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1
Stutzmann, Martin. „Editorial: phys. stat. sol. (a) 201/5“. physica status solidi (a) 201, Nr. 5 (April 2004): 825. http://dx.doi.org/10.1002/pssa.200490006.
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Pasa, Andr� Avelino. „Preface: phys. stat. sol. (a) 201/5“. physica status solidi (a) 201, Nr. 5 (April 2004): 835–36. http://dx.doi.org/10.1002/pssa.200490008.
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Campbell, Phil G., und Dennis L. Andress. „Plasmin degradation of insulin-like growth factor-binding protein-5 (IGFBP-5): regulation by IGFBP-5-(201—218)“. American Journal of Physiology-Endocrinology and Metabolism 273, Nr. 5 (01.11.1997): E996—E1004. http://dx.doi.org/10.1152/ajpendo.1997.273.5.e996.
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Using the major bone insulin-like growth factor-binding protein (IGFBP) IGFBP-5, we took a mechanistic approach in evaluating the role of the heparin-binding domain of IGFBP-5 in regulating plasmin (Pm) proteolysis of IGFBP-5. Using synthetic IGFBP-5 peptide fragments, we determined that the heparin-binding domain, IGFBP-5-(208—218), inhibits Pm proteolysis of intact IGFBP-5. The mechanism of action of IGFBP-5-(201—218) was by inhibiting Pm binding to substrate IGFBP-5. IGFBP-5-(201—218) action was independent of site of proteolysis, fluid, or solid phase interaction. In addition, IGFBP-5-(201—218) was found to inhibit plasminogen (Pg) activation to Pm. IGFBP-5-(201—218) did not directly inhibit the activity of Pm, urokinase Pg activator (PA), or tissue-type PA but acted as a competitive inhibitor of Pg activation by PA, which is in contrast to the stimulating effect of heparin on Pg activation. These data indicate that the heparin-binding domain contains the serine protease (Pg-to-Pm) binding site region of IGFBP-5, and that this region, which is presumed to represent a Pm-induced proteolytic product of IGFBP-5, is capable of regulating Pm action.
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BISHINIOTIS, T. „5-Fluorouracil (5-FU) cardiotoxicity detected by dipyridamole thallium-201 cardiac imaging“. Journal of Nuclear Cardiology 4, Nr. 1 (Februar 1997): S41. http://dx.doi.org/10.1016/s1071-3581(97)91277-0.
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Rodriguez, María Jose, Javier Sarraseca, Jesús Fominaya, Elena Cortés, Antonio Sanz und J. Ignacio Casal. „Identification of an immunodominant epitope in the C terminus of glycoprotein 5 of porcine reproductive and respiratory syndrome virus“. Journal of General Virology 82, Nr. 5 (01.05.2001): 995–99. http://dx.doi.org/10.1099/0022-1317-82-5-995.
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Glycoprotein 5 (GP5) is the major glycoprotein of porcine reproductive and respiratory syndrome virus (PRRSV). Expression of GP5 has been improved by removing the transmembrane regions. Vectors were constructed encoding complete GP5 plus three mutants: GP5 ΔNs (residues 28–201), GP5[30–67] (residues 30–67) and GP5[30–201] (residues 30–67/130–201). The three deletion mutants were expressed at levels 20–30 times higher than complete GP5. GP5[30–201] was well recognized in ELISA or immunoblotting by a collection of pig sera. All the fragments were tested for the generation of MAbs, but only the polyhistidine-tagged fragment GP5[30–201]H elicited an antibody response sufficient to produce MAbs. The two MAbs were positive for PRRSV in ELISA and immunoblotting, but negative for virus neutralization. MAb 4BE12 reacted with residues 130–170 and MAb 3AH9 recognized residues 170–201. This region was recognized strongly in immunoblotting by a collection of infected-pig sera. These results indicate diagnostic potential for this epitope.
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Fu, Siqing, Lisle Nabell, Alexander T. Pearson, Rom Leidner, Douglas Adkins, Marshall R. Posner, Jorge J. Nieva et al. „Recommended phase 2 dose (RP2D) of HB-200 arenavirus-based cancer immunotherapies in patients with HPV16+ cancers.“ Journal of Clinical Oncology 40, Nr. 16_suppl (01.06.2022): 2517. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2517.
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2517 Background: Treatment options are limited for patients with recurrent or metastatic human papillomavirus 16 positive (HPV16+) cancers. Generation and maintenance of HPV16+ cancers requires stable expression of HPV16-specific E7 and E6 oncoproteins, which are also a source of tumor-specific immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuated vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein and infect antigen presenting cells to induce tumor-specific T cell responses. The Phase 1 part of this study of HB-200 therapy (HB-201 single-vector therapy and HB-202/HB-201 two-vector alternating therapy) was conducted to determine RP2D for further exploration alone or in combination with pembrolizumab. Methods: The Phase 1 part used a 3+3 dose escalation design with up to 3 dose levels (DLs) of HB-201 and 4 DLs of HB-202/HB-201 explored. Patients with HPV16+ head and neck squamous cell carcinoma (HNSCC) or with other HPV16+ cancers were evaluated. Safety, tolerability, immunogenicity, and preliminary antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST were assessed to determine RP2D. Results: As of January 2022, 65 patients with a median of 3 prior anticancer treatments have been enrolled in the Phase 1 part of the study. All had HPV16+ confirmed genotype; the most common primary site was oropharynx, followed by anal and cervix. Adverse events were generally mild or moderate. For HB-201, 3 DLs, 2 dosing schedules and 2 administration routes were assessed across 40 patients. At DL3 of HB-201 administered intravenously (IV), dose-limiting toxicity (DLT) occurred in 1/6 patients in the HNSCC group (Grade 4 encephalopathy, fully recovered) and 1/2 patients in the non-HNSCC group (Grade 3 rash, fully recovered). Preliminary safety, efficacy, and immunogenicity data support IV injection of DL3 (5 × 107 units) every 3 weeks (Q3W) as the RP2D for HB-201 single-vector therapy. For HB-202/HB-201, 4 DLs and 2 administration routes were assessed across 25 patients. At DL4 of HB-202/HB-201 IV, 1/5 subjects in the HNSCC group reported a DLT (Grade 4 hepatitis, recovering at time of discontinuation). RP2D for HB-202/HB-201 will be determined in the very near future. Tumor control, including partial response, have been observed in subjects treated with either HB-201 or HB-202/HB-201 as monotherapy. Conclusions: HB-201 and HB-202/HB-201 were generally well tolerated and showed preliminary antitumor activity in heavily pre-treated patients with HPV16+ solid tumors. DL3 was selected as RP2D for HB-201 monotherapy. In the Phase 2 part of the study a combination of HB-201 at 5 × 106 units IV Q3W with pembrolizumab is being tested in HPV16+ HNSCC patients. Clinical trial information: NCT04180215.
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Tsang, Kwong yok, Massimo Fantini, Sharon A. Mavroukakis, Anjum Zaki, Christina M. Annunziata und Philip M. Arlen. „Development and Characterization of an Anti-Cancer Monoclonal Antibody for Treatment of Human Carcinomas“. Cancers 14, Nr. 13 (21.06.2022): 3037. http://dx.doi.org/10.3390/cancers14133037.
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NEO-201 is an IgG1 humanized monoclonal antibody (mAb) that binds to tumor-associated variants of carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-5 and CEACAM-6. NEO-201 reacts to colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive against most normal tissues. NEO-201 can kill tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) to directly kill tumor cells expressing its target. We explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 can block the interaction between CEACAM-5 expressed on tumor cells and CEACAM-1 expressed on natural killer (NK) cells to reverse CEACAM-1-dependent inhibition of NK cytotoxicity. Previous studies have demonstrated safety/tolerability in non-human primates, and in a first in human phase 1 clinical trial at the National Cancer Institute (NCI). In addition, preclinical studies have demonstrated that NEO-201 can bind to human regulatory T (Treg) cells. The specificity of NEO-201 in recognizing suppressive Treg cells provides the basis for combination cancer immunotherapy with checkpoint inhibitors targeting the PD-1/PD-L1 pathway.
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Vidan, E., L. Kostakoglu, M. Coleman, D. Jillapalli, S. M. Philips, J. Leonard und S. J. Goldsmith. „FDG-PET versus Thallium-201 SPECT in the evaluation of putative CNS lymphoma in AIDS patients“. Journal of Clinical Oncology 24, Nr. 18_suppl (20.06.2006): 1537. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.1537.
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1537 Background: The evaluation of CNS lesions in AIDS patients is challenging as both CNS lymphoma and non-neoplastic lesions can have similar clinical presentations and imaging findings. Both Tl-201 SPECT and FDG PET imaging have been used to differentiate malignancy from infection. This study investigates the accuracy of FDG PET compared to Tl-201 SPECT in the diagnosis of CNS lymphoma in patients with AIDS-associated CNS lesions. Methods: Nine patients with AIDS who were found to have rim enhancing brain lesions on MRI underwent both Tl-201 SPECT and FDG PET imaging prior to diagnosis. Diagnosis was made by stereotactic brain biopsy in 6 pts and clinical follow-up in the remaining 3. FDG PET of the brain was performed using a dedicated PET/CT instrument (GE Discovery) 1 hour after 444 MBq FDG. Brain SPECT was performed on a dual head gamma camera (GE Hawkeye) with 185 MBq Tl-201. Images were reviewed along with MRI for anatomic correlation by 2 experienced nuclear medicine physicians blinded to the diagnosis. Results: 43 MRI lesions in 9 patients were evaluated. Clinically, 5 pts (18 lesions) were diagnosed with lymphoma (4 biopsy proven, 1 with known history of lymphoma), and 4 pts (25 lesions) were diagnosed with toxoplasmosis (2 with negative biopsies for malignancy, 2 with clinical course consistent with toxoplasmosis). FDG PET had true positive results for lymphoma in 5 of 5 pts, while Tl-201 SPECT was true positive in only 2 of 5. FDG PET had true negative results in 4 of 4 pts with toxoplasmosis, while Tl-201 had false positive results in 2 of 4. FDG PET had positive and negative predictive values of 100%, while Tl-201 SPECT had PPV 50% and NPV 40%. On a lesion basis, PET showed increased uptake of FDG in 8 of 18 brain lesions in patients with lymphoma, while SPECT showed increased uptake of Tl-201 in 4 of 18 lesions. Tl-201 was positive in 2 lesions in patients diagnosed with toxoplasmosis, while FDG had no false positive lesions. Conclusion: In this limited study, FDG PET proved to be superior to Tl-201 SPECT in the differentiation of CNS lymphoma from toxoplasmosis (overall accuracy 100% vs 44%, respectively). With the increasing availability of FDG PET, this test should probably supplant Tl-201 SPECT as the study of choice following conventional imaging (CT, MRI) of CNS lesions in AIDS patients. No significant financial relationships to disclose.
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Konstantinopolskii, Mark A., Larisa G. Kolik, Irina V. Chernyakova, Nelli M. Sazonova und Tatyana A. Gudasheva. „Antidrug effects of GTS201 dipeptide, an imitation of the second bird BDNF, in morphine-addicted rats“. Psychopharmacology & biological narcology 14, Nr. 3 (11.10.2023): 185–91. http://dx.doi.org/10.17816/phbn567968.
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BACKGROUND: The V.V. Zakusov Research Institute of Pharmacology developed hybrid digital sensors for the first, second, and fourth BDNF patches (GSB-214, GTSB-201, and GSB-106, respectively). When tested in vitro, on an oxidative stress model, in the culture of hippocampal neurons NT-22, the compound GTS201 (hexamethylenediamide bis-hexanoyl-seryl-lys), a simulator of the 2nd series of BDNF, activates the TrkB spy receptor and MAPK/Erk kinase pathway but does not affect the PI3K/Akt signature pathway and has neuroprotective activity similar to BDNF.
AIM: To study the effect of GTS-201 dipeptide on the behavior of laboratory white rats during the formation of their dependency state and morphine withdrawal syndrome.
MATERIALS AND METHODS: Morphine dependence in rats was developed due to administration of morphine in a doses escalation manner ranging from 10 to 20 mg/kg twice daily at 8-h intervals for 5 days. GTS-201 was given in 1- or 5-mg/kg doses for once in 30 minutes before morphine on the 5th day of the experiment or daily (in one of the groups) for 5 days in the morning 30 minutes before morphine administration. On the 5th day of the experiment, animals were tested for the presence of specific signs of morphine withdrawal syndrome in an open field for 5 minutes. Four experimental groups were formed: group 1 morphine hr. + naloxone (active control group); group 2 morphine hr. + GTS-201 (1) + naloxone; group 3 morphine hr. + GTS-201 (5) + naloxone; and group 4 morphine hr. + GTS-201 (1 5) + naloxone. Designations: hr. morphine administration within 5 days; (1) and (5) doses of substances in mg/kg, (1 5) chronic administration of the peptide for 5 days.
RESULTS: When studying the effect of GTS-201 dipeptide on behavioral, somatic, and neurological markers of animal behavior after morphine withdrawal, significant changes in the severity of individual signs of withdrawal syndrome were noted. Manifestations of diarrhea were significantly decreased in all groups of animals injected with the peptide. In animals from group 3, morphine hr. + GTS201 (5) + naloxone showed the maximum effect: diarrhea was decreased by 71.0% (p 0.001), convulsions were decreased by 83.3 % (p 0.05), running was decreased by 71.4% (p 0.01), and vocalization was decreased by 62.5% (p 0.05). GTS-201, administered at a dose of 1 mg/kg once, eliminated the appearance of escape attempts in group 2, but the peptide at the same dose completely blocked convulsive reactions in rats in group 4. Despite significant changes in individual indicators, the total index (of morphine withdrawal syndrome for groups chronically injected with morphine) did not change statistically significantly compared with group 1 of active control. In the control group, its value in points was 7.3 0.36 (100%), whereas in groups 24, it ranged from 6.2 (84.9%) to 6.5 (89.0%; p 0.05).
CONCLUSIONS: It is assumed that the antiaddictive dipeptide activity of GTS-201 is mediated by activation of these receptors and markers/the Erk-kinase signaling pathway, which does not exclude the involvement of opioid receptor mechanisms in the implementation of the observed behavioral phenomena.
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Abrass, Christine K., Anne K. Berfield und Dennis L. Andress. „Heparin binding domain of insulin-like growth factor binding protein-5 stimulates mesangial cell migration“. American Journal of Physiology-Renal Physiology 273, Nr. 6 (01.12.1997): F899—F906. http://dx.doi.org/10.1152/ajprenal.1997.273.6.f899.
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Insulin-like growth factor I (IGF-I) binding protein-5 (IGFBP-5) is produced by mesangial cells (MCs) and likely functions to modulate glomerular IGF-I activity. Although IGFBP-5 may be inhibitory for IGF-stimulated MC activity, preliminary studies suggested that IGFBP-5 acts directly on MCs. To investigate this further, we evaluated the effects of IGFBP-5 on rat MC migration. We found that the carboxy-truncated fragment, IGFBP-5-(1–169), inhibited IGF-I-stimulated migration, but intact IGFBP-5 simulated migration when IGF-I was not present. Demonstration that125I-labeled IGFBP-5 directly binds to MCs further supports an independent role for IGFBP-5. Because heparin inhibited MC binding of125I-IGFBP-5, we tested the heparin binding peptide, IGFBP-5-(201–218), for stimulatory activity. IGFBP-5-(201–218) stimulated MC migration, and this effect was inhibited by heparin. Because the disintegrin, kistrin, blocked IGF-I-induced migration but not migration induced by IGFBP-5-(201–218), the migratory induction mechanism for the two peptides is different. These data indicate that separate, specific regions of IGFBP-5 are responsible for interactive effects with IGF-I as well as direct effects on MC activity.
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Karami, Hossein, Mohammad Jabbari und Amir Haji Mohammad Mehdi Arbab. „Tubeless Percutaneous Nephrolithotomy: 5 Years of Experience in 201 Patients“. Journal of Endourology 21, Nr. 12 (Dezember 2007): 1411–14. http://dx.doi.org/10.1089/end.2007.0406.
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Campbell, Phil G., und Dennis L. Andress. „Insulin-like growth factor (IGF)-binding protein-5-(201—218) region regulates hydroxyapatite and IGF-I binding“. American Journal of Physiology-Endocrinology and Metabolism 273, Nr. 5 (01.11.1997): E1005—E1013. http://dx.doi.org/10.1152/ajpendo.1997.273.5.e1005.
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Insulin-like growth factor-binding protein-5 (IGFBP-5), the major bone IGFBP, modifies the biological activity of IGFs within the osteoblastic pericellular environment. Because glycosaminoglycans modulate IGFBP-5 binding to osteoblast organic extracellular matrix (ECM), we assessed whether the heparin binding domain of IGFBP-5, IGFBP-5-(102—218), modifies the interaction of IGFBP-5 with the inorganic bone ECM hydroxyapatite (HA). Synthetic IGFBP-5-(201—218) peptide increased the binding of IGFBP-5 to HA as well as the binding of IGF-I to HA-bound IGFBP-5. This action was specific for the heparin-binding domain, because IGFBP-5-(130—138), IGFBP-5-(138—152), and IGFBP-5-(1—169) were without effect. IGFBP-5-(201—218) was found to bind directly to IGFBP-5 and cause a threefold enhancement of the IGF-I binding affinity for IGFBP-5, whether IGFBP-5 was bound to HA or was in a matrix-free fluid phase. Heparin inhibited the binding of IGFBP-5 to HA and blocked the interaction of IGFBP-5 with IGFBP-5-(201—218) in the fluid phase, suggesting that the primary heparin-binding domain of IGFBP-5 specifically enhances the binding of IGFBP-5 to HA and increases IGF-I binding to IGFBP-5.
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Andress, Dennis L. „Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates phosphorylation of the IGFBP-5 receptor“. American Journal of Physiology-Endocrinology and Metabolism 274, Nr. 4 (01.04.1998): E744—E750. http://dx.doi.org/10.1152/ajpendo.1998.274.4.e744.
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The finding that insulin-like growth factor (IGF)-binding protein-5 (IGFBP-5) binding to mouse osteoblasts was capable of being downregulated by IGFBP-5 suggested that the 420-kDa membrane protein, which interacted with IGFBP-5, may be a signaling receptor (Andress, D. L. J. Biol. Chem. 270: 28289–28296, 1995). In the current study, a carboxy-terminal IGFBP-5 peptide, IGFBP-5-(201—218), which was found to competitively inhibit125I-IGFBP-5 binding and to specifically bind to osteoblast monolayers, was used to affinity-purify the 420-kDa membrane protein. Coincubation of the affinity-purified membrane protein with [32P]ATP resulted in autophosphorylation at serine residues. Serine phosphorylation of the 420-kDa protein was enhanced by intact IGFBP-5, IGFBP-5-(1—169), and IGFBP-5-(201—218). When the IGFBP-5 receptor was incubated with dephosphorylated casein in the presence of [32P]ATP, casein became phosphorylated on serine residues. These data indicate that IGFBP-5 stimulates the phosphorylation of the IGFBP-5 receptor and suggest that serine/threonine kinase activation may be important in mediating some of the IGF-independent effects of IGFBP-5.
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Rodriguez, Cilina, Dario A. Vitturi, Jin He, Marianne Vandromme, Angela Brandon, Anne Hutchings, Loring W. Rue, Jeffrey D. Kerby und Rakesh P. Patel. „Sodium nitrite therapy attenuates the hypertensive effects of HBOC-201 via nitrite reduction1“. Biochemical Journal 422, Nr. 3 (27.08.2009): 423–32. http://dx.doi.org/10.1042/bj20090735.
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Hypertension secondary to scavenging of NO remains a limitation in the use of HBOCs (haemoglobin-based oxygen carriers). Recent studies suggest that nitrite reduction to NO by deoxyhaemoglobin supports NO signalling. In the present study we tested whether nitrite would attenuate HBOC-mediated hypertension using HBOC-201 (Biopure), a bovine cross-linked, low-oxygen-affinity haemoglobin. In a similar way to unmodified haemoglobin, deoxygenated HBOC-201 reduced nitrite to NO with rates directly proportional to the extent of deoxygenation. The functional importance of HBOC-201-dependent nitrite reduction was demonstrated using isolated aortic rings and a murine model of trauma, haemorrhage and resuscitation. In the former, HBOC-201 inhibited NO-donor and nitrite-dependent vasodilation when oxygenated. However, deoxygenated HBOC-201 failed to affect nitrite-dependent vasodilation but still inhibited NO-donor dependent vasodilation, consistent with a model in which nitrite-reduction by deoxyHBOC-201 counters NO scavenging. Finally, resuscitation using HBOC-201, after trauma and haemorrhage, resulted in mild hypertension (~5–10 mmHg). Administration of a single bolus nitrite (30–100 nmol) at the onset of HBOC-201 resuscitation prevented hypertension. Nitrite had no effect on mean arterial pressure during resuscitation with LR (lactated Ringer's solution), suggesting a role for nitrite–HBOC reactions in attenuating HBOC-mediated hypertension. Taken together these data support the concept that nitrite can be used as an adjunct therapy to prevent HBOC-dependent hypertension.
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Minnie, Simone A., Nicole S. Nemychenkov, Shuichiro Takahashi, Christine R. Schmidt, Samuel RW Legg, Kathleen S. Ensbey und Geoffrey R. Hill. „The IL-2/IL-15 Mimetic NL-201 Prevents Myeloma Relapse after ASCT By Expanding Highly Cytolytic T Cells in the Bone Marrow That Are Resistant to Exhaustion“. Blood 138, Supplement 1 (05.11.2021): 1609. http://dx.doi.org/10.1182/blood-2021-153095.
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Abstract Multiple myeloma (MM) is a bone marrow (BM) resident hematological malignancy that is becoming increasingly recognized as one amenable to immunotherapy, although no therapies have yet provided durable, long-term disease control. Autologous stem cell transplantation (ASCT), the standard of care in eligible patients, provides a window for intervention with immunotherapy due to the induction of inflammation in the context of lymphodepletion at a time where there is also minimal residual disease and a disrupted tumor microenvironment (TME). We have previously established that the addition of T cells to BM grafts results in enhanced long-term myeloma control post-transplant in mice. Novel approaches aimed at improving and/or expanding the endogenous T cell response early post-ASCT may therefore prove highly effective with the benefit of avoiding ex vivo processing associated with other cellular therapies. To explore this, we utilized the IL-2/IL-15 mimetic NL-201: a de novo cytokine mimetic that signals via the beta and gamma subunits of the IL-2 receptor without engaging IL-2Rα (CD25). In pre-clinical studies, NL-201 has demonstrated the ability to signal to effector CD4 and CD8 T cells while avoiding the toxicity usually associated with IL-2 signaling via IL-2Rα. We hypothesized that NL-201 would enhance control of myeloma progression by stimulating T cell proliferation and activation early post-ASCT. We transplanted lethally irradiated Vk*MYC myeloma-bearing B6 recipients with BM and T cells graft from B6 donors and administered NL-201 from D+7 to week 6 (225 μg/kg weekly I.P). NL-201 promoted potent anti-myeloma immunity that was dependent on CD4 and CD8 T cells, but not NK cells (median survival was 68 days for control mice, unreached at >120 days for NL-201 alone or with NK depletion, 86 days for NL-201 with CD8 depletion, and 74 days with CD4 depletion; PBS vs NL-201 p<0.01; PBS vs NL-201 + αNK1.1 p<0.01; NL-201 vs NL-201 + αCD4 or αCD8 p<0.05). To further elucidate potential mechanisms of action we harvested BM from PBS and NL-201-treated mice 2 days after the last dose was administered and performed comprehensive immunophenotyping with high parameter flow cytometry. We grouped recipients based on whether they had controlled myeloma (MM-controlled) or had active disease progression at the time of harvest (MM-relapsed) to reveal immunological phenotypes that were dependent and independent of myeloma in the TME. In these experiments, all NL-201-treated recipients had controlled myeloma at time of harvest. Mechanistically, NL-201 significantly expanded the total number of CD8 T cells in the BM compared to PBS-treated mice with controlled or relapsed MM (PBS-treated mean CD8 T cell number was 1.0 x 10 5/femur vs 7.7 x 10 5/femur in NL-201-treated mice) but did not impact CD8 T cell number in peripheral blood. Memory CD8 T cells (CD44+CD62L+) were preferentially expanded, while the frequency of exhausted CD8 T cells (TOX +PD-1 +TIGIT +CD39 +; T EX) was reduced in NL-201-treated mice compared to both PBS-treated MM-relapsed and MM-controlled mice (75% T EX in PBS MM-relapsed, 15% PBS MM-controlled, 2% in NL-201; p<0.001). Surprisingly, >80% of the memory CD8 T cells in NL-201-treated mice produced granzyme B compared to <10% in PBS-treated mice. Granzyme B production was also observed in conventional CD4 T cells in response to NL-201 treatment, and the frequency of regulatory T cells was reduced by 50% after NL-201 compared to PBS MM-controlled and MM-relapsed mice (p<0.001). NL-201 expanded bone marrow resident cytotoxic memory CD8 and CD4 T cells that are resistant to exhaustion, whilst reducing the frequency of regulatory T cells in the BM TME. Together, these data highlight the promising therapeutic potential of NL-201 in multiple myeloma and support testing NL-201 in clinical trials for the treatment of hematological malignancies. Disclosures Hill: NapaJen Pharma: Consultancy; Roche: Research Funding; Syndax Pharmaceuticals: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Applied Molecular Transport: Research Funding; Compass Therapeutics: Research Funding; NeoLeukin Therapeutics: Consultancy; Generon Corporation: Consultancy.
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Febrianto, Andhika Hendrawan, und Am Mufarrih. „Pengaruh volume gas argon terhadap kekuatan tarik pada pengelasan GTAW SUS 201“. Jurnal Teknik Mesin Indonesia 18, Nr. 2 (01.10.2023): 105–11. http://dx.doi.org/10.36289/jtmi.v18i2.480.
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Gas Tungsten Arc Welding (GTAW) berupa tahap las busur yang memakai elektroda yang tidak meleleh. Proses pengelasan GTAW dilakukan dengan cara mencairkan filler rod ke benda yang akan dilas. Proses GTAW pada material stainless steel khususnya tipe SUS 201 belum mendapatkan kekuatan sambungan yang optimum. Maka dari itu, perlu adanya kajian tentang kekuatan tarik hasil pengelasan GTAW pada SUS 201. Tujuan dari kajian ini yaitu guna mengamati dampak volume gas argon pada ketangguhan tarik perolehan sambungan las GTAW material SUS 201. Dengan menggunakan metode eksperimental dan analisis data menggunakan ANOVA. Variabel bebas yang digunakan volume gas argon adalah 5, 10, dan 15 l/menit dengan replikasi tiga kali dan variabel terikat kekuatan tarik. Hasil kajian ini menunjukkan bahwa volume gas argon berpengaruh signifikan terhadap kekuatan tarik hasil las GTAW material SUS 201. Nilai kekuatan tarik maksimum hasil las GTAW dengan volume gas argon 15 l/m sebesar 630,86 MPa dan nilai terendah terdapat pada volume gas argon 5 l/m sebesar 499,46 MPa. Semakin besar volume gas argon, maka semakin besar kekuatan tarik. Dari pengamatan struktur mikro, diketahui bahwa volume gas argon 5 l/menit menunjukkan struktur mikro ferrit lebih dominan dibandingkan perlit, maka dinyatakan kekuatan tarik minimum. Sedangkan pada volume gas argon 15 l/menit, struktur mikro lebih dominan perlit dibandingkan ferrit, maka dinyatakan kekuatan tarik maksimum.
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Rahman, M. Mostafizur, Shaon Talukdar, Mohammad Asaduzzaman Chowdhury, Rasel Khan, Abdullah A. Masum und Nurul Islam. „Effects of Acetylene on Deposition Rate of Stainless Steels Using Thermal Chemical Vapor Deposition“. International Journal of Engineering Research in Africa 23 (April 2016): 7–12. http://dx.doi.org/10.4028/www.scientific.net/jera.23.7.
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A hot filament thermal chemical vapor deposition (CVD) reactor was used to deposit solid thin films on stainless steel 316 (SS 316) and stainless steel 201 (SS 201) substrates at different flow rates of acetylene (C2H2) gas. The variation of thin film deposition rate with the variation of gas flow rate has been investigated experimentally. During experiments are conducted under gas flow rate (1-5) lit/min gas flow rate, duration of deposition (10-60 min), pressure (0.2-1 bar), average surface roughness (0.3-1.05) µm and temperature 800 °C considered. Experimental results show that deposition rate on SS 316 and SS 201 increases with the increase in gas flow rate. The deposition rate also shows increasing trend with pressure and duration of deposition. Under the above mentioned experimental conditions deposition is found to be maximum of SS-316 compared to SS-201. In relation to roughness the maximum deposition is found at 0.5 microns but comparing the both materials -316 and-201 highest of deposition rate is obtained from SS-316.
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Snuggs, J., R. Senter, J. Whitt und C. Le Maitre. „PCRX-201, A NOVEL GENE THERAPY TREATMENT APPROACH FOR INTERVERTEBRAL DISC DEGENERATION“. Orthopaedic Proceedings 105-B, SUPP_9 (17.04.2023): 91. http://dx.doi.org/10.1302/1358-992x.2023.9.091.
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Low back pain affects 80% of the population with half of cases attributed to intervertebral disc (IVD) degeneration. However, the majority of treatments focus on pain management, with none targeting the underlying pathophysiological causes. PCRX-201 presents a novel gene therapy approach that addresses this issue. PCRX-201 codes for interleukin-1 receptor antagonist (IL-1Ra), the natural inhibitor of the pro-inflammatory cytokine IL-1, which orchestrates the catabolic degeneration of the IVD. Our objective here is to determine the ability of PCRX-201 to infect human nucleus pulposus (NP) cells and tissue to increase the production of IL-1Ra and assess downstream effects on catabolic protein production.Degenerate human NP cells and tissue explants were infected with PCRX-201 at 0 or 3000 multiplicities of infection (MOI) and subsequently cultured for 5 days in monolayer (n=7), 21 days in alginate beads (n=6) and 14 days in tissue explants (n=5). Cell culture supernatant was collected throughout culture duration and downstream targets associated with pain and degeneration were assessed using ELISA.IL-1Ra production was increased in NP cells and tissue infected with PCRX-201. The production of downstream catabolic proteins such as IL-1β, IL-6, MMP3, ADAMTS4 and VEGF was decreased in both 3D-cultured NP cells and tissue explants.Here, we have demonstrated that a novel gene therapy, PCRX-201, is able to infect and increase the production of IL-1Ra in degenerate NP cells and tissue in vitro. The increase of IL-1Ra also resulted in a decrease in the production of a number of pro-inflammatory and catabolic proteins, suggesting PCRX-201 enables the inhibition of IL-1-driven IVD degeneration. At present, no treatments for IVD degeneration target the underlying pathology. The ability of FX201 to elicit anti-catabolic responses is promising and warrants further investigation in vitro and in vivo, to determine the efficacy of this exciting, novel gene therapy.
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Boyko, Hanna, Natalia Puzrina, Anatoliy Bondar und Volodymyr Hryb. „Вплив мікробних агентів і біопрепаратів на їх основі на біометричні показники сіянців Pinus sylvestris L.“ Наукові праці Лісівничої академії наук України, Nr. 23 (29.12.2021): 68–78. http://dx.doi.org/10.15421/412128.
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Найвищі показники проростання насіння Pinus sylvestris L. в умовах in vitro виявлено за умов їхнього оброблення штамами Trichoderma viride 2016, Trichoderma lignorum 201. Менш ефективними виявилися штами Fusarium oxysporum 206, Fusarium sambucinum 16, Penicillium lanosum 201, Trichothecium roseum 2016. У лісовому розсаднику для передпосівного оброблення насіння найефективнішими виявилися Trichoderma viride 2016, Trichoderma viride 16, Trichoderma lignorum 201, Alternaria alternata 2016. Фітотоксичний вплив виявили штами Fusarium sambucinum 2016, Penicillium variabile 16, Penicillium lanosum 201, Aspergillus fumigatus 20, Aspergillus fumigatus 2016.
Оброблення насіння штамами Trichoderma viride 2016, Trichoderma viride 16 забезпечило збільшення висоти сіянців сосни на 15-19%, діаметра на кореневій шийці – на 10-21% та маси коренів – на 39-40%. Використання штамів Trichoderma lignorum 201, Alternaria alternata 2016 збільшило ці ж показники сіянців, порівняно з контролем, на 5-14, 5 та 37% відповідно.
Водна витяжка із мортмаси листків Corylus avellana сприяла збільшенню висоти сіянців на 19%, діаметра на кореневій шийці – на 15%, маси коренів – на 30%, порівняно із контролем. За оброблення насіння витяжкою із мортмаси листків Tilia cordata Mill. збільшення згаданих показників становило 13, 13 та 23% відповідно.
За оброблення насіння водною витяжкою із мортмаси листків Quercus robur L. та Alnus glutinosa Gaertn. ріст сіянців пригнічувався: їхня висота, порівняно з контролем, зменшилася на 23 і 13%, діаметр на кореневій шийці – на 29 і 11%, маса корінців – на 9 і 33%.
За оброблення насіння біопрепаратами Триходермін, Гаупсин, Планриз у лабораторних умовах, його якісні показники в усіх варіантах були вищими, ніж на контролі. У лісовому розсаднику за передпосівного оброблення насіння зазначеними вище біопрепаратами висота сіянців збільшилася на 5-19%, діаметр на кореневій шийці – на 10-21%, а маса коренів – на 38-53%, порівняно із контролем. Менш ефективними виявилися біопрепарати Мікосан-Н і Фітоспорин.
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Shiga, Hideaki, Hiroshi Wakabayashi, Kohshin Washiyama, Tomohiro Noguchi, Tomo Hiromasa, Sadaharu Miyazono, Masami Kumai et al. „Thallium-201 Imaging in Intact Olfactory Sensory Neurons with Reduced Pre-Synaptic Inhibition In Vivo“. Molecular Neurobiology 57, Nr. 12 (20.08.2020): 4989–99. http://dx.doi.org/10.1007/s12035-020-02078-y.
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Abstract In this study, we determined whether the 201Tl (thallium-201)-based olfactory imaging is affected if olfactory sensory neurons received reduced pre-synaptic inhibition signals from dopaminergic interneurons in the olfactory bulb in vivo. The thallium-201 migration rate to the olfactory bulb and the number of action potentials of olfactory sensory neurons were assessed 3 h following left side nasal administration of rotenone, a mitochondrial respiratory chain complex I inhibitor that decreases the number of dopaminergic interneurons without damaging the olfactory sensory neurons in the olfactory bulb, in mice (6–7 animals per group). The migration rate of thallium-201 to the olfactory bulb was significantly increased following intranasal administration of thallium-201 and rotenone (10 μg rotenone, p = 0.0012; 20 μg rotenone, p = 0.0012), compared with that in control mice. The number of action potentials was significantly reduced in the olfactory sensory neurons in the rotenone treated side of 20 μg rotenone-treated mice, compared with that in control mice (p = 0.0029). The migration rate of thallium-201 to the olfactory bulb assessed with SPECT-CT was significantly increased in rats 24 h after the left intranasal administration of thallium-201 and 100 μg rotenone, compared with that in control rats (p = 0.008, 5 rats per group). Our results suggest that thallium-201 migration to the olfactory bulb is increased in intact olfactory sensory neurons with reduced pre-synaptic inhibition from dopaminergic interneurons in olfactory bulb glomeruli.
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Ding, Wei, Wei-Wei Chen, Yi-Qin Wang, Xue-Zhong Xu, Yi-Bo Wang, Yong-Min Yan und Yu-Lin Tan. „Immune-related long noncoding RNA zinc finger protein 710-AS1-201 promotes the metastasis and invasion of gastric cancer cells“. World Journal of Gastrointestinal Oncology 16, Nr. 2 (15.02.2024): 458–74. http://dx.doi.org/10.4251/wjgo.v16.i2.458.
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BACKGROUND Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal system. ZNF710 is a transcription factor (TF), and zinc finger protein 710 (ZNF710)-AS1-201 is an immune-related long noncoding RNA (lncRNA) that is upregulated in GC cells. AIM To assess the correlation between ZNF710-AS1-201 and immune microenvironment features and to investigate the roles of ZNF710-AS1-201 in the invasion and metastasis processes of GC cells. METHODS We obtained data from The Cancer Genome Atlas and Wujin Hospital. We assessed cell growth, migration, invasion, and programmed cell death using cell counting kit-8, EdU, scratch, Transwell, and flow cytometry assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to identify the potential downstream targets of ZNF710-AS1-201. RESULTS In GC tissues with low ZNF710-AS1-201 expression, immunoassays detected significant infiltration of various antitumor immune cells, such as memory CD8 T cells and activated CD4 T cells. In the low-expression group, the half-maximal inhibitory concentrations (IC50s) of 5-fluorouracil, cisplatin, gemcitabine, and trametinib were lower, whereas the IC50s of dasatinib and vorinostat were higher. The malignant degree of GC was higher and the stage was later in the high-expression group. Additionally, patients with high expression of ZNF710-AS1-201 had lower overall survival and disease-free survival rates. In vitro, the overexpression of ZNF710-AS1-201 greatly enhanced growth, metastasis, and infiltration while suppressing cell death in HGC-27 cells. In contrast, the reduced expression of ZNF710-AS1-201 greatly hindered cell growth, enhanced apoptosis, and suppressed the metastasis and invasion of MKN-45 cells. The expression changes in ZNF710 were significant, but the corresponding changes in isocitrate dehydrogenase-2, Semaphorin 4B, ARHGAP10, RGMB, hsa-miR-93-5p, and ZNF710-AS1-202 were not consistent or statistically significant after overexpression or knockdown of ZNF710-AS1-201, as determined by qRT-PCR. CONCLUSION Immune-related lncRNA ZNF710-AS1-201 facilitates the metastasis and invasion of GC cells. It appears that ZNF710-AS1-201 and ZNF710 have potential as effective targets for therapeutic intervention in GC. Nevertheless, it is still necessary to determine the specific targets of the ZNF710 TF.
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Renner, Ulrich, Juri Mojto, Manfred Lange, O. Albrecht Müller, Klaus von Werder und Günter K. Stalla. „Effect of bromocriptine and SMS 201-995 on growth of human somatotrophic and non-functioning pituitary adenoma cells in vitro“. European Journal of Endocrinology 130, Nr. 1 (Januar 1994): 80–91. http://dx.doi.org/10.1530/eje.0.1300080.
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Renner U, Mojto J, Lange M, Albrecht Müller O. von Werder K, Stalla GK. Effect of bromocriptine and SMS 201-995 on growth of human somatotrophic and non-functioning pituitary adenoma cells in vitro. Eur J Endocrinol 1994;130:80–91. ISSN 0804–4643 The effect of the dopamine agonist bromocriptine and the somatostatin analog SMS 201-995 on growth of 12 human somatotrophic and 13 non-functioning adenoma cell cultures was investigated. When adenoma cells were maintained in medium supplemented with 5% fetal calf serum. cell counts of 10 of 12 somatotrophic cultures increased to 145±6 and 171 ±9% (mean±sd) and in 12 of 13 non-functioning cell cultures up to 125±12 and 217±15% after 3 days of incubation. In most cases bromocriptine and SMS 201-995 dose dependently (1 nmol/l to 10 μmol/l) inhibited adenoma cell growth but there was only (1.10 μmol/l) a significant inhibitory effect at high doses of both drugs. A 1 μmol/l concentration of bromocriptine decreased cell counts of 5 of 12 somatotrophic cell cultures (range 84±3 to 76±6% vs control = 100%) and in 5 of 13 non-functioning cell cultures (range 85±4 to 71 ± 7%). A 10 μmol/l concentration of bromocriptine decreased cell counts in all 12 somatotrophic (range 87±1 to 61 ±8%) and in 12 of 13 non-functioning adenoma cultures (range 87±6 to 57±3%). Bromocriptine specifically inhibited growth because its effect could be reversed by the dopamine D2-receptor antagonist haloperidol. Both 1 and 10 μmol/l SMS 201-995 significantly decreased cell counts in three of six somatotrophic (87± 3 to 38 ±3%) cell cultures. In two of five cases growth of non-functioning adenoma cultures was suppressed by 1 μmol/ISMS 201-995, and in four of five cases by 10 μmol/l(86± 3 to 74 ±4%). The growth inhibitory effect of both bromocriptine and SMS 201-995 was not just due to an effect on growth of fibroblasts contaminating the adenoma cell cultures, because it could be observed also when adenoma cells were maintained in a d-valine-supplemented medium that suppresses fibroblast growth. In summary, both bromocriptine and SMS 201-995 at high doses were able to inhibit cell growth of cultured somatotrophic and non-functioning adenomas in vitro. However, the mechanism of this inhibitory effect is not yet well understood. Ulrich Renner, Max-Planck-Institute of Psychiatry, Clinical Institute, Kraepelinstr. 10, D-80804 Munich, Germany
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Yu, Binglan, Gian Paolo Volpato, Keqin Chang, Kenneth D. Bloch und Warren M. Zapol. „Prevention of the Pulmonary Vasoconstrictor Effects of HBOC-201 in Awake Lambs by Continuously Breathing Nitric Oxide“. Anesthesiology 110, Nr. 1 (01.01.2009): 113–22. http://dx.doi.org/10.1097/aln.0b013e318190bc4f.
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Background Hemoglobin-based oxygen-carrying solutions (HBOC) provide emergency alternatives to blood transfusion to carry oxygen to tissues without the risks of disease transmission or transfusion reaction. Two primary concerns hampering the clinical acceptance of acellular HBOC are the occurrence of systemic and pulmonary vasoconstriction and the maintenance of the heme-iron in the reduced state (Fe2+). We recently demonstrated that pretreatment with inhaled nitric oxide prevents the systemic hypertension induced by HBOC-201 (polymerized bovine hemoglobin) infusion in awake mice and sheep without causing methemoglobinemia. However, the impact of HBOC-201 infusion with or without inhaled nitric oxide on pulmonary vascular tone has not yet been examined. Methods The pulmonary and systemic hemodynamic effects of breathing nitric oxide both before and after the administration of HBOC-201 were determined in healthy, awake lambs. Results Intravenous administration of HBOC-201 (12 ml/kg) induced prolonged systemic and pulmonary vasoconstriction. Pretreatment with inhaled nitric oxide (80 parts per million [ppm] for 1 h) prevented the HBOC-201--induced increase in mean arterial pressure but not the increase of pulmonary arterial pressure, systemic vascular resistance, or pulmonary vascular resistance. Pretreatment with inhaled nitric oxide (80 ppm for 1 h) followed by breathing a lower concentration of nitric oxide (5 ppm) during and after HBOC-201 infusion prevented systemic and pulmonary vasoconstriction without increasing methemoglobin levels. Conclusions These findings demonstrate that pretreatment with inhaled nitric oxide followed by breathing a lower concentration of the gas during and after administration of HBOC-201 may enable administration of an acellular hemoglobin substitute without vasoconstriction while preserving its oxygen-carrying capacity.
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Timsit, José, Philippe Chanson, Etienne Larger, Michèle Duet, Arlette Mosse, Pierre Jean Guillausseau, Alan G. Harris, Michel Moulonguet, André Warnet und Jean Lubetzki. „The effect of subcutaneous infusion versus subcutaneous injections of a somatostatin analogue (SMS 201-995) on the diurnal GH profile in acromegaly“. Acta Endocrinologica 116, Nr. 1 (September 1987): 108–12. http://dx.doi.org/10.1530/acta.0.1160108.
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Abstract. Multiple sc injections of a long-acting somatostatin analogue (SMS 201-995) are currently used in the treatment of acromegaly. However, plasma GH concentration often reaches a pathological level (> 5 μg/l) between two injections. In seven patients with active acromegaly we compared, in a short-term trial, the effect of SMS 201-995 administered by continuous sc infusion (50 μg and 100 μg a day) and by three scinjections (100 μg each). In six patients, plasma GH levels were significantly reduced regardless of the mode and dose of treatment (P < 0.05). However, comparing diurnal profiles, 100 μg continuous sc infusion was more effective than discontinuous administration in reducing the number of GH levels above 5 μg/l (P < 0.01). In two patients, continuous infusion was the only way to decrease all plasma GH values below 5 μg/l during the diurnal profile determination. Moreover, even when, in a long-term study, the dose of multiple injections was progressively increased to 500 μg three times a day, GH levels remained consistently elevated in one of these patients. Thus, in some acromegalic patients continuous sc injection seems currently the most efficient way of treatment with SMS 201-995.
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Kaneez, Fatima-Shad, und M. White. „Patch Clamp Study of Serotonin-Gated Currents via 5-HT Type 3 Receptors by Using a Novel Approach SHAM for Receptor Channel Scanning“. Journal of Biomedicine and Biotechnology 2004, Nr. 1 (2004): 10–15. http://dx.doi.org/10.1155/s1110724304302020.
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We studied 5-hydroxy tryptamine type 3 (5-HT3) receptors transfected in tsA-201 cell line to examine serotonin-induced whole cell currents. Using the site-directed mutagenesis technique, we individually mutated each residue in the membrane-spanning M2 segment to histidine. A high proportion of tsA-201 cells cotransfected with the cDNAs of 5-HT3R and CD8 produced large amplitude responses (0.5–7.0 nA) to serotonin. The dose-response curve of wild-type (WT) receptor ranging from 0.5 to 500μmole increases its Kdvalues, andImaxof 5-HT3R falls at low external pH as if protonation of an acid group is enough to block the channel. Lysine at position 281, a basic residue, is more susceptible to acidification-induced blockade of the 5-HT3R channel. Dose-response curves of K281S (replacing lysine at the 281 position with serine) at different pH are not significantly modulated, and histidine substitutions at the three consecutive positions 293, 294, and 296 eliminate the pH block of the channel.
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Колик, Лариса Геннадьевна, Анна Владимировна Надорова, Екатерина Михайловна Григоревских, Татьяна Александровна Гудашева und Сергей Борисович Середенин. „Экспериментальное изучение анксиолитической активности низкомолекулярных миметиков 1-й, 2-й и 4-й петель мозгового нейротрофического фактора“. Экспериментальная и клиническая фармакология 83, Nr. 11 (04.12.2020): 3–7. http://dx.doi.org/10.30906/0869-2092-2020-83-11-3-7.
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Изучены анксиолитические свойства димерных дипептидных миметиков 1-й (ГСБ-214), 2-й (ГТС-201) и 4-й (ГСБ-106) петель мозгового нейротрофического фактора (BDNF), взаимодействующих с TrkB-рецепторами и по-разному активирующих пострецепторные сигнальные пути. Впервые в тесте «Приподнятый крестообразный лабиринт» выявлены анксиолитические свойства соединений ГСБ-106 и ГТС-201 в диапазоне доз 0,1 – 5 мг/кг (внутрибрюшинно) при однократном введении и показана зависимость эффекта от дозы у мышей-самцов CD-1. Активация МАРК/ERK1/2 и PI3K/AKT путей определяет наиболее выраженный анксиолитический эффект ГСБ-106 в дозе 1 мг/кг, по сравнению с умеренным действием ГТС-201, преимущественно активирующим МАРК/ERK1/2 путь и отсутствием эффекта у ГСБ-214, влияющего на PI3K/AKT путь. Таким образом, проявление анксиолитической активности миметиков BDNF связано с активацией ERK1/2 и AKT сигнальных путей.
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Fantini, Massimo, Christina M. Annunziata, Philip M. Arlen und Kwong Y. Tsang. „Abstract 5654: A therapeutic humanized anti-carcinoma monoclonal antibody (mAb) NEO-201 can also target human granulocytic myeloid-derived suppressor cells (gMDSCs) and regulatory T (Tregs) cells“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 5654. http://dx.doi.org/10.1158/1538-7445.am2023-5654.
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Abstract Background: NEO-201 is a humanized IgG1 mAb reactive against multiple human cancers but not against most normal epithelial tissues. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells, including neutrophils, various carcinomas, and some human hematological malignancies. NEO-201 can mediate antitumor activity through antibody-dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and blockade of the CEACAM5/CEACAM1 ICI pathway. A previous study using flow cytometry demonstrated that NEO-201+/CD4+ T cells were also CD25+/CD127−/Foxp3+/CD15s+ using PBMCs from healthy donors (HD). NEO-201 can kill these Treg cells through CDC in vitro. NEO-201 does not bind to the majority of CD4+ T cells and to other immune subsets. Human gMDSCs are increased in cancer patients and are a population of immature MDSCs deriving from immature neutrophils and alternative activation of mature neutrophils. gMDSC are characterized by HLA-DR−, CD11b+, CD33+, CD15+phenotype.We have shown that NEO-201 recognizes and kill human neutrophils through ADCC. This current investigation was designed to evaluate whether NEO-201 can target and mediate ADCC activity against human gMDSCs. Methods: gMDSCs were generated from human neutrophils from 5 HD isolated using EasySepTM direct human neutrophil isolation kit. Isolated neutrophils were cultured in complete RPMI1640 medium supplemented with human GM-CSF and human IL-6 for 7 days. Phenotypic analysis by flow cytometry was performed on the generated gMDSCs using NEO-201 and mAbs against human CD33, HLA-DR, CD15, CD14, CD66b. Flow cytometry based ADCC assay was performed using gMDSCs stained with both CD33 and HLA-DR as target. PBMCs from a separate HD were used as effectors at different E:T ratios. The ADCC activity of NEO-201 was evaluated comparing the percentage of CD33+/HLA-DR− viable cells in gMDSCs incubated with medium alone to the percentage of CD33+/HLA-DR− viable cells incubated with PBMCs alone and with PBMCs plus NEO-201. Results: Flow cytometry analysis revealed that gMDSCs can be generated from human neutrophils after 7 days of culture with GM-CSF and IL-6 and that they express the following phenotype: HLA-DR−/CD33+/CD15+/CD14−/CD66b+. NEO-201 bound to the majority of these gMDSCs. NEO-201 was functional in mediating ADCC to kill these gMDSCs. Conclusion: This study demonstrated that NEO-201 can be used to identify and kill suppressive gMDSCs in addition to Treg cells. Depletion of suppressive Tregs and gMDSCs in the TME could be an effective strategy to prevent hyperprogressive disease when anti-PD-1 is used in cancer immunotherapy. These data support the rationale for the ongoing phase II clinical trial using NEO-201 in combination with pembrolizumab in checkpoint refractory patients with metastatic solid tumors. Citation Format: Massimo Fantini, Christina M. Annunziata, Philip M. Arlen, Kwong Y. Tsang. A therapeutic humanized anti-carcinoma monoclonal antibody (mAb) NEO-201 can also target human granulocytic myeloid-derived suppressor cells (gMDSCs) and regulatory T (Tregs) cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5654.
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Berry, Donald A., Shobha Dhadda, Michio Kanekiyo, David Li, Chad J. Swanson, Michael Irizarry, Lynn D. Kramer und Scott M. Berry. „Lecanemab for Patients With Early Alzheimer Disease“. JAMA Network Open 6, Nr. 4 (11.04.2023): e237230. http://dx.doi.org/10.1001/jamanetworkopen.2023.7230.
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ImportanceBayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only continue to increase. Innovations possible when using the bayesian approach improve the efficiency of drug development and the accuracy of clinical trials, especially in the context of substantial data missingness.ObjectiveTo explain the foundations, interpretations, and scientific justification of the bayesian approach in the setting of lecanemab trial 201, a bayesian-designed phase 2 dose-finding trial; to demonstrate the efficiency of using a bayesian design; and to show how it accommodates innovations in the prospective design and also treatment-dependent types of missing data.Design, Setting, and ParticipantsThis study was a bayesian analysis of a clinical trial comparing the efficacy of 5 lecanemab 201 dosages for treatment of early Alzheimer disease. The goal of the lecanemab 201 trial was to identify the effective dose 90 (ED90), the dose achieving at least 90% of the maximum effectiveness of doses considered in the trial. This study assessed the bayesian adaptive randomization used, in which patients were preferentially assigned to doses that would give more information about the ED90 and its efficacy.InterventionsPatients in the lecanemab 201 trial were adaptively randomized to 1 of 5 dose regimens or placebo.Main Outcomes and MeasuresThe primary end point of lecanemab 201 was the Alzheimer Disease Composite Clinical Score (ADCOMS) at 12 months with continued treatment and follow-up out to 18 months.ResultsA total 854 patients were included in trial treatment: 238 were in the placebo group (median age, 72 years [range, 50-89 years]; 137 female [58%]) and 587 were assigned to a lecanemab 201 treatment group (median age, 72 years [range, 50-90 years]; 272 female [46%]). The bayesian approach improved the efficiency of a clinical trial by prospectively adapting to the trial’s interim results. By the trial’s end more patients had been assigned to the better-performing doses: 253 (30%) and 161 (19%) patients to 10 mg/kg monthly and 10 mg/kg biweekly vs 51 (6%), 52 (6%), and 92 (11%) patients to 5 mg/kg monthly, 2.5 mg/kg biweekly, and 5 mg/kg biweekly, respectively. The trial identified 10 mg/kg biweekly as the ED90. The change in ADCOMS of the ED90 vs placebo was −0.037 at 12 months and −0.047 at 18 months. The bayesian posterior probability that the ED90 was superior to placebo was 97.5% at 12 months and 97.7% at 18 months. The respective probabilities of super-superiority were 63.8% and 76.0%. The primary analysis of the randomized bayesian lecanemab 201 trial found in the context of missing data that the most effective dose of lecanemab nearly doubles its estimated efficacy at 18 months of follow-up in comparison with restricting analysis to patients who completed the full 18 months of the trial.Conclusions and RelevanceInnovations associated with the bayesian approach can improve the efficiency of drug development and the accuracy of clinical trials, even in the context of substantial data missingness.Trial RegistrationClinicalTrials.gov Identifier: NCT01767311
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Nan, Jing, Shaoran Zhang, Ping Zhan und Ling Jiang. „Evaluation of Bronopol and Disulfiram as Potential Candidatus Liberibacter asiaticus Inosine 5′-Monophosphate Dehydrogenase Inhibitors by Using Molecular Docking and Enzyme Kinetic“. Molecules 25, Nr. 10 (14.05.2020): 2313. http://dx.doi.org/10.3390/molecules25102313.
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Citrus huanglongbing (HLB) is a destructive disease that causes significant damage to many citrus producing areas worldwide. To date, no strategy against this disease has been established. Inosine 5′-monophosphate dehydrogenase (IMPDH) plays crucial roles in the de novo synthesis of guanine nucleotides. This enzyme is used as a potential target to treat bacterial infection. In this study, the crystal structure of a deletion mutant of CLas IMPDHΔ98-201 in the apo form was determined. Eight known bioactive compounds were used as ligands for molecular docking. The results showed that bronopol and disulfiram bound to CLas IMPDHΔ98-201 with high affinity. These compounds were tested for their inhibition against CLas IMPDHΔ98-201 activity. Bronopol and disulfiram showed high inhibition at nanomolar concentrations, and bronopol was found to be the most potent molecule (Ki = 234 nM). The Ki value of disulfiram was 616 nM. These results suggest that bronopol and disulfiram can be considered potential candidate agents for the development of CLas inhibitors.
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MøLler, Niels, Guyla Petrany, David Cassidy, William L. Sheldon, Desmond G. Johnston und Michael F. Laker. „Effects of the somatostatin analogue SMS 201–995 (sandostatin) on mouth-to-caecum transit time and absorption of fat and carbohydrates in normal man“. Clinical Science 75, Nr. 4 (01.10.1988): 345–50. http://dx.doi.org/10.1042/cs0750345.
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1. Somatostatin analogues, such as SMS 201–995 (sandostatin), have been suggested as treatment for a variety of disease states including acromegaly, secretory gastrointestinal tumours and diabetes mellitus. 2. Somatostatin-14 has actions to prolong gastrointestinal transit time and inhibit intestinal absorption, and we have therefore studied the effects of SMS 201–995 on these processes. Five male subjects received a test meal having been given either saline or 50 μg of SMS 201–995 subcutaneously 30 min before ingestion. 3. SMS 201–995 caused a delay in mouth-to-caecum transit time for lactulose assessed by breath hydrogen analysis (316 ± 17 vs 192 ± 14 min, mean ±sem, P < 0.01), a delay (234 vs 120 min, P < 0.05) in the plasma peak of the non-metabolizable glucose analogue 3-O-methylglucose and conversion of the expected postprandial rise in serum triglycerides (with saline 1.02 ± 0.20 to 1.51 ± 0.28 mmol/l, P < 0.05) to a decrease below basal values (with SMS 201–995 0.97 ±0.80 to 0.79 ± 0.11 mmol/l, P < 0.05). 4. After SMS 201–995, an enhancement of the increase in blood glucose (8.2 ±0.7 vs 4.7 ±0.2 mmol/l, P < 0.01) and inhibition and postponement of the postprandial rise in insulin (27.6 ±6.7 vs 9.9 ±2.1 m-units/l, P < 0.05) occurred. Furthermore, a rise in non-esterified fatty acids, glycerol and 3-hydroxybutyrate, compared with the decline in concentrations of these metabolites after saline, was observed. 5. We conclude that SMS 201–995 has actions to increase mouth-to-caecum transit time, to diminish the rate of active monosaccharide absorption and to lower basal and postprandial triglyceride levels. These effects probably relate to inhibition of exo- and endo-crine gastrointestinal secretion.
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Massard, Christophe, Teuvo L. J. Tammela, Egils Vjaters, Vilnis Lietuvietis, Petri Bono, Heidi Penttinen, Pirjo Nykänen, Amir Snapir, Leena Mattila und Karim Fizazi. „A study of two ODM-201 formulations with a safety and tolerability extension phase in patients with metastatic chemotherapy-naive castration-resistant prostate cancer (CRPC).“ Journal of Clinical Oncology 32, Nr. 4_suppl (01.02.2014): 115. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.115.
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115^ Background: This open phase I trial assessed the bioavailability, and the effect of food on the bioavailability of ODM-201 600mg tablets compared to a 600mg capsule formulation. Efficacy, safety, and tolerability of ODM-201 were studied in the extension period. Methods: The study had two parts: a pharmacokinetic (PK), and a safety and tolerability part. Dosing was 600mg bid with or without food. In the PK part, three single doses of ODM-201 were given over 3 weeks. In the extension part patients could continue treatment until disease progression or until an intolerable adverse event or condition that prevented further dosing of ODM-201. Results: Thirty men with metastatic chemotherapy-naïve castration-resistant prostate cancer (CRPC) were enrolled, the median age was 68. The median prostate-specific antigen (PSA) was 18.2 ng/mL and testosterone 23.1 ng/dL at baseline. Food interaction was observed when ODM-201 formulations were administered after a high fat content breakfast compared to administration at fast. AUC and Cmaxvalues were about 50% lower after fast. Twenty nine patients have completed the 4-week visit. The PSA response rate (50% or more PSA decline) was 86%, with a median PSA decrease of -66% (-96, 5) at week 4 (N=18/21). Most commonly reported adverse events so far are fatigue, abdominal pain, diarrhea, hematuria, and nausea. Conclusions: ODM-201 600mg bid as tablets has comparable PK to capsules used in the phase II ARADES trial. It is well tolerated and has good PSA response in chemotherapy-naïve patients with CRPC . Clinical trial information: NCT01784757.
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te Lintel Hekkert, Maaike, Gregory P. Dubé, Evelyn Regar, Martine de Boer, Pascal Vranckx, Wim J. van der Giessen, Patrick W. Serruys und Dirk J. Duncker. „Preoxygenated hemoglobin-based oxygen carrier HBOC-201 annihilates myocardial ischemia during brief coronary artery occlusion in pigs“. American Journal of Physiology-Heart and Circulatory Physiology 298, Nr. 3 (März 2010): H1103—H1113. http://dx.doi.org/10.1152/ajpheart.00667.2009.
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Because of their ability to perfuse remote regions and deliver oxygen, hemoglobin-based oxygen carriers (HBOCs) may be considered in the treatment of several ischemic conditions such as acute coronary syndromes or high-risk percutaneous intervention. Here we studied the effects of intracoronary infusion of ex vivo preoxygenated HBOC-201 during brief total coronary artery occlusion (CAOs) on myocardial oxygenation and left ventricular (LV) function in a large animal model and investigated the influence of HBOC-201 temperature and infusion rate on these effects. Thirteen open-chest anesthetized swine were instrumented for measurement of global and regional LV function and metabolism. CAOs were induced by inflating an intracoronary balloon catheter; preoxygenated HBOC-201 (12 g/dL) was infused distally through the central lumen of the balloon catheter. Animals underwent consecutive 3-min CAOs interspersed by 30 min of reperfusion, accompanied by different HBOC-201 infusion rates (0, 15, 23, 30, 40, and 50 ml/min) and/or two infusion temperatures (18°C or 37°C) in random order. CAO elicited immediate loss of systolic shortening (SS) in the ischemic region (19 ± 1% at baseline vs. −3 ± 2% at end of CAO), resulting in decreases in maximum rate of rise in LV pressure (15 ± 5%) and stroke volume (12 ± 4%; all P < 0.05). Balloon deflation resulted in marked coronary reactive hyperemia (to 472 ± 74% of baseline), increases in coronary venous concentrations of adenosine + inosine (to 218 ± 26% of baseline; both P < 0.05) and rapid restoration of SS toward baseline. HBOC-201 ameliorated the CAO-induced changes in SS, stroke volume, reactive hyperemia, and coronary venous adenosine + inosine. The effects were temperature and flow dependent with full preservation of SS at 50 ml/min HBOC-201 of 37°C. In conclusion, intracoronary preoxygenated HBOC-201 preserved myocardial oxygenation and LV function in swine during CAO in a dose- and temperature-dependent manner. In our study setting, preoxygenated HBOC-201 can match the oxygen delivery role of endogenous blood in the heart on an almost equivalent-volume basis.
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Delord, J., P. Schöffski, E. Brain, H. Dumez, J. Robert, S. Faivre, V. Dubois, K. Vialatte, J. Deshayes und D. Ravel. „Results of a phase I study of DTS-201, a peptidic prodrug of doxorubicin, in patients with solid tumors“. Journal of Clinical Oncology 25, Nr. 18_suppl (20.06.2007): 2547. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2547.
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2547 Background: DTS-201 is a promising prodrug of doxorubicin (dox) designed to preferentially deliver the parent compound to tumor cells and to limit cardiotoxicity. Based on animal studies showing that DTS-201 was markedly safer and more active than conventional dox, a phase I trial was conducted to determine safety, pharmacokinetics and the recommended dose (RD) for phase II studies. Methods: DTS-201 was given as 1-hour infusion every 3 weeks. Four dose levels were tested: 80, 160, 250 and 400 mg/m2 equivalent to 45 to 225 mg dox/m2. Toxicity was evaluated according to CTCAE v3.0 with specific attention to cardiotoxicity assessed by troponin I, echocardiography or cardio MUGA scan and 12-lead ECG. Results: Nineteen cancer patients (pts) with solid tumors (age range: 30–72 yrs) received DTS-201. Tolerance was good at 80 and 160 mg/m2. Three dose limiting toxicities (DLTs) were observed at cycle 1, one at 250 mg/m2 (grade 3 diarrhea) and two at 400 mg/m2 (one grade 3 vomiting and one grade 4 neutropenia = 5 days). Myelosuppression was the most common toxicity with 5 of the 6 pts treated at 400 mg/m2 experiencing transient asymptomatic grade 3–4 neutropenia on day 15 that spontaneously resolved. Other adverse reactions included mild to moderate asthenia, alopecia, anorexia and nausea. Neither cardiotoxicity or dox unrelated toxicities were observed. Disease stabilization for more than 4 cycles was observed in three pts with prostate cancer, pleural mesothelioma or bronchoalveolar carcinoma at 250 and 400 mg/m2. The pt with prostate cancer treated at 250 mg/m2 experienced a 60% decrease in serum PSA and a 23% reduction in lymph node size. The plasma AUCs and Cmax for DTS-201 and dox increased linearly with dose. At 400 mg/m2, the AUC of dox was within the range of values observed in pts receiving 60 mg/m2 of conventional dox. However the Cmax of dox, observed at 1 to 1.5 hours following DTS-201 administration, was 20 to 25 times lower. Conclusion: DTS-201 was well tolerated up to 400 mg/m2, corresponding to 3.750-fold the standard dose of dox. This dose, with no evidence of cardiac toxicity, was proposed to be the RD for future phase II studies. Six additional pts will be treated at that dose level to better characterize safety. No significant financial relationships to disclose.
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Morelli, Maria Pia, Massimo Fantini, Kwong Y. Tsang, Phillip Arlen, Paulette Fauceglia, Lidia Hernandez, Soumya Korrapati, Elijah Edmonson, Christopher Cole und Christina M. Annunziata. „Abstract 4185: Targeting variant of CEACAM5 and CEACAM6 using NEO-201 and IL-15 in gynecologic cancers“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 4185. http://dx.doi.org/10.1158/1538-7445.am2022-4185.
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Abstract Background: Uterine and ovarian cancers express glycosylated forms of CEACAMs 5 and 6 that regulate interactions with the tumor microenvironment. NEO-201 is a novel monoclonal antibody that binds a glycosylated variant of these CEACAMs that is upregulated in cancer compared to normal uterine or ovarian epithelia. Previous work has shown that NEO-201 induced cancer cell death predominantly by antibody-dependent cellular cytotoxicity (ADCC) that can be enhanced by the addition of IL-15. Methods: NEO-201 target expression was assessed on uterine and ovarian cancer cell lines, as well as a tissue microarray of primary uterine cancer samples. Cell lines were profiled with DNA and RNA sequencing. Chromium-release assays were performed to quantify ADCC without and with varying concentrations of IL-15 and varying target to effector ratios. In vivomodeling was performed using ovarian cancer cell line OV90, and mice were treated with NEO-201, with PBMC or NK cells, with or without IL-15. Results: NEO-201 target antigen was highly expressed in uterine cancer cell line ACI158 and ovarian cancer cell line OV90. The antigen was expressed in primary uterine cancer samples as well. IL-15 consistently increased the in vitro killing of both cell lines and was further enhanced with the use of NK cells compared to PBMC. These findings were replicated in the in vivo mouse model, where mice survived longest with the combination of NEO-201, IL-15 and NK cells. Conclusions: The ADCC activity of NEO-201 monoclonal antibody was enhanced with the addition of IL-15, especially in the presence of purified NK cells. NEO-201 with IL-15 shows promising results as a potential treatment for biomarker-selected gynecologic cancers. Citation Format: Maria Pia Morelli, Massimo Fantini, Kwong Y. Tsang, Phillip Arlen, Paulette Fauceglia, Lidia Hernandez, Soumya Korrapati, Elijah Edmonson, Christopher Cole, Christina M. Annunziata. Targeting variant of CEACAM5 and CEACAM6 using NEO-201 and IL-15 in gynecologic cancers [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 4185.
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Pöllänen, Pirjo. „Sirpa Lappalainen, Pirkko Hynninen, Tarja Kankkunen, Elina Lahelma, Tarja Tolonen (eds). Etnografia metodologiana. Lähtökohtana koulutuksen tutkimus“. Suomen Antropologi: Journal of the Finnish Anthropological Society 33, Nr. 4 (01.01.2008): 102–3. http://dx.doi.org/10.30676/jfas.v33i4.116469.
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SIRPA LAPPALAINEN, PIRKKO HYNNINEN, TARJA KANKKUNEN, ELINA LAHELMA, TARJA TOLONEN (eds). Etnografia metodologiana. Lähtökohtana koulutuksen tutkimus. Vastapaino: Tampere, 2007. Pp. 283. ISBN 978-951-768-201-5 (paper).
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Hutchings, Anne, Celina Rodriguez, Richard George, Paula Moon-Massat, Loring Rue und Jeffrey Kerby. „A hemoglobin based oxygen carrier (HBOC-201) has similar effects to conventional resuscitation fluids on cytokine responses in an acute trauma-hemorrhage model (96.12)“. Journal of Immunology 178, Nr. 1_Supplement (01.04.2007): S185. http://dx.doi.org/10.4049/jimmunol.178.supp.96.12.
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Abstract Although traumatic hemorrhagic shock may be acutely fatal, alterations in the immune response of survivors in the post injury setting may lead to infections, sepsis, multiple organ failure and death. Various fluids, including HBOC-201, have been evaluated as resuscitative fluids for hemorrhagic shock. This study investigated the effects of HBOC-201 on cytokine responses following trauma-hemorrhage. Anesthetized mice (n=8/group) received a 2 cm abdominal incision, and then were hemorrhaged over 30 min through a femoral artery catheter to a mean arterial pressure (MAP) of 25±5 mm Hg. After an additional 1h of sustained hypotension, animals were resuscitated with lactated Ringer’s (LR), shed blood, or HBOC-201 and allowed to recover for 24h. Peripheral blood and spleens were collected for analysis. Survival rates were equal. HBOC-201 significantly increased post-resuscitation MAP compared to LR, but had little effect on serum IL6, IL10, IL12, IFNγ, TNFα or MIP1α levels compared to other groups at 24h post-resuscitation. There were no significant differences between groups in cytokine production by splenocytes stimulated for 24h in vitro with LPS. These results suggest that low volume resuscitation with HBOC-201 is superior to LR for maintenance of blood pressure and has no obvious effects on peripheral blood or splenocyte cell function with regard to cytokine production. Supported by Biopure Corporation, Cambridge, MA.
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Müller, S. P., Ch Reiners, A. Bockisch und Katja Brandt-Mainz. „Relationship between Thyroglobulin and Tumor Detectabilily with Thallium-201 in Differentiated Thyroid Cancer“. Nuklearmedizin 39, Nr. 01 (2000): 10–15. http://dx.doi.org/10.1055/s-0038-1632238.
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Summary Aim: Tumor scintigraphy with 201-TICI is an established diagnostic method in the follow-up of differentiated thyroid cancer. We investigated the relationship between thyroglobulin (Tg) level and tumor detectability. Subject and methods: We analyzed the scans of 122 patients (66 patients with proven tumor). The patient population was divided into groups with Tg above (N = 33) and below (N = 33) 5 ng/ml under TSH suppression or above (N = 33) and below (N = 33) 50 ng/ml under TSH stimulation. Tumor detectability was compared by ROC-analysis (True-Positive-Fraction test, specificity 90%). Results: There was no significant difference (sensitivity 75% versus 64%; p = 0.55) for patients above and below 5 ng/ml under TSH suppression and a just significant difference (sensitivity 80% versus 58%; p = 0.04) for patients above and below 50 ng/ml under TSH stimulation. In 18 patients from our sample with tumor, Tg under TSH suppression was negative, but 201-TICI-scan was able to detect tumor in 12 patients. Conclusion: Our results demonstrate only a moderate dependence of tumor detectability on Tg level, probably without significant clinical relevance. Even in patients with slight Tg elevation 201-TICI scintigraphy is justified.
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Severe, Nicolas, Amanda Facklam, Liz McMichael, Biplab Das, Sara Lewandowski, Justin Trickett, Liyang Diao et al. „Abstract 742: PYX-201, a stroma-targeting ADC composed of an anti-EDB+FN antibody conjugated to Auristatin0101, demonstrates strong anti-tumor efficacy across multiple human cancer indications in pre-clinical PDX tumor models“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 742. http://dx.doi.org/10.1158/1538-7445.am2024-742.
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Abstract Stroma is crucial to support solid tumor growth, metastasis and resistance to treatment. While most antibody-drug conjugates (ADCs) directly bind to cancer cells, PYX-201, an investigational drug, is designed to target tumor stroma by binding to the extra-domain B splice variant of fibronectin (EDB+FN), a matrix protein abundantly expressed in the tumor microenvironment of many solid tumors with absent or low expression in normal adult tissues. In vitro studies demonstrated PYX-201 was strongly cytotoxic to EDB+FN positive Caki2 cells, but not to EDB+FN negative HT29 cells. In addition, PYX-201 was 30-times more potent than a non-targeted ADC control, demonstrating PYX-201 cytotoxic effects were EDB+FN dependent. Furthermore, when Caki2 and HT29-luciferase cancer cells were co-cultured, the luciferase activity was used to quantify the amount of EDB+FN negative HT29 cells only. Interestingly, PYX-201 was able to kill EDB+FN negative cancer cells in a co-culture assay as shown by a decrease in luciferase activity, demonstrating PYX-201 bystander activity. Pre-clinical mouse model studies were conducted to evaluate PYX-201 anti-tumor efficacy and pharmacokinetic (PK) properties. First, a comprehensive patient-derived xenograft (PDX) mouse model trial was designed to evaluate the anti-tumor efficacy of PYX-201. To fully represent the diversity and characteristics of human tumors, PDX models were pre-selected from ten solid tumor indications based on different levels of EDB+FN protein expression and stromal density. PYX-201 (Q4D × 4 at 3mg/kg) was well tolerated, and strong anti-tumor responses (% Tumor Growth Inhibition [TGI] >90%) were observed in PDX models across various cancer indications. Potential correlations between EDB+FN protein expression with anti-tumor activity will be evaluated. Remarkably, long-term anti-tumor efficacy of PYX-201 was observed as tumors did not relapse even after >100 days in a breast cancer PDX model. Additionally, plasma samples were analyzed from a cell line derived xenograft mouse model after a single dose of PYX-201 to determine its PK profile. At 3 mg/kg, the maximum concentration (Cmax) was 28.1 μg/mL, area under the curve (AUC) was 1,732.7 h*μg/mL, with a low clearance of 1.5 mL/h/kg, and the half-life of the mAb from PYX-201 was calculated at 81.2 h. These PK parameters were associated with strong PYX-201 anti-tumor efficacy (% TGI >90%) in the H1975 xenograft model. Altogether, PYX-201 was well tolerated and demonstrated strong anti-tumor efficacy in a variety of pre-clinical human PDX models. PYX-201 is a promising and innovative ADC which is currently under investigation in a Phase I clinical trial (NCT05720117). Citation Format: Nicolas Severe, Amanda Facklam, Liz McMichael, Biplab Das, Sara Lewandowski, Justin Trickett, Liyang Diao, Chengfeng Merriman, Chuan Shen, Jianwen Feng, Shawn Harriman, Marsha Crochiere, Philipp Steiner, Jan Pinkas. PYX-201, a stroma-targeting ADC composed of an anti-EDB+FN antibody conjugated to Auristatin0101, demonstrates strong anti-tumor efficacy across multiple human cancer indications in pre-clinical PDX tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 742.
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Andrews, June. „Psychosocial NursingPsychosocial Nursing Wilson H and Kneisl CAddison-Wesley228pp£13.450-201-11895-5“. Nursing Standard 2, Nr. 42 (23.07.1988): 36. http://dx.doi.org/10.7748/ns.2.42.36.s74.
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Smilowitz, J. „WE-AB-201-04: The Recommendations of MPPG #5 and Practical Implementation Strategies“. Medical Physics 42, Nr. 6Part37 (Juni 2015): 3662–63. http://dx.doi.org/10.1118/1.4925896.
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Tanaka, Atsushi, Massimo Fantini, Philip M. Arlen, Christina M. Annunziata, Kwong Y. Tsang und Shimon Sakaguchi. „Abstract 2716: The O-glycan epitope targeting anti-human carcinoma monoclonal antibody (mAb) NEO-201 can also target human regulatory T cells (Tregs)“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 2716. http://dx.doi.org/10.1158/1538-7445.am2024-2716.
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Abstract Introduction:NEO-201 is a humanized IgG1 mAb that targets Core 1 and/or extended Core 1 O-glycans expressed by several human solid and blood tumors, as well as neutrophils, but it does not bind to most normal tissues and human immune cell subsets (B cells, CD4+ T cells, CD8+ T cells, NK cells, monocytes). Functional analysis revealed that NEO-201 mediates the killing of its target cells through ADCC and CDC. Previous study has shown that approximately 4.6% of CD4+ T cells express NEO-201 target antigen and that those CD4+ T cells have Tregs phenotype. In addition, in a recent published phase 1 study we observed that NEO-201 binds to CD4+/CD25+/, CD127−/, Foxp3+/, CD15s+ cells from peripheral blood mononuclear cells (PBMCs) from cancer patients with solid tumors. The purpose of this study was to further characterize the phenotype of the specific subset of CD4+ T cells expressing the NEO-201 target antigen. Experimental Design: Human PBMCs were obtained from 7 healthy donors (HD) collected at Osaka University and 6 cancer patients from our ongoing phase II clinical trial (Clinical Trial NCT03476681) evaluating the efficiency of the combination of NEO-201 with pembrolizumab in adults with solid tumors resistant to checkpoint inhibitors. Phenotypic analysis was performed by flow cytometry using NEO-201 and antibodies CD3, CD4, CD25, CD45RA, FoxP3, and CD15s. The same gating strategy was applied for both normal donors and patients to evaluate which fraction of CD4+ T cells is recognized by NEO-201. Fraction (Fr) 1 is naïve Treg, Fr ll is effector Treg, Fr lll is non-Treg, Fr lV is effector CD4 T cells and Fr V is naïve CD4 T cells. Results: Flow cytometry analysis of PBMCs revealed that NEO-201 recognizes naïve Tregs (nTregs: CD3+/CD4+/CD45RA+/Foxp3low cells) while it does not bind to effector Tregs (eTregs: CD3+/CD4+/CD45RA−/Foxp3high cells) in both HD and cancer patients. The % of nTregs in cancer patients was higher than HD. Preliminary results from the ongoing Phase II clinical trial showed that subjects with durable SD had a reduction of circulating nTregs after treatment with NEO-201 compared to baseline levels. Conclusions: NEO-201 binds to human Tregs with significantly higher % of binding to Fr l and a greater % of Tregs expressing NEO-201 target antigen in cancer patients compared to HD. It is conceivable that naïve Tregs in cancer patients express high levels of Core 1 O-glycans. Furthermore, when subjected to TCR stimulation, naïve Tregs undergo proliferation and differentiate into eTregs. eTregs can then infiltrate into tumor microenvironment (TME). These data suggest that depletion of circulating nTregs in cancer patients after NEO-201 treatment may prevent the differentiation of nTregs into eTregs and their accumulation in the TME. This study suggests the potential use of NEO-201 to reduce the Treg-mediated suppression of anticancer immunity. Citation Format: Atsushi Tanaka, Massimo Fantini, Philip M. Arlen, Christina M. Annunziata, Kwong Y. Tsang, Shimon Sakaguchi. The O-glycan epitope targeting anti-human carcinoma monoclonal antibody (mAb) NEO-201 can also target human regulatory T cells (Tregs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2716.
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Kang, Hyeonju, Seungil Baek, Inyoung Lee, Manseok Ju, Seonggu Han, Eunjung Han, Sungmuk Kang et al. „Abstract 721: Novel and distinctive anti-HLA-G antibody, IMB-201, inhibits tumor progression by breaking immune escape mechanism and enhancing cytotoxicity“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 721. http://dx.doi.org/10.1158/1538-7445.am2024-721.
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Abstract Human leukocyte antigen-G (HLA-G), a type of MHC class I, is known to be expressed only in the placenta and acts as an immune suppressor to protect the fetus from maternal immunity. Recent studies have revealed that HLA-G suppresses various tumor-infiltrated immune cells, such as T cells, NK cells, and macrophages, through interaction with inhibitory receptors Ig-like transcript 2 (ILT2). HLA-G has recently emerged as an attractive anticancer target because HLA-G is a highly specific tumor antigen and has a role in immune evasion of cancer cells. Additionally, the expression pattern of ILT2 differs from that of PD-1 in tumor-infiltrated CD8+ T cells. Therefore, an HLA-G targeting strategy is expected to be an alternative to address unmet medical needs for those not responding to anti-PD(L)1 therapies. In this study, we screened the novel anti-HLA-G antibody, IMB-201, using phage display technique and confirmed that IMB-201 selectively bound to the membrane HLA-G of cancer cells. It exhibited superior activities in ILT2 blockade, NK cell activation, and antibody-dependent cellular cytotoxicity (ADCC) compared to the reference antibody. Furthermore, IMB-201 demonstrated more efficient suppression of tumor growth compared to the reference antibody in subcutaneous gastric cancer xenograft model. Notably, the group administered IMB-201 with NK92MI cells (CD16-negative NK cells) in the ovarian cancer xenograft model showed stronger tumor growth inhibition compared to the group treated only IMB-201, indicating that NK92MI cells were activated by IMB-201. This result indicates that one of the mechanisms of action (MoA) of IMB-201 worked effectively in vivo. In addition, to maximize the efficacy of IMB-201 and differentiate it from competitors, various efficacy enhancing modality could be applicable. We aim to develop biopharmaceuticals by selecting the optimized modality. Based on these results, IMB-201 could overcome the limitations of existing cancer immunotherapy, potentially becoming highly influential in cancer treatment as a novel immune checkpoint inhibitor. It is also expected to exhibit higher anticancer efficacy in combination therapy with immune checkpoint inhibitors. Citation Format: Hyeonju Kang, Seungil Baek, Inyoung Lee, Manseok Ju, Seonggu Han, Eunjung Han, Sungmuk Kang, Jihye Koo, Yoojin Kim, Suho Park, Eunyoung Cho, Chungmin Lee, Gyongsik Ha. Novel and distinctive anti-HLA-G antibody, IMB-201, inhibits tumor progression by breaking immune escape mechanism and enhancing cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 721.
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Lim, Jinback, Jinho Kang, Hyo-Hyun Park, Jin Kyeong Choi, Jee Hyun Choi, Seong-Yong Jang, Min-Ah Kim et al. „Abstract 4114: AST-201 (pUMVC3-hIGFBP2 N-terminus) demonstrates anti-tumor effect in an ovarian cancer mouse model“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 4114. http://dx.doi.org/10.1158/1538-7445.am2024-4114.
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Abstract Background: IGFBP2, known to enhance the invasion capacity of ovarian cancer cells, has been suggested that its inhibition could be potentially a treatment strategy of ovarian cancer. AST-201 (pUMVC3-hIGFBP2) is a therapeutic cancer vaccine using a plasmid DNA encoding IGFBP2 N-terminus. In a phase 1 study (NCT01322802) completed, 100 μg AST-201 (intradermal immunization, id) showed not only a significant efficacy by inducing the Th1-cell immunity against IGFBP2 but also safety and tolerability profiles in ovarian cancer patients. The primary objective of this study is to evaluate whether the administration of AST-201 alone and the combination with pembrolizumab could show anti-tumor efficacy and/or synergic effect in the ID8-Luc2 ovarian cancer mouse model. Also, immunological responses were observed as explorative endpoint. Methods: AST-201 (100 μg/animal, id, mixed with mGM-CSF as an immune adjuvant) was immunized to mice (C57BL/6) once a week for a total of 4 times on different days, either alongside pembrolizumab (10 mg/kg, intraperitoneal injection) twice a week for a total of 3 times on different days. Also, AST-201 was immunized was a mono treatment. The efficacy was evaluated by a tumor growth inhibition (TGI) rate at the last day, and immune cell profiling via FACS analysis was conducted with splenocytes and tumor tissues collected at 8 weeks after the first injection. Results: As a primary endpoint, a TGI rate at Day 55 of AST-201 mono treatment was 67%, comparing to a control group (p<0.05). The anti-tumor effect of AST-201 combining with pembrolizumab was better than standard dose pembrolizumab, based on a TGI rate at Day 55 (78% vs 66%, not significant). Immune profiling showed that AST-201 and pembrolizumab combination regimen could inhibit a tumor growth by transforming TME into inflamed-type (‘hot’) form the low immunoreactivity, which was supported by increased CD4+TEM, and CD8+TEM and T helper cells in splenocyte and TIL analysis. Conclusion: A study demonstrated that AST-201 (IGFBP2 cancer vaccine) showed an anti-tumor effect as mono treatment and would be potentially leading to a synergistic effect with a combination regimen of pembrolizumab. Phase 2 randomized-controlled study of AST-201 in ovarian cancer will be initiated under the MRCT strategy (CornerStone-004 study, NCT05794659). Citation Format: Jinback Lim, Jinho Kang, Hyo-Hyun Park, Jin Kyeong Choi, Jee Hyun Choi, Seong-Yong Jang, Min-Ah Kim, Myeong-Kyu Park, Mary L Disis, Eunkyo Joung, Ashley Yongmin Kim, Hun Jung. AST-201 (pUMVC3-hIGFBP2 N-terminus) demonstrates anti-tumor effect in an ovarian cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4114.
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Spinas, G. A., J. Zapf, A. M. Landolt, G. Stuckmann und E. R. Froesch. „Pre-operative treatment of 5 acromegalics with a somatostatin analogue: endocrine and clinical observations“. Acta Endocrinologica 114, Nr. 2 (Februar 1987): 249–56. http://dx.doi.org/10.1530/acta.0.1140249.
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Abstract. Five acromegalic patients were treated pre-operatively over a period of 1–4 weeks with the somatostatin analogue SMS 201-995. The patients received daily 3 × 100 μg of SMS 201-995 subcutaneously. This schedule resulted in a rapid improvement of the clinical symptoms in 4 out of 5 patients. In these same patients plasma growth hormone concentrations decreased markedly. However, only in one patient were growth hormone concentrations normalized. Plasma IGF I, which was elevated in all patients, was normalized only in this same patient. Tumour volume as determined by thin section CT-scans decreased only in one case by 17%. All tumours appeared extraordinarily soft upon operation. Conventional light microscopy showed no difference between tumours of SMS-pre-treated and untreated patients. Ultrastructural investigation showed the usual heterogeneity.
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Brunetto, A. T., J. E. Ang, R. Lal, D. Olmos, S. Frentzas, A. Mais, B. Hauns, M. Mollenhauer, G. Lahu und J. S. de Bono. „A first-in-human phase I study of 4SC-201, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors“. Journal of Clinical Oncology 27, Nr. 15_suppl (20.05.2009): 3530. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.3530.
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3530 Background: 4SC-201 (former code BYK408740) is a specific, potent, pan-HDAC inhibitor with improved ADME properties. Methods: Patients (pts) with advanced refractory solid tumors were dosed once daily (QD) d1–5 in a 14-day cycle in sequential cohorts of 3–6 pts with 50 or 100% dose increments. Primary objectives were to determine safety, tolerability, pharmacokinetics (PK) and maximum tolerated dose (MTD) of 4SC-201. Pharmacodynamic assessment (histone acetylation and HDAC enzyme activity) and anti-tumor efficacy were secondary objectives. Blood samples for PK and PD were taken on days 1, 5 and 47 of treatment. Results: 18 pts (9M/9F) with a median age of 58.5 yrs (range 40–70) were treated at five dose levels: 3 pts each at 100mg, 200mg, 400mg and 600mg and 6 pts at 800mg. All pts were evaluable for toxicity and received at least 2 treatment cycles. Grade 3 DLT of nausea and vomiting occurred in 1 pt dosed at 800mg. Most common adverse events included nausea, vomiting and fatigue. 8 of 9 pts treated in the 600mg and 800mg cohorts had stable disease during the main phase of the study (4 treatment cycles). A patient with liposarcoma and another with thymoma (marginal response) continued treatment beyond 6 months. PK parameters were dose-proportional with a low inter-individual variability and indicated good bioavailability. The apparent t1/2 of oral 4SC-201 ranged from 2.3 to 4.4 hours. The degree of HDAC inhibition measured in a peripheral blood mononuclear cell functional assay was dose- dependent and increased from 50 to 100 %, although histone H4 acetylation accumulation after dosing did not differ significantly between dose levels. Conclusions: Oral 4SC-201 has favorable disposition and can be safely administered; 600mg QD d1–5 in a 14-day cycle is recommended for phase II evaluation. Safely administered doses modulate target with antitumor activity. [Table: see text]
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Johns, Terrance G. „Abstract B027: Repurposing ion channel drugs: the Na+ channel modifying drug DPI-201-106 significantly enhances the anti-tumor activity of multiple classes of drugs targeting DNA damage repair“. Cancer Research 84, Nr. 5_Supplement_1 (04.03.2024): B027. http://dx.doi.org/10.1158/1538-7445.brain23-b027.
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Abstract High-grade glioma (HGG) cells intimately interact with neurons in a two-way dance that drives tumorigenicity in one direction, and neuronal dysfunction in the other. Recent studies have highlighted the role of ion channels in mediating neuron/HGG interactions, including the formation of synapses. The FDA has approved hundreds of drugs that target ion channels, many of which are used for the treatment of neurological conditions, and therefore cross the blood brain barrier. We used an unbiased approach to drug discovery and screened patient-derived HGG cell lines against a library of ion channel drugs. Less than 15% of ion channel drugs inhibited the growth of HGG cells in vitro. Many active drugs were Ca2+ channel blockers, a class of drugs previously identified. One novel compound identified was DPI-201-106, a Na+ channel modifier, that blocks some Na+ channels and activates others. DPI-201-106 is an off-patent drug previously evaluated in a Phase 2 trial for the treatment of heart failure. DPI-201-106 had a cytostatic effect on numerous HGG cell lines that mechanistically was mediated through arresting cells in S-phase of the cell cycle. Activation of Chk1 kinase is a critical mediator of both S and G2/M cell cycle arrest. Blockade of Chk1 kinase activity with the small molecule Prexasertib forces cells to continue through the S-phase without pausing. The combination of DPI-201-106 and Prexasertib showed greater than additive anti-tumor activity in vitro against HGG cell lines by significantly increasing apoptosis. Treatment of mice bearing GBM6 or WK1 orthotopic xenografts with the combination of DPI-201-106 and Prexasertib resulted in synergistic anti-tumor activity. Extending this work, the combination of DPI-201-106 with small molecule inhibitors of ATR and Wee1, two kinases directly upstream of Chk1, also resulted in greater than additive inhibition of HGG growth. A major function of the CHK1 pathway is to pause the cell cycle, allowing cells time to repair DNA damage before completing the cycle. As such we examined the efficacy of DPI-201-106 in combination with PARP inhibitors, which target a different aspect of DNA damage repair. The combination of DPI-201-106 and the clinically approved PARP inhibitor niraparib showed significant anti-tumor activity. Overall, DPI-201-106 dramatically enhances the activity of different classes of agents targeting DNA damage repair. We have patented the combination of DPI-201-106 with DNA damaging agents and are working with several biotech companies to bring this discovery to the clinic. Citation Format: Terrance G. Johns. Repurposing ion channel drugs: the Na+ channel modifying drug DPI-201-106 significantly enhances the anti-tumor activity of multiple classes of drugs targeting DNA damage repair [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B027.
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Ho, Alan Loh, Marshall R. Posner, Jiaxin Niu, Siqing Fu, Rom S. Leidner, Alexander T. Pearson, Ki Y. Chung et al. „First report of the safety/tolerability and preliminary antitumor activity of HB-201 and HB-202, an arenavirus-based cancer immunotherapy, in patients with HPV16+ cancers.“ Journal of Clinical Oncology 39, Nr. 15_suppl (20.05.2021): 2502. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2502.
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2502 Background: Human papillomavirus 16 (HPV16) is linked to several cancer types. Treatment options are limited for patients with HPV16 positive (HPV16+) recurrent or metastatic cancers. Generation and maintenance of HPV16+ malignant state require stable expression of HPV16-specific E7 and E6 oncoproteins, also a source of immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuated vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein to induce tumor-specific T-cell responses. This is a first-in-human phase 1/2 study of HB-201 monotherapy and HB-201 & HB-202 alternating 2-vector therapy. Dose escalation is ongoing with a 3+3 design. Methods: Phase 1 is assessing different regimens and dose levels of HB-201 monotherapy and HB-201 & HB-202 alternating 2-vector therapy given intravenously (IV) with or without an initial intratumoral administration. The patient population includes HPV16+ head and neck squamous cell carcinoma (HNSCC) and other HPV16+ cancers. Safety, tolerability, and preliminary antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST are assessed. Results: As of Jan 2021, 25 patients with a median of 3 prior anticancer treatments have been enrolled. All had HPV16+ confirmed genotype; the most common primary site was oropharynx (72%). No dose-limiting toxicities were reported. Treatment-emergent adverse events (TEAEs) occurred in 21 patients (84%), were generally mild or moderate, with events related to study drug reported in 14 patients (56%). TEAEs reported in >10% of patients regardless of causality included fatigue, pyrexia, nausea, decreased appetite, anemia, arthralgia, chills, constipation, diarrhea, hypertension, influenza-like illness, pneumonia, and vomiting. Serious TEAEs developed in 6 patients (24%), including 1 with grade 5 hemorrhagic shock deemed unrelated to study drug. Grade 3 fatigue was the only serious or grade ≥3 TEAE assessed as related to study drug. TEAEs caused no treatment discontinuation. There were 18 patients evaluable for efficacy. For the 16 patients on HB-201 monotherapy, assessment of target lesions showed 2 partial responses (including 1 patient with an unconfirmed immune CR) and 6 patients had stable disease (SD). For the 2 patients on HB-201 & HB-202 alternating therapy, both had SD. So far, the longest duration of response was 4.8 months (144 days) and the maximum decrease in tumor diameter was 60%, both seen in HNSCC patients receiving HB-201 IV. Conclusions: HB-201 monotherapy and HB-201 & HB-202 2-vector alternating therapy were generally well-tolerated and showed preliminary antitumor activity as monotherapy in heavily pre-treated patients with HPV16+ HNSCC and other solid tumors. Clinical trial information: NCT04180215.
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Lim, Hoyong, Amanda Medcalf, Lisa Guerrettaz, Eun Ji Choi, Hansol Kim, Bitna Yang, Eun Ji Kim et al. „129 Development of AB-201, a novel allogeneic anti-HER2-specific CAR-NK cell therapy for the treatment of HER2+ tumors“. Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A138. http://dx.doi.org/10.1136/jitc-2021-sitc2021.129.
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BackgroundHuman Epidermal Growth Factor Receptor 2 (HER2), is a receptor tyrosine kinase that is highly expressed on the surface of many solid tumors. While many patients derive meaningful benefit from the approved HER2-directed therapies, most will eventually suffer relapse or progression of their disease highlighting the need for additional treatment options. Currently there are no FDA-approved cellular therapies targeting HER2. Over the past decade, however, cellular therapy has been shown to be a viable treatment option in different cancer types. Here we present AB-201, an off-the-shelf, cryopreserved cord blood (CB)-derived HER2 chimeric antigen receptor (CAR)-natural killer (NK) cell therapy as a safe, active, and readily available option for patients with HER2+ solid tumors.MethodsAB-201 is comprised of ex vivo expanded allogeneic CB-derived NK cells that have been genetically modified to express a HER2-directed CAR and presented as a cryopreserved infusion-ready product. The manufacturing process utilizes a feeder-cell line engineered to express factors specifically identified as supportive to NK cell expansion and a lentiviral transduction step to introduce the HER2 CAR construct. In vitro characterization of AB-201 included evaluation of the purity and expression of cell surface markers by flow cytometry and short- (4 hour) and long-term (over 5 days) cytotoxicity assays in the presence of HER2+ tumor cell lines at various effector to target ratios. In addition, AB-201 efficacy was assessed in vivo in established ovarian (intraperitoneal, SKOV-3), breast (intraperitoneal, HCC1954) and gastric (subcutaneous, N87) xenograft models in NSG mice.ResultsHER2 CAR expression was detected in 93.1% of AB-201 cells. AB-201 is 97.9% CD3-/CD56+ cells and 94.6% CD56+/CD16+. Further characterization of AB-201 demonstrated high expression of NK activating receptors such as NKG2D, NKp30, NKp46, and DNAM-1 and expression of the chemokine receptor, CXCR3. AB-201 demonstrated concentration-dependent and HER2 targeted short-term cytotoxic activity and sustained long-term cell killing against the tumor cell lines SKOV-3, HCC1954, and NCI-N87. Efficacy, as evidenced by a significant reduction in bioluminescent signal or tumor volume, was observed in all xenograft models. A significant survival benefit over non-transduced NK cells or trastuzumab controls was demonstrated in the HCC1954 model.ConclusionsData presented herein suggests that AB-201, a highly pure and readily expandable HER2-directed CAR NK cell product, has potential to be an effective therapy in the treatment of HER2+ tumors.Ethics ApprovalThe animal studies were conducted in accordance with an Institutional Animal Care and Use Committee-approved protocol and with the approval of an IACUC committee at each center where the studies took place
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Morelli, Maria Pia, Justin M. David, Nicole D. Houston, Stan Lipkowitz, Jung-min Lee, Alexandra Dos Santos Zimmer, Farah Z. Zia et al. „Phase 1 with expansion cohorts in a study of NEO-201 in adults with chemo-resistant solid tumors.“ Journal of Clinical Oncology 37, Nr. 15_suppl (20.05.2019): TPS2645. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps2645.
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TPS2645 Background: NEO-201 is a novel humanized IgG1 monoclonal antibody (mAb) generated against the Hollinshead allogenic colorectal cancer vaccine platform. Briefly, tumor-associated antigens (TAA) derived from tumor membrane fractions pooled from colorectal cancer surgical specimens were screened for delayed-type hypersensitivity and evaluated in clinical trials. The original vaccine was used to generate monoclonal antibodies, one of which is NEO-201. In preclinical data generated in our laboratory, we have demonstrated that NEO-201 exert anti-tumor activity by natural killer (NK)-mediated antibody-dependent cytotoxicity (ADCC) against several tumor type including colorectal and pancreatic cancer models (Fantini, et al. 2018). We have identified NEO-201 antigen as a glycosylated form of CEACAM-5 and -6, which is expressed by tumor tissue but is not present in the surrounding healthy tissue (David, et al. 2018). This could result in a specific anti-tumor activity without significant normal tissue toxicity. Nevertheless, toxicity was further assessed in non-human primates and transient neutropenia was the only adverse event observed. Based on this data we designed a first in human phase I trial to evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized monoclonal antibody NEO-201. Methods: This is a first-in-human phase 1 study with expansion cohort to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NEO-201 in adults with advanced solid tumors that have high likelihood pof expression NEO201 antigen and have progressed to standard of treatments and have a PS0-2 ECOG. Study design is a classic Fibonacci (3+3) dose escalation, with a cohort expansion at the MTD. NEO-201 is administered intravenously every two weeks, and four different dose levels will be explored (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). No intra-patient dose escalation is allowed. Patients will be evaluated for safety every two weeks, with weekly laboratory testing, according to CTCAEv4.0. and with a DLT window of 28 days (cycle 1). Response will be assessed every 8 weeks (2 cycles of treatment) according to RECISTv1.1. Additionally, biological samples will be collected to understand NEO-201 pharmacokinetic, the effect on the immune process and their correlation with treatment toxicity and response. As of February 2019 we have completed enrollment in the first DL and are evaluating for DLT. Clinical trial information: NCT03476681.
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Aranda García, Nuria. „Mangas Navarro, Natalia Anaís (ed.) (2022), La Criança y virtuosa doctrina de Pedro Gracia Dei. Alicante: Universitat d’Alacant («Cancionero, Romancero e imprenta», 5).“ Revista de Poética Medieval 37 (19.10.2023): 430–35. http://dx.doi.org/10.37536/rpm.2023.37.1.98688.
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Reseña de:
Mangas Navarro, Natalia Anaís (2022), La Criança y virtuosa doctrina de Pedro Gracia Dei. Edición crítica de Natalia Anaís Mangas Navarro. Alicante: Universitat d’Alicant («Cancionero, Romancero e imprenta», 5). 151 pp. ISBN: 978-84-1302-201-7.