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1
Isaikina, Polina, Ching-Ju Tsai, Nikolaus Dietz, et al. "Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist." Science Advances 7, no. 25 (2021): eabg8685. http://dx.doi.org/10.1126/sciadv.abg8685.
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The human CC chemokine receptor 5 (CCR5) is a G protein–coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.
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Joseph, Megan D., Elena Tomas Bort, Richard P. Grose, Peter J. McCormick, and Sabrina Simoncelli. "Quantitative Super-Resolution Imaging for the Analysis of GPCR Oligomerization." Biomolecules 11, no. 10 (2021): 1503. http://dx.doi.org/10.3390/biom11101503.
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G-protein coupled receptors (GPCRs) are known to form homo- and hetero- oligomers which are considered critical to modulate their function. However, studying the existence and functional implication of these complexes is not straightforward as controversial results are obtained depending on the method of analysis employed. Here, we use a quantitative single molecule super-resolution imaging technique named qPAINT to quantify complex formation within an example GPCR. qPAINT, based upon DNA-PAINT, takes advantage of the binding kinetics between fluorescently labelled DNA imager strands to complementary DNA docking strands coupled to protein targeting antibodies to quantify the protein copy number in nanoscale dimensions. We demonstrate qPAINT analysis via a novel pipeline to study the oligomerization of the purinergic receptor Y2 (P2Y2), a rhodopsin-like GPCR, highly expressed in the pancreatic cancer cell line AsPC-1, under control, agonistic and antagonistic conditions. Results reveal that whilst the density of P2Y2 receptors remained unchanged, antagonistic conditions displayed reduced percentage of oligomers, and smaller numbers of receptors in complexes. Yet, the oligomeric state of the receptors was not affected by agonist treatment, in line with previous reports. Understanding P2Y2 oligomerization under agonistic and antagonistic conditions will contribute to unravelling P2Y2 mechanistic action and therapeutic targeting.
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Mo, Fei, Zhiya Yu, Peng Li, et al. "An engineered IL-2 partial agonist promotes CD8+ T cell stemness and anti-tumor efficacy." Journal of Immunology 204, no. 1_Supplement (2020): 221.7. http://dx.doi.org/10.4049/jimmunol.204.supp.221.7.
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Abstract Adoptive cell transfer of antigen specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in a subset of patients. To achieve effective responses, both the number of transferred T cells and their cell differentiation state are critical determinants. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and IL-2 but this can also lead to T cell differentiation into effector T cells, resulting in diminished therapeutic efficacy, whereas maintenance of a more stem-like prior to adoptive transfer is beneficial. Here, we show that an engineered IL-2 partial agonist generated on the super-IL-2 background promoted T-cell expansion without driving terminal differentiation. The partial agonist exhibited altered signaling and mediated distinctive downstream transcriptional, epigenetic, and metabolic programs. Moreover, it sustained expression of transcription factor TCF-1 (T cell transcription factor 1) and promoted mitochondrial fitness, facilitating the maintenance of a stem cell-like state. Accordingly, TCR transgenic and CAR-modified CD8+ T cells expanded with this engineered molecule displayed robust anti-tumor activity in vivo in established models of melanoma and acute lymphoblastic leukemia. Thus, tempering cytokine signaling with the IL-2 partial agonist provides a strategy for enhancing therapeutic efficacy by limiting exhaustion while preserving stemness. Moreover, our findings demonstrate the distinctive power of generation cytokine partial agonists with distinctive activities.
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Yokomizo, Yumiko, Narihiko Hayashi, Akitoshi Takizawa, et al. "Multicenter prospective study of switching from GnRH agonists to GnRH antagonist for patients with early stage of castration resistant prostate cancer as a second-line hormonal therapy." Journal of Clinical Oncology 36, no. 6_suppl (2018): 183. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.183.
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183 Background: It was reported that GnRH antagonist could extend progression free survival for prostate cancer patients significantly longer than GnRH agonist in a first line hormonal therapy. However, the usefulness of switching from GnRH agonist to GnRH antagonist as a second hormonal therapy remains obscure. We performed a multicentral prospective study to investigate whether the switching from GnRH agonist to GnRH antagonist (degalerix) for patients with castration resistant prostate cancer (CRPC) as the 2nd line hormonal therapy was effective. Methods: 37 patients who were pathologically diagnosed as prostatic adenocarcinoma and developed CRPC after 1st line hormonal therapy with GnRH agonist plus anti-androgens were enrolled. After confirming anti-androgen withdrawal syndrome, they were treated with switching from GnRH agonists to degalerix. The primary endpoint was PSA response (PSA decline or up to 10% over baseline PSA). Secondary endpoints were the time to 25% PSA increase from the baseline (PSA response time), PSA progression free survival (PPFS), the time to treatment failure, cancer specific survival, radiographic PFS (rPFS), and safety. Results: Mean age was 76 years old, super high risk; 20 cases (54.1%), high risk; 11 cases (29.7%), intermediate risk; 5 cases (13.5%), low risk; one case (2.7%). PSA responder rate was 24.3% (9 cases). In responders, the median PSA response time was 5.75 months, the median PPFS was 1.77 months, and rPFS rate at 3 months was 96%. Regarding safety, only 2 cases (5.4%) showed G3 of AE. The PSA response had no relationship with the change of serum testosterone, LH nor FSH. Conclusions: The effectiveness of switching from GnRH agonist to GnRH antagonist showed to be limited. Although no predictive factor of the switching was recognized, some long-term responders were seen. We expect the possibility of switching to GnRH antagonist for patients in the early stage of CRPC, especially non-metastatic status. Clinical trial information: UNKNOWN.
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To, Minh D., Manjunatha Ankathatti Munegowda, Rosemina Merchant, and Aanchal Sharma. "Abstract 5532: An ‘anti-PD1-IL2 beta-only super-agonist’ displays potent anti-tumor efficacy." Cancer Research 82, no. 12_Supplement (2022): 5532. http://dx.doi.org/10.1158/1538-7445.am2022-5532.
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Abstract Introduction: Combination studies with engineered IL-2 variants and immune-checkpoint blockade have demonstrated synergy in both pre-clinical models and the clinic. Co-administration of those 2 agents can potentially face challenges related to overlapping toxicities in obtaining optimal doses for synergistic effects. We propose to potentiate the synergy by enabling cis activation of IL-2 agonism and blockade of PD-1/PDL-2 binding with a single anti-PD1-IL2 to generate Bifunctional SuperKines for ImmunoTherapy (BiSKIT). Both human (h) and mouse (m) versions of anti-PD1 are fused with MDNA109FEAA, an IL-2 superkine with enhanced affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25). Experimental Procedure: Studies included binding analyses with Biacore/SPR, signaling analyses in an IL-2 cell reporter assay, cell proliferation assay, in vitro pSTAT5 signaling in human PBMCs, PD1/PDL-1 cell reporter assay and efficacy in syngeneic tumor models. Summary of Data: Anti-hPD1-MDNA109FEAA and surrogate anti-mPD1-MDNA109FEAA were tested in both in vitro and in vivo assays. Both constructs demonstrated selective binding to either hPD1 or mPD1 as expected, and the MDNA109FEAA motif retained its receptor selectivity (enhanced affinity to CD122 and no binding to CD25). In both HEK-Blue IL-2 reporter and CTLL-2 proliferation bioassays, anti-PD1-MDNA109FEAA exhibited similar agonistic effect as MDNA109FEAA-Fc, demonstrating that potency towards the IL-2 axis was not diminished. This was further confirmed with pSTAT5 signaling in primary human PBMCs where anti-PD1-MDNA109FEAA showed enhanced activation of CD8 T-cells and NK cells with reduced activity on Treg when compared to rhIL-2. Both constructs were also effective at inhibiting PD1/PDL-1 pathway in respective human and mouse specific cell-based reporter assays. In a CT26 syngeneic colon tumor model, anti-mPD1-MDNA109FEAA exhibited superior efficacy over monotherapy and combination with anti-mPD1 and MDNA109FEAA-Fc when administered at equal molar dosage and same schedule. Conclusion: We have engineered anti-PD1-MDNA109FEAA to enable cis engagement with IL-2 receptor and PD1 as an approach to activate immune cells while reducing their exhaustion. Anti-mPD1-MDNA109FEAA achieved potent efficacy in a CT26 colon tumor model and is currently being evaluated in additional syngeneic tumor models with varying responsiveness to immune checkpoint blockade. Citation Format: Minh D. To, Manjunatha Ankathatti Munegowda, Rosemina Merchant, Aanchal Sharma. An ‘anti-PD1-IL2 beta-only super-agonist’ displays potent anti-tumor efficacy [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 5532.
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Hsiung, Hansen M., JeAnne Hertel, Xing-yue Zhang та ін. "A Novel and Selective β-Melanocyte-Stimulating Hormone-Derived Peptide Agonist for Melanocortin 4 Receptor Potently Decreased Food Intake and Body Weight Gain in Diet-Induced Obese Rats". Endocrinology 146, № 12 (2005): 5257–66. http://dx.doi.org/10.1210/en.2005-0177.
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αMSH has generally been accepted as the endogenous ligand for melanocortin 4 receptor (MC4R), which plays a major role in energy homeostasis. Targeting MC4R to develop antiobesity agents, many investigators have performed a structure-activity relationship (SAR) studies based on αMSH structure. In this report, we performed a SAR study using human βMSH (5–22 ) (DEGPYRMEHFRWGSPPKD, peptide 1) as a lead sequence to develop potent and selective agonists for MC4R and MC3R. The SAR study was begun with a truncation of N terminus of βMSH (5–22 ) together with acetylation of the N terminus and amidation of the C terminus of the peptide. Introduction of a cyclic disulfide constrain and replacement of L-Phe with D-Phe afforded a super potent agonist (peptide 5). Furthermore truncation at the C terminus generated a small and potent MC4R and MC3R agonist (Ac-YRcyclo[CEHdFRWC]amide, peptide 6), which exhibited no MC5R and greatly reduced MC1R activity. Molecular modeling of Ac-YRcyclo[CEHdFRWC]amide (peptide 6) revealed that Arg2 in the peptide formed a salt bridge with Glu4. Subcutaneous or intracerebroventricular administration of peptide 6 in rats showed potent in vivo efficacy as evidenced by its effects in reducing energy balance, increasing fat use, and decreasing weight gain in both acute and chronic rat metabolic studies. Furthermore, the antiobesity effect by peptide 6 was manifested only in wild-type but not MC4R-deficient mice, indicating that antiobesity effects of the peptide were attributed largely through MC4R but not MC3R agonist activity of the peptide.
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Liu, Guizhong, Peter Cheung, Jun Chen, Xiaohong She, Felix Fangyong Du, and Peter Luo. "Development of a unique anti-CD137 therapeutic antibody: Efficacy and safety profiles in mono and combination therapy." Journal of Clinical Oncology 35, no. 15_suppl (2017): e23079-e23079. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23079.
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e23079 Background: Abstract: CD137 (4-1BB), a member of the TNFR super family, is expressed on several subsets of activated immune cells and acts as co-stimulatory receptor for T-cells to promote cellular proliferation, survival and cytokine production. Agonist antibodies against human CD137 in early clinical trials show strikingly different toxicology profiles, ranging from severe liver toxicity at low doses, to manageable adverse effects at modest doses. Whereas preclinical studies in mouse show intense liver T-cell infiltration and toxicity by surrogate agonist mAb. The preclinical efficacy and pharmacology of anti-CD137 were extensively tested and validated in various tumor models with intact immune system. Since none of the available anti-CD137 agonist antibodies display multiple species cross reactivity including rodent, the translational significance of these mAbs is limited concerning their efficacy and safety profile. Methods: Through our proprietary Dynamic Precision Library (DPL) technology, we have discovered multiple agonistic antibodies that exhibit high affinity and broad species cross-reactivity against a unique epitope shared among human, monkey and rodent CD137. Results: These mAbs, after crosslinking, strongly activate CD137 mediated cellular NFkB signaling, as well as stimulate T-cell proliferation and IFNg release in the presence of suboptimal concentrations of anti-CD3 antibodies. The broad species cross-reactivity by a single therapeutic agent enabled us to evaluate their potentiation of host immune responses that gives rise to the anti-tumor efficacy and potential toxicity in relevant rodent and monkey models. Our lead anti-CD137 agonist mAb has demonstrated robust anti-tumor activities in multiple mouse syngeneic tumor models, with durable antigen specific protective memory T-cell responses. Conclusions: In sharp contrast to surrogate anti-mouse CD137 mAbs, no toxicities including liver inflammation or other adverse effects were observed. These preclinical results warrant further clinical development of our lead as a novel immunotherapeutic anti-cancer agent.
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Geng, Shuo, Ruoxi Yuan, and Liwu Li. "Dynamic programming and memory of monocytes by varying signal strengths of innate stimulants." Journal of Immunology 198, no. 1_Supplement (2017): 221.14. http://dx.doi.org/10.4049/jimmunol.198.supp.221.14.
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Abstract In response to changing external signal strength, innate monocytes may be dynamically programmed into distinct functional states, which may bear significance relevance in host pathophysiology. However, molecular mechanisms that control innate memory dynamics are not well understood nor extensively studied. Using lipopolysaccharide (LPS), the model stimulant of Toll-Like-Receptor 4 (TLR4), we observed that the expressions of pro-inflammatory mediators are preferentially sustained in monocytes adapted by subclinical super-lower dose LPS, and suppressed/tolerized in monocytes programmed by higher dosages of LPS. These phenomena are well conserved in both mice and human monocytes. At the molecular level, we observed that monocytes programmed by super-low dose LPS maintain higher levels of transcription factor IRF5. We also observed that the inflammatory monocyte programming is dependent upon TRAM/TRIF but not MyD88. Similar to LPS, we also observed biphasic inflammatory adaptation and tolerance in monocytes challenged with varying dosages of TLR7 agonist. In sharp contrast, rising doses of TLR3 agonist preferentially caused inflammatory adaptation without inducing tolerance. At the functional level, we observed that in vivo programming of monocytes by subclinical dose LPS exacerbates the progression of atherosclerosis. Taken together, our study provides novel mechanisms for the dynamic programming/memory of innate monocytes and their pathological implications in atherosclerosis.
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Brown, Laurence A., Makoto Ihara, Steven D. Buckingham, Kazuhiko Matsuda, and David B. Sattelle. "Neonicotinoid insecticides display partial and super agonist actions on native insect nicotinic acetylcholine receptors." Journal of Neurochemistry 99, no. 2 (2006): 608–15. http://dx.doi.org/10.1111/j.1471-4159.2006.04084.x.
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Felices, M., S. Chu, B. Kodal, et al. "IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer." Gynecologic Oncology 145, no. 3 (2017): 453–61. http://dx.doi.org/10.1016/j.ygyno.2017.02.028.
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Rosethorne, Elizabeth M., Michelle E. Bradley, Karolina Gherbi та ін. "Long Receptor Residence Time of C26 Contributes to Super Agonist Activity at the Human β2 Adrenoceptor". Molecular Pharmacology 89, № 4 (2016): 467–75. http://dx.doi.org/10.1124/mol.115.101253.
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Hong, Bangxing, Sung-Hyung Lee, Xiao-Tong Song, et al. "A Super TLR Agonist to Improve Efficacy of Dendritic Cell Vaccine in Induction of Anti-HCV Immunity." PLoS ONE 7, no. 11 (2012): e48614. http://dx.doi.org/10.1371/journal.pone.0048614.
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IHARA, Makoto, Kazuhiko MATSUDA, Masaru SHIMOMURA, David B. SATTELLE та Koichiro KOMAI. "Super Agonist Actions of Clothianidin and Related Compounds on the SADβ2 Nicotinic Acetylcholine Receptor Expressed inXenopus laevisOocytes". Bioscience, Biotechnology, and Biochemistry 68, № 3 (2004): 761–63. http://dx.doi.org/10.1271/bbb.68.761.
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Saini, Ankita, Shasha Li, Jennifer K. Bando, et al. "Functional dissection of a novel IL-22 super-enhancer." Journal of Immunology 200, no. 1_Supplement (2018): 111.10. http://dx.doi.org/10.4049/jimmunol.200.supp.111.10.
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Abstract Innate lymphoid cells (ILCs) are an emerging family of immune cells that serve essential roles in initiation, regulation and resolution of different immune responses. ILCs respond promptly to various signals present in their microenvironment by producing an array of cytokines and thereby directing the immune responses. These cells have been categorized as ILC1, ILC2 and ILC3 depending upon the effector cytokines secreted and transcription factors expressed by them. The signature effector cytokines produced by ILC3s are IL-22 and IL-17, providing protective immunity against extracellular pathogens. Another crucial facet of IL-22 function is its maintenance of mucosal homeostasis by modulating processes like tissue repair. However, there is a void of knowledge about genomic regions regulating IL-22 in different immune cells. In this regard, recent studies from our lab revealed a novel super-enhancer (SE), regulatory region composed of a large cluster of conventional enhancers, which likely regulates IL-22 and, perhaps, the neighboring IFNG gene. To dissect ILC3-specific functions of enhancers within the SE regulatory region, we are exploiting a murine cell line, MNK3, which mimics ILC3 functions in vitro and in vivo. We found that CRISPR-Cas9 mediated deletion of 5′ and 3′ end of this novel SE abrogated IL-22 expression in MNK3 cells. Furthermore, to identify cell and/or agonist specific elements of SE we set up a CRISPRi screen for which we generated a stable line of MNK3 expressing Dox inducible KRAB-dCas9. Together, our approach will define the cis-elements that regulate IL-22 in distinct immune cells and hence opening the field for novel therapeutic interventions for inflammatory diseases including autoimmune disorders.
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Fromm, George, Suresh de Silva, Arpita Patel, Kellsey Johannes, Josiah Hornblower та Taylor H. Schreiber. "Agonist Redirected Checkpoint (ARC), SIRPα-Fc-CD40L, for Cancer Immunotherapy". Journal of Immunology 200, № 1_Supplement (2018): 58.18. http://dx.doi.org/10.4049/jimmunol.200.supp.58.18.
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Abstract Combination immunotherapy with bispecific abs, linked scFv’s or T cell engagers have not shown that both checkpoint blockade and TNF receptor activation can be achieved with a single molecule, likely due to a loss of target avidity. Fusion proteins incorporating the extracellular domain of type I membrane proteins (eg. Enbrel) or type II membrane proteins (eg. SIRPα-Fc), linked via an antibody Fc domain, are both functional despite the ECDs being in opposite orientation. We report the generation of a two-sided fusion protein (ARC) incorporating the ECD of SIRPα (CD172a) and the ECD of CD40L, adjoined by a central Fc domain. The SIRPα end of the ARC binds CD47 at 3.59 nM affinity, but does not cause hemolysis, compared to CD47 mAbs. The CD40L end binds CD40 at 756 pM affinity and binds CD40 on primary macrophages. The SIRPα-Fc-CD40L ARC stimulates NFκB-functional activity (independent of Fc receptor cross-linking) and IL2 and TNFα secretion in an ex vivo super-antigen (SEB) assay. Furthermore, live cell imaging shows that SIRPα-Fc-CD40L enhanced phagocytosis of tumor cells by primary macrophages. Finally, the therapeutic activity of SIRPα-Fc-CD40L in established murine MC38 and CT26 tumors was superior to either CD47 blocking antibody, CD40 agonist antibody or their combination. Finally, treatment of cynomolgus macaques with SIRPα-Fc-CD40L was safe, and no evidence of hemolysis or thrombocytopenia was observed. These data demonstrate feasibility of a novel chimeric fusion protein platform, providing checkpoint blockade and TNF superfamily costimulation in a single molecule, which may uniquely poise macrophages in the TME for activation and cross-presentation of tumor antigens following enhanced tumor cell phagocytosis.
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Olaniru, Oladapo E., Jordan Cheng, Julia Ast та ін. "SNAP-tag-enabled super-resolution imaging reveals constitutive and agonist-dependent trafficking of GPR56 in pancreatic β-cells". Molecular Metabolism 53 (листопад 2021): 101285. http://dx.doi.org/10.1016/j.molmet.2021.101285.
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Hatao, Fumihiko, Naoki Hiki, Yoshikazu Mimura, et al. "THE INDUCTION OF SUPER-RESISTANCE USING SYNTHETIC LIPOPOLYSACCHARIDE RECEPTOR AGONIST RESCUES FATAL ENDOTOXEMIA IN RATS WITHOUT EXCESSIVE IMMUNOSUPPRESSION." Shock 23, no. 4 (2005): 365–70. http://dx.doi.org/10.1097/01.shk.0000158961.01456.b9.
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Sato, K., S. Cavallin, K. T. Sato, and F. Sato. "Secretion of Ions and Pharmacological Responsiveness in the Mouse Paw Sweat Gland." Clinical Science 86, no. 2 (1994): 133–39. http://dx.doi.org/10.1042/cs0860133.
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1. Some of the basic functional features of the mouse paw eccrine sweat gland were delineated to allow comparison with those of transgenic mice in the future. 2. The mouse sweat secretory coil responds to methacholine, elaborating a K+-rich (> 120 mmol/l), Na+-poor (< 70 mmol/l) primary fluid as does the rat paw sweat gland, as previously reported. The methacholine-induced sweat rate increases with age in parallel with the growth of the sweat gland over the first 6 weeks of life. 3. The sweating response to cyclic AMP-elevating agents, such as isoprenaline or forskolin, is as much as 40% of the methacholine-induced sweat rate at 1 week of age, but falls to 10% by 6 weeks of age despite the fact that the agonist-induced tissue accumulation of cyclic AMP expressed on a per μg of protein basis triples with age over the same period. 4. A marked K+ outflux was also noted in response to methacholine and a small K+ outflux was seen in response to cyclic AMP-elevating agonists in super-fused adult mouse secretory coils in vitro. 5. Since sweat secretion is usually associated with activation of either K+ channels or Cl− channels or both, and since the sweating occurred in response to cyclic AMP-elevating agonists, we speculate that the cyclic AMP-activated Cl− channels (the mouse version of the cystic fibrosis transmembrane conductance regulator) may also occur in the mouse sweat gland, but that the degree of their expression may be influenced by the age of the mice.
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Smelt, Charles L. C., Victoria R. Sanders, Alin M. Puinean, Stuart J. Lansdell, Jim Goodchild, and Neil S. Millar. "Agonist and antagonist properties of an insect GABA-gated chloride channel (RDL) are influenced by heterologous expression conditions." PLOS ONE 16, no. 7 (2021): e0254251. http://dx.doi.org/10.1371/journal.pone.0254251.
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Pentameric ligand-gated ion channels (pLGICs) activated by the inhibitory neurotransmitter γ-aminobutyric acid (GABA) are expressed widely in both vertebrate and invertebrate species. One of the best characterised insect GABA-gated chloride channels is RDL, an abbreviation of ‘resistance to dieldrin’, that was originally identified by genetic screening in Drosophila melanogaster. Here we have cloned the analogous gene from the bumblebee Bombus terrestris audax (BtRDL) and examined its pharmacological properties by functional expression in Xenopus oocytes. Somewhat unexpectedly, the sensitivity of BtRDL to GABA, as measured by its apparent affinity (EC50), was influenced by heterologous expression conditions. This phenomenon was observed in response to alterations in the amount of cRNA injected; the length of time that oocytes were incubated before functional analysis; and by the presence or absence of a 3’ untranslated region. In contrast, similar changes in expression conditions were not associated with changes in apparent affinity with RDL cloned from D. melanogaster (DmRDL). Changes in apparent affinity with BtRDL were also observed following co-expression of a chaperone protein (NACHO). Similar changes in apparent affinity were observed with an allosteric agonist (propofol) and a non-competitive antagonist (picrotoxinin), indicating that expression-depended changes are not restricted to the orthosteric agonist binding site. Interestingly, instances of expression-dependent changes in apparent affinity have been reported previously for vertebrate glycine receptors, which are also members of the pLGIC super-family. Our observations with BtRDL are consistent with previous data obtained with vertebrate glycine receptors and indicates that agonist and antagonist apparent affinity can be influenced by the level of functional expression in a variety of pLGICs.
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Melo, Bruno Silva, Fabianne Ribeiro, Althiéris S. Saraiva, et al. "The multigenerational effects of clothianidin on Chironomus xanthus: Larvae exposed to this acetylcholine super agonist show no clear resistance." Ecotoxicology and Environmental Safety 245 (October 2022): 114092. http://dx.doi.org/10.1016/j.ecoenv.2022.114092.
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Otegbeye, Folashade, Nathan Mackowski, Evelyn Ojo, Stephen Moreton, Marcos de Lima, and David Wald. "Enhancing the Functional Activity of Natural Killer Cells Against Myeloid Leukemia with the IL-15 Super-Agonist, ALT-803." Biology of Blood and Marrow Transplantation 22, no. 3 (2016): S144. http://dx.doi.org/10.1016/j.bbmt.2015.11.485.
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M, Shirakawa, Kanamoto Y, Nagaoka H, Honda H, and Bando H. "Diabetic cases controlled with low carbohydrate diet (LCD) and GLP-1 receptor agonist (GLP-1 RA)." Asploro Journal of Biomedical and Clinical Case Reports 2, S1 (2019): 38–46. http://dx.doi.org/10.36502/2019/asjbccr.6137.
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Recent treatment for type 2 diabetes mellitus (T2DM) has included glucagon-like peptide-1 receptor agonist (GLP-1 RA), indicating clinical efficacy for better glucose variability. Subjects were seven patients with T2DM associated with the obese tendency. Their average age was 63.8 ± 21.7 years old (5 males, 2 females) who received a new administration of GLP-1 RA (Mean ± standard deviation). For GLP-1 RA, dulaglutide (TRULICITY R, single-dose pen) was administered by subcutaneous injection 0.75 mg once a week. Basal data at 0 month revealed that body weight 76.0 ± 11.6 kg, body mass index (BMI) 29.2 ± 11.6, blood C-peptide immunoreactivity (CPR) 2.68 ± 0.49 ng/mL, respectively. After the intervention of dulaglutide, decreased value of BMI for 3 and 6-9 months was 0.78 ± 0.45 and 1.16 ± 0.85, and HbA1c for 3 and 6-9 months was 1.60 ± 1.52% and 2.01 ± 1.44%, respectively. Though these cases have various complications besides T2DM, they showed clinical effects of weight reduction and lowering blood glucose. Diabetic treatment for current cases would suggest that GLP-1 RA would be effective in various situations such as a super-aged patient, medical practice in the remote area, family care and visiting nursing.
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Ciortea, Viorela Mihaela, Irina Motoașcă, Ileana Monica Borda, et al. "Effects of High-Intensity Electromagnetic Stimulation on Reducing Upper Limb Spasticity in Post-Stroke Patients." Applied Sciences 12, no. 4 (2022): 2125. http://dx.doi.org/10.3390/app12042125.
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Super Inductive System (SIS) stimulation of spastic limbs by tissue-induced electromagnetic field may have the effect of reducing spasticity and improving functionality in patients with post-stroke spasticity. The aim of the study was to evaluate two different protocols for the application of SIS on upper limb spasticity after stroke. We included 60 patients with post-stroke upper limb spasticity, who were randomized into two groups: the study group, with a 9 min application protocol (1 min for agonist muscles, 8 min for antagonistic muscles); and the control group, with an 8 min protocol applied only to the antagonistic muscles. The duration of therapy was 10 days, and the results were assessed using the Modified Ashworth Scale (MAS) and the Barthel Index. Both the MAS and the Barthel Index improved significantly after 10 days of treatment (p < 0.001), but 30 days after the completion of therapy, there was an attenuation of the effects in both study groups. The study group had a significantly higher percentage of patients with improved MAS after 10 days (p = 0.004) and within 30 days (p < 0.001) than the control group. An SIS protocol applied on both agonist and antagonist muscles has a more pronounced and longer lasting spasticity-reducing and improved functionality effect than its application on only antagonistic muscles.
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Redmond, William, Todd Triplett, Kevin Floyd, and Andrew Weinberg. "Dual TCR/common gamma chain cytokine signaling regulates OX40 expression and synergizes with OX40 ligation to augment anti-tumor immunity (66.42)." Journal of Immunology 186, no. 1_Supplement (2011): 66.42. http://dx.doi.org/10.4049/jimmunol.186.supp.66.42.
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Abstract The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of the OX40 receptor can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, several agonist OX40-specific agents are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, whether additional downstream signals are needed to regulate OX40 remains unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2R-directed cytokine therapy synergized to augment anti-tumor immunity by reviving the anti-tumor efficacy of anergic tumor-reactive CD8 T cells in vivo. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 receptor expression and demonstrate a novel means of augmenting cancer immunotherapy by restoring the function of tumor-specific T cells.
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Otegbeye, Folashade, Nathan Mackowski, Evelyn Ojo, Marcos De Lima, and David N. Wald. "The IL-15 Super-Agonist ALT-803 Promotes Superior Activation and Cytotoxicity of Ex Vivo Expanded NK Cells Against AML." Blood 126, no. 23 (2015): 3090. http://dx.doi.org/10.1182/blood.v126.23.3090.3090.
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Abstract Introduction: A crucial component of the innate immune response system, natural killer (NK) cells are uniquely competent to mediate anti-myeloid leukemia responses. NKG2D is an activating receptor on the surface of NK cells that engages stress ligands MICA and MICB, typically upregulated on myeloid leukemia cells. Adoptive transfer of NK cells is a promising treatment strategy for AML. Strategies to optimize the anti-leukemia effect of NK cell adoptive transfer are an area of active research. These include attempts to enhance NK cell activity and to maintain the activation status and proliferation of the NK cells in vivo. Traditionally, IL-2 has been used to maintain the in vivo proliferation of adoptively transferred NK cells, but it leads to unwanted proliferation of regulatory T cells and suboptimal NK cell proliferation. IL-15 may be superior to IL-2, without the effects on T regulatory cells. The IL-15 superagonist, ALT-803 exhibits >25 fold enhancement in biological activity as compared to IL-15. ALT-803 is a fusion protein of an IL-15 mutant and the IL-15Rα/Fc complex that has recently entered clinical trials as a direct immunomodulatory agent in cancer clinical trials We hypothesized ALT-803 would augment the activity and/or proliferation of adoptively transferred NK cells in vitro and in a mouse model system.. Methods: Human NK cells were isolated from healthy donor peripheral blood and were expanded over a 21-day period in co-culture with irradiated K562 cells genetically modified to express membrane-bound IL-21. (Somanchi et al. 2011 JoVE 48. doi: 10.3791/2540) The NK cells were expanded with IL-2 (50mU/mL) and/or ALT-803 (200ng/mL). On Day 21, NK cells were examined for cytotoxicity against AML cells as well as by flow cytometry for expression of known activating receptors. An NSG murine xenograft model of human AML was developed to test the in vivo function of NK cells expanded above. Briefly, NSG mice (n=5 per group) were non-lethally irradiated and each injected IV with 5 x106 OCI-AML3 leukemic cells. Two days later, each mouse received weekly NK cell infusions for 2 weeks. Mice that received NK cells expanded with IL2 got cytokine support with IL-2 (75kU IP three times a week). Mice infused with ALT-803 expanded cells (alone or in combination with IL2) received ALT-803 (0.2mg/kg IV weekly). One control group received OCI cells but were infused weekly only with 2% FBS vehicle, no NK cells. Leukemic burden in each mouse was assessed by flow cytometry of bone marrow aspirates on day 28 following start of NK cell infusions). This time point was chosen as the control mice appeared moribund. Results: ALT-803 did not have any differential effect on the proliferation of the NK cells ex vivo as compared to IL-2. However, the presence of ALT-803 either alone or in combination with IL-2 resulted in a significant increase (30% increase, p<0.0001) in the cytotoxic activity of the NK cells against leukemia cells as compared with IL-2 alone in vitro (figure 1). In addition, the percentages of NK cells that express the activating receptor NKG2D as well as CD16 were significantly higher (p<0.001 for both) after ALT-803 exposure (figure 1). Finally, in the murine xenograft AML model, ALT-803 expanded NK cells, which were also supported in vivo with ALT-803, resulted in an 8-fold reduction in disease burden in the bone marrow (p<0.0001). Importantly the efficacy of NK cells in the ALT-803 injected mice was significantly higher (3-fold, p= 0.0447) than IL-2 treated mice (figure 2). Discussion: Our results suggest that the presence of ALT-803 during ex-vivo expansion of NK cells results in increased activation and cytotoxicity against AML cells. In addition our results using a murine model of human AML show that the use of ALT-803 in combination with adoptively transferred NK cells provides a significant anti-leukemic benefit as compared to IL-2. Future studies to test larger panels of leukemia cells as well as other cancer cell lines are currently in progress. It is hoped that this work will lead to an improvement in the efficacy of adoptively transferred NK cells for AML patients due to an improvement in survival and activity of the NK cells. Disclosures Wald: Invenio Therapeutics: Equity Ownership.
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Niemczyk, Stanisław, Hanna Sikorska, Andrzej Więcek, et al. "A super-agonist of growth hormone–releasing hormone causes rapid improvement of nutritional status in patients with chronic kidney disease." Kidney International 77, no. 5 (2010): 450–58. http://dx.doi.org/10.1038/ki.2009.480.
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De Pascali, Francesco, Mohammed Akli Ayoub, Riccardo Benevelli, et al. "Pharmacological Characterization of Low Molecular Weight Biased Agonists at the Follicle Stimulating Hormone Receptor." International Journal of Molecular Sciences 22, no. 18 (2021): 9850. http://dx.doi.org/10.3390/ijms22189850.
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Follicle-stimulating hormone receptor (FSHR) plays a key role in reproduction through the activation of multiple signaling pathways. Low molecular weight (LMW) ligands composed of biased agonist properties are highly valuable tools to decipher complex signaling mechanisms as they allow selective activation of discrete signaling cascades. However, available LMW FSHR ligands have not been fully characterized yet. In this context, we explored the pharmacological diversity of three benzamide and two thiazolidinone derivatives compared to FSH. Concentration/activity curves were generated for Gαs, Gαq, Gαi, β-arrestin 2 recruitment, and cAMP production, using BRET assays in living cells. ERK phosphorylation was analyzed by Western blotting, and CRE-dependent transcription was assessed using a luciferase reporter assay. All assays were done in either wild-type, Gαs or β-arrestin 1/2 CRISPR knockout HEK293 cells. Bias factors were calculated for each pair of read-outs by using the operational model. Our results show that each ligand presented a discrete pharmacological efficacy compared to FSH, ranging from super-agonist for β-arrestin 2 recruitment to pure Gαs bias. Interestingly, LMW ligands generated kinetic profiles distinct from FSH (i.e., faster, slower or transient, depending on the ligand) and correlated with CRE-dependent transcription. In addition, clear system biases were observed in cells depleted of either Gαs or β-arrestin genes. Such LMW properties are useful pharmacological tools to better dissect the multiple signaling pathways activated by FSHR and assess their relative contributions at the cellular and physio-pathological levels.
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Brodovskaya, Anastasia, Shinnosuke Shiono, and Jaideep Kapur. "Activation of the basal ganglia and indirect pathway neurons during frontal lobe seizures." Brain 144, no. 7 (2021): 2074–91. http://dx.doi.org/10.1093/brain/awab119.
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Abstract There are no detailed descriptions of neuronal circuit active during frontal lobe motor seizures. Using activity reporter mice, local field potential recordings, tissue clearing, viral tracing, and super-resolution microscopy, we found neuronal activation after focal motor to bilateral tonic-clonic seizures in the striatum, globus pallidus externus, subthalamic nucleus, substantia nigra pars reticulata and neurons of the indirect pathway. Seizures preferentially activated dopamine D2 receptor-expressing neurons over D1 in the striatum, which have different projections. Furthermore, the D2 receptor agonist infused into the striatum exerted an anticonvulsant effect. Seizures activate structures via short and long latency loops, and anatomical connections of the seizure focus determine the seizure circuit. These studies, for the first time, show activation of neurons in the striatum, globus pallidus, subthalamic nucleus, and substantia nigra during frontal lobe motor seizures on the cellular level, revealing a complex neuronal activation circuit subject to modulation by the basal ganglia.
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Daramola, Alfred S., Monika Perez, Oscar S. Sias-Garcia, et al. "Rara Is a Druggable Super-Enhancer Regulated Dependency in Pediatric AML." Blood 134, Supplement_1 (2019): 281. http://dx.doi.org/10.1182/blood-2019-125425.
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Introduction: New approaches to find and then drug pediatric acute myeloid leukemia (AML)-specific targets are clearly needed to help the nearly 35% of patients who still die from the disease. While RARA is a known druggable target in acute promyelocytic leukemia (APL), the utility of using retinoic acid agonists in non-APL AML has not proven consistently beneficial. Super enhancers (SEs), large regions of highly active chromatin, define cell state and cell identity by regulating oncogenes in many cancers. Recent enhancer profiling of 66 adult non-APL AML patient samples revealed SE-defined, prognostically relevant subgroups. An SE was detected at the retinoic acid receptor alpha (RARA) gene locus in 59% of the samples, which were sensitive to the second-generation retinoic acid agonist tamibarotene which has led to a phase II clinical trial. This study confirms that characterization of the chromatin-defined dependencies in specific cancers can pinpoint targets which can be drugged. We are delineating the transcriptional regulation of pediatric AML (pAML) by SE analysis, which has already elucidated deeper insights into pediatric leukemogenesis, as typified by strong RARA dependence in a majority of pAML. Methods: Three AML cell lines and 19 pAML primary samples were enhancer profiled by H3K27Ac chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq). SEs were detected and assigned to genes using the rank ordering of super-enhancers (ROSE) algorithm. Tamibarotene treatment of cell lines and patient samples were assessed for gene and protein expression changes and phenotypic differences. For in vivo assessment, 200,000 cells of a RARA SE+ pAML patient sample were injected into each NSGS mouse by tail-vein injection. One week after injection, tamibarotene (6mg/kg) or vehicle treatment was initiated by gavage (n=7 each arm). Peripheral blood monitoring of leukemia burden was determined flow cytometry. Results: The primary pAML sample cohort encompassed the diverse pAML cytogenetic subtypes (Fig 1a), with an overrepresentation of KMT2A rearrangements (n=9, 47%). The number of unique enhancer regions was nearly saturated in the 19 samples. Median SE size was 3,780bp, much larger than the 511bp of typical enhancers. When SE regions across all samples were clustered together, a RARA SE was seen in two of the ten clusters (Fig 1b). Eleven of the 19 samples (58%) contained a RARA SE, crossing multiple cytogenetic subtypes (Fig 1c). Tamibarotene treatment of RARA SE+ pAML cell lines and patient samples suppressed proliferation and increased apoptosis (detected by annexin V+), with minimal effect in Kasumi, a pAML cell line without a RARA SE (Fig 2a). In the RARA SE+ cell lines and samples only, tamibarotene increased CD38 (a myeloid differentiation marker usually suppressed by ligand-unbound RARA) (Fig 2b). High RARA mRNA levels confirmed the SE assignments in both cell lines and patient samples (Fig 2c). Tamibarotene induced the transcription of DHRS3 (another RARA target gene used as a pharmacodynamic biomarker in the adult tamibarotene phase II trial) (Fig 2d). Tamibarotene suppressed colony formation ability in RARA SE+ cell lines. An ongoing RARA SE+ patient-derived pAML xenograft confirmed tamibarotene markedly suppressed disease progression (Fig 3), with vehicle mice requiring euthanasia 42 days after tail-vein injection for significant disease burden, while the tamibarotene treated mice continued to be well-appearing at the same timepoint. Conclusion: We have profiled the enhancer landscapes of 19 primary pAML samples, the largest dataset of its kind, and seen a high frequency of a RARA SE in pAML. Tamibarotene has anti-proliferative, proapoptotic, and on-target pro-differentiation effects in RARA SE+ pAML in vitro and marked anti-leukemia activity in vivo. Given these positive findings, we are evaluating combinations of other AML-active agents with tamibarotene. Additionally, as there is a range of sensitivity to tamibarotene in RARA SE+ samples, we are also interrogating other SE-regulated genes interacting with RARA that may predict degree of response or resistance to tamibarotene. Our studies confirm that studying the transcriptional regulation of pAML samples through SE analysis can identify druggable targets and also lay the preclinical foundation for a biomarker-defined tamibarotene trial in pediatric AML. Disclosures Wei: NHI NHLBI Grant: Other: received funding . Lin:Syros Pharmaceuticals: Equity Ownership, Patents & Royalties.
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Raksaseri, Promporn, Varanuj Chatsudthipong, Chatchai Muanprasat, and Sunhapas Soodvilai. "Activation of liver X receptors reduces CFTR-mediated Cl− transport in kidney collecting duct cells." American Journal of Physiology-Renal Physiology 305, no. 4 (2013): F583—F591. http://dx.doi.org/10.1152/ajprenal.00579.2012.
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Liver X receptors (LXRs) are transcription factors belonging to the nuclear receptor super family, which act as regulators of lipid and glucose metabolism. However, LXRs have been shown to regulate the function of transporters in the kidney, including the Na-Pi cotransporter, organic anion transporter, and epithelial Na+ channel. In this report, we demonstrated the ability of LXR ligands, both endogenous [22 ( R)-hydroxycholesterol] and synthetic (T0901317 and GW3965), to reduce CFTR-mediated Cl− secretion in a type I Madin-Darby canine kidney (MDCK) cell line and in murine primary inner medullary collecting duct (IMCD) cells, based on measurements of [Arg8]-vasopressin-induced Cl− current. However, treatment of MDCK cell monolayers with 5 μM T0901317 for 24 h did not alter ouabain-senstive current or Na+-K+-ATPase-α protein content. Furthermore, basolateral membranes permeabilization of MDCK cell monolayers still resulted in a decrease in apical Cl− current stimulated by both [Arg8]-vasopressin and 8-cholorophenyl-thio-cAMP, indicating that the factor(s) encoded by the target gene(s) of agonist-activated LXRs might be located at the apical membrane. Western blot analysis revealed that inhibition of Cl− secretion occurred via a decrease in CFTR protein, which was not due to downregulation of its mRNA expression. In addition, both synthetic LXR agonists significantly retarded the growth of forskolin-induced cysts formed in MDCK cells cultured in collagen gel. This is the first evidence showing that ligand-activated LXRs are capable of downregulating CFTR-mediated Cl− secretion of kidney cells and of retarding cyst growth in a MDCK cell model.
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Yanlong, Song, Jiang Yinjun, Chen Ji, et al. "Effects of Secretoneurin and Gonadotropin-Releasing Hormone Agonist on the Spawning of Captive Greater Amberjack (Seriola dumerili)." Life 12, no. 9 (2022): 1457. http://dx.doi.org/10.3390/life12091457.
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The greater amberjack (Seriola dumerili), a pelagic marine species with a global distribution, has considerable worldwide potential as an aquaculture species. However, difficulties have been encountered in inducing spontaneous spawning in cultured fish stocks. In this study, we analysed the key regulatory factors, secretoneurin (SN) and gonadotropin-releasing hormone (GnRH), in greater amberjack. Active peptides of SN and GnRH, SdSNa, and SdGnRH, respectively, were obtained by comparative analysis of homologous proteins from different species. Amino acid substitutions of the SdGnRH decapeptide at position 6 with a dextrorotatory (D) amino acid and at position 10 with an ethylamide group yielded a super-active agonist (SdGnRHa). The injection of SdSNa and SdGnRHa elevated luteinizing hormone, thyroid-stimulating hormone, and oxytocin levels in the sera of sexually mature fish, whereas it reduced the level of follicle-stimulating hormone. Furthermore, in response to the SdSNa and SdGnRHa injections, we detected an increase in the expression of genes associated with oocyte development and spermatogenesis. We established that the greater amberjack cultured along the southern coast of China reached sexual maturity at three years of age, and its reproductive season extended from February to April. Spawning of the cultured greater amberjack was successfully induced with a single injection of SdGnRHa/SdSN/DOM/HCG. Our findings indicate that similar to GnRHa, SNa is a potential stimulator of reproduction that can be used to artificially induce spawning in marine fish.
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Frasca, Daniela, Gino Doria, Paola Barattini, et al. "Activation of gp130 signalingin vivo by the IL-6 super-agonist K-7 / D-6 accelerates repopulation of lymphoid organs after irradiation." European Journal of Immunology 29, no. 1 (1999): 300–310. http://dx.doi.org/10.1002/(sici)1521-4141(199901)29:01<300::aid-immu300>3.0.co;2-j.
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Hugues Beauchemin, Peiman Shooshtharizadeh, Jordan Pinder, Graham Dellaire, and Tarik Möröy. "Dominant negative Gfi1b mutations cause moderate thrombocytopenia and an impaired stress thrombopoiesis associated with mild erythropoietic abnormalities in mice." Haematologica 105, no. 10 (2019): 2457–70. http://dx.doi.org/10.3324/haematol.2019.222596.
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GFI1B-related thrombocytopenia (GFI1B-RT) is a rare bleeding disorder mainly caused by the presence of truncated GFI1B proteins with dominant-negative properties. The disease is characterized by low platelet counts, the presence of abnormal platelets, a megakaryocytic expansion and mild erythroid defects. However, no animal models faithfully reproducing the GFI1B-RT phenotype observed in patients exist. We had previously generated mice with floxed Gfi1b alleles that can be eliminated by Cre recombinase, but those animals developed a much more severe phenotype than GFI1B-RT patients and were of limited interest in assessing the disease. Using CRISPR/Cas9 technology, we have now established three independent mouse lines that carry mutated Gfi1b alleles producing proteins lacking DNA binding zinc fingers and thereby acting in a dominant negative (DN) manner. Mice heterozygous for these Gfi1b-DN alleles show reduced platelet counts and an expansion of megakaryocytes similar to features of human GFI1B-RT but lacking the distinctively large agranular platelets. In addition, Gfi1b-DN mice exhibit an expansion of erythroid precursors indicative of a mildly abnormal erythropoiesis but without noticeable red blood cell defects. When associated with megakaryocyte-specific ablation of the remaining allele, the Gfi1b-DN alleles triggered erythroid-specific deleterious defects. Gfi1b-DN mice also showed a delayed recovery from platelet depletion, indicating a defect in stress thrombopoiesis. However, injecting Gfi1b-DN mice with romiplostim, a thrombopoietin receptor super agonist, increased platelet numbers even beyond normal levels. Thus, our data support a causal link between DN mutations in GFI1B and thrombocytopenia and suggest that patients with GFI1B-RT could be treated successfully with thrombopoietin agonists.
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Kumar, Y. Shravan, R. Gowthami, Sujitha H, et al. "Formulation and Evaluation of Sumatriptan Succinate Fast Disintegrating Films and Tablets." International Journal of Pharmaceutical Sciences and Nanotechnology 6, no. 2 (2013): 2087–96. http://dx.doi.org/10.37285/ijpsn.2013.6.2.11.
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Sumatriptan succinate is a 5-HT1B/1D receptor agonist which has well established efficacy in treating migraine. The main objective of the study was to formulate Oral Fast Disintegrating Films (ODF) and Oral Fast Disintegrating Tablets (ODT) to achieve a better dissolution rate and further improving the bioavailability of the drug. ODFs were prepared by solvent casting method using film forming polymers like HPMC – E15,5cps,50cps in different ratios & prepared batches of films were evaluated for the drug content, film thickness, disintegration time and in vitro dissolution studies. Among the prepared formulation F7 containing HPMC – 50cps (drug: polymer ratios = 1:1) was found to be best formulations which releases 98.2±1.1of the drug within 17±0.02 sec. ODTs prepared by direct compression method using in different concentrations of super-disintegrants. The prepared formulation T12 (combination of disintegrants) containing CP + CCS (6%) was considered to be the best formulation, which releases up to 100±0.38% of the drug in 23±0.75 sec, respectively. Based on these results, it is suggested that ODFs have faster disintegration time and drug release than ODTs.
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Cook, Rachel J., Eytan Stein, David P. Steensma, et al. "A biomarker-directed phase 2 trial of SY-1425, a selective retinoic acid receptor alpha agonist, in adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)." Journal of Clinical Oncology 35, no. 15_suppl (2017): TPS7071. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps7071.
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TPS7071 Background: SY-1425 (tamibarotene) is an orally available, synthetic retinoid approved in Japan for the treatment of relapsed/refractory (R/R) APL. SY-1425 is a more potent and selective retinoic acid receptor alpha (RARα) agonist with improved pharmacologic properties compared to all-trans retinoic acid (ATRA) including increased half-life and lack of metabolism by CYP26A1 resulting in extended relative exposures. SY-1425 binding to RARα relieves pathogenic repression of myeloid differentiation. Super-enhancers associated with RARA and upregulation of RARA expression correlate with increased sensitivity to SY-1425 in vitro and predict for response to SY-1425 with induced differentiation and reduced proliferation in RARA-high PDX AML models, but not in RARA-low models. SY-1425 also induces the RARα target gene DHRS3 in RARA-high AML cell lines. This study is designed to demonstrate pharmacodynamic (PD) and clinical effects of SY-1425 in non-APL AML and MDS patients (pts) positive for the RARA super-enhancer associated biomarker or exploratory RARA pathway biomarker, IRF8. Methods: This study is enrolling pts with R/R AML, R/R higher-risk MDS, newly-diagnosed AML ≥60 yrs unlikely to respond to or tolerate standard therapy, and transfusion dependent lower-risk MDS pts without del 5q who are unlikely to respond to or have failed ESAs. Pts must be biomarker positive based on centralized testing of tumor cells from blood. All pts receive SY-1425 at 6 mg/m2/day PO with continuous twice daily dosing. Primary objectives are to characterize the activity of SY-1425 by ORR in AML and higher-risk MDS pts or transfusion independence in lower-risk MDS pts. Secondary objectives include event-free and relapse-free survival, duration of response, overall survival, hematologic improvement and safety. PD evaluation includes induction of DHRS3 and expression of myeloid differentiation markers. Target enrollment is 80 pts. This trial opened in September 2016. Through a protocol amendment, SY-1425 treatment in combination with azacitidine will also be evaluated. ClinicalTrials.gov identifier: NCT02807558.
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Horn, Lucas A., Kristen Fousek, Duane H. Hamilton, et al. "Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy." Cancers 13, no. 5 (2021): 968. http://dx.doi.org/10.3390/cancers13050968.
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Resistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhance antitumor efficacy through the expansion of tumor-reactive T cells. Utilizing murine models of colon and mammary carcinoma, here we investigated the effect of adding a recombinant adenovirus-based vaccine targeting tumor-associated antigens with an IL-15 super agonist adjuvant to a multimodal regimen consisting of a bifunctional anti-PD-L1/TGF-βRII agent along with a CXCR1/2 inhibitor. We demonstrate that the addition of vaccine induced a greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity. In addition to this enhancement of cytotoxic T cells, combination therapy showed a restructured tumor microenvironment with reduced Tregs and CD11b+Ly6G+ myeloid cells. Tumor-infiltrating immune cells exhibited an upregulation of gene signatures characteristic of a Th1 response and presented with a more diverse T-cell receptor (TCR) repertoire. These results provide the rationale for the addition of vaccine-to-immune checkpoint blockade-based therapies being tested in the clinic.
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Hu, Fen, Yali Zhao, Zhenhai Hui, et al. "Regulation of intracellular Ca2+/CaMKII signaling by TRPV4 membrane translocation during osteoblastic differentiation." Biophysics Reports 5, no. 5-6 (2019): 254–63. http://dx.doi.org/10.1007/s41048-019-00100-y.
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AbstractBone constantly remodels between resorption by osteoclasts and formation by osteoblasts; therefore the functions of osteoblasts are pivotal for maintaining homeostasis of bone mass. Transient receptor potential vanilloid 4 (TRPV4), a type of mechanosensitive channel, has been reported to be a key regulator in bone remodeling. However, the relationship between TRPV4 and osteoblast function remains largely elusive. Only little is known about the spatial distribution change of TRPV4 during osteoblastic differentiation and related signal events. Based on three-dimensional super-resolution microscopy, our results clearly showed a different distribution of TRPV4 in undifferentiated and differentiated osteoblasts, which reflected the plasma membrane translocation of TRPV4 along with prolonged differentiation. GSK1016790A (GSK101), the most potent agonist of TRPV4, triggered rapid calcium entry and calmodulin-dependent protein kinase II (CaMKII) phosphorylation via TRPV4 activation in a differentiation-dependent manner, indicating that the abundance of TRPV4 at the cell surface resulting from differentiation may be related to the modulation of Ca2+ response and CaMKII activity. These data provide compelling evidences for the plasma membrane translocation of TRPV4 during osteoblastic differentiation as well as demonstrate the regulation of downstream Ca2+/CaMKII signaling.
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Scesney, Susanne, and Alexander Ibraghimov. "In vitro cytokine release assays for commercially available biologics for predicting cytokine storm in human patients (P6321)." Journal of Immunology 190, no. 1_Supplement (2013): 184.22. http://dx.doi.org/10.4049/jimmunol.190.supp.184.22.
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Abstract Therapeutic antibodies undergo numerous safety tests to ensure in vivo safety. One required safety assay looks at the cytokine release from either human whole blood or human peripheral blood mononuclear cells (PBMC) when incubated with the therapeutic antibody. Recently TGN1412, a CD28 super-agonist antibody, while not causing cytokine release from purified PBMC, when administered in vivo, resulted in cytokine storm in all six volunteers. Since that incident, many laboratories have been working to design a cytokine release assay (CRA) that will show cytokine release in response to TGN1412. In this study we compare two CRA formats. In one assay, test antibody is coated to a polypropylene plate, then incubated with freshly purified PBMC for two days. In the second assay, human PBMC are pre-incubated at high density to make the cells more “lymph node like” (LNL) before incubation with soluble antibody. The response of PBMC from multiple donors to TGN1412 and multiple commercially available antibodies were compared. The plastic fixed antibody tends to generate exaggerated cytokine responses probably due to excessive crosslinking. The LNL format has the advantage of using soluble antibody which may better reflect how PBMC in vivo encounter antibody.
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Grigoriadis, N., and I. Grigoriadis. "LWPQ: an in silico designed multi-core super-agonist motif-like regulatory peptide for the activation of human stem cell transcripts using an integrated computational approach." Cytotherapy 16, no. 4 (2014): S59. http://dx.doi.org/10.1016/j.jcyt.2014.01.200.
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Dolanc, Dorian, Tomaž M. Zorec, Zala Smole, et al. "The Activation of GPR27 Increases Cytosolic L-Lactate in 3T3 Embryonic Cells and Astrocytes." Cells 11, no. 6 (2022): 1009. http://dx.doi.org/10.3390/cells11061009.
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G-protein-coupled receptors (GPCRs) represent a family with over 800 members in humans, and one-third of these are targets for approved drugs. A large number of GPCRs have unknown physiologic roles. Here, we investigated GPR27, an orphan GPCR belonging to the family of super conserved receptor expressed in the brain, with unknown functions. Cytosolic levels of L-lactate ([lactate]i), the end product of aerobic glycolysis, were measured with the Laconic fluorescence resonance energy transfer nanosensor. In single 3T3 wild-type (WT) embryonic cells, the application of 8535 (1 µM), a surrogate agonist known to activate GPR27, resulted in an increase in [lactate]i. Similarly, an increase was recorded in primary rat astrocytes, a type of neuroglial cell abundant in the brain, which contain glycogen and express enzymes of aerobic glycolysis. In CRISPR-Cas9 GPR27 knocked out 3T3 cells, the 8535-induced increase in [lactate]i was reduced compared with WT controls. Transfection of the GPR27-carrying plasmid into the 3T3KOGPR27 cells rescued the 8535-induced increase in [lactate]i. These results indicate that stimulation of GPR27 enhances aerobic glycolysis and L-lactate production in 3T3 cells and astrocytes. Interestingly, in the absence of GPR27 in 3T3 cells, resting [lactate]i was increased in comparison with controls, further supporting the view that GPR27 regulates L-lactate homeostasis.
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Zhou, Kai, Qi Zhong, Yan-Chun Wang та ін. "Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis". Journal of Cerebral Blood Flow & Metabolism 37, № 3 (2016): 967–79. http://dx.doi.org/10.1177/0271678x16648712.
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Inflammation mediated by the peripheral infiltration of inflammatory cells plays an important role in intracerebral hemorrhage (ICH) induced secondary injury. Previous studies have indicated that regulatory T lymphocytes (Tregs) might reduce ICH-induced inflammation, but the precise mechanisms that contribute to ICH-induced inflammatory injury remain unclear. Our results show that the number of Tregs in the brain increases after ICH. Inducing Tregs deletion using a CD25 antibody or Foxp3DTR-mice increased neurological deficient scores (NDS), the level of inflammatory factors, hematoma volumes, and neuronal degeneration. Meanwhile, boosting Tregs using a CD28 super-agonist antibody reduced the inflammatory injury. Furthermore, Tregs depletion shifted microglia/macrophage polarization toward the M1 phenotype while boosting Tregs shifted this transition toward the M2 phenotype. In vitro, a transwell co-culture model of microglia and Tregs indicated that Tregs changed the polarization of microglia, decreased the expression of MHC-II, IL-6, and TNF-α and increased CD206 expression. IL-10 originating from Tregs mediated the microglia polarization by increasing the expression of Glycogen Synthase Kinase 3 beta (GSK3β), which phosphorylates and inactivates Phosphatase and Tensin homologue (PTEN) in microglia, TGF-β did not participate in this conversion. Thus, Tregs ameliorated ICH-induced inflammatory injury by modulating microglia/macrophage polarization toward the M2 phenotype through the IL-10/GSK3β/PTEN axis.
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Shohreh, Rugia, Carlos A. Pardo, Federica Guaraldi, Andrew V. Schally, and Roberto Salvatori. "GH, But Not GHRH, Plays a Role in the Development of Experimental Autoimmune Encephalomyelitis." Endocrinology 152, no. 10 (2011): 3803–10. http://dx.doi.org/10.1210/en.2011-1317.
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GH has been suggested to influence the function of the immune system in several species. Experimental autoimmune encephalomyelitis (EAE) (an animal model for multiple sclerosis) has been reported not to occur in GH-deficient (GHD) mice. The aim of this study was to elucidate the effects of GH and GHRH replacement on development of EAE in a mouse model of isolated GHD due to removal of the GHRH gene [GHRH knockout (GHRHKO)]. We studied two groups of adult female mice: 12 GH-sufficient animals (control) and 36 GHRHKO animals. All mice were immunized with myelin oligodendrocyte glycoprotein peptide, a peptide known to induce EAE. GHRHKO mice were left untreated or were treated for 4 wk with daily sc injections of recombinant GH or of a GHRH super agonist JI-38 (JI38-GHD). Evaluation of EAE symptoms was carried out daily, and T-proliferative assay and histopathological analysis of the spinal cord were performed. GHRHKO mice were less prone to develop EAE when compared with control mice. GH (but not JI-38) restored the original susceptibility of mice to the disease, despite lack of complete serum IGF-I normalization. GH treatment was also associated with a markedly increase in spleen size and T-cell proliferation specific to myelin oligodendrocyte glycoprotein peptide. GH (but not GHRH) plays an important role in the development of EAE.
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Little, Alexander, Kari Gaither, Alisha McBride, et al. "Immune cell responses to combined treatment of murine melanoma with ALT-803 and Sunitinib in normal and chronic alcohol consuming mice (TUM2P.1032)." Journal of Immunology 194, no. 1_Supplement (2015): 69.29. http://dx.doi.org/10.4049/jimmunol.194.supp.69.29.
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Abstract The immune enhancing IL-15 super agonist ALT-803 and Sunitinib, a tyrosine kinase inhibitor that inhibits immunosuppressive myeloid derived suppressor cells (MDSC) and T regulatory (Treg) cells, were examined for their single and combined effects on immune cell phenotype in normal and chronic alcohol consuming (CAC) mice inoculated with s.c. B16BL6 melanoma. ALT-803 alone and in combination with Sunitinib initially increased CD8+CD44hi and CD8+CD44hiCD62Llo memory phenotype T cells in the spleen and PBL. IFN-γ producing CD8+CD44hi T cells increased in the spleen and the increase was more robust in CAC versus normal mice. These responses decayed during the later stages of tumor growth, and declined more rapidly in the CAC mice. Sunitinib alone did not affect CD8+ T cells or their IFN-γ production. Sunitinib alone and in combination with ALT-803 prevented the increase in CD11b+Gr-1int MDSC in the spleen associated with no treatment or ALT-803 treatment in normal mice; however, the effect was less pronounced in CAC mice where MDSC did not increase in the untreated group over time. MDSC in the PBL increased over time in untreated and ALT-803-treated normal mice. Sunitinib prevented this increase until the late stages of tumor progression. Sunitinib alone and in combination suppressed CD4+CD25+FoxP3+ Treg cells in the spleen during tumor progression.
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Yanaka-Okada, Saeko, Emiko Sano, Norio Naruse, et al. "Targeted-glycosylation of "non-core region" of interleukin-11 modulates its biological function. (57.15)." Journal of Immunology 186, no. 1_Supplement (2011): 57.15. http://dx.doi.org/10.4049/jimmunol.186.supp.57.15.
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Abstract Human interleukin-11 (hIL-11) is a pleiotropic cytokine administered to patients for recovering low platelet counts. From a structural point of view hIL-11 belongs to the long-helix cytokine superfamily, which is characterized by a conserved core motif consisting of four alpha-helices. We have investigated the region of hIL-11 that does not belong to the alpha-helical bundle motif, which we have termed “non-core region”. The interleukin was N- or O-glycosylated at specific positions within the non-core region, and the functional consequences of these modifications were examined in cell-based as well as biophysical assays. The data indicated that the non-core region modulates the function of hIL-11 in two ways. First, most of the muteins displayed enhanced cell-stimulatory properties (super-agonist behavior) in a glycosylation-dependent manner, suggesting that the non-core region is biologically designed to limit the cell-proliferative potential of hIL-11. Second, glycosylation of a predicted mini alpha-helix led to cytokine inactivation, demonstrating that this structural element interacts with a second gp130 receptor. These findings have unveiled new and unexpected elements modulating the biological activity of hIL-11, which may be exploited to develop more versatile medications based on this important cytokine. Yanaka S et al. J. Biol. Chem. in press. (2011)
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Obradović, Aleksandar Lj, Srđan Joksimović, Michael M. Poe, et al. "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects." Brain Research 1554 (March 2014): 36–48. http://dx.doi.org/10.1016/j.brainres.2014.01.036.
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Mercado, Jose, Rachael Baylie, Manuel F. Navedo, et al. "Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle." Journal of General Physiology 143, no. 5 (2014): 559–75. http://dx.doi.org/10.1085/jgp.201311050.
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Transient receptor potential vanilloid 4 (TRPV4) channels are Ca2+-permeable, nonselective cation channels expressed in multiple tissues, including smooth muscle. Although TRPV4 channels play a key role in regulating vascular tone, the mechanisms controlling Ca2+ influx through these channels in arterial myocytes are poorly understood. Here, we tested the hypothesis that in arterial myocytes the anchoring protein AKAP150 and protein kinase C (PKC) play a critical role in the regulation of TRPV4 channels during angiotensin II (AngII) signaling. Super-resolution imaging revealed that TRPV4 channels are gathered into puncta of variable sizes along the sarcolemma of arterial myocytes. Recordings of Ca2+ entry via single TRPV4 channels (“TRPV4 sparklets”) suggested that basal TRPV4 sparklet activity was low. However, Ca2+ entry during elementary TRPV4 sparklets was ∼100-fold greater than that during L-type CaV1.2 channel sparklets. Application of the TRPV4 channel agonist GSK1016790A or the vasoconstrictor AngII increased the activity of TRPV4 sparklets in specific regions of the cells. PKC and AKAP150 were required for AngII-induced increases in TRPV4 sparklet activity. AKAP150 and TRPV4 channel interactions were dynamic; activation of AngII signaling increased the proximity of AKAP150 and TRPV4 puncta in arterial myocytes. Furthermore, local stimulation of diacylglycerol and PKC signaling by laser activation of a light-sensitive Gq-coupled receptor (opto-α1AR) resulted in TRPV4-mediated Ca2+ influx. We propose that AKAP150, PKC, and TRPV4 channels form dynamic subcellular signaling domains that control Ca2+ influx into arterial myocytes.
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Shaikh Zinnat Ara Nasreen, Nusrat Mahjabeen, Naima Sharmin Haque, and Tasmia Chowdhury. "Fibroid: A common problem and its advanced management." Z H Sikder Women’s Medical College Journal 2, Number 2 (2020): 28–37. http://dx.doi.org/10.47648/zhswmcj.2020.v0202.06.
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Uterine fibroids are the most common gynaecological disorder, classically requiring surgery when symptomatic. Although attempts at finding a nonsurgical cure date back to centuries, it is only around the middle of the last century that serious attempts at a medical treatment were carried out. Initially, both progestins and estrogen–progestin combinations have been utilized, although proof of their usefulness is lacking. A major step forward was achieved when peptide analogues of the GnRH were introduced, first those with super agonist properties and subsequently those acting as antagonists. Because both types of analogues produce hypoestrogenism, their use is limited to a maximum of 6 months and, so they can’t be used routinely but utilized as an adjuvant treatment before surgery with overall good results. Over the last decade, new, nonpeptidic, orally active GnRH-receptor blockers Elagolix and another development of selective progesterone receptor modulators, sometimes referred to as “antiprogestins of choice is Ulipristal acetate are promising.Large clinical trials have proven the effectiveness of Ulipristal in the long-term medical therapy of fibroids, caution must taken for liver complications. All selective progesterone receptor modulators produce unique endometrial changes that are today considered benign, reversible, and without negative consequences. Long-term medical treatment of fibroids seems possible today, especially in premenopausal women. Surgical treatments are myomectomy, radiofrequency ablation procedure, endometrial ablation, uterine artery embolization, magnetic resonance-guided focused ultrasound myolysis are effective and reserved for the women who desires to keep uterus, and morcellation . Still Hysterectomy is the definitive treatment for fibroid and the techniques of surgery is inclining towards minimum invasive surgery.
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Kumar, Y. Shravan, Prashanthi Patel, Sravanthi Ch, and Rashmi B. "Formulation and Evaluation of Taste Masked Oral Disintegrating Tablets of Aripiprazole." International Journal of Pharmaceutical Sciences and Nanotechnology 8, no. 1 (2015): 2723–34. http://dx.doi.org/10.37285/ijpsn.2015.8.1.4.
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Aripiprazole is an atypical antipsychotic agent used for treatment of schizophrenia, bipolar disorder and major depressive disorders. In the present work, oral disintegrating tablets of aripiprazole were developed to enhance the patient compliance and provide rapid onset of action. The efficacy of aripiprazole is mediated through a combination of partial agonist activity at dopamine D2 and serotonin 5HT-1A receptors and antagonist activity at 5HT-2A receptors. It has a bitter taste and poor-solubility in water. Thus, the main objective of the study is to formulate taste masked oral disintegrating tablets of aripiprazole by using inclusion complex beta-cyclodextrin to achieve a better dissolution rate and further improving the bioavailability of the drug. Oral disintegrating tablets were prepared by direct compression method using super disintegrant like crospovidone, croscarmellose sodium, sodium starch glycolate and combinations of cros-povidone with croscarmellose sodium, and crospovidone with sodium starch glycolate in different concentrations. They were evaluated for the pre-compression parameters such as bulk density, compressibility, Hausner ratio and angle of repose. The prepared batches of tablets were evaluated for hardness, weight variation, thickness, friability, drug content, disintegration time, wetting time, in vitro dispersion time, and in vitro dissolution profile. All these parameters were found to be satisfactory. Among all, the formulation F15 containing crospovidone 5% + cros-povidone with croscarmellose sodium 5% was considered to be the optimum formulation, which released nearly 99% of the drug in 20 minutes with a disintegration time of 10. 20 seconds. These studies indicate the viability and benefits of oral disintegrating tablets of aripiprazole.
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Park, Jun, Cindy Chen, Victor Yeh, and Ross Booth. "Dynamic live cell imaging of immune cell interactions using microfluidics cell trap." Journal of Immunology 200, no. 1_Supplement (2018): 174.40. http://dx.doi.org/10.4049/jimmunol.200.supp.174.40.
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Abstract While providing indispensable insight into immune processes, the live cell imaging of immune cells poses unique challenges due to their non-adherent nature. Suspension cells such as immune cells can easily move away from the FOV (field of view) during imaging by any physical perturbations such as introduction of agonist or even simple media change, often necessitating the use of surface coating to artificially immobilize cells. In addition, unlike adherent cells, interacting suspension cells form aggregates, making it very difficult to track and analyze individual cells during imaging. Previously, we have described the novel microfluidic-based dynamic live cell imaging platform CellASIC ONIX2, where microenvironmental parameters such as the perfusion of media/reagent, temperature, and gas compositions can be precisely controlled on demand via software during the entire imaging experiment. We now report further utility of the system with a new non-adherent cell trap culture plate comprising an array of walled ~100μm square pads with a 12μm height restriction and 3μm wall gap, allowing physical trapping of immune cells within FOV while enabling their natural movement, and preventing vertical cell stacking of aggregated cells while preserving cell-cell interactions. Using Jurkat T cells and super antigen loaded Raji B cells, we demonstrate dynamic live cell imaging of immune cell interactions. Unlike systems where cells are artificially immobilized, we show that these cells are extremely motile and behave in much more complex and dynamic fashion during their interactions. The technology should benefit live cell imaging of any suspension cells and is amendable for wider applications in addition to immune cell imaging.
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Proietti-Cecchini, A., J. Áfra, and J. Schoenen. "Intensity Dependence of the Cortical Auditory Evoked Potentials as A Surrogate Marker of Central Nervous System Serotonin Transmission in Man: Demonstration of A Central Effect for the 5Ht1B/1D Agonist Zolmitriptan (311C90, Zomig®)." Cephalalgia 17, no. 8 (1997): 849–54. http://dx.doi.org/10.1046/j.1468-2982.1997.1708849.x.
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As shown in animal studies, 5HT1B/1D agonists can inhibit activity in the trigeminal nucleus caudalis, which may be advantageous for their antimigraine effect. To demonstrate a possible central nervous system (CNS) action of these compounds in man we studied their effect on the intensity dependence of the cortical auditory evoked potentials (IDAPs), thought to be inversely related to central serotonergic transmission. An amplitude/stimulus intensity function (ASF) slope was computed in healthy volunteers and migraine patients between attacks before and 2 h after oral 311C90 (zolmitriptan “Zomig”) 10 mg ( n=14), 311C90 5 mg ( n=7), sumatriptan 100 mg ( n=14), dexfenfluramine 15 mg ( n=4), lorazepam 1.25 mg ( n=4) and placebo ( n=14). 311C90 10 mg and, to a lesser degree, 5 mg significantly increased the mean ASF slope ( p=0.007 and 0.05 vs placebo). There was a significant positive correlation between plasma levels of 311C90 and ASF slope changes. Sumatriptan and lorazepam had little effect, but dexfenfluramine produced a significant ASF slope decrease. 311C90 is able to modify a CNS activity that is modulated by serotonin, i.e. the IDAP. This effect is probably the consequence of its super or lipophilicity compared to sumatriptan and of activation of prejunctional 5HT1B/1D autoreceptors, which lowers central serotonin release and thus the preactivation level of sensory cortices.