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Article ; Online: Artesunate Switches Monocytes to an Inflammatory Phenotype with the Ability to Kill Leukemic Cells

Rubia Isler Mancuso / Sara Teresinha Olalla Saad / Juliana Hofstätter Azambuja

International Journal of Molecular Sciences, Vol 22, Iss 2, p

2021 Volume 608

Abstract: Monocytes are components of the tumor microenvironment related to cancer progression and immune escape. Therapeutic strategies for reprogramming monocytes from a tumor-supporting phenotype towards a tumoricidal phenotype are of great interest. Artesunate ...

Abstract	Monocytes are components of the tumor microenvironment related to cancer progression and immune escape. Therapeutic strategies for reprogramming monocytes from a tumor-supporting phenotype towards a tumoricidal phenotype are of great interest. Artesunate (ART) may be an interesting option for cancer treatment; however, the role of ART in regulating the inflammatory tumor microenvironment has not yet been investigated. Our aim is to evaluate the immunomodulatory potential of ART in vitro in human primary monocytes. ART treatment induced an increase in inflammatory monocytes (CD14 high CD16 − ) with HLA-DR high expression and MCP-1/IL-1β release. On the other hand, ART treatment reduced CD206 and CD163 expression, and abolished the monocyte population known as non-classical and intermediate. Leukemia cells in contact with monocytes programmed with ART presented enhanced in vitro apoptosis suggesting that monocytes acquired the ability to kill leukemic cells. ART induced changes in the monocyte phenotype were mediated by JAK2/STAT3 downregulation. The induction of immunosuppressive environment is an important step for cancer progression. ART showed an immunomodulatory activity, leading immune cells to an antitumor phenotype and could be a candidate for immunotherapy in cancer patients.
Keywords	artesunate ; hematologic malignancies ; immunotherapy ; monocytes ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610 ; 700
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Hematopoietic Cell Kinase (HCK) Is a Player of the Crosstalk Between Hematopoietic Cells and Bone Marrow Niche Through CXCL12/CXCR4 Axis

Fernanda Marconi Roversi / Maura Lima Pereira Bueno / Fernando Viera Pericole / Sara Teresinha Olalla Saad

Frontiers in Cell and Developmental Biology, Vol

2021 Volume 9

Abstract: The crosstalk between hematopoietic stem/progenitor cells (HSC), both normal and leukemic, and their neighboring bone marrow (BM) microenvironment (niche) creates a reciprocal dependency, a master regulator of biological process, and chemotherapy ... ...

Abstract	The crosstalk between hematopoietic stem/progenitor cells (HSC), both normal and leukemic, and their neighboring bone marrow (BM) microenvironment (niche) creates a reciprocal dependency, a master regulator of biological process, and chemotherapy resistance. In acute myeloid leukemia (AML), leukemic stem/progenitor cells (LSC) anchored in the protective BM microenvironment, reprogram and transform this niche into a leukemia-supporting and chemoprotective environment. One most important player involved in this crosstalk are CXCL12, produced by the BM mesenchymal stromal cells, and its receptor CXCR4, present onto HSC. The downstream molecular mechanisms involved in CXCL12/CXCR4 axis have many targets, including the Src family members of non-receptor tyrosine kinase (SFK). We herein study the role of one SFK member, the Hematopoietic Cell Kinase (HCK), in CXCL12/CXCR4 pathway and its contribution to the AML pathogenesis. We verified that the inhibition of HCK severely impaired CXCL12-induced migration of leukemic cell lines and CD34 positive cells from AML patients bone marrow, through a disruption of the activation of CXCL12/CXCR4/PI3K/AKT and CXCL12/CXCR4/MAPK/ERK signaling, and by a decreased cytoskeleton dynamic through a lower rate of actin polymerization. We provide new insights into the key role of HCK in conferring a migratory advantage to leukemic cells thought CXCL12/CXCR4 axis. HCK represents an important protein of the main pathway involved in the crosstalk between HSC, and their surrounding milieu. Thus, HCK inhibition could represent a novel approach for the treatment of the acute myeloid leukemia.
Keywords	acute myeloid leukemia ; cancer therapeutic target ; CXCL12/CXCR4 axis ; hematopoietic cell kinase ; PI3K/MAPK pathway ; crosstalk ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Motivating medical students to learn basic science concepts using chronic myeloid leukemia as an integration theme

Sara Teresinha Olalla Saad / Hernandes Faustino Carvalho

Revista Brasileira de Hematologia e Hemoterapia, Vol 37, Iss 1, Pp 63-

2015 Volume 66

Abstract: Objective: To report on the use of chronic myeloid leukemia as a theme of basic clinical integration for ﬁrst year medical students to motivate and enable in-depth understanding of the basic sciences of the future physician. Methods: During the past ... ...

Abstract	Objective: To report on the use of chronic myeloid leukemia as a theme of basic clinical integration for ﬁrst year medical students to motivate and enable in-depth understanding of the basic sciences of the future physician. Methods: During the past thirteen years we have reviewed and updated the curriculum of the medical school of the Universidade Estadual de Campinas. The main objective of the new curriculum is to teach the students how to learn to learn. Since then, a case of chronic myeloid leukemia has been introduced to ﬁrst year medical students and discussed in horizontal integration with all themes taught during a molecular and cell biology course. Cell structure and components, protein, chromosomes, gene organization, proliferation, cell cycle, apoptosis, signaling and so on are all themes approached during this course. At the end of every topic approached, the students prepare in advance the corresponding topic of clinical cases chosen randomly during the class, which are then presented by them. During the ﬁnal class, a paper regarding mutations in the abl gene that cause resistance to tyrosine kinase inhibitors is discussed. After each class, three tests are solved in an interactive evaluation. Results: The course has been successful since its beginning, 13 years ago. Great motivation of those who participated in the course was observed. There were less than 20% absences in the classes. At least three (and as many as nine) students every year were interested in starting research training in the ﬁeld of hematology. At the end of each class, an interactive evaluation was performed and more than 70% of the answers were correct in each evaluation. Moreover, for the ﬁnal evaluation, the students summarized, in a written report, the molecular and therapeutic basis of chronic myeloid leukemia, with scores ranging from 0 to 10. Considering all 13 years, a median of 78% of the class scored above 5 (min 74%-max 85%), and a median of 67% scored above 7. Conclusion: Chronic myeloid leukemia is an excellent ...
Keywords	Academic teaching ; Medicine education ; Cell biology ; Translation course ; Diseases of the blood and blood-forming organs ; RC633-647.5
Subject code	410
Language	English
Publishing date	2015-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: (–)-Epigallocatechin-3-gallate induces apoptosis and differentiation in leukaemia by targeting reactive oxygen species and PIN1

Fernanda Isabel Della Via / Rodrigo Naoto Shiraishi / Irene Santos / Karla Priscila Ferro / Myriam Janeth Salazar-Terreros / Gilberto Carlos Franchi Junior / Eduardo Magalhães Rego / Sara Teresinha Olalla Saad / Cristiane Okuda Torello

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 11

Abstract: Abstract (–)-Epigallocatechin-3-gallate (EGCG), the major active polyphenol extracted from green tea, has been shown to induce apoptosis and inhibit cell proliferation, cell invasion, angiogenesis and metastasis. Herein, we evaluated the in vivo effects ... ...

Abstract	Abstract (–)-Epigallocatechin-3-gallate (EGCG), the major active polyphenol extracted from green tea, has been shown to induce apoptosis and inhibit cell proliferation, cell invasion, angiogenesis and metastasis. Herein, we evaluated the in vivo effects of EGCG in acute myeloid leukaemia (AML) using an acute promyelocytic leukaemia (APL) experimental model (PML/RARα). Haematological analysis revealed that EGCG treatment reversed leucocytosis, anaemia and thrombocytopenia, and prolonged survival of PML/RARα mice. Notably, EGCG reduced leukaemia immature cells and promyelocytes in the bone marrow while increasing mature myeloid cells, possibly due to apoptosis increase and cell differentiation. The reduction of promyelocytes and neutrophils/monocytes increase detected in the peripheral blood, in addition to the increased percentage of bone marrow cells with aggregated promyelocytic leukaemia (PML) bodies staining and decreased expression of PML-RAR oncoprotein corroborates our results. In addition, EGCG increased expression of neutrophil differentiation markers such as CD11b, CD14, CD15 and CD66 in NB4 cells; and the combination of all-trans retinoic acid (ATRA) plus EGCG yield higher increase the expression of CD15 marker. These findings could be explained by a decrease of peptidyl-prolyl isomerase NIMA-interacting 1 (PIN1) expression and reactive oxygen species (ROS) increase. EGCG also decreased expression of substrate oncoproteins for PIN1 (including cyclin D1, NF-κB p65, c-MYC, and AKT) and 67 kDa laminin receptor (67LR) in the bone marrow cells. Moreover, EGCG showed inhibition of ROS production in NB4 cells in the presence of N-acetyl-L-cysteine (NAC), as well as a partial blockage of neutrophil differentiation and apoptosis, indicating that EGCG-activities involve/or are in response of oxidative stress. Furthermore, apoptosis of spleen cells was supported by increasing expression of BAD and BAX, parallel to BCL-2 and c-MYC decrease. The reduction of spleen weights of PML/RARα mice, as well as apoptosis induced by EGCG in NB4 cells in a dose-dependent manner confirms this assumption. Our results support further evaluation of EGCG in clinical trials for AML, since EGCG could represent a promising option for AML patient ineligible for current mainstay treatments.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Arhgap21 Deficiency Results in Increase of Osteoblastic Lineage Cells in the Murine Bone Marrow Microenvironment

Mariana Ferreira Pissarra / Cristiane Okuda Torello / Rafael Gonçalves Barbosa Gomes / Rodrigo Naoto Shiraishi / Irene Santos / Karla Priscila Vieira Ferro / Matheus Rodrigues Lopes / Patricia Maria Bergamo Favaro / Sara Teresinha Olalla Saad / Mariana Lazarini

Frontiers in Cell and Developmental Biology, Vol

2021 Volume 9

Abstract: ARHGAP21 is a member of the RhoGAP family of proteins involved in cell growth, differentiation, and adhesion. We have previously shown that the heterozygous Arhgap21 knockout mouse model (Arhgap21+/−) presents several alterations in the hematopoietic ... ...

Abstract	ARHGAP21 is a member of the RhoGAP family of proteins involved in cell growth, differentiation, and adhesion. We have previously shown that the heterozygous Arhgap21 knockout mouse model (Arhgap21+/−) presents several alterations in the hematopoietic compartment, including increased frequency of hematopoietic stem and progenitor cells (HSPC) with impaired adhesion in vitro, increased mobilization to peripheral blood, and decreased engraftment after bone marrow transplantation. Although these HSPC functions strongly depend on their interactions with the components of the bone marrow (BM) niche, the role of ARHGAP21 in the marrow microenvironment has not yet been explored. In this study, we investigated the composition and function of the BM microenvironment in Arhgap21+/− mice. The BM of Arhgap21+/− mice presented a significant increase in the frequency of phenotypic osteoblastic lineage cells, with no differences in the frequencies of multipotent stromal cells or endothelial cells when compared to the BM of wild type mice. Arhgap21+/− BM cells had increased capacity of generating osteogenic colony-forming units (CFU-OB) in vitro and higher levels of osteocalcin were detected in the Arhgap21+/− BM supernatant. Increased expression of Col1a1, Ocn and decreased expression of Trap1 were observed after osteogenic differentiation of Arhgap21+/− BM cells. In addition, Arhgap21+/− mice recipients of normal BM cells showed decreased leucocyte numbers during transplantation recovery. Our data suggest participation of ARHGAP21 in the balanced composition of the BM microenvironment through the regulation of osteogenic differentiation.
Keywords	osteocalcin ; myelodysplastic syndromes ; acute myeloid leukemia ; RhoGAP ; Rho GTPase ; RhoA ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CXCR7 participates in CXCL12-mediated migration and homing of leukemic and normal hematopoietic cells

Rita de Cassia Carvalho Melo / Karla Priscila Viera Ferro / Adriana da Silva Santos Duarte / Sara Teresinha Olalla Saad

Stem Cell Research & Therapy, Vol 9, Iss 1, Pp 1-

2018 Volume 5

Abstract: Abstract CXCR4 was the first receptor identified for CXCL12, but a second receptor, CXCR7, has also been described and its function in hematopoietic cells remains unknown. By inhibition of CXCR4 and/or CXCR7, we showed that CXCR7 participates in normal ... ...

Abstract	Abstract CXCR4 was the first receptor identified for CXCL12, but a second receptor, CXCR7, has also been described and its function in hematopoietic cells remains unknown. By inhibition of CXCR4 and/or CXCR7, we showed that CXCR7 participates in normal CD34+ and U937 cell migration and prevents downregulation of CXCR4 by CXCL12 stimulation. In addition, CXCR7 contributes to homing of acute myeloid leukemia and normal progenitor cells to the bone marrow and spleen of NOD/SCID mice. In summary, this study shows an essential role of CXCR7, together with CXCR4, in the control of normal and malignant hematopoietic cell migration and homing induced by CXCL12.
Keywords	CXCR7 ; Cell migration ; Homing ; Hematopoiesis ; Leukemia ; Medicine (General) ; R5-920 ; Biochemistry ; QD415-436
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The polyphenol quercetin induces cell death in leukemia by targeting epigenetic regulators of pro-apoptotic genes

Marisa Claudia Alvarez / Victor Maso / Cristiane Okuda Torello / Karla Priscilla Ferro / Sara Teresinha Olalla Saad

Clinical Epigenetics, Vol 10, Iss 1, Pp 1-

2018 Volume 11

Abstract: Abstract Background In the present study, we investigated the molecular mechanisms underlying the pro-apoptotic effects of quercetin (Qu) by evaluating the effect of Qu treatment on DNA methylation and posttranslational histone modifications of genes ... ...

Abstract	Abstract Background In the present study, we investigated the molecular mechanisms underlying the pro-apoptotic effects of quercetin (Qu) by evaluating the effect of Qu treatment on DNA methylation and posttranslational histone modifications of genes related to the apoptosis pathway. This study was performed in vivo in two human xenograft acute myeloid leukemia (AML) models and in vitro using HL60 and U937 cell lines. Results Qu treatment almost eliminates DNMT1 and DNMT3a expression, and this regulation was in part STAT-3 dependent. The treatment also downregulated class I HDACs. Furthermore, treatment of the cell lines with the proteasome inhibitor, MG132, together with Qu prevented degradation of class I HDACs compared to cells treated with Qu alone, indicating increased proteasome degradation of class I HDACS by Qu. Qu induced demethylation of the pro-apoptotic BCL2L11, DAPK1 genes, in a dose- and time-dependent manner. Moreover, Qu (50 μmol/L) treatment of cell lines for 48 h caused accumulation of acetylated histone 3 and histone 4, resulting in three- to ten fold increases in the promoter region of DAPK1, BCL2L11, BAX, APAF1, BNIP3, and BNIP3L. In addition, Qu treatment significantly increased the mRNA levels of all these genes, when compared to cells treated with vehicle only (control cells) (*p < 0.05). Conclusions In summary, our results showed that enhanced apoptosis, induced by Qu, might be caused in part by its DNA demethylating activity, by HDAC inhibition, and by the enrichment of H3ac and H4ac in the promoter regions of genes involved in the apoptosis pathway, leading to their transcription activation.
Keywords	Quercetin ; HDACs ; DNMTs ; Epigenetics ; Leukemia ; Medicine ; R ; Genetics ; QH426-470
Subject code	570
Language	English
Publishing date	2018-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pilot randomized controlled trial to evaluate the effect of aquatic and land physical therapy on musculoskeletal dysfunction of sickle cell disease patients

Camila Tatiana Zanoni / Fábio Galvão / Alberto Cliquet Junior / Sara Teresinha Olalla Saad

Revista Brasileira de Hematologia e Hemoterapia, Vol 37, Iss 2, Pp 82-

2015 Volume 89

Abstract: Objective: To compare the effect of aquatic and land-based physiotherapy in reducing musculoskeletal hip and lower back pain and increasing overall physical capabilities of sickle cell disease patients. Methods: Informed written consent was obtained from ...

Abstract	Objective: To compare the effect of aquatic and land-based physiotherapy in reducing musculoskeletal hip and lower back pain and increasing overall physical capabilities of sickle cell disease patients. Methods: Informed written consent was obtained from all volunteers who were submitted to evaluations using different functional scales: Lequesne's Algofunctional Questionnaire and Oswestry Disability Index, trunk and hip range of motion, goniometry, trunk and hip muscle strength assessment using load cell, and surface electromyography of the iliocostalis, long dorsal (longissimus), gluteus maximus, gluteus medius and tensor fasciae latae muscles. Ten patients were randomized into two groups: aquatic physiotherapy with a mean age of 42 years (range: 25-67) and conventional physiotherapy with a mean age of 49 years (range: 43-59). Both groups were submitted to a twelve-week program of two sessions weekly. Results: After the intervention, signiﬁcant improvements were observed regarding the Lequesne index (p-value = 0.0217), Oswestry Disability Index (p-value = 0.0112), range of motion of trunk extension (p-value = 0.0320), trunk ﬂexion muscle strength (p-value = 0.0459), hip extension and abduction muscle strength (p-value = 0.0062 and p-value = 0.0257, respec- tively). Range of motion of trunk and hip ﬂexion, extension, adduction and abduction, trunk extensor muscle strength and all surface electromyography variables showed no signiﬁcant statistical difference. Conclusion: Physical therapy is efﬁcient to treat musculoskeletal dysfunctions in sickle cell disease patients, irrespective of the technique; however, aquatic therapy showed a trend toward improvement in muscle strength. Further studies with a larger patient sample and longer periods of therapy are necessary to conﬁrm these results.
Keywords	Anemia ; sickle cell ; Hydrotherapy ; Physical therapy modalities ; Internal medicine ; RC31-1245 ; Medicine ; R
Subject code	796 ; 610
Language	English
Publishing date	2015-04-01T00:00:00Z
Publisher	Sociedade Brasileira de Hematologia e Hemoterapia
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Myelodysplastic syndrome with synchronous gastric cancer

Paula de Melo Campos / Fabiola Traina / Irene Lorand-Metze / Sara Teresinha Olalla Saad

Revista Brasileira de Hematologia e Hemoterapia, Vol 36, Iss 6, Pp 442-

when the symptoms suggest something else

2014 Volume 444

Abstract: Although myelodysplastic syndromes have a clear definition in theory, the morphologic dysplasia associated with ineffective hematopoiesis may be subtle and difficult to recognize and can commonly be mimicked by systemic conditions, such as infections, ... ...

Abstract	Although myelodysplastic syndromes have a clear definition in theory, the morphologic dysplasia associated with ineffective hematopoiesis may be subtle and difficult to recognize and can commonly be mimicked by systemic conditions, such as infections, autoimmune disorders, nutritional deficiencies, toxic factors and non-hematological malignancies. However, myelodysplastic syndromes may truly coexist with other systemic diseases, which can be masked when the patient's symptoms are attributed exclusively to myelodysplastic syndromes without further investigation. To better illustrate this, we herein describe two cases associated with synchronous gastric cancers.
Keywords	Pancytopenia ; Myelodysplastic syndromes ; Hematologic neoplasms ; Secondary neoplasms ; Primary neoplasms ; Internal medicine ; RC31-1245 ; Medicine ; R
Language	English
Publishing date	2014-12-01T00:00:00Z
Publisher	Sociedade Brasileira de Hematologia e Hemoterapia
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Obesity and inflammation and the effect on the hematopoietic system

Bruno Deltreggia Benites / Simone Cristina Olenscki Gilli / Sara Teresinha Olalla Saad

Revista Brasileira de Hematologia e Hemoterapia, Vol 36, Iss 2, Pp 147-

2014 Volume 151

Abstract: Bone marrow is organized in specialized microenvironments known as 'marrow niches'. These are important for the maintenance of stem cells and their hematopoietic progenitors whose homeostasis also depends on other cell types present in the tissue. ... ...

Abstract	Bone marrow is organized in specialized microenvironments known as 'marrow niches'. These are important for the maintenance of stem cells and their hematopoietic progenitors whose homeostasis also depends on other cell types present in the tissue. Extrinsic factors, such as infection and inflammatory states, may affect this system by causing cytokine dysregulation (imbalance in cytokine production) and changes in cell proliferation and self-renewal rates, and may also induce changes in the metabolism and cell cycle. Known to relate to chronic inflammation, obesity is responsible for systemic changes that are best studied in the cardiovascular system. Little is known regarding the changes in the hematopoietic system induced by the inflammatory state carried by obesity or the cell and molecular mechanisms involved. The understanding of the biological behavior of hematopoietic stem cells under obesity-induced chronic inflammation could help elucidate the pathophysiological mechanisms involved in other inflammatory processes, such as neoplastic diseases and bone marrow failure syndromes.
Keywords	Obesity ; Inflammation ; Hematopoietic system ; Internal medicine ; RC31-1245 ; Medicine ; R
Subject code	616
Language	English
Publishing date	2014-04-01T00:00:00Z
Publisher	Sociedade Brasileira de Hematologia e Hemoterapia
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Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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