المؤلفون: Samuel Rivero-Hinojosa, Melanie Grant, Aswini Panigrahi, Huizhen Zhang, Veronika Caisova, Catherine M. Bollard, Brian R. Rood

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021)

مصطلحات موضوعية: Science

الوصف: Targeting tumor-associated antigens in paediatric medulloblastomas (MB) is challenging due to their low mutational burden. Here, the authors develop a sensitive proteogenomic approach to identify tumour specific neoantigens, which may enable personalised T cell immunotherapy in paediatric MB.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/840da9f71cf2490ba9c63c3c085c7058Test

المؤلفون: Ayenachew Bezawork-Geleta, He Wen, LanFeng Dong, Bing Yan, Jelena Vider, Stepana Boukalova, Linda Krobova, Katerina Vanova, Renata Zobalova, Margarita Sobol, Pavel Hozak, Silvia Magalhaes Novais, Veronika Caisova, Pavel Abaffy, Ravindra Naraine, Ying Pang, Thiri Zaw, Ping Zhang, Radek Sindelka, Mikael Kubista, Steven Zuryn, Mark P. Molloy, Michael V. Berridge, Karel Pacak, Jakub Rohlena, Sunghyouk Park, Jiri Neuzil

المصدر: Nature Communications, Vol 9, Iss 1, Pp 1-17 (2018)

مصطلحات موضوعية: Science

الوصف: Mitochondrial complex II is normally composed of four subunits. Here the authors show that bioenergetic stress conditions give rise to a partially assembled variant of complex II, which shifts the anabolic pathways to less energy demanding processes.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/762a6e8dd0c245dd8c980ced8121b927Test

المؤلفون: Ondrej Uher, Thanh-Truc Huynh, Boqun Zhu, Lucas A. Horn, Veronika Caisova, Katerina Hadrava Vanova, Rogelio Medina, Herui Wang, Claudia Palena, Jindrich Chmelar, Zhengping Zhuang, Jan Zenka, Karel Pacak

المصدر: Cancers, Vol 13, Iss 16, p 3942 (2021)

مصطلحات موضوعية: pheochromocytoma, intratumoral immunotherapy, immune memory, toll-like receptor, bilateral tumor model, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Immunotherapy has become an essential component in cancer treatment. However, the majority of solid metastatic cancers, such as pheochromocytoma, are resistant to this approach. Therefore, understanding immune cell composition in primary and distant metastatic tumors is important for therapeutic intervention and diagnostics. Combined mannan-BAM, TLR ligand, and anti-CD40 antibody-based intratumoral immunotherapy (MBTA therapy) previously resulted in the complete eradication of murine subcutaneous pheochromocytoma and demonstrated a systemic antitumor immune response in a metastatic model. Here, we further evaluated this systemic effect using a bilateral pheochromocytoma model, performing MBTA therapy through injection into the primary tumor and using distant (non-injected) tumors to monitor size changes and detailed immune cell infiltration. MBTA therapy suppressed the growth of not only injected but also distal tumors and prolonged MBTA-treated mice survival. Our flow cytometry analysis showed that MBTA therapy led to increased recruitment of innate and adaptive immune cells in both tumors and the spleen. Moreover, adoptive CD4+ T cell transfer from successfully MBTA-treated mice (i.e., subcutaneous pheochromocytoma) demonstrates the importance of these cells in long-term immunological memory. In summary, this study unravels further details on the systemic effect of MBTA therapy and its use for tumor and metastasis reduction or even elimination.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/13/16/3942Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/be21110636cf4ca7906f35724ac679deTest

المؤلفون: Yang Liu, Ying Pang, Veronika Caisova, Jianyi Ding, Di Yu, Yiqiang Zhou, Thanh-Truc Huynh, Hans Ghayee, Karel Pacak, Chunzhang Yang

المصدر: Cancers, Vol 12, Iss 2, p 280 (2020)

مصطلحات موضوعية: nrf2, glutathione metabolism, sdhb mutation, pheochromocytoma, paraganglioma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Succinate dehydrogenase subunit B (SDHB) deficiency frequently occurs in cluster I pheochromocytomas and paragangliomas (PCPGs). SDHB-mutated PCPGs are characterized by alterations in the electron transport chain, metabolic reprogramming of the tricarboxylic cycle, and elevated levels of reactive oxygen species (ROS). We discovered that SDHB-deficient PCPG cells exhibit increased oxidative stress burden, which leads to elevated demands for glutathione metabolism. Mechanistically, nuclear factor erythroid 2-related factor 2 (NRF2)-guided glutathione de novo synthesis plays a key role in supporting cellular survival and the proliferation of SDHB-knockdown (SDHBKD) cells. NRF2 blockade not only disrupted ROS homeostasis in SDHB-deficient cells but also caused severe cytotoxicity by the accumulation of DNA oxidative damage. Brusatol, a potent NRF2 inhibitor, showed a promising effect in suppressing SDHBKD metastatic lesions in vivo, with prolonged overall survival in mice bearing PCPG allografts. Our findings highlight a novel therapeutic strategy of targeting the NRF2-driven glutathione metabolic pathway against SDHB-mutated PCPG.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/12/2/280Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/dbf8173940ee4c3ebac4589e51f3436dTest

المؤلفون: Veronika Caisova, Liping Li, Garima Gupta, Ivana Jochmanova, Abhishek Jha, Ondrej Uher, Thanh-Truc Huynh, Markku Miettinen, Ying Pang, Luma Abunimer, Gang Niu, Xiaoyuan Chen, Hans Kumar Ghayee, David Taïeb, Zhengping Zhuang, Jan Zenka, Karel Pacak

المصدر: Cancers, Vol 11, Iss 5, p 654 (2019)

مصطلحات موضوعية: pheochromocytoma, paraganglioma, metastatic, immunotherapy, innate immunity, adaptive immunity, toll-like receptor, pathogen-associated molecular patterns, neutrophil, T cell, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Therapeutic options for metastatic pheochromocytoma/paraganglioma (PHEO/PGL) are limited. Here, we tested an immunotherapeutic approach based on intratumoral injections of mannan-BAM with toll-like receptor ligands into subcutaneous PHEO in a mouse model. This therapy elicited a strong innate immunity-mediated antitumor response and resulted in a significantly lower PHEO volume compared to the phosphate buffered saline (PBS)-treated group and in a significant improvement in mice survival. The cytotoxic effect of neutrophils, as innate immune cells predominantly infiltrating treated tumors, was verified in vitro. Moreover, the combination of mannan-BAM and toll-like receptor ligands with agonistic anti-CD40 was associated with increased mice survival. Subsequent tumor re-challenge also supported adaptive immunity activation, reflected primarily by long-term tumor-specific memory. These results were further verified in metastatic PHEO, where the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 into subcutaneous tumors resulted in significantly less intense bioluminescence signals of liver metastatic lesions induced by tail vein injection compared to the PBS-treated group. Subsequent experiments focusing on the depletion of T cell subpopulations confirmed the crucial role of CD8+ T cells in inhibition of bioluminescence signal intensity of liver metastatic lesions. These data call for a new therapeutic approach in patients with metastatic PHEO/PGL using immunotherapy that initially activates innate immunity followed by an adaptive immune response.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/11/5/654Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/a3ffa00498a04078acc70eee28d851eeTest

المؤلفون: Karel Pacak, Chunzhang Yang, Mark Levine, Jiri Neuzil, Hans Kumar Ghayee, Katerina Hadrava Vanova, David Taieb, Thanh-Truc Huynh, Veronika Caisova, Ondrej Uher, Boqun Zhu, Ying Pang, Yang Liu

الوصف: Supplemental Figure 2

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5147324c4fe44829b19d41bc6549b8e3Test
https://doi.org/10.1158/1078-0432.22476003.v1Test

المؤلفون: Karel Pacak, Chunzhang Yang, Mark Levine, Jiri Neuzil, Hans Kumar Ghayee, Katerina Hadrava Vanova, David Taieb, Thanh-Truc Huynh, Veronika Caisova, Ondrej Uher, Boqun Zhu, Ying Pang, Yang Liu

الوصف: Supplemental Figure 3

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::29c5bbb0a7611c41d965bda12d679f8aTest
https://doi.org/10.1158/1078-0432.22476000Test

المؤلفون: Chunzhang Yang, Karel Pacak, David Taïeb, Igor Hartmann, Zdenek Frysak, Di Yu, Yiqiang Zhou, Thanh-Truc Huynh, Petra Bullova, Yang Liu, Veronika Caisova, Yanxin Lu, Ying Pang

الوصف: Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors.Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft.Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423–32. ©2018 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c573d5686b5aefb81ac0f1c35b3d4bf2Test
https://doi.org/10.1158/1078-0432.c.6527448.v1Test

المؤلفون: Karel Pacak, Chunzhang Yang, Mark Levine, Jiri Neuzil, Hans Kumar Ghayee, Katerina Hadrava Vanova, David Taieb, Thanh-Truc Huynh, Veronika Caisova, Ondrej Uher, Boqun Zhu, Ying Pang, Yang Liu

الوصف: Supplementary Table

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::16a92f13b4593df18d2f8ae45aee8242Test
https://doi.org/10.1158/1078-0432.22475997.v1Test

المؤلفون: Chunzhang Yang, Karel Pacak, David Taïeb, Igor Hartmann, Zdenek Frysak, Di Yu, Yiqiang Zhou, Thanh-Truc Huynh, Petra Bullova, Yang Liu, Veronika Caisova, Yanxin Lu, Ying Pang

الوصف: Supplementary Figures S1 A. Quantitative PCR showed CA9, PNMT, and VEGFA expression in MTT cells. Higher expressions of hypoxia related genes were detected in SDHBKD cells. B. NAD+ quantification confirmed depletion of NAD+ by Nampt inhibitors FK866 and CHS828. C. Blue native gel analysis on mitochondrial complex formation in MTT cells (left panel). Mitochondrial complex I formation is increased in SDHBKD cells. In gel enzyme activity assay (IGA) showed elevated mitochondrial complex I activity in SDHBKD cells (right panel). D. Re-expression of SDHB in MTT cells (upper panel). The re-expression of SDHB reduced pADPR formation in SDHBKD cells, with a corresponding increased of γH2A.X expression (lower panel). E. Quantification of NAD+/NADH ratio in MTT cells. Re-expression of SDHB partially reversed the elevated NAD+/NADH ratio in SDHBKD cells. F. Quantification of flow cytometry data. A significant G2/M arrest is seen in combination treated group. G. Western blot for MGMT detection in MTT cells. No MGMT expression was seen in either SDHBWT or SDHBKD cells.ï€ ï�¢-actin was used as loading control. H. Cell viability test showing enhanced cytotoxic effect of combination treatment. **p

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7390baae7a15d016f064b6b06bd2feffTest
https://doi.org/10.1158/1078-0432.22470177.v1Test