Biology:Thymidine kinase in clinical chemistry

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Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21[1][2] that catalyzes the reaction: Thd + ATP → TMP + ADP

where Thd is (deoxy)thymidine, ATP is adenosine 5’-triphosphate, TMP is (deoxy)thymidine 5’-phosphate and ADP is adenosine 5’-diphosphate. In clinical chemistry it has been suggested as a proliferation marker for prognosis, verification of diagnosis, control of treatment (particularly as a companion diagnostic) and follow-up of malignant disease. It is used mainly in relation to hematological malignancies but the developments of more sensitive assays have stimulated investigations for its use in relation to solid tumors.

History

The incorporation of thymidine in DNA was demonstrated around 1950.[3] Somewhat later, it was shown that this incorporation was preceded by phosphorylation[4] and around 1960, the enzyme responsible was purified and characterized.[5][6] The potential use as a tumor marker was suggested by Gronowitz et al.[7]

Biochemistry

Mammals have two isoenzymes that are chemically very different, Thymidine Kinase 1 (TK1) and Thymidine Kinase 2 (TK2). The former was first found in fetal tissue, the second was found to be more abundant in adult tissue, and so initially they were termed fetal and adult thymidine kinases. Soon it was shown that TK1 is present in the cytoplasm only in anticipation of cell division (cell cycle-dependent)[8][9] whereas the presence of TK2, which is located in the mitochondria, is cell cycle-independent.[10][11] TK1 is synthesized by the cell during the S phase of cell division. After cell division is completed, TK1 is degraded intracellularly, so that it does not pass into body fluids after normal cell division.[12] The TK enzyme suggested as a tumor marker is the cytosolic cell cycle dependent TK1. It is present during cell division in much higher concentrations than TK2 and it is released in quantities that completely dominate the thymidine kinase activity in blood and other body fluids.

In addition to cellular TKs, virus specific thymidine kinases have been identified in Herpes simplex virus, Varicella zoster virus and Epstein-Barr virus.[13][14][15][16][17][18][19] They differ biochemically from thymidine kinase from mammalian cells and are inhibited by specific inhibitors that do not influence the activity of mammalian thymidine kinases. Determination of viral thymidine kinase has been suggested for confirmation of diagnosis and for control of treatment of viral infections.

2'-Desoxythymidin.svg + ATP ---> 2'-Desoxythymidinmonophosphat.svg + ADP

Thymidine reacts with ATP to give thymidine monophosphate and ADP.

Physiological context

Thymidine monophosphate, the product of the reaction catalyzed by thymidine kinase, is in turn phosphorylated to thymidine diphosphate by the enzyme thymidylate kinase and further to thymidine triphosphate by the enzyme nucleoside diphosphate kinase. The triphosphate is included in a DNA molecule, a reaction catalyzed by a DNA polymerase and a complementary DNA molecule (or an RNA molecule in the case of reverse transcriptase, an enzyme present in retrovirus). Thymidine monophosphate is produced by the cell in two different reactions - either by phosphorylation of thymidine as described above or by methylation of deoxyuridine monophosphate, a product of other metabolic pathways unrelated to thymidine, by the enzyme thymidylate synthase (De novo synthesis). This second route is used by the cell under normal conditions, and it is sufficient to supply thymidine monophosphate for DNA repair. When a cell prepares to divide, a complete new set-up of DNA is required, and the requirement for building blocks, including thymidine triphosphate, increases. Cells prepare for cell division by making some of the enzymes required during the division. They are not normally present in the cells and are down-regulated and degraded afterwards. Such enzymes are called salvage enzymes. Thymidine kinase 1 is such a salvage enzyme, whereas thymidine kinase 2 is not cell cycle-dependent.[20][21][22][23][24][25][26][27][28]

Thymidine kinase in serum

Background

Thymidine kinase is a salvage enzyme that is only present in anticipation of cell division. The enzyme is not set free from cells undergoing normal division where the cells have a special mechanism to degrade the proteins no longer needed after cell division is completed.[9] In normal subjects, the amount of thymidine kinase in serum or plasma is, therefore, very low. Tumor cells release enzyme to the circulation, probably in connection with the disruption of dead or dying tumor cells. The thymidine kinase level in serum, therefore, serves as a measure of malignant proliferation and, indirectly, as a measure of the aggressivity of the tumor. The form of enzyme present in the circulation does not correspond to the protein as encoded by the gene: the gene corresponds to a protein with molecular weight around 25 kD. It is a dimer with a molecular weight of around 50 kD, if activated by ATP a tetramer with molecular weight around 100 kD.[29] The main fraction of the active enzyme in the circulation has a molecular weight of 730 kD and is probably bound in a complex to other proteins.[30]

Measurement

Thymidine kinase 1 (TK1) levels in serum or plasma may be measured based on their enzymatic activity or in terms of mass using immunoassays. In enzyme activity assays, this is done by incubation of a serum sample with a substrate analogue. The oldest commercially available technique uses iodo-deoxyuridine (idoxuridine) wherein a methyl group in thymidine has been replaced with radioactive iodine.[31][32][33] This substrate is well accepted by the enzyme. The monophosphate of iodo deoxyuridine is adsorbed on aluminum oxide that is suspended in the incubation medium. After decantation and washing the radioactivity of the aluminum oxide gives a measure of the amount of thymidine kinase in the sample. Kits using this principle are commercially available from the companies Immunotech/Beckman and DiaSorin.

Idoxuridine

A non-radioactive assay method has been developed by the company Dia-Sorin. In this technique 3'-azido-2',3'-deoxythymidine (Zidovudine, AZT) is first phosphorylated to AZT 5'-monophosphate (AZTMP) by the TK1 in the sample. AZTMP is measured in an immunoassay with anti-AZTMP antibodies and AZTMP-labeled peroxidase. The assay runs in a closed system on the laboratory robot from DiaSorin.[34][35] The DiviTum assay from Biovica International uses another thymidine analogue, bromodeoxyuridine, as substrate to the enzyme. The product of the reaction is further phosphorylated to tri-phosphate and incorporated in DNA-strings of polythymidine. The polythymidine binds to strings of polyadenine coupled to the bottom of the wells in microtiter plates. There it is detected with an ELISA technique: The wells are filled with a solution of a monoclonal antibody to bromo-deoxyuridine. The monoclonal antibody has been bound (conjugated) to the enzyme alkaline phosphatase. After the unbound antibody-conjugate has been washed away, a solution of a substrate to the alkaline phosphatase, para-nitrophenylphosphate, is added. The product of the reaction, para-nitrophenol, is yellow at alkaline pH and can be measured by photometry.[36] This method has been evaluated against the previous radioactive technique. It is considerably more sensitive than the previous enzymatic methods and may be, therefore, more suitable for use with solid tumors where lower elevations of TK1 are found in body fluids. Comparisons of the methods have been published.[37][38] In the study by Nisman et al.,[37] while the Divitum was on the whole more sensitive than the Liaison method, the authors suggested that the Liaison method may have been more sensitive for the TK1 forms found in normal subjects. A continuous and homogeneous fluorescent method based on quenching technology has recently been published. This technique utilizes natural thymidine as substrate and can also determine deoxycytidine kinase simultaneously with TK1.[39]

Immunoassays enabling the direct determination of TK1 protein have now been developed.[40][41][42] Immunoassays have advantages over enzyme activity methods in that they can measure TK1 isoforms that are enzymatically inactive plus that they are unaffected by serum TK1 inhibitors.[41] The specific activity of serum TK1 differs between cancer types[43] and using an immunoassay method may aid in comparing TK1 levels between subjects and malignancy types. Due to the basic differences in assay methods, results obtained with TK1 activity assays and immunoassay may differ, e.g. an ELISA based on antibodies against the TK1 TK 210 epitope was shown to be twice as sensitive as a TK1 activity assay in distinguishing between healthy women and subjects with breast cancer[44]

Two immunoassays have been developed against the exposed ‘210’ epitope covering the C-terminal amino acid sequence 194-225,[45] a direct dot-blot assay with chemiluminescence end point[46] and a microtiter sandwich ELISA.[44] The dot-blot assay is a nitrocellulose membrane based assay with a chemiluminsecent substrate utilising a primary chicken IgY antibody and a secondary labeled anti-IgY antibody. In brief, the sample is spotted onto a nitrocellulose membrane where the proteins in the sample bind. After blocking, the membrane is incubated with a primary anti-TK1 antibody which binds to the TK1 on the membrane. After washing, a biotinylated second antibody directed against IgY antibodies is added followed by streptavidin labelled HRP and a chemiluminescent substrate. A microtiter ELISA based on monoclonal antibodies directed against the “210” epitope is available from AroCell. The AroCell TK 210 ELISA system uses a pre-treatment buffer to break up the high molecular weight TK1 complexes and expose the TK 210 epitope. The treated samples are added to a microtiter plate coated with anti TK 210 monoclonal antibodies. After incubating and washing, a second anti-TK 210 antibody labeled with biotin is added. After further washing, the color is developed with streptavidin labelled horse radish peroxidase with TMP as substrate.

A microchip electrophoresis immunoaffinity assay for determination of serum thymidine kinase concentration has been described. Its function was demonstrated using recombinant TK1. It is claimed to be fast and simple to perform.[47]

Serum thymidine kinase 1 in different malignancies

Hematologic malignancies

The most dramatic increases of serum TK1 are seen in hematologic malignancies. The increases seen in both TK1 activity and concentration are greater in hematologic malignancies compared with solid tumors.[43][48]

Non-Hodgkin lymphoma

The main use of serum TK1 activity assays is in non-Hodgkin lymphoma. This disease has a wide range of aggressivity, from slow-growing indolent disease that hardly requires treatment to highly aggressive, rapidly growing forms that should be treated urgently. This is reflected in the values of serum TK1 activity, that range from close to the normal range for slow-growing tumors to very high levels for rapidly growing forms.[7][49][50][51][52][53][54][55][56][57][58][59]

Leukemias

Leukemias normally do not normally present major diagnostic difficulties, as the microscopic analysis of the cells in blood usually provides unequivocal results. TK1 assays, however, may give supplementary information about the aggressivity and the risk for progression.[60][61][62][63][64][65][66][67]

Myeloma

Myelomas also often constitute a diagnostic challenge. The malignant cells are often not available for microscopic analysis, and the prognosis is often uncertain. Therefore, information on the prognosis may be essential in the decision of the treatment. Several studies verify the close connection between prognosis and thymidine kinase activity in myelomas.[38][68][69]

Myelodysplastic syndrome

A very interesting case is the myelodysplastic syndrome: some rapidly change to acute leukemia, whereas others remain indolent for very long time. Identification of those tending to change to overt leukemia is important for the treatment. A relationship between the prognosis and the serum TK1 values has been demonstrated in myelodysplastic syndrome .[70][71]

Solid tumors

Increased serum TK1 levels may be found in subjects with solid tumors. The increases in serum TK1 activity levels in subjects with solid tumors are not as large as they are for hematologic malignancies. The first methods for determination of serum TK1 activity had a limited sensitivity. In the case of the methods employing radioactivity, one reason was that the quantity of radioactivity allowed by law in normal radioimmunoassay laboratories is strictly limited. The experimental method first developed by Gronowitz et al.[31] used quantities of radioisotope much higher than those used in commercial radioassays and, therefore, the sensitivity was sufficient to detect increases in serum TK1 in subjects with solid tumors. With commercial radioassays this was difficult, and the results were not very convincing. Later, more sensitive, non-radioactive techniques enabled the lower increases from solid tumors to be measured accurately. The lower TK1 concentrations and lower TK1 specific activity found in solid tumors may make TK1 immunoassays more suitable.[46][44]

Lung cancer

Lung cancer is one of the commonest malignancies, both by incidence (about 15% for both men and women in USA and in Europe) and by mortality (25% for women and 30% for men). One major reason why the mortality is higher than the incidence is that lung cancer is mostly detected and diagnosed at a late stage. Early detection could reduce the mortality. Another reason is that lung cancer, particularly small cell lung cancer, is very aggressive with very low five-year survival rates.

There are several reports of the utility of TK1 activity measurements in serum in lung cancer.[72][73][74][75][76] For diagnosis, combination of TK1 immunoassay with other biomarkers may be especially valuable[77] while falls in TK1 concentration following therapy may provide prognostic information.[78]

Breast cancer

Breast cancer is the commonest cancer in women by incidence (about 25% of cancer cases in USA and Europe) and the second largest by mortality (about 15%). The reason for this difference is the advances during the last decennia in the treatment of breast cancer cases and, above all, the public awareness that has allowed earlier diagnosis. One contributing factor is the widespread use of mammography for early detection, self-examination is another.

Many tumor markers including TK1 are used for the follow-up and detection of recurrences in breast cancer patients.[37][79][80][81][82][83][84] Immunoassays may be more sensitive than enzyme activity assays for detecting the TK1 forms found in the serum of subjects with breast cancer.[44] For diagnosis, combination of TK1 assays with other biomarkers, e.g. CA 15-3, may be especially valuable.[44]

Prostate cancer

Among men, prostate cancer is by far the commonest cancer form, forming about 25% of the total cancer incidence among men in USA and Europe. The mortality is much lower than would be expected from the incidence, around 10% of the total cancer mortality of men in USA and Europe. A major reason for the lower mortality is that many prostate cancers grow slowly so that the patients do not die from this cancer but from other unrelated reasons.

In the management of prostate cancer, it is, therefore, very important to be able to discriminate between slowly and rapidly growing cancers. Thymidine kinase has been suggested as a supplement to PSA (prostate-specific antigen), the tumor marker most frequently used in prostate cancer. Whereas PSA is considered to give an indication of the tumor mass, thymidine kinase activity indicates the rate of proliferation and the markers thus supplement each other.[85][86][87][88]

Other solid tumors

TK1 elevations have also been reported in association with many types of solid tumors including kidney cancer,[89] bladder cancer,[90] gastric cancer,[91][92][93] liver cancer,[94] neurological cancers,[95] melanoma,[96] ovarian, cervical and esophageal cancers.[97]

Non-malignant elevations

There are several non-malignant causes for elevation of thymidine kinase in serum including vitamin B12 deficiency, leading to pernicious anemia[98][99] viral infections (particularly by virus from the herpes group) [100][101][99] and wound healing after trauma and operation.

Thymidine kinase in domestic animals

There are also reports of the use of thymidine kinase as a tumor marker in domestic animals, in horse,[102] in dogs[34][103][104][105][106][107] in cats[108] and in cows.[109] Elevations in dogs with bacterial infections have also been reported.[110]

Thymidine kinase in tissue

Thymidine kinase has been determined in tissue samples after extraction of the tissue and a relation between the results and disease progression has been shown. However, no standard method for the extraction or for the assay has been developed and TK determination in extracts from cells and tissues have not been validated in relation to any specific clinical question, see however Arnér et al.[111] Romain et al.[112] and Alegre et al.[113]

In the studies referred to below the methods used and the way the results are reported are so different that comparisons between different studies are not possible.

The TK1 levels in fetal tissues during development are higher than those of the corresponding tissues later.[114][115][116][117]

Certain non-malignant diseases also give rise to dramatic elevation of TK values in cells and tissue: in peripheral lymphocytes during monocytosis[118] and in bone marrow during pernicious anemia.[119][120] As TK1 is present in cells during cell division, it is reasonable to assume that the TK activity in malignant tissue should be higher than in corresponding normal tissue. This is also confirmed in most studies: a higher TK activity is found in neoplastic than in normal tissue,[115][121][122][123] in brain tumors,[124] in hematological malignancies,[125] in cancer and polyps in colon,[126][127][128][129][130][131] in breast cancer,[132][133][134][135][136][137] in lung cancer,[138][139][140] in gastric cancers,[141] in ovarian cancer,[142] in mesotheliomas,[143] in melanomas,[144] in thyroid tumors[145][146] in leukemia[147] and in breast cancer.[148]

Therapy that influences the rate of cell proliferation influences the TK values correspondingly. Although most studies do not show this, it seems probable that differences between samples from healthy tissue and samples from tumor tissue primarily represents changes in the levels of TK1, since this enzyme is much more strongly coupled to cell proliferation than TK2.

A method has been developed for specific determination of TK2 in cell extracts using the substrate analogue 5-Bromovinyl 2'-deoxyuridine.[117]

Uses of thymidine kinase determinations

Tumor markers may be used for the following purposes:

  • Screening either for specific cancers or generally for malignant growth. Broad screening for all or most types of cancer was early suggested[149][150] but has since been shown not to be a realistic goal. Screening for specific cancer types or locations requires a level of specificity and sensitivity that for tumor markers has so far only been reached by PSA.[151] Thymidine kinase neither reaches the clinical sensitivity nor the clinical specificity to be useful for screening purposes, see however Huang et al.,[152] Xiang et al.[153] and Cao et al.[154]
  • Monitoring of cancer survivors after treatment, detection of recurrent disease is the most common use of tumor markers including thymidine kinase, that is used as a standard methods for monitoring hematological disorders, particularly lymphoma, but is also studied for monitoring solid tumors.
  • Diagnosis of specific tumor types. The tumor types that are of interest for thymidine kinase are diagnosed by other techniques than measurement of tumor markers.
  • Confirmation of diagnosis to verify the characteristics such as size and aggressivity of a tumor and thereby to help in the evaluation of a suitable treatment schedule has been verified as a suitable application of thymidine kinase determination for several types of tumors. Thymidine kinase has been confirmed as a valuable tool to verify the aggressivity of both hematologic tumors (particularly non-Hodgkin's lymphoma) and prostate carcinoma.
  • Staging: thymidine kinase has been suggested for inclusion in the staging criteria for non-Hodgkin's lymphoma [63]
  • Prognosis: thymidine kinase has been shown to be an important prognostic parameter particularly in hematologic malignancies (lymphoma and leukemia).
  • Verification of the effect of treatment is an important use of thymidine kinase. As this tumor marker reacts to the activity of the tumor rather than to the tumor mass it gives a very early indication of the effect of the treatment.
  • A companion diagnostic is used to verify if the treatment is suited for the type or subtype of tumor particularly in personalized medicine. The strong coupling of TK1 expression to the cell cycle provides a special rationale for investigating thymidine kinase as marker of effect of inhibitors to cyclin-dependent kinases. These inhibitor compounds constitute promising new cancer therapies. Cyclin-dependent kinases promote transition through the cell cycle and cyclin-dependent kinase inhibitors are intended to stop the transition to the S phase of the cell cycle, where thymidine kinase is synthesized. Serum TK-activity is therefore now included as a biomarker in clinical trials of these inhibitor compounds.[155]

See also

Further reading

References

  1. ↑ "Thymidine kinase". Microbiol. Sci. 2 (12): 369–75. 1985. PMID 3939993. 
  2. ↑ "Regulation and biological function of thymidine kinase". Biochem. Soc. Trans. 25 (1): 303–8. 1997. doi:10.1042/bst0250303. PMID 9056888. 
  3. ↑ "Utilization of desoxyribosides in the synthesis of polynucleotides". J. Biol. Chem. 188 (2): 839–46. 1951. doi:10.1016/S0021-9258(19)77758-8. PMID 14824173. 
  4. ↑ "Enzymic synthesis of deoxyribonucleic acid". Biochim. Biophys. Acta 21 (1): 197–8. 1956. doi:10.1016/0006-3002(56)90127-5. PMID 13363894. 
  5. ↑ "Incorporation of thymidine into deoxyribonucleic acid by enzymes from rat tissues". J. Biol. Chem. 233 (2): 478–82. 1958. doi:10.1016/S0021-9258(18)64787-8. PMID 13563524. 
  6. ↑ "Studies on the biosynthesis of deoxyribonucleic acid by extracts of mammalian cells. IV. The phosphorylation of thymidine". Biochim. Biophys. Acta 45: 101–10. 1960. doi:10.1016/0006-3002(60)91430-x. PMID 13784139. 
  7. ↑ 7.0 7.1 "The use of serum deoxythymidine kinase as a prognostic marker, and in the monitoring of patients with non-Hodgkin's lymphoma". Br. J. Cancer 47 (4): 487–95. 1983. doi:10.1038/bjc.1983.78. PMID 6849793. 
  8. ↑ "Sequence and evolutionary relationships of African swine fever virus thymidine kinase". Virology 178 (1): 301–4. 1990. doi:10.1016/0042-6822(90)90409-k. PMID 2389555. 
  9. ↑ 9.0 9.1 "The periodic synthesis of thymidine kinase in mouse fibroblasts". Biochim. Biophys. Acta 114 (2): 398–403. 1966. doi:10.1016/0005-2787(66)90319-4. PMID 4223355. 
  10. ↑ "A genetically distinct thymidine kinase in mammalian mitochondria. Exclusive labeling of mitochondrial deoxyribonucleic acid". J. Biol. Chem. 248 (8): 2722–9. 1973. doi:10.1016/S0021-9258(19)44066-0. PMID 4735344. 
  11. ↑ "Mitochondrial-specific thymidine kinase". Arch. Biochem. Biophys. 154 (2): 563–5. 1973. doi:10.1016/0003-9861(73)90009-x. PMID 4632422. 
  12. ↑ "Effect of C-terminal of human cytosolic thymidine kinase (TK1) on in vitro stability and enzymatic properties". Nucleosides Nucleotides Nucleic Acids 25 (9–11): 1185–8. 2006. doi:10.1080/15257770600894436. PMID 17065087. 
  13. ↑ "Acquisition of thymidine kinase activity by herpes simplex-infected mouse fibroblast cells". Biochem. Biophys. Res. Commun. 11: 55–9. 1963. doi:10.1016/0006-291x(63)90027-5. PMID 14033128. 
  14. ↑ "The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene". Nucleic Acids Res. 8 (24): 5949–64. 1980. doi:10.1093/nar/8.24.5949. PMID 6258156. 
  15. ↑ "Mapping of the thymidine kinase genes of type 1 and type 2 herpes simplex viruses using intertypic recombinants". J. Gen. Virol. 49 (2): 235–53. 1980. doi:10.1099/0022-1317-49-2-235. PMID 6255066. 
  16. ↑ "Location and cloning of the herpes simplex virus type 2 thymidine kinase gene". J. Virol. 33 (3): 1221–4. 1980. doi:10.1128/JVI.33.3.1221-1224.1980. PMID 6245273. 
  17. ↑ "Nucleotide sequence of the herpes simplex virus type 2 (HSV-2) thymidine kinase gene and predicted amino acid sequence of thymidine kinase polypeptide and its comparison with the HSV-1 thymidine kinase gene". Biochim. Biophys. Acta 741 (2): 158–70. 1983. doi:10.1016/0167-4781(83)90056-8. PMID 6317035. 
  18. ↑ "Mapping of the varicella zoster virus deoxypyrimidine kinase gene and preliminary identification of its transcript". Virology 149 (1): 1–9. 1986. doi:10.1016/0042-6822(86)90081-4. PMID 3004022. https://zenodo.org/record/1258274. 
  19. ↑ "Identification of an Epstein-Barr virus-coded thymidine kinase". EMBO J. 5 (8): 1959–66. 1986. doi:10.1002/j.1460-2075.1986.tb04450.x. PMID 3019675. 
  20. ↑ "Cell cycle-dependent regulation of thymidine kinase activity introduced into mouse LMTK- cells by DNA and chromatin-mediated gene transfer". Proc. Natl. Acad. Sci. U.S.A. 78 (2): 1119–23. 1981. doi:10.1073/pnas.78.2.1119. PMID 6940130. Bibcode: 1981PNAS...78.1119S. 
  21. ↑ "Control of thymidine kinase mRNA during the cell cycle". Mol. Cell. Biol. 7 (8): 2925–32. 1987. doi:10.1128/MCB.7.8.2925. PMID 3670299. 
  22. ↑ "Evidence for transcriptional and post-transcriptional control of the cellular thymidine kinase gene". Mol. Cell. Biol. 7 (3): 1156–63. 1987. doi:10.1128/MCB.7.3.1156. PMID 3561412. 
  23. ↑ "The activities of thymidine metabolising enzymes during the cell cycle of a human lymphocyte cell line LAZ-007 synchronised by centrifugal elutriation". Biochim. Biophys. Acta 633 (3): 400–9. 1980. doi:10.1016/0304-4165(80)90198-1. PMID 6260157. 
  24. ↑ "Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cell fractions enriched according to cell cycle stages by way of centrifugal elutriation". Leukemia 1 (3): 182–7. 1987. PMID 3669741. 
  25. ↑ "Regulation of human thymidine kinase during the cell cycle". J. Biol. Chem. 263 (17): 8350–8. 1988. doi:10.1016/S0021-9258(18)68484-4. PMID 3372530. 
  26. ↑ "The chicken thymidine kinase gene is transcriptionally repressed during terminal differentiation: the associated decline in TK mRNA cannot account fully for the disappearance of TK enzyme activity". Dev. Biol. 122 (2): 439–51. 1987. doi:10.1016/0012-1606(87)90308-3. PMID 3596017. 
  27. ↑ "Cell cycle regulation of thymidine kinase: residues near the carboxyl terminus are essential for the specific degradation of the enzyme at mitosis". Mol. Cell. Biol. 11 (5): 2538–46. 1991. doi:10.1128/MCB.11.5.2538. PMID 1708095. 
  28. ↑ "Carboxy-terminal residues of mouse thymidine kinase are essential for rapid degradation in quiescent cells". J. Mol. Biol. 259 (3): 383–92. 1996. doi:10.1006/jmbi.1996.0327. PMID 8676376. 
  29. ↑ "Structures of thymidine kinase 1 of human and mycoplasmic origin". Proc. Natl. Acad. Sci. U.S.A. 101 (52): 17970–5. 2004. doi:10.1073/pnas.0406332102. PMID 15611477. Bibcode: 2004PNAS..10117970W. 
  30. ↑ "Molecular forms in human serum of enzymes synthesizing DNA precursors and DNA". Mol. Cell. Biochem. 92 (1): 23–35. 1990. doi:10.1007/BF00220716. PMID 2155379. 
  31. ↑ 31.0 31.1 "Optimized assay for thymidine kinase and its application to the detection of antibodies against herpes simplex virus type 1- and 2-induced thymidine kinase". Infection and Immunity 29 (2): 425–34. 1980. doi:10.1128/iai.29.2.425-434.1980. PMID 6260651. 
  32. ↑ "Application of an in vitro assay for serum thymidine kinase: results on viral disease and malignancies in humans". International Journal of Cancer 33 (1): 5–12. 1984. doi:10.1002/ijc.2910330103. PMID 6693195. 
  33. ↑ "A sensitive assay for detection of deoxythymidine kinase and its application to herpesvirus diagnosis". Current Topics in Microbiology and Immunology 104: 235–45. 1983. doi:10.1007/978-3-642-68949-9_14. ISBN 978-3-642-68951-2. PMID 6307593. 
  34. ↑ 34.0 34.1 "A non-radiometric method for measuring serum thymidine kinase activity in malignant lymphoma in dogs". Research in Veterinary Science 80 (1): 17–24. 2006. doi:10.1016/j.rvsc.2005.05.001. PMID 16140350. 
  35. ↑ "Sensitive nonradiometric method for determining thymidine kinase 1 activity". Clinical Chemistry 50 (9): 1597–606. 2004. doi:10.1373/clinchem.2003.030379. PMID 15247154. 
  36. ↑ Gronowitz JS, "A method and kit for determination of thymidine kinase activity and use thereof", WO patent application 2006000246, published 2006-02-24
  37. ↑ 37.0 37.1 37.2 "Comparison of diagnostic and prognostic performance of two assays measuring thymidine kinase 1 activity in serum of breast cancer patients". Clin. Chem. Lab. Med. 51 (2): 439–47. 2013. doi:10.1515/cclm-2012-0162. PMID 23093267. 
  38. ↑ 38.0 38.1 "Analysis of thymidine kinase serum levels by novel method DiviTum in multiple myeloma and monoclonal gammopathy of undetermined significance - comparison with imaging methods 99mTc-MIBI scintigraphy and 18F-FDG PET/CT". Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia 159 (1): 135–8. 2015. doi:10.5507/bp.2014.008. PMID 24572488. 
  39. ↑ "Homogeneous assay for real-time and simultaneous detection of thymidine kinase 1 and deoxycytidine kinase activities". Anal. Biochem. 432 (2): 155–64. 2013. doi:10.1016/j.ab.2012.08.004. PMID 22902741. 
  40. ↑ Alegre, MM; Weyant, MJ; Bennett, DT; Yu, JA; Ramsden, MK; Elnaggar, A; Robison, RA; O'Neill, KL (May 2014). "Serum detection of thymidine kinase 1 as a means of early detection of lung cancer.". Anticancer Research 34 (5): 2145–51. PMID 24778016. 
  41. ↑ 41.0 41.1 He, Q; Zhang, P; Zou, L; Li, H; Wang, X; Zhou, S; Fornander, T; Skog, S (October 2005). "Concentration of thymidine kinase 1 in serum (S-TK1) is a more sensitive proliferation marker in human solid tumors than its activity.". Oncology Reports 14 (4): 1013–9. PMID 16142366. 
  42. ↑ Jagarlamudi, KK; Hansson, LO; Eriksson, S (18 February 2015). "Breast and prostate cancer patients differ significantly in their serum Thymidine kinase 1 (TK1) specific activities compared with those hematological malignancies and blood donors: implications of using serum TK1 as a biomarker.". BMC Cancer 15: 66. doi:10.1186/s12885-015-1073-8. PMID 25881026. 
  43. ↑ 43.0 43.1 "Breast and prostate cancer patients differ significantly in their serum Thymidine kinase 1 (TK1) specific activities compared with those hematological malignancies and blood donors: implications of using serum TK1 as a biomarker". BMC Cancer 15: 66. 2015. doi:10.1186/s12885-015-1073-8. PMID 25881026. 
  44. ↑ 44.0 44.1 44.2 44.3 44.4 Kumar, JK; Aronsson, AC; Pilko, G; Zupan, M; Kumer, K; Fabjan, T; Osredkar, J; Eriksson, S (September 2016). "A clinical evaluation of the TK 210 ELISA in sera from breast cancer patients demonstrates high sensitivity and specificity in all stages of disease.". Tumour Biology 37 (9): 11937–11945. doi:10.1007/s13277-016-5024-z. PMID 27079872. 
  45. ↑ He, Q; Skog, S; Wang, N; Eriksson, S; Tribukait, B (June 1996). "Characterization of a peptide antibody against a C-terminal part of human and mouse cytosolic thymidine kinase, which is a marker for cell proliferation.". European Journal of Cell Biology 70 (2): 117–24. PMID 8793383. 
  46. ↑ 46.0 46.1 "The clinical significance of thymidine kinase 1 measurement in serum of breast cancer patients using anti-TK1 antibody". The International Journal of Biological Markers 15 (2): 139–46. 2000. doi:10.1177/172460080001500203. PMID 10883887. 
  47. ↑ "Microchip immunoaffinity electrophoresis of antibody-thymidine kinase 1 complex". Electrophoresis 36 (5): 813–7. 2015. doi:10.1002/elps.201400436. PMID 25486911. 
  48. ↑ "Serum deoxythymidine kinase as a progressive marker of hematological malignancy". Nagoya J Med Sci 52 (1–4): 19–26. 1990. PMID 2381458. 
  49. ↑ "Thymidine kinase isoenzymes in human malignant lymphoma". Cancer Res. 41 (2): 691–5. 1981. PMID 7448815. 
  50. ↑ "Biochemical markers in non-Hodgkin's lymphoma stages III and IV and prognosis: a multivariate analysis". Scand J Haematol 33 (1): 59–67. 1984. doi:10.1111/j.1600-0609.1984.tb02211.x. PMID 6379852. 
  51. ↑ "Thymidine kinase: a tumor marker with prognostic value for non-Hodgkin's lymphoma and a broad range of potential clinical applications". Ann. Hematol. 65 (1): 1–5. 1992. doi:10.1007/bf01715117. PMID 1643153. 
  52. ↑ "Thymidine kinase (TK) activity as a prognostic parameter of survival in lymphoma patients". J. Biol. Regul. Homeost. Agents 8 (4): 121–5. 1994. PMID 7660854. 
  53. ↑ "Deoxythymidine kinase in the tumor cells and serum of patients with non-Hodgkin lymphomas". Br. J. Cancer 71 (5): 1099–105. 1995. doi:10.1038/bjc.1995.213. PMID 7734308. 
  54. ↑ "Risk classification for large cell lymphoma using lactate dehydrogenase, beta-2 microglobulin, and thymidine kinase". Leukemia & Lymphoma 18 (1–2): 87–92. 1995. doi:10.3109/10428199509064927. PMID 8580834. 
  55. ↑ "High thymidine kinase activity is a strong predictive factor for poor prognosis in peripheral T-cell lymphoma treated with cyclophosphamide, adriamycin, vincristine and prednisone". Leukemia & Lymphoma 53 (5): 849–54. 2012. doi:10.3109/10428194.2011.635858. PMID 22035416. 
  56. ↑ "High baseline serum thymidine kinase 1 level predicts unfavorable outcome in patients with follicular lymphoma". Leukemia & Lymphoma 53 (7): 1306–10. 2012. doi:10.3109/10428194.2011.654339. PMID 22263569. 
  57. ↑ "Prognostic value of high thymidine kinase activity in patients with previously untreated diffuse large B-cell lymphoma treated by rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone". Leukemia & Lymphoma 54 (11): 2412–7. 2013. doi:10.3109/10428194.2013.779690. PMID 23488601. 
  58. ↑ "Predictors of the necessity for lymph node biopsy of cervical lymphadenopathy". J Craniomaxillofac Surg 43 (10): 2200–4. 2015. doi:10.1016/j.jcms.2015.09.010. PMID 26545929. 
  59. ↑ "Thymidine kinase levels correlate with prognosis in aggressive lymphoma and can discriminate patients with a clinical suspicion of indolent to aggressive transformation". Anticancer Research 35 (5): 3019–26. 2015. PMID 25964590. 
  60. ↑ "Serum deoxythymidine kinase gives prognostic information in chronic lymphocytic leukemia". Cancer 54 (11): 2450–5. 1984. doi:10.1002/1097-0142(19841201)54:11<2450::aid-cncr2820541123>3.0.co;2-r. PMID 6498737. 
  61. ↑ "Serum deoxythymidine kinase correlates with peripheral lymphocyte thymidine uptake in chronic lymphocytic leukemia". Eur. J. Haematol. 38 (4): 331–7. 1987. doi:10.1111/j.1600-0609.1987.tb00007.x. PMID 3609253. 
  62. ↑ "Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma". Leukemia & Lymphoma 22 (5–6): 439–47. 1996. doi:10.3109/10428199609054782. PMID 8882957. 
  63. ↑ 63.0 63.1 "Identifying the stage of new CLL patients using TK, ZAP-70, CD38 levels". Experimental Oncology 33 (2): 99–103. 2011. PMID 21716207. 
  64. ↑ "Predicting survival in chronic lymphocytic leukemia". Expert Review of Anticancer Therapy 12 (3): 393–403. 2012. doi:10.1586/era.12.2. PMID 22369330. 
  65. ↑ "Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia". Blood 124 (1): 49–62. 2014. doi:10.1182/blood-2014-02-556399. PMID 24797299. 
  66. ↑ "Clinical significance of thymidine kinase in Egyptian children with acute lymphoblastic leukemia". South Asian Journal of Cancer 4 (2): 72–4. 2015. doi:10.4103/2278-330X.155675. PMID 25992345. 
  67. ↑ "Thymidine Kinase: A Biomarker for Recently Diagnosed Acute Leukemia in Pediatric Patients According to the Cell Line Involved". Arch. Med. Res. 46 (8): 630–4. 2015. doi:10.1016/j.arcmed.2015.11.005. PMID 26656666. 
  68. ↑ "Evaluation of serum deoxythymidine kinase as a marker in multiple myeloma". British Journal of Haematology 61 (2): 215–24. 1985. doi:10.1111/j.1365-2141.1985.tb02820.x. PMID 4041368. 
  69. ↑ "Biochemical markers in multiple myeloma: a multivariate analysis". British Journal of Haematology 69 (1): 47–53. 1988. doi:10.1111/j.1365-2141.1988.tb07601.x. PMID 3289607. 
  70. ↑ "Prognostic relevance of serum thymidine kinase in primary myelodysplastic syndromes: relationship to development of acute myeloid leukaemia". British Journal of Haematology 90 (1): 125–30. 1995. doi:10.1111/j.1365-2141.1995.tb03390.x. PMID 7786774. 
  71. ↑ "[The prognostic significance of serum thymidine kinase in the myelodysplastic syndrome]" (in de). Deutsche Medizinische Wochenschrift 121 (37): 1113–8. 1996. doi:10.1055/s-2008-1043114. PMID 8925725. 
  72. ↑ "Serum deoxythymidine kinase in small cell carcinoma of the lung. Relation to clinical features, prognosis, and other biochemical markers". Cancer 58 (1): 111–8. 1986. doi:10.1002/1097-0142(19860701)58:1<111::aid-cncr2820580120>3.0.co;2-k. PMID 3011236. 
  73. ↑ "Clinical and serologic markers of stage and prognosis in small cell lung cancer. A multivariate analysis". Cancer 66 (4): 722–32. 1990. doi:10.1002/1097-0142(19900815)66:4<722::aid-cncr2820660421>3.0.co;2-j. PMID 2167141. 
  74. ↑ "Serum thymidine kinase 1 levels correlates with FDG uptake and prognosis in patients with non small cell lung cancer". Biomarkers 18 (1): 88–94. 2013. doi:10.3109/1354750X.2012.738250. PMID 23116493. 
  75. ↑ "Serum thymidine kinase 1 activity in the prognosis and monitoring of chemotherapy in lung cancer patients: a brief report". Journal of Thoracic Oncology 9 (10): 1568–72. 2014. doi:10.1097/JTO.0000000000000276. PMID 25521401. 
  76. ↑ "Serum detection of thymidine kinase 1 as a means of early detection of lung cancer". Anticancer Research 34 (5): 2145–51. 2014. PMID 24778016. 
  77. ↑ Jiang, ZF; Wang, M; Xu, JL (1 February 2018). "Thymidine kinase 1 combined with CEA, CYFRA21-1 and NSE improved its diagnostic value for lung cancer.". Life Sciences 194: 1–6. doi:10.1016/j.lfs.2017.12.020. PMID 29247745. 
  78. ↑ Lou, X; Zhou, J; Ma, H; Xu, S; He, E; Skog, S; Wang, H (August 2017). "The Half-Life of Serum Thymidine Kinase 1 Concentration Is an Important Tool for Monitoring Surgical Response in Patients with Lung Cancer: A Meta-Analysis.". Genetic Testing and Molecular Biomarkers 21 (8): 471–478. doi:10.1089/gtmb.2017.0003. PMID 28817340. 
  79. ↑ "Serum thymidine kinase 1 levels predict cancer-free survival following neoadjuvant, surgical and adjuvant treatment of patients with locally advanced breast cancer". Molecular and Clinical Oncology 1 (5): 894–902. 2013. doi:10.3892/mco.2013.149. PMID 24649267. 
  80. ↑ "Serum thymidine kinase 1 activity in breast cancer". Cancer Biomarkers 7 (2): 65–72. 2010. doi:10.3233/CBM-2010-0148. PMID 21178264. 
  81. ↑ "Elevated thymidine kinase 1 in serum following neoadjuvant chemotherapy predicts poor outcome for patients with locally advanced breast cancer". Experimental and Therapeutic Medicine 3 (2): 331–335. 2012. doi:10.3892/etm.2011.395. PMID 22969891. 
  82. ↑ "Increased proliferative background in healthy women with BRCA1/2 haploinsufficiency is associated with high risk for breast cancer". Cancer Epidemiol. Biomarkers Prev. 22 (11): 2110–5. 2013. doi:10.1158/1055-9965.EPI-13-0193. PMID 23966579. 
  83. ↑ "Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial". Breast Cancer Research and Treatment 139 (3): 751–8. 2013. doi:10.1007/s10549-013-2579-x. PMID 23736998. 
  84. ↑ "Serum thymidine kinase 1 activity in solid tumor (breast and colorectal cancer) patients treated with adjuvant chemotherapy". Journal of Clinical Laboratory Analysis 27 (3): 220–6. 2013. doi:10.1002/jcla.21587. PMID 23686779. 
  85. ↑ "Prostate specific acid phosphatase versus five other possible tumor markers: a comparative study in men with prostatic carcinoma". Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum 179: 81–8. 1985. PMID 2417306. 
  86. ↑ "Tumour markers as prognostic aids in prostatic carcinoma". British Journal of Urology 66 (2): 182–7. 1990. doi:10.1111/j.1464-410x.1990.tb14900.x. PMID 1697204. 
  87. ↑ "Serum tumour markers in human prostatic carcinoma. The value of a marker panel for prognostic information". Acta Oncol 30 (2): 173–5. 1991. doi:10.3109/02841869109092345. PMID 2029401. 
  88. ↑ "Deoxythymidine kinase in the staging of prostatic adenocarcinoma". The Prostate 29 (1): 15–9. 1996. doi:10.1002/(SICI)1097-0045(199607)29:1<15::AID-PROS2>3.0.CO;2-H. PMID 8685050. 
  89. ↑ "Circulating tumor M2 pyruvate kinase and thymidine kinase 1 are potential predictors for disease recurrence in renal cell carcinoma after nephrectomy". Urology 76 (2): 513.e1–6. 2010. doi:10.1016/j.urology.2010.04.034. PMID 20573390. 
  90. ↑ "Muscle-invasive bladder cancer is characterized by overexpression of thymidine kinase 1". Urologic Oncology 33 (10): 426.e21–9. 2015. doi:10.1016/j.urolonc.2015.06.007. PMID 26231311. 
  91. ↑ Liu, Y; Ling, Y; Qi, Q; Tang, Y; Xu, J; Tong, Z; Sheng, G; Yang, Q et al. (November 2011). "Changes in serum thymidine kinase 1 levels during chemotherapy correlate with objective response in patients with advanced gastric cancer.". Experimental and Therapeutic Medicine 2 (6): 1177–1181. doi:10.3892/etm.2011.338. PMID 22977640. 
  92. ↑ "Changes in serum thymidine kinase 1 levels during chemotherapy correlate with objective response in patients with advanced gastric cancer". Experimental and Therapeutic Medicine 2 (6): 1177–1181. 2011. doi:10.3892/etm.2011.338. PMID 22977640. 
  93. ↑ "Serum thymidine kinase 1 levels correlate with clinical characteristics of esophageal squamous cell carcinoma". Int J Clin Exp Med 8 (8): 12850–7. 2015. PMID 26550200. 
  94. ↑ "Evaluation of the diagnostic value of alpha-l-fucosidase, alpha-fetoprotein and thymidine kinase 1 with ROC and logistic regression for hepatocellular carcinoma". FEBS Open Bio 5: 240–4. 2015. doi:10.1016/j.fob.2015.03.010. PMID 25870783. 
  95. ↑ "Protein expression of BIRC5, TK1, and TOP2A in malignant peripheral nerve sheath tumours--A prognostic test after surgical resection". Molecular Oncology 9 (6): 1129–39. 2015. doi:10.1016/j.molonc.2015.02.005. PMID 25769404. 
  96. ↑ "Increased serum level of thymidine kinase 1 correlates with metastatic site in patients with malignant melanoma". Tumour Biology 34 (2): 643–8. 2013. doi:10.1007/s13277-012-0591-0. PMID 23179401. 
  97. ↑ Wang, Y; Jiang, X; Dong, S; Shen, J; Yu, H; Zhou, J; Li, J; Ma, H et al. (11 March 2016). "Serum TK1 is a more reliable marker than CEA and AFP for cancer screening in a study of 56,286 people.". Cancer Biomarkers 16 (4): 529–36. doi:10.3233/CBM-160594. PMID 27002755. 
  98. ↑ "Expression of fetal thymidine kinase in human cobalamin or folate deficient lymphocytes". Biochemical and Biophysical Research Communications 89 (1): 103–7. 1979. doi:10.1016/0006-291x(79)90949-5. PMID 475797. 
  99. ↑ 99.0 99.1 "Detection and characteristics of DNA polymerase activity in serum from patients with malignant, viral, or B12-deficiency disease". Enzyme 41 (1): 6–16. 1989. doi:10.1159/000469045. PMID 2543552. 
  100. ↑ "Rapid diagnosis of varicella-zoster virus infection by detection of viral deoxythymidine kinase in serum and vesicle fluid". Journal of Clinical Microbiology 17 (2): 280–7. 1983. doi:10.1128/JCM.17.2.280-287.1983. PMID 6339548. 
  101. ↑ "Serum thymidine-kinase and cytomegalovirus-specific antibodies after renal transplantation". Transplantation Proceedings 20 (3): 405–7. 1988. PMID 2837850. 
  102. ↑ "Serum thymidine kinase activity in clinically healthy and diseased horses: a potential marker for lymphoma". Veterinary Journal 205 (2): 313–6. 2015. doi:10.1016/j.tvjl.2015.01.019. PMID 25744802. 
  103. ↑ "Serum thymidine kinase activity in dogs with malignant lymphoma: a potent marker for prognosis and monitoring the disease". Journal of Veterinary Internal Medicine 18 (5): 696–702. 2004. doi:10.1111/j.1939-1676.2004.tb02608.x. PMID 15515587. 
  104. ↑ "Properties of cellular and serum forms of thymidine kinase 1 (TK1) in dogs with acute lymphocytic leukemia (ALL) and canine mammary tumors (CMTs): implications for TK1 as a proliferation biomarker". BMC Veterinary Research 10: 228. 2014. doi:10.1186/s12917-014-0228-1. PMID 25293656. 
  105. ↑ "Serum thymidine kinase 1 and C-reactive protein as biomarkers for screening clinically healthy dogs for occult disease". Veterinary and Comparative Oncology 13 (4): 373–84. 2015. doi:10.1111/vco.12052. PMID 23859156. https://researchrepository.murdoch.edu.au/id/eprint/53494/. 
  106. ↑ "Thymidine kinase assay in canine lymphoma". Veterinary and Comparative Oncology 11 (1): 1–13. 2013. doi:10.1111/j.1476-5829.2011.00296.x. PMID 22236202. 
  107. ↑ "A New Sandwich ELISA for Quantification of Thymidine Kinase 1 Protein Levels in Sera from Dogs with Different Malignancies Can Aid in Disease Management". PLOS ONE 10 (9): e0137871. 2015. doi:10.1371/journal.pone.0137871. PMID 26366881. Bibcode: 2015PLoSO..1037871J. 
  108. ↑ "Serum thymidine kinase activity in clinically healthy and diseased cats: a potential biomarker for lymphoma". Journal of Feline Medicine and Surgery 15 (2): 142–7. 2013. doi:10.1177/1098612X12463928. PMID 23076596. 
  109. ↑ "Utility of serum thymidine kinase activity measurements for cases of bovine leukosis with difficult clinical diagnoses". The Journal of Veterinary Medical Science 75 (9): 1167–72. 2013. doi:10.1292/jvms.12-0572. PMID 23628971. 
  110. ↑ "Elevation of serum thymidine kinase 1 in a bacterial infection: canine pyometra". Theriogenology 79 (1): 17–23. 2013. doi:10.1016/j.theriogenology.2012.09.002. PMID 23102844. 
  111. ↑ "Selective assays for thymidine kinase 1 and 2 and deoxycytidine kinase and their activities in extracts from human cells and tissues". Biochemical and Biophysical Research Communications 188 (2): 712–8. 1992. doi:10.1016/0006-291x(92)91114-6. PMID 1359886. 
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  113. ↑ "Thymidine kinase 1 upregulation is an early event in breast tumor formation". J Oncol 2012: 1–5. 2012. doi:10.1155/2012/575647. PMID 22778736. 
  114. ↑ "Thymidine kinase in rat tissues during growth and differentiation". Biochimica et Biophysica Acta (BBA) - General Subjects 286 (2): 375–81. 1972. doi:10.1016/0304-4165(72)90273-5. PMID 4660462. 
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  124. ↑ "Thymidine kinase in extracts of human brain tumours". Acta Neurochirurgica 80 (3–4): 123–7. 1986. doi:10.1007/bf01812286. PMID 3012969. 
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  131. ↑ "Thymidine kinase activity in familial adenomatous polyposis". The Tohoku Journal of Experimental Medicine 168 (2): 291–301. 1992. doi:10.1620/tjem.168.291. PMID 1339104. 
  132. ↑ "Increased activities of thymidine kinase isozymes in human mammary tumours". The British Journal of Surgery 73 (4): 272–3. 1986. doi:10.1002/bjs.1800730409. PMID 3697655. 
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  146. ↑ "TPS, thymidine kinase, VEGF and endostatin in cytosol of thyroid tissue samples". Anticancer Research 25 (3A): 1517–21. 2005. PMID 16033053. 
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