scholarly journals Interleukin 6 is a permissive factor for monocytic colony formation by human hematopoietic progenitor cells.

1992 ◽  
Vol 175 (4) ◽  
pp. 1151-1154 ◽  
Author(s):  
J H Jansen ◽  
J C Kluin-Nelemans ◽  
J Van Damme ◽  
G J Wientjens ◽  
R Willemze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Progenitor Cells ◽  
Interleukin 6 ◽  
Colony Formation ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Marrow Cells

Since monocytes and macrophages that arise during the culture of bone marrow progenitor cells are potential sources of interleukin 6 (IL-6), we investigated whether auto- or paracrine production of this factor is involved in colony formation by normal hematopoietic progenitor cells. We added a polyclonal anti-IL-6 antiserum and a monoclonal anti-IL-6 antibody to cultures of monocyte- and T cell-depleted bone marrow cells. Colony formation was stimulated with granulocyte/monocyte-colony-stimulating factor (GM-CSF), monocyte-CSF, or IL-3. Addition of anti-IL-6 antibody resulted in decreased numbers of monocytic colonies to 40-50% of control values, whereas the numbers of granulocytic colonies were not altered. The inhibitory effect was preserved in cultures of CD34(+)-enriched bone marrow cells. As a second approach, we added a monoclonal antibody directed against the IL-6 receptor to cultures of monocyte- and T cell-depleted bone marrow cells. This antibody almost completely inhibited the growth of monocytic colonies, again without decreasing the number of granulocytic colonies. Finally, the importance of IL-6 in monocytopoiesis was demonstrated in serum-deprived bone marrow cultures: addition of exogenous IL-6 to cultures stimulated with GM-CSF resulted in increased numbers of monocytic colonies. Our results indicate that the permissive presence of IL-6 is required for optimal monocytic colony formation by bone marrow progenitor cells.

Mitotic Arrest Deficiency 2 (Mad2) Is Required for Proliferative Synergy of GM-CSF Plus SCF in Hematopoietic Progenitors Via Effects on Apoptosis and Is Mediated by Ligand-Dependent Association of Mad2 with SCF and GM-CSF Receptors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4225-4225
Author(s):  
Shigeki Ito ◽  
Charlie Mantel ◽  
Yoji Ishida ◽  
Hal E. Broxmeyer
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Human Growth ◽  
Underlying Mechanism ◽  
Mitotic Arrest ◽  
Hematopoietic Progenitor Cells ◽  
Cytokine Signaling ◽  
Hematopoietic Progenitor ◽  
Gm Csf

Abstract Mitotic arrest deficiency 2 (Mad2) is a component of the mitotic spindle checkpoint complex and is essential for accurate chromosome segregation. We previously reported that Mad2 is involved in synergistic proliferation of hematopoietic progenitor cells in response to SCF combined with GM-CSF, but the underlying mechanism remains unclear. Recently, it was reported that Mad2 physically associates with common β chain (βc) of GM-CSF receptor. Because c-Kit constitutively binds to βc, we hypothesized that Mad2 protein physically associates with c-Kit receptor. We examined if Mad2 interacts with c-Kit using human growth factor-dependent cell line, MO7e, which expresses both c-Kit and GM-CSF receptors. Immunoprecipitation assays demonstrated interaction of c-Kit with Mad2. We then examined whether the interaction of Mad2 with c-Kit is cytokine dependent. Mad2 dissociates from c-Kit after stimulation with SCF plus GM-CSF, but not with SCF or GM-CSF alone. Additionally, because bone marrow hematopoietic progenitor cells from Mad2+/− mice lack synergy in response to SCF plus GM-CSF, it is possible that interaction of Mad2 with c-Kit mediates their synergistic proliferative effects. To address this, we examined intracellular cytokine signaling and apoptosis in MO7e cells depleted of Mad2 by RNA interference. We observed no difference between control and Mad2-depleted cells in phosphorylation of Erk1/2 at Thr202/Tyr204 and Akt at Ser473 after synergistic stimulation with SCF plus GM-CSF. In contrast, the percent of apoptosis of Mad2-depleted cells was significantly higher than that of control (26.2±0.7% vs. 20.3±0.4%, P<0.01). This was compatible with the results of apoptosis assays using c-Kit+Lineage− bone marrow cells from Mad2+/− and wild type mice. These results suggest that Mad2 may be involved in synergistic proliferation of hematopoietic progenitor cells via regulation of apoptosis rather than early cytokine signaling. These effects are likely mediated through Mad2 interaction with c-Kit and the beta chain of the GM-CSF receptor.

Lack of evidence for infection of or effect on growth of hematopoietic progenitor cells after in vivo or in vitro exposure to human immunodeficiency virus

Blood ◽  
1990 ◽  
Vol 76 (12) ◽  
pp. 2476-2482 ◽  
Author(s):  
JM Molina ◽  
DT Scadden ◽  
M Sakaguchi ◽  
B Fuller ◽  
A Woon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Marrow Cells

The pathogenesis of the hematologic abnormalities commonly observed in patients with acquired immunodeficiency syndrome (AIDS) is incompletely understood. We report here that in vitro growth of myeloid (CFU-GM) and erythroid (BFU-E) progenitor cells from six patients with AIDS was not significantly different from that of normal human immunodeficiency virus (HIV) seronegative donors: 25.3 +/- 5 CFU-GM per 5 x 10(4) low density marrow cells and 33.5 +/- 5 BFU-E were observed in AIDS patients versus 32.7 +/- 5 CFU-GM and 42.1 +/- 5 BFU-E in controls. Furthermore, no HIV-DNA in individual colonies (CFU-GM and BFU-E) could be detected using the polymerase chain reaction (PCR) technique, although HIV-1 DNA was detected in peripheral blood mononuclear cells from the same patients. Similarly, normal bone marrow cells exposed in vitro to different isolates of HIV or recombinant purified HIV-1 envelope glycoprotein (gp) 120 did not exhibit any difference in growth of CFU-GM or BFU-E as compared with mock exposed bone marrow cells. HIV- 1 DNA could not be detected by the PCR technique in individual colonies derived from HIV exposed marrow. This study suggests that committed myeloid and erythroid progenitors from AIDS patients are responsive to hematopoietic growth factors in vitro and do not appear to contain HIV- 1 DNA. Also, HIV or its envelope gp did not alter the growth of hematopoietic progenitor cells in vitro. No evidence of HIV infection of progenitor cells could be demonstrated. Impaired hematopoiesis in patients with AIDS may not be related to direct effects of HIV on committed progenitor cells.

Impairment of lymphopoiesis and myelopoiesis in mice reconstituted with bone marrow–hematopoietic progenitor cells expressing SDF-1–intrakine

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2074-2080 ◽  
Author(s):  
Nobuyuki Onai ◽  
Yan-yun Zhang ◽  
Hiroyuki Yoneyama ◽  
Toshio Kitamura ◽  
Sho Ishikawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
B Lymphopoiesis ◽  
Hematopoietic Progenitor ◽  
Fcm Analysis ◽  
Marrow Cells

Both SDF-1 and CXCR4 disruption are lethal to mice at the embryonic stage and cause abnormalities in B lymphopoiesis, myelopoiesis, cardiogenesis, vasculogenesis, and cerebellar development. To investigate the role of SDF-1 and CXCR4 in hematopoiesis during the adult stage, mice reconstituted with bone marrow–derived hematopoietic progenitor cells transduced with either the SDF-1 or a genetically modified SDF-1–intrakine gene using a retroviral expression vector were analyzed. Flow cytometric (FCM) analysis showed a dramatic reduction of CXCR4 expression on the cells of intrakine-transduced mice, whereas CCR7 and CCR1 expression was unchanged or marginally decreased on splenocytes. Migration of splenocytes and bone marrow cells to SDF-1 was markedly suppressed in intrakine-transduced mice. FCM analysis of bone marrow cells of intrakine-transduced mice exhibited decreased numbers of pro-B (B220+ CD43+), pre-B (B220+CD43−), and immature B (B220+IgM+) cells and a decreased number of granulocytes/myeloid (Gr1+ CD11b+) cells. Impaired B lymphopoiesis and myelopoiesis in intrakine-transduced mice were confirmed by an in vitro colony-forming assay of bone marrow cells. In contrast, B lymphopoiesis and myelopoiesis were enhanced in SDF-1–transduced mice. Interestingly, T-cell maturation in the thymus was impaired both in intrakine- and SDF-1–transduced mice, suggesting that SDF-1 and CXCR4 play an important role in T lymphopoiesis as well as in B lymphopoiesis and myelopoiesis in adults. These results demonstrate an essential role of CXCR4 and its ligand SDF-1 in adult hematopoiesis, and they indicate the intrakine method as a powerful tool for functional analysis of chemokines/chemokine receptors in vivo and as a potential therapeutic approach for acquired immunodeficiency syndrome.

scholarly journals Functional differences between CD38- and DR- subfractions of CD34+ bone marrow cells

Blood ◽  
1994 ◽  
Vol 84 (5) ◽  
pp. 1473-1481 ◽  
Author(s):  
LS Rusten ◽  
SE Jacobsen ◽  
O Kaalhus ◽  
OP Veiby ◽  
S Funderud ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Flow Cytometric Analysis ◽  
Hematopoietic Progenitor Cells ◽  
Proliferative Potential ◽  
Hematopoietic Progenitor ◽  
Erythroid Progenitor ◽  
Cd34 Cells ◽  
Marrow Cells

Abstract Several studies have previously demonstrated enrichment in primitive progenitor cells in subfractions of CD34+ bone marrow (BM) cells not expressing CD38 or HLA-DR (DR) antigens. However, no studies have directly compared these two cell populations with regard to their content of primitive and more committed progenitor cells. Flow cytometric analysis of immunomagnetic isolated CD34+ cells demonstrated little overlap between CD34+CD38- and CD34+DR- progenitor subpopulations in that only 12% to 14% of total CD34+DR- and CD34+CD38- cells were double negative (CD34+CD38-DR-). Although the number of committed myeloid progenitor cells (colony-forming units granulocyte- macrophage) was reduced in both subpopulations, only CD34+CD38- cells were significantly depleted in committed erythroid progenitor cells (burst-forming units-erythroid). In single-cell assay, CD34+CD38- cells showed consistently poorer response to single as opposed to multiple hematopoietic growth factors as compared with unfractionated CD34+ cells, indicating that the CD34+CD38- subset is relatively enriched in primitive hematopoietic progenitor cells. Furthermore, CD34+CD38- and CD34+DR- cells, respectively, formed 3.2-fold and 1.6-fold more high proliferative potential colony-forming cell (HPP-CFC) colonies than did unfractionated CD34+ cells. Finally, CD34+CD38-DR- cells were depleted in HPP-CFCs as compared with CD34+CD38+DR+ cells. The results of the present study suggest that both the CD38- and DR- subfractions of CD34+ bone marrow cells are enriched in primitive hematopoietic progenitor cells, with the CD34+CD38- subpopulation being more highly enriched than CD34+DR- cells.

Impairment of lymphopoiesis and myelopoiesis in mice reconstituted with bone marrow–hematopoietic progenitor cells expressing SDF-1–intrakine

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2074-2080 ◽  
Author(s):  
Nobuyuki Onai ◽  
Yan-yun Zhang ◽  
Hiroyuki Yoneyama ◽  
Toshio Kitamura ◽  
Sho Ishikawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
B Lymphopoiesis ◽  
Hematopoietic Progenitor ◽  
Fcm Analysis ◽  
Marrow Cells

Abstract Both SDF-1 and CXCR4 disruption are lethal to mice at the embryonic stage and cause abnormalities in B lymphopoiesis, myelopoiesis, cardiogenesis, vasculogenesis, and cerebellar development. To investigate the role of SDF-1 and CXCR4 in hematopoiesis during the adult stage, mice reconstituted with bone marrow–derived hematopoietic progenitor cells transduced with either the SDF-1 or a genetically modified SDF-1–intrakine gene using a retroviral expression vector were analyzed. Flow cytometric (FCM) analysis showed a dramatic reduction of CXCR4 expression on the cells of intrakine-transduced mice, whereas CCR7 and CCR1 expression was unchanged or marginally decreased on splenocytes. Migration of splenocytes and bone marrow cells to SDF-1 was markedly suppressed in intrakine-transduced mice. FCM analysis of bone marrow cells of intrakine-transduced mice exhibited decreased numbers of pro-B (B220+ CD43+), pre-B (B220+CD43−), and immature B (B220+IgM+) cells and a decreased number of granulocytes/myeloid (Gr1+ CD11b+) cells. Impaired B lymphopoiesis and myelopoiesis in intrakine-transduced mice were confirmed by an in vitro colony-forming assay of bone marrow cells. In contrast, B lymphopoiesis and myelopoiesis were enhanced in SDF-1–transduced mice. Interestingly, T-cell maturation in the thymus was impaired both in intrakine- and SDF-1–transduced mice, suggesting that SDF-1 and CXCR4 play an important role in T lymphopoiesis as well as in B lymphopoiesis and myelopoiesis in adults. These results demonstrate an essential role of CXCR4 and its ligand SDF-1 in adult hematopoiesis, and they indicate the intrakine method as a powerful tool for functional analysis of chemokines/chemokine receptors in vivo and as a potential therapeutic approach for acquired immunodeficiency syndrome.

scholarly journals 939 Autocrine/paracrine factors in cancer associated fibroblasts drive immunosuppression through impaired myeloid cell functions

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A985-A985
Author(s):  
Nikita Sharma ◽  
Priya Govindaraju ◽  
Shermineh Bradford ◽  
Yarong Wang ◽  
Brianna Flynn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Progenitor Cells ◽  
Tumor Antigen ◽  
Bone Marrow Cells ◽  
Pancreatic Stellate Cells ◽  
Hematopoietic Progenitor Cells ◽  
Cancer Associated Fibroblasts ◽  
Hematopoietic Progenitor ◽  
Marrow Cells

BackgroundCancer associated fibroblasts (CAFs) promote tumorigenesis by secreting immunosuppressive cytokines, stimulating angiogenesis, and supporting the growth of tumor cells. Through their interactions with immune cells, CAFs are known to directly impact the functionality of T cells and macrophages. However, CAF interaction with dendritic cells (DCs) and DC progenitor cells and its impact on DC function is relatively understudied and was the main focus of this study.MethodsTwo types of coculture systems were used in this study. For the human system, fibroblasts from lung squamous cell carcinoma (LUSC) were cocultured with MUTZ3 cells (hematopoietic progenitor cells) in the presence of DC differentiation stimuli, sometimes followed by DC maturation stimuli. For the mouse coculture system, activated (YPSC-c) and inactivated (PSC-b) pancreatic stellate cells (PSCs) were isolated from the pancreas of C57BL/6 mice by the density gradient method and co-cultured in the presence of bone marrow cells in the presence of DC differentiation and maturation stimuli. For human tumor antigen processing and cross presentation assay MART1 peptide (10mer and 20mer) was used.ResultsCo-culture of human and murine hematopoietic progenitor cells with fibroblasts (human LUSC CAFs and murine PSC results in decrease in differentiation and maturation of DCs. DCs differentiated and matured in the presence of fibroblasts have impaired ability to process and present tumor antigen to T cells. In the presence of PSC fibroblasts DC differentiation from murine bone marrow cells is skewed more towards MDSC and macrophages. In contrast to inactivated PSC-b, activated PSC-c influence DC differentiation in a contact dependent manner. Furthermore, PSC-b and PSC-c show transcriptionally distinct signatures which translate to unique secretory profiles as measured by Luminex. Analysis of the conditioned media from the coculture demonstrated that PSC-c secrete (among others) CXCL1, IL6, and CCL5 chemo/cytokines. These and other factors may play an important role in mediating fibroblast induced suppression of DC differentiation from monocytes.ConclusionsOur study demonstrates that cancer associated fibroblasts, or their precursors directly impact DC differentiation and antigen presentation via cytokines that could be targeted therapeutically to improve DC expansion and activity in the tumor microenvironment.

scholarly journals Lack of evidence for infection of or effect on growth of hematopoietic progenitor cells after in vivo or in vitro exposure to human immunodeficiency virus

Blood ◽  
1990 ◽  
Vol 76 (12) ◽  
pp. 2476-2482 ◽  
Author(s):  
JM Molina ◽  
DT Scadden ◽  
M Sakaguchi ◽  
B Fuller ◽  
A Woon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Marrow Cells

Abstract The pathogenesis of the hematologic abnormalities commonly observed in patients with acquired immunodeficiency syndrome (AIDS) is incompletely understood. We report here that in vitro growth of myeloid (CFU-GM) and erythroid (BFU-E) progenitor cells from six patients with AIDS was not significantly different from that of normal human immunodeficiency virus (HIV) seronegative donors: 25.3 +/- 5 CFU-GM per 5 x 10(4) low density marrow cells and 33.5 +/- 5 BFU-E were observed in AIDS patients versus 32.7 +/- 5 CFU-GM and 42.1 +/- 5 BFU-E in controls. Furthermore, no HIV-DNA in individual colonies (CFU-GM and BFU-E) could be detected using the polymerase chain reaction (PCR) technique, although HIV-1 DNA was detected in peripheral blood mononuclear cells from the same patients. Similarly, normal bone marrow cells exposed in vitro to different isolates of HIV or recombinant purified HIV-1 envelope glycoprotein (gp) 120 did not exhibit any difference in growth of CFU-GM or BFU-E as compared with mock exposed bone marrow cells. HIV- 1 DNA could not be detected by the PCR technique in individual colonies derived from HIV exposed marrow. This study suggests that committed myeloid and erythroid progenitors from AIDS patients are responsive to hematopoietic growth factors in vitro and do not appear to contain HIV- 1 DNA. Also, HIV or its envelope gp did not alter the growth of hematopoietic progenitor cells in vitro. No evidence of HIV infection of progenitor cells could be demonstrated. Impaired hematopoiesis in patients with AIDS may not be related to direct effects of HIV on committed progenitor cells.

scholarly journals Functional differences between CD38- and DR- subfractions of CD34+ bone marrow cells

Blood ◽  
1994 ◽  
Vol 84 (5) ◽  
pp. 1473-1481 ◽  
Author(s):  
LS Rusten ◽  
SE Jacobsen ◽  
O Kaalhus ◽  
OP Veiby ◽  
S Funderud ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Flow Cytometric Analysis ◽  
Hematopoietic Progenitor Cells ◽  
Proliferative Potential ◽  
Hematopoietic Progenitor ◽  
Erythroid Progenitor ◽  
Cd34 Cells ◽  
Marrow Cells

Several studies have previously demonstrated enrichment in primitive progenitor cells in subfractions of CD34+ bone marrow (BM) cells not expressing CD38 or HLA-DR (DR) antigens. However, no studies have directly compared these two cell populations with regard to their content of primitive and more committed progenitor cells. Flow cytometric analysis of immunomagnetic isolated CD34+ cells demonstrated little overlap between CD34+CD38- and CD34+DR- progenitor subpopulations in that only 12% to 14% of total CD34+DR- and CD34+CD38- cells were double negative (CD34+CD38-DR-). Although the number of committed myeloid progenitor cells (colony-forming units granulocyte- macrophage) was reduced in both subpopulations, only CD34+CD38- cells were significantly depleted in committed erythroid progenitor cells (burst-forming units-erythroid). In single-cell assay, CD34+CD38- cells showed consistently poorer response to single as opposed to multiple hematopoietic growth factors as compared with unfractionated CD34+ cells, indicating that the CD34+CD38- subset is relatively enriched in primitive hematopoietic progenitor cells. Furthermore, CD34+CD38- and CD34+DR- cells, respectively, formed 3.2-fold and 1.6-fold more high proliferative potential colony-forming cell (HPP-CFC) colonies than did unfractionated CD34+ cells. Finally, CD34+CD38-DR- cells were depleted in HPP-CFCs as compared with CD34+CD38+DR+ cells. The results of the present study suggest that both the CD38- and DR- subfractions of CD34+ bone marrow cells are enriched in primitive hematopoietic progenitor cells, with the CD34+CD38- subpopulation being more highly enriched than CD34+DR- cells.

scholarly journals Functional activity of animal bone marrow cells after their treatment with nanocomplexes

2021 ◽  
Vol 29 (2) ◽  
pp. 9-21
Author(s):  
A. M. Goltsev ◽  
T. G. Dubrava ◽  
Yu. O. Gaevska ◽  
N. M. Babenko ◽  
M. O. Bondarovych ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Toxic Effect ◽  
Progenitor Cells ◽  
Functional Activity ◽  
Therapeutic Dose ◽  
Bone Marrow Cells ◽  
Earth Metal ◽  
Hematopoietic Progenitor Cells ◽  
National Academy Of Sciences ◽  
Hematopoietic Progenitor

Background. Previously, the antitumor activity of nanocomplexes (NCs) containing nanoparticles of rare earth metal orthovanadates GdYEuVO4 and cholesterol has been approved when applied in 9:1 ratio (the cells-to-NCs), which can be considered as a conditionally therapeutic dose. Therefore, studying the potential risks of NCs exposure in terms of functional activity of hematopoietic progenitor cells is relevant. Рurpose – determining a toxic effect of NCs on functional activity of hematopoietic cells of bone marrow (BM). Materials and Methods. The study was performed in BM cells of CBA/H mice. Nanocomplexes were synthesized at Institute for Scintillation Materials of the National Academy of Sciences of Ukraine. BM cells with NCs were incubated in the ratios as follows: 9BM:1NCs; 1BM:1NCs; 1BM:9NCs, followed by assessing the number of apoptotic/necrotic cells in BM using FITC Annexin V Apoptosis Detection Kit I (BD, USA) by means of “FACS Calibur” flow cytometer (“BD”, USA). Hematopoietic progenitor cells of BM were functionally evaluated in vivo by determining the content of colony-forming units of the spleen (CFUs) and the number of myelokaryocytes in lethally irradiated recipients on day 8 after administering BM cells, pre-incubated with NCs. Survival of irradiated recipient mice after BM administration was recorded 12 days long. Results and discussion. The dose-dependent effect of functional potential in- hibition for BM hematopoietic progenitor cells under NCs influence has been established. Although, in vitro processing the BM cells with a conditionally therapeutic dose of NCs (9BM:1NCs) before administration to irradiated animal caused remodeling of cell membranes and contributed to apoptotic manifes- tations, but it did not lead to strong changes in their colony-forming potential and did not reduce the number of BM cells in animals if compared with the introduced BM cells without NCs treatment. Increasing the NCs concentration five- and tenfold significantly reduced the colony-forming potential of BM cells, caused BM hypoplasia and a crucial reduction in the survival of recipient animals, indicating possible toxic effects of this compound when administered at high concentrations. Conclusions. The toxic effect of NCs is detected only when certain concen- trations, significantly exceeding the conditionally therapeutic dose previously determined when treating the experimental oncology diseases, are used.

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