Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have... more Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines, little is known about the intracellular signaling pathways that are activated by cytokines upon binding to their receptors. Our study showed that Growth factor receptor-bound protein 2 (Grb2) mRNAs are preferentially expressed in HSC compared to progenitors and differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a rapid decline of erythroid and myeloid progenitors and a progressive decline of HSC numbers in steady state conditions. We showed that when transplanted, Grb2 deleted bone marrow cells could not reconstitute irradiated recipients. Strinkingly, Grb2 deletion did not modify HSPC quiescence, but impaired LT-HSC and progenitors ability to respond a proliferative signal induced by 5FU in vivo and by various cytokines in vitro. We showed finally that Grb2 links I...
Proceedings of the National Academy of Sciences of the United States of America, Jan 17, 2013
The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors ... more The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk(-/-) mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk(-/-) HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk(-/-) HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphoryla...
Cytokine storm refers to the dysregulated production of inflammatory mediators leading to hyperin... more Cytokine storm refers to the dysregulated production of inflammatory mediators leading to hyperinflammation. They are often detrimental, and worsen the severity of COVID-19 and other infectious or inflammatory diseases. Cannabinoids are known to have anti-inflammatory effects but their possible therapeutic value on cytokine storms has not been fully elucidated. In vivo and ex vivo studies were carried out to investigate the effects of high-THC and high-CBD extracts on cytokine production in immune cells. Significant differences between the extracts were observed. Subsequent experiments focusing on a specific high CBD extract (CBD-X) showed significant reductions in pro-inflammatory cytokines in human-derived PBMCs, neutrophils and T cells. In vivo mouse studies, using a systemically inflamed mouse model, showed reductions in pro-inflammatory cytokines TNFα and IL-1β and a concurrent increase in the anti-inflammatory cytokine IL-10 in response to CBD-X extract treatment. Lung inflamm...
Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuh... more Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. ...
Introduction: Activating mutation of FLT3 by internal tandem duplications (ITD) is the most commo... more Introduction: Activating mutation of FLT3 by internal tandem duplications (ITD) is the most common molecular aberration found in AML. FLT3-ITD mutation induces a proliferation signal and is associated with leukocytosis and poor prognosis. The co-existence of FLT3-ITD with translocation t(5:11) that yields fusion transcript of Nucleoporin98 and the nuclear receptor binding SET-domain protein 1 (NUP98/NSD1) was recently reported to be associated with chemo-resistance. Relapse risk of the majority of FLT3-ITD positive AML patients who are negative to NUP98/NSD1 is increased compared to other AML with normal karyotype, despite similar remission rates. The mechanism of FLT3-ITD contribution to relapse development in patients who achieved remission is unknown. Aims: To explore potential mechanisms that allow relapse in FLT3-ITD positive AML in the presence or absence of NUP98/NSD1 fusion gene. In addition, time sequence of the emergence of both mutations is suggested from a case with rela...
Introduction: Human leukocyte antigen (HLA) molecules are membrane-bound transporters carrying pe... more Introduction: Human leukocyte antigen (HLA) molecules are membrane-bound transporters carrying peptides from the cytoplasm to the cell surface where they become exposed to T lymphocytes. Soluble HLA molecules (sHLA) bound to their specific peptides are present in human plasma. Patient-based evidence that most of these peptides are derived from cancerous cells may lead to the identification of cancer-related sHLA peptidomes in the disease state. Leukemic cells in the bone marrow (BM) are usually composed of several malignant subclones even within the same patient. These leukemic subclones may vary in their sensitivity to chemotherapy. During the first days of chemotherapy, a dynamic change in the blast mass and subclonal cell composition is observed. We have thus hypothesized that the repertoire and amount of peptides bound to sHLA molecules derived from the BM plasma of acute myeloid leukemia (AML) patients will be changing during induction. Our study has aimed at identifying peptid...
Introduction: Leukemic sub-clones which survive chemotherapy during induction period may remain d... more Introduction: Leukemic sub-clones which survive chemotherapy during induction period may remain dormant and subsequently lead to relapse in patients with acute myeloid leukemia (AML). No mechanism linking clonal selection to a specific leukemia-associated genetic aberration is known. Clonal selection is a common phenomenon; therefore, any suggested mechanism should be applicable to all kinds of leukemia-specific genetic aberrations. We hypothesized that clonal selection might result from differences in differentiation capacity among sub-clones and that chemo-resistance is not necessarily directly affected by specific mutations. Patients and Methods: We tested this hypothesis in vitro using the kasumi-1 leukemia cell line, which undergoes limited differentiation while growing and is composed of both CD34+ and CD34- sub-populations. Kasumi-1 cells were sorted by fluorescence-activated cell sorting (FACS-Aria IIIu, BD Biosciences) to CD34+CD117+ and CD34-CD117+ sub-populations. Each su...
16 Enhancement of the Immunoadjuvant Activity of Immunostimulatory DNA Sequence By Liposomal Deli... more 16 Enhancement of the Immunoadjuvant Activity of Immunostimulatory DNA Sequence By Liposomal Delivery Eli Kedar, Igal Louria-Hayon, Aviva Joseph, Zichria Zakay-Rones, Tomoko Hayashi, Kenji Takabayashi, and Yechezkel Barenholz 1. INTRODUCTION Bacterial ...
Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have... more Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines, little is known about the intracellular signaling pathways that are activated by cytokines upon binding to their receptors. Our study showed that Growth factor receptor-bound protein 2 (Grb2) mRNAs are preferentially expressed in HSC compared to progenitors and differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a rapid decline of erythroid and myeloid progenitors and a progressive decline of HSC numbers in steady state conditions. We showed that when transplanted, Grb2 deleted bone marrow cells could not reconstitute irradiated recipients. Strinkingly, Grb2 deletion did not modify HSPC quiescence, but impaired LT-HSC and progenitors ability to respond a proliferative signal induced by 5FU in vivo and by various cytokines in vitro. We showed finally that Grb2 links IL3 signaling to the ERK/MAPK proliferative pathway and that both SH2 and SH3 domains of Grb2 are crucial for IL3 signaling in progenitor cells. Our findings position Grb2 as a key adaptor that integrates various cytokines response in cycling HSPC.
A liposomal influenza vaccine (INFLUSOME-VAC) was developed with the objective of overcoming the ... more A liposomal influenza vaccine (INFLUSOME-VAC) was developed with the objective of overcoming the major drawbacks of the currently used influenza vaccines: their relatively low efficacy in certain high-risk groups (the elderly, infants, the immunosuppressed) and the need for annual immunization. INFLUSOME-VAC consists of liposomes containing the viral surface proteins hemagglutinin (HA) and neuraminidase (NA) derived from various influenza strains and IL-2 or GM-CSF, as an adjuvant. Vaccination of mice showed that, whereas conventional vaccines induced a low- and short-term response against HA and very low or no anti-NA response, INFLUSOME-VAC produced high titers of both anti-HA and anti-NA antibodies (Abs) in young and old mice that persisted for at least 6 months. Moreover, the anti-NA Abs efficiently cross-reacted with several N2 viral subtypes spanning 20 years, and such vaccines afforded partial protection against heterosubtypic viral infection.
16 Enhancement of the Immunoadjuvant Activity of Immunostimulatory DNA Sequence By Liposomal Deli... more 16 Enhancement of the Immunoadjuvant Activity of Immunostimulatory DNA Sequence By Liposomal Delivery Eli Kedar, Igal Louria-Hayon, Aviva Joseph, Zichria Zakay-Rones, Tomoko Hayashi, Kenji Takabayashi, and Yechezkel Barenholz 1. INTRODUCTION Bacterial ...
Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have... more Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines, little is known about the intracellular signaling pathways that are activated by cytokines upon binding to their receptors. Our study showed that Growth factor receptor-bound protein 2 (Grb2) mRNAs are preferentially expressed in HSC compared to progenitors and differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a rapid decline of erythroid and myeloid progenitors and a progressive decline of HSC numbers in steady state conditions. We showed that when transplanted, Grb2 deleted bone marrow cells could not reconstitute irradiated recipients. Strinkingly, Grb2 deletion did not modify HSPC quiescence, but impaired LT-HSC and progenitors ability to respond a proliferative signal induced by 5FU in vivo and by various cytokines in vitro. We showed finally that Grb2 links I...
Proceedings of the National Academy of Sciences of the United States of America, Jan 17, 2013
The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors ... more The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk(-/-) mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk(-/-) HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk(-/-) HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphoryla...
Cytokine storm refers to the dysregulated production of inflammatory mediators leading to hyperin... more Cytokine storm refers to the dysregulated production of inflammatory mediators leading to hyperinflammation. They are often detrimental, and worsen the severity of COVID-19 and other infectious or inflammatory diseases. Cannabinoids are known to have anti-inflammatory effects but their possible therapeutic value on cytokine storms has not been fully elucidated. In vivo and ex vivo studies were carried out to investigate the effects of high-THC and high-CBD extracts on cytokine production in immune cells. Significant differences between the extracts were observed. Subsequent experiments focusing on a specific high CBD extract (CBD-X) showed significant reductions in pro-inflammatory cytokines in human-derived PBMCs, neutrophils and T cells. In vivo mouse studies, using a systemically inflamed mouse model, showed reductions in pro-inflammatory cytokines TNFα and IL-1β and a concurrent increase in the anti-inflammatory cytokine IL-10 in response to CBD-X extract treatment. Lung inflamm...
Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuh... more Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. ...
Introduction: Activating mutation of FLT3 by internal tandem duplications (ITD) is the most commo... more Introduction: Activating mutation of FLT3 by internal tandem duplications (ITD) is the most common molecular aberration found in AML. FLT3-ITD mutation induces a proliferation signal and is associated with leukocytosis and poor prognosis. The co-existence of FLT3-ITD with translocation t(5:11) that yields fusion transcript of Nucleoporin98 and the nuclear receptor binding SET-domain protein 1 (NUP98/NSD1) was recently reported to be associated with chemo-resistance. Relapse risk of the majority of FLT3-ITD positive AML patients who are negative to NUP98/NSD1 is increased compared to other AML with normal karyotype, despite similar remission rates. The mechanism of FLT3-ITD contribution to relapse development in patients who achieved remission is unknown. Aims: To explore potential mechanisms that allow relapse in FLT3-ITD positive AML in the presence or absence of NUP98/NSD1 fusion gene. In addition, time sequence of the emergence of both mutations is suggested from a case with rela...
Introduction: Human leukocyte antigen (HLA) molecules are membrane-bound transporters carrying pe... more Introduction: Human leukocyte antigen (HLA) molecules are membrane-bound transporters carrying peptides from the cytoplasm to the cell surface where they become exposed to T lymphocytes. Soluble HLA molecules (sHLA) bound to their specific peptides are present in human plasma. Patient-based evidence that most of these peptides are derived from cancerous cells may lead to the identification of cancer-related sHLA peptidomes in the disease state. Leukemic cells in the bone marrow (BM) are usually composed of several malignant subclones even within the same patient. These leukemic subclones may vary in their sensitivity to chemotherapy. During the first days of chemotherapy, a dynamic change in the blast mass and subclonal cell composition is observed. We have thus hypothesized that the repertoire and amount of peptides bound to sHLA molecules derived from the BM plasma of acute myeloid leukemia (AML) patients will be changing during induction. Our study has aimed at identifying peptid...
Introduction: Leukemic sub-clones which survive chemotherapy during induction period may remain d... more Introduction: Leukemic sub-clones which survive chemotherapy during induction period may remain dormant and subsequently lead to relapse in patients with acute myeloid leukemia (AML). No mechanism linking clonal selection to a specific leukemia-associated genetic aberration is known. Clonal selection is a common phenomenon; therefore, any suggested mechanism should be applicable to all kinds of leukemia-specific genetic aberrations. We hypothesized that clonal selection might result from differences in differentiation capacity among sub-clones and that chemo-resistance is not necessarily directly affected by specific mutations. Patients and Methods: We tested this hypothesis in vitro using the kasumi-1 leukemia cell line, which undergoes limited differentiation while growing and is composed of both CD34+ and CD34- sub-populations. Kasumi-1 cells were sorted by fluorescence-activated cell sorting (FACS-Aria IIIu, BD Biosciences) to CD34+CD117+ and CD34-CD117+ sub-populations. Each su...
16 Enhancement of the Immunoadjuvant Activity of Immunostimulatory DNA Sequence By Liposomal Deli... more 16 Enhancement of the Immunoadjuvant Activity of Immunostimulatory DNA Sequence By Liposomal Delivery Eli Kedar, Igal Louria-Hayon, Aviva Joseph, Zichria Zakay-Rones, Tomoko Hayashi, Kenji Takabayashi, and Yechezkel Barenholz 1. INTRODUCTION Bacterial ...
Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have... more Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines, little is known about the intracellular signaling pathways that are activated by cytokines upon binding to their receptors. Our study showed that Growth factor receptor-bound protein 2 (Grb2) mRNAs are preferentially expressed in HSC compared to progenitors and differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a rapid decline of erythroid and myeloid progenitors and a progressive decline of HSC numbers in steady state conditions. We showed that when transplanted, Grb2 deleted bone marrow cells could not reconstitute irradiated recipients. Strinkingly, Grb2 deletion did not modify HSPC quiescence, but impaired LT-HSC and progenitors ability to respond a proliferative signal induced by 5FU in vivo and by various cytokines in vitro. We showed finally that Grb2 links IL3 signaling to the ERK/MAPK proliferative pathway and that both SH2 and SH3 domains of Grb2 are crucial for IL3 signaling in progenitor cells. Our findings position Grb2 as a key adaptor that integrates various cytokines response in cycling HSPC.
A liposomal influenza vaccine (INFLUSOME-VAC) was developed with the objective of overcoming the ... more A liposomal influenza vaccine (INFLUSOME-VAC) was developed with the objective of overcoming the major drawbacks of the currently used influenza vaccines: their relatively low efficacy in certain high-risk groups (the elderly, infants, the immunosuppressed) and the need for annual immunization. INFLUSOME-VAC consists of liposomes containing the viral surface proteins hemagglutinin (HA) and neuraminidase (NA) derived from various influenza strains and IL-2 or GM-CSF, as an adjuvant. Vaccination of mice showed that, whereas conventional vaccines induced a low- and short-term response against HA and very low or no anti-NA response, INFLUSOME-VAC produced high titers of both anti-HA and anti-NA antibodies (Abs) in young and old mice that persisted for at least 6 months. Moreover, the anti-NA Abs efficiently cross-reacted with several N2 viral subtypes spanning 20 years, and such vaccines afforded partial protection against heterosubtypic viral infection.
16 Enhancement of the Immunoadjuvant Activity of Immunostimulatory DNA Sequence By Liposomal Deli... more 16 Enhancement of the Immunoadjuvant Activity of Immunostimulatory DNA Sequence By Liposomal Delivery Eli Kedar, Igal Louria-Hayon, Aviva Joseph, Zichria Zakay-Rones, Tomoko Hayashi, Kenji Takabayashi, and Yechezkel Barenholz 1. INTRODUCTION Bacterial ...
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