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Sökning: WFRF:(Shah Kinjal)

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1.
  • Jobby, Renitta, et al. (författare)
  • Differential expression of antioxidant enzymes under arsenic stress in Enterobacter sp.
  • 2016
  • Ingår i: Environmental Progress & Sustainable Energy. - : Whiley. - 1944-7442. ; 35:6, s. 1642-1645
  • Tidskriftsartikel (refereegranskat)abstract
    • Arsenic is a major contaminating heavy metal due to its frequent occurrence and toxicity. Out of different remediation approaches, bioremediation using bacteria has been extensively studied. In this study, 29 bacterial isolates were screened for their arsenic tolerance capacity. One of the isolate, MUM2 showed maximum arsenic tolerance (10mM). Antioxidant enzymes were assayed in this isolate under arsenic stress. Although, the CAT activity was found to increase significantly, the SOD activity showed a significant decrease under 9mM arsenic stress. The results obtained suggest a possible role of CAT in combating arsenic stress. Further studies at genetic level would help in developing highly tolerant strains for remediation of arsenic.
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2.
  • Barretina, Jordi, et al. (författare)
  • Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
  • 2010
  • Ingår i: Nature genetics. - 1546-1718. ; 42:8, s. 715-21
  • Tidskriftsartikel (refereegranskat)abstract
    • Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
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3.
  • Chougule, Rohit A., et al. (författare)
  • Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation
  • 2019
  • Ingår i: npj Genomic Medicine. - : Nature Publishing Group. - 2056-7944. ; 4:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.
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4.
  • Kazi, Julhash U, et al. (författare)
  • ABL2 suppresses FLT3-ITD-induced cell proliferation through negative regulation of AKT signaling
  • 2017
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:7, s. 12194-12202
  • Tidskriftsartikel (refereegranskat)abstract
    • The type III receptor tyrosine kinase FLT3 is one of the most commonly mutated oncogenes in acute myeloid leukemia (AML). Inhibition of mutated FLT3 in combination with chemotherapy has displayed promising results in clinical trials. However, one of the major obstacles in targeting FLT3 is the development of resistant disease due to secondary mutations in FLT3 that lead to relapse. FLT3 and its oncogenic mutants signal through associating proteins that activate downstream signaling. Thus, targeting proteins that interact with FLT3 and their downstream signaling cascades can be an alternative approach to treat FLT3-dependent AML. We used an SH2 domain array screen to identify novel FLT3 interacting proteins and identified ABL2 as a potent interacting partner of FLT3. To understand the role of ABL2 in FLT3-mediated biological and cellular events, we used the murine pro-B cell line Ba/F3 as a model system. Overexpression of ABL2 in Ba/F3 cells expressing an oncogenic mutant of FLT3 (FLT3-ITD) resulted in partial inhibition of FLT3-ITD-dependent cell proliferation and colony formation. ABL2 expression did not alter the kinase activity of FLT3, its ubiquitination or its stability. However, it partially blocked FLT3-induced AKT phosphorylation without affecting ERK1/2 and p38 activation. Taken together our data suggest that ABL2 acts as negative regulator of signaling downstream of FLT3.
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5.
  • Moharram, Sausan A., et al. (författare)
  • Efficacy of the CDK inhibitor dinaciclib in vitro and in vivo in T-cell acute lymphoblastic leukemia
  • 2017
  • Ingår i: Cancer Letters. - : Elsevier. - 0304-3835. ; 405, s. 73-78
  • Tidskriftsartikel (refereegranskat)abstract
    • T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease of the blood affecting children, adolescents and adults. Although current treatment protocols for T-ALL have improved overall survival, a portion of T-ALL patients still experiences treatment failure. Thus, the development of novel therapies is needed. In this study, we used several patient-derived T-ALL cell lines to screen for an effective drug for T-ALL. Using a panel of 378 inhibitors against different kinases, we identified the CDK inhibitor dinaciclib as a potential drug for T-ALL. Dinaciclib treatment significantly reduced cell viability and completely blocked colony formation. Furthermore, cells treated with dinaciclib showed decreased expression of several pro-survival proteins including survivin, cyclin T1 and c-MYC. Dinaciclib treatment also increased accumulation of cells in G2/M phase and significantly induced apoptosis. Finally, dinaciclib extended survival of mice in a T-ALL cell xenograft model. Collectively, these data suggest that the CDK inhibitor dinaciclib is an active drug for T-ALL in the preclinical settings.
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6.
  • Moharram, Sausan A., et al. (författare)
  • T-cell acute lymphoblastic leukemia cells display activation of different survival pathways
  • 2017
  • Ingår i: Journal of Cancer. - : Ivyspring International Publisher. - 1837-9664. ; 8:19, s. 4124-4129
  • Tidskriftsartikel (refereegranskat)abstract
    • T-cell acute lymphoblastic leukemia (T-ALL) is a disease of the blood affecting T-lymphocytes. Although notable improvements have been achieved in T-ALL treatment, half of the adult T-ALL patients still experience treatment failure. In order to develop a targeted therapy, we need a better understanding of T-ALL pathogenesis. In this study, we used patient-derived cell lines which display resistance to glucocorticoids. We observed that different cell lines are dependent on different survival signaling pathways. Aberrant activation of AKT, p38, S6K or ERK signaling was not found to the same degree in all cell lines studied. To understand the molecular differences in T-ALL cells, we compared gene expression and somatic mutations. Gene set enrichment analysis showed enrichment of the mTORC1, MAPK or TGF-beta signaling pathways. Loss-of-function mutations in the TP53 and FBXW7 genes were identified in all cell lines investigated. Thus, we suggest that T-ALL cells from different patients are addicted to different mutations and thereby to different signaling pathways. Therefore, understanding the enrichment of molecular pathways for each individual patient will provide us with a more precise and specific treatment plan.
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7.
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8.
  • Shah, Kinjal, et al. (författare)
  • Acute leukemia cells resistant to PI3K/mTOR inhibition display upregulation of P2RY14 expression
  • 2018
  • Ingår i: Clinical Epigenetics. - : BioMed Central (BMC). - 1868-7075. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The PI3K/mTOR pathway is the second most frequently deregulated pathway in a majority of cancers such as breast cancer, lung cancer, and melanomas as well as leukemia. Mutations in the genes coding for receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs) are quite common in all forms of acute leukemia. This can be a major cause of deregulation of the PI3K-mTOR pathway. To understand how cells display resistance to the dual PI3K/mTOR inhibitor, we used a panel of 25 acute leukemia cell lines. We observed that while a number of cell lines displayed sensitivity to the dual PI3K/mTOR pathway inhibitor PKI-587, many cells displayed substantial resistance. Cells sensitive to PKI-587 also showed aberrant activation of PI3K/mTOR pathway components such as AKT and S6K and also displayed sensitivity to a panel of various other PI3K/mTOR inhibitors. Using RNA sequencing data, we observed that expression of a G protein-coupled receptor, P2RY14, was upregulated nine-fold in cells showing resistance to the PI3K/mTOR inhibitor. P2RY14 has not been much studied in hematologic malignancies. However, this receptor seems to have a role in the localization of hematopoietic stem cells (HSCs) and in promoting regenerative capabilities following injury. We observed that acute lymphoblastic leukemia (ALL) and FLT3-ITD-positive acute myeloid leukemia (AML) patients with higher expression of P2RY14 mRNA displayed relatively poor survival compared to patients carrying lower expression of P2RY14 suggesting a role of P2RY14 in patient survival. To understand the role of this receptor in cell signaling, we used phospho-protein arrays and observed activation of distinct signaling cascades. Furthermore, array data were verified using murine pro-B cell line Ba/F3 stably transfected with P2RY14. We observed that activation of P2RY14 by its ligand, UDP-glucose, resulted in selective induction of ERK1/2 phosphorylation. Taken together, our data suggest that acute leukemia cells resistant to PI3K/mTOR inhibition display upregulation of a GPCR, P2RY14, which has a role in patient survival and also couples to the activation of ERK signaling.
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9.
  • Shah, Kinjal (författare)
  • Mechanisms of therapy resistance in acute lymphoblastic leukemia
  • 2021
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Acute lymphoblastic leukemia (ALL) is a highly aggressive pediatric cancer that can affect both B cells and T cells. The advent of new therapies has increased the cure rates for both B-ALL and T-ALL patients. However, some patients still experience relapse with a variable response to the treatment and display poor survival. Thus,identification of novel predictive biomarkers that can predict therapy resistance may help to stratify this group of patients. This could also aid in developing an effective treatment strategy.Glucocorticoids are widely used along with the chemotherapeutic regimens for treating ALL patients. The response to glucocorticoids can predict long-term remission outcome. To understand the mechanisms of resistance to glucocorticoids, such as dexamethasone, we generated dexamethasone-resistant B-ALL cell lines in paper I. One such resistant cell line was found to possess increased FLT3 expression levels with FLT3-ITD and FLT3-R845G mutations that led to the activation of oncogenic RTK signaling. Further, second-generation FLT3 inhibitors, such as AC220 and crenolanib, suppressed this signaling both in vitro and in vivo.We continued exploring the dexamethasone resistance mechanisms in paper II using a different approach. We observed that dexamethasone exposure caused upregulation of Aurora kinase and its various downstream effector kinases such as JAK, p38, mTOR, and S6K. These kinases lead to β-catenin stabilization through phosphorylation-dependent inactivation of GSK-3β either directly or indirectly. Indeed, we observed partial restoration of dexamethasone sensitivity with a combination of dexamethasone and inhibitors targeting either these kinases or β-catenin.The expression of BCL2 varies in T-ALL depending on its stage of maturation, thereby T-ALL displays a heterogenous response to the BCL2-specific inhibitor venetoclax. We thus studied the mechanisms of venetoclax resistance using a panel of T-ALL cell lines in paper III. We observed that all the venetoclax-resistant T-ALL cell lines displayed non-universal changes in the expression of BCL2 family members and cancer stem cell markers, along with specific enrichment of cytokine signaling pathways. However, further investigations are warranted to identify additional mechanisms of venetoclax resistance in T-ALL.Combination therapy is usually the choice of treatment to overcome monotherapy resistance. With this in mind, in paper IV we identified that inhibiting BCL2 by venetoclax synergizes with PLK1 inhibition by volasertib in T-ALL cell lines and PDX models. We observed that BCL2L13 and PMAIP1 genes get upregulated upon PLK1 inhibition, probably through transcriptional regulation by FOXOs in interaction with β-catenin. Thus, the pro-apoptotic functions exhibited by BCL2L13 and PMAIP1 probably synergize with BCL2 inhibition in T-ALL, with the help of sustained β-catenin levels. Moreover, we also identified upregulation of oxidative phosphorylation (OXPHOS) in T-ALL PDXs that didn’t display synergy, which could be treated with a combination of venetoclax and oligomycin. However, additional experiments will be required to verify the above results.
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10.
  • Shah, Kinjal, et al. (författare)
  • The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia
  • 2021
  • Ingår i: NPJ precision oncology. - 2397-768X. ; 5:1, s. 13-13
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucocorticoids, such as dexamethasone and prednisolone, are widely used in cancer treatment. Different hematological malignancies respond differently to this treatment which, as could be expected, correlates with treatment outcome. In this study, we have used a glucocorticoid-induced gene signature to develop a deep learning model that can predict dexamethasone sensitivity. By combining gene expression data from cell lines and patients with acute lymphoblastic leukemia, we observed that the model is useful for the classification of patients. Predicted samples have been used to detect deregulated pathways that lead to dexamethasone resistance. Gene set enrichment analysis, peptide substrate-based kinase profiling assay, and western blot analysis identified Aurora kinase, S6K, p38, and β-catenin as key signaling proteins involved in dexamethasone resistance. Deep learning-enabled drug synergy prediction followed by in vitro drug synergy analysis identified kinase inhibitors against Aurora kinase, JAK, S6K, and mTOR that displayed synergy with dexamethasone. Combining pathway enrichment, kinase regulation, and kinase inhibition data, we propose that Aurora kinase or its several direct or indirect downstream kinase effectors such as mTOR, S6K, p38, and JAK may be involved in β-catenin stabilization through phosphorylation-dependent inactivation of GSK-3β. Collectively, our data suggest that activation of the Aurora kinase/β-catenin axis during dexamethasone treatment may contribute to cell survival signaling which is possibly maintained in patients who are resistant to dexamethasone.
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