111 results on '"Delic, J"'
Search Results
2. Personal perception and impact of work aggravated asthma: P225
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Bradshaw, L M, Sumner, J, Delic, J, and Fishwick, D
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- 2017
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3. Comparative Effects of X Irradiation on the Testes of Adult Sprague-Dawley and Wistar Rats
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Delic, J. I., Schlappack, O. K., Harwood, J. R., and Stanley, J. A.
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- 1987
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4. Aberrant telomere structure is characteristic of resistant chronic lymphocytic leukaemia cells
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Brugat, T, Gault, N, Baccelli, I, Maës, J, Roborel de Climens, A, Nguyen-Khac, F, Davi, F, Merle-Béral, H, Gilson, E, Goodhardt, M, and Delic, J
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- 2010
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5. Absence of microsatellite instability in human chronic lymphocytic leukaemia B cells
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Praz, F, Le Page, F, Vallat, L, Davi, F, Nguyen-Khac, F, Maloum, K, Delic, J, and Merle-Béral, H
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- 2008
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6. Patients with West syndrome - what happened after five years?: SC238
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Nikolic, D. M., Dimitrijevic, N., Bogicevic, D., Delic, J., and Medjo, B.
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- 2012
7. Wild thyme (Thymus serpyllum L.) supercritical extract as antioxidant in precooked pork chops during chilled storage.
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Jokanovic, M, Ivic, M, Skaljac, S, Tomovic, V, Sojic, B, Pavlic, B, Ikonic, P, Peulic, T, and Delic, J
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- 2021
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8. Quality standardization and certification of traditional food products.
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Ikonic, P, Peulic, T, Delic, J, Novakovic, A, Dapcevic-Hadnadjev, T, and Skrobot, D
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- 2021
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9. Textural properties of extruded snack products formulated with deboned poultry meat and brewer’s spent grain.
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Delic, J, Ikonic, P, Jokanovic, M, Banjac, V, Peulic, T, Ikonic, B, Vidosavljevic, S, and Stojkov, V
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- 2021
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10. High levels of chromosome aberrations correlate with impaired in vitro radiation-induced apoptosis and DNA repair in human B-chronic lymphocytic leukaemia cells.
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Blaise, R., Alapetite, C., Masdehors, P., Merle-Beral, H., Roulin, C., Delic, J., and Sabatier, L.
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CHROMOSOME abnormalities ,APOPTOSIS ,DNA repair ,LYMPHOCYTIC leukemia - Abstract
Purpose: To investigate the relationship between the susceptibility of B-chronic lymphoid leukaemia (B-CLL) cells to DNA damage-induced apoptosis, the kinetics of DNA strand-break rejoining, and chromosome damage after exposure to ionizing irradiation. Materials and methods: Lymphocytes from B-CLL patients were γ-irradiated in vitro with 0.2-5 Gy and stimulated by Staphylococcus aureus cowan I (SAC I) for estimation of chromosomal damage. Induction of apoptosis after irradiation was studied in 50 patients by two methods: morphological characterization of apoptotic cells after fluorescent staining (Hoechst), and specific quantification of mono- and oligonucleosomes in cytoplasmic cell fractions (ELISA assay). Morphological chromosome damage was scored in the first cell generation after irradiation (13 patients). In parallel, the kinetics of DNA single-strand break rejoining were investigated by the alkaline comet assay (12 patients). Results: Ionizing irradiation did not induce apoptosis in lymphocytes from a subset of B-CLL patients. The results suggest that B-CLL cells resistant to radiation-induced apoptosis could repair DNA strand-breaks more rapidly and showed a higher level of chromosome aberrations than radiation-sensitive B-CLL cells. Conclusion: Each of three biological effects observed (apoptosis, kinetics of DNA single-strand-break repair, chromosomal damage) might be explained by different modifications occurring in irradiated B-CLL cells. Their convergence strongly suggests that resistance to apoptotic death initiation by DNA damage may be impeded by a rapid engaging of the DNA repair mechanisms. The higher level of chromosome aberrations observed in these cells suggests that the type of DNA repair system involved may generate inaccurate repair. [ABSTRACT FROM AUTHOR]
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- 2002
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11. Attempted Protection of Spermatogenesis From Single Doses of Gamma-Irradiation in the Androgen Pretreated Rat.
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Schlappack, O. K., Delic, J. I., Harwood, J. R., and Stanley, J. A.
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- 1987
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12. Testicular Function in Adult Rats Treated with the Alkylating Agent Chlorambucil.
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Delic, J. I., Stanley, J. A., and Harwood, J. R.
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- 1986
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13. Dermal Uptake of Solvents from the Vapour Phase; an Experimental Study in Humans.
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BROOKE, I., COCKER, J., DELIC, J. I., PAYNE, M., JONES, K., GREGG, N. C., and DYNE, D.
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DERMATOTOXICOLOGY ,HAZARDOUS substances ,TOXICOLOGY of poisonous gases ,BODY burden ,METABOLITES ,XYLENE ,TOLUENE - Abstract
The control of exposure to hazardous substances in the workplace has traditionally focused on uptake via the inhalation route. Control of skin uptake has generally been considered for solids and liquids but the potential for uptake from vapours and gases has received relatively little attention. The current work was undertaken to establish a methodology to study the dermal uptake from vapours and to provide new and comparative information on a range of substance vapours. Groups of human volunteers were exposed to a small range of substances either ‘whole body’ or via the skin only. Substances (xylene, toluene, tetrahydrofuran [THF], methyl ethyl ketone [MEK] and 1-methoxypropan-2-ol [M2P]) were selected on the basis of their predicted dermal uptake from the vapour phase; their industrial use and potential for occupational exposure; the existence of a health-based occupational exposure limit; the availability of an analytical technique(s) for the substance and/or metabolite(s); and as representatives of chemical classes. Exposures were for four hours generally at the level of the UK Occupational Exposure Standard. Uptake was assessed by monitoring of parent or metabolite in blood, single breath or urine following exposure. Uptake of xylene, toluene and THF vapours via the skin under the conditions of this study was estimated to contribute around 1–2% of the body burden received following whole body (including inhalation)exposure. MEK showed more uptake via the skin, contributing around 3–3.5% of the body burden. Most dermal uptake was seen for the glycol ether M2P for which estimates of between 5-10% of whole body exposure body burden were obtained. The results of this and other studies indicate that uptake of vapours across the skin can occur but that for some substances (e.g. xylene, toluene, THF) this is likely to contribute little to the body burden. For other substances, such as the glycol ethers, skin uptake from vapours may be an important contributor to total uptake, particularly in situations where respiratory protective equipment is used to control inhalation exposure. Crown Copyright.© 1998. Published by Elsevier Science Ltd on behalf of BOHS. [ABSTRACT FROM AUTHOR]
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- 1998
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14. Dose and time related responses of the irradiated prepubertal rat testis.
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Delic, J. I., Hendry, J. H., Morris, I. D., and Shalet, S. M.
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- 1985
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15. γ-Ray-induced Transcription and Apoptosis-associated Loss of 28S rRNA in Interphase Human Lymphocytes.
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Delic, J., Coppey-Moisan, M., and Magdelenat, H.
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- 1993
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16. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis.
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Delic, J, Masdehors, P, Ömura, S, Cosset, J-M, Dumont, J, Binet, J-L, Magdelénat, H, Omura, S, and Magdelénat, H
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- 1998
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17. Protection of Spermatogenesis During Cancer Chemotherapy.
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Delic, J. I.
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- 1987
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18. Serum Follicle Stimulating Hormone, Androgen Binding Protein, and Regeneration of the Seminiferous Epithelium after Local Testicular Irradiation.
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DELIC, J. I., HENDRY, J. H., MORRIS, I. D., and SHALET, S. M.
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- 1984
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19. Letter to the Editor In vitro radiation-induced apoptosis and tumour response to radiotherapy: a prospective study in patients with non-Hodgkin lymphomas treated by low-dose irradiation.
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Dubray, B., Breton, C., Delic, J., Klijanienko, J., Maciorowski, Z., Vielh, P., Fourquet, A., Dumont, J., Magdelenat, H., and Cosset, J. M.
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APOPTOSIS ,RADIOTHERAPY ,TUMOR treatment - Abstract
Comments on a review on the contribution of apoptosis to tumor radiation response. Conflicting results of clinical studies relating to spontaneous apoptosis levels of treatment outcome in human tumors; Approaches to measuring in vitro radiation-induced apoptosis in patients with non-Hodgkin's lymphoma.
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- 1997
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20. ChemInform Abstract: Heterocyclic Quinones. Part 13. Dimerization in the Series of 5,8-Quinazolinediones: Synthesis and Antitumor Effects of Bis(4-amino-5,8-quinazolinediones).
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GIORGI-RENAULT, S., RENAULT, J., BARON, M., GEBEL-SERVOLLES, P., DELIC, J., CROS, S., and PAOLETTI, C.
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- 1989
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21. Duchenne muscular dystrophy and epilepsy — rare comorbidity: Case report.
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Anonymous, Raus, M., Delic, J., Medjo, B., Atanaskovic-Markovic, M., and Nikolic, D.
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- 2013
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22. Brain MRI findings and case history in a boy with repeated epileptic seizures: Case report.
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Anonymous, Zecevic, T., Delic, J., Nedovic, S., Medjo, B., and Nikolic, D.
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- 2013
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23. B-cell chronic lymphocytic leukaemia: a polymorphic family unified by genomic features.
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Guipaud O, Deriano L, Salin H, Vallat L, Sabatier L, Merle-Béral H, Delic J, Guipaud, Olivier, Deriano, Ludovic, Salin, Hélène, Vallat, Laurent, Sabatier, Laure, Merle-Béral, Hélène, and Delic, Jozo
- Abstract
Human cancer is characterised by complex molecular aberrations which result in a wide variety of clinical manifestations. B-cell chronic lymphocytic leukaemia (B-CLL) is particularly diverse, both in terms of molecular changes and clinical course, and consequently our understanding of the pathology of this disease is generally poor. Furthermore, the heterogeneity of this tumour type coupled with the absence of an obvious genetic "hallmark", such as gain of oncogene function or loss of suppressor-gene function, has led many investigators to question whether B-CLL is a single disease entity. In most cases, B-CLL does not show specific reciprocal chromosomal translocations as found in other haemopoietic malignant diseases. The genomic instability of B-CLL results in numerous different types of chromosomal losses and gains, giving rise to unsettled karyotypes among individuals with this disease. Nevertheless, genetic data imply that B-CLL is a single disease characterised by a common gene-expression profile and by the existence of specific subtypes that may have clinical correlates in patients. [ABSTRACT FROM AUTHOR]
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- 2003
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24. Apoptose radio-induite in vitro des lymphocytes circulants chez 25 patients atteints de leucémie lymphoïde chronique: variabilité individuelle et prédiction possible de l'efficacité de l'irradiation splénique à faible dose
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Cosset, JM, Delic, J, Dumont, J, Tchemia, G, Pellae-Cosset, B, Tertian, G, and Dubray, B
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- 1998
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25. Response to "'Optimal energy provision early in ICU stay for critically ill patients receiving parenteral nutrition': A commentary".
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Nagy A, Delic J, Hollands JM, Oh S, Pasciolla S, Pontiggia L, Solomon D, and Bingham AL
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- Humans, Critical Care methods, Length of Stay statistics & numerical data, Critical Illness therapy, Parenteral Nutrition methods, Intensive Care Units, Energy Intake
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- 2024
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26. Optimal energy provision early in ICU stay for critically ill patients receiving parenteral nutrition.
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Nagy A, Delic J, Hollands JM, Oh S, Pasciolla S, Pontiggia L, Solomon D, and Bingham AL
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- Humans, Male, Retrospective Studies, Female, Middle Aged, Aged, Adult, Critical Illness therapy, Critical Illness mortality, Parenteral Nutrition methods, Parenteral Nutrition statistics & numerical data, Intensive Care Units, Energy Intake, Length of Stay statistics & numerical data, Hospital Mortality
- Abstract
Background: Literature on optimal energy provision via parenteral nutrition (PN) is limited and the evidence quality is low. The purpose of this study is to determine if there is a difference in outcomes in adult critically ill patients when receiving lower vs higher calorie provision via PN early in intensive care unit (ICU) stay., Methods: Adult patients initiated on PN within the first 10 days of ICU stay from May 2014 to June 2021 were included in this retrospective study. The primary outcome was to determine the impact of lower (<20 kcal/kg/day) vs higher (>25 kcal/kg/day) calorie provision on all-cause, in-hospital mortality. Secondary outcomes were to determine the impact of calorie provision on hospital or ICU length of stay and incidence of complications., Results: This study included 133 patients: a lower calorie provision group (n = 77) and a higher calorie provision group (n = 56). There was a significant difference in all-cause, in-hospital mortality between the lower and the higher calorie provision groups (36.36% and 17.86%, respectively; P = 0.02). However, upon a multivariate analysis of death at discharge, the specific calorie provision group did not affect the probability of death at hospital discharge. The secondary outcomes were not significantly different between groups., Conclusion: When comparing lower calorie provision with higher calorie provision in adult critically ill patients receiving PN early within their ICU stay, there were no differences in outcomes after controlling for significant confounders. Future larger prospective studies should further evaluate optimal caloric provision via PN in this population., (© 2023 American Society for Parenteral and Enteral Nutrition.)
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- 2024
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27. Oral Glyburide for the Prevention of Cerebral Edema in Acute Ischemic Stroke.
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Wilkinson B, Delic J, Igneri L, and Pasciolla S
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- Humans, Female, Male, Aged, Middle Aged, Retrospective Studies, Administration, Oral, Aged, 80 and over, Hypoglycemia prevention & control, Hospital Mortality, Adult, Brain Edema prevention & control, Brain Edema etiology, Glyburide therapeutic use, Glyburide administration & dosage, Ischemic Stroke prevention & control, Hypoglycemic Agents therapeutic use, Hypoglycemic Agents administration & dosage
- Abstract
Objective: The purpose of this study was to describe the impact of enteral glyburide on cerebral edema formation and hypoglycemia when used to treat patients diagnosed with acute ischemic stroke (AIS)., Methods: This study was a single-center, retrospective medical record review that included all patients aged ≥18 years diagnosed with AIS who received ≥1 dose of enteral glyburide for the prevention of cerebral edema from January 1, 2018 to March 31, 2022. The primary outcome was the percentage of patients requiring intervention for cerebral edema management after glyburide initiation, and the safety outcome was the occurrence of hypoglycemia in this patient population., Results: The final evaluation included 44 patients, with 6 patients (14%) requiring intervention for cerebral edema after glyburide initiation. The average baseline National Institutes of Health stroke scale score was 19. Overall, in-hospital mortality was 36% (n = 17), and hypoglycemia occurred in 7 patients (15%). Of the 44 patients, 20 (45%) received a partial duration of enteral glyburide (1-4 doses) and 24 (55%) received a full duration of enteral glyburide (5-7 doses). The rate of intervention for cerebral edema (10% vs. 17%) and the incidence of hypoglycemia (5% vs. 23%) were lower in the partial duration than in the full duration group. The in-hospital all-cause mortality rate was higher in the partial duration group than in the full duration group (43% vs. 31%)., Conclusions: Despite the relatively low rates of intervention for cerebral edema, hypoglycemia was common, especially for patients receiving 5-7 doses of enteral glyburide for the prevention of cerebral edema after moderate-to-severe AIS., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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28. Prevalence and Value of Board Certification Among Pharmacy Practice Faculty in the United States.
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Fedkiv V, Delic J, Hollands JM, Pasciolla S, Pontiggia L, and Bingham AL
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- United States, Humans, Prevalence, Certification, Faculty, Education, Pharmacy, Pharmacy
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Objective: To determine the prevalence of board certification among pharmacy practice faculty in the United States, motivators and barriers to certification, and association between board certification and professional achievements and accomplishments that may support career advancement., Methods: In phase I, the prevalence of board-certified pharmacy practice faculty in the United States was determined by cross-referencing lists of faculty and board-certified pharmacists. In phase II, faculty were stratified by rank and invited to participate in a survey regarding professional characteristics, motivators and barriers to board certification, and professional achievements and accomplishments that may support career advancement for pharmacy practice faculty., Results: The prevalence of board certification among the 3276 pharmacy practice faculty was 56%. The prevalence was the highest among assistant professors (61%). A total of 746 faculty completed the survey (33% response rate). Of those respondents, 73% reported being currently certified, 23% never certified, and 4% previously certified. Overall, to be recognized as an expert in the field was identified as the most commonly perceived reason faculty obtain board certification (44%). Currently and previously certified faculty ranked the desire to be recognized as an expert in the field as the most common reason they obtained board certification (61%). There was a positive correlation between board certification and certain professional accomplishments., Conclusion: The prevalence of board-certified pharmacy practice faculty has increased since 2011, but motivators and barriers for board certification remain similar. Board certification may support career advancement for pharmacy practice faculty., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Volodymyra Fedkiv reports financial support was provided by Board of Pharmacy Specialties. Angela L. Bingham reports a relationship with Board of Pharmacy Specialties that includes: board membership., (Copyright © 2023 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)
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- 2024
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29. Phospho-Ku70 induced by DNA damage interacts with RNA Pol II and promotes the formation of phospho-53BP1 foci to ensure optimal cNHEJ.
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Schellenbauer A, Guilly MN, Grall R, Le Bars R, Paget V, Kortulewski T, Sutcu H, Mathé C, Hullo M, Biard D, Leteurtre F, Barroca V, Corre Y, Irbah L, Rass E, Theze B, Bertrand P, Demmers JAA, Guirouilh-Barbat J, Lopez BS, Chevillard S, and Delic J
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- Cell Line, Cell Line, Tumor, DNA Damage, Humans, Phosphorylation, Protein Binding, RNA Polymerase II metabolism, Tumor Suppressor p53-Binding Protein 1 metabolism, DNA End-Joining Repair, Ku Autoantigen metabolism
- Abstract
Canonical non-homologous end-joining (cNHEJ) is the prominent mammalian DNA double-strand breaks (DSBs) repair pathway operative throughout the cell cycle. Phosphorylation of Ku70 at ser27-ser33 (pKu70) is induced by DNA DSBs and has been shown to regulate cNHEJ activity, but the underlying mechanism remained unknown. Here, we established that following DNA damage induction, Ku70 moves from nucleoli to the sites of damage, and once linked to DNA, it is phosphorylated. Notably, the novel emanating functions of pKu70 are evidenced through the recruitment of RNA Pol II and concomitant formation of phospho-53BP1 foci. Phosphorylation is also a prerequisite for the dynamic release of Ku70 from the repair complex through neddylation-dependent ubiquitylation. Although the non-phosphorylable ala-Ku70 form does not compromise the formation of the NHEJ core complex per se, cells expressing this form displayed constitutive and stress-inducible chromosomal instability. Consistently, upon targeted induction of DSBs by the I-SceI meganuclease into an intrachromosomal reporter substrate, cells expressing pKu70, rather than ala-Ku70, are protected against the joining of distal DNA ends. Collectively, our results underpin the essential role of pKu70 in the orchestration of DNA repair execution in living cells and substantiated the way it paves the maintenance of genome stability., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2021
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30. Work aggravated asthma in Great Britain: a cross-sectional postal survey.
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Bradshaw L, Sumner J, Delic J, Henneberger P, and Fishwick D
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- Adult, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Prevalence, Surveys and Questionnaires, United Kingdom epidemiology, Asthma epidemiology, Occupational Diseases epidemiology
- Abstract
Objective: Work aggravated asthma (WAA), asthma made worse by but not caused by workplace exposures, can have a negative impact on personal, social, financial and societal costs. There is limited data on prevalence levels of WAA in Great Britain (GB). The objective of this study was to estimate the prevalence of WAA in GB, and to assess its potential causes.Materials and methodsA cross-sectional postal questionnaire study was carried out. A total of 1620 questionnaires were sent to three populations of adults with asthma. The questionnaire recorded; demographic details, current job, self-reported health status, presence of asthma and respiratory symptoms, duration and severity of symptoms and medication requirements. Questions relating to work environment and employers' actions were included, and each participant completed an assessment of health-related quality of life using the EuroQol Research Foundation EQ-5D., Results: There were 207 completed questionnaires; response rates were 6% primary care, 45% secondary care and 71% Asthma UK. This represented a 13% overall response rate. Self-reported prevalence of WAA was 33% (95% CI 24.4-41.6%). In all, 19% of workers had changed their job because of breathing problems. Workers with WAA reported higher levels of work-related stress. Quality of life using the EQ-5D utility index was lower in those with WAA., Conclusion: WAA is a common problem in asthmatics in GB. This result is in keeping with international prevalence rates. Further research could assist the understanding of the most significant aggravants to asthma at work and help define appropriate interventions by workplaces.
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- 2018
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31. Differences in Callosal and Forniceal Diffusion between Patients with and without Postconcussive Migraine.
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Alhilali LM, Delic J, and Fakhran S
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- Adult, Anisotropy, Corpus Callosum diagnostic imaging, Corpus Callosum injuries, Corpus Callosum pathology, Female, Fornix, Brain diagnostic imaging, Fornix, Brain injuries, Fornix, Brain pathology, Humans, Male, Middle Aged, Migraine Disorders diagnostic imaging, Neuropsychological Tests, Post-Concussion Syndrome diagnostic imaging, Regression Analysis, White Matter injuries, Young Adult, Diffusion Tensor Imaging methods, Migraine Disorders etiology, Migraine Disorders pathology, Post-Concussion Syndrome pathology
- Abstract
Background and Purpose: Posttraumatic migraines are common after mild traumatic brain injury. The purpose of this study was to determine if a specific axonal injury pattern underlies posttraumatic migraines after mild traumatic brain injury utilizing Tract-Based Spatial Statistics analysis of diffusion tensor imaging., Materials and Methods: DTI was performed in 58 patients with mild traumatic brain injury with posttraumatic migraines. Controls consisted of 17 patients with mild traumatic brain injury without posttraumatic migraines. Fractional anisotropy and diffusivity maps were generated to measure white matter integrity and were evaluated by using Tract-Based Spatial Statistics regression analysis with a general linear model. DTI findings were correlated with symptom severity, neurocognitive test scores, and time to recovery with the Pearson correlation coefficient., Results: Patients with mild traumatic brain injury with posttraumatic migraines were not significantly different from controls in terms of age, sex, type of injury, or neurocognitive test performance. Patients with posttraumatic migraines had higher initial symptom severity ( P = .01) than controls. Compared with controls, patients with mild traumatic brain injury with posttraumatic migraines had decreased fractional anisotropy in the corpus callosum ( P = .03) and fornix/septohippocampal circuit ( P = .045). Injury to the fornix/septohippocampal circuit correlated with decreased visual memory ( r = 0.325, P = .01). Injury to corpus callosum trended toward inverse correlation with recovery ( r = -0.260, P = .05)., Conclusions: Injuries to the corpus callosum and fornix/septohippocampal circuit were seen in patients with mild traumatic brain injury with posttraumatic migraines, with injuries in the fornix/septohippocampal circuit correlating with decreased performance on neurocognitive testing., (© 2017 by American Journal of Neuroradiology.)
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- 2017
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32. High throughput toxicity screening and intracellular detection of nanomaterials.
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Collins AR, Annangi B, Rubio L, Marcos R, Dorn M, Merker C, Estrela-Lopis I, Cimpan MR, Ibrahim M, Cimpan E, Ostermann M, Sauter A, Yamani NE, Shaposhnikov S, Chevillard S, Paget V, Grall R, Delic J, de-Cerio FG, Suarez-Merino B, Fessard V, Hogeveen KN, Fjellsbø LM, Pran ER, Brzicova T, Topinka J, Silva MJ, Leite PE, Ribeiro AR, Granjeiro JM, Grafström R, Prina-Mello A, and Dusinska M
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- Animals, Cell Line, Cytological Techniques, Humans, Intracellular Space chemistry, Intracellular Space metabolism, Mice, High-Throughput Screening Assays methods, Nanostructures toxicity, Toxicity Tests methods
- Abstract
With the growing numbers of nanomaterials (NMs), there is a great demand for rapid and reliable ways of testing NM safety-preferably using in vitro approaches, to avoid the ethical dilemmas associated with animal research. Data are needed for developing intelligent testing strategies for risk assessment of NMs, based on grouping and read-across approaches. The adoption of high throughput screening (HTS) and high content analysis (HCA) for NM toxicity testing allows the testing of numerous materials at different concentrations and on different types of cells, reduces the effect of inter-experimental variation, and makes substantial savings in time and cost. HTS/HCA approaches facilitate the classification of key biological indicators of NM-cell interactions. Validation of in vitro HTS tests is required, taking account of relevance to in vivo results. HTS/HCA approaches are needed to assess dose- and time-dependent toxicity, allowing prediction of in vivo adverse effects. Several HTS/HCA methods are being validated and applied for NM testing in the FP7 project NANoREG, including Label-free cellular screening of NM uptake, HCA, High throughput flow cytometry, Impedance-based monitoring, Multiplex analysis of secreted products, and genotoxicity methods-namely High throughput comet assay, High throughput in vitro micronucleus assay, and γH2AX assay. There are several technical challenges with HTS/HCA for NM testing, as toxicity screening needs to be coupled with characterization of NMs in exposure medium prior to the test; possible interference of NMs with HTS/HCA techniques is another concern. Advantages and challenges of HTS/HCA approaches in NM safety are discussed. WIREs Nanomed Nanobiotechnol 2017, 9:e1413. doi: 10.1002/wnan.1413 For further resources related to this article, please visit the WIREs website., (© 2016 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.)
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- 2017
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33. White Matter Injuries in Mild Traumatic Brain Injury and Posttraumatic Migraines: Diffusion Entropy Analysis.
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Delic J, Alhilali LM, Hughes MA, Gumus S, and Fakhran S
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- Adolescent, Adult, Child, Entropy, Female, Humans, Male, Middle Aged, Retrospective Studies, White Matter diagnostic imaging, Young Adult, Brain Injuries, Traumatic complications, Brain Injuries, Traumatic diagnostic imaging, Diffusion Tensor Imaging methods, Migraine Disorders diagnostic imaging, Migraine Disorders etiology, White Matter injuries
- Abstract
Purpose To determine the performance of Shannon entropy (SE) as a diagnostic tool in patients with mild traumatic brain injury (mTBI) with posttraumatic migraines (PTMs) and those without PTMs on the basis of analysis of fractional anisotropy (FA) maps. Materials and Methods The institutional review board approved this retrospective study, with waiver of informed consent. FA maps were obtained and neurocognitive testing was performed in 74 patients with mTBI (57 with PTM, 17 without PTM). FA maps were obtained in 22 healthy control subjects and in 20 control patients with migraine headaches. Mean FA and SE were extracted from total brain FA histograms and were compared between patients with mTBI and control subjects and between patients with and those without PTM. Mean FA and SE were correlated with clinical variables and were used to determine the areas under the receiver operating characteristic curve (AUCs) and likelihood ratios for mTBI and development of PTM. Results Patients with mTBI had significantly lower SE (P < .001) and trended toward lower mean FA (P = .07) compared with control subjects. SE inversely correlated with time to recovery (TTR) (r = -0.272, P = .02). Patients with mTBI with PTM had significantly lower SE (P < .001) but not mean FA (P = .15) than did other patients with mTBI. SE provided better discrimination between patients with mTBI and control subjects than mean FA (AUC = 0.92; P = .01), as well as better discrimination between patients with mTBI with PTM and those without PTM (AUC = 0.85; P < .001). SE of less than 0.751 resulted in a 16.1 increased likelihood of having experienced mTBI and a 3.2 increased likelihood of developing PTM. Conclusion SE more accurately reveals mTBI than mean FA, more accurately reveals those patients with mTBI who develop PTM, and inversely correlates with TTR. (©) RSNA, 2016.
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- 2016
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34. In vitro biocompatibility of mesoporous metal (III; Fe, Al, Cr) trimesate MOF nanocarriers.
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Grall R, Hidalgo T, Delic J, Garcia-Marquez A, Chevillard S, and Horcajada P
- Abstract
The high porosity and versatile composition of the benchmarked mesoporous metal (Fe, Al, Cr) trimesate metal-organic frameworks (MIL-100(Fe, Al, Cr)) make them very promising solids in different strategic industrial and societal domains (separation, catalysis, biomedicine, etc.). In particular, MIL-100(Fe) nanoparticles (NPs) have been recently revealed to be one of the most promising and innovative next generation tools enabling multidrug delivery to overcome cancer resistance. Here, we analyzed the in vitro toxicity of the potential drug nanocarrier MIL-100(Fe) NPs and the effect of the constitutive cation by comparing its cytotoxicity with that one of its Cr and Al analogue NPs. Lung (A549 and Calu-3) and hepatic (HepG2 and Hep3B) cell lines were selected considering pulmonary, ingestion or intravenous exposure modes. First, the complete physicochemical characterization (structural, chemical and colloidal stability) of the MIL-100(Fe, Al, Cr) NPs was performed in the cell culture media. Then, their cytotoxicity was evaluated in the four selected cell lines using a combination of methods from cell impedance, cell survival/death and ROS generation to DNA damage for measuring genotoxicity. Thus, MIL-100(Fe, Al, Cr) NPs did not induce in vitro cell toxicity, even at high doses in the p53 wild type cell lines (A549 and calu-3 (lung) and HepG2 (liver)). The only toxic effect of MIL100-Fe was observed in the hepatocarcinoma cell line Hep3B, which is stress sensitive because it does not express TP53, the guardian of the genome.
- Published
- 2015
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35. A new phosphorylated form of Ku70 identified in resistant leukemic cells confers fast but unfaithful DNA repair in cancer cell lines.
- Author
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Bouley J, Saad L, Grall R, Schellenbauer A, Biard D, Paget V, Morel-Altmeyer S, Guipaud O, Chambon C, Salles B, Maloum K, Merle-Béral H, Chevillard S, and Delic J
- Subjects
- Blotting, Western, Cell Line, Tumor, Comet Assay, DNA Repair, Electrophoresis, Gel, Two-Dimensional, Flow Cytometry, Fluorescent Antibody Technique, Humans, Immunoprecipitation, Ku Autoantigen, Mass Spectrometry, Phosphorylation, Protein Isoforms genetics, RNA, Small Interfering, Transfection, Antigens, Nuclear metabolism, DNA End-Joining Repair genetics, DNA-Binding Proteins metabolism, Drug Resistance, Neoplasm genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Ku70-dependent canonical nonhomologous end-joining (c-NHEJ) DNA repair system is fundamental to the genome maintenance and B-cell lineage. c-NHEJ is upregulated and error-prone in incurable forms of chronic lymphocytic leukemia which also displays telomere dysfunction, multiple chromosomal aberrations and the resistance to DNA damage-induced apoptosis. We identify in these cells a novel DNA damage inducible form of phospho-Ku70. In vitro in different cancer cell lines, Ku70 phosphorylation occurs in a heterodimer Ku70/Ku80 complex within minutes of genotoxic stress, necessitating its interaction with DNA damage-induced kinase pS2056-DNA-PKcs and/or pS1981-ATM. The mutagenic effects of phospho-Ku70 are documented by a defective S/G2 checkpoint, accelerated disappearance of γ-H2AX foci and kinetics of DNA repair resulting in an increased level of genotoxic stress-induced chromosomal aberrations. Together, these data unveil an involvement of phospho-Ku70 in fast but inaccurate DNA repair; a new paradigm linked to both the deregulation of c-NHEJ and the resistance of malignant cells.
- Published
- 2015
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36. Impairing the radioresistance of cancer cells by hydrogenated nanodiamonds.
- Author
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Grall R, Girard H, Saad L, Petit T, Gesset C, Combis-Schlumberger M, Paget V, Delic J, Arnault JC, and Chevillard S
- Subjects
- Cell Line, Tumor, Cell Survival drug effects, Humans, Materials Testing, Nanodiamonds chemistry, Nanodiamonds ultrastructure, Neoplasms, Experimental pathology, Radiation-Sensitizing Agents administration & dosage, Treatment Outcome, Cell Survival radiation effects, Hydrogen chemistry, Nanodiamonds administration & dosage, Neoplasms, Experimental radiotherapy, Radiation Tolerance drug effects, Radiation-Sensitizing Agents chemical synthesis
- Abstract
Hydrogenated nanodiamonds (H-NDs) exhibit a negative electron affinity that confers a high reactivity with oxygen species and a positive charge in aqueous solutions. It allows electron emission from H-NDs following irradiation by photons and in consequence may enhance the effects of radiation on cancer cells. By using three human radioresistant cancer cell lines, we showed a potentialization of cytotoxicity after a co-exposure to H-NDs and irradiation; an event occurring through the induction of DNA damage and reactive oxygen species. This occurred together with a decrease in cell impedance, the activation of G1/S, an unlocking of G2 cell cycle check-points and early low cell death rate. At later stage of exposure, persistent increases in heterochromatinization, large γ-H2AX foci and β-galactosidase activity were detected providing evidence of cells' entrance into senescence. Similar potentialization was observed with neocarzinostatin (NCS), a radiomimetic drug. This original finding underlines a wide clinical potential of H-NDs to intensify radiation effects on radio-resistant cancer cells., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2015
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37. Variations in diameters of vertebro-basilar tree in patients with or with no aneurysm.
- Author
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Mehinovic A, Isakovic E, and Delic J
- Subjects
- Bosnia and Herzegovina, Female, Humans, Magnetic Resonance Angiography, Male, Posterior Cerebral Artery anatomy & histology, Basilar Artery anatomy & histology, Intracranial Aneurysm pathology, Vertebral Artery anatomy & histology
- Abstract
Introduction: The morphological anatomy of the posterior circulation is very complex and variable. Aims of this research were to document the morphological anatomy of the posterior circulation along with variations in the Bosnian population, in patients with or without aneurysm. Measurements of the outer diameters of the vertebral artery, basilar artery and posterior cerebral artery were taken. The second aim was to determine the possible relationship between diameters of the area with subsequent aneurysm formation., Material and Methods: The study involved 60 consecutive patients, adults of both sexes, treated in the UKC Tuzla. The patients were divided into two groups. One group consisted of the patients without aneurysm of basilar artery, and the other group of patients with aneurysm. All the 60 patients were treated by means of MRI angiography., Results: The mean diameter of the vertebral artery was 2.43 mm; 3.61 mm on the right and 2.83 mm; 3.94 mm on the left. The diameter of the basilar artery varied from 3.8 mm; 3.43 mm. The diameter of the posterior cerebral arteries 2.5 mm; 2.52 mm on the right and 2.46 mm; 2.62 mm on the left., Conclusions: We have documented the various morphometry variations as well as the differences of the anatomy in this area in Bosnian population as compared to the medicine literature.
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- 2014
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38. Frequency of superficial and deep vein thrombosis in patients with variations of superficial veins of lower extremities.
- Author
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Lovic S, Delic J, Ljuca F, Mujanovic E, Custendil-Delic S, Zabic A, and Suljkanovic-Mahmutovic A
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- Aged, Female, Humans, Male, Middle Aged, Phlebography, Saphenous Vein abnormalities, Saphenous Vein diagnostic imaging, Venous Thrombosis diagnostic imaging, Leg blood supply, Veins abnormalities, Venous Thrombosis pathology
- Abstract
Unlabelled: Anatomical variations of veins often play a crucial role in formation of thrombotic changes in superficial and deep veins of lower extremities. THE AIM of this study was to determine the frequency of the dominant type of the lower extremity superficial veins, and to determine the eventual influence of such variations to the formation of superficial and deep vein thrombosis (DVT)., Material and Methods: The sample used in this study consisted of 180 patients subjected to ascedent contrast phlebography of lower extremities. The total sample was divided into following groups: patients with and without variations of the lower extremity superficial veins., Results and Discussion: Dominant type of the superficial veins (without variation) consisted of 97 patients (53.89%), while the rest of 83 patients showed some kind of anatomical variation (46.11%). The most frequent variation was the duplicated form ofv. saphena magna in 53.85%, while this procentage in women was 57.89%. Most frequent variations of duplicated v. saphena magna were: simple duplicated form, closed loop form, branching form and combined form. Topographical variation of saphenopopliteal junction besides fossa poplitea in the group of men showed procentage of 53.85%, while in the group of women that value accounted 63.16%., Conclusion: The percentage of varicose veins was more frequent in men and women without variations, but deep vein DVT showed higher frequency in patients with anatomical variations of superficial veins of lower extremities.
- Published
- 2012
39. Concomitant telomere shortening, acquisition of multiple chromosomal aberrations and in vitro resistance to apoptosis in a single case of progressive CLL.
- Author
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Brugat T, Nguyen-Khac F, Merle-Béral H, and Delic J
- Subjects
- Apoptosis genetics, Cells, Cultured, Disease Progression, Fatal Outcome, Follow-Up Studies, Humans, Telomere metabolism, Telomere pathology, Apoptosis physiology, Chromosome Aberrations, Drug Resistance, Neoplasm genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Telomere genetics
- Published
- 2011
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40. Nucleotides affect neurogenesis and dopaminergic differentiation of mouse fetal midbrain-derived neural precursor cells.
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Delic J and Zimmermann H
- Abstract
The fetal midbrain is a preferred source for isolating and producing dopaminergic neurons for subsequent grafting and replacement of damaged or lost dopaminergic midbrain neurons. We analysed the potential of a variety of nucleotides and of adenosine to support dopaminergic neuron formation from primary mouse fetal midbrain-derived cells, harvested at E10.5 and at E13.5 and subjected to adherent cell culture. In contrast to cells derived at E13.5, cells derived at E10.5 have the potential to produce dopaminergic neurons in culture. These neurons express tyrosine hydroxylase and the dopamine transporter. The fetal ventral midbrain contained mRNA encoding almost all P2X and P2Y receptors, all adenosine receptors as well as the ectonucleotidases nucleoside triphosphate diphosphohydrolase 2 and tissue nonspecific alkaline phosphatase. Essentially, all components of the purinergic signalling pathway were also expressed by the cultured cells. ATP, ADPβS, 2MeSATP, 2ClATP and adenosine increased neuron formation. There was, however, no preference for the formation of dopaminergic neurons-with the exception of 2ClATP that increased the relative contribution of tyrosine hydroxylase-positive neurons. In cells isolated at E13.5 UTP promoted neuron survival but ADPβS and ATPγS essentially eliminated neurons. These data showed that the outcome of nucleotide application was different even though cells isolated at E10.5 and E13.5 expressed very similar receptor mRNA profiles. They suggest that purinergic agonists carry potential for stimulating neurogenesis and enriching the contribution of dopaminergic neurons in vitro. Nucleotide receptor agonists may be of value for contributing to the formation and survival of dopaminergic neurons in vivo.
- Published
- 2010
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41. Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males.
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Marteau JB, Rigaud O, Brugat T, Gault N, Vallat L, Kruhoffer M, Orntoft TF, Nguyen-Khac F, Chevillard S, Merle-Beral H, and Delic J
- Subjects
- Aged, Aged, 80 and over, Apoptosis genetics, Case-Control Studies, DNA Methylation, Female, Gene Expression Profiling, Heterochromatin genetics, Histones chemistry, Histones metabolism, Humans, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Lysine metabolism, Male, Middle Aged, Promoter Regions, Genetic genetics, Sex Characteristics, Down-Regulation genetics, Gene Silencing, Heterochromatin metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Transcription Factor RelB deficiency, Transcription Factor RelB genetics
- Abstract
Background: The sensitivity of chronic lymphocytic leukemia (CLL) cells to current treatments, both in vitro and in vivo, relies on their ability to activate apoptotic death. CLL cells resistant to DNA damage-induced apoptosis display deregulation of a specific set of genes., Methods: Microarray hybridization (Human GeneChip, Affymetrix), immunofluorescent in situ labeling coupled with video-microscopy recording/analyses, chromatin-immunoprecipitation (ChIP), polymerase chain reactions (PCR), real-time quantitative PCR (RT-QPCR) and bisulfite genome sequencing were the main methods applied. Statistical analyses were performed by applying GCRMA and SAM analysis (microarray data) and Student's t-test or Mann & Whitney's U-test., Results: Herein we show that, remarkably, in a resistant male CLL cells the vast majority of genes were down-regulated compared with sensitive cells, whereas this was not the case in cells derived from females. This gene down-regulation was found to be associated with an overall gain of heterochromatin as evidenced by immunofluorescent labeling of heterochromatin protein 1α (HP-1), trimethylated histone 3 lysine 9 (3metH3K9), and 5-methylcytidine (5metC). Notably, 17 genes were found to be commonly deregulated in resistant male and female cell samples. Among these, RELB was identified as a discriminatory candidate gene repressed in the male and upregulated in the female resistant cells., Conclusion: The molecular defects in the silencing of RELB involve an increase in H3K9- but not CpG-island methylation in the promoter regions. Increase in acetyl-H3 in resistant female but not male CLL samples as well as a decrease of total cellular level of RelB after an inhibition of histone deacetylase (HDAC) by trichostatin A (TSA), further emphasize the role of epigenetic modifications which could discriminate two CLL subsets. Together, these results highlighted the epigenetic RELB silencing as a new marker of the progressive disease in males.
- Published
- 2010
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42. Telomere dysfunction-induced foci arise with the onset of telomeric deletions and complex chromosomal aberrations in resistant chronic lymphocytic leukemia cells.
- Author
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Brugat T, Nguyen-Khac F, Grelier A, Merle-Béral H, and Delic J
- Subjects
- Adult, Aged, Aged, 80 and over, Apoptosis genetics, Chromatin Immunoprecipitation, Chromosome Aberrations, Female, Fluorescent Antibody Technique, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Prognosis, Drug Resistance, Neoplasm genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Telomere genetics, Telomere pathology
- Abstract
In somatic cells, eroded telomeres can induce DNA double-strand break signaling, leading to a form of replicative senescence or apoptosis, both of which are barriers to tumorigenesis. However, cancer cells might display telomere dysfunctions which in conjunction with defects in DNA repair and apoptosis, enables them to circumvent these pathways. Chronic lymphocytic leukemia (CLL) cells exhibit telomere dysfunction, and a subset of these cells are resistant to DNA damage-induced apoptosis and display short telomeres. We show here that these cells exhibit significant resection of their protective telomeric 3' single-stranded overhangs and an increased number of telomere-induced foci containing gammaH2AX and 53BP1. Chromatin immunoprecipitation and immunofluorescence experiments demonstrated increased levels of telomeric Ku70 and phospho-S2056-DNA-PKcs, 2 essential components of the mammalian nonhomologous end-joining DNA repair system. Notably, these CLL cells display deletions of telomeric signals on one or 2 chromatids in parallel with 11q22 deletions, or with 13q14 deletions associated with another chromosomal aberration or with a complex karyotype. Taken together, our results indicate that a subset of CLL cells from patients with an unfavorable clinical outcome harbor a novel type of chromosomal aberration resulting from telomere dysfunction.
- Published
- 2010
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43. Effectiveness of treating the renal anemia in chronic hemodialyzed patients by epoietin alpha and beta.
- Author
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Ostrvica E, Mesic E, Ostrvica D, Delic J, Delic-Custendil S, and Hukic F
- Subjects
- Adult, Aged, Aged, 80 and over, Anemia blood, Anemia etiology, Epoetin Alfa, Female, Humans, Injections, Intravenous, Injections, Subcutaneous, Kidney Failure, Chronic therapy, Male, Middle Aged, Recombinant Proteins, Treatment Outcome, Anemia therapy, Erythropoietin administration & dosage, Hematinics administration & dosage, Kidney Failure, Chronic complications, Renal Dialysis
- Abstract
Introduction: Anemia is an early sign of chronic kidney dysfunction, caused by many different factors, but the insufficient erythropoietin synthesis is the crucial factor in its development., Objectives: The objective of our study was to compare effectiveness of epoietin alpha and beta application in the treatment of renal anemia in chronic hemodialyzed patients., Patients and Methods: The group included 60 patients of both sexes, randomly chosen. Criteria for including patients into the study were: older than 18 years, haemodialyzed longer than three months and treated by epoietin beta, stable level of hemoglobin, between 9 and 11 g/dL at least two successive measurements and no malignant disease present. The patients were then randomized into groups: 20 patients were administered epoietin alpha intravenously instead of epoietin beta subcutaneously (experimental group); 20 patients were administered intravenously epoietin beta instead of epoietin beta subcutaneously (control group A), the rest of 20 patients were administered epoietin beta subcutaneously (control group B). All the testees were administered epoietin alpha or beta three times weekly after haemodialysis, intravenously or subcutaneously., Results: Comparison among mean values of hematological and biochemical parameters before starting the treatment by erythropoietin, and third and sixth months after therapy in the studied groups, no significant difference was found (p > 0.05)., Conclusion: Epoietin alpha and beta showed approximate degree of efficacy in renal anemia treatment of hemodialysis patients. The way of erythropoetin administration did not significantly effect the level of hemoglobin and hematocrit in six months research period.
- Published
- 2010
44. Disorders of hemostasis in the course and after laparoscopic cholecystectomy.
- Author
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Custendil-Delic S, Delic J, Mott-Divkovic S, Petrov-Raslic J, Ostrvica E, and Hukic F
- Subjects
- Adult, Aged, Aged, 80 and over, Blood Coagulation Disorders blood, Female, Fibrin Fibrinogen Degradation Products analysis, Fibrinogen analysis, Humans, Male, Middle Aged, Thromboembolism etiology, Young Adult, Blood Coagulation Disorders etiology, Cholecystectomy, Laparoscopic adverse effects
- Abstract
Introduction: Hemostasis is a very important mechanism, whose changes can cause different complications. In the course of surgical interventions some changes in the system of coagulation happen. Laparoscopic cholecystectomy is a method of choice in the treatment of gallbladder calculosis. In the course of the procedure, parameters of hemostasis change, which stimulates a possible appearance of thromboembolic complications. The objective of our research was to reveal the changes in the system of coagulation in patients treated by laparoscopic cholecystectomy., Examinees and Methods: Total sample involved 60 patients, divided into two groups, who were treated either by classical or laparoscopic method. Parameters of primary and secondary hemostasis were determined for the patients of both groups in Polyclinic for Transfusiology UKC Tuzla, before the operation, in the course, and 24 hours after the operation, and on the 5th day after the surgery., Results: Patients from both groups showed changes in the process of coagulation. The changes were more expressed in the group of patients treated by laparoscopic cholecystectomy. Very important result was the increased value of D-dimer measured on the 5th day after the operation in the patients operated by laparoscopic cholecystectomy, where value was 2.5 times higher in the relation to preoperative value (263.5 microg/l, so it was out of referential value). Increase of fibrinogen in both groups were an important result of this study., Discussion and Conclusion: Results of the study showed changes in the process of coagulation in both groups, and increased fibrinolytic activity of the organism after laparoscopic cholecystectomy (requires a discussion on longer and thorough prophylaxis of tromboembolism).
- Published
- 2009
45. Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia.
- Author
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Poncet D, Belleville A, t'kint de Roodenbeke C, Roborel de Climens A, Ben Simon E, Merle-Beral H, Callet-Bauchu E, Salles G, Sabatier L, Delic J, and Gilson E
- Subjects
- Antigens, CD19 blood, Gene Expression Profiling, Humans, Leukemia, Lymphocytic, Chronic, B-Cell enzymology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation, Shelterin Complex, Telomere ultrastructure, Telomere-Binding Proteins, Gene Expression Regulation, Neoplastic, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Telomerase genetics, Telomere genetics
- Abstract
In this study, we explored the telomeric changes that occur in B-chronic lymphocytic leukemia (B-CLL), in which telomere length has recently been demonstrated to be a powerful prognostic marker. We carried out a transcriptomic analysis of telomerase components (hTERT and DYSKERIN), shelterin proteins (TRF1, TRF2, hRAP1, TIN2, POT1, and TPP1), and a set of multifunctional proteins involved in telomere maintenance (hEST1A, MRE11, RAD50, Ku80, and RPA1) in peripheral B cells from 42 B-CLL patients and 20 healthy donors. We found that, in B-CLL cells, the expressions of hTERT, DYSKERIN, TRF1, hRAP1, POT1, hEST1A, MRE11, RAD50, and KU80 were more than 2-fold reduced (P < .001), contrasting with the higher expression of TPP1 and RPA1 (P < .001). This differential expression pattern suggests that both telomerase down-regulation and changes in telomeric proteins composition are involved in the pathogenesis of B-CLL.
- Published
- 2008
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46. Natural phosphorylation of CD5 in chronic lymphocytic leukemia B cells and analysis of CD5-regulated genes in a B cell line suggest a role for CD5 in malignant phenotype.
- Author
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Gary-Gouy H, Sainz-Perez A, Marteau JB, Marfaing-Koka A, Delic J, Merle-Beral H, Galanaud P, and Dalloul A
- Subjects
- CD5 Antigens genetics, Gene Expression Profiling, Mutation genetics, Phenotype, Phosphorylation, Phosphotyrosine metabolism, Signal Transduction, CD5 Antigens metabolism, Gene Expression Regulation, Neoplastic, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Chronic lymphocytic leukemia (CLL) results in the accumulation of B cells, presumably reflecting the selection of malignant cell precursors with Ag combined with complex alterations in protein activity. Repeated BCR stimulation of normal B cells leads to anergy and CD5 expression, both of which are features of CLL. Because CD5 is phosphorylated on tyrosine following BCR engagement and negatively regulates BCR signaling in normal B cells, we investigated its phosphorylation status and found it to be naturally phosphorylated on tyrosine but not on serine residues in CLL samples. To analyze the role of CD5, we established a B cell line in which CD5 is phosphorylated. Gene profiling of vector vs CD5-transfected B cells pointed out gene groups whose expression was enhanced: Apoptosis inhibitors (BCL2), NF-kappaB (RELB, BCL3), Wnt, TGFbeta, VEGF, MAPKs, Stats, cytokines, chemokines (IL-10, IL-10R, IL-2R, CCL-3, CCL-4, and CCR7), TLR-9, and the surface Ags CD52, CD54, CD70, and CD72. Most of these gene groups are strongly expressed in CLL B cells as compared with normal B cells. Unexpectedly, metabolic pathways, namely cholesterol synthesis and adipogenesis, are also enhanced by CD5. Conversely, CD5 inhibited genes involved in RNA splicing and processing, ribosome biogenesis, proteasome, and CD80 and CD86 Ags, whose expression is low in CLL. Comparison of CD5- vs tailless CD5-transfected cells further demonstrated the role of CD5 phosphorylation in the regulation of selected genes. These results support a model where CLL cells are chronically stimulated, leading to CD5 activation and cell survival. In addition to CD5 itself, we point to several CD5-induced genes as potential therapeutic targets.
- Published
- 2007
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47. Mutagenicity of non-homologous end joining DNA repair in a resistant subset of human chronic lymphocytic leukaemia B cells.
- Author
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Deriano L, Merle-Béral H, Guipaud O, Sabatier L, and Delic J
- Subjects
- Aged, Apoptosis genetics, Base Sequence, Cell Line, Tumor, Cloning, Molecular methods, DNA genetics, Drug Resistance, Neoplasm, Female, Genomic Instability genetics, Humans, Male, Middle Aged, Mutation, Polymerase Chain Reaction, Prognosis, Up-Regulation genetics, B-Lymphocytes physiology, DNA Repair genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Non-homologous end joining (NHEJ) is an important determinant of genomic stability in mammalian cells. This DNA repair pathway is upregulated in a subset of B-cell chronic lymphocytic leukaemia (B-CLL) cells resistant to DNA damage-induced apoptosis. Using an in vitro assay for double-strand breaks (DSB) end ligation, we studied the fidelity of DSB repair in B-CLL cells which were resistant or sensitive to in vitro DSB-induced apoptosis with concomitant patients' resistance or sensitivity to chemotherapy, respectively. The fidelity of DNA repair was determined by DNA sequencing of polymerase chain reaction products cloned in pGEM-T vector. Sequence analysis of DNA end junctions showed that the frequency of accurate ligation was higher in sensitive B-CLL cells and control cell lines, than in resistant cells where end joining was associated with extended deletions. Upregulated and error-prone NHEJ in resistant cells could be a quite possible mechanism underlying both genomic instability and poor clinical outcome.
- Published
- 2006
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48. New molecular markers in resistant B-CLL.
- Author
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Bouley J, Deriano L, Delic J, and Merle-Béral H
- Subjects
- Biomarkers analysis, Epigenesis, Genetic, Genomic Instability genetics, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Somatic Hypermutation, Immunoglobulin genetics, Drug Resistance, Neoplasm genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis
- Abstract
B-chronic lymphocytic leukemia (B-CLL) is characterized by a highly variable clinical course which has long remained a stumbling block for clinicians. This variability appears to arise from complex molecular alterations identified in malignant cells from patient subsets. Recent studies have focused in particular on identifying new molecular markers to help predict the most effective and adapted treatments. In addition to the mutation status of immunoglobulin variable heavy-chain region (IgVH) genes, which is a well-established predictive factor in B-CLL, these new markers include defects of cell factors involved in the maintenance of genome stability, such as telomere function, DNA repair, ATM and p53. Other predictive factors, such as tyrosine kinase Zap-70 and soluble factors found in patient sera, may be associated with B-cell receptor signal transduction. Interestingly, an alteration of these factors fits closely, though not strikingly, with the absence of somatic mutations in IgVH genes, suggesting that the latter may be due either to epigenetic events leading to an unstable genome or to an inherited defect in the immune response of malignant B-cells. Recent lessons from Zap-70 expression/phosphorylation suggest that some of these markers may reflect the defective pathways in B-CLL cells rather than being markers of cell malignancy per se. Furthermore, specific subsets of markers are found in patient cells resistant to treatment. Current studies on gene expression profiling and proteomic analyses should soon lead to a better understanding of how these pathways are affected, especially in multi-drug resistant B-CLL.
- Published
- 2006
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49. Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway.
- Author
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Deriano L, Guipaud O, Merle-Béral H, Binet JL, Ricoul M, Potocki-Veronese G, Favaudon V, Maciorowski Z, Muller C, Salles B, Sabatier L, and Delic J
- Subjects
- Androstadienes pharmacology, Antibiotics, Antineoplastic pharmacology, Antigens, Nuclear metabolism, Antineoplastic Agents, Phytogenic pharmacology, B-Lymphocytes pathology, Blotting, Western, Cell Line, Transformed, Cell Line, Tumor, Cell-Free System, Chromones pharmacology, DNA metabolism, DNA Damage, DNA-Binding Proteins metabolism, Dimerization, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Etoposide pharmacology, Gamma Rays, Humans, Ku Autoantigen, Morpholines pharmacology, Okadaic Acid pharmacology, Phosphatidylinositol 3-Kinases pharmacology, Protein Binding, Telomere ultrastructure, Time Factors, Wortmannin, Zinostatin pharmacology, Apoptosis, DNA Repair, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Nonhomologous end-joining (NHEJ) DNA factors maintain genomic stability through their DNA double-strand break (DSB) repair and telomere-associated activities. Unrepaired or misrepaired DSBs can lead to apoptotic death or chromosomal damage. The B cells of some B-chronic lymphocytic leukemia (B-CLL) patients are resistant to radiation-induced apoptosis in vitro. We show here that the novel DNA-dependent protein kinase (DNA-PK) inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), and the phosphatidylinositol 3 (PI-3) kinase inhibitor, wortmannin, restored sensitivity to DNA damage-induced apoptosis of otherwise resistant cells. These resistant malignant B cells also escaped DSB-induced apoptosis following exposure to etoposide or neocarzinostatin. We found that at 15 minutes after irradiation, the levels of NHEJ (as measured by an in vitro DSB end-ligation assay) and DNA-PK catalytic subunit (DNA-PKcs) activity were, respectively, 2-fold and 4-fold higher in radio-resistant than in radio-sensitive B-CLL cells or Epstein-Barr virus (EBV)-transformed B cells. Ku70/Ku80 heterodimer DNA end-binding activity was also 2- to 3-fold higher in the resistant B-CLL cell subset compared with the sensitive B-CLL cell subset. Our results provide the first evidence that overactivating the NHEJ DNA repair pathway impairs DNA damage-induced apoptosis in malignant B cells and that this may contribute to their resistance to current chemotherapy.
- Published
- 2005
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50. The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays.
- Author
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Vallat L, Magdelénat H, Merle-Béral H, Masdehors P, Potocki de Montalk G, Davi F, Kruhoffer M, Sabatier L, Orntoft TF, and Delic J
- Subjects
- Apoptosis genetics, Biomarkers, Tumor analysis, DNA Damage radiation effects, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell radiotherapy, Lymphocyte Subsets, Oligonucleotide Array Sequence Analysis, Tumor Suppressor Protein p53 physiology, Apoptosis radiation effects, DNA Damage physiology, Gene Expression Profiling methods, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
B-cell chronic lymphoid leukemia (BCLL) is a highly heterogeneous human malignancy, presumably reflecting specific molecular alterations in gene expression and protein activity that are thought to underlie the variable disease outcome. Most B-CLL cell samples undergo apoptotic death in response to DNA damage. However, a clinically distinct aggressive subset of B-CLL is completely resistant in vitro to irradiation-induced apoptosis. We therefore addressed 2 series of microarray analyses on 4 sensitive and 3 resistant B-CLL cell samples and compared their gene expression patterns before and after apoptotic stimuli. Data analysis pointed out 16 genes whose expression varied at least 2-fold specifically in resistant cells. We validated these selected genes by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) on 7 microarray samples and confirmed their altered expression level on 15 additional B-CLL cell samples not included in the microarray analysis. In this manner, in 11 sensitive and 11 resistant B-CLL cell samples tested, 13 genes were found to be specific for all resistant samples: nuclear orphan receptor TR3, major histocompatibility complex (MHC) class II glycoprotein HLA-DQA1, mtmr6, c-myc, c-rel, c-IAP1, mat2A, and fmod were up-regulated, whereas MIP1a/GOS19-1 homolog, stat1, blk, hsp27, and ech1 were down-regulated. In some cases, the expression profile may be dependent on the status of p53. Some of these genes encode general apoptotic factors but also exhibit lymphoid cell specificities that could potentially be linked to the development of lymphoid malignancies (MIP1alpha, blk, TR3, mtmr6). Taken together, our data define new molecular markers specific to resistant B-CLL subsets that might be of clinical relevance.
- Published
- 2003
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