TKTL1 RESEARCH

From Evolution to Early Detection

From its role in the evolution of modern humans to its importance in the treatment of cancer and viral diseases: Researchers from around the world are documenting the relevance of the transketolase-like-1 gene in an increasing number of studies. Most recently, the Swedish physician and biologist Prof. Dr. Svante Pääbo, who conducts research in Germany, caused quite a stir when he was awarded the Nobel Prize for Medicine for his research on the genome of the Neanderthal man. In the process, his team and he discovered the relevance of the TKTL1 gene for the development of modern humans.

They were able to show that modern humans have a higher density of neurons in certain brain regions compared to Neanderthals. The researchers found that a variant of the protein TKTL1, which in modern humans differs from the Neanderthal version by only a single amino acid, plays a crucial role in the formation of neurons in the brain. This mutation is responsible for the increased neuron formation in the developing frontal lobe of the neocortex of modern humans.

From Evolution to Early Detection

From its role in the evolution of modern humans to its importance in the treatment of cancer and viral diseases: Researchers from around the world are documenting the relevance of the transketolase-like-1 gene in an increasing number of studies. Most recently, the Swedish physician and biologist Prof. Dr. Svante Pääbo, who conducts research in Germany, caused quite a stir when he was awarded the Nobel Prize for Medicine for his research on the genome of the Neanderthal man. In the process, his team and he discovered the relevance of the TKTL1 gene for the development of modern humans.

They were able to show that modern humans have a higher density of neurons in certain brain regions compared to Neanderthals. The researchers found that a variant of the protein TKTL1, which in modern humans differs from the Neanderthal version by only a single amino acid, plays a crucial role in the formation of neurons in the brain. This mutation is responsible for the increased neuron formation in the developing frontal lobe of the neocortex of modern humans.

Key Role in Cell Division

Moreover, in 2019, it was proven that TKTL1 plays a crucial role in the cell division process (cell duplication). The previously held view that increased consumption of ribose-5-phophate during cell doubling triggers replenishment of the same, thus “pulling” the cell into doubling (the so-called “pull-effect”) could be refuted. In fact, TKTL1 is expressed first, a heterodimer of TKTL1 and TKT is formed, and this leads to an increase in the concentration of ribose-5-phosphate, which ultimately pushes the cell into doubling – the so-called “push effect”.

Key Role in Cell Division

Moreover, in 2019, it was proven that TKTL1 plays a crucial role in the cell division process (cell duplication). The previously held view that increased consumption of ribose-5-phophate during cell doubling triggers replenishment of the same, thus “pulling” the cell into doubling (the so-called “pull-effect”) could be refuted. In fact, TKTL1 is expressed first, a heterodimer of TKTL1 and TKT is formed, and this leads to an increase in the concentration of ribose-5-phosphate, which ultimately pushes the cell into doubling – the so-called “push effect”.

Sie konnten zeigen, dass der moderne Mensch im Vergleich zu Neandertalern eine höhere Dichte an Neuronen in bestimmten Gehirnregionen aufweist. Die Forscher haben herausgefunden, dass eine Variante des Proteins TKTL1, die sich bei modernen Menschen nur um eine einzige Aminosäure von der Neandertaler-Version unterscheidet, eine entscheidende Rolle bei der Bildung von Nervenzellen im Gehirn spielt. Dies führt zu einer vermehrten Bildung von Nervenzellen im sich entwickelnden Frontallappen des Neokortex von modernen Menschen.

Pioneering Studies

In 2019 and 2022, studies were published in the journals Nature and Science which examplify the importance of TKTL1 to us humans, our evolutionary history, and our health:

APC/CCDH1 synchronizes ribose-5-phosphate levels and DNA synthesis to cell cycle progression

NATURE | 2019

The 2019 study disproves the previously common assumption of a “pull effect” in cell division. The production of the basic building block ribose-5-phosphate formed by TKTL1 is not triggered by its consumption; instead, an overproduction of the substance controlled by TKTL1 “pushes” the cell into duplication, the so-called “push effect.” TKTL1 thus controls the cell cycle by providing the building block necessary for DNA synthesis.

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Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals

SCIENCE | 2022

The research team led by Svante Pääbo and Wieland Huttner published the sensational study on brain development in Neanderthals and modern humans in September 2022. This study revealed that a mutation on the TKTL1 gene caused modern humans to form more neurons in the neocortex than Neanderthals. The crucial mutation resulted in the alteration of only a single amino acid on the TKTL1 gene and yet had far-reaching consequences for our development.

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TKTL1 Cancer-Related Studies

Especially in the field of early cancer detection and cancer diagnostics, the findings and studies on TKTL1 are increasing rapidly. A selection of important studies from recent years:

„Blood-Test Based Targeted Visualization Enables Early Detection of Premalignant and Malignant Tumors in Asymptomatic Individuals“

The largest study to date on TKTL1 addresses the question of whether the TKTL1 protein serves as a universal tumor marker in cancer diagnostics.
The background to the study is that in Germany there are still no screening tests for 55% of new cancer cases each year. With PanTum Detect®, Zyagnum AG has developed a blood test that provides a universal indication of a possible tumor on the basis of TKTL1 and DNaseX as biomarkers. If the result is conspicuous, it is clarified by means of imaging procedures.

The study involved 5,000 individuals aged 50 to 70 years. In 82% of the participants with abnormal blood samples, a previously undetected tumor or tumor precursor was ultimately discovered.

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“Epitope Detection in Monocytes (EDIM) As a New Method of Liquid Biopsy in Pediatric Rhabdomyosarcoma”

Researchers from the Eberhard Karls University in Tübingen, Germany, investigated whether the biomarkers TKTL1 and DNaseX (Apo10) differ in children and adolescents with rhabdomyosarcoma compared to a healthy control group.

Rhabdomyosarcoma is a malignant cancer that affects muscle tissue. It is the most common soft tissue tumor in childhood. In advanced stages, only 25% of treated patient:s are cancer-free after three years. The disease is currently diagnosed based on clinical signs, imaging techniques such as MRI, laboratory parameters and by bone marrow aspiration.
Twenty-nine infants, children and adolescents aged 0 to 21 years suffering from rhabdomyosarcoma participated in the study. The control group included 27 healthy individuals. The PanTum Detect® blood test developed by Zyagnum AG was used. This so-called biological biopsy, based on EDIM® technology, detects elevated TKTL1 and DNaseX (Apo10) levels in macrophages.
Significantly elevated TKTL1 and DNaseX (Apo10) levels were detected in 28 of the 29 rhabdomyosarcoma patients. In the control group, none of the participants showed elevated levels of TKTL1 and DNaseX (Apo10).

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Study List

2024

Xing, L., Huttner, W. B., & Namba, T. (2024). Role of cell metabolism in the pathophysiology of brain size-associated neurodevelopmental disorders. Neurobiology of disease 2024, 106607. Advance online publication.

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Fernández, V., & Borrell, V. (2024). Epi-regulate my brain: unlocking mechanisms of brain growth evolution. The EMBO Journal 2024, 43(8), 1385–1387.

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Zeberg, H., Jakobsson, M., & Pääbo, S. (2024). The genetic changes that shaped Neandertals, Denisovans, and modern humans. Cell, 2024

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2023

Hao, S., Meng, Q., Sun, H., Yang, X., Liu, B., Zhang, Y., Zhou, H., Xu, Z., & Wang, Y. (2023). Human papillomavirus type 16 E6 promotes cervical cancer proliferation by upregulating transketolase enzymatic activity through the activation of protein kinase B. Molecular Carcinogenesis, 2023.

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Xie, C., Wang, S., Guo, C. et al. Apo10 and TKTL1 in blood macrophages as biomarkers for differentiating lung cancer from benign lung lesions: a comparative study with conventional biomarkers. Cellular Oncology 2023.

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Burg S.; Smeets R.; Gosau M.; Failing K.; Grust A.: Case Report: Early detection of lung carcinoid in an asymptomatic individual by blood-test initiated PET-CT imaging. Frontiers in Oncology 2023, 13.

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2022

Li Y.; Xu C.; Wang B.; Xu F.; Ma F.; Qu Y. et al.: Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies. Nature Communications 2022.

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Pinson A.; Xing L.; Xinnan L.; Namba T.; Kalebic N; Peters J. et al.: Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals. Science 2022.

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Qi L.; Fangming Z.; Xinnan L.; Ying L.; Ke Y.; Na T.; et al.: Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics. Nature Metabolism 2022.

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Shiming, H.; Qingfei, M.; Huihui S.; Yunkuo L.; Yao L.; et al.: The role of transketolase in human cancer progression and therapy. Elsevier 2022.

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Urla, C.; Stagno, M.J.; Schmidt, A.; Handgretinger, R.; Fuchs, J.; Warmann, S.W.; Schmid, E. Epitope Detection in Monocytes (EDIM) As a New Method of Liquid Biopsy in Pediatric Rhabdomyosarcoma. Biomedicines 2022.

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Burg, S.; Grust, AC.; Feyen, O.; Failing, K.; Banat, GA.; Coy, JF. et al. Blood-Test Based Targeted Visualization Enables Early Detection of Premalignant and Malignant Tumors in Asymptomatic Individuals. Journal of Clinical and Medical Images 2022, 6.

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Stagno, M.; Schmidt, A.; Bochem, J. et al. Epitope detection in monocytes (EDIM) for liquid biopsy including identification of GD2 in childhood neuroblastoma—a pilot study. British Journal of Cancer 2022, 7.

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Baptista, I.; Karakitsou, E.; Cazier, JB.; Günther, UL.; Marin, S.; Cascante, M. TKTL1 Knockdown Impairs Hypoxia-Induced Glucose-6-phosphate Dehydrogenase and Glyceraldehyde-3-phosphate Dehydrogenase Overexpression. International Journal of Molecular Sciences 2022, 23, 3574.

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Li, M.; Zhao, X.; Yong, H.; Xu, J.; Qu, P.; Qiao, S. et al. Transketolase promotes colorectal cancer metastasis through regulating AKT phosphorylation. Cell Death and Disease 2022, 13, 99.

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Niu, C.; Qiu, W.; Li, X.; Li, H.; Zhou, J.; Zhu, H. Transketolase Serves as a Biomarker for Poor Prognosis in Human Lung Adenocarcinoma. Journal of Cancer 2022, 13, 2584–93.

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Zhang, L.; Huang, Z.; Cai, Q.; Zhao, C.; Xiao, Y.; Quan, X.; et al. Inhibition of Transketolase Improves the Prognosis of Colorectal Cancer. Frontiers in Medicine 2022, 9, 837143.

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2021

He, X.; Ding, J.; Cheng, X.; Xiong, M. Hypoxia-Related Gene-Based Signature Can Evaluate the Tumor Immune Microenvironment and Predict the Prognosis of Colon Adenocarcinoma Patients. International Journal of General Medicine 2021, 14, 9853–62.

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Wang, J.; Li, Y.; Zhang, C.; Chen, X.; Zhu, L.; Luo, T. A hypoxia-linked gene signature for prognosis prediction and evaluating the immune microenvironment in patients with hepatocellular carcinoma. Trans Cancer Research 2021, 10, 3979–92.

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Zhu, Y.; Qiu, Y.; Zhang, X. TKTL1 participated in malignant progression of cervical cancer cells via regulating AKT signal mediated PFKFB3 and thus regulating glycolysis. Cancer Cell International 2021, 21, 678.

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Ahopelto, K.; Saukkonen, K.; Hagström, J.; Kauhanen, S.; Seppänen, H.; Böckelman, C.; et al. TKTL1 as a Prognostic Marker in Pancreatic Ductal Adenocarcinoma and Its Correlation with FDG-PET-CT. Oncology 2021, 99, 177–85.

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Cymbaluk-Płoska, A.; Chudecka, K.; Chudecka-Głaz, A.; Piotrowska, K.; Kwiatkowski, S.; Tarnowski, M. Importance of Potential New Biomarkers in Patient with Serouse Ovarian Cancer. Diagnostics (Basel) 2021, 11, 1026.

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2020

Saman, S.; Stagno, M.;, Warmann, SW.; Malek, NP.; Plentz, RR.; Schmid, E. Biomarkers Apo10 and TKTL1: Epitope-detection in monocytes (EDIM) as a new diagnostic approach for cholangiocellular, pancreatic and colorectal carcinoma. Cancer Biomarkers 2020, 27, 129–37.

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Peltonen, R.; Ahopelto, K.; Hagström, J.; Böckelman, C.; Haglund, C.; Isoniemi, H. High TKTL1 expression as a sign of poor prognosis in colorectal cancer with synchronous rather than metachronous liver metastases. Cancer Biology Therapy 2020, 21, 826–31.

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Sequeda-JuÁrez, A.; Jiménez, A.; Espinosa-Montesinos, A.; Del Carmen Cardenas-Aguayo, M.; RamÓn-Gallegos, E. Use of AKR1C1 and TKTL1 in the Diagnosis of Low-grade Squamous Intraepithelial Lesions from Mexican Women. Anticancer Research 2020, 40, 6273–84.

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Ahopelto, K.; Laitinen. A.; Hagström, J.; Böckelman, C.; Haglund, C. Transketolase-Like Protein 1 and Glucose Transporter 1 in Gastric Cancer. Oncology 2020, 98, 643–52.

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2018

Zheng, X.; Li, H. TKTL1 modulates the response of paclitaxel-resistant human ovarian cancer cells to paclitaxel. Biochemical and Biophysical Research Communications 2018.

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Heller, S.; Maurer, G.D.; Wanka, C.; Hofmann, U.; Luger, A.; Bruns, I. et al. Gene Suppression of Transketolase-Like Protein 1 (TKTL1) Sensitizes Glioma Cells to Hypoxia and Ionizing Radiation. International Journal of Molecular Sciences 2018, 19, 2068.

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2017

Dong, Y.; Wang, M. Knockdown of TKTL1 additively complements cisplatin-induced cytotoxicity in nasopharyngeal carcinoma cells by regulating the levels of NADPH and ribose-5-phosphate. Biomedicine & Pharmacotherapy 2018, 85.

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2013

Grimm, M., Schmitt, S., Teriete, P., Biegner, T., Stenzl, A., Hennenlotter, J., Muhs, H. J., Munz, A., Nadtotschi, T., König, K., Sänger, J., Feyen, O., Hofmann, H., Reinert, S., & Coy, J. F. A biomarker based detection and characterization of carcinomas exploiting two fundamental biophysical mechanisms in mammalian cells. BMC cancer 201313, 569. https://doi.org/10.1186/1471-2407-13-569

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Bentz, S., Cee, A., Endlicher, E., Wojtal, K. A., Naami, A., Pesch, T., Lang, S., Schubert, P., Fried, M., Weber, A., Coy, J. F., Goelder, S., Knüchel, R., Hausmann, M., & Rogler, G. Hypoxia induces the expression of transketolase-like 1 in human colorectal cancer. Digestion 201388(3), 182–192.

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Grimm, M., Hoefert, S., Luz, O., Reinert, S., & Polligkeit, J. Transketolase-like protein 1 expression in recurrent oral squamous cell carcinoma after curative resection: a case report. Oral surgery, oral medicine, oral pathology and oral radiology 2013116(3), e173–e178. https://doi.org/10.1016/j.oooo.2011.12.022

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Rotmann, A. The use of new diagnostic tests for the monitoring of new and existing therapies for breast cancer patients. Journal of Clinical Oncology 2013.

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Jansen, N., & Coy, J. F. Diagnostic use of epitope detection in monocytes blood test for early detection of colon cancer metastasis. Future oncology (London, England) 20139(4), 605–609.

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Li, B.; Iglesias-Pedraz, J. M.; Chen L.; Yin F.; Cadenas E.;Reddy S.; Comai L. Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. Aging Cell 2013, 13,2.

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2012

Feyen, O., Coy, J. F., Prasad, V., Schierl, R., Saenger, J., & Baum, R. P. EDIM-TKTL1 blood test: a noninvasive method to detect upregulated glucose metabolism in patients with malignancies. Future oncology (London, England) 20128(10), 1349–1359.

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Lange, C. A., Tisch-Rottensteiner, J., Böhringer, D., Martin, G., Schwartzkopff, J., & Auw-Haedrich, C. Enhanced TKTL1 expression in malignant tumors of the ocular adnexa predicts clinical outcome. Ophthalmology 2012119(9), 1924–1929.

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Feyen, O., Coy, J. F., Prasad, V., Schierl, R., Saenger, J., & Baum, R. P. EDIM-TKTL1 blood test: a noninvasive method to detect upregulated glucose metabolism in patients with malignancies. Future oncology (London, England) 20128(10), 1349–1359.

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Wanka, C., Steinbach, J. P., & Rieger, J. Tp53-induced glycolysis and apoptosis regulator (TIGAR) protects glioma cells from starvation-induced cell death by up-regulating respiration and improving cellular redox homeostasis. The Journal of biological chemistry 2012287(40), 33436–33446.

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Wani, K., Armstrong, T. S., Vera-Bolanos, E., Raghunathan, A., Ellison, D., Gilbertson, R., Vaillant, B., Goldman, S., Packer, R. J., Fouladi, M., Pollack, I., Mikkelsen, T., Prados, M., Omuro, A., Soffietti, R., Ledoux, A., Wilson, C., Long, L., Gilbert, M. R., Aldape, K., … Collaborative Ependymoma Research Network A prognostic gene expression signature in infratentorial ependymoma. Acta neuropathologica 2012123(5), 727–738.

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Fritz, P., Coy, J. F., Mürdter, T. E., Ott, G., Alscher, M. D., & Friedel, G. TKTL-1 expression in lung cancer. Pathology, research and practice 2012208(4), 203–209.

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Maslova, A. O., Meshalkina, L. E., & Kochetov, G. A. Computer modeling of transketolase-like protein, TKTL1, a marker of certain tumor tissues. Biochemistry. Biokhimiia 201277(3), 296–299.

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2011

Kayser, G., Sienel, W., Kubitz, B., Mattern, D., Stickeler, E., Passlick, B., Werner, M., & Zur Hausen, A. Poor outcome in primary non-small cell lung cancers is predicted by transketolase TKTL1 expression. Pathology 201143(7), 719–724.

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Hartmannsberger, D., Mack, B., Eggert, C., Denzel, S., Stepp, H., Betz, C. S., & Gires, O. Transketolase-like protein 1 confers resistance to serum withdrawal in vitro. Cancer letters 2011300(1), 20–29.

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Diaz-Moralli, S., Tarrado-Castellarnau, M., Alenda, C., Castells, A., & Cascante, M. Transketolase-like 1 expression is modulated during colorectal cancer progression and metastasis formation. PloS one 20116(9), e25323.

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Schwaab, J., Horisberger, K., Ströbel, P., Bohn, B., Gencer, D., Kähler, G., Kienle, P., Post, S., Wenz, F., Hofmann, W. K., Hofheinz, R. D., & Erben, P. Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy. BMC cancer 201111, 363.

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2010

Mitschke, L., Parthier, C., Schröder-Tittmann, K., Coy, J., Lüdtke, S., & Tittmann, K. The crystal structure of human transketolase and new insights into its mode of action. The Journal of biological chemistry 2010285(41), 31559–31570.

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Mayer, A., Von Wallbrunn, A., & Vaupel, P. Glucose metabolism of malignant cells is not regulated by transketolase-like (TKTL)-1. International journal of oncology 201037(2), 265–271.

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Krockenberger, M., Engel, J. B., Schmidt, M., Kohrenhagen, N., Häusler, S. F., Dombrowski, Y., Kapp, M., Dietl, J., & Honig, A. Expression of transketolase-like 1 protein (TKTL1) in human endometrial cancer. Anticancer research 201030(5), 1653–1659.

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Yuan, W., Wu, S., Guo, J., Chen, Z., Ge, J., Yang, P., Hu, B., & Chen, Z. Silencing of TKTL1 by siRNA inhibits proliferation of human gastric cancer cells in vitro and in vivo. Cancer biology & therapy 20109(9), 710–716.

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Sun, W., Liu, Y., Glazer, C. A., Shao, C., Bhan, S., Demokan, S., Zhao, M., Rudek, M. A., Ha, P. K., & Califano, J. A. TKTL1 is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis through increased aerobic glycolysis and HIF1alpha stabilization. Clinical cancer research : an official journal of the American Association for Cancer Research 201016(3), 857–866.

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Demetrius, L. A., Coy, J. F., & Tuszynski, J. A. Cancer proliferation and therapy: the Warburg effect and quantum metabolism. Theoretical biology & medical modelling 20107, 2.

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2009

Xu, X., Zur Hausen, A., Coy, J. F., & Löchelt, M. Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells. International journal of cancer 2009124(6), 1330–1337.

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2008

Zerilli, M., Amato, M. C., Martorana, A., Cabibi, D., Coy, J. F., Cappello, F., Pompei, G., Russo, A., Giordano, C., & Rodolico, V. Increased expression of transketolase-like-1 in papillary thyroid carcinomas smaller than 1.5 cm in diameter is associated with lymph-node metastases. Cancer 2008113(5), 936–944.

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Völker, H. U., Hagemann, C., Coy, J., Wittig, R., Sommer, S., Stojic, J., Haubitz, I., Vince, G. H., Kämmerer, U., & Monoranu, C. M. Expression of transketolase-like 1 and activation of Akt in grade IV glioblastomas compared with grades II and III astrocytic gliomas. American journal of clinical pathology 2008130(1), 50–57.

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Langbein, S., Frederiks, W. M., zur Hausen, A., Popa, J., Lehmann, J., Weiss, C., Alken, P., & Coy, J. F. Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. International journal of cancer 2008122(11), 2422–2428.

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Otto, C., Kaemmerer, U., Illert, B., Muehling, B., Pfetzer, N., Wittig, R., Voelker, H. U., Thiede, A., & Coy, J. F. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC cancer 20088, 122.

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Wittig, R., & Coy, J. F. The role of glucose metabolism and glucose-associated signalling in cancer. Perspectives in medicinal chemistry 20081, 64–82.

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2007

Földi, M.; Stickeler, E.; Bau, L.; Kretz, O.; Watermann, D.; Gitsch, G.; Kayser, G.; Zur Hausen, A.; Coy, J. F. Transketolase protein TKTL1 overexpression: A potential biomarker and therapeutic target in breast cancer. Oncology reports 200717(4), 841–845.

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Krockenberger, M., Honig, A., Rieger, L., Coy, J. F., Sutterlin, M., Kapp, M., Horn, E., Dietl, J., & Kammerer, U. Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 200717(1), 101–106.

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2006

Staiger, W. I.; Coy, J. F.; Grobholz, R.; Hofheinz, R.-D.; Lukan, N.; Post, S.; Schwarzbach, M. H.; Willeke, F. Expression of the mutated transketolase TKTL1, a molecular marker in gastric cancer. Oncology reports 200616(4), 657–661.

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Langbein, S.; Zerilli, M.; Zur Hausen, A.; Staiger, W.; Rensch-Boschert, K.; Lukan, N.; Popa, J.; Ternullo, M. P.; Steidler, A.; Weiss, C.; Grobholz, R.; Willeke, F.; Alken, P.; Stassi, G.; Schubert, P.; Coy, J. F. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. British journal of cancer 200694(4), 578–585.

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2005

Coy, J. F.; Dressler, D.; Wilde, J.; Schubert, P. Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. Clinical laboratory 200551(5-6), 257–273.

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1996

Coy, J. F.; Dübel, S.; Kioschis, P.; Thomas, K.; Micklem, G.; Delius, H.; Poustka, A. Molecular cloning of tissue-specific transcripts of a transketolase-related gene: implications for the evolution of new vertebrate genes. Genomics 199632(3), 309–316.

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