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1. Spectroscopy of deeply bound orbitals in neutron-rich Ca isotopes

Author

Li, P. J., Lee, J., Doornenbal, P., Chen, S., Wang, S., Obertelli, A., Chazono, Y., Holt, J. D., Hu, B. S., Ogata, K., Utsuno, Y., Yoshida, K., Achouri, N. L., Baba, H., Browne, F., Calvet, D., Château, F., Chiga, N., Corsi, A., Cortés, M. L., Delbart, A., Gheller, J-M., Giganon, A., Gillibert, A., Hilaire, C., Isobe, T., Kobayashi, T., Kubota, Y., Lapoux, V., Liu, H. N., Motobayashi, T., Murray, I., Otsu, H., Panin, V., Paul, N., Rodriguez, W., Sakurai, H., Sasano, M., Steppenbeck, D., Stuhl, L., Sun, Y. L., Togano, Y., Uesaka, T., Wimmer, K., Yoneda, K., Aktas, O., Aumann, T., Boretzky, K., Caesar, C., Chung, L. X., Flavigny, F., Franchoo, S., Gasparic, I., Gerst, R. -B., Gibelin, J., Hahn, K. I., Kahlbow, J., Kim, D., Koiwai, T., Kondo, Y., Körper, D., Koseoglou, P., Lehr, C., Linh, B. D., Lokotko, T., MacCormick, M., Miki, K., Moschner, K., Nakamura, T., Park, S. Y., Rossi, D., Sahin, E., Schindler, F., Simon, H., Söderström, P-A., Sohler, D., Takeuchi, S., Toernqvist, H., Tscheuschner, J., Vaquero, V., Wagner, V., Werner, V., Xu, X., Yamada, H., Yan, D., Yang, Z., Yasuda, M., and Zanetti, L.

Subjects
Nuclear Experiment, Nuclear Theory
Abstract

The calcium isotopes are an ideal system to investigate the evolution of shell structure and magic numbers. Although the properties of surface nucleons in calcium have been well studied, probing the structure of deeply bound nucleons remains a challenge. Here, we report on the first measurement of unbound states in $^{53}$Ca and $^{55}$Ca, populated from \ts{54,56}Ca($p,pn$) reactions at a beam energy of around 216 MeV/nucleon at the RIKEN Radioactive Isotopes Beam Factory. The resonance properties, partial cross sections, and momentum distributions of these unbound states were analyzed. Orbital angular momentum $l$ assignments were extracted from momentum distributions based on calculations using the distorted wave impulse approximation (DWIA) reaction model. The resonances at excitation energies of 5516(41)\,keV in $^{53}$Ca and 6000(250)\,keV in $^{55}$Ca indicate a significant $l$\, =\,3 component, providing the first experimental evidence for the $\nu 0f_{7/2}$ single-particle strength of unbound hole states in the neutron-rich Ca isotopes. The observed excitation energies and cross-sections point towards extremely localized and well separated strength distributions, with some fragmentation for the $\nu 0f_{7/2}$ orbital in $^{55}$Ca. These results are in good agreement with predictions from shell-model calculations using the effective GXPF1Bs interaction and \textit{ab initio} calculations and diverge markedly from the experimental distributions in the nickel isotones at $Z=28$., Comment: 13 pages, 7 figures

Published
2024
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2. Level Structures of $^{56,58}$Ca Cast Doubt on a doubly magic $^{60}$Ca

Author

Chen, S., Browne, F., Doornenbal, P., Lee, J., Obertelli, A., Tsunoda, Y., Otsuka, T., Chazono, Y., Hagen, G., Holt, J. D., Jansen, G. R., Ogata, K., Shimizu, N., Utsuno, Y., Yoshida, K., Achouri, N. L., Baba, H., Calvet, D., Château, F., Chiga, N., Corsi, A., Cortés, M. L., Delbart, A., Gheller, J. -M., Giganon, A., Gillibert, A., Hilaire, C., Isobe, T., Kobayashi, T., Kubota, Y., Lapoux, V., Liu, H. N., Motobayashi, T., Murray, I., Otsu, H., Panin, V., Paul, N., Rodriguez, W., Sakurai, H., Sasano, M., Steppenbeck, D., Stuhl, L., Sun, Y. L., Togano, Y., Uesaka, T., Wimmer, K., Yoneda, K., Aktas, O., Aumann, T., Chung, L. X., Flavigny, F., Franchoo, S., Gasparic, I., Gerst, R. -B., Gibelin, J., Hahn, K. I., Kim, D., Koiwai, T., Kondo, Y., Koseoglou, P., Lehr, C., Linh, B. D., Lokotko, T., MacCormick, M., Moschner, K., Nakamura, T., Park, S. Y., Rossi, D., Sahin, E., Söderström, P. -A., Sohler, D., Takeuchi, S., Törnqvist, H., Vaquero, V., Wagner, V., Wang, S., Werner, V., Xu, X., Yamada, H., Yan, D., Yang, Z., Yasuda, M., and Zanetti, L.

Subjects
Nuclear Experiment, Nuclear Theory
Abstract

Gamma decays were observed in $^{56}$Ca and $^{58}$Ca following quasi-free one-proton knockout reactions from $^{57,59}$Sc beams at $\approx 200$ MeV/nucleon. For $^{56}$Ca, a $\gamma$ ray transition was measured to be 1456(12) keV, while for $^{58}$Ca an indication for a transition was observed at 1115(34) keV. Both transitions were tentatively assigned as the $2^+_1 \rightarrow 0^+_{gs}$ decays, and were compared to results from ab initio and conventional shell-model approaches. A shell-model calculation in a wide model space with a marginally modified effective nucleon-nucleon interaction depicts excellent agreement with experiment for $2^+_1$ level energies, two-neutron separation energies, and reaction cross sections, corroborating the formation of a new nuclear shell above the $N$ = 34 shell. Its constituents, the $0f_{5/2}$ and $0g_{9/2}$ orbitals, are almost degenerate. This degeneracy precludes the possibility for a doubly magic $^{60}$Ca and potentially drives the dripline of Ca isotopes to $^{70}$Ca or even beyond., Comment: 8 pages, 3 figures

Published
2023
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4. A First Glimpse at the Shell Structure beyond $^{54}$Ca: Spectroscopy of $^{55}$K, $^{55}$Ca, and $^{57}$Ca

Author

Koiwai, T., Wimmer, K., Doornenbal, P., Obertelli, A., Barbieri, C., Duguet, T., Holt, J. D., Miyagi, T., Navrátil, P., Ogata, K., Shimizu, N., Somà, V., Utsuno, Y., Yoshida, K., Achouri, N. L., Baba, H., Browne, F., f, D. Calvet, Château, F., Chen, S., Chiga, N., Corsi, A., Cortés, M. L., Delbart, A., Gheller, J. -M., Giganon, A., Gillibert, A., Hilaire, C., Isobe, T., Kobayashi, T., Kubota, Y., Lapoux, V., Liu, H. N., Motobayashi, T., Murray, I., Otsu, H., Panin, V., Paul, N., Rodriguez, W., Sakurai, H., Sasano, M., Steppenbeck, D., Stuhl, L., Sun, Y. L., Togano, Y., Uesaka, T., Yoneda, K., Aktas, O., Aumann, T., Chung, L. X., Flavigny, F., Franchoo v, S., Gasparic, I., Gerst, R. -B., Gibelin, J., Hahn, K. I., Kim, D., Kondo, Y., Koseoglou, P., Lee, J., Lehr, C., Linh, B. D., Lokotko, T., MacCormick, M., Moschner, K., Nakamura, T., Park, S. Y., Rossi, D., Sahin, E., Söderström, P-A., Sohler, D., Takeuchi, S., Toernqvist, H., Vaquero, V., Wagner, V., Wang, S., Werner, V., Xu, X., Yamada, H., Yan, D., Yang, Z., Yasuda, M., and Zanetti, L.

Subjects
Nuclear Experiment
Abstract

States in the $N=35$ and 37 isotopes $^{55,57}$Ca have been populated by direct proton-induced nucleon removal reactions from $^{56,58}$Sc and $^{56}$Ca beams at the RIBF. In addition, the $(p,2p)$ quasi-free single-proton removal reaction from $^{56}$Ca was studied. Excited states in $^{55}$K, $^{55}$Ca, and $^{57}$Ca were established for the first time via in-beam $\gamma$-ray spectroscopy. Results for the proton and neutron removal reactions from $^{56}$Ca to states in $^{55}$K and $^{55}$Ca for the level energies, excited state lifetimes, and exclusive cross sections agree well with state-of-the-art theoretical calculations using different approaches. The observation of a short-lived state in $^{57}$Ca suggests a transition in the calcium isotopic chain from single-particle dominated states at $N=35$ to collective excitations at $N=37$., Comment: accepted Phys. Lett. B

Published
2022
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5. Investigation of the ground-state spin inversion in the neutron-rich 47,49Cl isotopes

Author

Linh, B. D., Corsi, A., Gillibert, A., Obertelli, A., Doornenbal, P., Barbieri, C., Chen, S., Chung, L. X., Duguet, T., Gómez-Ramos, M., Holt, J. D., Moro, A., Navrátil, P., Ogata, K., Phuc, N. T. T., Shimizu, N., Somà, V., Utsuno, Y., Achouri, N. L., Baba, H., Browne, F., Calvet, D., Château, F., Chiga, N., Cortés, M. L., Delbart, A., Gheller, J. -M., Giganon, A., Hilaire, C., Isobe, T., Kobayashi, T., Kubota, Y., Lapoux, V., Liu, H. N., Motobayashi, T., Murray, I., Otsu, H., Panin, V., Paul, N., Rodriguez, W., Sakurai, H., Sasano, M., Steppenbeck, D., Stuhl, L., Sun, Y. L., Togano, Y., Uesaka, T., Wimmer, K., Yoneda, K., Aktas, O., Aumann, T., Flavigny, F., Franchoo, S., Gašparić, I., Gerst, R. -B., Gibelin, J., Hahn, K. I., Khai, N. T., Kim, D., Koiwai, T., Kondo, Y., Koseoglou, P., Lee, J., Lehr, C., Lokotko, T., MacCormick, M., Moschner, K., Nakamura, T., Park, S. Y., Rossi, D., Sahin, E., Sohler, D., Söderström, P. -A., Takeuchi, S., Ton, N. D., Törnqvist, H., Vaquero, V., Wagner, V., Wang, H., Werner, V., Xu, X., Yamada, Y., Yan, D., Yang, Z., Yasuda, M., and Zanetti, L.

Subjects
Nuclear Experiment, Nuclear Theory
Abstract

A first gamma-ray study of 47,49Cl spectroscopy was performed at the Radioactive Isotope Beam Factory with 50Ar projectiles at 217 MeV/nucleon, impinging on the liquid hydrogen target of the MINOS device. Prompt de-excitation gamma-rays were measured with the NaI(Tl) array DALI2+. Through the one-proton knockout reaction 50Ar(p,2p), a spin assignment could be determined for the low-lying states of 49Cl from the momentum distribution obtained with the SAMURAI spectrometer. A spin-parity J = 3/2+ is deduced for the ground state of 49Cl, similar to the recently studied N = 32 isotope 51K.

Published
2021
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6. $\boldsymbol{N=32}$ shell closure below calcium: Low-lying structure of $^{50}$Ar

Author

Cortés, M. L., Rodriguez, W., Doornenbal, P., Obertelli, A., Holt, J. D., Menéndez, J., Ogata, K., Schwenk, A., Shimizu, N., Simonis, J., Utsuno, Y., Yoshida, K., Achouri, L., Baba, H., Browne, F., Calvet, D., Château, F., Chen, S., Chiga, N., Corsi, A., Delbart, A., Gheller, J-M., Giganon, A., Gillibert, A., Hilaire, C., Isobe, T., Kobayashi, T., Kubota, Y., Lapoux, V., Liu, H. N., Motobayashi, T., Murray, I., Otsu, H., Panin, V., Paul, N., Sakurai, H., Sasano, M., Steppenbeck, D., Stuhl, L., Sun, Y. L., Togano, Y., Uesaka, T., Wimmer, K., Yoneda, K., Aktas, O., Aumann, T., Chung, L. X., Flavigny, F., Franchoo, S., Gašparić, I., Gerst, R. -B., Gibelin, J., Hahn, K. I., Kim, D., Koiwai, T., Kondo, Y., Koseoglou, P., Lee, J., Lehr, C., Linh, B. D., Lokotko, T., MacCormick, M., Moschner, K., Nakamura, T., Park, S. Y., Rossi, D., Sahin, E., Söderström, P. -A., Sohler, D., Takeuchi, S., Toernqvist, H., Vaquero, V., Wagner, V., Wang, S., Werner, V., Xu, X., Yamada, H., Yan, D., Yang, Z., Yasuda, M., and Zanetti, L.

Subjects
Nuclear Experiment
Abstract

Low-lying excited states in the $N=32$ isotope $^{50}$Ar were investigated by in-beam $\gamma$-ray spectroscopy following proton- and neutron-knockout, multi-nucleon removal, and proton inelastic scattering at the RIKEN Radioactive Isotope Beam Factory. The energies of the two previously reported transitions have been confirmed, and five additional states are presented for the first time, including a candidate for a 3$^-$ state. The level scheme built using $\gamma\gamma$ coincidences was compared to shell-model calculations in the $sd-pf$ model space, and to ab initio predictions based on chiral two- and three-nucleon interactions. Theoretical proton- and neutron-knockout cross sections suggest that two of the new transitions correspond to $2^+$ states, while the previously proposed $4^+$ state could also correspond to a $2^+$ state., Comment: Accepted for Phys. Rev. C

Published
2020
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7. Shell evolution of $N=40$ isotones towards $^{60}$Ca: First spectroscopy of $^{62}$Ti

Author

Cortés, M. L., Rodriguez, W., Doornenbal, P., Obertelli, A., Holt, J. D., Lenzi, S. M., Menéndez, J., Nowacki, F., Ogata, K., Poves, A., Rodríguez, T. R., Schwenk, A., Simonis, J., Stroberg, S. R., Yoshida, K., Achouri, L., Baba, H., Browne, F., Calvet, D., Château, F., Chen, S., Chiga, N., Corsi, A., Delbart, A., Gheller, J-M., Giganon, A., Gillibert, A., Hilaire, C., Isobe, T., Kobayashi, T., Kubota, Y., Lapoux, V., Liu, H. N., Motobayashi, T., Murray, I., Otsu, H., Panin, V., Paul, N., Sakurai, H., Sasano, M., Steppenbeck, D., Stuhl, L., Sun, Y. L., Togano, Y., Uesaka, T., Wimmer, K., Yoneda, K., Aktas, O., Aumann, T., Chung, L. X., Flavigny, F., Franchoo, S., Gašparić, I., Gerst, R. -B., Gibelin, J., Hahn, K. I., Kim, D., Koiwai, T., Kondo, Y., Koseoglou, P., Lee, J., Lehr, C., Linh, B. D., Lokotko, T., MacCormick, M., Moschner, K., Nakamura, T., Park, S. Y., Rossi, D., Sahin, E., Sohler, D., Söderström, P. -A., Takeuchi, S., Toernqvist, H., Vaquero, V., Wagner, V., Wang, S., Werner, V., Xu, X., Yamada, H., Yan, D., Yang, Z., Yasuda, M., and Zanetti, L.

Subjects
Nuclear Experiment, Nuclear Theory
Abstract

Excited states in the $N=40$ isotone $^{62}$Ti were populated via the $^{63}$V$(p,2p)$$^{62}$Ti reaction at $\sim$200~MeV/u at the Radioactive Isotope Beam Factory and studied using $\gamma$-ray spectroscopy. The energies of the $2^+_1 \rightarrow 0^{+}_{\mathrm{gs}}$ and $4^+_1 \rightarrow 2^+_1$ transitions, observed here for the first time, indicate a deformed $^{62}$Ti ground state. These energies are increased compared to the neighboring $^{64}$Cr and $^{66}$Fe isotones, suggesting a small decrease of quadrupole collectivity. The present measurement is well reproduced by large-scale shell-model calculations based on effective interactions, while ab initio and beyond mean-field calculations do not yet reproduce our findings. The shell-model calculations for $^{62}$Ti show a dominant configuration with four neutrons excited across the $N=40$ gap. Likewise, they indicate that the $N=40$ island of inversion extends down to $Z=20$, disfavoring a possible doubly magic character of the elusive $^{60}$Ca.

Published
2019
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8. How Robust is the N = 34 Subshell Closure? First Spectroscopy of $^{52}$Ar

Author

Liu, H. N., Obertelli, A., Doornenbal, P., Bertulani, C. A., Hagen, G., Holt, J. D., Jansen, G. R., Morris, T. D., Schwenk, A., Stroberg, R., Achouri, N., Baba, H., Browne, F., Calvet, D., Château, F., Chen, S., Chiga, N., Corsi, A., Cortés, M. L., Delbart, A., Gheller, J. -M., Giganon, A., Gillibert, A., Hilaire, C., Isobe, T., Kobayashi, T., Kubota, Y., Lapoux, V., Motobayashi, T., Murray, I., Otsu, H., Panin, V., Paul, N., Rodriguez, W., Sakurai, H., Sasano, M., Steppenbeck, D., Stuhl, L., Sun, Y. L., Togano, Y., Uesaka, T., Wimmer, K., Yoneda, K., Aktas, O., Aumann, T., Chung, L. X., Flavigny, F., Franchoo, S., Gašparić, I., Gerst, R. -B., Gibelin, J., Hahn, K. I., Kim, D., Koiwai, T., Kondo, Y., Koseoglou, P., Lee, J., Lehr, C., Linh, B. D., Lokotko, T., MacCormick, M., Moschner, K., Nakamura, T., Park, S. Y., Rossi, D., Sahin, E., Sohler, D., Söderström, P. -A., Takeuchi, S., Törnqvist, H., Vaquero, V., Wagner, V., Wang, S., Werner, V., Xu, X., Yamada, H., Yan, D., Yang, Z., Yasuda, M., and Zanetti, L.

Subjects
Nuclear Experiment, Nuclear Theory
Abstract

The first $\gamma$-ray spectroscopy of $^{52}$Ar, with the neutron number N = 34, was measured using the $^{53}$K(p,2p) one-proton removal reaction at $\sim$210 MeV/u at the RIBF facility. The 2$^{+}_{1}$ excitation energy is found at 1656(18) keV, the highest among the Ar isotopes with N $>$ 20. This result is the first experimental signature of the persistence of the N = 34 subshell closure beyond $^{54}$Ca, i.e., below the magic proton number Z = 20. Shell-model calculations with phenomenological and chiral-effective-field-theory interactions both reproduce the measured 2$^{+}_{1}$ systematics of neutron-rich Ar isotopes, and support a N = 34 subshell closure in $^{52}$Ar.

Published
2018
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9. The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Author

Ayachi, Ikbale El, Fatima, Iram, Wend, Peter, Alva-Ornelas, Jackelyn A, Runke, Stephanie, Kuenzinger, William L, Silva, Julio, Silva, Wendy, Gray, Joseph K, Lehr, Stephan, Barch, Hilaire C, Krutilina, Raisa I, White, Andrew C, Cardiff, Robert, Yee, Lisa D, Yang, Lily, O'Regan, Ruth M, Lowry, William E, Seagroves, Tiffany N, Seewaldt, Victoria, Krum, Susan A, and Miranda-Carboni, Gustavo A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Women's Health, Breast Cancer, Cancer, Genetics, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Acetylation, Alleles, Animals, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Doxorubicin, Drug Resistance, Neoplasm, Drug Synergism, Enhancer of Zeste Homolog 2 Protein, Female, HMGA2 Protein, Humans, Lymphoid Enhancer-Binding Factor 1, Mice, Mice, Transgenic, Middle Aged, Neoplasm Metastasis, Proto-Oncogene Proteins, Pyrimidinones, Survival Rate, Transcription Factor 4, Triple Negative Breast Neoplasms, Wnt Proteins, beta Catenin, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for β-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for β-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on β-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC. SIGNIFICANCE: These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/5/982/F1.large.jpg.

Published
2019

10. Spectrum of germline and somatic mitochondrial DNA variants in Tuberous Sclerosis Complex

Author

Krinio Giannikou, Katie R. Martin, Ahmad G. Abdel-Azim, Kaila J. Pamir, Thomas R. Hougard, Shefali Bagwe, Yan Tang, Jeffrey P. MacKeigan, David J. Kwiatkowski, Elizabeth P. Henske, and Hilaire C. Lam

Subjects
mTORC1, buccal swab, angiomyolipoma, lymphangioleiomyomatosis, renal cell carcinoma, Genetics, QH426-470
Abstract

Tuberous Sclerosis Complex (TSC) is caused by loss of function variants in either TSC1 or TSC2 and is characterized by broad phenotypic heterogeneity. Currently, there is limited knowledge regarding the role of the mitochondrial genome (mtDNA) in TSC pathogenesis. In this study, we aimed to determine the prevalence and spectrum of germline and somatic mtDNA variants in TSC and identify potential disease modifiers. Analysis of mtDNA amplicon massively parallel sequencing (aMPS) data, off-target mtDNA from whole-exome sequencing (WES), and/or qPCR, revealed mtDNA alterations in 270 diverse tissues (139 TSC-associated tumors and 131 normal tissue samples) from 199 patients and six healthy individuals. Correlation of clinical features to mtDNA variants and haplogroup analysis was done in 102 buccal swabs (age: 20–71 years). No correlation was found between clinical features and either mtDNA variants or haplogroups. No pathogenic variants were identified in the buccal swab samples. Using in silico analysis, we identified three predicted pathogenic variants in tumor samples: MT-ND4 (m.11742G>A, p. Cys328Tyr, VAF: 43%, kidney angiomyolipoma), MT-CYB (m.14775T>C, p. Leu10Pro, VAF: 43%, LAM abdominal tumor) and MT-CYB (m.15555C>T, p. Pro270Leu, VAF: 7%, renal cell carcinoma). Large deletions of the mitochondrial genome were not detected. Analysis of tumors from 23 patients with corresponding normal tissue did not reveal any recurrent tumor-associated somatic variants. The mtDNA/gDNA ratio between tumors and corresponding normal tissue was also unchanged. Overall, our findings demonstrate that the mitochondrial genome is highly stable across tissues and within TSC-associated tumors.

Published
2023
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11. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

Author

Nicola Alesi, Elie W. Akl, Damir Khabibullin, Heng-Jia Liu, Anna S. Nidhiry, Emma R. Garner, Harilaos Filippakis, Hilaire C. Lam, Wei Shi, Srinivas R. Viswanathan, Manrico Morroni, Shawn M. Ferguson, and Elizabeth P. Henske

Subjects
Science
Abstract

Tuberous sclerosis complex (TSC) is a multiorgan disease that can lead to hyperactive mTORC1 due to deficient TSC1 or TSC2 protein function. Here, the authors find that despite high mTORC1 activity, TFEB localizes to the nucleus and drives lysosomal gene expression via a non-canonical Rag-dependent mechanism.

Published
2021
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13. mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury

Author

Hyunwook Lee, Qinqin Fei, Adam Streicher, Wenjuan Zhang, Colleen Isabelle, Pragi Patel, Hilaire C. Lam, Antonio Arciniegas-Rubio, Miguel Pinilla-Vera, Diana P. Amador-Munoz, Diana Barragan-Bradford, Angelica Higuera-Moreno, Rachel K. Putman, Lynette M. Sholl, Elizabeth P. Henske, Christopher M. Bobba, Natalia Higuita-Castro, Emily M. Shalosky, R. Duncan Hite, John W. Christman, Samir N. Ghadiali, Rebecca M. Baron, and Joshua A. Englert

Subjects
Pulmonology, Medicine
Abstract

The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.

Published
2021
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14. Striated preferentially expressed gene deficiency leads to mitochondrial dysfunction in developing cardiomyocytes

Author

Li, Gu, primary, Huang, He, additional, Wu, Yanshuang, additional, Shu, Chang, additional, Hwang, Narae, additional, Li, Qifei, additional, Zhao, Rose, additional, Lam, Hilaire C., additional, Oldham, William M., additional, EI-Chemaly, Souheil, additional, Agrawal, Pankaj B., additional, Tian, Jie, additional, Liu, Xiaoli, additional, and Perrella, Mark A., additional

Published
2023
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16. Vps34-mediated macropinocytosis in Tuberous Sclerosis Complex 2-deficient cells supports tumorigenesis

Author

Harilaos Filippakis, Amine Belaid, Brian Siroky, Constance Wu, Nicola Alesi, Thomas Hougard, Julie Nijmeh, Hilaire C. Lam, and Elizabeth P. Henske

Subjects
Tuberous Sclerosis Complex, TSC2-deficient Cells, Dextran Uptake, Mouse Embryonic Fibroblasts (MEFs), Ethylisopropylamiloride (EIPA), Medicine, Science
Abstract

Abstract Tuberous Sclerosis Complex (TSC), a rare genetic disorder with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivation, is characterized by multi-organ hamartomatous benign tumors including brain, skin, kidney, and lung (Lymphangioleiomyomatosis). mTORC1 hyperactivation drives metabolic reprogramming including glucose and glutamine utilization, protein, nucleic acid and lipid synthesis. To investigate the mechanisms of exogenous nutrients uptake in Tsc2-deficient cells, we measured dextran uptake, a polysaccharide internalized via macropinocytosis. Tsc2-deficient cells showed a striking increase in dextran uptake (3-fold, p

Published
2018
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17. Level structures of 56,58Ca cast doubt on a doubly magic 60Ca

Author

Chen, S., primary, Browne, F., additional, Doornenbal, P., additional, Lee, J., additional, Obertelli, A., additional, Tsunoda, Y., additional, Otsuka, T., additional, Chazono, Y., additional, Hagen, G., additional, Holt, J.D., additional, Jansen, G.R., additional, Ogata, K., additional, Shimizu, N., additional, Utsuno, Y., additional, Yoshida, K., additional, Achouri, N.L., additional, Baba, H., additional, Calvet, D., additional, Château, F., additional, Chiga, N., additional, Corsi, A., additional, Cortés, M.L., additional, Delbart, A., additional, Gheller, J.-M., additional, Giganon, A., additional, Gillibert, A., additional, Hilaire, C., additional, Isobe, T., additional, Kobayashi, T., additional, Kubota, Y., additional, Lapoux, V., additional, Liu, H.N., additional, Motobayashi, T., additional, Murray, I., additional, Otsu, H., additional, Panin, V., additional, Paul, N., additional, Rodriguez, W., additional, Sakurai, H., additional, Sasano, M., additional, Steppenbeck, D., additional, Stuhl, L., additional, Sun, Y.L., additional, Togano, Y., additional, Uesaka, T., additional, Wimmer, K., additional, Yoneda, K., additional, Aktas, O., additional, Aumann, T., additional, Chung, L.X., additional, Flavigny, F., additional, Franchoo, S., additional, Gasparic, I., additional, Gerst, R.-B., additional, Gibelin, J., additional, Hahn, K.I., additional, Kim, D., additional, Koiwai, T., additional, Kondo, Y., additional, Koseoglou, P., additional, Lehr, C., additional, Linh, B.D., additional, Lokotko, T., additional, MacCormick, M., additional, Moschner, K., additional, Nakamura, T., additional, Park, S.Y., additional, Rossi, D., additional, Sahin, E., additional, Söderström, P.-A., additional, Sohler, D., additional, Takeuchi, S., additional, Törnqvist, H., additional, Vaquero, V., additional, Wagner, V., additional, Wang, S., additional, Werner, V., additional, Xu, X., additional, Yamada, H., additional, Yan, D., additional, Yang, Z., additional, Yasuda, M., additional, and Zanetti, L., additional

Published
2023
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19. Level Structures of $^{56,58}$Ca Cast Doubt on a doubly magic $^{60}$Ca

Author

Chen, S, Browne, F, Doornenbal, P, Lee, J, Obertelli, A, Tsunoda, Y, Otsuka, T, Chazono, Y, Hagen, G, Holt, J.D, Jansen, G.R, Ogata, K, Shimizu, N, Utsuno, Y, Yoshida, K, Achouri, N.L, Baba, H, Calvet, D, Château, F, Chiga, N, Corsi, A, Cortés, M.L, Delbart, A, Gheller, J.-M, Giganon, A, Gillibert, A, Hilaire, C, Isobe, T, Kobayashi, T, Kubota, Y, Lapoux, V, Liu, H.N, Motobayashi, T, Murray, I, Otsu, H, Panin, V, Paul, N, Rodriguez, W, Sakurai, H, Sasano, M, Steppenbeck, D, Stuhl, L, Sun, Y.L, Togano, Y, Uesaka, T, Wimmer, K, Yoneda, K, Aktas, O, Aumann, T, Chung, L.X, Flavigny, F, Franchoo, S, Gasparic, I, Gerst, R.-B, Gibelin, J, Hahn, K.I, Kim, D, Koiwai, T, Kondo, Y, Koseoglou, P, Lehr, C, Linh, B.D, Lokotko, T, Maccormick, M, Moschner, K, Nakamura, T, Park, S.Y, Rossi, D, Sahin, E, Söderström, P.-A, Sohler, D, Takeuchi, S, Törnqvist, H, Vaquero, V, Wagner, V, Wang, S, Werner, V, Xu, X, Yamada, H, Yan, D, Yang, Z, Yasuda, M, Zanetti, L, Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de physique corpusculaire de Caen (LPCC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique des 2 Infinis Irène Joliot-Curie (IJCLab), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Kastler Brossel (LKB [Collège de France]), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF (institution))-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Nuclear Theory (nucl-th), [PHYS.NUCL]Physics [physics]/Nuclear Theory [nucl-th], Nuclear Theory, FOS: Physical sciences, Shell evolution, Nuclear Experiment (nucl-ex), Nuclear Experiment, Ray spectroscopy
Abstract

Gamma decays were observed in $^{56}$Ca and $^{58}$Ca following quasi-free one-proton knockout reactions from $^{57,59}$Sc beams at $\approx 200$ MeV/nucleon. For $^{56}$Ca, a $\gamma$ ray transition was measured to be 1456(12) keV, while for $^{58}$Ca an indication for a transition was observed at 1115(34) keV. Both transitions were tentatively assigned as the $2^+_1 \rightarrow 0^+_{gs}$ decays, and were compared to results from ab initio and conventional shell-model approaches. A shell-model calculation in a wide model space with a marginally modified effective nucleon-nucleon interaction depicts excellent agreement with experiment for $2^+_1$ level energies, two-neutron separation energies, and reaction cross sections, corroborating the formation of a new nuclear shell above the $N$ = 34 shell. Its constituents, the $0f_{5/2}$ and $0g_{9/2}$ orbitals, are almost degenerate. This degeneracy precludes the possibility for a doubly magic $^{60}$Ca and potentially drives the dripline of Ca isotopes to $^{70}$Ca or even beyond., Comment: 8 pages, 3 figures

Published
2023
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21. Data from Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling

Author

Dwyer, Amy R., primary, Kerkvliet, Carlos Perez, primary, Krutilina, Raisa I., primary, Playa, Hilaire C., primary, Parke, Deanna N., primary, Thomas, Warner A., primary, Smeester, Branden A., primary, Moriarity, Branden S., primary, Seagroves, Tiffany N., primary, and Lange, Carol A., primary

Published
2023
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23. Supplemental Methods including references, Supplemental Table 1, and Supplemental Figures 1-5 from Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling

Author

Dwyer, Amy R., primary, Kerkvliet, Carlos Perez, primary, Krutilina, Raisa I., primary, Playa, Hilaire C., primary, Parke, Deanna N., primary, Thomas, Warner A., primary, Smeester, Branden A., primary, Moriarity, Branden S., primary, Seagroves, Tiffany N., primary, and Lange, Carol A., primary

Published
2023
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30. Level structures of Ca cast doubt on a doubly magic Ca

Author

Chen, S., Browne, F., Doornenbal, P., Lee, J., Obertelli, A., Tsunoda, Y., Otsuka, T., Chazono, Y., Hagen, G., Holt, J.D., Jansen, G.R., Ogata, K., Shimizu, N., Utsuno, Y., Yoshida, K., Achouri, N.L., Baba, H., Calvet, D., Château, F., Chiga, N., Corsi, A., Cortés, M.L., Delbart, A., Gheller, J.M., Giganon, A., Gillibert, A., Hilaire, C., Isobe, T., Kobayashi, T., Kubota, Y., Lapoux, V., Liu, H.N., Motobayashi, T., Murray, I., Otsu, H., Panin, V., Paul, N., Rodriguez, W., Sakurai, H., Sasano, M., Steppenbeck, D., Stuhl, L., Sun, Y.L., Togano, Y., Uesaka, T., Wimmer, K., Yoneda, K., Aktas, O., Aumann, T., Chung, L.X., Flavigny, F., Franchoo, S., Gasparic, I., Gerst, R.B., Gibelin, J., Hahn, K.I., Kim, D., Koiwai, T., Kondo, Y., Koseoglou, P., Lehr, C., Linh, B.D., Lokotko, T., MacCormick, M., Moschner, K., Nakamura, T., Park, S.Y., Rossi, D., Sahin, E., Söderström, P.A., Sohler, D., Takeuchi, S., Törnqvist, H., Vaquero, V., Wagner, V., Wang, S., Werner, V., Xu, X., Yamada, H., Yan, D., Yang, Z., Yasuda, M., and Zanetti, L.

Abstract

Gamma decays were observed in $^{56}$Ca and $^{58}$Ca following quasi-free one-proton knockout reactions from $^{57,59}$Sc beams at ≈200 MeV/nucleon. For $^{56}$Ca, a γ ray transition was measured to be 1456(12) keV, while for $^{58}$Ca an indication for a transition was observed at 1115(34) keV. Both transitions were tentatively assigned as the 21+→0gs+ decays, and were compared to results from ab initio and conventional shell-model approaches. A shell-model calculation in a wide model space with a marginally modified effective nucleon-nucleon interaction depicts excellent agreement with experiment for 21+ level energies, two-neutron separation energies, and reaction cross sections, corroborating the formation of a new nuclear shell above the N = 34 shell. Its constituents, the 0f5/2 and 0g9/2 orbitals, are almost degenerate. This degeneracy precludes the possibility for a doubly magic $^{60}$Ca and potentially drives the dripline of Ca isotopes to $^{70}$Ca or even beyond.

Published
2023

33. Figure S4 from An Orally Available Tubulin Inhibitor, VERU-111, Suppresses Triple-Negative Breast Cancer Tumor Growth and Metastasis and Bypasses Taxane Resistance

Author

Wei Li, Tiffany N. Seagroves, Duane D. Miller, Hao Chen, Hilaire C. Playa, Deanna N. Parke, Zongtao Lin, Qinghui Wang, Raisa I. Krutilina, and Shanshan Deng

Abstract

Figure S4 shows that FACS analysis profiles of MDA-MB-231 and MDA-MB-468 TNBC cells following treatment with vehicle (Control), colchicine or paclitaxel, showing VERU-111 induces G2/M checkpoint arrest and apoptosis in TNBC cells. (A) Representative cell cycle distribution images after VERU-111 (10, 20, 50 and 100 nM), colchicine (100 nM) and paclitaxel (100 nM) treatment. Cells were treated for 24 h and stained with anti-phospho-histone H3 (Ser10) and propidium iodide (PI). (B) Representative FACS analysis profiles of apoptotic TNBC cells after 24 h treatment with VERU-111, colchicine or paclitaxel as detected by Annexin-V-FITC/PI staining. (C) Representative FACS analysis profiles of apoptotic TNBC cells after treating with 100 nM VERU-111 for 24, 48 or 72 h, cells were stained with Annexin-V-FITC and PI.

Published
2023
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34. Data from Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling

Author

Carol A. Lange, Tiffany N. Seagroves, Branden S. Moriarity, Branden A. Smeester, Warner A. Thomas, Deanna N. Parke, Hilaire C. Playa, Raisa I. Krutilina, Carlos Perez Kerkvliet, and Amy R. Dwyer

Abstract

Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of patients with breast cancer; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of triple-negative breast cancer (TNBC) remain undefined. In a mouse model of TNBC, manipulation of PTK6 levels (i.e., via knock-out or add-back) had little effect on primary tumor volume, but altered lung metastasis. To delineate the mechanisms of PTK6 downstream signaling, we created kinase-dead (KM) and kinase-intact domain structure mutants of PTK6 via in-frame deletions of the N-terminal SH3 or SH2 domains. While the PTK6 kinase domain contributed to soft-agar colony formation, PTK6 kinase activity was entirely dispensable for cell migration. Specifically, TNBC models expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were unresponsive to growth factor–stimulated cell motility relative to SH3-del, KM, or wild-type PTK6 controls. Reverse-phase protein array revealed that while intact PTK6 mediates spheroid formation via p38 MAPK signaling, the SH2 domain of PTK6 limits this biology, and instead mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Inhibition of RhoA and/or AhR blocked TNBC cell migration as well as the branching/invasive morphology of PTK6+/AhR+ primary breast tumor tissue organoids. Inhibition of RhoA also enhanced paclitaxel cytotoxicity in TNBC cells, including in a taxane-refractory TNBC model.Implications:The SH2-domain of PTK6 is a potent effector of advanced cancer phenotypes in TNBC via RhoA and AhR, identified herein as novel therapeutic targets in PTK6+ breast tumors.

Published
2023
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35. Data from TSC2 Interacts with HDLBP/Vigilin and Regulates Stress Granule Formation

Author

Elizabeth P. Henske, Paul J. Anderson, Nancy L. Kedersha, Jane Yu, Hilaire C. Lam, Michal Turkiewicz, Damir Khabibullin, Harilaos Filippakis, and Kosmas Kosmas

Abstract

Tuberous sclerosis complex (TSC) is caused by mutations of either the TSC1 or TSC2 tumor suppressor gene. TSC causes tumors of the brain, heart, kidney, skin and lymphangioleiomyomatosis (LAM). Here we report that the TSC2 protein physically binds to high-density lipoprotein binding protein (HDLBP), also called vigilin, a core stress granule (SG) protein, and that TSC2 localizes to SGs. SGs contain mRNAs and translation initiation complexes, and regulate gene expression by sequestering specific transcripts, thereby serving a cytoprotective role. TSC2 has never before been shown to localize to SGs and knocking down vigilin impacts SG translocation of TSC2. TSC2-deficient cells showed a striking increase in the number of SGs after thermal shock and arsenite treatment relative to Tsc2-expressing cells. Our findings also show that murine kidney lysates from a model of TSC have increased levels of SG components including G3BP1 and Caprin1. G3BP1 and Caprin are elevated in renal angiomyolipomas (a renal tumor common in patients with TSC) compared with control normal kidney. G3BP1 is also elevated in TSC-associated subependymal giant cell astrocytomas. We found that genetic inhibition of G3BP1 inhibits the proliferation of TSC2-deficient cells in vitro. Finally, in a mouse model of TSC, genetic inhibition of SGs suppresses cell growth, suggesting that targeting SGs may have efficacy in the therapy of TSC.Implications:This study demonstrates that TSC2 physically interacts with HDLBP/vigilin, a component of SGs, that TSC2 localizes to SG and that TSC2-deficient cells have more SGs, suggesting that SGs represent a novel therapeutic target in TSC.

Published
2023
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36. Table S1 from An Orally Available Tubulin Inhibitor, VERU-111, Suppresses Triple-Negative Breast Cancer Tumor Growth and Metastasis and Bypasses Taxane Resistance

Author

Wei Li, Tiffany N. Seagroves, Duane D. Miller, Hao Chen, Hilaire C. Playa, Deanna N. Parke, Zongtao Lin, Qinghui Wang, Raisa I. Krutilina, and Shanshan Deng

Abstract

Table S1 shows anti-proliferating effects of VERU-111 against various human cancer cell lines (mean {plus minus} SEM, n = 4 biological replicate experiments).

Published
2023
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37. Supplemental Methods including references, Supplemental Table 1, and Supplemental Figures 1-5 from Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling

Author

Carol A. Lange, Tiffany N. Seagroves, Branden S. Moriarity, Branden A. Smeester, Warner A. Thomas, Deanna N. Parke, Hilaire C. Playa, Raisa I. Krutilina, Carlos Perez Kerkvliet, and Amy R. Dwyer

Abstract

Table S1. Oligonucleotide sequences used in this study. Figure S1. Amino acid sequence used to generate PTK6 domain mutant models. Figure S2. Characterization of PTK6 genetically modified MDA-MB-231 TNBC cell lines. Figure S3. PTK6 silencing reduces tumor-sphere formation. Figure S4: Dose-dependent effects of CT04 or CH223191 on growth inhibition in MDA-MB-231 and cHCI-10 TNBC cells. Figure S5: GR and AHR expression alone are not predictive of patient outcome.

Published
2023
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38. Supplementary Table S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
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39. Supplementary Data from The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Author

El Ayachi, Ikbale, primary, Fatima, Iram, primary, Wend, Peter, primary, Alva-Ornelas, Jackelyn A., primary, Runke, Stephanie, primary, Kuenzinger, William L., primary, Silva, Julio, primary, Silva, Wendy, primary, Gray, Joseph K., primary, Lehr, Stephan, primary, Barch, Hilaire C., primary, Krutilina, Raisa I., primary, White, Andrew C., primary, Cardiff, Robert, primary, Yee, Lisa D., primary, Yang, Lily, primary, O'Regan, Ruth M., primary, Lowry, William E., primary, Seagroves, Tiffany N., primary, Seewaldt, Victoria, primary, Krum, Susan A., primary, and Miranda-Carboni, Gustavo A., primary

Published
2023
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40. Data from The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Author

El Ayachi, Ikbale, primary, Fatima, Iram, primary, Wend, Peter, primary, Alva-Ornelas, Jackelyn A., primary, Runke, Stephanie, primary, Kuenzinger, William L., primary, Silva, Julio, primary, Silva, Wendy, primary, Gray, Joseph K., primary, Lehr, Stephan, primary, Barch, Hilaire C., primary, Krutilina, Raisa I., primary, White, Andrew C., primary, Cardiff, Robert, primary, Yee, Lisa D., primary, Yang, Lily, primary, O'Regan, Ruth M., primary, Lowry, William E., primary, Seagroves, Tiffany N., primary, Seewaldt, Victoria, primary, Krum, Susan A., primary, and Miranda-Carboni, Gustavo A., primary

Published
2023
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41. Raw data for Supplementary Table 1 and 2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
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42. Figure S4 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
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43. Supplementary Materials and Methods from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
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44. Data from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
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45. Figure S2 from Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex

Author

Kovalenko, Andrii, primary, Sanin, Andres, primary, Kosmas, Kosmas, primary, Zhang, Long, primary, Wang, Ji, primary, Akl, Elie W., primary, Giannikou, Krinio, primary, Probst, Clemens K., primary, Hougard, Thomas R., primary, Rue, Ryan W., primary, Krymskaya, Vera P., primary, Asara, John M., primary, Lam, Hilaire C., primary, Kwiatkowski, David J., primary, Henske, Elizabeth P., primary, and Filippakis, Harilaos, primary

Published
2023
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47. Figure S5 from Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex

Author

Harilaos Filippakis, Elizabeth P. Henske, David J. Kwiatkowski, Hilaire C. Lam, John M. Asara, Vera P. Krymskaya, Ryan W. Rue, Thomas R. Hougard, Clemens K. Probst, Krinio Giannikou, Elie W. Akl, Ji Wang, Long Zhang, Kosmas Kosmas, Andres Sanin, and Andrii Kovalenko

Abstract

Lipidomic analysis of ritanserin treated Tsc2-deficient cells

Published
2023
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48. Supplementary Table S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Elizabeth P. Henske, Carmen Priolo, Mustafa Sahin, Jorge Moscat, Maria T. Diaz-Meco, William M. Oldham, John M. Asara, Stephen Y. Chan, Adam Handen, Taylor Kavanagh, Julie Nijmeh, Barbara Ogorek, Damir Khabibullin, Ana Pereira, Jane J. Yu, Afshin Saffari, Darius Ebrahimi-Fakhari, Izabela A. Malinowska, Nicola Alesi, Heng-Jia Liu, Andrey A. Parkhitko, Alicia Llorente Lope, Christian V. Baglini, and Hilaire C. Lam

Abstract

Metabolites significantly changed by p62 knockdown in Tsc2-/- MEFs

Published
2023
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49. Data from The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Author

Gustavo A. Miranda-Carboni, Susan A. Krum, Victoria Seewaldt, Tiffany N. Seagroves, William E. Lowry, Ruth M. O'Regan, Lily Yang, Lisa D. Yee, Robert Cardiff, Andrew C. White, Raisa I. Krutilina, Hilaire C. Barch, Stephan Lehr, Joseph K. Gray, Wendy Silva, Julio Silva, William L. Kuenzinger, Stephanie Runke, Jackelyn A. Alva-Ornelas, Peter Wend, Iram Fatima, and Ikbale El Ayachi

Abstract

Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for β-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for β-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on β-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC.Significance:These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.

Published
2023
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50. Data from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Elizabeth P. Henske, Carmen Priolo, Mustafa Sahin, Jorge Moscat, Maria T. Diaz-Meco, William M. Oldham, John M. Asara, Stephen Y. Chan, Adam Handen, Taylor Kavanagh, Julie Nijmeh, Barbara Ogorek, Damir Khabibullin, Ana Pereira, Jane J. Yu, Afshin Saffari, Darius Ebrahimi-Fakhari, Izabela A. Malinowska, Nicola Alesi, Heng-Jia Liu, Andrey A. Parkhitko, Alicia Llorente Lope, Christian V. Baglini, and Hilaire C. Lam

Abstract

p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate that accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes tuberous sclerosis complex (TSC)1 or TSC2. Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2+/− and Tsc2f/f CAGGCreERT2+ mice crossed to p62−/− mice were protected from renal tumor development. Metabolic profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, glutamate, and glutathione (GSH). p62 positively regulated the glutamine transporter Slc1a5 and increased glutamine uptake in Tsc2-null cells. We also observed p62-dependent changes in Gcl, Gsr, Nqo1, and Srxn1, which were decreased by p62 attenuation and implicated in GSH production and utilization. p62 attenuation altered mitochondrial morphology, reduced mitochondrial membrane polarization and maximal respiration, and increased mitochondrial reactive oxygen species and mitophagy marker PINK1. These mitochondrial phenotypes were rescued by addition of exogenous GSH and overexpression of Sod2, which suppressed indices of mitochondrial damage and promoted growth of Tsc2-null cells. Finally, p62 depletion sensitized Tsc2-null cells to both oxidative stress and direct inhibition of GSH biosynthesis by buthionine sulfoximine. Our findings show how p62 helps maintain intracellular pools of GSH needed to limit mitochondrial dysfunction in tumor cells with elevated mTORC1, highlighting p62 and redox homeostasis as nodal vulnerabilities for therapeutic targeting in these tumors. Cancer Res; 77(12); 3255–67. ©2017 AACR.

Published
2023
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