scholarly journals Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 240 ◽  
Author(s):  
Marie Brachet-Botineau ◽  
Marion Polomski ◽  
Heidi A. Neubauer ◽  
Ludovic Juen ◽  
Damien Hédou ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Clinical Development ◽  
Signal Transducer ◽  
Hematopoietic Malignancies ◽  
Activating Mutations ◽  
The Subject ◽  
Hematopoietic Cancers

Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors.

scholarly journals FLT3 Inhibition in Acute Myeloid Leukaemia – Current Knowledge and Future Prospects

2020 ◽  
Vol 20 (7) ◽  
pp. 513-531 ◽  
Author(s):  
Francesca L. Hogan ◽  
Victoria Williams ◽  
Steven Knapper
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Current Knowledge ◽  
Clinical Development ◽  
Clinical Prognosis ◽  
Acquired Drug Resistance ◽  
Acute Myeloid

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in 30% of acute myeloid leukaemia (AML) patients at diagnosis and confer an adverse clinical prognosis. Mutated FLT3 has emerged as a viable therapeutic target and a number of FLT3-directed tyrosine kinase inhibitors have progressed through clinical development over the last 10-15 years. The last two years have seen United States Food and Drug Administration (US FDA) approvals of the multi-kinase inhibitor midostaurin for newly-diagnosed FLT3-mutated patients, when used in combination with intensive chemotherapy, and of the more FLT3-selective agent gilteritinib, used as monotherapy, for patients with relapsed or treatment-refractory FLT3-mutated AML. The ‘second generation’ agents, quizartinib and crenolanib, are also at advanced stages of clinical development. Significant challenges remain in negotiating a variety of potential acquired drug resistance mechanisms and in optimizing sequencing of FLT3 inhibitory drugs with existing and novel treatment approaches in different clinical settings, including frontline therapy, relapsed/refractory disease, and maintenance treatment. In this review, the biology of FLT3, the clinical challenge posed by FLT3-mutated AML, the developmental history of the key FLT3-inhibitory compounds, mechanisms of disease resistance, and the future outlook for this group of agents, including current and planned clinical trials, is discussed.

scholarly journals From Supply Chain 4.0 to Supply Chain 5.0: Findings from a Systematic Literature Review and Research Directions

Logistics ◽  
2021 ◽  
Vol 5 (3) ◽  
pp. 49
Author(s):  
Guilherme F. Frederico
Keyword(s):  
Supply Chain ◽  
Literature Review ◽  
Systematic Literature Review ◽  
Research Agenda ◽  
Industry 4.0 ◽  
Current Knowledge ◽  
Research Directions ◽  
The Subject ◽  
Strategy Innovation ◽  
Transition Issues

The main purpose of this paper is to present what the Industry 5.0 phenomenon means in the supply chain context. A systematic literature review method was used to get evidence from the current knowledge linked to this theme. The results have evidenced a strong gap related to Industry 5.0 approaches for the supply chain field. Forty-one (41) publications, including conference and journal papers, have been found in the literature. Nineteen (19) words, which were grouped in four (4) clusters, have been identified in the data analysis. This was the basis to form the four (4) constructs of Industry 5.0: Industry Strategy, Innovation and Technologies, Society and Sustainability, and Transition Issues. Then, an alignment with the supply chain context was proposed, being the basis for the incipient Supply Chain 5.0 framework and its research agenda. Industry 5.0 is still in an embryonic and ideal stage. The literature is scarce and many other concepts and discoveries are going to emerge. Although this literature review is based on few available sources, it provides insightful and novel concepts related to Industry 5.0 in the supply chain context. Moreover, it presents a clear set of constructs and a structured research agenda to encourage researchers in deploying further conceptual and empirical works linked to the subject herein explored. Organizations’ leadership, policymakers, and other practitioners involved in supply chains, and mainly those currently working with Industry 4.0 initiatives, can benefit from this research by having clear guidance regarding the dimensions needed to structurally design and implement an Industry 5.0 strategy. This article adds valuable insights to researchers and practitioners, by approaching the newest and revolutionary concept of the Industry 5.0 phenomenon in the supply chain context, which is still an unexplored theme.

scholarly journals Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 210-223 ◽  
Author(s):  
Eun Ji Gang ◽  
Hye Na Kim ◽  
Yao-Te Hsieh ◽  
Yongsheng Ruan ◽  
Heather A. Ogana ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Underlying Mechanism ◽  
Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

Impact of genotypic diversity on selection of subtype-specific drug resistance profiles during raltegravir-based therapy in individuals infected with B and BF recombinant HIV-1 strains

2020 ◽  
Vol 75 (6) ◽  
pp. 1567-1574
Author(s):  
Daniela Sánchez ◽  
Solange Arazi Caillaud ◽  
Ines Zapiola ◽  
Silvina Fernandez Giuliano ◽  
Rosa Bologna ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Current Knowledge ◽  
Phylogenetic Analyses ◽  
Genotypic Diversity ◽  
Resistance Testing ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Middle Income ◽  
Subtype B ◽  
Hiv 1

Abstract Background Current knowledge on HIV-1 resistance to integrase inhibitors (INIs) is based mostly on subtype B strains. This contrasts with the increasing use of INIs in low- and middle-income countries, where non-B subtypes predominate. Materials and methods HIV-1 drug resistance genotyping was performed in 30 HIV-1-infected individuals undergoing virological failure to raltegravir. Drug resistance mutations (DRMs) and HIV-1 subtype were characterized using Stanford HIVdb and phylogenetic analyses. Results Of the 30 integrase (IN) sequences, 14 were characterized as subtype F (47%), 8 as subtype B (27%), 7 as BF recombinants (23%) and 1 as a putative CRF05_DF (3%). In 25 cases (83%), protease and reverse transcriptase (PR-RT) sequences from the same individuals confirmed the presence of different BF recombinants. Stanford HIVdb genotyping was concordant with phylogenetic inference in 70% of IN and 60% of PR-RT sequences. INI DRMs differed between B and F IN subtypes, with Q148K/R/H, G140S and E138K/A being more prevalent in subtype B (63% versus 0%, P = 0.0021; 50% versus 0%, P = 0.0096; and 50% versus 0%, P = 0.0096, respectively). These differences were independent of the time on raltegravir therapy or viral load at the time of genotyping. INI DRMs in subtype F IN genomes predicted a lower level of resistance to raltegravir and no cross-resistance to second-generation INIs. Conclusions Alternative resistance pathways to raltegravir develop in subtypes B and F IN genomes, with implications for clinical practice. Evaluating the role of HIV-1 subtype in development and persistence of mutations that confer resistance to INIs will be important to improve algorithms for resistance testing and optimize the use of INIs.

Social capital in the theory and research of LIS professionals in the light of the literature on the subject. Review of current knowledge

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Maja Dorota Wojciechowska
Keyword(s):  
Social Capital ◽  
Current Knowledge ◽  
Future Research ◽  
Content Type ◽  
Individual Social Capital ◽  
Rural Libraries ◽  
The Subject ◽  
The Moment ◽  
The Impact

Purpose The purpose of the paper is to present the latest scholarly trends in the field of social capital in libraries, to review research concepts published by LIS professionals and to suggest further research possibilities in this area. Design/methodology/approach This paper presents a review and critical analysis of literature associated with research on social capital in libraries to highlight its importance for the development of LIS and its impact on the functioning of environments linked with various types of libraries. The goal of literature analysis was to determine the current condition of research on social capital in libraries. The main trends were identified and the need for further qualitative analyses, which are missing at the moment, was confirmed. Findings It was determined that, so far, LIS professionals have focussed mainly on the role of municipal libraries in developing social capital, the problem of building trust, especially in immigrant circles and the impact of libraries on promoting a civil society. Academic libraries, rural libraries, organisational capital in libraries and individual social capital of librarians were a much less frequent subject of research. The role of libraries in developing social capital in educational (primary and secondary education) and professional (non-university professionals) circles is practically non-existent in research, and it will require in-depth studies and analyses in the coming years. Originality/value This paper constitutes a synthetic review of the latest research concepts concerning social capital in libraries. It identifies the most important research trends and areas that so far have not been explored and suggests research methods to help LIS professionals design future research in this area more effectively.

Service quality, loyalty, and co-creation behaviour: a customer perspective

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Rafael P. Albuquerque ◽  
João J. Ferreira
Keyword(s):  
Service Quality ◽  
Design Methodology ◽  
Positive Impact ◽  
Current Knowledge ◽  
Quantitative Methodology ◽  
Content Type ◽  
Customer Perspective ◽  
The Subject ◽  
Customers Perspective

Purpose This paper aims to verify co-creation behavior and understand a relationship between perception of service quality, loyalty and co-creation, from Starbucks customers' perspective. Design/methodology/approach A quantitative methodology was carried out, operationalized by applying a questionnaire to a sample of 385 respondents. Findings The results showed that service quality has a positive impact on loyalty and co-creation behavior in all its aspects; loyalty can be considered an important attribute in the intention of co-creation by customers. Originality/value This research extends the current knowledge on the subject and examines the associations between other attributes discussed. The implications of the study suggest strategic directions for using the clients' co-creation as a competitive alternative and generating value.

Gene regulation by tyrosine kinases: src protein activates various promoters, including c-fos

1989 ◽  
Vol 9 (6) ◽  
pp. 2493-2499
Author(s):  
M Fujii ◽  
D Shalloway ◽  
I M Verma
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Cellular Transformation ◽  
Membrane Association ◽  
Protein Tyrosine Phosphorylation ◽  
Promoter Activation ◽  
Tyrosine Kinase Activity ◽  
Atp Binding Site ◽  
Src Gene

A promoter of the nuclear proto-oncogene fos was activated by cotransfection with the viral src gene. Ability to transactivate the c-fos promoter was dependent on tyrosine kinase activity, because (i) src mutants which have reduced tyrosine kinase activity due to mutation of Tyr-416 to Phe showed lower promoter activation, (ii) pp60c-src mutants which have increased tyrosine kinase activity due to mutation of Tyr-527 to Phe also augmented c-fos promoter induction, and (iii) mutation in the ATP-binding site of pp60v-src strongly suppressed c-fos promoter activation. Tyrosine kinase activity alone, however, was not sufficient for promoter activation, because of pp60v-src mutant which lacked its myristylation site and consequently membrane association showed no increased c-fos promoter activation. Both the tyrosine kinase- and membrane-association-defective mutants were also unable to induce transformation. Therefore, phosphorylation of membrane-associated substrates appears to be required for both gene expression and cellular transformation by the src protein. Two regions of the c-fos promoter located between positions -362 and -324 and positions -323 and -294 were responsive to src stimulation. We believe that protein tyrosine phosphorylation represents an important step of signal transduction from the membrane to the nucleus.

Sign in / Sign up

Export Citation Format

Share Document