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Применить Всего найдено 9. Отображено 9.
27-01-2022 дата публикации

METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA BY ERADICATING LEUKEMIC STEM CELLS

Номер: US20220025058A1
Автор: LARRUE Clément, RECHER Christian, SARRY Jean-Emmanuel
Принадлежит:

After intensive chemotherapy, the emergence of cells with dmg resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). Herein the inventors first uncovered that the adrenomedullin receptor CALCRL is overexpressed in AML patients comparing with normal cells and preferentially in the immature CD34 CD38 compartment. Then they demonstrated its role in the maintenance of leukemic stem cell function in vivo. Moreover, CALCRL depletion strongly affected leukemic growth in xenograft models and sensitized to chemotherapeutic agent cytarabine in vivo. It Accordingly, the inventors showed that ADM-CALCRL axis drove cell cycle, DNA integrity, and high OxPHOS status of chemoresistant AML stem cells in an E2F1- and BCL2-dependent manner. Furthermore, CALCRL depletion sensitizes cells to cytarabine and its CT expression predicted the response to chemotherapy in vivo in mice. Further, using the combination of limiting dilution assays, single-cell RNA-seq analysis of primary AMF samples at diagnosis and relapse and before and after transplantation in NSG mice, the inventors revealed the pre-existence of a chemoresistant leukemic stem cell sub-population harboring a CALCRL-driven gene signature. Finally the inventors strongly demonstrated that chemoresistant LSC are dependent for CALCRL. All of these data highlight the critical role of CALCRL in stem cell survival, proliferation and metabolism and identify this receptor as a new marker of chemoresistant leukemic stem cell population and a promising therapeutic target to specifically eradicate them and overcome relapse in AML. 1. A method of depleting leukemic stem cells in a subject suffering from acute myeloid leukemia comprising administering to the subject a therapeutically effective amount of an antibody that specifically binds to CALCRL thereby depleting said leukemic stem cells.2. A method of depleting leukemic stem cells in a subject suffering from ...

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Номер записи: 1
15-09-2022 дата публикации

USE OF PYRVINIUM FOR THE TREATMENT OF A RAS PATHWAY MUTATED ACUTE MYELOID LEUKEMIA

Номер: US20220288040A1
Автор: BIRSEN Rudy, Bouscary Didier, DECROOCQ Justine, SARRY Jean-Emmanuel, TAMBURINI Jérôme
Принадлежит:

Acute myeloid leukemia (AML) are heterogeneous malignancies arising from the multistep transformation of bone marrow immature cells. The inventors showed that RAS pathway mutations were detected in 40% of FLT3- and NPM1-unmutated AML cases and correlated with higher white blood cell count, blast cell percentage and reduced survival after intensive therapy. Building on genetic models of RAS activation, they highlighted the leukemogenic potential of RAS pathway alterations, and the efficacy and limitations of MEK inhibitors in this context. From high-content chemical screens, the inventors unraveled pyrvinium pamoate—an anthelminthic drug approved in human patients—as displaying a preferential cytotoxicity against RAS activated cells. This potential clinical candidate demonstrated a robust synergistic activity with the MEK inhibitor trametinib, including in primary samples from AML patients. Together the data suggest that RAS pathway altered cases may represent a specific AML subtype, in which the anti-leukemic molecule pyrvinium pamoate may represent a new promising therapeutic strategy. 1. A method of treating a RAS pathway mutated acute myeloid leukemia and/or treating a RAS pathway mutated acute myeloid leukemia resistant to MEK inhibitors in a patient in need thereof comprising administering to the patient a therapeutically effective amount of pyrvinium.2. A method of treating a RAS pathway mutated acute myeloid leukemia in a patient in need thereof and/or enhancing the potency of a MEK inhibitor administered to a subject suffering from a RAS pathway mutated acute myeloid leukemia as part of a treatment regimen , comprising administering to the subject a therapeutically effective combination comprising MEK inhibitor and pyrvinium.3. (canceled)4. (canceled)5. A method of preventing resistance to an administered MEK inhibitor in a subject suffering from a RAS pathway mutated acute myeloid leukemia comprising administering to the subject a therapeutically effective ...

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Номер записи: 2
11-07-2019 дата публикации

PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF CHEMORESISTANT ACUTE MYELOID LEUKEMIA (AML)

Номер: US20190209594A1
Автор: AROUA Nesrine, DE TONI-COSTES Fabienne, RECHER Christian, SARRY Jean-Emmanuel
Принадлежит:

The present invention relates to pharmaceutical compositions for use in the treatment of chemoresistant acute myeloid leukemia (AML). The inventors have established a powerful preclinical model to screen in vivo responses to conventional genotoxics and to mimic the chemoresistance and minimal residual disease as observed in AML patients after chemotherapy. The inventors showed that cytarabine-resistance mechanism involves the CD39-dependent crosstalk between energetic niche and AML mitochondrial functions through CD39-P2Y13-cAMP-PKA signaling axis. In particular, the present invention relates to an inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis for use in a method of treating chemoresistant acute myeloid leukemia (AML) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of said inhibitor. 1. A method of treating chemoresistant acute myeloid leukemia (AML) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis.2. The method of wherein the leukemia is resistant to a combination of daunorubicin claim 1 , or idarubicin plus cytarabine (AraC).3. A method of preventing relapse of a patient suffering from AML who was treated with chemotherapy comprising administering to the patient a therapeutically effective amount of an inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis.4. The method of wherein the chemotherapy consists in a combination of daunorubicin claim 3 , or idarubicin plus cytarabine (AraC)5. The method of wherein the inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis is a CD39 inhibitor.6. The method of wherein the inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis is a P2Y13 inhibitor.7. The method of wherein the inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis is an antibody having specificity for CD39.8. The method of wherein the inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis is an ...

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Номер записи: 3
28-09-2022 дата публикации

Inhibitors of adrenomedullin for the treatment of acute myeloid leukemia by eradicating leukemic stem cells

Номер: EP4061944A1
Автор: Clément LARRUE, Jean-Emmanuel SARRY
Принадлежит: Institut National de la Sante et de la Recherche Medicale INSERM, Universite Toulouse III Paul Sabatier

The emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). LSCs are heterogeneous for their phenotypes and their sensitivity to chemotherapeutic agents in vivo. Using in silico and functional approaches, the inventors uncovered that CALCRL is overexpressed in LSCs compared with normal hematopoietic cells. They further demonstrated that the CALCRL ligand adrenomedullin (ADM) is highly expressed in AML cells and that increased transcript level was markedly associated with decreased complete remission rates, 5-year overall and event7free survival. The inventors also showed that CALCRL depletion strongly affected leukemic growth in vivo and increased mice survival. Targeting ADM phenocopies the biological and anti-leukemic effects of the CALCRL depletion. These data highlight the critical role of ADM and disclose a promising therapeutic target to specifically eradicate R-LSCs and overcome relapse in AML.

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Номер записи: 4
14-05-2020 дата публикации

Methods and pharmaceutical compositions for the treatment of acute myeloid leukemia by eradicating leukemic stem cells

Номер: WO2020094609A1
Автор: Christian RECHER, Clément LARRUE, Jean-Emmanuel SARRY
Принадлежит: Centre Hospitalier Universitaire De Toulouse, Inserm (Institut National de la Sante et de la Recherche Medicale), UNIVERSITE PAUL SABATIER TOULOUSE III

After intensive chemotherapy, the emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). Herein the inventors first uncovered that the adrenomedullin receptor CALCRL is overexpressed in AML patients comparing with normal cells and preferentially in the immature CD34 + CD38 - compartment. Then they demonstrated its role in the maintenance of leukemic stem cell function in vivo . Moreover, CALCRL depletion strongly affected leukemic growth in xenograft models and sensitized to chemotherapeutic agent cytarabine in vivo . Accordingly, the inventors showed that ADM-CALCRL axis drove cell cycle, DNA integrity, and high OxPHOS status of chemoresistant AML stem cells in an E2F1- and BCL2- dependent manner. Furthermore, CALCRL depletion sensitizes cells to cytarabine and its expression predicted the response to chemotherapy in vivo in mice. Further, using the combination of limiting dilution assays, single-cell RNA-seq analysis of primary AMF samples at diagnosis and relapse and before and after transplantation in NSG mice, the inventors revealed the pre-existence of a chemoresistant leukemic stem cell sub-population harboring a CALCRL-driven gene signature. Finally the inventors strongly demonstrated that chemoresistant LSC are dependent for CALCRL. All of these data highlight the critical role of CALCRL in stem cell survival, proliferation and metabolism and identify this receptor as a new marker of chemoresistant leukemic stem cell population and a promising therapeutic target to specifically eradicate them and overcome relapse in AML.

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Номер записи: 5
27-05-2021 дата публикации

Inhibitors of adrenomedullin for the treatment of acute myeloid leukemia by eradicating leukemic stem cells

Номер: WO2021099600A1
Автор: Clément LARRUE, Jean-Emmanuel SARRY
Принадлежит: Inserm (Institut National de la Sante et de la Recherche Medicale), Université Toulouse Iii – Paul Sabatier

The emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). LSCs are heterogeneous for their phenotypes and their sensitivity to chemotherapeutic agents in vivo. Using in silico and functional approaches, the inventors uncovered that CALCRL is overexpressed in LSCs compared with normal hematopoietic cells. They further demonstrated that the CALCRL ligand adrenomedullin (ADM) is highly expressed in AML cells and that increased transcript level was markedly associated with decreased complete remission rates, 5-year overall and event7free survival. The inventors also showed that CALCRL depletion strongly affected leukemic growth in vivo and increased mice survival. Targeting ADM phenocopies the biological and anti-leukemic effects of the CALCRL depletion. These data highlight the critical role of ADM and disclose a promising therapeutic target to specifically eradicate R-LSCs and overcome relapse in AML.

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Номер записи: 6
19-04-2021 дата публикации

Pharmaceutical compositions for the treatment of chemoresistant acute myeloid leukemia (AML)

Номер: ES2820173T3
Автор: Christian RECHER, Jean-Emmanuel SARRY, Nesrine Aroua, Toni-Costes Fabienne De
Принадлежит: Centre Hospitalier Universitaire De Toulouse, Institut National de la Sante et de la Recherche Medicale INSERM, UNIVERSITE PAUL SABATIER TOULOUSE III

Un inhibidor del eje de señalización CD39-P2Y13-cAMP-PKA para su uso en el tratamiento de la leucemia mieloide aguda (LMA) quimiorresistente en un paciente que lo necesita, en el que la leucemia es resistente a una combinación de daunorubicina o idarubicina, más citarabina (AraC), y en el que el inhibidor es un anticuerpo que tiene especificidad por CD39. An inhibitor of the CD39-P2Y13-cAMP-PKA signaling axis for use in the treatment of chemoresistant acute myeloid leukemia (AML) in a needy patient, in whom the leukemia is resistant to a combination of daunorubicin or idarubicin, plus cytarabine (AraC), and wherein the inhibitor is an antibody that has specificity for CD39.

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Номер записи: 7
26-05-2022 дата публикации

Pharmaceutical compositions for the treatment of chemoresistant acute myeloid leukemia (AML)

Номер: ES2912453T3
Автор: Christian RECHER, Jean-Emmanuel SARRY, Nesrine Aroua, Toni-Costes Fabienne De
Принадлежит: Centre Hospitalier Universitaire De Toulouse, Institut National de la Sante et de la Recherche Medicale INSERM, Universite Toulouse III Paul Sabatier

Un inhibidor del eje de señalización CD39-P2Y13-cAMP-PKA para su uso en el tratamiento de la leucemia mieloide aguda (LMA) quimiorresistente en un paciente que lo necesita, en el que la leucemia es resistente a citarabina, y en el que el inhibidor es un anticuerpo que tiene especificidad por CD39.

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Номер записи: 8
10-01-2019 дата публикации

Transducer for the monitoring of metabolic status of a biological entity

Номер: WO2019008136A1
Автор: Emilie Vanhove, Fadhila SEKLI BELAIDI, Gabriel LEMERCIER, Jean-Emmanuel SARRY, Jerome Launay, Pierre Temple-Boyer, Stephane Arbault
Принадлежит: Centre National De La Recherche Scientifique - CNRS -, Inserm (Institut National de la Sante et de la Recherche Medicale), UNIVERSITE PAUL SABATIER TOULOUSE III

The present invention relates to a transducer (1) comprising: a transparent substrate (11); a transparent microelectrode (13) on top of the transparent substrate (11); a first insulator layer (14) on top of the transparent microelectrode (13) and a second insulator layer (15) on top of the first insulator layer (14) with wells (17) defined therethrough; the transducer (1) further comprises: a layer of annular working electrodes (16) sandwiched between the first and second insulator layers (14, 15) so that each well (17) is provided with an annular working electrode; adhesion enhancing agent (18) at the bottom of the wells (17) on the transparent microelectrode (13); and antibiofouling agent (19) at the free surface of the second insulator layer (15). The invention also relates to a chip and cable assembly comprising this transducer and an optoelectrochemical system comprising this chip and cables assembly.

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Номер записи: 9