Готові списки джерел за темами / STAT inhibitors

Добірка наукової літератури з теми "STAT inhibitors"

Автор: Grafiati

Опубліковано: 22 червня 2024

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Статті в журналах з теми "STAT inhibitors":

Ebersbach, Celina, Alicia-Marie K. Beier, Christian Thomas, and Holger H. H. Erb. "Impact of STAT Proteins in Tumor Progress and Therapy Resistance in Advanced and Metastasized Prostate Cancer." Cancers 13, no. 19 (September 28, 2021): 4854. http://dx.doi.org/10.3390/cancers13194854.

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Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in several biological processes such as immune response, cell survival, and cell growth. However, they have also been implicated in the development and progression of several cancers, including prostate cancer (PCa). Although the members of the STAT protein family are structurally similar, they convey different functions in PCa. STAT1, STAT3, and STAT5 are associated with therapy resistance. STAT1 and STAT3 are involved in docetaxel resistance, while STAT3 and STAT5 are involved in antiandrogen resistance. Expression of STAT3 and STAT5 is increased in PCa metastases, and together with STAT6, they play a crucial role in PCa metastasis. Further, expression of STAT3, STAT5, and STAT6 was elevated in advanced and high-grade PCa. STAT2 and STAT4 are currently less researched in PCa. Since STATs are widely involved in PCa, they serve as potential therapeutic targets. Several inhibitors interfering with STATs signaling have been tested unsuccessfully in PCa clinical trials. This review focuses on the respective roles of the STAT family members in PCa, especially in metastatic disease and provides an overview of STAT-inhibitors evaluated in clinical trials.

Lee, Hyun-Ku, Gita Singh, and Sujay Singh. "STAT reporter cell line systems as a tool for cancer therapeutic target screening." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 169.8. http://dx.doi.org/10.4049/jimmunol.200.supp.169.8.

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Abstract Signal transducer and activator of transcription (STAT) proteins as cytoplasmic transcription factors respond to cytokines and growth factors that mediate downstream signaling. STATs are closely related with cancers as they are frequently found to be dysregulated in primary tumors, leading to enhanced survival of tumors and increased angiogenesis. Among seven STAT family members, STAT3, STAT4 and STAT5 are considered to primarily promote cancer development and progression, while STAT1 may function either as a tumor suppressor or tumor promoter. STAT3, 4 and 5 are persistently activated in many human cancer cell lines, leading to increased cancer cell survival. Several studies demonstrate that inhibition of STAT3 or STAT5 signaling decreases cancer cell proliferation leading to apoptosis. Taken together, these indicate that STAT proteins can be ideal targets for anti-cancer therapy, and so it is crucial to develop assay systems that can identify inhibitors targeting those pro-tumorigenic STATs. Hence we developed the four reporter cell lines, each of which stably expresses STAT1-, STAT3-, STAT4-, or STAT5-response element that controls an optimized Renilla luciferase reporter gene upon stimulation. Functional activity of each cell line was evaluated through dose response of various cytokines such as IFNs, IL-3 and IL-6. One of the STAT inhibitors, curcumin as well as other putative STAT suppressors were utilized to characterize how each STAT can differentially respond to each test molecule and how its response can affect the host cells.

Jones, Dan, Justin Windham, Brian Stewart, Luis Fayad, Alma Rodriguez, and Fredrick B. Hagemeister. "Differential JAK-STAT Pathway Activation in Primary Mediastinal Large B-Cell Lymphoma: Two Subgroups with Differential Cytokine Activation Patterns and Predicted Responses to Kinase Inhibitors." Blood 114, no. 22 (November 20, 2009): 968. http://dx.doi.org/10.1182/blood.v114.22.968.968.

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Abstract Abstract 968 Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a specialized type of diffuse large B-cell lymphoma which shows diagnostic and pathogenetic overlap with mediastinal classical Hodgkin lymphoma. Approximately 60% of patients with PMBCL have good response to conventional chemoradiotherapy with the rest often showing distant relapses. Microarray studies of PMBCL have revealed overexpression of components and targets of the JAK-STAT signaling pathways including upregulation of IL13 receptor and STAT1; a subset of PMBCL have genome amplification of JAK2 or deletion of the JAK suppressor SOCS1. Given this complexity, we examined the most common mechanism and effects of JAK-STAT dysregulation in a series of newly diagnosed and recurrent PMBCL. Methods: Fifty-three biopsies from 23 patients with PMBCL were assessed and correlated with outcome. JAK2 and SOCS1 copy number status were determined by quantitative PCR on genomic DNA. JAK-STAT pathway activation was probed using reverse transcription quantitative (RQ)-PCR for JAK2, JAK3, and a panel of IL-4 and IL-13 transcriptional targets. JAK-STAT activation was assessed in tissue arrays using antisera against phospho-activation epitopes of STAT1, STAT3, STAT5, and STAT6 using immunohistochemistry (IHC). Activation patterns were modeled in the PMBCL cell line Karpas (K)1106P at baseline and following IL-4 and IL-13 stimulation with or without a range of small molecule inhibitors and blocking antibodies. Growth parameters were measured by MTT and protein levels by flow cytometry, Western blot, RQ-PCR and kinase profiling. Results: JAK2 genomic amplification was present in 40% of PMBCL and SOCS1 deletion in 10% as well as in the K1106P line. By phospho-activation IHC, tumors in 20/23 (87%) patients showed STAT activation, mostly due to STAT1 (60.8%) followed by STAT3 (26.1%), with 6 cases showing mixed patterns. In different tumors, localized and uniform STAT activation patterns were seen. Constitutive STAT activation was correlated with high expression of IL-4 transcription targets including CCL17 and IL13RA as well as JAK2 autophosphorylation and inferior outcome (p = .007). Tumors with more localized foci of activation were associated with alternate transcription patterns. In the K1106P cell line, IL-4 but not IL-13 treatment led to inducible STAT1 activation whereas baseline STAT3/6 activation was highly regulated by cytokine exposure. The JAK2 inhibitor JSI124 blocked IL-4 induced STAT1 activation whereas the JAK inhibitors AG-490, NSC7908 and WHI-P154 did not but did block IL-4/IL-13-induced STAT3 activation. The JAK3 inhibitor ZM39923 was most effective in blocking cell growth but did not block STAT1 activation. Conclusions: JAK2-STAT pathway activation characterizes nearly all cases of PMBCL but genetic mechanisms are distinct leading to distinct patterns of STAT1 activation (driven predominantly through the type I IL-4 receptor) and STAT3/6 activation (driven predominantly through the type II IL13RA/IL4RA) with differential effects on growth parameters and gene regulation. The patterns of STAT activation and target gene expression in primary tumors comprising these two groups mirrored the response to small molecule inhibitors following cytokine exposure in vitro in the K1106P line and highlights differences between IL-4 and IL-13 signaling in PMBCL. Profiling of PMBCL biopsies with phosphoactivation IHC for STAT isoforms may be useful to subcategorize cases and select the optimal JAK-STAT pathway inhibitors for adjuvant therapy. Disclosures: No relevant conflicts of interest to declare.

Standing, David, Emma Feess, Satvik Kodiyalam, Michael Kuehn, Zachary Hamel, Jaimie Johnson, Sufi Mary Thomas, and Shrikant Anant. "The Role of STATs in Ovarian Cancer: Exploring Their Potential for Therapy." Cancers 15, no. 9 (April 26, 2023): 2485. http://dx.doi.org/10.3390/cancers15092485.

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Ovarian cancer (OvCa) is a deadly gynecologic malignancy that presents many clinical challenges due to late-stage diagnoses and the development of acquired resistance to standard-of-care treatment protocols. There is an increasing body of evidence suggesting that STATs may play a critical role in OvCa progression, resistance, and disease recurrence, and thus we sought to compile a comprehensive review to summarize the current state of knowledge on the topic. We have examined peer reviewed literature to delineate the role of STATs in both cancer cells and cells within the tumor microenvironment. In addition to summarizing the current knowledge of STAT biology in OvCa, we have also examined the capacity of small molecule inhibitor development to target specific STATs and progress toward clinical applications. From our research, the best studied and targeted factors are STAT3 and STAT5, which has resulted in the development of several inhibitors that are under current evaluation in clinical trials. There remain gaps in understanding the role of STAT1, STAT2, STAT4, and STAT6, due to limited reports in the current literature; as such, further studies to establish their implications in OvCa are necessitated. Moreover, due to the deficiency in our understanding of these STATs, selective inhibitors also remain elusive, and therefore present opportunities for discovery.

Rodman, Esther, Michael Emch, Elizabeth Bruinsma, Xiaonan Hou, John Weroha, and John Hawse. "Abstract 1129: Interrogating JAK/STAT signaling in ovarian cancer as a potential oncogenic driver and therapeutic target." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1129. http://dx.doi.org/10.1158/1538-7445.am2022-1129.

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Abstract Ovarian cancer is the 7th most common cancer in women. It is the most fatal of all female reproductive cancers, due to the 5-year overall survival of 10-30% and over half of patients being diagnosed with late-stage disease. Despite initial response to front line platinum- and taxol-based chemotherapies, over 70% of patients develop recurrent and chemotherapy resistant disease and nearly all of these women die of their disease. Recently, the use of targeted therapies such as bevacizumab and PARP inhibitors have been shown to improve progression-free survival. However, these regimens have thus far failed to improve overall survival in patients without specific genetic signatures, highlighting the urgent need for alternative therapies. We have identified lestaurtinib as a potent inhibitor of many ovarian cancer cell lines, including platinum and PARP inhibitor resistant models, and patient derived organoid models. RNA-sequencing following lestaurtinib treatment identified JAK/STAT signaling as one of the most profoundly downregulated pathways. Additionally, it was recently reported via single cell RNA sequencing of patient tumors that downstream mediators of the JAK/STAT pathway are among the most highly expressed genes in ovarian tumor cells. Further, we have discovered that STAT1 and STAT3 are constitutively activated in chemotherapy and PARP inhibitor resistant cell lines as reflected by high levels of Tyr701/705 and Ser727 phosphorylation suggesting induction of this pathway may drive resistance. Selective siRNA-mediated knockdown of STAT1/3 resulted in significant growth inhibition confirming their importance in maintaining cell viability. Surprisingly, we have identified profound differences in the ability of various JAK/STAT inhibitors to suppress ovarian cancer cell growth. For example, ruxolitinib, the only JAK/STAT inhibitor currently in clinical trials for ovarian cancer, failed to inhibit the growth sensitive, platinum resistant or PARP inhibitor resistant cell lines. Our preliminary data indicate that JAK/STAT inhibitor efficacy in preventing ovarian cancer cell growth is related to their ability to block specific phosphorylation events on STAT1/3 proteins. We believe that precise and selective inhibition of STAT1 and STAT3 signaling represents a robust, durable, and novel approach for the treatment of highly aggressive and resistant forms of ovarian cancer. Further we plan to elucidate the molecular mechanisms by which STAT1 and STAT3 function to support ovarian cancer cell viability and growth, in order to substantially advance our understanding of JAK/STAT signaling in ovarian cancer and to identify the most effective ways to pharmacologically inhibit JAK/STAT signaling in ovarian cancer cells. Outcomes from this work will have both immediate and long-term impacts for our patients and will lay the foundation for future biomarker-driven clinical trials. Citation Format: Esther Rodman, Michael Emch, Elizabeth Bruinsma, Xiaonan Hou, John Weroha, John Hawse. Interrogating JAK/STAT signaling in ovarian cancer as a potential oncogenic driver and therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1129.

Zhou, Jianbiao, Chonglei Bi, Lai Fong Poon, Viraj J. Janakakumara, Jiaying Khng, Hanry Yu, Keith B. Glaser, Daniel H. Albert, Davidsen K. Davidsen, and Chien-Shing Chen. "Overactivation of STAT Pathways and Overexpression of Survivin Confer Resistance to FLT3 Inhibitors and Could Be Therapeutic Targets in AML." Blood 110, no. 11 (November 16, 2007): 2367. http://dx.doi.org/10.1182/blood.v110.11.2367.2367.

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Abstract Internal tandem duplication (ITD) of fms-like tyrosine kinase 3 (FLT3) receptor plays an important role in the pathogenesis of acute myeloid leukemia (AML). A number of small molecule kinase inhibitors are currently proceeding in different phases of clinical trials. As with imatinib in CML, leukemic cells could develop resistance to these RTK inhibitors when used as monotherapy. Mutations in the ATP-binding pocket have been identified through PCR-based mutagenesis screening in Ba/F3-FLT3-ITD cells and selected for growth in the presence of PKC412, or in a resistant Ba/F3-FLT3-ITD cell line developed by cocultured with SU5416. Resistance to PKC412 resulting from the N676K point mutation in the FLT3 kinase domain has been described in a clinical trial patient. Selection of activating Ras mutations has been found in 2 out of 6 FLT3 inhibitor resistant cell lines, but no point mutation of FLT3 kinase domain was found in all 6 resistant cell lines. To further investigate other potential mechanisms of resistance to FLT3 inhibitors, we developed a resistant cell line by long-term culture of MV4-11 cells with ABT-869, designated as MV4-11-R (IC50: 52 vs 6 nM for the parental MV4-11 cell line), which is also cross resistant to other structurally unrelated inhibitors including SU5416, AG1296 and a FLT3 inhibitor III (MERCK). No point mutation in the kinase domain of FLT3 was found in MV4-11-R cells. Western blot and FACS analysis excluded overexpression of p-FLT3, FLT3 or 3 multidrug resistance related proteins (MDR, MRP1 and LRP) in this resistant line. Gene expression profiling revealed up-regulation of FLT3 ligand (FLT3LG) (2.4 fold) and Survivin (2 fold), while down-regulation of SOCS1, SOCS2, and SOCS3 was observed in MV4-11-R compared to MV4-11 parental cells. Overexpression of FLT3LG and Survivin was also demonstrated at the protein level. Survivin is a unique member of the inhibitor of apoptosis proteins (IAP) family and a known target of the STAT3 pathway. Down-regulation of suppressor of cytokine signaling (SOCS) proteins (negative regulators of STAT pathways) was observed even in the presence of overactivation of the STAT1, STAT3 and STAT5 pathways in the MV4-11-R line. We screened a panel of small molecule inhibitors including a STAT inhibitor (indirubin derivative IDR E804), 3 JAK inhbitors (Tyrene CR4, AG490, and JAK3 Inhibitor II), and a CDK/survivin inhibitor (NU6140). We found that MV4-11-R is most sensitive to IDR E804 (an inhibitor of CDKs and the SRC-STAT3 pathway). The IC50 value of ABT-869 in MV4-11-R was decreased from 52 to 6.2 nM in the presence of 2 nM of IDR E804. Further validation of the therapeutic effect of IDR E804 in combination with ABT-869 in the MV4-11-R mouse xenograft model is ongoing. Targeting Survivin by shRNA and a dominant-negative vector (survivin-T34A) induced MV4-11-R to undergo apoptosis. Taken together, these results demonstrate that overactivation of STAT pathways and overexpression of survivin are the main mechanism of resistance to ABT-869; suggesting that the STAT pathways and survivin could be potential targets for the treatment of patients who develop resistance to FLT3 inhibitors.

Suzuki, Asuka, Toshikatsu Hanada, Keiichi Mitsuyama, Takafumi Yoshida, Shintaro Kamizono, Tomoaki Hoshino, Masato Kubo, et al. "Cis3/Socs3/Ssi3 Plays a Negative Regulatory Role in Stat3 Activation and Intestinal Inflammation." Journal of Experimental Medicine 193, no. 4 (February 12, 2001): 471–82. http://dx.doi.org/10.1084/jem.193.4.471.

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Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6–deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell–dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

Galli Sanchez, Ana Paula, Tatiane Ester Aidar Fernandes, and Gustavo Martelli Palomino. "The JAK-STAT Pathway and the JAK Inhibitors." Journal of Clinical Research in Dermatology 7, no. 5 (November 30, 2020): 1–6. http://dx.doi.org/10.15226/2378-1726/7/5/001128.

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Dozens of cytokines that bind Type I and Type II receptors use the Janus Kinases (JAK) and the Signal Transducer and Activator of Transcription (STAT) proteins pathway for intracellular signaling, orchestrating hematopoiesis, inducing inflammation, and controlling the immune response. Currently, oral JAK inhibitors are being used to treat many inflammatory and myeloproliferative diseases and are also under investigation in several clinical trials for skin diseases. Thus, dermatologists should understand how the JAK-STAT pathway works as well as the mechanism of action of the JAK inhibitors which will certainly become an important part of the dermatologist’s treatment armamentarium in the next few years. Keywords: JAK inhibitors; Janus Kinases; JAK-STAT Pathway List of Abbreviations: AD: Atopic Dermatitis ADP: Adenosine diphosphate Dmards: Disease-Modifying Antirheumatic Drugs JAK: Janus kinase(s) Jaki: Janus kinase Inhibitor(s) PIAS: Protein Inhibitor of Activated STAT P-STAT: Phosphorylated STAT STAT: Signal Transducer and Activator of Transcription TYK2: Tyrosine Kinase 2 Wsxws: Tryptophan-Serine-X-Tryptophan-Serine

Wang, Weiyuan, Melanie Cristina Lopez McDonald, Rajashree Hariprasad, Tiara Hamilton, and David A. Frank. "Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation." Cancers 16, no. 7 (March 31, 2024): 1387. http://dx.doi.org/10.3390/cancers16071387.

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Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.

Hu, Cheng-Ping, Jun-Tao Feng, Yu-Ling Tang, Jin-Qi Zhu, Min-Juan Lin, and Ming-En Yu. "LIF Upregulates Expression of NK-1R in NHBE Cells." Mediators of Inflammation 2006 (2006): 1–8. http://dx.doi.org/10.1155/mi/2006/84829.

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Leukemia inhibitory factor (LIF), a cytokine at the interface between neurobiology and immunology, is mainly mediated through JAK/STAT pathway and MAPK/ERK pathway. Evidence suggested LIF is related to the higher expression of neurokinin-1 receptor (NK-1R) in asthma. In this study, the immunohistochemistry stain showed the expressions of NK-1R, LIF, p-STAT3, and p-ERK1/2 in the lung tissues of allergic rats were increased compared with the controls, and the main positive cell type was airway epithelial cell. Normal human bronchial epithelial cells were treated with LIF in the presence or absence of AG490 (JAK2 inhibitor), PD98059 (MEK inhibitor), and the siRNA against STAT3. Western blot and RT-PCR indicated that LIF induced the expression of NK-1R, which was inhibited by the inhibitors mentioned above. No significant interaction was found between JAK/STAT pathway and MAPK/ERK pathway. In summary, bronchial epithelial cell changes in asthma are induced by LIF which promotes the expression of NK-1R, and JAK/STAT pathway and MAPK/ERK pathway may participate in this process.

Більше джерел

Дисертації з теми "STAT inhibitors":

Etter, Jonathan Parker. "Development of Inhibitors in the IL-6/GP130/JAK/STAT Pathway as Therapeutic Agents." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376525461.

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Ghafoory, Shima. "Development of a screening assay for inhibitors of inflammation useful against pancreatic cancer." Thesis, Mälardalen University, Mälardalen University, School of Sustainable Development of Society and Technology, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-7797.

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Pancreatic cancer is the fourth most lethal cancer and ranks as the eighth most commonly diagnosed cancer worldwide. This is due to its rapid proliferation, strong metastatic potential and its delayed detection. One major risk factor for developing pancreatic cancer is the aggressive inflammatory disease chronic pancreatitis. Chronic inflammation frequently precedes the development of certain pancreatic cancers.

Inflammation is a protective and necessary process by which the body can alert the immune system of the existence of a wound or infection and mount an immune response to remove the harmful stimuli and start wound healing. The cross-talking of cells of the immune system and infected cells happens through cytokines, soluble proteins that activate and recruit other immune cells to increase the system’s response to the pathogen. Failure to resolve the injury can result in persistent cytokine production that in turn allows a cell that is damaged or altered to survive when in normal conditions it would be killed. Inflammation is thought to create a microenvironment that facilitates the initiation and/or growth of pancreatic cancer cells.

Cytokines use two important kinases for their signaling: Janus Kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs). The JAKs are activated upon the binding of cytokines to their corresponding receptors. When activated, the JAKs activate STATs through tyrosine phosphorylation. The STATs transduce signals to the nucleus of the cells to induce expression of critical genes essential in normal physiological cellular events such as differentiation, proliferation, cell survival, apoptosis and angiogenesis. STAT3 (a member of the STAT family) is constitutively activated in some pancreatic cancers, promoting cell cycle progression, cellular transformations and preventing apoptosis. Therefore, STAT3 is a promising target for cancer treatment. Novel therapies that inhibit STAT3 activity in cancers are urgently needed. Natural products are a very good resource for the discovery of new drugs against pancreatic cancer.

Covering more than 70% of the Earths surface, The Ocean is an excellent source of bioactive natural products. Harbor Branch Oceanographic Institute’s Center for Marine Biomedical and Biotechnology Research (HBOI-CMBBR) situated in Florida, aims to find new marine natural products useful in disease prevention and drug therapy. Their current focus is to look for novel treatments for preventing both the formation of new pancreatic tumors and the metastasis of existing tumors.

The hypothesis of this degree project was that novel inhibitors of STAT3 useful in the treatment of pancreatitis and/or pancreatic cancer could be found from marine-natural products. The first specific aim of this degree project was to set up an assay to identify bioactive marine natural products as inhibitors of inflammation. Furthermore the assay was validated using a commercially available inhibitor of inflammation (Cucurbitacin I). The last aim was to further validate the assay by screening pure compounds and peak library material from the HBOI marine specimen collection.

At the end of the experimentation time, the assay still was not set-up as there were difficulties in proper cell culture techniques and the cell line did not respond as advertised. While the results were not as expected, the work performed resulted in familiarization with research laboratory practices and increased laboratory skills. Moreover, the results from the assays point to future directions to accomplish this project.

Development of a screening assay for inhibitors of inflammation useful against pancreatic cancer

Berrabah, Sofia. "Etude de nouvelles cibles thérapeutiques dans les lymphomes compliquant la maladie cœliaque." Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5201.

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La maladie cœliaque réfractaire de type II (MCRII), autrement appelé lymphome intraépithélial, est une complication rare mais sévère de la maladie cœliaque caractérisée par une expansion clonale d'une population particulière de lymphocytes intraépithéliaux (LIE) innés, présents dans l'intestin normal chez l'Homme comme chez la souris. Notre laboratoire a montré que cette population particulière de LIE innés partage des caractéristiques communes à celles des lymphocytes T et des cellules NK. Ces « LIE iCD3+ innés » sont caractérisées par une expression de CD3 au niveau intracellulaire mais pas à la surface, de récepteurs NK et présentent des réarrangements des gènes codant le récepteur T. En outre, le laboratoire a montré que ces cellules se développent dans l'épithélium intestinal à partir de précurseurs de la moëlle osseuse en réponse à une combinaison de signaux induits à travers la voie NOTCH et l'interleukine 15. Durant la lymphomagénèse, les LIE iCD3+ innés acquièrent des mutations somatiques gain-de-fonction dans JAK1et/ou STAT3. Ces mutations pourraient favoriser l'expansion clonale des LIE iCD3+ mutés aux dépens des lymphocytes T normaux résidents en leur conférant une sensibilité accrue à l'interleukine 15 (IL-15), une cytokine surexprimée dans l'intestin des patients. Ainsi, notre hypothèse est que ces mutations ont un rôle central dans l'initiation de la lymphomagénèse dans un contexte de production chronique d'IL-15 et, de ce fait, représentent une cible thérapeutique. Le premier objectif de ma thèse a été d'étudier l'intérêt des inhibiteurs de la voie JAK/STAT dans le traitement de la MCRII. Dans un premier temps, nous avons testé in vitro différents inhibiteurs de JAK/STAT sur des lignées cellulaires IL-15-dépendantes issues soit de LIE de MCRII soit de LIE T normaux. Nous avons démontré que ces drogues inhibent la prolifération et la phosphorylation de STAT3 et augmentent l'apoptose cellulaire aussi bien dans les LIE MCRII que dans les LIE T normaux. Dans un second temps, nous avons généré un modèle de xénogreffe en injectant des cellules issues de biopsies intestinales ou du sang d'un patient MCRII dans des souris immunodéficientes surexprimant l'IL-15 humaine dans l'épithélium intestinal (Rag-/-Gc-/-IL-15TgE ou IRGC) afin de tester l'efficacité des inhibiteurs de JAK/STAT in vivo. Le traitement des souris xénogreffées par le ruxolitinib, inhibiteur de JAK1/JAK2, a permis une diminution de la fréquence et du nombre ainsi que de l'activité cytotoxique des cellules tumorales humaines et une amélioration de l'état général des souris. Ces résultats encourageants restent à confirmer. Le second objectif de ma thèse a été de vérifier si la mutation pD661V de STAT3 était suffisante pour induire le développement de la MCRII dans un contexte de surproduction d'IL-15 dans des souris IRGC. Nous avons généré avec succès les LIE iCD3+ innés murins semblables aux LIE iCD3+ innés humaines à partir de précurseurs communs aux cellules lymphoïdes (CLP) en combinant un signal NOTCH et IL-15. Nous avons ensuite transduit les CLP avec un vecteur rétroviral contenant Stat3 sauvage ou muté (D661V). Les cellules transduites ont alors été injectées chez des souris IRGC suivies pendant 8 semaines. Les résultats préliminaires ont montré que les LIE iCD3+ innés se logent préférentiellement dans l'intestin mais aucun développement d'un lymphome intraépithélial n'a été observé au bout de 8 semaines suggérant que la mutation pD661V de STAT3 seule ne suffit pas en présence d'IL-15 à induire in vivo un lymphome intraépithélial. Ces résultats préliminaires sont toutefois à reproduire et à confirmer. Le modèle mise en place pour l'étude de STAT3 va désormais être utilisé afin d'évaluer la contribution respective de mutations canoniques de JAK1 et STAT3 et des autres mutations récurrentes retrouvées dans le lymphome intraépithélial
Refractory coeliac disease type II (RCDII), also called intraepithelial lymphoma, is a rare but severe complication of coeliac disease characterized by the clonal expansion of a small subset of innate intraepithelial lymphocytes (IEL), present in the normal human and murine intestine. Our lab has shown that this population displays shared features between T and natural killer (NK) cells. These so-called iCD3+ innate IEL are mainly characterized by intracellular expression of CD3, which is not detected at the cell surface, expression of NK receptors as well as DNA rearrangement of T cell receptor genes. Our lab has also shown that iCD3+ innate IEL originate from bone marrow precursors through coordinated NOTCH1 and interleukin (IL)-15 signals. During lymphomagenesis, iCD3+ innate IEL of most RCDII patients were shown to have acquired somatic gain-of-function mutations in JAK1 and/or STAT3 that confer increased sensitivity to interleukin-15, a cytokine overexpressed in the intestine of coeliac patients, thereby promoting their clonal expansion. Thus, our hypothesis is that JAK1/STAT3 mutations play a key role in initiating lymphomagenesis associated to coeliac disease in an IL-15-rich environment and that they could represent an attractive therapeutic target.The first objective of my thesis was to study the interest of JAK/STAT inhibitors for RCDII treatment. First, we have tested in vitro different JAK/STAT inhibitors on IL-15-dependent RCDII or normal IEL-T cell lines. We have shown that these inhibitors decrease the proliferation and phosphorylation of STAT3 and increase cellular apoptosis in both RCDII and normal T cell lines. Secondly, we have established a xenograft model based on the injection of cells derived from biopsy or blood from one RCDII patient into immunodeficient mice overexpressing the human IL-15 transgene in their gut epithelium (Rag-/-Gc-/- IL-15TgE; IRGC) to test the efficacy of JAK/STAT inhibitors in vivo. Treatment of xenografted mice with ruxolitinib, a potent inhibitor of JAK1/JAK2 decreased the frequency, number and cytotoxic potential of human tumoral cells and allowed clinical restoration. These preliminary results are encouraging but need to be confirmed. The second objective of my thesis was to test whether the Stat3 pD661V mutation is sufficient to induce the intraepithelial lymphoma in an IL-15-rich context in IRGC mice. We have successfully generated murine iCD3+ innate IEL in vitro, resembling their human counterparts from common lymphoid precursors by combining NOTCH and IL-15 signals. We then transduced CLP with a retroviral vector containing wild-type or mutated Stat3 pD661V. The transduced cells were injected into IRGC mice that subsequently were followed-up during a period of 8 weeks. In vitro generated iCD3+ innate IEL preferentially homed to the intestine. However, no development of intraepithelial lymphoma was observed suggesting that the Stat3 pD661V variant alone is not sufficient to induce the intraepithelial lymphoma. These preliminary results need to be reproduced and confirmed. The murine model used to test the role of STAT3 will now be used to evaluate the respective contribution of canonical mutations in JAK1 and STAT3 and of other recurrent mutations identified in RCDII

Gomes, Guilherme Wataru. "Expressão gênica dos transportadores de membrana ABCB1,ABCG2, SLC22A1 e SLCO1A2 em linhagens celulares tratadas com inibidor comercial da via JAK-STAT." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-16032016-095918/.

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INTRODUÇÃO: A desregulação da via de sinalização JAK-STAT é uma característica marcante das neoplasias mieloproliferativas (NMPs), doenças clonais da célula tronco hematopoética, dentre as quais encontra-se a mielofibrose (MF). Diversos inibidores de JAK foram desenvolvidos para o tratamento da MF e encontram-se em diferentes fases de desenvolvimento clínico. Devido ao seu desenvolvimento recente, pouco se sabe a respeito do papel de transportadores de membrana na farmacocinética desses compostos. Essas proteínas realizam o influxo e efluxo celular de substratos endógenos e xenobióticos, e alterações na expressão desses transportadores podem influenciar a resposta a esses fármacos. OBJETIVO: Avaliar o efeito de um inibidor comercial da via JAK-STAT na expressão gênica dos transportadores de membrana ABCB1, ABCG2, SLC22A1 e SLCO1A2 em células HepG2, Caco-2 e HEL92.1.7. MÉTODOS: Linhagens de carcinoma hepatocelular (HepG2), adenocarcinoma colorretal (Caco-2) e eritroleucemia humana homozigotas para JAK2V617F (HEL92.1.7) foram cultivadas e tratadas o inibidor comercial da via JAK-STAT JAK Inhibitor I. Para determinar a concentração ideal para o tratamento com o inibidor, as células foram tratadas com diversas concentrações do inibidor de JAK por 24 horas e foram feitos testes de viabilidade celular e fragmentação do DNA. Com as condições de tratamento padronizadas, foi extraído o RNA total das células e sintetizado o cDNA, para análise das expressões de RNAm dos genes ABCB1, ABCG2, SLC22A1 e SLCO1A2 por PCR em tempo real. Foi também avaliada a expressão dos transportadores de efluxo ABCB1 e ABCG2 por citometria de fluxo, utilizando anticorpos primários direcionados a essas proteínas. RESULTADOS: Nas células HepG2, foi observado um aumento da expressão de RNAm de ABCB1 nas células tratadas com 4,00 µM do inibidor de JAK, quando comparado com o controle (células incubadas apenas com o veículo) (P=0,041). Não foi observada alteração da expressão de RNAm de ABCG2 e SLC22A1 com o tratamento com o inibidor de JAK nessa linhagem (P>0,05); a expressão de RNAm de SLCO1A2 não foi detectada nessa linhagem. Nas células Caco-2, a expressão de ABCB1, ABCG2, SLC22A1 e SLCO1A2 não se alterou com o tratamento com o inibidor de JAK nas concentrações utilizadas (0,25 µM a 1,00 µM) por 24 horas (P>0,05). Para as células HEL92.1.7, não foi observada diferença na expressão de RNAm de ABCB1, ABCG2 e SLC22A1 com o tratamento com 1,00 µM do inibidor de JAK por 24 horas em comparação ao controle (P>0,05); nessa linhagem, a expressão de RNAm de SLCO1A2 não foi detectada. A expressão proteica dos transportadores ABCB1 e ABCG2 não sofreu alteração com o tratamento com o inibidor de JAK nas condições utilizadas nas três linhagens celulares estudadas (P>0,05). CONCLUSÕES: Apenas as células HepG2 apresentaram um aumento da expressão de RNAm do transportador de efluxo ABCB1 em concentrações elevadas do inibidor de JAK, sugerindo que os inibidores de JAK podem modular a expressão do gene desse transportador no fígado. O tratamento com o inibidor da via JAK-STAT não foi associado com alterações na expressão proteica de ABCB1 e ABCG2 em todas as células estudadas.
BACKGROUND: JAK-STAT pathway signaling disregulation is a hallmark of myeloproliferative neoplasms (MPN), hematopoietic stem cell clonal diseases, among which is myelofibrosis (MF). Several JAK inhibitors have been developed for MF treatment and are found in different stages of clinical development. Because the recent development of these compounds, the role of drug transporters in their pharmacokinetics is poorly understood. These proteins perform celular influx and effux of endogenous substrates and xenobiotics, and changes in the expression of these drugs transporters may affect the response to these drugs. AIM: To evaluate the effect of a JAK-STAT pathway commercial inhibitor in gene expression of drug transporters ABCB1, ABCG2, SLC22A1 and SLCO1A2 in HepG2, Caco-2 and HEL92.1.7 cells. METHODS: Hepatocellular carcinoma cell line HepG2, colorectal adenocarcinoma cell line Caco-2 and human erythroleukemia homozygous JAK2V617F cell line HEL92.1.7 were grown and treated with the JAK-STAT pathway inhibitor JAK Inhibitor I. In order to determine the optimal concentration for treatment with the inhibitor, cells were treated with several concentrations of JAK inhibitor by 24 hours, and cell viability and DNA fragmentation tests were performed. Once the treatment conditions were standardized, total RNA were obtained from the cells, and cDNA was synthesized in order to evaluate the mRNA expression of ABCB1, ABCG2, SLC22A1 and SLCO1A2 genes, performed by real time PCR. We also evaluate the expression of drug efflux transporters ABCB1 and ABCG2 by flow cytometry, using primary antibodies directed to these proteins. RESULTS: In HepG2 cells, it was observed an increase in ABCB1 mRNA expression in cells treated with 4,00 µM of JAK inhibitor, when compared with controls (cells exposed only to the vehicle) (P=0.041). There was no change in ABCB2 and SLC22A1 mRNA expression with the treatment with JAK inhibitor in this cell line (P>0.05); SLCO1A2 mRNA was not detected in this cell line. In Caco-2 cells, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression did not change with treatment with the JAK inhibitor at the concentrations used (0.25 µM to 1.00 µM) by 24 hours (P>0.05). In HEL92.1.7 cells, it was not observed differences in ABCB1, ABCG2 and SLC22A1 mRNA expression with the treatment with 1 µM of JAK inhibitor by 24 hours when compared with controls (P>0.05); in this cell line, SLCO1A2 mRNA was not detected. Protein expression of ABCB1 and ABCG2 drug transporters has not changed with treatment with the JAK inhibitor under the conditions used in the three cell lines studied. CONCLUSIONS: Only HepG2 cells presented an increase in mRNA expression of drug efflux transporter ABCB1 in presence of high levels of JAK inhibitor, suggesting that JAK inhibitors could modulate this transporter gene expression in liver. Treatment with JAK-STAT pathway inhibitor was not associated with changes in ABCB1 and ABCG2 protein expression in all cell lines studied.

Khatchaturyan, Levon [Verfasser], Udo [Akademischer Betreuer] Markert, Uta-Christina [Akademischer Betreuer] Hipler, and Ulrike [Akademischer Betreuer] Kämmerer. "Die Rolle von PIAS (Protein Inhibitors of Activated STATs) in der Regulation von STAT (Signal Transducer and Activator of Transcription) : vermittelten Funktionen trophoblastärer Zellen / Levon Khachaturyan. Gutachter: Udo Markert ; Uta-Christina Hipler ; Ulrike Kämmerer." Jena : Thüringer Universitäts- und Landesbibliothek Jena, 2012. http://d-nb.info/1020402113/34.

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Aubert-Jürgens, Ana. "STAT3 inhibitors for cancer treatment." [S.l.] : [s.n.], 2005. http://elib.tu-darmstadt.de/diss/000563.

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Hill, Jacqueline M. "Transition state analogues as inhibitors of metallo-proteases." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260112.

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Fisher, Michael I. "Transition state analogue inhibitors of the aspartyl proteases." Thesis, University of Huddersfield, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363233.

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Bhasin, Deepak. "Small Molecule Inhibitors asAnticancer Agents." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305826098.

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Haque, Mohammad Rashedul. "Novel STAT3 small-molecule inhibitors as potential anticancer agents." Thesis, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535504.

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Книги з теми "STAT inhibitors":

Ward, Alister C., ed. STAT Inhibitors in Cancer. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-42949-6.

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Bernhard, Elsener, European Federation of Corrosion, and Institute of Materials (Great Britain), eds. Corrosion inhibitors for steel in concrete: State of the art report. London: published for the European Federation of Corrosion by Maney on behalf of the Institute of Materials, 2001.

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Ward, Alister C. STAT Inhibitors in Cancer. Humana, 2018.

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Ward, Alister C. STAT Inhibitors in Cancer. Humana, 2016.

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Ward, Alister C. STAT Inhibitors in Cancer. Springer London, Limited, 2016.

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Fleischmann, Roy. Signalling pathway inhibitors. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0081.

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Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and SyK pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Tofacitinib is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2 while baricitinib (formerly INCB028050) predominantly inhibits JAK1/2. Many of the proinflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Fostamatinib disodium is an orally available inhibitor of spleen tyrosine kinase (SyK), which is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling may interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib has been investigated in multiple phase 2 and phase 3 trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα‎) and in patients who have failed TNFα‎ inhibitors. The efficacy of fostamatinib and baricitinib has been investigated in phase 2 trials; both are in large phase 3 clinical programmes. Each of these medications has demonstrated efficacy; their safety profile has been shown to be different from each other and from currently approved biological agents. This chapter discusses what is currently known and understood about their efficacy and safety.

Wu, Joseph M., and Tze-Chen Hsieh. Resveratrol : State-Of-The-Art Science and Health Applications: Actionable Targets and Mechanisms of Resveratrol. World Scientific Publishing Co Pte Ltd, 2019.

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Young, Benjamin. Classes of Antiretrovirals. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190493097.003.0019.

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Results of the randomized, international INSIGHT START clinical trial provide definitive proof of the benefit of antiretroviral therapy initiation in asymptomatic individuals with CD4+ counts greater than 500 cells/mm3. There are six different classes of antiretroviral agents: two types of reverse transcriptase inhibitors, two types of entry inhibitors, one class of inhibitors of HIV protease, and one class of inhibitors of HIV integrase. Combination antiretroviral therapy is recommended for all people living with HIV. The primary goal of combination antiretroviral therapy is to achieve viral suppression. Each antiretroviral class targets a unique step in the replication cycle of HIV-1.

(Editor), A. Raman, and Paul Labine (Editor), eds. Reviews on Corrosion Inhibitors Science and Technology: Papers Presented at the Corrosion/89 Symposium "Review of Corrosion Inhibition Science." Sponsored ... Group T-3A-15 N Inhibitors, State-Of-The a. Nace, 1993.

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Elsener, B. Matsci : Corrosion Inhibitors for Steel In Concrete : State of the Art Report: Proceedings of an Efc Workshop. Taylor & Francis Group, 2001.

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Частини книг з теми "STAT inhibitors":

Kumar, Janani. "Inhibitors of Upstream Inducers of STAT Activation." In Cancer Drug Discovery and Development, 177–90. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-42949-6_7.

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Liu, Suhu, and David Frank. "Translating STAT Inhibitors from the Lab to the Clinic." In Cancer Drug Discovery and Development, 49–68. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-42949-6_3.

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Shouksmith, Andrew E., and Patrick T. Gunning. "Chapter 6. Targeting Signal Transducer and Activator of Transcripion (STAT) 3 with Small Molecules." In Small-molecule Transcription Factor Inhibitors in Oncology, 147–68. Cambridge: Royal Society of Chemistry, 2018. http://dx.doi.org/10.1039/9781782624011-00147.

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Yang, Jennifer, and Gregory B. Lesinski. "Curcumin Analogs as Inhibitors of the Jak-STAT Signal Transduction Pathway." In Novel Apoptotic Regulators in Carcinogenesis, 247–66. Dordrecht: Springer Netherlands, 2012. http://dx.doi.org/10.1007/978-94-007-4917-7_10.

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Scott, Linda M. "Inhibitors of the JAK/STAT Pathway, with a Focus on Ruxolitinib and Similar Agents." In Resistance to Targeted Anti-Cancer Therapeutics, 107–34. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-75184-9_6.

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Dempsey, Brian R., Anne C. Rintala-Dempsey, Gary S. Shaw, Yuan Xiao Zhu, A. Keith Stewart, Jaime O. Claudio, Constance E. Runyan, et al. "SSI (STAT-Induced STAT Inhibitor)." In Encyclopedia of Signaling Molecules, 1787. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_101283.

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Argyropoulos, Vasilike, Stamatis C. Boyatzis, Maria Giannoulaki, Elodie Guilminot, and Aggeliki Zacharopoulou. "Organic Green Corrosion Inhibitors Derived from Natural and/or Biological Sources for Conservation of Metals Cultural Heritage." In Microorganisms in the Deterioration and Preservation of Cultural Heritage, 341–67. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-69411-1_15.

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AbstractIn the last decade, there has been an increase in research related to green corrosion inhibitors for conservation of metals cultural heritage to help promote sustainable practices in the field that are safe, environmentally friendly, and ecologically acceptable. The most common are organic substances derived either from natural and/or biological sources: plant extracts and oils, amino acids, microorganisms, and biopolymers. The chapter will provide a review of these substances as corrosion inhibitors for metals conservation, by discussing the state-of-the-art research to date, with a special focus on cysteine. Most of the research has focused on the examination of such inhibitors on metal coupons with or without corrosion products using electrochemical techniques or weight-loss measurements to determine their effectiveness. Some of these studies have also considered the conservation principles for practice, i.e., reversibility of the treatment and the visual aspect of the modification of the treated metal surface. However, before such green inhibitors can be routinely applied by conservators, more research is required on their application to real artefacts/monuments using in situ corrosion measurements. Furthermore, given that the composition of a green inhibitor is highly dependent on its extraction process, research must also involve identifying the specific adsorption models and involved mechanisms to ensure reproducibility of results.

Revhaug, A. "Use of Cyclooxygenase Inhibitors in the Acute Catabolic State." In Acute Catabolic State, 217–25. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-48801-6_19.

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Luly, Jay R., Anthony K. L. Fung, Jacob J. Plattner, Patrick A. Marcotte, Nwe BaMaung, Jeffrey L. Soderquist, and Herman H. Stein. "Transition-state analog inhibitors of human renin." In Peptides, 487–89. Dordrecht: Springer Netherlands, 1988. http://dx.doi.org/10.1007/978-94-010-9595-2_145.

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Bharadwaj, Uddalak, Moses M. Kasembeli, and David J. Tweardy. "STAT3 Inhibitors in Cancer: A Comprehensive Update." In Cancer Drug Discovery and Development, 95–161. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-42949-6_5.

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Тези доповідей конференцій з теми "STAT inhibitors":

Fanouriakis, Antonis. "28 JAK-STAT inhibitors in systemic lupus erythematosus." In 12th Annual Meeting of the Lupus Academy; Virtual Pre-meeting: September 1, 2023; Hybrid Annual Meeting (Barcelona): September 8–10, 2023. Lupus Foundation of America, 2023. http://dx.doi.org/10.1136/lupus-2023-la.28.

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Hu, Wanting. "Progress of JAK/STAT 3 and its inhibitors in the treatment of cancer." In 2ND INTERNATIONAL CONFERENCE ON FRONTIERS OF BIOLOGICAL SCIENCES AND ENGINEERING (FSBE 2019). AIP Publishing, 2020. http://dx.doi.org/10.1063/5.0000440.

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Morena, Isabel de la, Juan Alberto Paz Solarte, Diego Bedoya, and Pilar Trenor Larraz. "AB0435 REAL WORLD DATA OF A PATIENT COHORT WITH RHEUMATOID ARTRITIS TREATED WITH JAK/STAT INHIBITORS." In Annual European Congress of Rheumatology, EULAR 2019, Madrid, 12–15 June 2019. BMJ Publishing Group Ltd and European League Against Rheumatism, 2019. http://dx.doi.org/10.1136/annrheumdis-2019-eular.8254.

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Breedy, Sloan, Wishrawana S. Ratnayake, Christopher Apostolatos, Avijit Dey та Mildred Acevedo-Duncan. "Abstract 5216: Atypical PKC inhibitors ICA-1S and ζ-Stat show inhibition of neuroblastoma cell proliferation". У Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-5216.

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Abdelhamid, Dalia, Mike Corcoran, Jonathan P. Etter, Sheng Hu, Bulbul Pandit, Chenglong Li, Pui-Kai Li, and James R. Fuchs. "Abstract 4502: Synthesis and evaluation of curcumin-like compounds as inhibitors of the JAK/STAT pathway in cancer." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-4502.

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Cairo, Stefano, Olivier Déas, Truong-an Tran, and Jean-Gabriel Judde. "Abstract 2811: High IFN/STAT-related gene expression is associated with sensitivity to PARP inhibitors of triple negative breast cancer." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-2811.

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Cortez, Maria A., Lauren Averett Byers, You Hong Fan, Lixia Diao, Philip Groth, Julianne Paul, Jing Wang, et al. "Abstract 2498: Proteomic analysis reveals Src/Stat and EGFR/MAPK pathways as potential mechanism of resistance to PI3K inhibitors in lung cancer." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-2498.

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Mao, Yumeng, Isabel Poschke, Yago Pico de Coaña, Erik Wennerberg, Andreas Lundqvist, and Rolf Kiessling. "Abstract A63: Melanoma-educated CD14+ monocytes become myeloid-derived suppressor cell-like and are potent inhibitors of autologous T cells through Cox-2 production and STAT-3 signaling." In Abstracts: AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; December 2-5, 2012; Miami, FL. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.tumimm2012-a63.

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Tan, Bee Chea, Ismail Mohd Saaid, Siti Qurratu'Aini Mahat, Suzalina Zainal, Petrus Tri Bhaskoro, and Astriyana Anuar. "Evaluation of Polyamidoamine-Assisted Scale Inhibitors to Mitigate Silicate Scale Formation in Near Wellbore Region." In SPE/IATMI Asia Pacific Oil & Gas Conference and Exhibition. SPE, 2023. http://dx.doi.org/10.2118/215266-ms.

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Abstract Silicate scaling is a concern that could result in formation damage and flow assurance issue. Phosphonates and phosphino-polyacrylates are widely used to treat many types of scale but they are not intended to treat silicate scale. Besides that, these inhibitors may have been considered as harmful substances due to their reported inherent biodegradability. Synergistic silicate scale inhibitors are current trends since cationic or anionic polymers alone is found not effective for silicate scale inhibition. The objective of this work is to assess the performance of polyamidoamine-assisted scale inhibitors for silicates. The experiment settings are simulating the environment in near wellbore region, such that higher temperatures and brine that is mostly pH neutral. The effectiveness of scale inhibitors is investigated through static bottle test and dynamic scale loop (DSL) test. The scale inhibitors are also characterized to determine their functional groups in aqueous state. The tendency of scale inhibitors to impede silicate polymerization process is also determined through the remaining concentration of monomeric silica in water after 72 hours. FTIR revealed that all scale inhibitors exhibit amine characteristic in water. Experimental results show that the polyamidoamine-assisted scale inhibitor, PAMAM G-2/PteGlu, is the most effective in mitigating silicate scale formation. It reduces scaling brine's turbidity as much as 94.8% after 72 hours at 90°C. In addition, it also minimizes silicate polymerization process by retaining almost half of the initial monomeric silica concentration. This also implies that PAMAM G-2/PteGlu inhibitor could reduce the tendency of silicate scale formation to 46% as compared to 97% of silicate scale formation without any inhibition at 95°C. From DSL test, PAMAM G-2/PteGlu inhibitor is also the most effective inhibitor. It prolongs the scaling time from 7 minutes to 339 minutes at 0.01 g/L inhibitor concentration. It is also 7% more effective than PAMAM G-1/PteGlu inhibitor in DSL test. In general, the performance of scale inhibitors for silicates can be arranged as: PAMAM G-2/PteGlu > PAMAM G-1/PteGlu > PteGlu > PAMAM G-2 > PAMAM G-1 from top to bottom. In this work, these environment-friendly products had demonstrated good silicate scale inhibition as well as synergistic effect. They could offer as alternatives to commercial scale inhibitors.

Covey, Todd M., Santosh Putta, Michael Gulrajani, Aileen C. Cohen, and Alessandra Cesano. "Abstract B182: Single cell network profiling (SCNP) by flow cytometry as a tool to measure potency and selectivity of JAK/STAT inhibitors in PBMC and whole blood discrete cell subsets." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-b182.

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Звіти організацій з теми "STAT inhibitors":

Tian, Cong, Jianlong Shu, Wenhui Shao, Zhengxin Zhou, Huayang Guo та Jingang Wang. The efficacy and safety of IL Inhibitors, TNF-α Inhibitors, and JAK Inhibitor on ankylosing spondylitis: A Bayesian network meta-analysis of a “randomized, double-blind, placebo-controlled” trials. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, вересень 2022. http://dx.doi.org/10.37766/inplasy2022.9.0117.

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Review question / Objective: In this study, we conducted a Bayesian network meta-analysis to evaluate the efficacy and safety of interleukin (IL) inhibitors, tumor necrosis factor-alpha (TNF-α) inhibitors, and Janus kinase (JAK) inhibitors on ankylosing spondylitis (AS).The purpose of this study is to compare the effectiveness and safety of different interventions for treating AS to provide insights into the decision-making in clinicalpractice. Condition being studied: Ankylosing spondylitis. Based on the Bayesian hierarchical model, we conducted a network meta-analysis using the gemtc package in R software (version 4.1.3) and Stata software (version 15.1). Cong Tian and Jianlong Shu contributed to the conception and design of the study and supervised the tweet classification. All authors drafted the manuscript. Wenhui Shao, Zhengxin Zhou, Huayang Guo and Jingang Wang contributed to data management and tweet classification. Cong Tian, Jianlong Shu and Zhengxin Zhou performed the statistical analysis. Cong Tian, Jianlong Shu, Wenhui Shao and Zhengxin Zhou reviewed the manuscript.

Schneider, Brandt. Role of the Cdk Inhibitor Sic 1 in Start. Fort Belvoir, VA: Defense Technical Information Center, August 1998. http://dx.doi.org/10.21236/ada359281.

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Schneider, Brandt. Role of the Cdk Inhibitor Sic 1 in Start. Fort Belvoir, VA: Defense Technical Information Center, September 2000. http://dx.doi.org/10.21236/ada392485.

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Schneider, Brandt. Role of the Cdk Inhibitor Sic 1 in Start. Fort Belvoir, VA: Defense Technical Information Center, August 1999. http://dx.doi.org/10.21236/ada378108.

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Seto, Christopher T. Anticancer Agents Based on a New Class of Transition- State Analog Inhibitors for Serine and Cysteine Proteases. Fort Belvoir, VA: Defense Technical Information Center, August 1999. http://dx.doi.org/10.21236/ada377205.

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Seto, Christopher. Anticancer Agents Based on a New Class of Transition-State Analog Inhibitors for Serine and Cysteine Proteases. Fort Belvoir, VA: Defense Technical Information Center, August 2000. http://dx.doi.org/10.21236/ada383963.

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Coiwell, J., S. Pednekar, and M. Han. L51540 Corrosion Criteria for J-Tube Risers. Chantilly, Virginia: Pipeline Research Council International, Inc. (PRCI), November 1987. http://dx.doi.org/10.55274/r0011426.

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The state-of-the-art survey showed that a number of risers have been installed, using the J-tube method, in a variety of water depths and in a range of diameters. Many different coating types have been used, but neoprene appears to be the most popular. There was one reported riser failure after 10 years of service that was attributed to a damaged coating and an improperly set bottom plug. In the experimental program, two coating types were used, and the riser pipes were pulled through the 3-tube test stand that was constructed in Houston; these were a two-part urethane and 1/2-inch thick neoprene. The use of inhibitors was also studied.

Bhagawati, Rishiraj, Dolf J. H. te Lintelo, John Msuya, and Tumaini Mikindo. Nutrition Accountability through Sub-National Scorecards in Tanzania – Policy Innovations and Field Realities. Institute of Development Studies (IDS), December 2021. http://dx.doi.org/10.19088/ids.2021.067.

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Over the past decade, the Government of Tanzania has paid increasing attention to accountability in its nutrition policies. This has coincided with the introduction of truly innovative efforts to advance and monitor government action towards and accountability for nutrition at subnational level. A multisectoral nutrition scorecard (MNS) has been rolled out across all districts in the country, with quarterly updates on district performance. Moreover, a Nutrition Compact instrument was introduced to incentivise senior civil servants within regional and district administrations to advance efforts to promote nutrition. This paper explores how the government has used these initiatives to give accountability a particular form and meaning, pertinent to context. The paper analyses a series of policy documents and complements analysis this with field-based interviews with local officials across five regions. We find that the MNS and Compact are designed predominantly for internal purposes of government. This renders ‘accountability tools’ largely in the service of a centralised state, advancing vertical accountability. Such a narrow framing and design inhibits the potential of these instruments for galvanising social accountability, whereby citizens can hold public service providers and subnational government actors to account directly.

Barash, Itamar, J. Mina Bissell, Alexander Faerman, and Moshe Shani. Modification of Milk Composition via Transgenesis: The Role of the Extracellular Matrix in Regulating Transgene Expression. United States Department of Agriculture, July 1995. http://dx.doi.org/10.32747/1995.7570558.bard.

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Altering milk composition via transgenesis depends on three main factors. (1) The availability of an efficient regulatory sequences for targeting transgene(s) to the mammary gland; (2) a reliable in vitro model to test the expression of transgenes prior to their introduction to the animal genome; and (3) better understanding of the major factors which determine the rate of gene expression and protein synthesis. The current studies provide the necessary means and knowledge to alter milk protein composition via transgenesis. The following specific goals were achieved: a: Identifying regulatory regions in the b-lactoglobulin (BLG) gene and the cross-talk between elements which enabled us to construct an efficient vector for the expression of desirable cDNA's in the mammary gland. b: The establishment of a sheep mammary cell line that serves as a model for the analysis of endogenous and exogenous milk protein synthesis in the mammary gland of livestock. c: An accurate comparison of the potency of the 5' regulatory sequences from the BLG and whey acidic protein (WAP) promoters in directing the expression of human serum albumin (HSA) to the mammary gland in vitro and in vivo. In this study we have also shown that sequences within the coding region may determine a specific pattern of expression for the transgene, distinct from that of the native milk protein genes. d: Characterizing the dominant role of ECM in transgene expression in mammary epithelial cells. e: Further characterization of the BCE-1 enhancer element in the promoter of the b-casein gene as a binding site for the c/EBP-b and Stat5. Identifying its interaction with chromatin and its up regulation by inhibitors of histone deacetylation. f: Identifying a mechanism of translational control as a mediator for the synergistic effect of insulin and prolactin on protein synthesis in the mammary gland.

Altstein, Miriam, and Ronald J. Nachman. Rational Design of Insect Control Agent Prototypes Based on Pyrokinin/PBAN Neuropeptide Antagonists. United States Department of Agriculture, August 2013. http://dx.doi.org/10.32747/2013.7593398.bard.

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The general objective of this study was to develop rationally designed mimetic antagonists (and agonists) of the PK/PBAN Np class with enhanced bio-stability and bioavailability as prototypes for effective and environmentally friendly pest insect management agents. The PK/PBAN family is a multifunctional group of Nps that mediates key functions in insects (sex pheromone biosynthesis, cuticular melanization, myotropic activity, diapause and pupal development) and is, therefore, of high scientific and applied interest. The objectives of the current study were: (i) to identify an antagonist biophores (ii) to develop an arsenal of amphiphilic topically active PK/PBAN antagonists with an array of different time-release profiles based on the previously developed prototype analog; (iii) to develop rationally designed non-peptide SMLs based on the antagonist biophore determined in (i) and evaluate them in cloned receptor microplate binding assays and by pheromonotropic, melanotropic and pupariation in vivo assays. (iv) to clone PK/PBAN receptors (PK/PBAN-Rs) for further understanding of receptor-ligand interactions; (v) to develop microplate binding assays for screening the above SMLs. In the course of the granting period A series of amphiphilic PK/PBAN analogs based on a linear lead antagonist from the previous BARD grant was synthesized that incorporated a diverse array of hydrophobic groups (HR-Suc-A[dF]PRLa). Others were synthesized via the attachment of polyethylene glycol (PEG) polymers. A hydrophobic, biostablePK/PBAN/DH analog DH-2Abf-K prevented the onset of the protective state of diapause in H. zea pupae [EC50=7 pmol/larva] following injection into the preceding larval stage. It effectively induces the crop pest to commit a form of ‘ecological suicide’. Evaluation of a set of amphiphilic PK analogs with a diverse array of hydrophobic groups of the formula HR-Suc-FTPRLa led to the identification of analog T-63 (HR=Decyl) that increased the extent of diapause termination by a factor of 70% when applied topically to newly emerged pupae. Another biostablePK analog PK-Oic-1 featured anti-feedant and aphicidal properties that matched the potency of some commercial aphicides. Native PK showed no significant activity. The aphicidal effects were blocked by a new PEGylated PK antagonist analog PK-dF-PEG4, suggesting that the activity is mediated by a PK/PBAN receptor and therefore indicative of a novel and selective mode-of-action. Using a novel transPro mimetic motif (dihydroimidazole; ‘Jones’) developed in previous BARD-sponsored work, the first antagonist for the diapause hormone (DH), DH-Jo, was developed and shown to block over 50% of H. zea pupal diapause termination activity of native DH. This novel antagonist development strategy may be applicable to other invertebrate and vertebrate hormones that feature a transPro in the active core. The research identifies a critical component of the antagonist biophore for this PK/PBAN receptor subtype, i.e. a trans-oriented Pro. Additional work led to the molecular cloning and functional characterization of the DH receptor from H. zea, allowing for the discovery of three other DH antagonist analogs: Drosophila ETH, a β-AA analog, and a dF analog. The receptor experiments identified an agonist (DH-2Abf-dA) with a maximal response greater than native DH. ‘Deconvolution’ of a rationally-designed nonpeptide heterocyclic combinatorial library with a cyclic bis-guanidino (BG) scaffold led to discovery of several members that elicited activity in a pupariation acceleration assay, and one that also showed activity in an H. zea diapause termination assay, eliciting a maximal response of 90%. Molecular cloning and functional characterization of a CAP2b antidiuretic receptor from the kissing bug (R. prolixus) as well as the first CAP2b and PK receptors from a tick was also achieved. Notably, the PK/PBAN-like receptor from the cattle fever tick is unique among known PK/PBAN and CAP2b receptors in that it can interact with both ligand types, providing further evidence for an evolutionary relationship between these two NP families. In the course of the granting period we also managed to clone the PK/PBAN-R of H. peltigera, to express it and the S. littoralis-R Sf-9 cells and to evaluate their interaction with a variety of PK/PBAN ligands. In addition, three functional microplate assays in a HTS format have been developed: a cell-membrane competitive ligand binding assay; a Ca flux assay and a whole cell cAMP ELISA. The Ca flux assay has been used for receptor characterization due to its extremely high sensitivity. Computer homology studies were carried out to predict both receptor’s SAR and based on this analysis 8 mutants have been generated. The bioavailability of small linear antagonistic peptides has been evaluated and was found to be highly effective as sex pheromone biosynthesis inhibitors. The activity of 11 new amphiphilic analogs has also been evaluated. Unfortunately, due to a problem with the Heliothis moth colony we were unable to select those with pheromonotropic antagonistic activity and further check their bioavailability. Six peptides exhibited some melanotropic antagonistic activity but due to the low inhibitory effect the peptides were not further tested for bioavailability in S. littoralis larvae. Despite the fact that no new antagonistic peptides were discovered in the course of this granting period the results contribute to a better understanding of the interaction of the PK/PBAN family of Nps with their receptors, provided several HT assays for screening of libraries of various origin for presence of PK/PBAN-Ragonists and antagonists and provided important practical information for the further design of new, peptide-based insecticide prototypes aimed at the disruption of key neuroendocrine physiological functions in pest insects.