination (adjusted AUC after bootstrapping of 0.77 and 0.71). CONCLUSIONS: Dizziness in older age was predicted by multiple factors. A multifactorial approach, targeting potentially modifiable predictors (e.g., physical exercise for impaired function of lower extremities), may add to the current diagnosis-oriented approach. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2318-14-133) contains supplementary material, which is available to authorized users

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO