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1
Akarca, Ayse. "Immunohistochemical studies for identification of biomarkers in haematological malignancies: An approach for potential novel therapeutic targets." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1127626.
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Lymphoid neoplasms are a subgroup of haematological malignancies that affect circulating lymphocytes. The clinical and biological heterogeneity of lymphoid neoplasms can lead to difficulty in accurate diagnosis in this group of diseases. The advancement in effective and feasible detection platforms has enabled novel biomarkers to improve diagnosis and prognosis, in addition to assist in patient stratification and personalised treatments for these diseases. Although there have been improvements in high-throughput diagnostic techniques, the conventional immunohistochemistry (IHC) remains the most widely used platform for biomarker assessment in the field of tissue pathology. As this conventional technique has certain limitations, multiplex IHC (MIHC) approaches have found ways to overcome these challenges, therefore becoming the main focus of immunotherapy for lymphoid neoplasms. This particular effective and proficient technology can simultaneously target multiple molecule/protein of interest within the tumor microenvironment to determine the status of immune cell activation and the presence of protein expression. MIHC is advantageous in providing information about the underlying immune evasion mechanisms, which play a vital role in the development of prognostic and diagnostic biomarkers. This thesis focuses on the novel use of IHC/MIHC approaches and their current role in biomarker development to be used in diagnosis, prognosis, and the potential treatment strategies within haematological malignancies in specific lymphoid neoplasms.
2
Schouten, Hendricus Constantinus. "Chromosomal abnormalities in hematological malignancies." Maastricht : Maastricht : Datawyse ; University Library, Maastricht University [Host], 1991. http://arno.unimaas.nl/show.cgi?fid=5640.
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Runarsson, Gudmundur. "Biosynthesis of leukotriene B₄ in hematological malignancies /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-386-8/.
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Gorkin, David Uscher. "Hematological malignancies: the possible role of BCL11A." Thesis, Boston University, 2004. https://hdl.handle.net/2144/32867.
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Thesis (B.A.)--Boston University. University Professors Program Senior theses.PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
2031-01-01
5
Buldini, Barbara. "Flow cytometry application in hematological malignancies of childhood." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425984.
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The PhD research work was performed, for the first part (1 year) at the Pediatric Haematology-Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia University and for the second part (2 years) at the Pediatric Haematology-Oncology Department, Padova University, two excellent setting for a specialized training in pediatric haematology-oncology. The PhD program was targeted in both a clinical and laboratory research experience in order to perform a translational research on pediatric patients affected by a wide range of hematological disorders, both malignant and non-malignant. The efforts were coordinated to study the biology and therapy of pediatric Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS).
6
Kim, Mee Hye. "Optimisation and application of comparative genomic hybridisation (CGH) in cancer cytogenetics." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272858.
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Cherif, Honar. "Infections in patients with hematological malignancies : etiology, trends and management /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-501-1/.
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Hishizawa, Masakatsu. "Identification of tumor-associated antigens in hematological malignancies by SEREX." Kyoto University, 2006. http://hdl.handle.net/2433/143835.
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Romano, Alessandra. "High resolution molecular karyotyping and proteomic analysis in hematological malignancies." Thesis, Universita' degli Studi di Catania, 2011. http://hdl.handle.net/10761/96.
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Il presente lavoro di tesi ha applicato i risultati della genomica funzionale in termini traslazionali a due neoplasie ematologiche: le sindromi mielodislastiche (MDS), e il loro potenziale ventaglio di evoluzione a leucemia mieloide acuta, e l'altrettanto ampio spettro di gammopatie monoclonali, fino alla condizione di mieloma multiplo (MM). In entrambi i casi, infatti, le recenti acquisizioni derivanti dall`applicazione dei nuovi farmaci hanno evidenziato la necessita' di indirizzare l`approccio terapeutico contemporaneamente alle cellule neoplastiche e a quelle del microambiente.
Nelle MDS l`ultima generazione delle piattaforme Affymetrix, capace di identificare polimorfismi di singoli nucleotidi (SNP) e alterazioni del numero di copie (CNA) sul genoma e' stata utilizzata al fine di identificare CNA somatici e germinali associati a tumore e perdite di eterozigosita' (LOH) e piu in gerale anomalie genomiche ricorrenti, particolarmente nelle MDS ad alto rischio di trasformazione in leucemie mieloidi acute. Un singolo paziente e' stato studiato nel tempo seguendo l'evoluzione clinica della sua MDS in leucemia acuta, con l'obiettivo di definire le univoche caratteristiche del clone neoplastico attraverso un approccio bioinformatico.
Per il MM, abbiamo sviluppato un saggio ex-vivo capace di identificare il segnale associato a trattamenti diversificati di campioni di midollo a fresco, confermando come in ogni paziente si abbia un pattern singolare di attivazione, in presenza di una risposta generalmente differenziata tra plasmacellule neoplastiche ed elementi del microambiente.
Grazie a una tecnica globale proteomica (RPMA) abbiamo identificato vie di trasduzione del segnale che si attivano come meccanismo compensatorio al trattamento farmacologico, potenzialmente responsabili di chemioresistenza sia nelle MDS che nel MM, sostenute dai segnali di autofagia e sopravvivenza. In particolare sono stati identificati:
- Msi-2 come potenziale biomarcatore di staminalita' e aggressivita' nelle MDS,
- la via di PLC 1Tyr783, SrcTyr416 and STAT-5Tyr694 responsabile di alcuni effetti collaterali del trattamento con Azacitidina nelle MDS,
- il livello di fosforilazione di NFkB quale potenziale mediatore di chemioresistenza al Desametasone nel MM,
- la via di AkT/mTOR quale marcatore di aggressivita` delle plasmacellule nel MM,
- una patologica compartimentalizzazione di serotonina nel MM nel sangue periferico e midollare, correlata alla malattia ossea mielomatosa.
Nell`insieme, i nostri dati suggeriscono nuove potenziali applicazioni in campo diagnostico e prognostico, e/o nuovi approcci terapeutici per MDS e MM, attraverso un approccio integrato genomico e proteomico.In this work we focused on two hematological malignancies to apply the translational meaning of functional genomics: myelodysplastic syndrome (MDS) and its potential evolution to frank acute myeloid leukaemia, and the broad set of monoclonal gammopathies up to multiple myeloma (MM). In both diseases the recent advances obtained thanks to the application of novel therapeutic agents have enlighten the need to target at the same time both neoplastic and surrounding microenvironment cells. In MDS we applied the last generation of Affymetrix single nucleotide polymorphism (SNP)/copy number aberrations (CNA) platform to distinguish somatic and germline tumor-associated CNAs and loss of heterozigosity (LOHs) to identify possible recurring genomic abnormalities in high risk MDS evolving to AML. In particular in one patient, strictly followed in the clinical evolution from MDS to AML, we were able to define the unique features of the aberrant clone through a bioinformatic-based strategy. For MM, we developed ex-vivo assay to identify signalling associated with differential treatments of fresh bone marrow aspirate samples, confirming the unique constellation of activation in the single patient, and the general trend of a differential behavior among neoplastic and surrounding cells. Thanks to a global proteomic technique (RPMA) we identified compensatory pathways potentially responsible of chemoresistance, in both MDS and MM, sustained by the activation of autophagy and pro-survival signalling. In particular, we identified: - Msi-2 as potential biomarker of stemness and aggressivity in MDS, - PLC-y1Tyr783, SrcTyr416 and STAT-5Tyr694 as compensatory pathway responsible of side effects of treatment with azacitidine in MDS, - NFkB status as potential mediator of chemoresistance to dexamethasone in MM, - Akt/mTOR as biomarker of aggressiveness of plasmacells in MM; - an abnormal compartmentalization of serotonin in MM peripheral blood and bone marrow, related to bone disease. Taken together, our data provide potential insights into diagnosis, prognosis, and/or treatment strategies for MDS/AML and MM, through an integrative genomic and proteomic approach.
10
BANDINI, CECILIA. "FUNCTIONAL GENOMIC APPROACHES TO SENSITIZE HEMATOLOGICAL MALIGNANCIES TO PROTEASOME INHIBITORS." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/708377.
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Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma (MM) and
mantle-cell lymphoma (MCL). Nevertheless, patients continuously relapse or are intrinsically
resistant to PIs.Here, to identify druggable targets that synergize with PIs, we carried out a functional screening in
MM cell lines using a shRNA library targeting cancer driver genes. The Isocitrate Dehydrogenase 2
(IDH2) and Lysin Specific-Demethylases 1 (LSD1) genes were identified as top candidates, showing
a synthetic lethal activity with the PI Carfilzomib (CFZ). We first validated the role of IDH2 in
mediating PIs sensitivity. Combinations of the pharmacological IDH2 inhibitor AGI-6780 with FDA
approved PIs significantly increased apoptotic cell death in ten MM cell lines, both sensitive and
resistant to PIs. Combined treatments triggered synergistic cytotoxicity also in others hematological
malignancies, such as Burkitt’s lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma.
Importantly, CFZ/AGI-6780 treatment increased death of primary MM cells from nine patients and
exhibited a favorable cytotoxicity profile towards normal human cells. Mechanistically, CFZ/AGI-
6780 combination decreased TCA cycle activity and ATP levels, due to enhanced IDH2 enzymatic
inhibition. Specifically, CFZ treatment decreased nicotinamide phosphoribosyltransferase (NAMPT)
expression, a rate-limiting enzyme required for IDH2 activation, through the NAD+-dependent
deacetylase SIRT3. Consistently, combination of CFZ with either NAMPT or SIRT3 inhibitors
impaired IDH2 activity and increased MM cells death, thus phenocopying CFZ/AGI-6780 effects and
putting the proteasome in a direct link with IDH2 inhibition. Moreover, inducible IDH2 knock-down
enhanced the therapeutic efficacy of CFZ in xenograft mouse models of MM, resulting in inhibition
of tumor progression and extended survival.
Finally, preliminary results also showed that LSD1 may represent a potential therapeutic target to
combine with PIs. Indeed, genetic inhibition of LSD1 increased sensitivity to CFZ in MM cell lines,
both sensitive and resistant to PIs. Remarkably, treatment with the non-competitive LSD1 inhibitor
SP2509 significantly increased CFZ efficacy in eighth out of ten MM cell lines, both sensitive and
resistant to PIs. However, GSK2879552 and GSK-LSD1, two LSD1 enzymatic inhibitors, did not
display synergistic activity with CFZ, thus establishing the basis for future research of non-canonical
functions of LSD1 or alternative SP2509 targets.
In conclusion, our data demonstrate that IDH2 inhibition increases the therapeutic efficacy of PIs,
thus providing compelling evidence for treatments with lower and less toxic doses and broadening
the application of PIs to other malignancies. Moreover, preliminary results suggest LSD1 targeting
as an alternative promising strategy to enhance PIs sensitivity in multiple myeloma.
11
Flordal, Thelander Emma. "Genetic characterization of hematological malignancies with focul on mantle cell lymphoma /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-161-6/.
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12
Wang, Ling, Zhi Q. Yao, Jonathan P. Moorman, Yanji Xu, and Shunbin Ning. "Gene Expression Profiling Identifies IRF4-associated Molecular Signatures in Hematological Malignancies." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/6538.
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The lymphocyte-specific transcription factor Interferon (IFN) Regulatory Factor 4 (IRF4) is implicated in certain types of lymphoid and myeloid malignancies. However, the molecular mechanisms underlying its interactions with these malignancies are largely unknown. In this study, we have first profiled molecular signatures associated with IRF4 expression in associated cancers, by analyzing existing gene expression profiling datasets. Our results show that IRF4 is overexpressed in melanoma, in addition to previously reported contexts including leukemia, myeloma, and lymphoma, and that IRF4 is associated with a unique gene expression pattern in each context. A pool of important genes involved in B-cell development, oncogenesis, cell cycle regulation, and cell death including BATF, LIMD1, CFLAR, PIM2, and CCND2 are common signatures associated with IRF4 in non-Hodgkin B cell lymphomas. We confirmed the correlation of IRF4 with LIMD1 and CFLAR in a panel of cell lines derived from lymphomas. Moreover, we profiled the IRF4 transcriptome in the context of EBV latent infection, and confirmed several genes including IFI27, IFI44, GBP1, and ARHGAP18, as well as CFLAR as novel targets for IRF4. These results provide valuable information for understanding the IRF4 regulatory network, and improve our knowledge of the unique roles of IRF4 in different hematological malignancies.
13
YAMADA, KAZUMASA, KAZUYUKI NAITO, and SATORU DOI. "Serum Deoxythymidine Kinase as a Progressive Marker of Hematological Malignancy." Nagoya University School of Medicine, 1990. http://hdl.handle.net/2237/17512.
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14
Persson, Lennart. "Neutropenic fever during treatment of hematological malignancy : etiology and diagnostics /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-194-6/.
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15
Kuittinen, O. (Outi). "Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) in hematological malignancies." Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:951426942X.
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Abstract
Gelatinases (MMP-2 and MMP-9) play a key role during
invasion and metastazising of malignant cells and they have been
shown to be associated to invasive phenotype and poor prognosis in
several solid tumours. However little is known about their role in
hematological malignancies. In the present work, gelatinase
expression and its clinicopathological correlations were studied
with immunohistochemical staining in 10 cases representing normal
bone marrow aspirate smears, 123 cases representing diagnostic
bone marrow samples of patients with different leukaemias (35 AML,
7 CLL, 6 CML, 75 ALL), 67 diagnostic paraffin-embedded lymph node
biopsies from patients with Hodgkin's lymphoma and 57 biopsies
from patients with non-Hodgkin's lymphomas. The lymphoma samples
were also stained with factor VIII antibody to evaluate the extent
of new vessel formation and the non-Hodgkin's lymphoma cases also
with tissue inhibitor of metalloproteinases -1 (TIMP-1) antibody.
CLL did not express either of the MMP enzymes, while CML in the
chronic phase expressed strongly both of the enzymes. In ALL,
gelatinase expression was weak and detectable in pediatric cases
in only 12.7% and in the adults in 65% of the cases. In adult ALL,
MMP-2 expression correlated strongly with an extramedullary and
invasive pattern of disease presentation. In AML MMP-2 positivity
had markedly favorable prognostic and predictive power. In
lymphoma studies, no correlations could be detected between
gelatinase expression and the clinical parameters of invasion.
MMP-9 positivity was related to the presence of B symptoms, which
difference was statistically significant in Hodgkin's lymphoma. In
Hodgkin's lymphoma, strong MMP-9 expression also implicated
decreased neovascularization. In both lymphoma types, strong MMP-9
expression correlated with unfavorable prognosis, which difference
was statistically significant in non-Hodgkin's lymphomas and
remained as a tendency in Hodgkin's lymphoma. MMP-2 had
statistically significant association with a favorable prognosis
in Hodgkin's lymphoma. Combination of the results of both
stainings further increased prognostic power. All together these
findings implicate that gelatinases could be used as prognostic
tools in AML and lymphomas albeit this needs to be verified in
larger materials.
16
Malec, Maria. "Standardization and application of quantitative PCR methods in patients with hematological malignancies /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-099-0/.
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Forjaz, Maria João. "Comparing Quality of Life: American and Portuguese Cancer Patients with Hematological Malignancies." Thesis, University of North Texas, 1997. https://digital.library.unt.edu/ark:/67531/metadc278317/.
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The purpose of this study is to investigate the differences and similarities of quality of life (QoL) in American and Portuguese cancer patients with hematological malignancies as well as the robustness of the measures cross-culturally. Portuguese participants were 98 patients and 49 accompanying persons and the American participants were 55 patients and 22 accompanying persons. Fifty (Portuguese sample) to 40% (American sample) of the patients came with an accompanying person who answered the questionnaire concerning the patient's QoL. The two cultural groups were characterized in terms of QoL (measured by the SF-36 and the FLIC), social support (Social Support Scale), socio-demographic and clinical variables. Portuguese patients reported a higher QoL. However, this result could be attributable to the fact that the two cultural samples differ in socio-economic status. The measures seem to be comparable for the Portuguese and American samples, at least in what concerns reliability and concurrent validity.
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Leskov, Ilya Ph D. Massachusetts Institute of Technology. "Modeling hematologic malignancies and their treatment in humanized mice." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/61884.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.Cataloged from PDF version of thesis.
Includes bibliographical references.
Approximately 10% of all cancer deaths in the United States are due to neoplasms of the hematopoietic system, such as leukemias and lymphomas. Genetically engineered mouse models of these diseases have yielded invaluable insights into the ways normal processes become corrupted, leading to cancer development, progression, and spreading. Yet, as our understanding of cancer in mice grows more sophisticated, it is important to be aware of vital differences between murine models and human patients, differences in basic physiology, immunology, and in susceptibility to cancer itself. Furthermore, as anti-neoplastic therapy becomes increasingly focused on human-specific therapies, mouse models become less useful in screening and evaluating potential new therapies. Humanized mice - immunodeficient animals engrafted with human hematopoietic stem cells (HSCs) that subsequently give rise to various mature blood lineage cells - are an elegant solution to these problems, as they offer an ethical and practical way to study human cell biology in vivo. Recent advances in human HSC culture and expansion make it possible not only to generate large cohorts of humanized mice, but also to modify HSCs genetically prior to their engraftment. Such transgenesis of adult human stem cells permits modeling of hematologic malignancies in human cells. To that end, a lentiviral vector capable of stoichiometric expression of up to three transgenes in a B cell-specific manner was constructed; in this case, these transgenes included the GFP reporter and the clinically-important oncogenes Bcl-2 and Myc. Enforced overexpression of Bcl-2 resulted in a benign B cell hyperplasia, but overexpression of Bcl-2 in combination with Myc led to a rapid development of an aggressive disease that recapitulated the histopathological and clinical aspects of human progenitor B cell acute lymphoblastic leukemia (pro-B ALL). Leukemic cells that arise in these mice expressed CD52 and were transplantable into secondary recipients; these were subsequently used to test the efficacy of a human specific monoclonal antibody to CD52, alemtuzumab, which is currently approved for treatment of chronic lymphocytic leukemia, but not ALL. Alemtuzumab treatment of secondary mice resulted in an almost complete clearance of leukemic blasts from the periphery and a significant improvement in life expectancy, and antibody-dependent tumor cell killing was shown to be mediated by macrophages. The lack of alemtuzumab activity in the brain and bone marrow of the mice was investigated, and overcome by combining alemtuzumab with the commonly used chemotherapeutic agent cyclophosphamide. Great synergy between alemtuzumab and cyclophosphamide seen in this model suggests that a further investigation into this clinically relevant drug combination is well warranted.
by Ilya Leskov.
Ph.D.
19
Ishino, Ryo. "Oncolytic virus therapy with HSV-1 for hematologic malignancies." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263570.
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Statler, Abby. "Modernizing the Design of Hematologic Malignancy Clinical Trials." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1544007858228785.
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Li, Yu. "The hematopoiesis supporting function of bone marrow stroma cells in patients with hematological malignancies." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976034395.
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Svensson, Tobias. "Infectious and bleeding complications in patients with hematological malignancies : Studies on diagnosis and prevention." Doctoral thesis, Uppsala universitet, Hematologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-316461.
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The overall aim of this thesis is to improve knowledge about the prevention of infectious and bleeding complications in patients with hematological malignancies, primarily in those with chronic lymphocytic leukemia (CLL) and myelodysplatic syndrome (MDS). Hypogammaglobulinemia, impaired production of immunoglobulins (Ig), is an established risk factor for infection, but the impact of IgG pure subclass deficiency (IgG subclass deficiency with adequate production of IgG, IgA, and IgM) has been debated. In a retrospective single institution study, we concluded that pure IgG subclass deficiency in CLL patients is rare and is not associated with an increased risk of infection. Hence, routine analysis of IgG subclasses in patients with CLL is not warranted. There is no consensus on recommending vaccination against Streptococcus pneumoniae to CLL patients mainly because comparative studies are lacking. In our randomized trial, the efficacy of a conjugated pneumococcal vaccine on immune response was superior or equal to a polysaccharide vaccine for all pneumococcal serotypes common for the two vaccines. A conjugate pneumococcal vaccine should therefore be included in vaccination programs for patients with CLL. Bronchoalveolar lavage (BAL) is a well-established invasive method to identify the cause of pulmonary infiltrates in immunocompromised patients. In a retrospective trial, we have studied the diagnostic yield of BAL in patients with hematological malignancies. We concluded that BAL is highly useful in either verifying or excluding some of the important respiratory tract infections affecting these patients, particularly invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). However, standardized procedures for BAL sampling should be continually revised to avoid unnecessary microbiological tests. Thrombocytopenia, an adverse prognostic factor in patients with MDS, can be aggravated by azacitidine, first-line treatment for high-risk MDS. Eltrombopag, a thrombopoietin-receptor agonist (TPO-R), alleviates thrombocytopenia in patients with immune thrombocytopenic purpura (ITP). In a phase I clinical trial, we concluded that the combination of eltrombopag and azacitidine in high-risk MDS patients with thrombocytopenia is feasible and well tolerated in doses up to 200 mg eltrombopag daily.
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Weagel, Evita Giraldez. "Biomarker Analysis and Clinical Relevance of Thymidine Kinase 1 in Solid and Hematological Malignancies." BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/6881.
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Despite the global effort to discover and improve ways to detect, treat, and monitor cancer, it still remains the second leading cause of death in the United States and poses a major health and economic burden worldwide. While traditional treatments like surgery, chemotherapy, radiation therapy, and hormone therapy have been successful and have decreased cancer mortality, cancer incidence in all sites continues to rise. Consequently, there is an immediate need to find new therapeutics for the treatment of cancer. In recent years, and with the continuing push towards personalized medicine, cancer biomarkers have become crucial to detect, treat, and monitor cancer. Thymidine kinase 1 (TK1) has been identified as a cancer biomarker with diagnostic, prognostic, and therapeutic potential. TK1 is a nucleotide salvage pathway enzyme responsible for maintaining a balance in the cell nucleotide pool and providing the cell with thymidine monophosphate, which upon further phosphorylation is incorporated into DNA during cell replication. TK1 has been found to be upregulated in the serum of cancer patients. Serum TK1 (sTK1) has been used as an early diagnostic and prognostic biomarker in many types of cancer and has been shown to be a better proliferation biomarker than Ki67. In this dissertation, we described the characterization of TK1 as a cancer biomarker that associates with the plasma membrane of hematological malignancies such as Burkitt's lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, acute T cell lymphoma, and solid malignancies such as lung, breast, and colon cancer. We also describe the different oligomeric TK1 forms that are found on the cell membrane and show that membrane TK1 has activity. We assess the clinical relevance of TK1 in all these malignancies, looking at tissue expression as well as gene expression from patients from The Cancer Genome Atlas database. We find that TK1 is not expressed on the surface of normal cells, whether they are proliferating or not, making TK1 a unique cancer biomarker, with the potential to be used in targeted therapy. We also find that TK1 expressed on the surface may be involved in the invasion potential of cancer cells. The knowledge gained from this study will help researchers working in clinical research and cancer immunotherapeutics to potentially use TK1 as a biomarker and cancer target, and thus providing another weapon against cancer. In this dissertation, we described the characterization of TK1 as a cancer biomarker that associates with the plasma membrane of hematological malignancies such as Burkitt's lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, acute T cell lymphoma, and solid malignancies such as lung, breast, and colon cancer. We also describe the different oligomeric TK1 forms that are found on the cell membrane and show that membrane TK1 has activity. We assess the clinical relevance of TK1 in all these malignancies, looking at tissue expression as well as gene expression from patients from The Cancer Genome Atlas database. We find that TK1 is not expressed on the surface of normal cells, whether they are proliferating or not, making TK1 a unique cancer biomarker, with the potential to be used in targeted therapy. We also find that TK1 expressed on the surface may be involved in the invasion potential of cancer cells. The knowledge gained from this study will help researchers working in clinical research and cancer immunotherapeutics to potentially use TK1 as a biomarker and cancer target, and thus providing another weapon against cancer.
24
SAITTA, CLAUDIA. "Predisposition to hematological malignancies in children and adults: from genetic profiling to clonal evolution." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/365155.
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Recenti evidenze hanno dimostrato come la predisposizione rivesta un ruolo cruciale nel 5-10% dei tumori pediatrici. Ciò nonostante, è ancora un ambito nebuloso, che va ulteriormente investigato. Nell’adulto, l’evoluzione clonale agisce in modo simile: l’accumulo di mutazioni somatiche dovuto all’età, aumenta la prevalenza di neoplasie mieloidi tra gli individui più anziani. Come specifici pathway di co-occorrenza predispongano a tumori ematologici, è da indagare in modo più approfondito.
In questo studio, ci siamo focalizzati sul ruolo della predisposizione genetica nei tumori ematologici del bambino e dell’adulto, allo scopo di migliorare le conoscenze riguardo alle alterazioni genetiche che agiscono nella fase pre-leucemica. Abbiamo realizzato il nostro studio attraverso diverse tasks, caratterizzate dall’obiettivo comune di scandagliare il ruolo della predisposizione genetica nel promuovere la trasformazione neoplastica.
Innanzitutto, abbiamo sequenziato una corte di 120 diagnosi consecutive di pazienti pediatrici affetti da Leucemia Linfoblastica Acuta e casi sporadici con altri tumori ematologici, così come casi con ricorrenza familiare. Il profiling genetico ha confermato il ruolo cruciale di alcuni geni nella Leucemogenesi, come quelli appartenenti al pathway di RAS, sia in termini di incidenza, sia di patogenicità. Inoltre, ha fatto luce sulle mutazioni germinali nelle Coesine: queste alterazioni, solitamente associate a sindromi genetiche denominate Coesinopatie, non sono eventi sporadici, ma si presentano con una frequenza non trascurabile (6%) e degna di ulteriori approfondimenti. Considerando questa evidenza, ci siamo focalizzati sulle varianti germinali dei geni STAG1 e RAD21. I nostri risultati hanno dimostrato che queste alterazioni sono responsabili di una scarsa coesione cromatinica, promuovono quindi instabilità genetica spontanea e sono caratterizzati da meccanismi di riparo al danno del DNA difettivi. Pertanto, geni che non sono classicamente correlati alla fase conclamata delle neoplasie ematologiche pediatriche promuovono condizioni che predispongono al cancro, aggravando infatti il rischio di eventi somatici responsabili dell’insorgere della neoplasia.
Al fine di valutare il contributo della predisposizione genetica considerando tutto l’arco della vita, abbiamo investigato il ruolo dell’Evoluzione Clonale nell’adulto. Nonostante sia considerato un fenomeno fisiologico nell’invecchiamento, è anche significativamente associato a malattie cardiovascolari, tumori solidi e neoplasie ematologiche. Lo screening mutazionale di 1794 individui anziani (oltre 80 anni) ha permesso di stabilire un modello basato su tre gruppi di rischio, in cui l’accumulo differenziale di mutazioni somatiche dipendente dall’età aumenta la prevalenza di neoplasie mieloidi o malattie associate all’infiammazione. Nello specifico, le mutazioni dei geni dello Splicing, di JAK2, o la presenza di mutazioni multiple (DNMT3A, TET2, ASXL1 con lesioni genetiche aggiuntive), nonché le varianti con frequenza allelica ≥ 0,096, hanno un valore predittivo positivo per le neoplasie mieloidi. Infine, abbiamo sottolineato il ruolo delle mutazioni dei geni dello Splicing non solo come eventi precoci nella patogenesi, ma anche in una fase precedente, figure chiave nel determinare l’insorgenza della malattia mielodisplasica.
In conclusione, una migliore conoscenza e caratterizzazione di queste alterazioni può avere impatti clinici differenti. In primo luogo, può garantire una migliore comprensione del processo di tumorigenesi, aprendo nuovi scenari in merito al contributo della Predisposizione genetica e dell’Evoluzione Clonale nelle neoplasie ematologiche. Inoltre, può avere conseguenze significative sia nella terapia dei pazienti, sia nella consulenza genetica familiare: consentirebbe quindi strategie di sorveglianza mirate e aggiustamenti terapeutici paziente-specifici.Despite genetic predisposition occurs in 5-10 % of pediatric cancer, it is still a nebulous field, that has to be better characterized. In the adult setting, clonal evolution acts similarly, and age-dependent accumulation of somatic mutations increases the prevalence of myeloid neoplasms among older individuals. How the specific co-occurrence of somatic events predisposes to hematological malignancies have to be further clarified. In the present project, we focused our attention in dissecting the role of genetic predisposition in both childhood and adult hematological malignancies, with the purpose of improving knowledge about genetic alterations that act in pre-leukemic phase. We planned and developed our study through several tasks, characterized by the joint purpose of investigating the contribution of genetic predisposition in promote tumor transformation. Firstly, we screened a cohort of 120 consecutive diagnosis of pediatric patients affected by Acute Lymphoblastic Leukemia and sporadic cases with other hematological malignancies, as well as cases with familiar recurrence. Genetic profiling confirmed the crucial role of some genes in Leukemogenesis, like those belonging to Ras pathway, both in term of incidence and pathogenicity. Moreover, it shed light on germline mutations in Cohesins: these alterations, usually associated to genetic syndromes called Cohesinopathies, are not random or sporadic events, but occur with a frequency (6%) that is not negligible and worthy of further study. Considering this evidence, we made a focus on STAG1 and RAD21 germline variants. Our results demonstrated that they lead to a poor chromosomal strength and promote spontaneous instability, resulting in a lowered response to exogenous and endogenous agents, as well as defective DNA repair mechanisms. So, genes that are not classically related to full-blown stage of hematological disease, promote cancer prone conditions in pediatric patients, aggravating the risk of somatic events that are responsible of the disease’ onset. In order to evaluate the contribution of genetic predisposition in cancer considering overall the time of life, we investigated the role of clonal evolution in the adult setting. Despite it is considered normal in aging, it is also significantly associated with cardiovascular disease, as well as solid tumors and hematological malignancies. The mutational screening of 1794 oldest-old individuals allowed to establish a model based on 3 risk groups, in which differential age-dependent accumulation of somatic mutations increases prevalence of myeloid malignancies or inflammatory-associated diseases. Specifically, mutations in Splicing genes, JAK2 or the presence of multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions), as well as variants with allele frequency ≥0.096, have a positive predictive value for myeloid neoplasms. Finally, we underlined the role of Splicing genes mutations not only as early events in pathogenesis, but also in a previous phase, as key players in determine the onset of myelodysplastic disease. Overall, a better knowledge and characterization of these alterations will have different impacts: it will improve the understanding of tumorigenesis, opening new scenarios regarding the contribution of genetic predisposition and clonal evolution to hematological malignancies. Moreover, it could have significative effects on both patients’ care and familial genetic counseling, enabling targeted surveillance strategies, and tailored therapeutical adjustments that include familiar screening in case of familiar donor in hematopoietic stem cell transplantation.
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Jaramillo, Melba Concepcion Corrales, and Melba Concepcion Corrales Jaramillo. "Manganese Porphyrin, MnTE-2-PyP5+, Enhances Chemotherapeutic Response in Hematologic Malignancies." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/626138.
Full textAbstract:
The prognosis for multiple myeloma (MM) and the activated B-cell subtype of diffuse large B-cell lymphoma (ABC DLBCL) is poor. Gene expression profiling studies have identified that the transcription factor, nuclear factor kappa B (NF-κB) is overexpressed and confers a poor prognosis in MM and ABC DLBCL. NF-κB regulates the transcription of genes involved in cell proliferation and survival. Thus, several groups have tried to identify and/or develop agents that target NF-κB to improve therapy and patient prognosis for MM and ABC DLBCL. Our laboratory has shown that the manganese porphyrin MnTE-2-PyP5+ inhibits NF-κB in a murine lymphoma cell culture model and enhances tumor cell death in combination with dexamethasone and cyclophosphamide, two agents that are routinely used to treat these neoplasms. MnTE-2-PyP5+ inhibits NF-κB by glutathionylating p65, a member of the NF-κB family. The objective of the following studies was to determine whether MnTE-2-PyP5+ enhances the chemotherapeutic response in human MM and ABC DLBCL cells that overexpress and depend on NF-κB for survival. The following studies demonstrate that MnTE-2-PyP5+ glutathionylates and inhibits NF-κB in human MM and ABC DLBCL cells. MnTE-2-PyP5+ also synergizes with several MM and DLBCL chemotherapeutics, including dexamethasone, cyclophosphamide, vincristine and bortezomib to enhance cell death. The data from these human cell lines will provide the basis for future studies to test MnTE-2-PyP5+ in animal models and for translating MnTE-2-PyP5+ to the clinic.
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Townsend, Michelle Hannah. "The Clinical Significance of HPRT as a Diagnostic and Therapeutic Biomarker for Hematological and Solid Malignancies." Thesis, Brigham Young University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10846744.
Full textAbstract:
An estimated 1,735,350 new cancer diagnosis and 609,640 cancer related deaths are predicted to occur in the United States in 2018. To improve patient prognosis, biomarkers are needed to identify cancer in early stages. When diagnosed at an early stage, cancer is more likely to respond to treatments and patients have a higher survival rate. Consequently, there is an ever-present need to identify biomarkers that can aid in the detection of cancer. Additionally, there is a paradigm shift in the field of cancer treatment towards immunotherapy. Traditional cancer treatments include chemotherapy, radiation, and hormone therapy and are not cancer-specific, which leads to bystander effects on the patient’s normal organs that often harm the patient and create unnecessary hardship. To alleviate this, immunotherapy utilizes a patient’s own immune cells to attack and destroy cancer cells via cancer-specific biomarkers. These biomarkers are ideally on the surface of cancer cells and absent from the patient’s normal cells to avoid healthy tissue destruction. With this new therapy, there is a recent push to find surface antigens for immunotherapy techniques.
This dissertation describes the characterization of HPRT as a diagnostic and therapeutic biomarker for the detection and possible treatment of hematological and solid malignancies. We describe the general upregulation of HPRT upon malignancy and show that this elevation in protein expression is independent of stage, which indicates that it would be useful as an early stage diagnostic companion tool. We have preliminarily linked the elevation in HPRT to a mutation in one of its prime transcription factors, p53. Specific mutation in p53 called Gain of Function mutations have shown to influence salvage pathway enzyme expression, and we have shown that mutations in p53 are relevant to the elevated levels of HPRT within several cancer types. In addition, we also found that HPRT associates significantly with the membrane of several cancer cell lines as well as patient samples. We found that HPRT has insignificant expression on normal cells, which suggests it may be useful as a targetable biomarker for immunotherapy. Throughout our analysis, we also determined that HPRT might have a role in immune regulation as an elevation of the protein correlates to the decrease of several pro-inflammatory genes involved in immune activation. The knowledge gained from the data presented in this dissertation have opened up new functions for HPRT outside of simple nucleotide production and have confirmed that HPRT has a unique role in cancer that has not been previously reported.
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Vo, Dang Nghiem. "Natural Killer cell subsets in hematological diseases : learning for immunotherapy." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT013/document.
Full textAbstract:
Les cellules Natural Killer (NK) sont des lymphocytes cytotoxiques innés qui jouent un rôle important dans le contrôle immunitaire de la formation de cellules tumorales et de l'infection virale. Chez les personnes en bonne santé, les cellules NK représentent des populations hétérogènes définies par différents marqueurs phénotypiques et exécutant des fonctions spécifiques. Les cellules NK provenant de patients présentant des tumeurs malignes néoplasiques et une infection virale sont cependant typiquement distinctes des personnes en bonne santé par l'apparition de sous-ensembles de cellules NK, qui sont différenciées par leur profil d'isoformes CD45. CD45 est une tyrosine phosphatase leucocytaire commune abondamment exprimée sur toutes les cellules immunitaires hématopoïétiques nucléées. Un variant d'épissage alternatif a entraîné la génération de l'isoforme CD45RA longue et de l'isoforme courte CD45RO, qui s'expriment différemment sur les cellules T naïves et effectrices / mémoires. L'expression des isoformes CD45 sur les cellules NK est largement inconnue. Nous avons précédemment montré que l'expression différentielle des isoformes CD45RA et CD45RO a identifié des sous-ensembles de cellules NK spécifiques dans les maladies hématologiques. Une question reste floue: comment ces cellules CD45RARO + NK changent-elles lorsque leurs cellules cibles disparaissent? Nous avons utilisé des cellules NK de patients traités avec Lenalidomide et l'anticorps anti-CD20 Obinutuzumab pour étudier cela et montré une réduction des cellules CD45RARO / CD45RO + NK après la clairance des cellules tumorales (Chater 4). Nous avons observé la même chose chez les patients atteints de LMA après une chimiothérapie. Dans ce cas, le sous-ensemble de cellules CD45RARO + NK est fortement corrélé avec la trogocytose du marqueur monocyte / macrophage CD14 (Chapitre 5). L'immunophénotypage de cellules NK provenant de patients infectés par le VIH a révélé la présence de cellules CD45RAdim et CD45RO + avec une expression réduite de CD16 et une diminution de la modulation NKG2D totale. En résumé, les cellules NK des cancers hématologiques et l'infection par le VIH présentaient des caractéristiques dysfonctionnelles et l'analyse du profil isoforme CD45 dans ces conditions pathologiques dévoile ces caractéristiques.Enfin, afin de retrouver la réponse immunitaire anti-tumorale chez les patients cancéreux, nous présentons une méthode efficace pour l'expansion in vitro de cellules NK hautement activées à partir du sang du cordon ombilical (UCB). Ces cellules NK prouvent une cytotoxicité cellulaire dépendante des anticorps (ADCC) importante lorsqu'elles sont utilisées en combinaison avec des anticorps monoclonaux approuvés sur le plan clinique ciblant divers antigènes tumoraux. Ceci ouvre leur utilisation dans les immunothérapies à base de cellules NK allogéniquesNatural Killer (NK) cells are innate cytotoxic lymphocytes that play an important role in immune control of tumor cell formation and virus infection. In healthy people, NK cell represents heterogeneous populations defined by different phenotypical markers and performing specific functions. NK cells from patients with neoplastic malignancies and viral infection are however typically distinctive from healthy people by the appearance of NK cell subsets, which are differentiated by their CD45 isoform profile. CD45 is a common-leukocyte tyrosine phosphatase abundantly expressed on all nucleated hematopoietic immune cells. Alternative splicing variant resulted in generation of the long-isoform CD45RA and the short-isoform CD45RO, which express differently on naïve and effector/memory T cells. Expression of CD45 isoforms on NK cells is largely unknown. We have previously shown that differential expression of CD45RA and CD45RO isoforms identified specific NK cell subsets in hematological diseases. One question remained unclear: how do these CD45RARO+ NK cell changes when their target cells disappeared? We used NK cells from patients treated with Lenalidomide and the anti-CD20 antibody Obinutuzumab to investigate this and showed a reduction in CD45RARO/CD45RO+ NK cells upon clearance of tumor cells (Chater 4). We observed the same in AML patients after chemotherapy. In this case the CD45RARO+ NK cell subset strongly correlates with trogocytosis of the monocyte/macrophage marker CD14 (Chapter 5). Immunophenotyping of NK cells from HIV-infected patients revealed the presence of CD45RAdim and CD45RO+ cells with reduced CD16 expression and total NKG2D down-modulation. In summary, NK cell from hematological cancers and HIV infection displayed dysfunctional hallmarks and analyzing CD45 isoform profile in these pathological conditions unveils these hallmarks.Finally, in order to regain the anti-tumor immune response in cancer patients, we present an efficient method for expansion of highly activated NK cells from umbilical cord blood (UCB) in vitro. These NK cells prove substantial antibody-dependent cell cytotoxicity (ADCC) when used in combination with clinical-approved monoclonal antibodies targeting various tumor antigens. This paves their use in allogeneic NK cell-based immunotherapies
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Binatti, Andrea. "The genomic landscape of solid and hematologic malignancies characterized by new bioinformatics tools." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3424919.
Full textAbstract:
Whole Exome Sequencing (WES) has high power to discover variants in cancer cells, allowing the identification of molecular features underlying diseases development and progression, with important outcomes for cancer diagnosis/prognostication as well as for development and selection of molecularly targeted therapies in personalized medicine. WES projects pose as well different challenges due to biological factors, such as tumour heterogeneity, altered ploidy, low tumor purity, and technical artifacts, that make not obvious the identification of relevant variants.
IWhale, an easy-to-use and customizable pipeline based on Docker and SCons, was developed to analyze cancer WES data, to detect and annotate somatic mutations by a combination of four different callers and integration of information deriving from different databases. Moreover, a systems genetics approach and custom data structures were built up to construct pathway-derived meta-networks of mutated genes depicting their direct interactions and functional relations, to ultimately identify key functions and pathways recurrently hit in cancer cells.
In collaboration with different groups, increasingly refined and customized versions of the pipeline were applied in three WES studies regarding Large granular lymphocyte leukemia (LGL-L), pediatric follicular lymphomas (PTNFL and PFLT) and High-Risk Neuroblastoma (HR-NB).
LGL-L is a rare chronic leukemia with persistent clonal increase of cytotoxic T cells or natural killer (NK) cells often associated to JAK/STAT pathway activation. By analysis of WES data in 19 patients, including cases without STAT mutations (STAT- patients), novel somatic mutations in recurrently mutated genes were identified. 16 selected variants, including those in the tumor suppressor gene FAT4 and in the epigenetic regulator KMT2D, were validated. The new Q706L and S715F STAT5B variants has been also functionally characterized. With pathway-derived network analysis, functional modules composed by several STAT-interacting or STAT-functional connected genes mutated in STAT-negative patients were discovered. Additional modules with putative pathogenic relevance in LGL-L and mutated in the absence of STAT mutations were identified.
In PTNFL, recently recognized as a defined clinicopathological entity, WES analysis of the largest cohort collected so far uncovered mutations in the few genes, TNFRSF14, IRF8 and MAP2K1 previously associated to PTNFL, identifying as well novel mutations and genes. Eleven validated variants prioritized as possible drivers hit the recurrently mutated ARHGEF1, MAP2K1 and TNFRSF14 genes, as well as ATG7, GNA13, RSF1, UBAP2, and ZNF608. G-protein coupled receptor signaling and chromatin modifying enzyme alterations was linked for the first time to PTNFL and PFLT according to obtained findings.
NB, a solid cancer arising from primitive neural crest cells and accounting for 9% of pediatric tumors, is characterized by high clinical heterogeneity and low mutation recurrence even in known driver (MYCN, ALK, ATRX). To clarify the biological basis of disease aggressiveness, WES was used to examine the genomic landscape of HR-NB patients at metastatic stage with short survival (SS) and long survival (LS). A few genes, including SMARCA4, SMO, ZNF44 and CHD2, were recurrently mutated only in the SS group and HotNet2 analysis revealed that in the two patient groups, mutations occurred in different pathways. Notably mutations of SS patients clustered into a six significantly mutated subnetworks, involved into MAPK pathway associated with the organization of the extracellular matrix, to cell motility through PTK2 signaling, to matrix metalloproteinase activity, to centrosome maturation and chromosome remodeling, to metabolism of nucleotides and lipoproteins, and to transport of small molecules. Since FDA-approved compounds targeting the deregulated pathways are available these findings may help to improve the treatment of HR-NB patients with most aggressive disease.Il sequenziamento dell’esoma (WES) rileva efficacemente varianti in cellule tumorali, identificando le caratteristiche molecolari coinvolte nella patogenesi e nella progressione della malattia, con importanti risvolti per la diagnosi e per lo sviluppo e la scelta di terapie personalizzate. L’analisi di dati WES di tumori presenta tuttavia varie complicazioni dovute all’eterogeneità tumorale, ad alterazioni della ploidia, a contaminazioni dei campioni o ad artefatti tecnici. La pipeline iWhale, basata su Docker e SCons, è stata sviluppata per analizzare dati WES di tumori con l’obiettivo di rilevare ed annotare mutazioni somatiche tramite l’uso di quattro diversi software (MuTect, MuTect2, Strelka2 e VarScan2) e l’integrazione di informazioni provenienti da vari database. Inoltre, ho collaborato allo sviluppo di un metodo per la costruzione di meta-reti di geni mutati che sono annotati in database di pathway e ho costruito una struttura di dati customizzata per rilevare statisticamente pathway ricorrentemente mutati in cellule tumorali. In collaborazione con diversi gruppi di ricerca, ho utilizzato ed adattato di volta in volta versioni progressivamente più rifinite della mia pipeline in studi riguardanti la leucemia linfocitica granulare a grandi cellule T (LGL-L), due tipi di linfomi follicolari pediatrici (PTNFL e PFLT) e Neuroblastoma ad alto rischio (HR-NB). LGL-L è una leucemia cronica rara caratterizzata da una persistente crescita clonale di cellule citotossiche T o natural killer (NK) dovuta all’attivazione del pathway JAK/STAT. Mediante analisi WES sono state identificate nuove mutazioni somatiche in geni ricorrentemente mutati in 19 pazienti con LGL-L, comprendenti casi senza mutazioni nei geni STAT. Sono state selezionate per validazione con sequenziamento Sanger 16 varianti in diversi geni, tra le quali l’oncosoppressore FAT4 e il regolatore epigenetico KMT2D. Nuove varianti Q706L e S715F in STAT5B sono state anche caratterizzate funzionalmente. Grazie ad analisi di reti derivate da pathway, sono state identificate delle componenti funzionali composte da geni mutati, funzionalmente o direttamente interagenti con i geni STAT, in pazienti STAT negativi. Altre componenti funzionali con una possibile rilevanza nella patogenesi di LGL-L in assenza di mutazioni nei geni STAT sono emerse dalle analisi. Una coorte di pazienti affetti da linfomi follicolari pediatrici è stata analizzata tramite WES. Sono state confermate mutazioni presenti in TNFRSF14, IRF8 e MAP2K1, geni precedentemente associati a PTNFL, e sono stati caratterizzati nuove mutazioni e geni con possibile coinvolgimento nello sviluppo di PTNFL. Undici varianti presenti in ARHGEF1, MAP2K1, TNFRSF14, ATG7, GNA13, RSF1, UBAP2 e ZNF608 sono state validate e selezionate come possibili eventi driver in PTNFL e PFLT. I nostri risultati hanno per la prima volta permesso di associare il pathway GPCR ed enzimi modificatori della cromatina ai linfomi follicolari pediatrici. NB è un tumore solido che origina dalle cellule della cresta neurale primitiva ed è caratterizzato da un’alta eterogeneità clinica e da pochi geni ricorrentemente mutati (MYCN, ALK, ATRX). Per investigare sulle basi biologiche coinvolte nell’aggressività di NB, è stato effettuato WES di pazienti affetti da HR-NB con metastasi e divisi in base alla sopravvivenza (pazienti SS e LS, rispettivamente con sopravvivenza inferiore o uguale e superiore a 5 anni). Solo i geni SMARCA4, SMO, ZNF44 e CHD2 sono stati trovati mutati ricorrentemente in modo specifico in pazienti SS. HotNet2 ha rivelato che le mutazioni rilevate nei due gruppi ricadevano in pathway diversi. Le mutazioni dei pazienti SS si sono raggruppate in sei sotto-reti significativamente mutate, coinvolte nell’organizzazione della matrice extracellulare tramite MAPK pathway, nella motilità cellulare tramite PTK2, nell’attività delle metalloproteinasi della matrice, nella maturazione del centrosoma e nel rimodellamento dei cromosomi. Grazie all’esistenza di farmaci già approvati dalla FDA che hanno come bersaglio alcune delle proteine mutate o delle pathway identificate, i risultati ottenuti possono facilitare lo sviluppo di terapie mirate ai pazienti con le forme più aggressive di HR-NB.
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Ruiz, Cánovas Eugenia. "Compound F: A novel nuclear receptor modulator and its potential application on hematologic malignancies." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/666667.
Full textAbstract:
Compound F has been reported to possess important antioxidant, anti-inflammatory, anti- diabetic and anti-cancer effects, among other interesting properties. Although Compound F has been extensively investigated, its underlying mechanism of action has not been elucidated yet. In this thesis we describe a novel modulation of several nuclear receptors carried out by Compound F and other ABCs. Focusing on steroid receptors, we also report a direct interaction between Compound F and the glucocorticoid and androgen receptor. Despite the nature of the modulation has not been fully clarified, we propose that it could explain at least some of Compound F bioactivities. Precisely, amid all these potential applications of Compound F, we have centered in the treatment of hematologic malignancies. We report the deleterious effects of Compound F on different cell models of hematologic malignancies, concentrating on acute myeloid leukemia. Current findings also suggest that Compound F could have additive effects in combination with standard of care drugs. An important drawback for the use of Compound F in health applications is its poor water solubility and its low bioavailability. Here, we have developed an albumin-based nanoparticle formulation that overcomes this problem. Additionally, a primary evaluation of its toxicity and pharmacokinetic parameters after intravenous and oral administration to mice has been performed.El Compuesto F es conocido por poseer diversos efectos antioxidantes, antinflamatorios, anti- diabetes y anticancerígenos, entre otras propiedades interesantes. Aunque dicho compuesto ha sido ampliamente investigado, su mecanismo de acción aún no ha sido identificado. En la presente tesis describimos una novedosa modulación de varios receptores nucleares llevada a cabo por el compuesto F y otros de su familia. Centrándonos en receptores esteroidales, también reportamos una interacción directa entre el compuesto F y los receptores de glucocorticoides y de andrógenos. A pesar de que la naturaleza de esta modulación no ha sido del todo elucidada, proponemos que dicha modulación podría explicar, por lo menos, algunas de las bioactividades del Compuesto F. Precisamente, entre estas potenciales aplicaciones del compuesto F, nos hemos centrado en el tratamiento de cánceres hematológicos. Así pues, describimos los efectos citotóxicos del Compuesto F en diferentes modelos celulares de cánceres hematológicos, concentrándonos en la leucemia mieloide aguda. Los presentes resultados sugieren también que el Compuesto F podría tener efectos aditivos en combinación con fármacos de primera línea. Un importante inconveniente para el uso del Compuesto F en aplicaciones clínicas es su baja solubilidad en agua y su limitada biodisponibilidad. En este trabajo hemos desarrollado una formulación de nanopartículas basada en albúmina que consigue solventar dicho inconveniente. Adicionalmente, se ha llevado a cabo una evaluación primaria de su toxicidad y perfil farmacocinético tras administración intravenosa y oral.
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Colosimo, Dominic. "Multiple aspects of natural killer cell expansion in relevance to immunotherapy for hematologic malignancies." Honors in the Major Thesis, University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/1537.
Full textAbstract:
Natural Killer (NK) cells are a subset of lymphocytes that regulate adaptive immune responses and utilize "missing self" recognition to activate anti-tumor and anti-viral cytotoxicity. Clinical research, as well as murine and ex vivo models, have shown that a variety of NK cell applications have proven useful as immunotherapeutic treatments for patients with hematologic malignancies. However, the selective expansion of NK cells to yield relevant amounts of these lymphocytes has been a major hurdle in the development of methods for clinical therapeutic use. Here, we demonstrate a novel ex vivo expansion method utilizing k562 leukemic cell lines and soluble cytokines as well as a novel method utilizing isolated plasma membranes of genetically engineered tumor cell lines that could be of relevance to in vivo NK cell expansion. Also, the ligand expression by canonical feeder cell lines used for NK cell expansion and our isolated plasma membranes were compared via ligand quantification by western blot quantification of 4-1BB ligand. In an adjunct study, we sought to better characterize these expansion environments by investigating the glucose metabolism of NK cells using fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) and the glycolysis inhibitor 2-Deoxy-D-Glucose (2-DG).ID: 031908455; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Accepted in partial fulfillment of the requirements for honors in the major in DEPT HERE.; Thesis (B.A.)--University of Central Florida, 2012.; Includes bibliographical references.
B.S.
Bachelors
Burnett School of Biomedical Sciences
Molecular Biology and Microbiology
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Pan, Feng. "Understanding Ten-Eleven Translocation-2 in Hematological and Nervous Systems." FIU Digital Commons, 2014. http://digitalcommons.fiu.edu/etd/1925.
Full textAbstract:
I proposed the study of two distinct aspects of Ten-Eleven Translocation 2 (TET2) protein for understanding specific functions in different body systems.
In Part I, I characterized the molecular mechanisms of Tet2 in the hematological system. As the second member of Ten-Eleven Translocation protein family, TET2 is frequently mutated in leukemic patients. Previous studies have shown that the TET2 mutations frequently occur in 20% myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), 10% T-cell lymphoma leukemia and 2% B-cell lymphoma leukemia. Genetic mouse models also display distinct phenotypes of various types of hematological malignancies. I performed 5-hydroxymethylcytosine (5hmC) chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq) of hematopoietic stem/progenitor cells to determine whether the deletion of Tet2 can affect the abundance of 5hmC at myeloid, T-cell and B-cell specific gene transcription start sites, which ultimately result in various hematological malignancies. Subsequent Exome sequencing (Exome-Seq) showed that disease-specific genes are mutated in different types of tumors, which suggests that TET2 may protect the genome from being mutated. The direct interaction between TET2 and Mutator S Homolog 6 (MSH6) protein suggests TET2 is involved in DNA mismatch repair. Finally, in vivo mismatch repair studies show that the loss of Tet2 causes a mutator phenotype. Taken together, my data indicate that TET2 binds to MSH6 to protect genome integrity.
In Part II, I intended to better understand the role of Tet2 in the nervous system. 5-hydroxymethylcytosine regulates epigenetic modification during neurodevelopment and aging. Thus, Tet2 may play a critical role in regulating adult neurogenesis. To examine the physiological significance of Tet2 in the nervous system, I first showed that the deletion of Tet2 reduces the 5hmC levels in neural stem cells. Mice lacking Tet2 show abnormal hippocampal neurogenesis along with 5hmC alternations at different gene promoters and corresponding gene expression downregulation. Through the luciferase reporter assay, two neural factors Neurogenic differentiation 1 (NeuroD1) and Glial fibrillary acidic protein (Gfap) were down-regulated in Tet2 knockout cells. My results suggest that Tet2 regulates neural stem/progenitor cell proliferation and differentiation in adult brain.
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陳衛 and Wai Chan. "Clonal rearrangement of T-cell receptor delta gene in hematological malignancies and applications in detection of minimal residualdisease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1995. http://hub.hku.hk/bib/B31212852.
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Carpenter, Kent James. "Inhibition of PIM and AXL Kinases As Potential Treatments for a Variety of Hematological Malignancies and Solid Tumors." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/3842.
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This thesis is divided into three chapters. In each case, the goal is to achieve inhibition of a growth kinase (PIM or AXL) and subsequent arrest of cell growth and induction of apoptosis (in vitro cell culture models) or decrease in tumor volume (in vivo xenograft studies). Chapter one and chapter two discuss inhibition of proviral integration site for Moloneymurine leukemia virus (PIM) kinases. The three PIM kinases, PIM-1, PIM-2, and PIM-3, are a subfamily of serine/threonine kinases that are known to be involved in signaling pathways as downstream effectors of signal transducer and activator of transcription-5 (STAT5) signaling and inhibitors of apoptosis. PIM kinases are implicated in a large percentage of hematological malignancies and solid tumors. Because they have been shown to correlate with disease progression and poor prognosis in many of these conditions, PIM kinase inhibitors are being developed and investigated for therapeutic use. The aim of this study in chapter one was to evaluate the role of PIM 1, 2 and 3 in urothelial carcinomas, using second generation Pan-PIM kinase inhibitor TP-3654. Retrospective immunohistochemical analysis of bladder cancer specimens found that PIM 1, 2, and 3 was expressed in a significant number of cases. PIM-1 was expressed in 4 bladder cancer cell lines and TP-3654 treatment was able to inhibit BAD phosphorylation to induce apoptosis. The second aim of this study was to investigate the effects of TP-3654 on the interaction of c-MYC with PIM kinase family members. The data indicate that PIM-1 only interacts with c-MYC in the acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines studied, and that PIM-1 siRNA knockdown or treatment with TP-3654 is able to decrease this interaction. The third chapter discusses inhibition of the receptor tyrosine kinase Axl. Pancreatic cancer is a highly lethal disease characterized by malignant cells that rapidly disseminate from the primary tumor to form local and distant metastases. Axl is overexpressed in over 50% of pancreatic cancers and expression of Axl in these cancers is highly associated with a poor prognostic outcome for patients. Small molecule inhibitors of AXL are currently under investigation, as AXL is associated with cell migration mediated by epithelial-mesenchymal transition (EMT). The aim of this study was to investigate the effects of a small molecule inhibitor of AXL, TP-0903, on pancreatic cancer cell lines. Consistent with the known function of Axl, TP-0903 inhibited Gas6-induced migration and invasion of pancreatic cancer cells invitro and potently induced apoptosis. Additionally, we found that inhibition of AXL decreased expression of EMT marker genes and induced mesenchymal pancreatic cancer cell lines to take on an epithelial phenotype. TP-0903 also significantly inhibited the growth of pancreatic cancer cell lines grown in xenograft tumor mouse model and taken together, the results suggest Axl is a potential therapeutic target in pancreatic cancer and TP-0903 as a potential therapeutic agent.
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Chan, Wai. "Clonal rearrangement of T-cell receptor delta gene in hematological malignancies and applications in detection of minimal residual disease /." Hong Kong : University of Hong Kong, 1995. http://sunzi.lib.hku.hk/hkuto/record.jsp?B1705512X.
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Leijon, Arvesved Ellinore, and Christina Johansson. "Patienters upplevelser i samband med en hematologisk malignitet : En kvalitatitv litteraturöversikt." Thesis, University of Skövde, School of Life Sciences, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-3650.
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Tidigare studier har fokuserat på barn och deras familjers upplevelser i samband med en hematologisk malignitet, framförallt leukemi. Hematologiska maligniteter är ett samlingsnamn för leukemi och några andra blodsjukdomar. Prevalensen för sjukdomarna ökar och främst vuxna drabbas. Syftet med studien var att beskriva patienters upplevelser av att leva med en hematologisk malignitet. Metoden för denna litteraturöversikt var kvalitativ. Fem artiklar och två avhandlingar analyserades. Studiens resultat utvecklades till fyra huvudteman:
att få en sjukdom, att genomgå behandling, upplevelse av vårdmöten och att skakas om i sin livsvärld. Resultatet visar att sjukdomen upplevs som ett osynligt hot och att det ibland förekommer ett vårdlidande som beror på bristfälligt engagemang för människan bakom den sjuka kroppen. Att genomgå en svår tid med lidandets olika aspekter, förändrade oftast människors syn på sig själva och sina medmänniskor. Relationer fördjupades. Förbättringar i omvårdnadsarbetet kan göras genom ökad fokus på patienters känslomässiga lidande då studien visar att denna aspekt ibland förbises och detta resulterar i en objektifiering av patienter.
Previous studies have focused on children and their families' experiences in connection with a haematological malignancy, especially leukemia. Hematolocical malignancies is a collective name for leukemia and other blood diseases. The prevalence of diseases is increasing and affects mainly adults. The purpose of this study is to describe patients' experiences of living with a haematological malignancy. The methodology for this literature review was qualitative. Five articles and two dissertations were analyzed. Results of the study, developed into four main themes:
to get a disease, to undergo treatment, experience of care meetings and to shake in their life-world. The result shows that the disease is perceived as an invisible threat, and that sometimes there is a health suffering due to inadequate involvement of the person behind the disease body. To undergo a difficult time with various aspects of suffering often alters people's views of themselves and their fellow human beings and relationships deepen. Improvements in care work can be done by increasing the focus on patients' emotional distress when the study shows that this aspect is sometimes overlooked and it results in an objectification of patients.
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Kinal, Mena. "Resistance to vorinostat in hematological malignancies may involve cytoprotective UPR and correlates with increased sensitvity to bortezomib induced cell death." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119545.
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Histone deacetylase inhibitors (HDACi) are anti-cancer agents, which have shown promising activity in hematological malignancies. However, only a small percentage of patients initially respond to treatment and all will eventually develop resistance. HDACi are known to inhibit deacetylation of histones as well as various non-histone proteins. Revealing mechanisms of HDACi resistance will help elucidate their modes of action, as well as help overcome de novo and acquired resistance in the clinic. We chose to conduct our studies on vorinostat, which is a pan-HDACi and the first HDACi to be approved by the FDA for cancer treatment. To study HDACi resistance in hematological malignancies, we developed two vorinostat resistant cell lines from the diffuse-large B cell lymphoma (DLBCL) cell line SUDHL6 and the monocytic-like lymphoma cell line U937, which is associated with acute myeloid leukemia (AML). The resistant clones are called SUDHL6-X and U937-B8. Our lab has previously shown that these clones are also cross-resistant to other HDACi (such as LBH). However they are highly sensitive to autophagy inhibitors such as chloroquine, suggesting that elevated autophagy is necessary to maintain vorinostat resistance. Endoplasmic reticulum (ER) stress is caused by an accumulation of misfolded proteins in the ER lumen. This causes a multifaceted response that is primarily cytoprotective called the unfolded protein response (UPR). The misfolded proteins that are deemed unsalvageable by the ER are targeted for degradation by the proteasome. We found that, in addition to elevated autophagy, vorinostat resistant cells have dilated ER and an accumulation of ubiquitinated proteins compared to their parental counterparts. Moreover, they show increased sensitivity to induction of cell death by the proteasome inhibitor bortezomib. We hypothesized that activation of UPR could be a mechanism of vorinostat resistance, because the UPR induces the upregulation of pro-survival genes and may induce autophagy. Understanding vorinostat resistance holds clinical relevance in terms of improving HDACi therapy and being able to identify subsets of patients who would benefit most from combination therapy such as vorinostat with bortezomib.Les inhibiteurs d'histones deacetylases (HDACi) ont démontré des résultats prometteurs chez des patients atteints de cancers hématologiques. Cependant, une faible proportion de patients répondent favorablement à cette thérapie et de ce nombre, la presque totalité tombera en rechute. Une meilleure connaissance des mécanismes moléculaires menant à la résistance aux HDACi permettra de surmonter la résistance acquise en clinique et, aiderait à développer des combinatoires permettant d'augmenter leur efficacité. Afin de mieux comprendre les mécanismes de résistance aux HDACi, nous avons développé des lignées cellulaires résistantes au vorinostat dans un modèle en culture de de lymphome diffus à grandes cellules B, les SUDHL6, et de lymphome d'apparence monocytique, les U937. Notre laboratoire a récemment démontré que ces lignées cellulaires résistantes, les SUDHL6-X et les U937-B8 sont également résistantes à plusieurs autres HDACi, tel le LBH589 (panobinostat). En contraste, ces lignées cellulaires présentent une plus grande sensibilité aux inhibiteurs d'autophagie que leurs lignées parentales respectives. L'autophagie est activée en réponse à un stress au niveau du réticulum endoplasmique (ER). Ce dernier est causée par un mauvais repliement des protéines nouvellement synthétisées, ce qui occasionne l'activation de la réponse UPR (Unfolded Protein Response) ayant pour fonction entres autres, de diriger les protéines mal repliées vers la dégradation par le protéasome. Nous avons découvert que, les cellules résistantes au vorinostat présentent certaines caractéristiques de stress au niveau du ER dont notamment, un ER dilaté, et une accumulation considérable de protéines ubiquitinées contrairement à leur lignée parentale respective. Ainsi, nous avons émis l'hypothèse que l'activation de la réponse UPR est responsable de la survie des cellules résistantes. Par l'activation de gènes favorisant la survie et l'autophagie, l'activation de la réponse UPR pourrait être un mécanisme de résistance au vorinostat.
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Watatani, Yosaku. "Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling." Kyoto University, 2020. http://hdl.handle.net/2433/253204.
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Mehdipour, P. "DISSECTING THE ROLE OF HISTONE DEACETYLASE 3 (HDAC3) IN LEUKEMOGENESIS." Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/356617.
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Histone deacetylases (HDACs) are epigenetic enzymes that modulate chromatin structure through the deacetylation of lysine residues in histones, playing a crucial role in cell viability, cell cycle progression and tumorigenesis. Yet the role of individual HDACs in these biological processes remains enigmatic. Inappropriate recruitment of HDACs is involved in the pathogenesis of several forms of leukemia and several lines of evidence point to a role for HDACs in tumor progression, consistent with the anti-proliferative and apoptotic effects of HDAC inhibitors (HDACi). In this regard, HDACs are considered promising targets for development of new molecules for cancer therapy. To date, some HDACi which have a broad antitumor activity and low toxicity towards normal cells, such as Romidepsin (Depsipeptide or FK228) and SAHA have been approved by U.S. food and drug administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL). Moreover, HDACi are undergoing clinical trials for the treatment of hematological malignancies as well as for solid tumors. Most of the HDACi available at the moment are not isoform specific, being active on more than one HDAC. Thus, to design more selective HDACi for cancer therapy it is important to elucidate the role of individual HDACs.
Acute Promyelocytic Leukemia (APL) is the first model disease in which the involvement of HDACs has been documented. APL is a subtype of Acute Myeloid Leukemia (AML), a cancer of blood and bone marrow, which is characterized by hyperproliferation of immature granulocytes blocked at the promyelocytic stage. It is genetically associated with a chromosomal translocation t(15;17)(q22;q21), which encodes the oncogenic fusion protein PML-RARα found in more than 90% of APL patients. In murine models of APL that recapitulate the human disease, PML-RARα induces a “pre-leukemic” stage with long latency and without an overtly dramatic phenotype before full leukemic transformation. In fact, for this reason it is assumed that in addition to this oncogenic fusion protein, other genetic hits are required for clonal expansion of leukemic blasts. This fusion protein recruits a number of chromatin modifier enzymes such as HDACs and DNA methyltransferases (DNMTs) to the promoter of retinoic acid (RA) target genes and transcriptionally silence them, leading to the myeloid differentiation block. Furthermore, PML-RARα causes the impairment of p53 pathway by deacetylation and degradation of p53 through the recruitment of HDAC- containing complexes. HDACs from class I (HDACs 1, 2 and 3) have been found associated with PML-RARα paving the way for the use of HDACi for APL treatment. Recently, a study on APL, which has been conducted by Santoro et al., showed that among class I HDACs, HDAC1 and to a lesser extent HDAC2 have a dual role in APL development and maintenance. In fact, while they behave as oncosuppressors at the early stages, they function as oncogenes in established tumor cells. Since inhibition of HDAC1 and HDAC2 in pre-leukemic stage leads to the acceleration of the disease in murine models of leukemia, it suggests caution in the clinical utility of epidrugs that target any of these two HDAC isoforms. Moreover, it has been shown that the expression of HDAC3, which associates with nuclear hormone corepressor and silencing mediator of retinoid hormone (NCoR/SMRT) complex, is frequently increased in tumors, while Hdac3 downregulation results in reduced proliferation and survival of tumor cells. In view of these observations, in this study we functionally assessed the role of HDAC3 in the development and maintenance of APL. To achieve our goal, we have dissected the role of HDAC3 in two different phases of the disease: pre-leukemic phase and full-established leukemia. The murine model of APL, which we used, is the mCGPR/PR mouse model in which PML-RARα is expressed under the control of the cathepsin G promoter. The mice show a very long latency (the pre-leukemic phase) associated with high penetrance (more than 90% of the mice develop APL).
We characterized the role of HDAC3 through a functional knock-down approach, assessing its impact on cellular differentiation, proliferation and the ability to influence the transplantation of HSCs and APL cells. Indeed, Hdac3-KD in vitro reduced the proliferative potential of both pre-leukemic and full leukemic cells and boosted their differentiation, suggesting that HDAC3 plays the role of an oncogene in APL initiation and progression. These results were not restricted to APL, because lymphoma driven by c-myc overexpression and leukemia driven by MLL-AF9, were both impaired in cell growth upon Hdac3-KD. In vivo, inoculation of Hdac3-KD pre-leukemic cells into lethally irradiated recipient mice or inoculation of Hdac3-KD APL cells into the recipient mice did not result in leukemia development or progression, respectively. These results suggest that HDAC3 can be considered as a target for epidrugs in the treatment of hematological malignancies. Thus, we assessed this hypothesis with the treatment of pre-leukemic and leukemic cells with the HDAC3 selective inhibitor, RGFP966. Indeed, inhibition of HDAC3 enzymatic activity with RGFP966, phenocopied Hdac3-KD phenotypes in pre-leukemic and leukemic cells confirming the putative oncogenic role of HDAC3.
In conclusion, my PhD project has expanded our comprehension about the role of HDAC3 in hematological malignancies and is beginning to unravel alternative views on the targets of epidrugs for the treatment of leukemic patients.
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Olsson, Cecilia. "Sexuality in patients treated for hematologic malignancies - Problems and need for support from patients’ and nurses’ perspectives." Doctoral thesis, Karlstads universitet, Institutionen för hälsovetenskaper, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-31827.
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Aim: The overall aim of this thesis was to describe and explore how sexuality, body image and HRQoL were affected in patients treated for hematologic malignancies, and their need for support. A further aim was to describe nurses’ conceptions of dialogues about sexuality. Methods: Ten nurses in cancer care (I) and twelve patients were interviewed (II). Data were analysed according to phenomenography (I-II). Data were also collected from patients (≥45 years) included consecutively: at baseline (n=32), one month (n=25; III-IV) and six months (n=20; IV) after treatment. Three instruments were used: SAQ-S, BIS and EORTC QLQ-C30. The data were analysed statistically. Main findings: The nurses (I) conceived that they should talk about sexuality with cancer patients, but usually did not due to their own attitudes, lack of knowledge about sexuality, communication skills and environmental conditions. The patients (II) experienced negative effects on sexual function and sexual relationship due to affected strength and sexual desire. The patients’ sexuality, body image and HRQoL were affected during (II-III) and one month after treatment (III-IV). Patients recovered with regard to these issues within six months, except for sexual relationship (IV). However, when the disease and side effects were experienced as severe, thoughts about and interest in sexuality were overshadowed, and the need or wish for support related to this issue was low (II). Sexuality and body image seemed to influence changes in HRQoL (IV). Conclusion: Patients above the age of 45 treated for hematologic malignancies with chemoimmunotherapy experienced problems related to sexuality, body image and HRQoL. However, as sexuality was found to be of low priority due to concerns for life when the disease and side effects were severe, support must be timely and individualized. Patient-centered care, with patients continuously meeting a nurse guided by the idea of holistic individual nursing care throughout the care trajectory, is suggested.Sexuality is to a large extent seen as a private and sensitive topic by both patients and nurses in cancer care. The patients in this thesis were above the age of 45 and treated with chemo- or chemoimmunotherapy for hematologic malignancies. They experienced affected sexuality, body image and HRQoL during and after treatment. The importance of sexuality was low and sexuality seemed to be overshadowed when the disease and side effects were experienced as severe. Few patients described that information might have been helpful. In order to avoid violating patients’ integrity, one challenge is to identify patients who ascribe importance to sexuality and who also want support regarding sexuality. One way is to organize care in a patient-centered way, with patients continuously meeting a nurse guided by the idea of holistic individual nursing care throughout the care trajectory. Furthermore, nurse educators’ need to acknowledge this area and the health care leaders should provide nurses opportunities to discuss attitudes and personal barriers to sensitive issues such as sexuality
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PIEVANI, ALICE SILVIA. "Cytokine-induced killer (cik) cell cultures for the adoptive immunotherapy of hematological malignancies: characterization and new therapeutic strategies for clinical application." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2011. http://hdl.handle.net/10281/20178.
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Cytokine-induced killer (CIK) cells are a heterogeneous population of lymphocytes obtained in vitro within 21 days from mononuclear cells under the influence of cytokines. CIK cells show potent MHC-unrestricted cytotoxicity against a variety of tumor cells, in particular hematological malignancies, and minimal tendency to induce graft-versus-host disease.
The expanded bulk CIK culture consists of over 90% CD3+ cells, of which the majority coexpress CD56 and the remaining cells are CD56-. CD3+CD56+ “true” CIK cells are terminally differentiated non dividing lymphocytes which could deliver potent MHC-unrestricted cytotoxicity for the immediate destruction of tumor cells. The other less cytotoxic CD3+CD56- cell subset represents a progenitor reservoir that could proliferate and differentiate into CD3+CD56+ CIK cells. CD3+CD56+ CIK cells express activating NK receptors including NKG2D, DNAM-1 and low levels of NKp30. Cell signalling not only through TCR/CD3, but also through NKG2D, DNAM-1 and NKp30, leads to CIK cell activation resulting in granule exocytosis and cytotoxicity. Antibody blocking experiments revealed that NKG2D, DNAM-1 and NKp30 are actually involved in tumor cell recognition and killing. Anti-CMV specific CIK cells could be expanded in standard CIK conditions and mediate both specific, MHC-restricted recognition of a CMV-pulsed autologous target and NK-like non specific cytolytic activity against leukemic cell targets. Antibody blocking of NKG2D and NKp30 only inhibited NK-like cytotoxicity. Their dual effector function suggests that CIK cells, when used in a clinical setting, may control both neoplastic relapses and viral infections, two frequently associated complications in transplanted patients.
B-cell non-Hodgkin lymphoma is only partially susceptible to CIK-mediated lysis. The addition of anti-CD20 monoclonal antibodies GA101 or rituximab increased cytotoxicity mediated by CIK cell cultures by 35% and 15%, respectively. This enhancement was mainly due to antibody-dependent cytotoxicity mediated by the 1%-10% NK cells contaminating CIK cultures. The addition of human serum inhibited NK-cell activation induced by rituximab, but not activation induced by GA101. Overall lysis in presence of serum, even of a resistant B-NHL cell line, was significantly increased by 100 mcg/mL of rituximab, but even more so by GA101, with respect to CIK cultures alone. The combined use of CIK cells with anti-CD20 mAbs could represent a novel immunotherapy protocol for the treatment of B lymphoma patients with resistant disease.
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Hammarström, Viera. "B-cell immunity in patients with hematological malignancies and after stem cell transplantation : studies with special reference to tetanus and pneumococcal immunity /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980828hamm.
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Correia, Rodolfo Patussi. "Estudo da distribuição de células T naive e subtipos de células T de memória em neoplasias hematológicas." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-19042013-092628/.
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Células T de memória são a marca registrada da imunidade adaptativa, e podem ser caracterizadas em central memory (TCM) e effector memory (TEM) T cells. A participação destas células no curso de doenças hematológicas é descrita como mecanismo relacionado à evolução das mesmas. Neste trabalho, analisamos o sangue periférico de doadores de sangue e pacientes com Mielodisplasia (SMD), Mieloma Múltiplo (MM) e Leucemia linfocítica crônica B (LLC), e avaliamos a distribuição das células T CD4+ e CD8+ naive e de memória. SMD e MM não apresentaram resultados significativos, mas na LLC, as células T CD4+ estavam alteradas e dependentes do prognóstico, com aumento das células TCM somente nos pacientes com prognóstico ruim. Essas evidências sugerem que interações imunológicas entre células B da LLC e células T CD4+ possa ser um mecanismo próprio da doença que venha interferir na fisiopatologia e favorecer a geração de células TCM, que podem fornecer sinais de sobrevivência, como citocinas e CD40L, contribuindo assim para o estabelecimento e agressividade da LLC.Memory T cells are the hallmark of adaptive immunity and are characterized as central (TCM) and effector memory (TEM) T cells. The influence of T cells in the course of hematological malignancies has been described as a mechanism related to the evolution. In this study, we analyzed the peripheral blood of healthy donors and patients with myelodysplastic syndrome (MDS), multiple myeloma (MM) and chronic lymphocytic leukemia B (CLL), and analyzed the distribution of CD4+ and CD8+ naive and memory T cells. MDS and MM revealed no significant difference, but CLL patients showed changes in CD4+ T cell and it were dependent on the prognosis. Patients with poor prognosis presented increased in frequency and absolute number of TCM cells. These evidences show that immunological interactions between CLL and CD4+ T cells could be a disease mechanism that could interfere in pathophysiology and result in the generation of TCM cells, that provide survival signals to the tumor clone, such as cytokines and CD40L, thus contributing to establishment and more aggressive CLL progression.
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Söderberg, Karin. "Risk factors for haemagological malignancies : immune-mediated diseases, body mass index and magnetic fields /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-819-3/.
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Karius, Tommy Verfasser], and Jörn [Akademischer Betreuer] [Walter. "Optimizing epigenetic therapies of hematological malignancies : identification of novel epigenetic biomarkers and mechanistic study of 5-aza-2'-deoxycytidine / Tommy Karius. Betreuer: Jörn Walter." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2012. http://d-nb.info/1052338844/34.
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Baum, Natalie [Verfasser]. "Targeting the EGF-receptor and the CD38/NADase in solid and hematological malignancies with nanobody-based heavy chain antibodies and AAV vectors / Natalie Baum." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2020. http://d-nb.info/1241743088/34.
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Zehnder, Aina Romina. "Prognosis in pediatric hematologic malignancies is associated with serum concentration of mannose-binding lectin-associated serine protease-2 (MASP-2) /." [S.l.] : [s.n.], 2009. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Yarde, Danielle N. "The Fanconi Anemia (FA)/BRCA DNA Damage Repair Pathway is Regulated by NF-κB and Mediates Drug Resistance in Multiple Myeloma." Scholar Commons, 2010. https://scholarcommons.usf.edu/etd/1818.
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The Fanconi Anemia (FA)/BRCA DNA damage repair pathway plays a critical role in the cellular response to stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA DNA damage repair pathway genes are overexpressed and causative for resistance in multiple myeloma (MM) cell lines selected for resistance to melphalan. We hypothesized that the FA/BRCA DNA damage repair pathway mediates response and resistance to chemotherapeutic agents used to treat multiple myeloma and other cancers, and targeting this pathway is vital to overcoming drug resistance. In this dissertation, we show that FA/BRCA pathway genes are collectively overexpressed in MM, prostate, and ovarian cancer cell lines selected for resistance to melphalan and cisplatin, respectively. Interestingly, cells selected for resistance to topoisomerase II inhibitors selectively overexpress only FANCF. We also show that FA/BRCA pathway expression can be inhibited by the proteasome inhibitor bortezomib. FA/BRCA pathway mRNA expression was inhibited by bortezomib in myeloma cell lines and patient samples. FANCD2 gene and protein expression are downregulated by bortezomib, and remain attenuated in the face of melphalan treatment. Melphalan-induced FANCD2 foci formation was also inhibited by bortezomib, and this drug enhanced melphalan-induced DNA damage, likely via inhibition of FA-mediated DNA damage repair. Next, we analyzed regulation of the FA/BRCA pathway. We demonstrate that NF-kappaB, specifically the Re1B/p50 subunits, transcriptionally regulates members of the FA/BRCA pathway, and inhibition of these subunits by siRNA, BMS-345541, and bortezomib reduces FA/BRCA pathway expression. Furthermore, knocking down Re1B and p50 simultaneously attenuates FANCD2 protein expression and results in diminished DNA repair and enhanced sensitivity to melphalan. Importantly, melphalan resistance was restored when FANCD2 was re-expressed in these cells. We also show that bortezomib regulates FANCD2 protein expression directly, by inhibiting FANCD2 synthesis. Finally, we demonstrate that low-dose bortezomib arrests cells in G0/G1 and also overcomes the S-phase arrest induced by melphalan, likely via inhibition of ATR.
Overall, our findings provide evidence for targeting the FA/BRCA pathway, either directly or indirectly, via inhibition of NF-kappaB or ATR, to enhance chemotherapeutic response and reverse drug resistance in multiple myeloma and other cancers.
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Mi, Jin. "Evaluation du potentiel clinique de l'expression ectopique de gènes dans les Leucémies Lymphoblastiques Aigues." Thesis, Grenoble, 2013. http://www.theses.fr/2013GRENV046/document.
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Les mécanismes épigénétiques, tels que la méthylation et les modifications d'histones, sont impliqués dans le contrôle à grande échelle de l'expression du génôme et contribuent à la mise en place des profils d'expression des gènes spécifiques de tissus et de types cellulaires. Dans les cellules en cours ou en fin de différenciation, ces mécanismes sont aussi impliqués dans la mise en place et le maintien de la repression d'un grand nombre de gènes. La transformation oncogénique est presque toujours associée à des anomalies de la signalisation épigénétique cellulaire, dont certaines, comme les méthylations aberrantes de gènes suppresseurs de tumeur, sont considérées comme des événements oncogènes. Un aspect beaucoup moins étudié de ces dérégulations épigénétiques est l'activation aberrante de gènes tissu-spécifiques dans des cellules pré-cancéreuses et transformées. De nombreuses études rapportent l'activation « hors contexte » de gènes spécifiques du testicule dans plusieurs cancers somatiques. Ces gènes sont décrits sous le nom de gènes « cancer testis » ou C/T. Il a été suggéré que ces expressions illégitimes pourraient être de bons indicateurs des cancers, et fournir de nouvelles cibles pour une immunothérapie anticancéreuse. Au cours de cette thèse, nous avons développé une approche basée sur ce concept d'activation ectopique de gènes pour identifier les gènes exprimés de manière aberrante dans les lymphoblastes des patients atteints de leucémies lymphoblastiques aigues (LAL). Nous avons ensuite évalué leur intérêt pour une utilisation comme marqueurs pronostics et de prédiction de la réponse au traitement. Nous avons ainsi identifié une signature de huit gènes spécifiques de la lignée germinale / cellules souches embryonnaires, exprimés de manière aberrante dans les LAL pédiatriques et adultes : 4 gènes prédictifs de mauvais pronostic et 4 gènes associés à une issue favorable. Nous avons par la suite montré qu'une combinaison de l'expression de ces 8 gènes peut identifier les formes agressives de LAL chez les enfants ainsi que chez les adultes. Une étude prospective clinique a mis en évidence que notre système de détection des 8 gènes, basé sur un test RT- qPCR, pourrait aider à prédire la réponse précoce à un traitement (induction) dans un groupe de 31 patients adultes nouvellement recrutés, atteints de LAL. Enfin, en exploitant notre méthode de classification, nous avons découvert des traits biologiques communs entre les formes agressives de LAL chez les enfants et chez les adultes. Nos données montrent que les formes les plus agressives de LAL présentent les caractéristiques de cellules souches hématopoïétiques au repos. Cette information pourrait être utilisée pour adapter les approches thérapeutiques. Enfin, en plus de l'amélioration de la détection et du suivi des patients LAL, ce travail a un fort potentiel dans la définition de nouvelles stratégies thérapeutiques ainsi que d'ors et déjà dans les choix thérapeutiques les plus appropriés pour les patients porteurs des formes les plus agressivesEpigenetic mechanisms such as methylation and histone modifications are involved in large-scale control of the expression of the genome and contribute to the development of specific gene expression profiles of tissues and cell types. In cells, during and after differentiation, these mechanisms are also involved in the establishment and maintenance of the repression of many genes. Oncogenic transformation is almost always associated with abnormalities of cellular epigenetic signalling, some of which, such as aberrant methylation of tumour suppressor genes, are considered as oncogenic events. One much less studied aspect epigenetic deregulations, is the aberrant activation of tissue-specific genes in pre-cancerous and transformed cells. Many studies have reported the “out of context” activation of specific testicular genes in several somatic cancers. These genes are described as the "cancer / testis" genes or C/T. It has been suggested that these illegitimate expressions could be good indicators of cancer and provide new targets for cancer immunotherapy. In this thesis, based on the concept of ectopic activation of genes, we have identified genes aberrantly expressed in lymphoblasts of patients with acute lymphoblastic leukemia (ALL). We have then assessed their potential for a use as markers for prognosis and prediction of treatment response. We have identified a signature of eight genes specific of germline/embryonic stem cells, aberrantly expressed in adult and paediatric ALL. The ectopic activation of four genes was predictive of poor prognosis and the expression of four other genes was associated with a favourable outcome. We have subsequently shown that the combination of the expression of these eight genes can identify aggressive forms of ALL in children and adults. A prospective clinical study showed that a test based on the detection of these 8 genes, by RT- qPCR could help predicting an early response to treatment (induction) in a group of 31 newly recruited ALL adult patients. Finally, using our classification method, we discovered common biological traits between aggressive forms of ALL in children and adults. Our data show that the most aggressive forms of ALL have characteristics of dormant hematopoietic stem cells. This information could be used to refine therapeutic approaches. Finally, in addition to improving the detection and monitoring of ALL patients, this work has great potentials in the definition of new therapeutic strategies as well as in the choice of the most appropriate therapeutic approaches for patients with aggressive forms of ALL
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Magnani, Giovanni [Verfasser], Olaf [Akademischer Betreuer] Groß, Philipp J. [Gutachter] Jost, and Florian C. [Gutachter] Bassermann. "Tyrosine kinase inhibitors as NLRP3 inflammasome activators and its role in hematologic malignancies / Giovanni Magnani ; Gutachter: Philipp J. Jost, Florian C. Bassermann ; Betreuer: Olaf Groß." München : Universitätsbibliothek der TU München, 2017. http://d-nb.info/1153882523/34.
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Schwarzbold, Alexandre Vargas. "Modelagem de um escore de mielotoxicidade quimioterápica na predição de neutropenia febril em tumores hematológicos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2006. http://hdl.handle.net/10183/16362.
Full textAbstract:
A neutropenia induzida pela quimioterapia é o mais comum efeito adverso da quimioterapia sistêmica para o câncer e é frequentemente complicada por neutropenia febril (NF). O uso profilático de fatores de crescimento hematopoiéticos pode reduzir o risco, a severidade e a duração da NF. Na prática clínica atual, a decisão de administrar ao paciente profilaxia com fatores de crescimento é baseada principalmente no potencial mielotóxico dos esquemas de QT, mas riscos específicos dos regimes não são definidos. Em muitos estudos, a toxicidade da quimioterapia é analizada em termos de alta dosagem versus baixa dosagem, sem uma regra geral que considere os diferentes esquemas de QT em uma única escala. O objetivo desse estudo é validar uma classificação de toxicidade de um esquema de QT e avaliar sua utilidade em um modelo de predição de risco de neutropenia febril em pacientes com câncer hematológico no começo de um ciclo de quimioterapia. Foram avaliados prospectivamente duzentos e sessenta e oito pacientes e acompanhados durante 1053 ciclos de quimioterapia na Bélgica, entre 2001 e 2005. Informações relevantes foram coletadas no começo do primeiro ciclo e o número de dias de neutropenia febril foi contabilizado no acompanhamento dos pacientes [dicotomizada (sem neutropenia versus >= dia de NF)]. A relação entre o desfecho e as co-variáveis foi analisada usando a Equação de Estimativa Generalizada (GEE). Um regime de quimioterapia agressiva é o maior preditor de NF [razão de chances (OR) 5.2 (3.2-8.4)]. Os outros preditores independentes são: doença subjacente, o comprometimento de medula óssea, superfície corporal <= 2m², uma contagem pré-tratamento de monócitos <150µl e a interação entre o primeiro ciclo na mesma linha de tratamento e uma dosagem de hemoglobina pré-tratamento. Usando as estimativas dos coeficientes de regressão, uma regra de predição clínica de NF foi desenvolvida com essas características: sensibilidade 78.6%, especificidade 62.3%, valor preditivo positivo de 42.7%% e um valor preditivo negativo de 89.1%. Estudos posteriores são necessários para validar esse escore bem como investigar novos potenciais fatores com o intuito de melhor prever a NF.Chemotherapy-induced neutropenia is the most common adverse effect of chemotherapy and is often complicated by febrile neutropenia (FN). As prophylactic use of colonystimulating factors (CSF) can reduce the risk, severity, and duration of FN, it is of great importance to identify as soon as possible after or even before the start of chemotherapy, the patients who will develop FN. In the current clinical practice, the decision to give to the patient a colony-stimulating factor (CSF) prophylaxis is mainly based on the myelosuppressive potential of the chemotherapy regimen. The objective of this study is to validate a classification of aggressiveness of a chemotherapy regimen and to evaluate its usefulness in a risk prediction model of FN in patients with hematological cancer at the beginning of a chemotherapy cycle. Two hundred and sixty-six patients were prospectively enrolled and followed during 1053 cycles. Relevant patient informations were collected at the beginning of the first cycle and the number of days of FN were counted in the follow-up [dichotomized (no FN versus>= 1 day of FN)]. Aggressive chemotherapy regimen is the major predictor of FN [odds ratio 5.2 (3.2 - 8.4)]. The other independent predictors are the underlying disease, an involvement of bone marrow, body surface<= 2m², a baseline monocyte count <150/µl and the interaction between the first cycle in the same treatment line and a baseline hemoglobin dosage. A rule of prediction of FN was computed with these characteristics: sensitivity 78.6%, specificity 62.3%, positive predictive value 42.7% and negative predictive value 89.1%. Further studies are needed to validate this score.