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1. Effect of FADS1 SNPs rs174546, rs174547 and rs174550 on blood fatty acid profiles and plasma free oxylipins

Author

Miriam Rabehl, Zeren Wei, Can G. Leineweber, Jörg Enssle, Michael Rothe, Adelheid Jung, Christoph Schmöcker, Ulf Elbelt, Karsten H. Weylandt, and Anne Pietzner

Subjects
steatosis hepatis, MAFLD, FADS1, Oxylipins, PUFA, Nutrition. Foods and food supply, TX341-641
Abstract

IntroductionPrevious studies have indicated that activity of fatty acid desaturase 1 (FADS1), is involved in cardiometabolic risk. Recent experimental data have shown that FADS1 knockdown can promote lipid accumulation and lipid droplet formation in liver cells. In this study, we aimed to characterize whether different FADS1 genotypes affect liver fat content, essential fatty acid content and free oxylipin mediators in the blood.MethodsWe analyzed the impact of FADS1 single-nucleotide polymorphisms (SNPs) rs174546, rs174547, and rs174550 on blood fatty acids and free oxylipins in a cohort of 85 patients from an academic metabolic medicine outpatient center. Patients were grouped based on their genotype into the homozygous major (derived) allele group, the heterozygous allele group, and the homozygous minor (ancestral) allele group. Omega-3 polyunsaturated fatty acids (n-3 PUFA) and omega-6 polyunsaturated fatty acids (n-6 PUFA) in the blood cell and plasma samples were analyzed by gas chromatography. Free Oxylipins in plasma samples were analyzed using HPLC–MS/MS. Liver fat content and fibrosis were evaluated using Fibroscan technology.ResultsPatients with the homozygous ancestral (minor) FADS1 genotype exhibited significantly lower blood levels of the n-6 PUFA arachidonic acid (AA), but no significant differences in the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There were no significant differences in liver fat content or arachidonic acid-derived lipid mediators, such as thromboxane B2 (TXB2), although there was a trend toward lower levels in the homozygous ancestral genotype group.DiscussionOur findings suggest that FADS1 genotypes influence the blood levels of n-6 PUFAs, while not significantly affecting the n-3 PUFAs EPA and DHA. The lack of significant differences in liver fat content and arachidonic acid-derived lipid mediators suggests that the genotype-related variations in fatty acid levels may not directly translate to differences in liver fat or inflammatory lipid mediators in this cohort. However, the trend towards lower levels of certain lipid mediators in the homozygous ancestral genotype group warrants further investigation to elucidate the underlying mechanisms of different FADS1 genotypes and potential implications for cardiometabolic risk.

Published
2024
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2. Corrigendum: Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Author

Can G. Leineweber, Miriam Rabehl, Anne Pietzner, Nadine Rohwer, Michael Rothe, Maciej Pech, Bruno Sangro, Rohini Sharma, Chris Verslype, Bristi Basu, Christian Sengel, Jens Ricke, Nils Helge Schebb, Karsten-H. Weylandt, and Julia Benckert

Subjects
hepatocellular carcinoma, cytochrome P450, sorafenib, EET, EDP, omega-3 fatty acids, Therapeutics. Pharmacology, RM1-950
Published
2024
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3. Harnessing Oxylipins and Inflammation Modulation for Prevention and Treatment of Colorectal Cancer

Author

Julius Gretschel, Racha El Hage, Ruirui Wang, Yifang Chen, Anne Pietzner, Andreas Loew, Can G. Leineweber, Jonas Wördemann, Nadine Rohwer, Karsten H. Weylandt, and Christoph Schmöcker

Subjects
colorectal cancer, omega-3 PUFA, arachidonic acid, ASA, aspirin, statin, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, ranking as the third most malignant. The incidence of CRC has been increasing with time, and it is reported that Westernized diet and lifestyle play a significant role in its higher incidence and rapid progression. The intake of high amounts of omega-6 (n − 6) PUFAs and low levels of omega-3 (n − 3) PUFAs has an important role in chronic inflammation and cancer progression, which could be associated with the increase in CRC prevalence. Oxylipins generated from PUFAs are bioactive lipid mediators and have various functions, especially in inflammation and proliferation. Carcinogenesis is often a consequence of chronic inflammation, and evidence has shown the particular involvement of n − 6 PUFA arachidonic acid-derived oxylipins in CRC, which is further described in this review. A deeper understanding of the role and metabolism of PUFAs by their modifying enzymes, their pathways, and the corresponding oxylipins may allow us to identify new approaches to employ oxylipin-associated immunomodulation to enhance immunotherapy in cancer. This paper summarizes oxylipins identified in the context of the initiation, development, and metastasis of CRC. We further explore CRC chemo-prevention strategies that involve oxylipins as potential therapeutics.

Published
2024
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4. Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Author

Can G. Leineweber, Miriam Rabehl, Anne Pietzner, Nadine Rohwer, Michael Rothe, Maciej Pech, Bruno Sangro, Rohini Sharma, Chris Verslype, Bristi Basu, Christian Sengel, Jens Ricke, Nils Helge Schebb, Karsten-H. Weylandt, and Julia Benckert

Subjects
hepatocellular carcinoma, cytochrome P450, sorafenib, EET, EDP, omega-3 fatty acids, Therapeutics. Pharmacology, RM1-950
Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.

Published
2023
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5. The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

Author

Amrita M. Nargund, Can G. Pham, Yiyu Dong, Patricia I. Wang, Hatice U. Osmangeyoglu, Yuchen Xie, Omer Aras, Song Han, Toshinao Oyama, Shugaku Takeda, Chelsea E. Ray, Zhenghong Dong, Mathieu Berge, A. Ari Hakimi, Sebastien Monette, Carl L. Lekaye, Jason A. Koutcher, Christina S. Leslie, Chad J. Creighton, Nils Weinhold, William Lee, Satish K. Tickoo, Zhong Wang, Emily H. Cheng, and James J. Hsieh

Subjects
kidney cancer, ccRCC, mouse tumor model, VHL, PBRM1, HIF1, STAT3, MTOR, genetics, epigenetics, Biology (General), QH301-705.5
Abstract

PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.

Published
2017
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6. Assessment of the Effect of Sorafenib on Omega-6 and Omega-3 Epoxyeicosanoid Formation in Patients with Hepatocellular Carcinoma

Author

Can G. Leineweber, Anne Pietzner, Ingrid W. Zhang, Usha B. Blessin, Michael Rothe, Eckart Schott, Nils H. Schebb, and Karsten H. Weylandt

Subjects
hepatocellular carcinoma, hcc, soluble epoxide hydrolase, sorafenib, eet, edp, omega-3 fatty acids, n-3 pufa, arachidonic acid, docosahexaenoic acid, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death. The multikinase inhibitor sorafenib is widely used for systemic therapy in advanced HCC. Sorafenib might affect epoxyeicosanoids, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of epoxides derived from long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding diols. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) showed that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this pilot study, we assessed the effect of sorafenib treatment on the presence of lipid mediators, such as EETs, in blood of the patients with HCC using the lipidomics technology. We found a significant increase in 11,12-EET and 14,15-EET levels in HCC patients treated with sorafenib. Furthermore, while not significant in this small sample set, the data presented indicate that sorafenib can also increase the level of omega-3 DHA-derived 19,20-EDP. While the effect on EETs might hamper the anti-tumor effect of sorafenib, we hypothesize that supplementation of DHA in sorafenib-treated HCC patients could increase the level of 19,20-EDP and thereby enhance its anti-tumor effect.

Published
2020
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7. Life expectancy associated with different ages at diagnosis of type 2 diabetes in high-income countries: 23 million person-years of observation

Author

Kaptoge, S, Seshasai, SRK, Sun, L, Walker, M, Bolton, T, Spackman, S, Ataklte, F, Willeit, P, Bell, S, Burgess, S, Pennells, L, Altay, S, Assmann, G, Ben-Shlomo, Y, Best, LG, Björkelund, C, Blazer, DG, Brenner, H, Brunner, EJ, Dagenais, GR, Cooper, JA, Cooper, C, Crespo, CJ, Cushman, M, D'Agostino, RB, Sr, Daimon, M, Daniels, LB, Danker, R, Davidson, KW, de Jongh, RT, Donfrancesco, C, Ducimetiere, P, Elders, PJM, Engström, G, Ford, I, Gallacher, I, Bakker, SJL, Goldbourt, U, de La Cámara, G, Grimsgaard, S, Gudnason, V, Hansson, PO, Imano, H, Jukema, JW, Kabrhel, C, Kauhanen, J, Kavousi, M, Kiechl, S, Knuiman, MW, Kromhout, D, Krumholz, HM, Kuller, LH, Laatikainen, T, Lowler, DA, Meyer, HE, Mukamal, K, Nietert, PJ, Ninomiya, T, Nitsch, D, Nordestgaard, BG, Palmieri, L, Price, JF, Ridker, PM, Sun, Q, Rosengren, A, Roussel, R, Sakurai, M, Salomaa, V, Schöttker, B, Shaw, JE, Strandberg, TE, Sundström, J, Tolonen, H, Tverdal, A, Verschuren, WMM, Völzke, H, Wagenknecht, L, Wallace, RB, Wannamethee, SG, Wareham, NJ, Wassertheil-Smoller, S, Yamagishi, K, Yeap, BB, Harrison, S, Inouye, M, Griffin, S, Butterworth, AS, Wood, AM, Thompson, SG, Sattar, N, Danesh, J, Di Angelantonio, E, Tipping, RW, Russell, S, Johansen, M, Bancks, MP, Mongraw-Chaffin, M, Magliano, D, Barr, ELM, Zimmet, PZ, Whincup, PH, Willeit, J, Leitner, C, Lawlor, DA, Elwood, P, Sutherland, SE, Hunt, KJ, Selmer, RM, Haheim, LL, Ariansen, I, Tybjaer-Hansen, A, Frikkle-Schmidt, R, Langsted, A, Lo Noce, C, Balkau, B, Bonnet, F, Fumeron, F, Pablos, DL, Ferro, CR, Morales, TG, Mclachlan, S, Guralnik, J, Khaw, KT, Holleczek, B, Stocker, H, Nissinen, A, Vartiainen, E, Jousilahti, P, Harald, K, Massaro, JM, Pencina, M, Lyass, A, Susa, S, Oizumi, T, Kayama, T, Chetrit, A, Roth, J, Orenstein, L, Welin, L, Svärdsudd, K, Lissner, L, Hange, D, Mehlig, K, Tilvis, RS, Dennison, E, Westbury, L, Norman, PE, Almeida, OP, Hankey, GJ, Hata, J, Shibata, M, Furuta, Y, Bom, MT, Rutters, F, Muilwijk, M, Kraft, P, Lindstrom, S, Turman, C, Kiyama, M, Kitamura, A, Gerber, Y, Salonen, JT, van Schoor, LN, van Zutphen, EM, Melander, O, Psaty, BM, Blaha, M, de Boer, IH, Kronmal, RA, Grandits, G, Shin, H-C, Albertorio, JR, Gillum, RF, Hu, FB, Humphries, S, Hill- Briggs, F, Vrany, E, Butler, M, Schwartz, JE, Iso, H, Amouyel, P, Arveiler, D, Ferrieres, J, Gansevoort, RT, de Boer, R, Kieneker, L, Trompet, S, Kearney, P, Cantin, B, Després, JP, Lamarche, B, Laughlin, G, McEvoy, L, Aspelund, T, Thorsson, B, Sigurdsson, G, Tilly, M, Ikram, MA, Dorr, M, Schipf, S, Fretts, AM, Umans, JG, Ali, T, Shara, N, Davey-Smith, G, Can, G, Yüksel, H, Özkan, U, Nakagawa, H, Morikawa, Y, Ishizaki, M, Njølstad, I, Wilsgaard, T, Mathiesen, E, Buring, J, Cook, N, Arndt, V, Rothenbacher, D, Manson, J, Tinker, L, Shipley, M, Tabak, AG, Kivimaki, M, Packard, C, Robertson, M, Feskens, E, and Geleijnse, M

Published
2023
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10. Quality control for next-generation liquefaction case histories

Author

Zimmaro, P, Brandenberg, SJ, Bozorgnia, Y, Stewart, JP, Kwak, DY, Cetin, KO, Can, G, Ilgac, M, Franke, KW, Moss, RES, Kramer, SL, Stamatakos, J, Juckett, M, and Weaver, T

Subjects
liquefaction, relational database
Abstract

The Next-Generation Liquefaction (NGL) database is an open-source, global database of liquefaction and non-ground failure case-histories. The database is part of a multi-year research effort with the main goal of developing improved procedures to evaluate liquefaction susceptibility, triggering, and consequences. In NGL, a case-history is defined as the intersection of three components: (1) a site, (2) an earthquake event, and (3) post-earth-quake observations. The NGL database hosts case-histories used to develop existing liquefaction models, as well as new data derived from recent earthquakes such as the 2010-2011 Canterbury earthquake sequence, the 2011 Tohoku-Oki earthquake, and the 2012 Emilia earthquake. The database also hosts lateral spread case-histories, and a substantial number of liquefaction sites characterized by the presence of co-located recording stations. All of the data present in the NGL database are reviewed by the NGL Database Working Group. The NGL formal vetting process is described for an example case-history.

Published
2019

13. Harnessing Oxylipins and Inflammation Modulation for Prevention and Treatment of Colorectal Cancer.

Author

Gretschel, Julius, El Hage, Racha, Wang, Ruirui, Chen, Yifang, Pietzner, Anne, Loew, Andreas, Leineweber, Can G., Wördemann, Jonas, Rohwer, Nadine, Weylandt, Karsten H., and Schmöcker, Christoph

Subjects
OMEGA-6 fatty acids, IRINOTECAN, OXYLIPINS, COLORECTAL cancer, CANCER treatment, INFLAMMATION, CANCER invasiveness
Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, ranking as the third most malignant. The incidence of CRC has been increasing with time, and it is reported that Westernized diet and lifestyle play a significant role in its higher incidence and rapid progression. The intake of high amounts of omega-6 (n − 6) PUFAs and low levels of omega-3 (n − 3) PUFAs has an important role in chronic inflammation and cancer progression, which could be associated with the increase in CRC prevalence. Oxylipins generated from PUFAs are bioactive lipid mediators and have various functions, especially in inflammation and proliferation. Carcinogenesis is often a consequence of chronic inflammation, and evidence has shown the particular involvement of n − 6 PUFA arachidonic acid-derived oxylipins in CRC, which is further described in this review. A deeper understanding of the role and metabolism of PUFAs by their modifying enzymes, their pathways, and the corresponding oxylipins may allow us to identify new approaches to employ oxylipin-associated immunomodulation to enhance immunotherapy in cancer. This paper summarizes oxylipins identified in the context of the initiation, development, and metastasis of CRC. We further explore CRC chemo-prevention strategies that involve oxylipins as potential therapeutics. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.

Author

Leineweber, Can G., Rabehl, Miriam, Pietzner, Anne, Rohwer, Nadine, Rothe, Michael, Pech, Maciej, Sangro, Bruno, Sharma, Rohini, Verslype, Chris, Basu, Bristi, Sengel, Christian, Ricke, Jens, Schebb, Nils Helge, Weylandt, Karsten-H., and Benckert, Julia

Subjects
CYTOCHROME P-450, HEPATOCELLULAR carcinoma, SORAFENIB, UNSATURATED fatty acids, EPOXIDE hydrolase
Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHAderived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP-metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Stimuli-responsive nanoparticle-nanofiber hybrids for drug delivery and photodynamic therapy

Author

Kaleli-Can, G., Mutlu, M., Shim, B.S., Eom, T., Kabay, G., Meydan, A.E., Kaleli-Can, G., Mutlu, M., Shim, B.S., Eom, T., Kabay, G., and Meydan, A.E.

Abstract

Hybrid nanomaterials possess integrated multi-components to syncretize various properties and functions within a single entity. Owing to this synergistic effect, they promise efficient anti-cancer therapy. In line with this target, we produced stimuli-responsive nanoparticle-nanofiber hybrids (NNHs) via embedding photoresponsive natural melanin nanoparticles (MNPs) within a biocompatible polycaprolactone (PCL) nanofiber matrix. Electrospinning was performed to produce monolithic and core–shell structured NNHs using a single and a coaxial nozzle. The NNHs were upgraded to drug delivery systems by model hydrophilic drug-ampicillin (amp)-loading. The drug release results showed that monolithic PCL meshes displayed a burst release, whereas nanohybrid formation with MNPs improved the release profile toward Fickian diffusion. Core-shell NNH presented a more sustained drug release profile than its MNP-free replica and monolithic NNH because its encapsulating shell layer hindered the diffusion of the drug. The photodynamic therapy accompanied by UV-A-irradiation on monolithic and core–shell NNHs yielded up to 34 % and 37 % malignant melanoma cell death. Moreover, this study proved the potency of MNPs-enhanced NNHs in drug delivery and photodynamic therapy applications. Even so, more efforts should be concerted to unlock unknown features of the NNHs, which have the power to advance emerging areas, including but not limited to material science, biosensing, and theranostics. © 2022 Elsevier B.V., BSS acknowledges the funding support from NRF-2021R1A4A1022920 and NRF-2020R1F1A1075944.

Published
2023

18. Stimuli-responsive nanoparticle-nanofiber hybrids for drug delivery and photodynamic therapy

Author

Meydan, A.E., Kabay, G., Eom, T., Shim, B.S., Mutlu, M., Kaleli-Can, G., Meydan, A.E., Kabay, G., Eom, T., Shim, B.S., Mutlu, M., and Kaleli-Can, G.

Abstract

Hybrid nanomaterials possess integrated multi-components to syncretize various properties and functions within a single entity. Owing to this synergistic effect, they promise efficient anti-cancer therapy. In line with this target, we produced stimuli-responsive nanoparticle-nanofiber hybrids (NNHs) via embedding photoresponsive natural melanin nanoparticles (MNPs) within a biocompatible polycaprolactone (PCL) nanofiber matrix. Electrospinning was performed to produce monolithic and core–shell structured NNHs using a single and a coaxial nozzle. The NNHs were upgraded to drug delivery systems by model hydrophilic drug-ampicillin (amp)-loading. The drug release results showed that monolithic PCL meshes displayed a burst release, whereas nanohybrid formation with MNPs improved the release profile toward Fickian diffusion. Core-shell NNH presented a more sustained drug release profile than its MNP-free replica and monolithic NNH because its encapsulating shell layer hindered the diffusion of the drug. The photodynamic therapy accompanied by UV-A-irradiation on monolithic and core–shell NNHs yielded up to 34 % and 37 % malignant melanoma cell death. Moreover, this study proved the potency of MNPs-enhanced NNHs in drug delivery and photodynamic therapy applications. Even so, more efforts should be concerted to unlock unknown features of the NNHs, which have the power to advance emerging areas, including but not limited to material science, biosensing, and theranostics. © 2022 Elsevier B.V., BSS acknowledges the funding support from NRF-2021R1A4A1022920 and NRF-2020R1F1A1075944.

Published
2023

19. Life expectancy associated with different ages at diagnosis of type 2 diabetes in high-income countries:23 million person-years of observation

Author

Sun, L., Best, L. G., Cooper, C., Bakker, S. J.L., Kavousi, M., Meyer, H. E., Thompson, S. G., Hunt, K. J., Bom, M. T., Kraft, P., Psaty, B. M., de Boer, R., Trompet, S., Tilly, M., Ikram, M. A., Dorr, M., Can, G., Geleijnse, M., Sun, L., Best, L. G., Cooper, C., Bakker, S. J.L., Kavousi, M., Meyer, H. E., Thompson, S. G., Hunt, K. J., Bom, M. T., Kraft, P., Psaty, B. M., de Boer, R., Trompet, S., Tilly, M., Ikram, M. A., Dorr, M., Can, G., and Geleijnse, M.

Abstract

Background:The prevalence of type 2 diabetes is increasing rapidly, particularly among younger age groups. Estimates suggest that people with diabetes die, on average, 6 years earlier than people without diabetes. We aimed to provide reliable estimates of the associations between age at diagnosis of diabetes and all-cause mortality, cause-specific mortality, and reductions in life expectancy. Methods:For this observational study, we conducted a combined analysis of individual-participant data from 19 high-income countries using two large-scale data sources: the Emerging Risk Factors Collaboration (96 cohorts, median baseline years 1961–2007, median latest follow-up years 1980–2013) and the UK Biobank (median baseline year 2006, median latest follow-up year 2020). We calculated age-adjusted and sex-adjusted hazard ratios (HRs) for all-cause mortality according to age at diagnosis of diabetes using data from 1 515 718 participants, in whom deaths were recorded during 23·1 million person-years of follow-up. We estimated cumulative survival by applying age-specific HRs to age-specific death rates from 2015 for the USA and the EU. Findings: For participants with diabetes, we observed a linear dose–response association between earlier age at diagnosis and higher risk of all-cause mortality compared with participants without diabetes. HRs were 2·69 (95% CI 2·43–2·97) when diagnosed at 30–39 years, 2·26 (2·08–2·45) at 40–49 years, 1·84 (1·72–1·97) at 50–59 years, 1·57 (1·47–1·67) at 60–69 years, and 1·39 (1·29–1·51) at 70 years and older. HRs per decade of earlier diagnosis were similar for men and women. Using death rates from the USA, a 50-year-old individual with diabetes died on average 14 years earlier when diagnosed aged 30 years, 10 years earlier when diagnosed aged 40 years, or 6 years earlier when diagnosed aged 50 years than an individual without diabetes. Using EU death rates, the corresponding estimates

Published
2023

21. Supplementary Figures 1 - 11, Tables 1 - 2 from Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Author

Voss, Martin H., primary, Hakimi, A. Ari, primary, Pham, Can G., primary, Brannon, A. Rose, primary, Chen, Ying-Bei, primary, Cunha, Luis F., primary, Akin, Oguz, primary, Liu, Han, primary, Takeda, Shugaku, primary, Scott, Sasinya N., primary, Socci, Nicholas D., primary, Viale, Agnes, primary, Schultz, Nikolaus, primary, Sander, Chris, primary, Reuter, Victor E., primary, Russo, Paul, primary, Cheng, Emily H., primary, Motzer, Robert J., primary, Berger, Michael F., primary, and Hsieh, James J., primary

Published
2023
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22. Supplementary Table 4 from Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Author

Voss, Martin H., primary, Hakimi, A. Ari, primary, Pham, Can G., primary, Brannon, A. Rose, primary, Chen, Ying-Bei, primary, Cunha, Luis F., primary, Akin, Oguz, primary, Liu, Han, primary, Takeda, Shugaku, primary, Scott, Sasinya N., primary, Socci, Nicholas D., primary, Viale, Agnes, primary, Schultz, Nikolaus, primary, Sander, Chris, primary, Reuter, Victor E., primary, Russo, Paul, primary, Cheng, Emily H., primary, Motzer, Robert J., primary, Berger, Michael F., primary, and Hsieh, James J., primary

Published
2023
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23. Supplementary Methods from Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Author

Voss, Martin H., primary, Hakimi, A. Ari, primary, Pham, Can G., primary, Brannon, A. Rose, primary, Chen, Ying-Bei, primary, Cunha, Luis F., primary, Akin, Oguz, primary, Liu, Han, primary, Takeda, Shugaku, primary, Scott, Sasinya N., primary, Socci, Nicholas D., primary, Viale, Agnes, primary, Schultz, Nikolaus, primary, Sander, Chris, primary, Reuter, Victor E., primary, Russo, Paul, primary, Cheng, Emily H., primary, Motzer, Robert J., primary, Berger, Michael F., primary, and Hsieh, James J., primary

Published
2023
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24. Supplementary Table 3 from Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Author

Voss, Martin H., primary, Hakimi, A. Ari, primary, Pham, Can G., primary, Brannon, A. Rose, primary, Chen, Ying-Bei, primary, Cunha, Luis F., primary, Akin, Oguz, primary, Liu, Han, primary, Takeda, Shugaku, primary, Scott, Sasinya N., primary, Socci, Nicholas D., primary, Viale, Agnes, primary, Schultz, Nikolaus, primary, Sander, Chris, primary, Reuter, Victor E., primary, Russo, Paul, primary, Cheng, Emily H., primary, Motzer, Robert J., primary, Berger, Michael F., primary, and Hsieh, James J., primary

Published
2023
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25. Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Author

Leineweber, Can G., primary, Rabehl, Miriam, additional, Pietzner, Anne, additional, Rohwer, Nadine, additional, Rothe, Michael, additional, Pech, Maciej, additional, Sangro, Bruno, additional, Sharma, Rohini, additional, Verslype, Chris, additional, Basu, Bristi, additional, Sengel, Christian, additional, Ricke, Jens, additional, Schebb, Nils Helge, additional, Weylandt, Karsten-H., additional, and Benckert, Julia, additional

Published
2023
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28. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4·4 million participants

Author

Zhou, B, Lu, Y, Hajifathalian, K, Bentham, J, Di Cesare, M, Danaei, G, Bixby, H, Cowan, MJ, Ali, MK, Taddei, C, Lo, WC, Reis-Santos, B, Stevens, GA, Riley, LM, Miranda, JJ, Bjerregaard, P, Rivera, JA, Fouad, HM, Ma, G, Mbanya, JC, McGarvey, ST, Mohan, V, Onat, A, Pilav, A, Ramachandran, A, Romdhane, HB, Paciorek, CJ, Bennett, JE, Ezzati, M, Abdeen, ZA, Abdul Kadir, K, Abu-Rmeileh, NM, Acosta-Cazares, B, Adams, R, Aekplakorn, W, Aguilar-Salinas, CA, Agyemang, C, Ahmadvand, A, Al-Othman, AR, Alkerwi, A, Amouyel, P, Amuzu, A, Andersen, LB, Anderssen, SA, Anjana, RM, Aounallah-Skhiri, H, Aris, T, Arlappa, N, Arveiler, D, Assah, FK, Avdicová, M, Azizi, F, Balakrishna, N, Bandosz, P, Barbagallo, CM, Barceló, A, Batieha, AM, Baur, LA, Benet, M, Bernabe-Ortiz, A, Bharadwaj, S, Bhargava, SK, Bi, Y, Bjertness, E, Bjertness, MB, Björkelund, C, Blokstra, A, Bo, S, Boehm, BO, Boissonnet, CP, Bovet, P, Brajkovich, I, Breckenkamp, J, Brenner, H, Brewster, LM, Brian, GR, Bruno, G, Bugge, A, Cabrera de León, A, Can, G, Cândido, AP, Capuano, V, Carlsson, AC, Carvalho, MJ, Casanueva, FF, Casas, JP, Caserta, CA, Castetbon, K, Chamukuttan, S, Chaturvedi, N, Chen, CJ, Chen, F, Chen, S, Cheng, CY, Chetrit, A, Chiou, ST, Cho, Y, Chudek, J, Cifkova, R, Claessens, F, Concin, H, Cooper, C, Cooper, R, Costanzo, S, Cottel, D, Cowell, C, Crujeiras, AB, D'Arrigo, G, Dallongeville, J, Dankner, R, Dauchet, L, de Gaetano, G, De Henauw, S, Deepa, M, Dehghan, A, Deschamps, V, Dhana, K, Di Castelnuovo, AF, Djalalinia, S, Doua, K, Drygas, W, Du, Y, Dzerve, V, Egbagbe, EE, Eggertsen, R, El Ati, J, Elosua, R, Erasmus, RT, Erem, C, Ergor, G, Eriksen, L, Escobedo-de la Peña, J, Fall, CH, Farzadfar, F, Felix-Redondo, FJ, Ferguson, TS, Fernández-Bergés, D, Ferrari, M, Ferreccio, C, Feskens, EJ, Finn, JD, Föger, B, Foo, LH, Forslund, AS, Francis, DK, Franco Mdo, C, Franco, OH, Frontera, G, Furusawa, T, Gaciong, Z, Garnett, SP, Gaspoz, JM, Gasull, M, Gates, L, Geleijnse, JM, Ghasemian, A, Ghimire, A, Giampaoli, S, Gianfagna, F, Giovannelli, J, Giwercman, A, Gross, MG, González Rivas, JP, Gorbea, MB, Gottrand, F, Grafnetter, D, Grodzicki, T, Grøntved, A, Gruden, G, Gu, D, Guan, OP, Guerrero, R, Guessous, I, Guimaraes, AL, Gutierrez, L, Hambleton, IR, Hardy, R, Hari Kumar, R, Hata, J, He, J, Heidemann, C, Herrala, S, Hihtaniemi, IT, Ho, SY, Ho, SC, Hofman, A, Hormiga, CM, Horta, BL, Houti, L, Howitt, C, Htay, TT, Htet, AS, Htike, MM, Hu, Y, Hussieni, AS, Huybrechts, I, Hwalla, N, Iacoviello, L, Iannone, AG, Ibrahim, MM, Ikeda, N, Ikram, MA, Irazola, VE, Islam, M, Iwasaki, M, Jacobs, JM, Jafar, T, Jamil, KM, Jasienska, G, Jiang, CQ, Jonas, JB, Joshi, P, Kafatos, A, Kalter-Leibovici, O, Kasaeian, A, Katz, J, Kaur, P, Kavousi, M, Keinänen-Kiukaanniemi, S, Kelishadi, R, Kengne, AP, Kersting, M, Khader, YS, Khalili, D, Khang, YH, Kiechl, S, Kim, J, Kolsteren, P, Korrovits, P, Kratzer, W, Kromhout, D, Kujala, UM, Kula, K, Kyobutungi, C, Laatikainen, T, Lachat, C, Laid, Y, Lam, TH, Landrove, O, Lanska, V, Lappas, G, Laxmaiah, A, Leclercq, C, Lee, J, Lehtimäki, T, Lekhraj, R, León-Muñoz, LM, Li, Y, Lim, WY, Lima-Costa, MF, Lin, HH, Lin, X, Lissner, L, Lorbeer, R, Lozano, JE, Luksiene, D, Lundqvist, A, Lytsy, P, Machado-Coelho, GL, Machi, S, Maggi, S, Magliano, DJ, Makdisse, M, Mallikharjuna Rao, K, Manios, Y, Manzato, E, Margozzini, P, Marques-Vidal, P, Martorell, R, Masoodi, SR, Mathiesen, EB, Matsha, TE, McFarlane, SR, McLachlan, S, McNulty, BA, Mediene-Benchekor, S, Meirhaeghe, A, Menezes, AM, Merat, S, Meshram, II, Mi, J, Miquel, JF, Mohamed, MK, Mohammad, K, Mohammadifard, N, Mohd Yusoff, MF, Møller, NC, Molnár, D, Mondo, CK, Morejon, A, Moreno, LA, Morgan, K, Moschonis, G, Mossakowska, M, Mostafa, A, Mota, J, Motta, J, Mu, TT, Muiesan, ML, Müller-Nurasyid, M, Mursu, J, Nagel, G, Námešná, J, Nang, EE, NangThetia, VB, Navarrete-Muñoz, EM, Ndiaye, NC, Nenko, I, Nervi, F, Nguyen, ND, Nguyen, QN, Nieto-Martínez, RE, Ning, G, Ninomiya, T, Noale, M, Noto, D, Nsour, MA, Ochoa-Avilés, AM, Oh, K, Ordunez, P, Osmond, C, Otero, JA, Owusu-Dabo, E, Pahomova, E, Palmieri, L, Panda-Jonas, S, Panza, F, Parsaeian, M, Peixoto, SV, Pelletier, C, Peltonen, M, Peters, A, Peykari, N, Pham, ST, Pitakaka, F, Piwonska, A, Piwonski, J, Plans-Rubió, P, Porta, M, Portegies, ML, Poustchi, H, Pradeepa, R, Price, JF, Punab, M, Qasrawi, RF, Qorbani, M, Radisauskas, R, Rahman, M, Raitakari, O, Rao, SR, Ramke, J, Ramos, R, Rampal, S, Rathmann, W, Redon, J, Reganit, PF, Rigo, F, Robinson, SM, Robitaille, C, Rodríguez-Artalejo, F, Rodriguez-Perez Mdel, C, Rodríguez-Villamizar, LA, Rojas-Martinez, R, Ronkainen, K, Rosengren, A, Rubinstein, A, Rui, O, Ruiz-Betancourt, BS, Russo Horimoto, RV, Rutkowski, M, Sabanayagam, C, Sachdev, HS, Saidi, O, Sakarya, S, Salanave, B, Salonen, JT, Salvetti, M, Sánchez-Abanto, J, Santos, D, dos Santos, RN, Santos, R, Saramies, JL, Sardinha, LB, Sarrafzadegan, N, Saum, KU, Scazufca, M, Schargrodsky, H, Scheidt-Nave, C, Sein, AA, Sharma, SK, Shaw, JE, Shibuya, K, Shin, Y, Shiri, R, Siantar, R, Sibai, AM, Simon, M, Simons, J, Simons, LA, Sjostrom, M, Slowikowska-Hilczer, J, Slusarczyk, P, Smeeth, L, Snijder, MB, So, HK, Sobngwi, E, Söderberg, S, Solfrizzi, V, Sonestedt, E, Soumare, A, Staessen, JA, Stathopoulou, MG, Steene-Johannessen, J, Stehle, P, Stein, AD, Stessman, J, Stöckl, D, Stokwiszewski, J, Stronks, K, Strufaldi, MW, Sun, CA, Sundström, J, Sung, YT, Suriyawongpaisal, P, Sy, RG, Tai, ES, Tamosiunas, A, Tang, L, Tarawneh, M, Tarqui-Mamani, CB, Taylor, A, Theobald, H, Thijs, L, Thuesen, BH, Tolonen, HK, Tolstrup, JS, Topbas, M, Torrent, M, Traissac, P, Trinh, OT, Tulloch-Reid, MK, Tuomainen, TP, Turley, ML, Tzourio, C, Ueda, P, Ukoli, FA, Ulmer, H, Uusitalo, HM, Valdivia, G, Valvi, D, van Rossem, L, van Valkengoed, IG, Vanderschueren, D, Vanuzzo, D, Vega, T, Velasquez-Melendez, G, Veronesi, G, Verschuren, WM, Verstraeten, R, Viet, L, Vioque, J, Virtanen, JK, Visvikis-Siest, S, Viswanathan, B, Vollenweider, P, Voutilainen, S, Vrijheid, M, Wade, AN, Wagner, A, Walton, J, Wan Mohamud, WN, Wang, F, Wang, MD, Wang, Q, Wang, YX, Wannamethee, SG, Weerasekera, D, Whincup, PH, Widhalm, K, Wiecek, A, Wijga, AH, Wilks, RJ, Willeit, J, Wilsgaard, T, Wojtyniak, B, Wong, TY, Woo, J, Woodward, M, Wu, FC, Wu, SL, Xu, H, Yan, W, Yang, X, Ye, X, Yoshihara, A, Younger-Coleman, NO, Zambon, S, Zargar, AH, Zdrojewski, T, Zhao, W, Zheng, Y, and Zuñiga Cisneros, J

Published
2016
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29. Striated muscle-specific β1D-integrin and FAK are involved in cardiac myocyte hypertrophic response pathway

Author

Pham, Can G, Harpf, Alice E, Keller, Rebecca S, Vu, Hoa T, Shai, Shaw-Yung, Loftus, Joseph C, and Ross, Robert S

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Cardiovascular, Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Amino Acid Sequence, Animals, Animals, Newborn, Antibodies, Atrial Natriuretic Factor, Cardiomegaly, Cardiotonic Agents, Cell Size, Cytoplasm, Extracellular Matrix, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Gene Expression Regulation, Developmental, Gene Expression Regulation, Enzymologic, Genes, Reporter, Heart Ventricles, Integrin beta1, Molecular Sequence Data, Muscle Fibers, Skeletal, Muscle, Skeletal, Myocardium, Phenylephrine, Phosphorylation, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Rats, Rats, Sprague-Dawley, Signal Transduction, neonatal rat ventricular myocytes, heart, cell signaling, extracellular matrix, focal adhesion kinase, Physiology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Medical physiology
Abstract

Alterations in the extracellular matrix occur during the cardiac hypertrophic process. Because integrins mediate cell-matrix adhesion and beta(1D)-integrin (beta1D) is expressed exclusively in cardiac and skeletal muscle, we hypothesized that beta1D and focal adhesion kinase (FAK), a proximal integrin-signaling molecule, are involved in cardiac growth. With the use of cultured ventricular myocytes and myocardial tissue, we found the following: 1) beta1D protein expression was upregulated perinatally; 2) alpha(1)-adrenergic stimulation of cardiac myocytes increased beta1D protein levels 350% and altered its cellular distribution; 3) adenovirally mediated overexpression of beta1D stimulated cellular reorganization, increased cell size by 250%, and induced molecular markers of the hypertrophic response; and 4) overexpression of free beta1D cytoplasmic domains inhibited alpha(1)-adrenergic cellular organization and atrial natriuretic factor (ANF) expression. Additionally, FAK was linked to the hypertrophic response as follows: 1) coimmunoprecipitation of beta1D and FAK was detected; 2) FAK overexpression induced ANF-luciferase; 3) rapid and sustained phosphorylation of FAK was induced by alpha(1)-adrenergic stimulation; and 4) blunting of the alpha(1)-adrenergically modulated hypertrophic response was caused by FAK mutants, which alter Grb2 or Src binding, as well as by FAK-related nonkinase, a dominant interfering FAK mutant. We conclude that beta1D and FAK are both components of the hypertrophic response pathway of cardiac myocytes.

Published
2000

30. Supplementary Figures 1 - 11, Tables 1 - 2 from Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Author

James J. Hsieh, Michael F. Berger, Robert J. Motzer, Emily H. Cheng, Paul Russo, Victor E. Reuter, Chris Sander, Nikolaus Schultz, Agnes Viale, Nicholas D. Socci, Sasinya N. Scott, Shugaku Takeda, Han Liu, Oguz Akin, Luis F. Cunha, Ying-Bei Chen, A. Rose Brannon, Can G. Pham, A. Ari Hakimi, and Martin H. Voss

Abstract

PDF file - 3248K, Supplementary Table S1. Histopathologic findings for multi-region analysis. Supplementary Table S2.IMPACT gene list and their respective chromosomal positions. Supplementary Table S5. WEC run statistics on patients #4 and #5. Supplementary Table S6.List of all non-variant mutations detected by IMPACT assays in individual patient samples. Supplementary Table S7. Non-variant mutations identified by WEC in patients #4 and #5. Supplementary Figure 1. Flow chart depicts the IMPACT assay mutation identification and filtering algorithm. Supplementary Figure 2. Flow chart depicts the WEC assay mutation identification and filtering algorithm. Supplementary Figure 3. Sanger validations of mutations in the targeted pathway indentified by IMPACT assay for R1 of patients #1,#2, and #3. Supplementary Figure 4. Sanger validations of mutations in the targeted pathway indentified by IMPACT assay for additional regions analyzed for patients #1, and #3. Supplementary Figure 5. The Q2223K mTOR mutation provokes hyperactivation of mTORC1 in serum free growth conditions. Supplementary Figure 6. Hyperactivation of mTORC1 induced by Q2223K is sensitive to rapalog-based mTOR inhibition. Supplementary Figure 7. Immunoblots detecting phosphorylated mTOR at serine residues 2448 (S2448) and 2481 (S2481). Supplementary Figure 8. Copy number plots for multiple tumor regions in patient #3 showing the loss of chromosome 9 only in tumor regions carrying the TSC1 nonsense mutation (R3, R4). Supplementary Figure 9. Copy number plots for patient with tuberous sclerosis complex and metastatic unclassified RCC with extended benefit from everolimus therapy (44+ months). Supplementary Figure 10. PI3K pathway alterations as reported across 418 cases of clear cell RCC in TCGA. Alterations are detected in 42% of cases. Supplementary Figure 11: Hematoxylin and eosin (H&E) stains and immunohistochemistry for 4EBP1 phosphorylation (Thr 37/46), an mTORC1 downstream effector, in primary kidney tumors and adjacent normal kidney tissue for patients 1-5.

Published
2023

31. Data from Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Author

James J. Hsieh, Michael F. Berger, Robert J. Motzer, Emily H. Cheng, Paul Russo, Victor E. Reuter, Chris Sander, Nikolaus Schultz, Agnes Viale, Nicholas D. Socci, Sasinya N. Scott, Shugaku Takeda, Han Liu, Oguz Akin, Luis F. Cunha, Ying-Bei Chen, A. Rose Brannon, Can G. Pham, A. Ari Hakimi, and Martin H. Voss

Abstract

Purpose: Rapalogs are allosteric mTOR inhibitors and approved agents for advanced kidney cancer. Reports of clonal heterogeneity in this disease challenge the concept of targeted monotherapy, yet a small subset of patients derives extended benefit. Our aim was to analyze such outliers and explore the genomic background of extreme rapalog sensitivity in the context of intratumor heterogeneity.Experimental Design: We analyzed archived tumor tissue of 5 patients with renal cell carcinoma, who previously achieved durable disease control with rapalogs (median duration, 28 months). DNA was extracted from spatially separate areas of primary tumors and metastases. Custom target capture and ultradeep sequencing was used to identify alterations across 230 target genes. Whole-exome sequence analysis was added to investigate genes beyond this original target list.Results: Five long-term responders contributed 14 specimens to explore clonal heterogeneity. Genomic alterations with activating effect on mTOR signaling were detected in 11 of 14 specimens, offering plausible explanation for exceptional treatment response through alterations in two genes (TSC1 and MTOR). In two subjects, distinct yet functionally convergent alterations activated the mTOR pathway in spatially separate sites. In 1 patient, concurrent genomic events occurred in two separate pathway components across different tumor regions.Conclusions: Analysis of outlier cases can facilitate identification of potential biomarkers for targeted agents, and we implicate two genes as candidates for further study in this class of drugs. The previously reported phenomenon of clonal convergence can occur within a targetable pathway which might have implications for biomarker development beyond this disease and this class of agents. Clin Cancer Res; 20(7); 1955–64. ©2014 AACR.

Published
2023

32. Supplementary Table 3 from Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Author

James J. Hsieh, Michael F. Berger, Robert J. Motzer, Emily H. Cheng, Paul Russo, Victor E. Reuter, Chris Sander, Nikolaus Schultz, Agnes Viale, Nicholas D. Socci, Sasinya N. Scott, Shugaku Takeda, Han Liu, Oguz Akin, Luis F. Cunha, Ying-Bei Chen, A. Rose Brannon, Can G. Pham, A. Ari Hakimi, and Martin H. Voss

Abstract

XLSX file - 13K, Supplementary Table S3. Impact assay run statistics on all samples.

Published
2023

33. Supplementary Methods from Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy

Author

James J. Hsieh, Michael F. Berger, Robert J. Motzer, Emily H. Cheng, Paul Russo, Victor E. Reuter, Chris Sander, Nikolaus Schultz, Agnes Viale, Nicholas D. Socci, Sasinya N. Scott, Shugaku Takeda, Han Liu, Oguz Akin, Luis F. Cunha, Ying-Bei Chen, A. Rose Brannon, Can G. Pham, A. Ari Hakimi, and Martin H. Voss

Abstract

PDF file - 132K

Published
2023

34. Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Author

Leineweber, Can G., Rabehl, Miriam, Pietzner, Anne, Rohwer, Nadine, Rothe, Michael, Pech, Maciej, Sangro, Bruno, Sharma, Rohini, Verslype, Chris, Basu, Bristi, Sengel, Christian, Ricke, Jens, Schebb, Nils Helge, Weylandt, Karsten-H., Benckert, Julia, and Apollo - University of Cambridge Repository

Subjects
Pharmacology, omega-3 fatty acids, cytochrome P450, oxylipins, lipidomics, Pharmacology (medical), sorafenib, hepatocellular carcinoma, EDP, EET
Abstract

Peer reviewed: True, Acknowledgements: We thank the SORAMIC research group for providing the samples, recruiting patients, collecting patient information, and processing blood samples, and the patients for their participation. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)., Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.

Published
2023
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36. Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331 288 participants

Author

Danaei, G, Fahimi, S, Lu, Y, Zhou, B, Hajifathalian, K, Di Cesare, M, Lo, WC, Reis-Santos, B, Cowan, MJ, Shaw, JE, Bentham, J, Lin, JK, Bixby, H, Magliano, D, Bovet, P, Miranda, JJ, Khang, YH, Stevens, GA, Riley, LM, Ali, MK, Ezzati, M, Abdeen, ZA, Kadir, KA, Abu-Rmeileh, M, Acosta-Cazares, B, Aekplakorn, W, Aguilar-Salinas, CA, Ahmadvand, A, Al Nsour, M, Alkerwi, A, Amouyel, P, Andersen, LB, Anderssen, SA, Andrade, DS, Anjana, RM, Aounallah-Skhiri, H, Aris, T, Arlappa, N, Arveiler, D, Assah, FK, Avdicová, M, Balakrishna, N, Bandosz, P, Barbagallo, CM, Barceló, A, Batieha, AM, Baur, LA, Ben Romdhane, H, Bernabe-Ortiz, A, Bhargava, SK, Bi, Y, Bjerregaard, P, Björkelund, C, Blake, M, Blokstra, A, Bo, S, Boehm, BO, Boissonnet, CP, Brajkovich, I, Breckenkamp, J, Brewster, LM, Brian, GR, Bruno, G, Bugge, A, Cabrera de León, A, Can, G, Cândido, AP, Capuano, V, Carvalho, MJ, Casanueva, FF, Caserta, CA, Castetbon, K, Chamukuttan, S, Chaturvedi, N, Chen, CJ, Chen, F, Chen, S, Cheng, CY, Chetrit, A, Chiou, ST, Cho, Y, Chudek, J, Cifkova, R, Claessens, F, Concin, H, Cooper, C, Cooper, R, Costanzo, S, Cottel, D, Cowell, C, Crujeiras, AB, D'Arrigo, G, Dallongeville, J, Dankner, R, Dauchet, L, de Gaetano, G, De Henauw, S, Deepa, M, Dehghan, A, Dhana, K, Di Castelnuovo, AF, Djalalinia, S, Doua, K, Drygas, W, Du, Y, Egbagbe, EE, Eggertsen, R, El Ati, J, Elosua, R, Erasmus, RT, Erem, C, Ergor, G, Eriksen, L, Escobedo-de la Peña, J, Fall, CH, Farzadfar, F, Felix-Redondo, FJ, Ferguson, TS, Fernández-Bergés, D, Ferrari, M, Ferreccio, C, Finn, JD, Föger, B, Foo, LH, Fouad, HM, Francis, DK, Franco Mdo, C, Frontera, G, Furusawa, T, Gaciong, Z, Galbarczyk, A, Garnett, SP, Gaspoz, JM, Gasull, M, Gates, L, Geleijnse, JM, Ghasemain, A, Giampaoli, S, Gianfagna, F, Giovannelli, J, Gonzalez Gross, M, González Rivas, JP, Gorbea, MB, Gottrand, F, Grant, JF, Grodzicki, T, Grøntved, A, Gruden, G, Gu, D, Guan, OP, Guerrero, R, Guessous, I, Guimaraes, AL, Gutierrez, L, Hardy, R, Hari Kumar, R, Heidemann, C, Hihtaniemi, IT, Ho, SY, Ho, SC, Hofman, A, Horimoto, AR, Hormiga, CM, Horta, BL, Houti, L, Hussieni, AS, Huybrechts, I, Hwalla, N, Iacoviello, L, Iannone, AG, Ibrahim, MM, Ikeda, N, Ikram, MA, Irazola, VE, Islam, M, Iwasaki, M, Jacobs, JM, Jafar, T, Jasienska, G, Jiang, CQ, Jonas, JB, Joshi, P, Kafatos, A, Kalter-Leibovici, O, Kasaeian, A, Katz, J, Kaur, P, Kavousi, M, Kelishadi, R, Kengne, AP, Kersting, M, Khader, YS, Kiechl, S, Kim, J, Kiyohara, Y, Kolsteren, P, Korrovits, P, Koskinen, S, Kratzer, W, Kromhout, D, Kula, K, Kurjata, P, Kyobutungi, C, Lachat, C, Laid, Y, Lam, TH, Lanska, V, Lappas, G, Laxmaiah, A, Leclercq, C, Lee, J, Lehtimäki, T, Lekhraj, R, León-Muñoz, LM, Li, Y, Lim, WY, Lima-Costa, MF, Lin, HH, Lin, X, Lissner, L, Lorbeer, R, Lozano, JE, Lundqvist, A, Lytsy, P, Ma, G, Machado-Coelho, GL, Machi, S, Maggi, S, Makdisse, M, Mallikharjuna v, K, Manios, Y, Manzato, E, Margozzini, P, Marques-Vidal, P, Martorell, R, Masoodi, SR, Matsha, TE, Mbanya, JC, McFarlane, SR, McGarvey, ST, McLachlan, S, McNulty, BA, Mediene-Benchekor, S, Meirhaeghe, A, Menezes, AM, Merat, S, Meshram, II, Mi, J, Miquel, JF, Mohamed, MK, Mohammad, K, Mohan, V, Mohd Yusoff, MF, Møller, NC, Molnar, D, Mondo, CK, Moreno, LA, Morgan, K, Moschonis, G, Mossakowska, M, Mostafa, A, Mota, J, Muiesan, ML, Müller-Nurasyid, M, Mursu, J, Nagel, G, Námešná, J, Nang, EE, Nangia, VB, Navarrete-Muñoz, EM, Ndiaye, NC, Nervi, F, Nguyen, ND, Nieto-Martínez, RE, Alvarado, L, Ning, G, Ninomiya, T, Noale, M, Noto, D, Ochoa-Avilés, M, Oh, K, Onat, A, Osmond, C, Otero, JA, Palmieri, L, Panda-Jonas, S, Panza, F, Parsaeian, M, Peixoto, SV, Pereira, AC, Peters, A, Peykari, N, Pilav, A, Pitakaka, F, Piwonska, A, Piwonski, J, Plans-Rubió, P, Porta, M, Portegies, ML, Poustchi, H, Pradeepa, R, Price, JF, Punab, M, Qasrawi, RF, Qorbani, M, Raitakari, O, Ramachandra Rao, S, Ramachandran, A, Ramos, R, Rampal, S, Rathmann, W, Redon, J, Reganit, PF, Rigo, F, Robinson, SM, Robitaille, C, Rodríguez, LA, Rodríguez-Artalejo, F, del Cristo Rodriguez-Perez, M, Rojas-Martinez, R, Romaguera, D, Rosengren, A, Rubinstein, A, Rui, O, Ruiz-Betancourt, BS, Rutkowski, M, Sabanayagam, C, Sachdev, HS, Saidi, O, Sakarya, S, Salanave, B, Salonen, JT, Salvetti, M, Sánchez-Abanto, J, Santos, RN, Santos, R, Sardinha, LB, Scazufca, M, Schargrodsky, H, Scheidt-Nave, C, Shibuya, K, Shin, Y, Shiri, R, Siantar, R, Sibai, AM, Simon, M, Simons, J, Simons, LA, Sjostrom, M, Slowikowska-Hilczer, J, Slusarczyk, P, Smeeth, L, Snijder, MB, Solfrizzi, V, Sonestedt, E, Soumare, A, Staessen, JA, Steene-Johannessen, J, Stehle, P, Stein, AD, Stessman, J, Stöckl, D, Stokwiszewski, J, Strufaldi, MW, Sun, CA, Sundström, J, Suriyawongpaisal, P, Sy, RG, Tai, ES, Tarawneh, M, Tarqui-Mamani, CB, Thijs, L, Tolstrup, JS, Topbas, M, Torrent, M, Traissac, P, Trinh, OT, Tulloch-Reid, MK, Tuomainen, TP, Turley, ML, Tzourio, C, Ueda, P, Ukoli, FM, Ulmer, H, Valdivia, G, van Valkengoed, IG, Vanderschueren, D, Vanuzzo, D, Vega, T, Velasquez-Melendez, G, Veronesi, G, Verschuren, M, Vioque, J, Virtanen, J, Visvikis-Siest, S, Viswanathan, B, Vollenweider, P, Voutilainen, S, Wade, AN, Wagner, A, Walton, J, Mohamud, WN, Wang, MD, Wang, YX, Wannamethee, SG, Weerasekera, D, Whincup, PH, Widhalm, K, Wiecek, A, Wilks, RJ, Willeit, J, Wojtyniak, B, Wong, TY, Woo, J, Woodward, M, Wu, AG, Wu, FC, Wu, SL, Xu, H, Yang, X, Ye, X, Yoshihara, A, Younger-Coleman, NO, Zambon, S, Zargar, AH, Zdrojewski, T, Zhao, W, and Zheng, Y

Published
2015
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38. Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin

Author

Xu, Jianing, Pham, Can G., Albanese, Steven K., Dong, Yiyu, Oyama, Toshinao, Lee, Chung-Han, Rodrik-Outmezguine, Vanessa, Yao, Zhan, Han, Song, Chen, David, Parton, Daniel L., Chodera, John D., Rosen, Neal, Cheng, Emily H., and Hsieh, James J.

Subjects
Gene mutations -- Health aspects, Cancer -- Genetic aspects, Rapamycin -- Usage -- Physiological aspects, Cellular signal transduction -- Genetic aspects, Health care industry
Abstract

Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domaincontaining MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1=mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases., Introduction mTOR is a serine-threonine kinase that forms 2 distinct signaling complexes, mTORC1 and mTORC2 (1, 2), which are composed of common subunits (mTOR, mLST8, DEPTOR) (3, 4) and uniquely [...]

Published
2016
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39. INCIDENCE OF ANTERIOR UVEITIS IN AXIAL SPONDYLOARTHRITIS DURING SECUKINUMAB TREATMENT: TWO YEARS REAL LIFE EXPERIENCE FROM TURKBIO REGISTRY

Author

Akleylek, C., Akar, S., Cinakli, H., Sagir, R. Piskin, COŞKUN, NEJDET, Karakas, A., Apaydin, H., Kardas, R. C., Isik, O. Ozdemir, Hakbilen, S., Okyar, B., Sosyal, O., Koca, S. S., PEHLİVAN, YAVUZ, DALKILIÇ, HÜSEYİN EDİZ, Can, G., Sari, I., BİRLİK, AHMET MERİH, Erten, S., ÖZTÜRK, AKİF MUHTAR, Yazici, A., Cefle, A., Yilmaz, S., ÇETİN, GÖZDE YILDIRIM, Akkoc, N., Yilmaz, N., and Onen, F.

Published
2022

40. COVID-19 VACCINATION OF SPONDYLOARTHRITIS PATIENTS RECEIVING BIOLOGICAL THERAPY: REAL-LIFE DATA

Author

Erten, S., Dalkiliç, E., Can, G., Sari, İ., Birlik, M., Onen, FATOŞ, Demirci Yildirim, TUBA, Akleylek, C., Cinakli, H., Yildirim, D., Hakbilen, S., Coşkun, B. N., Okyar, B., Ozdemir Isik, O., Piskin Sagir, R., Apaydin, H., Gulle, S., Erez, Y., Yüce İnel, Tuba, Yilmaz, N., Akar, S., Tufan, A., Yilmaz, S., Pehlivan, Y., Yildirim Cetin, G., Cefle, A., Koca, S. S., and Yazici, A.

Published
2022

45. A NEW SCREENING TOOL FOR PSORIATIC ARTHRITIS IN PSORIASIS PATIENTS: TURPAS

Author

Inanc, M., Kalyoncu, U., Yayli, S., UĞURLU, SERDAL, Onen, F., Kiraz, S., Hamuryudan, V., ENGİN, BURHAN, BORLU, MURAT, Baskan, E. Bulbul, Solak, E. Oksum, Yalici-Armagan, B., Bektas, M., Ozdede, A., Akdogan, N., Atakan, N., Adisen, E. Ozsoy, Yazici, S., Hatemi, G., Can, G., and AYAN, GİZEM

Published
2022

48. Risk factors for malignancy in systemic sclerosis patients

Author

Kaşifoğlu, T., Yaşar Bilge, Ş., Yıldız, F., Özen, G., Pehlivan, Y., Yılmaz, N., Tarhan, F., Yılmaz, S., Küçük, A., Emmungil, H., Koca, S. S., Çınar, M., Direskeneli, H., Erken, E., Can, G., Özmen, M., Gönüllü, E., Kisacik, B., Aksu, K., Karadağ, O., Kasifoglu, N., Arslantas, D., Sahin, F., Keser, G., Yavuz, S., Birlik, M., and Onat, A. M.

Published
2016
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49. The role of site effects on elevated seismic demands and corollary structural damage during the October 30, 2020, M7.0 Samos Island (Aegean Sea) Earthquake

Author

Cetin, KO, Cetin, KO, Papadimitriou, AG, Altun, S, Pelekis, P, Unutmaz, B, Rovithis, E, Akgun, M, Klimis, N, Askan, A, Ziotopoulou, K, Sezer, A, Kincal, C, Ilgac, M, Can, G, Cakir, E, Soylemez, B, Al-Suhaily, A, Elsaid, A, Zarzour, M, Stewart, J, Mylonakis, G, Cetin, KO, Cetin, KO, Papadimitriou, AG, Altun, S, Pelekis, P, Unutmaz, B, Rovithis, E, Akgun, M, Klimis, N, Askan, A, Ziotopoulou, K, Sezer, A, Kincal, C, Ilgac, M, Can, G, Cakir, E, Soylemez, B, Al-Suhaily, A, Elsaid, A, Zarzour, M, Stewart, J, and Mylonakis, G

Abstract

On October 30, 2020 14:51 (UTC), a moment magnitude (M) 7.0 (USGS, EMSC) earthquake occurred in the Aegean Sea. This paper presents the reconnaissance findings regarding the site effects on recorded strong ground motion intensities and duration, along with the resulting induced-structural damage in Izmir Bay and Samos Island, respectively. In all rock records, relatively high intensity long period rock spectral accelerations were observed in the mid to long period range of 0.5–1.5 s, which are attributed to the source, more specifically, to the slower rupture-mechanism of the event. These rich spectral intensities were further amplified by soil site effects and soil-superstructure resonance, leading to two to six times amplified overall responses and prolonged seismic shaking durations, more pronounced in Bayrakli and other Izmir Bay sites in Turkey. However, these amplified and prolonged excitations are still below design basis earthquake levels, which addresses the lack of proper structural design and construction deficiencies, as the underlying causes for the collapse to heavy damage performance of 795 buildings. On the other hand, although located only about 10 km from the rupture (22 km from the epicenter) and within the near fault zone, the town of Vathy on Samos Island (Greece) was rather lightly affected by the earthquake, with relatively few collapsed or heavily damaged buildings, partially attributed to the low height/low weight of structures in the area. However, a concentration of damage in low-rise buildings in Ano Vathy hill is considered indicative of a combination of coupled valley and topography effects on the strong motion. This event once again addressed the need to develop region-specific zonation and provisions, when more general code practices are proven to be inadequate to assess these extreme site effects.

Published
2022

50. Geotechnical reconnaissance findings of the October 30 2020, Mw7.0 Samos Island (Aegean Sea) earthquake

Author

Ziotopoulou, K, Ziotopoulou, K, Cetin, KO, Pelekis, P, Altun, S, Klimis, N, Sezer, A, Rovithis, E, Yılmaz, MT, Papadimitriou, AG, Gulerce, Z, Can, G, Ilgac, M, Cakır, E, Soylemez, B, Al-Suhaily, A, Elsaid, A, Zarzour, M, Ecemis, N, Unutmaz, B, Kockar, MK, Akgun, M, Kincal, C, Bayat, EE, Ozener, PT, Stewart, JP, Mylonakis, G, Ziotopoulou, K, Ziotopoulou, K, Cetin, KO, Pelekis, P, Altun, S, Klimis, N, Sezer, A, Rovithis, E, Yılmaz, MT, Papadimitriou, AG, Gulerce, Z, Can, G, Ilgac, M, Cakır, E, Soylemez, B, Al-Suhaily, A, Elsaid, A, Zarzour, M, Ecemis, N, Unutmaz, B, Kockar, MK, Akgun, M, Kincal, C, Bayat, EE, Ozener, PT, Stewart, JP, and Mylonakis, G

Abstract

On October 30, 2020 14:51 (UTC), a moment magnitude (Mw) of 7.0 (USGS, EMSC) earthquake occurred in the Aegean Sea north of the island of Samos, Greece. Turkish and Hellenic geotechnical reconnaissance teams were deployed immediately after the event and their findings are documented herein. The predominantly observed failure mechanism was that of earthquake-induced liquefaction and its associated impacts. Such failures are presented and discussed together with a preliminary assessment of the performance of building foundations, slopes and deep excavations, retaining structures and quay walls. On the Anatolian side (Turkey), and with the exception of the Izmir-Bayrakli region where significant site effects were observed, no major geotechnical effects were observed in the form of foundation failures, surface manifestation of liquefaction and lateral soil spreading, rock falls/landslides, failures of deep excavations, retaining structures, quay walls, and subway tunnels. In Samos (Greece), evidence of liquefaction, lateral spreading and damage to quay walls in ports were observed on the northern side of the island. Despite the proximity to the fault (about 10 km), the amplitude and the duration of shaking, the associated liquefaction phenomena were not pervasive. It is further unclear whether the damage to quay walls was due to liquefaction of the underlying soil, or merely due to the inertia of those structures, in conjunction with the presence of soft (yet not necessarily liquefied) foundation soil. A number of rockfalls/landslides were observed but the relevant phenomena were not particularly severe. Similar to the Anatolian side, no failures of engineered retaining structures and major infrastructure such as dams, bridges, viaducts, tunnels were observed in the island of Samos which can be mostly attributed to the lack of such infrastructure.

Published
2022

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