bcr abl fusion proteins


Summary: Translation products of a fusion gene derived from CHROMOSOMAL TRANSLOCATION of C-ABL GENES to the genetic locus of the breakpoint cluster region gene on chromosome 22. Several different variants of the bcr-abl fusion proteins occur depending upon the precise location of the chromosomal breakpoint. These variants can be associated with distinct subtypes of leukemias such as PRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMA; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; and NEUTROPHILIC LEUKEMIA, CHRONIC.

Top Publications

  1. Goldman J, Melo J. BCR-ABL in chronic myelogenous leukemia--how does it work?. Acta Haematol. 2008;119:212-7 pubmed publisher
  2. Lu Z, Jin Y, Qiu L, Lai Y, Pan J. Celastrol, a novel HSP90 inhibitor, depletes Bcr-Abl and induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation. Cancer Lett. 2010;290:182-91 pubmed publisher
    ..Celastrol induced mitochondrial-dependent apoptosis. In conclusion, celastrol exhibits potent activity against CML cells bearing wild-type Bcr-Abl or -the T315I-mutant. ..
  3. Bennour A, Sennana H, Laatiri M, Elloumi M, Khelif A, Saad A. Molecular cytogenetic characterization of variant Philadelphia translocations in chronic myeloid leukemia: genesis and deletion of derivative chromosome 9. Cancer Genet Cytogenet. 2009;194:30-7 pubmed publisher
    ..Proper assessment of the prognostic significance of variant translocations requires better categorization of these translocations based on their mechanisms of genesis and 9q34 deletion status...
  4. Zhang J, Adrian F, Jahnke W, Cowan Jacob S, Li A, Iacob R, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010;463:501-6 pubmed publisher
  5. Eck M, Manley P. The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl. Curr Opin Cell Biol. 2009;21:288-95 pubmed publisher
    ..As structural information accumulates for more of the 518 kinases encoded within the human genome, the design of many more highly selective, well-tolerated kinase inhibitors should be possible. ..
  6. Shah N, Kasap C, Weier C, Balbas M, Nicoll J, Bleickardt E, et al. Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. Cancer Cell. 2008;14:485-93 pubmed publisher
    ..In CML patients receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, thereby demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy. ..
  7. Quintas Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 2009;113:1619-30 pubmed publisher
    ..Herein, we synthesize the most relevant and current knowledge on such areas of the pathogenesis of CML. ..
  8. Nakahara F, Sakata Yanagimoto M, Komeno Y, Kato N, Uchida T, Haraguchi K, et al. Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. Blood. 2010;115:2872-81 pubmed publisher
    ..These results suggest that Hes1 is a key molecule in blast crisis transition in CML...
  9. Shi X, Jin Y, Cheng C, Zhang H, Zou W, Zheng Q, et al. Triptolide inhibits Bcr-Abl transcription and induces apoptosis in STI571-resistant chronic myelogenous leukemia cells harboring T315I mutation. Clin Cancer Res. 2009;15:1686-97 pubmed publisher
    ..These findings suggest that triptolide is a promising agent to overcome STI571-resistant CML cells, and warrant a clinical trial of triptolide derivatives for CML with Bcr-Abl-T315I mutation. ..

More Information


  1. Agarwal A, Bumm T, Corbin A, O Hare T, Loriaux M, VanDyke J, et al. Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease. Blood. 2008;112:1960-70 pubmed publisher
    ..Hence, stabilization of p27 by inhibiting its recognition by SCF(SKP2) may be therapeutically useful. ..
  2. Legros L, Hayette S, Nicolini F, Raynaud S, Chabane K, Magaud J, et al. BCR-ABL(T315I) transcript disappearance in an imatinib-resistant CML patient treated with homoharringtonine: a new therapeutic challenge?. Leukemia. 2007;21:2204-6 pubmed
  3. Weisberg E, Wright R, McMillin D, Mitsiades C, Ray A, Barrett R, et al. Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells. Mol Cancer Ther. 2008;7:1121-9 pubmed publisher
    ..This in vitro system helped to elucidate stromal-secreted viability factors that may play a role in stromal-mediated cytoprotection of tyrosine kinase inhibitor-treated leukemia cells. ..
  4. Morinaga K, Yamauchi T, Kimura S, Maekawa T, Ueda T. Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification. Int J Cancer. 2008;122:2621-7 pubmed publisher
    ..Because BCR-ABL gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients' leukemia. ..
  5. Hantschel O, Rix U, Schmidt U, Burckstummer T, Kneidinger M, Schütze G, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci U S A. 2007;104:13283-8 pubmed
    ..The observed inhibition of Tec kinases by dasatinib predicts immunosuppressive (side) effects of this drug and may offer therapeutic opportunities for inflammatory and immunological disorders. ..
  6. Maslak P, Dao T, Gomez M, Chanel S, Packin J, Korontsvit T, et al. A pilot vaccination trial of synthetic analog peptides derived from the BCR-ABL breakpoints in CML patients with minimal disease. Leukemia. 2008;22:1613-6 pubmed publisher
  7. Quintas Cardama A, Kantarjian H, Cortes J. Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov. 2007;6:834-48 pubmed
    ..Here, we discuss these emerging therapies, which have the potential to improve the outcome of patients with CML. ..
  8. Wu M, Kwon H, Rattis F, Blum J, Zhao C, Ashkenazi R, et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell. 2007;1:541-54 pubmed publisher
    ..These studies establish a system for tracking division of hematopoietic precursors and show that the balance of symmetric and asymmetric division can be influenced by the microenvironment and subverted by oncogenes. ..
  9. Sherbenou D, Druker B. Applying the discovery of the Philadelphia chromosome. J Clin Invest. 2007;117:2067-74 pubmed
    ..The development of imatinib validates an emerging paradigm in cancer, in which a tumor is defined by genetic abnormalities and effective therapies are developed that target events critical to the growth and survival of a specific tumor...
  10. Rojas J, Knight K, Wang L, Clark R. Clinical evaluation of BCR-ABL peptide immunisation in chronic myeloid leukaemia: results of the EPIC study. Leukemia. 2007;21:2287-95 pubmed
    ..BCR-ABL peptide vaccination may improve control of CML, especially in patients responding well to imatinib. Randomised trials are required to address this further. ..
  11. Rix U, Hantschel O, Dürnberger G, Remsing Rix L, Planyavsky M, Fernbach N, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110:4055-63 pubmed
    ..4) The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs. ..
  12. Kaur P, Feldhahn N, Zhang B, Trageser D, MUSCHEN M, Pertz V, et al. Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia. Mol Cancer. 2007;6:67 pubmed
    ..Because Ph-positive acute lymphoblastic leukemia only responds transiently to imatinib therapy, we have used mouse models to test the efficacy of nilotinib against lymphoblastic leukemia caused by the P190 form of Bcr/Abl...
  13. Melo J, Barnes D. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer. 2007;7:441-53 pubmed
    ..The causes of this transformation are still poorly understood. What mechanisms underlie this progression, and are they shared by other common cancers?..
  14. Jagani Z, Singh A, Khosravi Far R. FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis. Biochim Biophys Acta. 2008;1785:63-84 pubmed
  15. Copland M, Pellicano F, Richmond L, Allan E, Hamilton A, Lee F, et al. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood. 2008;111:2843-53 pubmed
    ..This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML. ..
  16. Zhao C, Blum J, Chen A, Kwon H, Jung S, Cook J, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528-41 pubmed
    ..These studies demonstrate that Wnt signaling is required for the self-renewal of normal and neoplastic stem cells in the hematopoietic system. ..
  17. O Hare T, Eide C, Tyner J, Corbin A, Wong M, Buchanan S, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib. Proc Natl Acad Sci U S A. 2008;105:5507-12 pubmed publisher
    ..These findings suggest that combination of a T315I inhibitor with the current clinically used inhibitors may be useful for reduction of Bcr-Abl mutants in Philadelphia chromosome-positive leukemia. ..
  18. Beissert T, Hundertmark A, Kaburova V, Travaglini L, Mian A, Nervi C, et al. Targeting of the N-terminal coiled coil oligomerization interface by a helix-2 peptide inhibits unmutated and imatinib-resistant BCR/ABL. Int J Cancer. 2008;122:2744-52 pubmed publisher
    ..These data provide evidence that the inhibition of tetramerization inhibits BCR/ABL-mediated transformation and can contribute to overcome Imatinib-resistance. ..
  19. Chu S, Li L, Singh H, Bhatia R. BCR-tyrosine 177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in chronic myelogenous leukemia. Cancer Res. 2007;67:7045-53 pubmed
    ..Our studies indicate that BCR/ABL-Y177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in CML. ..
  20. Giannoudis A, Davies A, Lucas C, Harris R, Pirmohamed M, Clark R. Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia. Blood. 2008;112:3348-54 pubmed publisher
    ..Efflux of dasatinib and imatinib appear similar via ABCB1. Dasatinib may therefore offer an advantage over imatinib in patients with low hOCT1 expression. ..
  21. Mancini M, Petta S, Martinelli G, Barbieri E, Santucci M. RAD 001 (everolimus) prevents mTOR and Akt late re-activation in response to imatinib in chronic myeloid leukemia. J Cell Biochem. 2010;109:320-8 pubmed publisher
    ..RAD 001 cytotoxicity on cells not expressing the BCR-ABL fusion gene or its p210 protein tyrosine kinase (TK) activity suggests that the inhibition of normal hematopoiesis may represent a drug side effect. ..
  22. Valent P. Emerging stem cell concepts for imatinib-resistant chronic myeloid leukaemia: implications for the biology, management, and therapy of the disease. Br J Haematol. 2008;142:361-78 pubmed publisher
  23. Palandri F, Iacobucci I, Soverini S, Castagnetti F, Poerio A, Testoni N, et al. Treatment of Philadelphia-positive chronic myeloid leukemia with imatinib: importance of a stable molecular response. Clin Cancer Res. 2009;15:1059-63 pubmed publisher
    ..5). These data confirm that achieving a MMolR is prognostically important but point out that the prognostic value of achieving a MMolR is greater if the response is confirmed and stable. ..
  24. Qin Y, Jiang B, Jiang Q, Jiang H, Li J, Zhang Y, et al. Molecular responses of late chronic phase chronic myeloid leukemia patients after achieving complete cytogenetic responses with imatinib treatment: a 6-year follow-up. Ann Hematol. 2009;88:37-41 pubmed publisher
    ..Therefore, imatinib could induce most late CP patients to achieve long-term durable responses after achieving CCyR. Both the time when CCyR was first achieved and the depth of BCR-ABL reduction after CCyR are relevant to long-term EFS. ..
  25. Burmeister T, Gökbuget N, Schwartz S, Fischer L, Hubert D, Sindram A, et al. Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia. Haematologica. 2010;95:241-6 pubmed publisher
    ..Both groups of patients are characterized by distinct clinicobiological features which facilitate their diagnostic identification. ..
  26. Lucansky V, Sobotkova E, Tachezy R, Duskova M, Vonka V. DNA vaccination against bcr-abl-positive cells in mice. Int J Oncol. 2009;35:941-51 pubmed
    ..The livers, spleens and bone marrows of the successfully immunized animals were tested for the presence of bcr-abl-positive cells by RT-PCR. The results were negative, this suggesting that these animals were free of any residual disease...
  27. Colavita I, Esposito N, Martinelli R, Catanzano F, Melo J, Pane F, et al. Gaining insights into the Bcr-Abl activity-independent mechanisms of resistance to imatinib mesylate in KCL22 cells: a comparative proteomic approach. Biochim Biophys Acta. 2010;1804:1974-87 pubmed publisher
    ..The data reported may be useful for further studies on mechanisms of imatinib resistance and for the screening of biomarkers to develop new combinatorial therapeutic approaches. ..
  28. Bonovolias I, Tsiftsoglou A. Hemin counteracts the repression of Bcl-2 and NrF2 genes and the cell killing induced by imatinib in human Bcr-Abl(+) CML cells. Oncol Res. 2009;17:535-47 pubmed
  29. Takimoto C. Maximum tolerated dose: clinical endpoint for a bygone era?. Target Oncol. 2009;4:143-7 pubmed publisher
    ..Definition of the optimal dose may need to be deferred until randomized phase II trials can be conducted. Future clinical trail designs in oncology drug development need to reflect this paradigm shift. ..
  30. Vargas M, Portero M, Rodriguez A, Reyes J, Fernández Novoa C. Cytogenetic, fluorescence in situ hybridization, and molecular characterization of chronic myeloid leukemia in chronic phase with four BCR/ABL1 fusion signals: a case report. Cancer Genet Cytogenet. 2009;195:71-4 pubmed publisher
    ..We discuss the implication of cytogenetic and molecular alterations in the patient's evolution and treatment. ..
  31. Muller M, Cortes J, Kim D, Druker B, Erben P, Pasquini R, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009;114:4944-53 pubmed publisher
    ..Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844. ..
  32. Gruber F, Ernst T, Kiselev Y, Hochhaus A, Mikkola I. Detection of drug-resistant clones in chronic myelogenous leukemia patients during dasatinib and nilotinib treatment. Clin Chem. 2010;56:469-73 pubmed publisher
    ..Compared with standard genotyping, such biased genotyping improves the detection of resistance or alternative features via quantitative analysis of the absolute amount of resistance. ..
  33. Yin O, Gallagher N, Tanaka C, Fisher D, Sethuraman V, Zhou W, et al. Effects of hepatic impairment on the pharmacokinetics of nilotinib: an open-label, single-dose, parallel-group study. Clin Ther. 2009;31 Pt 2:2459-69 pubmed publisher
    ..Nilotinib should be used with caution, and careful clinical monitoring is recommended in this population. ClinicalTrials.gov identifier: NCT00418626. ..
  34. Sylvester J, Kron S. A bead-based activity screen for small-molecule inhibitors of signal transduction in chronic myelogenous leukemia cells. Mol Cancer Ther. 2010;9:1469-81 pubmed publisher
    ..This method for analyzing a focused signaling network benefits from rigorous statistical analysis and short processing times, thereby offering a powerful tool for drug discovery and clinical testing. ..
  35. Park J, Kim K, Koh Y, Won N, Oh J, Lee D, et al. Establishment of a new Glivec-resistant chronic myeloid leukemia cell line, SNUCML-02, using an in vivo model. Exp Hematol. 2010;38:773-81 pubmed publisher
  36. O Hare T, Eide C, Deininger M. New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check. Expert Opin Investig Drugs. 2008;17:865-78 pubmed
    ..Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T315I inhibitor remains a high priority. ..
  37. Lilly M, Ottmann O, Shah N, Larson R, Reiffers J, Ehninger G, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol. 2010;85:164-70 pubmed publisher
    ..Compared with the 70 mg twice daily, dasatinib 140 mg once daily had similar overall efficacy and safety in patients with imatinib-resistant or intolerant Ph+ ALL. (clinicaltrials.gov identifier: NCT00123487). ..
  38. Uchida N, Hanawa H, Dan K, Inokuchi K, Shimada T. Leukemogenesis of b2a2-type p210 BCR/ABL in a bone marrow transplantation mouse model using a lentiviral vector. J Nippon Med Sch. 2009;76:134-47 pubmed
    ..We have demonstrated that b2a2-type BCR/ABL has leukemogenic activity similar to that of b3a2-type BCR/ABL. ..
  39. Aranaz P, Ormazábal C, Hurtado C, Erquiaga I, Calasanz M, García Delgado M, et al. A new potential oncogenic mutation in the FERM domain of JAK2 in BCR/ABL1-negative and V617F-negative chronic myeloproliferative neoplasms revealed by a comprehensive screening of 17 tyrosine kinase coding genes. Cancer Genet Cytogenet. 2010;199:1-8 pubmed publisher
    ..In summary, data presented here show that these genes are not frequently mutated or rearranged in CMPNs, suggesting that molecular events causing these disorders must be located in other genes. ..
  40. Lavallard V, Pradelli L, Paul A, Beneteau M, Jacquel A, Auberger P, et al. Modulation of caspase-independent cell death leads to resensitization of imatinib mesylate-resistant cells. Cancer Res. 2009;69:3013-20 pubmed publisher
    ..Therefore, drugs able to modulate GAPDH administered together with imatinib could find some therapeutic benefits in CML patients. ..
  41. Gotoh M, Tauchi T, Yoshizawa S, Kitahara T, Kiguchi T, Kimura Y, et al. Successful prior treatment with dasatinib followed by stem cell transplantation in a patient with CML in blastic crisis with a BCR-ABL mutation. Int J Hematol. 2010;91:128-31 pubmed publisher
    ..This successful case indicates that reduction of tumor burden by second-generation tyrosine kinase inhibitors, in combination with stem cell transplantation, might be effective to treat CML, even in the advanced phase. ..
  42. Ito T, Kwon H, Zimdahl B, Congdon K, Blum J, Lento W, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature. 2010;466:765-8 pubmed publisher
    ..These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias...
  43. Li Y, Zou D, Gu M, Mi Y, Wang J, Qiu L. [The role of BCR/ABL isoforms in the presentations and outcome of Philadelphia-positive acute lymphoblastic leukemia in adult patients]. Zhonghua Nei Ke Za Zhi. 2009;48:481-4 pubmed
  44. Vajpai N, Strauss A, Fendrich G, Cowan Jacob S, Manley P, Jahnke W, et al. Backbone NMR resonance assignment of the Abelson kinase domain in complex with imatinib. Biomol NMR Assign. 2008;2:41-2 pubmed publisher
    ..Here we report the first almost complete backbone assignment of c-ABL kinase domain in complex with imatinib. ..
  45. Piaggio G, Rosti V, Corselli M, Bertolotti F, Bergamaschi G, Pozzi S, et al. Endothelial colony-forming cells from patients with chronic myeloproliferative disorders lack the disease-specific molecular clonality marker. Blood. 2009;114:3127-30 pubmed publisher
  46. Nica A, Tsao C, Watt J, Jiffar T, Kurinna S, Jurasz P, et al. Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK. Cell Cycle. 2008;7:3362-70 pubmed
    ..The findings presented here suggest that Caspase-8, JNK, and perhaps MCL-1 may play important roles in regulating cell death and may represent new targets for therapeutic strategies for CML. ..
  47. Jones D, Luthra R, Cortes J, Thomas D, O Brien S, Bueso Ramos C, et al. BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome-positive leukemias. Blood. 2008;112:5190-2 pubmed publisher
    ..Therefore, higher kinase activity by mutation, transcriptional up-regulation or gene amplification appears required for lymphoid transformation by p210 BCR-ABL. ..
  48. Muller M, Cross N, Erben P, Schenk T, Hanfstein B, Ernst T, et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia. 2009;23:1957-63 pubmed publisher
    ..We provide recommendations for the propagation of the IS by national or regional laboratory networks. ..
  49. Albero M, Vaquer J, Andreu E, Villanueva J, Franch L, Ivorra C, et al. Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells. Oncogene. 2010;29:3276-86 pubmed publisher
    ..These results unravel a new molecular target of Btz, that is the Rb pathway, and open new possibilities in the treatment of CML especially for patients that become resistant to IM because of the presence of the T315I mutation. ..
  50. Verma D, Kantarjian H, Jones D, Luthra R, Borthakur G, Verstovsek S, et al. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood. 2009;114:2232-5 pubmed publisher
    ..P190(BCR-ABL) CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients. ..
  51. Breccia M, Alimena G. Nilotinib therapy in chronic myelogenous leukemia: the strength of high selectivity on BCR/ABL. Curr Drug Targets. 2009;10:530-6 pubmed
    ..We here review the development of nilotinib and the efficacy data in phase II and front-line trials. ..
  52. Mullighan C, Downing J. Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions. Leukemia. 2009;23:1209-18 pubmed publisher
    ..Here, we review recent data obtained from genome-wide profiling studies in ALL, and discuss potential avenues for future investigation. ..
  53. Okabe S, Tauchi T, Ohyashiki K. Establishment of a new Philadelphia chromosome-positive acute lymphoblastic leukemia cell line (SK-9) with T315I mutation. Exp Hematol. 2010;38:765-72 pubmed publisher
    ..Although strategies to overcome resistance-mediated T315I mutation may improve the survival of BCR-ABL-positive leukemia patients, there is little information on cell-based studies...