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See detailTargeting the tumor microenvironment for cancer therapy.
Sounni, Nor Eddine ULg; Noël, Agnès ULg

in Clinical Chemistry (2013), 59(1), 85-93

BACKGROUND: With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in ... [more ▼]

BACKGROUND: With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. CONTENT: The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix. SUMMARY: A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix. [less ▲]

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See detailCerebrospinal Fluid Collection Tubes: a critical issue for Alzheimer Disease diagnosis
Perret-Liaudet, Armand; Pelpel, Mathieu; Tholance, Yannick et al

in Clinical Chemistry (2012), 58

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See detailDoes echocardiographic stress test induced release of hsTnT and TnI II?
Le Goff, Caroline ULg; Laurent, Terry; Garweg, Christophe ULg et al

in Clinical Chemistry (2010, July), 56(S6), 128

Background: Cardiac troponins (cTn) are considered as the best biomarkers for detection of myocardial cell injury. In this study, cTnT and cTnI were measured by new commercially available high-sensitive ... [more ▼]

Background: Cardiac troponins (cTn) are considered as the best biomarkers for detection of myocardial cell injury. In this study, cTnT and cTnI were measured by new commercially available high-sensitive methods in patients undergoing brief exercise- or pharmacologicinduced stress. Our aim was to compare cTnT and cTnI levels before and after the stress tests, in the patients with or without reversible ischemia. Materials and Methods: Fifty patients (28 men and 22 women) underwent an echographic stress test (ST) for suspected ischemic heart disease. Of these 50 patients, 28 received pharmacological ST (dobutamine injection) and 22 dynamic ST (bicycle exercise). The patients were subdivided into two groups according to the presence or absence of documented transient reversible ischemia: 14 with reversible ischemia ( mean age: 67.71±9.66 y) and 36 without ischemia ( mean age: 63.17±11.72 y). In all patients, cTnT and cTnI concentrations were measured by high sensitive methods (hsTnT, Roche Diagnostics and TnI II, Abbott Diagnostics) on heparin plasma immediately before (T0) and after ST (T1).The lower detection limit of these assays was 0.005μg/L for hsTnT and 0.01μg/L for TnI II. The protocol was approved by the ethics committee of the University of Liège (Belgium). All patients gave informed consent. All statistical analyses were performed using Medcalc version 8.1 for Windows. P value <0.05 was regarded as statistically significant. Results: There was no significant difference between hsTnT concentrations at T0 and T1, neither in the whole patient group, nor in the subgroups of subjects who received pharmacological ST or dynamic ST. The same was true for TnI II. Although there was no change in hsTnT levels during test in ischemic and in non ischemic patients, the latter tend to demonstrate higher median T0 levels (25th, 75th percentiles) than the others [0.011 (0.007, 0.029) vs 0.007 (0.0047, 0.1125) ng/ml, p=0.09]. They also showed higher median T1 levels [0.014 (0.065, 0.03) vs 0.007 (0.003, 0.0102) ng/ml, p=0.08]. Higher TnI II levels were also recorded in ischemic patients as compared to non ischemic patients at T0[ 0.014 (0.0072; 0.0265) vs 0.005 (0.003; 0.01) ng/ml, p=0.08] and T1[ 0.013 (0.0085- 0.03) vs 0.006 (0.0035-0.008) ng/ml, p=0.08]. Also, TnI II levels did not change during test in both subgroups. Conclusions: Measurement of cardiac troponins by high sensitive methods did not allow to detect significant release of biomarkers from the heart during exercise-or pharmacologic-induced ST, even in patients who demonstrated reversible myocardial ischemia. The type of test – pharmacological or dynamic - was without effect. The patients with induced transient ischemia had however higher troponin T and I levels at baseline, this difference remaining during test. [less ▲]

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See detailNew use of VEGF in therapeutics: application in tendon lesions
Kaux, Jean-François ULg; Le Goff, Caroline ULg; Drion, Pierre ULg et al

in Clinical Chemistry (2010, July), 56(S6), 111

Introduction: As demonstrated in previous studies, mechanical overload, injury and inflammation, hypoxic condition or any combination of the above could lead to increased expression of VEGF in the tendon ... [more ▼]

Introduction: As demonstrated in previous studies, mechanical overload, injury and inflammation, hypoxic condition or any combination of the above could lead to increased expression of VEGF in the tendon. Thus, VEGF could participate in the healing of pathological tendons. Indeed, some authors are convinced that this neovascularization is the sign of a chronic tendinopathy while others plead in favour of it being a sign of healing processes. The VEGF111, which is a biologically active and proteolysis-resistant VEGF-A isoform, was recently identified. It is induced by ultraviolet B and genotoxic drugs. Experimentation shows that, in nude mice, tumors formed by HEK293 cells expressing VEGF111 develop a more widespread peritumoral neovascularisation than those expressing other VEGF isoforms. Good angiogenic activity and resistance to proteolysis makes VEGF111 a potential beneficial therapeutic option for ischemic diseases. The aim of our study was to determine whether if VEGF111 could have a therapeutic interest in the framework of tendinous pathology. Methods (*): A 5mm defect was surgically induced in Achilles tendon of 60 rats. Rats were divided into 2 groups of 30: A: a control group (no injection) and B: with a VEGF111 injection. The rats of group B received an injection of 100 ng of VEGF111 in situ 1 hour after surgery on the site of the tendon lesion. Afterwards, rats of both groups were placed in their cages without immobilization. After 5, 15 and 30 days, 10 rats of each group were euthanized. The traumatized Achilles tendon of each rat was dissected and removed. Immediately after sampling, tendons were submitted to a biomechanical tensile test up to rupture, using a tensile machine with “Cryo-jaw”. Statistical analyses were made with an ANOVA. Results: A significant increase over time of the force necessary to induce tendon rupture was observed for tendons which had been submitted to an injection of VEGF111 (p=0.016). The force required to break the tendon is always greater for the VEGF111 group (p<0.05). Discussion: We demonstrated that the force necessary to induce the rupture of a rat’s Achilles tendon during biomechanical tensile testing was greater for tendons which had been submitted to an injection of VEGF111. Thus, this experimentation showed that VEGF111 injections could accelerate the tendon healing process and increase the force needed to break tendons in their healing process. Conclusion: VEGF111 could be a new therapy for tendon lesions. However, other experimentation using a rat model with different concentrations of VEGF111 should be made to ascertain the best concentration for this healing process. Acknowledgement: This experimentation was partially financed by “Standard de Liège” and “Lejeune-Lechien” grants. (*) All experimental procedures and protocols used in this investigation were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Liège. [less ▲]

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See detailUse of clinical biology techniques in clinical practice: injections of platelet-rich plasma to heal tendon
Kaux, Jean-François ULg; Le Goff, Caroline ULg; Drion, Pierre ULg et al

in Clinical Chemistry (2010, July), 56(S6), 111

Introduction: A tendon is a tissue which does not heal easily. For example, tendinopathy is a condition which often becomes chronic in the case of bad or overdue management. Several studies, essentially ... [more ▼]

Introduction: A tendon is a tissue which does not heal easily. For example, tendinopathy is a condition which often becomes chronic in the case of bad or overdue management. Several studies, essentially in vitro and, more recently, a few in clinical practice, have demonstrated the positive effects of platelets on the healing process of tendons. A local injection of platelet–rich plasma (PRP), which releases many growth factors, has the potentiality to enhance the tendon healing process. The aim of our experiment was to ascertain whether the use of PRP could accelerate the healing process of an Achilles tendon after a surgically induced lesion. Methods (*): PRP was obtained from the blood of 12 Sprague Dawley rats by cardiac puncture under general anaesthesia until the heart stopped beating. Quantities of 1mL of anticoagulant, adenosine-citrate-dextrose-acid (ACD-A), were added immediately to each 4,5mL of blood. The blood was then centrifuged at 180g for 10 minutes. To improve platelet concentration of the PRP, the supernatant was centrifuged for a second time at 1000g for 10 minutes. The platelets were then collected using a gauge pipette. Cell and platelet counts were made by an auto-analyser. Platelet concentration was around 2.2 to 2.9 x106/mm³. A 5mm defect was surgically induced in the Achilles tendon of 60 rats. Rats were divided into 2 groups of 30: A: a control group (no injection) and B: with a PRP injection. The rats of group B received a PRP injection in situ 1 hour after the surgery on the site of the lesion of the Achilles tendon. Fifty micro-litres of PRP were injected in each rat of the PRP group. Platelets were activated by the local presence of collagen in the wound. Afterwards, the rats of both groups were placed in their cages without immobilization. After 5, 15 and 30 days, 10 rats of each group were euthanized. The traumatized Achilles tendon of each rat was dissected and removed. Immediately after sampling, tendons were submitted to a biomechanical tensile test up to rupture, using a tensile machine with a “Cryo-jaw”. Results: We demonstrated that the force necessary to induce tendon rupture during biomechanical tensile testing was greater for tendons which had been submitted to an injection of PRP. These results were observed and significant (p<0.05) from day 5 onwards. Discussion: This experimentation showed that PRP injections could accelerate the tendon healing process and increase the force needed to break tendons in their healing process. This “accelerating” process can be observed and is significant (p<0.05) as early as day 5. Conclusion: PRP, by the local release of growth factors, would be a new therapeutic tool to accelerate tendon healing. Acknowledgement: This experimentation was partially financed by “Standard de Liège” and “Lejeune-Lechien” grants. (*) All experimental procedures and protocols used in this investigation were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Liège. [less ▲]

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See detailAssessment of high sensitive troponin T and I immunoassays in patients with acute chest
Le Goff, Caroline ULg; Garweg, Christophe ULg; Laurent, Terry et al

in Clinical Chemistry (2010, July), 56(S6), 127

Introduction: Cardiac troponin I and T are specific markers of myocardial injury that are widely used for the diagnosis of acute coronary syndrome (ACS). In acute chest pain without ST-segment elevation ... [more ▼]

Introduction: Cardiac troponin I and T are specific markers of myocardial injury that are widely used for the diagnosis of acute coronary syndrome (ACS). In acute chest pain without ST-segment elevation, they are used to differentiate unstable angina from non ST-segment elevation myocardial infarction (NSTEMI). Recently, troponin assays with higher analytical sensitivities became available to enable the detection of minor myocardial damage and identify individuals at higher risk for ACS. As a result of its high tissue-specificity, cardiac troponin T and I are cardio-specific, highly sensitive markers for myocardial damage. The aim of this study was to evaluate the new higher sensitive troponin (T and I) in patients with stable angina and acute chest pain without ST-segment elevation. Methods: Sixty subjects (mean age : 65.5± 11 years), were included: 20 healthy controls, 20 patients with stable angina, 9 with unstable angina (troponin-) and 18 patients with NSTEMI myocardial infarction (troponin+). The protocol was approved by the ethic committee of the University of Liège (Belgium). High sensitive troponin T (hsTnT) determination was realized on heparin plasma by electrochemiluminescence immunoassay on Modular E (Roche Diagnostic). Troponin I II (TnI II) is a chemiluminescent microparticle immunoassay for the quantitative determination of cardiac troponin-I in heparine plasma on the ARCHITECT i System (Abbott Diagnostic). The lower detection limit of these assays was 0.005μg/L for hsTnT and 0.01μg/L for TnI II. Stastistical analysis was performed using t test. P value <0.05 was considered significant. Results: HsTNT levels were 0.003(0.003, 0.004) [median baseline (1st, 3rd quartile)]ng/ml in controls, 0.0075 (0.00475, 0.014) ng/ml in stable angina, 0.011(0.006, 0.012) ng/ml in unstable angina and 0.3715 (0.1795, 1.00725) ng/ml in NSTEMI ACS. TnI II levels were 0 (0, 0.001) ng/ml in controls and in patients with stable angina, 0.07 (0.005, 0.014) ng/ml in unstable angina and 1.4475 (0.0407, 2.656) ng/ml in NSTEMI. HsTNT and TnI II levels were significantly increased in NSTEMI as compared to control subjects, patients with stable and unstable angina. TnI II levels were also increased in unstable angina as compared to controls. Conclusion: In our population, TnI II was more sensitive than hsTNT to detect minor myocardial damage in patients with unstable angina as compared to controls. Therefore, future studies will have to determine whether TnI II might contribute to better risk stratification and treatment strategy in this group of patients. [less ▲]

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See detailAnalytical validation of the Abbott Architect urine NGAL
Cavalier, Etienne ULg; Saarbach, D.; Bekaert, Anne-Catherine ULg et al

in Clinical Chemistry (2010, June), 56(S6), 96

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See detailEvaluation of Liaison Calcitonin II Gen, a new kit for Calcitonin determination
Cavalier, Etienne ULg; Carlisi, Ignazia ULg; Bekaert, Anne-Catherine ULg et al

in Clinical Chemistry (2010, June), 56(S6), 188

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See detailValidation of the ImmunoCAP ISAC
Gadisseur, Romy ULg; Blanco Catafal, Anna; Chapelle, Jean-Paul ULg et al

in Clinical Chemistry (2010, June), 56(S6), 97

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See detailMeasurement of ribosomal RNA turnover in vivo by use of deuterium-labeled glucose.
Defoiche, Julien; Zhang, Yan; Lagneaux, Laurence et al

in Clinical Chemistry (2009), 55(10), 1824-33

BACKGROUND: Most methods for estimation of rates of RNA production are not applicable in human in vivo clinical studies. We describe here an approach for measuring ribosomal RNA turnover in vivo using [6 ... [more ▼]

BACKGROUND: Most methods for estimation of rates of RNA production are not applicable in human in vivo clinical studies. We describe here an approach for measuring ribosomal RNA turnover in vivo using [6,6-(2)H(2)]-glucose as a precursor for de novo RNA synthesis. Because this method involves neither radioactivity nor toxic metabolites, it is suitable for human studies. METHODS: For method development in vitro, a lymphocyte cell line (PM1) was cultured in the presence of [6,6-(2)H(2)]-glucose. RNA was extracted, hydrolyzed enzymatically to ribonucleosides, and derivatized to either the aldonitrile tetra-acetate or the pentafluoro triacetate derivative of the pentose before GC-MS. We identified optimum derivatization and analysis conditions and demonstrated quantitative incorporation of deuterium from glucose into RNA of dividing cells. RESULTS: Pilot clinical studies demonstrated the applicability of this approach to blood leukocytes and solid tissues. A patient with chronic lymphocytic leukemia received [6,6-(2)H(2)]-glucose (1 g/kg) orally in aliquots administered every 30 min for a period of 10 h. When we analyzed CD3(-) B cells that had been purified by gradient centrifugation and magnetic-bead adhesion, we observed deuterium enrichment, a finding consistent with a ribosomal RNA production rate of about 7%/day, despite the slow division rates observed in concurrent DNA-labeling analysis. Similarly, in 2 patients with malignant infiltration of lymph nodes, administration of [6,6-(2)H(2)]-glucose (by intravenous infusion for 24 h) before excision biopsy allowed estimation of DNA and RNA turnover in lymph node samples. CONCLUSIONS: Our study results demonstrate the proof-of-principle that deuterium-labeled glucose may be used to analyze RNA turnover, in addition to DNA production/cell proliferation, in clinical samples. [less ▲]

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See detailMisdiagnosis of vitamin D insufficiency in subjects who received vitamin D2
Cavalier, Etienne ULg; Wallace, Andrew Michael; Mistretta, Virginie ULg et al

in Clinical Chemistry (2008), 54(6), 110

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See detailNewborn Screening for Sickle Cell Disease Using Tandem Mass Spectrometry
Boemer, François ULg; Ketelslegers, Olivier; Minon, Jean-Marc et al

in Clinical Chemistry (2008), 54(12), 2036-2041

BACKGROUND: Neonatal screening programs for sickle cell disease are now widespread in North American and European countries. Most programs apply isoelectric focusing or HPLC to detect hemoglobin variants ... [more ▼]

BACKGROUND: Neonatal screening programs for sickle cell disease are now widespread in North American and European countries. Most programs apply isoelectric focusing or HPLC to detect hemoglobin variants. Because tandem mass spectrometry (MS/MS) is being used for screening of inherited metabolic disorders and allows protein identification, it was worth testing for hemoglobinopathy screening. METHODS: We minimized sample preparation and analysis times by avoiding prior purification, derivatization, or separation. We developed a tryptic digestion methodology to screen for the main clinically important variants (HbS, HbC, and HbE) and beta-thalassemia. To ensure proper discrimination between homozygote and heterozygote variants, we selected 4 transitions with good signal intensities for each specific peptide and calculated variant/HbA ratios for each. Method validation included intra- and interseries variability, carryover, and limit of detection. We also performed a comparative study with isoelectric focusing results on 2082 specimens. RESULTS: Intraassay imprecision values (CVs) varied between 2.5% and 30.7%. Interassay CVs were between 6.3% and 23.6%. Carryover was <0.03%, and the limit of detection was fixed at 1% of HbS. According to the MS/MS settings (detection of HbS, HbC, HbE, and beta-globin production defects), the comparative study did not yield any discrepant results between the 2 techniques. CONCLUSIONS: MS/MS is a reliable method for hemoglobinopathy neonatal screening. [less ▲]

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