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Micoli, Francesca, Simona Rondini, Renzo Alfini, Luisa Lanzilao, Francesca Necchi, Aurel Negrea, Omar Rossi, et al. "Comparative immunogenicity and efficacy of equivalent outer membrane vesicle and glycoconjugate vaccines against nontyphoidal Salmonella." Proceedings of the National Academy of Sciences 115, no. 41 (September 27, 2018): 10428–33. http://dx.doi.org/10.1073/pnas.1807655115.
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Nontyphoidal Salmonellae cause a devastating burden of invasive disease in sub-Saharan Africa with high levels of antimicrobial resistance. Vaccination has potential for a major global health impact, but no licensed vaccine is available. The lack of commercial incentive makes simple, affordable technologies the preferred route for vaccine development. Here we compare equivalent Generalized Modules for Membrane Antigens (GMMA) outer membrane vesicles and O-antigen-CRM197 glycoconjugates to deliver lipopolysaccharide O-antigen in bivalent Salmonella Typhimurium and Enteritidis vaccines. Salmonella strains were chosen and tolR deleted to induce GMMA production. O-antigens were extracted from wild-type bacteria and conjugated to CRM197. Purified GMMA and glycoconjugates were characterized and tested in mice for immunogenicity and ability to reduce Salmonella infection. GMMA and glycoconjugate O-antigen had similar structural characteristics, O-acetylation, and glucosylation levels. Immunization with GMMA induced higher anti–O-antigen IgG than glycoconjugate administered without Alhydrogel adjuvant. With Alhydrogel, antibody levels were similar. GMMA induced a diverse antibody isotype profile with greater serum bactericidal activity than glycoconjugate, which induced almost exclusively IgG1. Immunization reduced bacterial colonization of mice subsequently infected with Salmonella. S. Typhimurium numbers were lower in tissues of mice vaccinated with GMMA compared with glycoconjugate. S. Enteritidis burden in the tissues was similar in mice immunized with either vaccine. With favorable immunogenicity, low cost, and ability to induce functional antibodies and reduce bacterial burden, GMMA offer a promising strategy for the development of a nontyphoidal Salmonella vaccine compared with established glycoconjugates. GMMA technology is potentially attractive for development of vaccines against other bacteria of global health significance.
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Julles, Dinaura. "Tradução do conto “Unguided Tour”, de Susan Sontag." Cadernos de Literatura em Tradução, no. 23 (July 12, 2021): 279–305. http://dx.doi.org/10.11606/issn.2359-5388.i23p279-305.
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Uma das facetas menos conhecidas da caleidoscópica Susan Sontag, que já foi chamada de a “intelectual total”, é a de escritora de contos. Notabilizada no jornalismo literário norte-americano como ensaísta em obras seminais, Susan Sontag permanece inédita no Brasil como escritora de contos. O objetivo deste trabalho é apresentar o extremo oposto da racionalidade aplicada aos seus ensaios. Como em um giro no caleidoscópio, surge sua polêmica e conturbada vida pessoal, espelhada no conto agora intitulado “Turismo sem Guia”, originalmente Unguided Tour, encontrado por acaso em uma publicação da Revista Granta, de 1994. A tradução procura proporcionar ao leitor uma experiência estética semelhante àquela do leitor do original. Foi preciso desmontar Unguided Tour, conforme sugerido por Derrida na sua proposta de “Desconstrução”, fragmentá-lo para identificar suas especificidades, como o encobrimento do gênero dos personagens, descrições de cenas do passado, menções a profissões antigas, referências bíblicas e a outras obras, e recompô-lo, com toda sua polissemia. Que seja um passeio proveitoso a quem enveredar por esta experiência de “Turismo sem Guia”.
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Robinson, Patrick Gordon, Andrew Murray, Matt Watson, Graeme Close, and Denis F. Kinane. "Risk assessment and implementation of risk reduction measures is not associated with increased transmission of SARS-CoV-2 compared with standard isolation at professional golf events." BMJ Open Sport & Exercise Medicine 8, no. 2 (May 2022): e001324. http://dx.doi.org/10.1136/bmjsem-2022-001324.
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ObjectivesThe purpose of this prospective study was to report incidence and transmission of SARS-CoV-2, among professional golfers and essential support staff undergoing risk assessment and enhanced risk reduction measures when considered a close contact as opposed to standard isolation while competing on the DP World Tour during the 2021 season.MethodsThis prospective cohort study included all players and essential support staff participating in 26 DP World Tour events from 18 April 2021 to 21 November 2021. High-risk contacts were isolated for 10 days. Moderate-risk contacts received education regarding enhanced medical surveillance, had daily rapid antigen testing for 5 days, with reverse transcriptase-polymerase chain reaction (RT-PCR) tesing on day 5, mandated mask use and access to outside space for work purposes only. Low-risk contacts typically received rapid antigen testing every 48 hours and RT-PCR testing on day 5.ResultsThe total study cohort compromised 13 394 person-weeks of exposure. There were a total of 30 positive cases over the study period. Eleven contacts were stratified as ‘high risk’. Two of these subsequently tested positive for SARS-CoV-2. There were 79 moderate-risk contact and 73 low-risk contacts. One moderate-risk contact subsequently tested positive for SARS-CoV-2 but did not transmit the virus. All other contacts, remained negative and asymptomatic to the end of the tournament week.ConclusionsA risk assessment and risk reduction-based approach to contact tracing was safe in this professional golf event setting when Alpha and Delta were the predominant variants. It enabled professional golfers and essential support staff to work.
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Ozyilkan, O., E. Baltali, G. Takuzman, A. Kars, D. Firat, and S. Klrazli. "CA 15-3 ceruloplasmin (CRL) and tissue polypeptide specific antigen (TPS) as tour markers in female breast cancer." European Journal of Cancer 30 (January 1994): S23. http://dx.doi.org/10.1016/0959-8049(94)90765-x.
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Tamura, Yasuaki, Goro Kutomi, Jun Oura, Toshihiko Torigoe, and Noriyuki Sato. "Extracellular heat shock proteins (eHSPs) pilot exogenous antigen into cross-presentation pathway: A superguide from extracellular world to intracellular tour." Annals of Cancer Research and Therapy 15, no. 2 (2007): 41–49. http://dx.doi.org/10.4993/acrt.15.41.
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Pfau, Jean C., Jordan C. Schneider, Amy J. Archer, Jami Sentissi, Francisco J. Leyva, and Jennifer Cramton. "Environmental oxygen tension affects phenotype in cultured bone marrow-derived macrophages." American Journal of Physiology-Lung Cellular and Molecular Physiology 286, no. 2 (February 2004): L354—L362. http://dx.doi.org/10.1152/ajplung.00380.2002.
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This study tested the hypothesis that the unique phenotype of alveolar macrophages (AM) is maintained through adaptation to the relatively high oxygen partial pressure (Po2) of the lung, through modification of redox-sensitive transcription factors. BALB/c mouse bone marrowderived macrophages (BMC) were differentiated under different Po2and compared functionally to AM and peritoneal macrophages (PM). BMC differentiated in normoxia (Po2140 Torr, BMChigh) were similar to AM in having low phagocytic and antigen presenting cell (APC) activities. However, BMC grown in low oxygen tension as found in other tissues (<40 Torr, BMClow) were better phagocytes and APCs, similar to PM. BMChighwere more oxidative intracellularly than BMClow, based on oxidation of dichlorofluorescein and higher glutathione disulfide/glutathione (GSH) ratios, despite having more GSH. Finally, lipopolysaccharide-induced nuclear factor-κB translocation, measured by laser scanning cytometry, was reduced in BMChighand AM, compared with BMClowand PM, respectively. These data suggest that regulation of the AM phenotype may occur, at least in part, via inhibition of NF-κB by the unique redox environment.
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Ishida, K., L. J. Kelly, R. J. Thomson, L. L. Beattie, and R. R. Schellenberg. "Repeated antigen challenge induces airway hyperresponsiveness with tissue eosinophilia in guinea pigs." Journal of Applied Physiology 67, no. 3 (September 1, 1989): 1133–39. http://dx.doi.org/10.1152/jappl.1989.67.3.1133.
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To test the hypothesis that the development of airway hyperresponsiveness (AHR) lasting greater than or equal to 3 days after the last antigenic exposure required repeated mediator release, we compared dose-response changes in lung resistance (RL) to acetylcholine (ACh) in animals sensitized with 1% ovalbumin (OA), 4% Bordatella pertussis aerosol and subsequently challenged with 0.5% OA aerosol twice weekly for 4–6 wk vs. animals receiving saline aerosol instead of OA. Despite antihistamine pretreatment, each OA challenge produced cyanosis and inspiratory indrawing. Blood gas analysis in six guinea pigs revealed an immediate fall in arterial PO2 (PaO2) from 104.3 +/- 4.9 to 35.4 +/- 2.2 Torr after a 1-min exposure to aerosolized OA. ACh dose-response measurements of RL 3 days after the last OA challenge demonstrated a leftward shift and an increased magnitude of response. These differences were less marked at 7 days, and by 14 days after the last OA challenge, ACh dose-response curves were not different from those of control guinea pigs. Sensitization without repeated antigen challenge did not cause hyperresponsiveness. Morphometric analysis showed significantly increased numbers of eosinophils in the epithelium of airways in hyperresponsive guinea pigs, without neutrophil infiltration or alterations in epithelium and airway wall areas. We conclude that repeated antigenic challenge, but not sensitization alone, causes prolonged AHR in guinea pigs, which is associated with tissue eosinophilia.
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Tang, W., M. H. Weil, S. Sun, M. Noc, R. J. Gazmuri, and J. Bisera. "Gastric intramural PCO2 as monitor of perfusion failure during hemorrhagic and anaphylactic shock." Journal of Applied Physiology 76, no. 2 (February 1, 1994): 572–77. http://dx.doi.org/10.1152/jappl.1994.76.2.572.
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Indirect measurement of gastric intramural pH (pHG) utilizing a luminal tonometer in the stomach has been proposed for monitoring the severity and progression of perfusion failure. In the present study, we investigated gastric PCO2 and pHG as indicators and quantitators of the severity of perfusion failure in the experimental rodent model of both hemorrhagic and anaphylactic shock. Gastric intramural PCO2 (PGCO2) and pHG were directly measured with miniaturized sensors inserted into the anterior wall of the stomach. In hemorrhagic shock, animals were bled into a reservoir maintained at a pressure of 35 mmHg. pHG decreased from 7.39 +/- 0.08 to 6.67 +/- 0.11 (P < 0.01), and PGCO2 increased from 53 +/- 4 to 136 +/- 3 Torr (P < 0.01). Anaphylactic shock was induced in animals that had been sensitized 21 days before with crystallized ovalbumin. Antigen challenge produced an immediate reduction in mean aortic pressure from 144 to 60 mmHg. pHG decreased from 7.40 +/- 0.05 to 6.99 +/- 0.07 (P < 0.01), and PGCO2 increased from 48 +/- 5 to 133 +/- 9 Torr (P < 0.01). The increases in PGCO2 were highly correlated with decreases in gastric blood flow in both hemorrhagic (r = 0.96) and anaphylactic shock (r = 0.92). The correlations with pHG were more moderate. These experiments demonstrated prominent increases in PGCO2 and H+ during both hemorrhagic and anaphylactic shock. We further noted that the estimation of pHG based on the assumption that HCO3-concentrations of the stomach wall and arterial blood are the same was not fully sustained.
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Nakai, Takashi, Fumiyasu Momose, Kohei Yabuuchi, Makiko Yamane, Tae Hayashi, Linan Wang, Yoshiyuki Nakagawa, et al. "Abstract 6745: Crafting hyaluronic acid-based nanoparticles for enhanced LN targeting as a potent priming tool in immunotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6745. http://dx.doi.org/10.1158/1538-7445.am2024-6745.
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Abstract Background: Cholesterol-conjugated hyaluronic acid, synthesized by grafting cholesterol moieties onto hyaluronic acid, spontaneously formed nano-sized hydrogel of approximately 30-100nm in water. This hyaluronic acid derivative (HA nanogel) has demonstrated the ability to encapsulate various modalities, including low- and medium-sized molecules, peptides, and proteins. Previous reports have highlighted its efficacy in solubilizing poorly water-soluble drugs and serving as a sustained-release matrix. In this study, we explore the potential of HA nanogels encapsulating antigen peptides with adjuvant as a cancer vaccine and a priming tool for combinational immunotherapy. Method: We prepared HA nanogels as a novel peptide carrier for cancer vaccines and attempted to encapsulate various peptides, including neoantigen (mERK2) peptides expressed in immune checkpoint inhibitor (ICI) therapy-resistant fibrosarcoma cell line CMS5a, gp-100 peptides expressed in metastatic melanoma cell line B16F10, and MAGEA4. Our experiments covered APC uptake, antigen-specific CTL induction, and anti-tumor studies to demonstrate the utility of HA nanogels in these applications. Results: HA nanogel efficiently formed stable complexes with mERK2, gp-100 and MAGEA4 long peptides, each with diameters of 30-100nm. The facile and simple vaccine formulation processes with HA nanogel achieved high drug content and high encapsulation efficiency of 90% or higher. Fluorescently labeled mERK2 long peptide encapsulated in HA nanogel vaccines were subcutaneously administered to BALB/c mice, and uptake analysis of mERK2 long peptides in draining lymph nodes (dLN) was performed using flow cytometry. In comparison to the group receiving mERK2 long peptide without nanogel encapsulation, the HA nanogel group exhibited higher uptake by macrophages and dendritic cells in the dLN. Administering HA nanogel vaccines containing mERK2 long peptides with CpG oligoDNA resulted in higher antigen-specific CD8+ T cells compared to the group receiving mERK2 long peptides without encapsulation. Strong anti-tumor effects were demonstrated in mice models with subcutaneously transplanted CMS5a and B16F10 cell lines. The enhanced efficacy through co-administration with ICI was also confirmed. Conclusion: HA nanogel vaccines efficiently deliver antigen peptides to macrophages and dendritic cells, inducing antigen-specific CTL responses, thereby demonstrating anti-tumor effects against cold tumors such as CMS5a and B16F10. HA nanogels have the potential not only as carriers for cancer vaccines but also as priming tools for combinational immunotherapy. Citation Format: Takashi Nakai, Fumiyasu Momose, Kohei Yabuuchi, Makiko Yamane, Tae Hayashi, Linan Wang, Yoshiyuki Nakagawa, Shogo Aso, Toru Katsumata, Tsuyoshi Shimoboji, Yoshihiro Miyahara. Crafting hyaluronic acid-based nanoparticles for enhanced LN targeting as a potent priming tool in immunotherapy [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 6745.
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Harano, Kenichi, Shin Kaneko, Tetsuya Nakatsura, Junichiro Yuda, Nozomu Fuse, Akihiro Sato, Reiko Watanabe, et al. "Abstract 5185: First in human trial of off-the shelf iPS derived anti-GPC3 NK cells for recurrent ovarian clear cell carcinoma with peritoneal dissemination." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5185. http://dx.doi.org/10.1158/1538-7445.am2022-5185.
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Abstract Background: The development of chimeric antigen receptor (CAR) T cell therapy has introduced an effective strategy to guide and promote the immune response. Also, gene-engineering NK cells to express an exogenous CAR receptor allows the innate anti-tumor ability of NK cells to be directed against target tumor antigen. However, these autologous applications are limited by toxicities, restricted trafficking and infiltration into tumor, suboptimal persistence, and exhausted status of immune cells that may cause manufacturing failure. One approach to overcome those limitations is the development of “off-the-shelf” iPS-cell sources. The iCAR-ILC-N101 is an allogeneic human leukocyte antigen (HLA)-homozygous induced pluripotent stem cell (iPSC)-derived anti-glypican-3 (GPC3) CAR-expressing innate lymphoid cells/natural killer cell (ILC/NK), which has both antigen-specific and NK activating receptor-mediated cytotoxicity. The iCAR-ILC-N101 is produced from the established iPSC strain QHJI01s04, and there is theoretically no risk of developing graft-versus host disease because the product dose not have T cell receptor. The product has a relevant living period in the body, thereby has little concern about residual toxicity and reduces systemic side effects by topical treatment. GPC3 is a cancer-specific membranous protein that is expressed in hepatoblastoma, hepatocellular carcinoma and ovarian clear cell carcinoma (OCCC) but is not expressed in normal tissue. OCCC is a relatively rare malignancy and is associated with poor prognosis. Intraperitoneal administration of iCAR-ILC-N101 is expected to show antitumor activity for OCCC patients with peritoneal dissemination that express GPC3 and reduce systemic side effects, thereby ensuring safety and improving therapeutic efficacy. Preclinical study showed that intraperitoneal injection of iCAR-ILC-N101 for GPC3-positive ovarian tumor-bearing immunodeficient mouse model showed suppressed tumor growth. Method: This is a first-in human phase 1 study to evaluate safety, toxicity and efficacy of the iCAR-ILC-N101 in patients with GPC3-positive advanced or recurrent OCCC harboring peritoneal dissemination. Major inclusion criteria include histologically diagnosed GPC3-positive advanced or recurrent OCCC with peritoneal dissemination who are resistant to standard therapy and have matched HLA-A24 or B52. The study includes 3 cohorts (cohort -1, 0.5x106 cells/kg; cohort 1, 1x106 cells/kg; cohort 2, 3x106 cells/kg) and starts with cohort 1. The iCAR-ILC-N101 is administered intraperitoneally once a week for 4 weeks; for the first patient in each cohort, patient is observed for 14 days for safety evaluation after the first administration and then receive iCAR-ILC-N101 on day15 and 22. Enrollment initiated in July 2021 and one patient was enrolled. No dose-limiting toxicity was observed. Clinical trial registry number: jRCT2033200431 Citation Format: Kenichi Harano, Shin Kaneko, Tetsuya Nakatsura, Junichiro Yuda, Nozomu Fuse, Akihiro Sato, Reiko Watanabe, Genichiro Ishii, Toru Mukohara, Hiroshi Tanabe, Yukiko Ishiguro, Hideki Furuya, Masashi Wakabayashi, Miki Fukutani, Manami Shimomura, Tatsuki Ueda, Shoichi Iriguchi, Ayako Kumagai, Kengo Nakagoshi, Aki Sasaki, Toshihiko Doi. First in human trial of off-the shelf iPS derived anti-GPC3 NK cells for recurrent ovarian clear cell carcinoma with peritoneal dissemination [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 5185.
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Chen, Jia, Liang He, Xuemei Liu, Bruce Dinger, Larry Stensaas, and Salvatore Fidone. "Effect of the endothelin receptor antagonist bosentan on chronic hypoxia-induced morphological and physiological changes in rat carotid body." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 5 (May 2007): L1257—L1262. http://dx.doi.org/10.1152/ajplung.00419.2006.
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Previous experiments have repeatedly demonstrated that exposure to chronic hypoxia (CH) elicits remarkable structural changes and chemosensory hypersensitivity in the mammalian carotid body. Moreover, recent studies have shown that CH upregulates the neuroactive peptide, endothelin (ET), in oxygen-sensitive type I cells. The present study examines the possible involvement of ET in adaptation by concurrently exposing rats to hypobaric CH (BP = 380 Torr) and bosentan, a potent nonpeptide antagonist that blocks ETA and ETB receptors. Carotid body weight indicated that 14 days of CH induced organ enlargement, a response that was blunted in bosentan-treated rats (CH: 2.54 ± 0.19-fold increase; CH plus bosentan: 1.92 ± 0.14-fold increase; P < 0.05). Morphometric studies revealed that bosentan substantially eliminated CH-induced hyperplasia of chemosensory cell lobules as well as expansion of the connective tissue matrix. Vascular dilation associated with CH was not altered by the drug. In untreated animals exposed to 3 days of CH, expression of proliferating cell nuclear antigen (PCNA), a marker of mitosis, was increased in lobules of oxygen-sensitive type I cells and in extralobular vascular and connective tissue cells. The incidence of PCNA expression was significantly ( P < 0.05) reduced in bosentan-treated animals. In vitro assessments of carotid sinus nerve (CSN) activity showed that enhancement of basal and hypoxia-evoked chemosensory activity following 9 days of CH was significantly ( P < 0.001) blunted by concurrent treatment with bosentan. Collectively, our data are consistent with the hypothesis that CH-induced adaptation in the carotid body is at least partially mediated by signaling pathways involving ET receptors.
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Toor, Amir A., Kyle Payne, Harold M. Chung, Catherine H. Roberts, Roy T. Sabo, Maciej Kmieciak, William Clark, et al. "Adaptive Immunotherapy In Multiple Myeloma: Epigenetic Modification and Immunomodulation by Sequential Azacitidine and Lenalidomide to Generate Cancer Testis Antigen Specific Cellular Immune Response." Blood 118, no. 21 (November 18, 2011): 2926. http://dx.doi.org/10.1182/blood.v118.21.2926.2926.
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Abstract Abstract 2926 Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Maintenance therapy may delay recurrence but is associated with toxicities, highlighting the need for alternative strategies for long-term disease control. Malignant plasma cells in MM patients occasionally express highly immunogenic cancer testis antigens (CTA). CTA expression is regulated by DNA methylation, and may be increased by 5-azacitidine (Celgene corp., Summit, NJ) (Aza), a DNA hypomethylating agent. The addition of lenalidomide (Celgene corp.) (L) may augment any ensuing adoptive CTA-specific immune response. These immune effector cells may then be collected and adoptively transferred in a setting of lympho-depletion and minimal residual disease following SCT, serving a maintenance function. To demonstrate the feasibility of this approach, we initiated a phase II clinical trial of Aza administered sequentially with L in patients with residual disease following initial therapy (NCT01050790). Three cycles of Aza (75 mg/m2 day 1–5 SQ) and L (10 mg PO daily, day 6–21) were administered every 4 weeks; autologous lymphocytes (AL) were collected around day 21 of the 2nd and 3rd cycles of Aza-L and cryopreserved. Subsequent stem cell mobilization was followed by melphalan 200 mg/m2 and SCT. GM-CSF was used post-transplant for hematopoietic engraftment. Autologous lymphocyte infusion (ALI) was performed between day +30 to +60. Twelve patients have been enrolled; median age is 60 years (range 40–69). Eight are African American, 10 had disease in first partial remission (PR) and 2 in very good PR (VGPR) at the time of initiation of therapy. Median of 2 prior regimens had been administered (range 1–2) and 6 had prior therapy with L. Stage at diagnosis was II (n=6) and III (n=6) and 4 had abnormal cytogenetics. Eight patients have completed all three cycles of Aza-L; 2 developed grade 3 neutropenia, no other grade 3 to 4 toxicity has been observed. Eight patients have gone through both AL collections, 21 days following cycles 2 and 3 of Aza-L, yielding 0.90±0.41 and 0.81±0.36 ×108 CD3+ cells/kg (mean ± SD) with the first and second procedures. Three patients had further disease response, (1 near complete remission, 2 VGPR) and 5 had stable disease following three months of Aza-L, representing a median 18% decline in para-protein levels before and after therapy. So far 8 patients have undergone stem cell mobilization with either GCSF alone (n=6) or GCSF + plerixafor (n=2), and have collected 11.2±3.3 ×106 CD34+ cells/kg body weight. To date 6 patients have undergone SCT (tandem SCT in 1). Neutrophil engraftment was at median of 14 days (13–14), and no unexpected post transplant toxicities were observed. Four patients received ALI at a median 42 days following SCT with no immediate or remote infusional toxicities. With a median follow up of 9 months post-transplant, all four ALI recipients are progression free with either complete remission (n=1) or VGPR (n=3). Quantitative RT-PCR evaluating a panel of 10 CTA in unfractionated bone marrow specimens collected before and after Aza-L from five patients demonstrated 6–8 discrete CTA induced in each patient (Figure 1). This expression was seen in CD138+ plasma cells when tested. In one patient with an induced increase in NY-ESO 1 expression following Aza-L, an antigen specific immune response was recorded (IFN-g release assay) when blood mononuclear cells were co-cultured with recombinant NY-ESO 1 pulsed monocyte derived dendritic cells. This response was maintained for several months post-transplant (Figure 2). Consistent with this observation, CD3+ T cell counts before and after ALI demonstrated a marked increase in T cell counts at two (mean 959/μl; n=4) and eight (1277/μl) weeks, compared with baseline (414/μl; P=0.05); no difference was seen in the NK cell counts at these times. Further studies to confirm these observations in the remaining patients are ongoing. In conclusion, we demonstrate the safety and feasibility of epigenetic modification resulting in over-expression of antigenic targets in MM. This may then be exploited in formulating adaptive immunotherapy protocols in these patients. Adoptively transferred cells may maintain long-term surveillance against malignant plasma cells in patients with MM. Disclosures: Toor: Celgene corporation: Research Funding. Off Label Use: azacitidine in multiple myeloma. Manjili:Celgene corporation: Research Funding.
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Liang, Huichao, Yanan Guo, Meimei Yin, Aki Kawagishi, Takaho Terada, Yoshihiko Kihara, Toru Kanke, Chaoshe Guo, W. Frank An, and Yi Yang. "Abstract LB130: Identification of fully human CCR8 antibodies that demonstrate excellent ADCC function, potent blocking activity, and robust anti-tumor immune responses." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB130. http://dx.doi.org/10.1158/1538-7445.am2024-lb130.
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Abstract Immune checkpoint inhibitors have demonstrated significant benefits in treating various types of tumors. However, a considerable number of patients do not respond to this therapy. One proposed mechanism for resistance to immune checkpoint inhibitors is the infiltration of large numbers of regulatory T cells (Tregs) into tumors, which hinders the development of effective antitumor immunity and is often linked to poor prognosis. CCR8 is a G-protein-coupled receptor (GPCR) which is predominantly expressed on Tregs infiltrating tumors. The development of CCR8-specific human antibodies to deplete CCR8+ Tregs is a promising therapeutic strategy for cancer treatment. Here, we report the development and characterization of fully human monoclonal antibodies targeting CCR8 that exhibit potent antibody-dependent cellular cytotoxicity (ADCC) activity. These antibodies were generated in CCR8 knock-out RenMab® mice, which were immunized with native CCR8 antigen prepared via a proprietary cell-free membrane protein synthesis technology. Epitope mapping of the antibodies revealed recognition of a unique epitope on the N-terminus extracellular domain of CCR8. Binding assays indicated cross-reactivity of the antibodies across multiple species; importantly, however, these antibodies did not recognize related chemokine receptors, such as CCR2, CCR4, CCR5, or CX3CR1. In vitro, CCR8 antibodies effectively inhibited calcium flux induced by CCL1 binding to the CCR8 receptor. Furthermore, introduction of DE (S239D, I332E) mutations in the Fc region enhanced ADCC activity of these antibodies. To compare the efficacy of these antibodies with anti-CCR8 benchmarks in vivo, we generated benchmark analogs in-house with the same DE mutations and established syngeneic MC38 tumor models in humanized B-hCCR8 mice. In this assay, our CCR8 antibodies demonstrated potent anti-tumor activity. Notably, one mutant clone with optimized developability demonstrated robust inhibition of tumor growth when compared to both benchmark analogs and its original clone. Taken together, our fully human CCR8 antibodies demonstrate enhanced ADCC function, strong blocking activity, and superior in vivo anti-tumor activity, which may support further development into a novel cancer immunotherapy targeting Tregs. Citation Format: Huichao Liang, Yanan Guo, Meimei Yin, Aki Kawagishi, Takaho Terada, Yoshihiko Kihara, Toru Kanke, Chaoshe Guo, W. Frank An, Yi Yang. Identification of fully human CCR8 antibodies that demonstrate excellent ADCC function, potent blocking activity, and robust anti-tumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB130.
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Momose, Fumiyasu, Takashi Nakai, Kohei Yabuuchi, Makiko Yamane, Tae Hayashi, Linan Wang, Yoshiyuki Nakagawa, et al. "Abstract 4091: A novel cancer vaccine based on hyaluronic acid nanogel combined with adoptive T cell therapy induces complete regression of established tumors and long-lasting memory CD8+ T cells." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4091. http://dx.doi.org/10.1158/1538-7445.am2024-4091.
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Abstract Background: We have developed nanosized hydrogel particles (nanogels) to create new nanomaterials for biomedical applications. In particular, Hyaluronic Acid, partially hydrophobized by chemical modification with cholesteryl groups, has a distinguished characteristic to form physically cross-linked NanoGel particles. HANG efficiently forms a stable complex with an antigenic polypeptide (HANG-Vaccine) through hydrophobic interactions. In this study, we investigated the efficacy of HANG-V against tumors resistant to immune checkpoint inhibitors (ICIs) and adoptive TCR-T therapy. Methods: C57BL/6-derived B16F10 melanoma and BALB/c-derived CMS5a sarcoma are both known to be resistant to ICIs and adoptive TCR-T therapy. The efficacy of HANG-V was tested by using each tumor-bearing mice treatment model. HANG-V was prepared by mixing gp100 or CMS5a neoantigen (Ag) with HANG, respectively. Results: HANG-V was subcutaneously injected into B16F10-bearing C57BL/6 on days 7, 11, and 15, and CD8+ T cells from Pmel-1 mice were intravenously administered on days 8 and 12. Surprisingly, complete regression of established B16F10 tumors with more than 100 mm2 were observed. Vaccinated mice survived with changing hair color of mice into white, while non-vaccinated mice were all dead by day 25. Moreover, gp100-specific CTLs was observed abundantly in systemic including tumor site. Even two months after the treatment, transferred T cells with memory phenotype were persistently detected in peripheral bloods. Furthermore, booster vaccination elicited robust expansion of these memory T cells persisting for more than one year. In similar experimental settings, we treated CMS5a tumor-bearing mice by HANG-V combined with adoptive transfer of CD8+ T cells from DUC18 mice, whose T cells are specific for mutated ERK2 neoAg. All mice survived as well with complete reduction of established CMS5a tumors, rejected a rechallenge with CMS5a and induced an Ag-specific CTL responses on more than 2 years. Notably, by using neoantigen-knockout CMS5a, we obtained results suggesting that HANG-V with TCR-T therapy potently induced the so-called “antigen spreading”. Furthermore, induction of Ag-specific CTLs was associated with CD44 hyaluronic acid receptor which expressed in APCs crucial for cross-presentation to CD8+ T cells. Conclusions: HANG-V strongly enhanced the efficacy of adoptive TCR-T cell therapy against ICI refractory tumors leading to total tumor suppression. Furthermore, HANG-V induced potent and persistent Ag-specific CTLs systemically through interaction with CD44 hyaluronic receptor, allowing long-term protection of tumor recurrence with memory CD8+ T cells. Our studies may propose crucial insights for clinical application of HANG vaccine with adoptive T cell therapy in patient with ICI-resistant tumors with poor prognosis. Citation Format: Fumiyasu Momose, Takashi Nakai, Kohei Yabuuchi, Makiko Yamane, Tae Hayashi, Linan Wang, Yoshiyuki Nakagawa, Shogo Aso, Toru Katsumata, Tsuyoshi Shimoboji, Yoshihiro Miyahara. A novel cancer vaccine based on hyaluronic acid nanogel combined with adoptive T cell therapy induces complete regression of established tumors and long-lasting memory CD8+ T cells [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 4091.
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Croce, Marcela. "Ciudades latinoamericanas o la dialéctica entre la utopía entusiasta y la urbanización retobada." Hermenéutica Intercultural, no. 25 (January 3, 2017): 27. http://dx.doi.org/10.29344/07196504.25.515.
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ResumenEl propósito de este artículo es retomar el pensamiento sobre la ciudad como sede espacial, disparador de ideas, iniciativa política y social y manifestación cultural, enfatizando aquellas producciones discursivas típicas del fenómeno urbano como la crónica de la metrópolis, el rastreo antropológico que define los estratos culturales que coexisten en la sede urbana y el relato policial que restituye el entramado de vínculos que operan en el perímetro ciudadano. A esta última formulación se añaden las actividades delictivas que aprovechan un conjunto de disposiciones y servicios urbanos como infraestructura, tal como destacó Saskia Sassen.Con ese objetivo se propone un recorrido por un corpus de textos que se detienen en diversos núcleos urbanos y no se restringen a estudiar sus características geográficas y edilicias sino que las inscriben en el conjunto de cada nación, en la historia de los países que integran América Latina (remarcando la tensión entre ciudad y nación que atraviesa la historia occidental) y asimismo en una serie continental que establece una jerar- quía de ciudades. Las antiguas capitales virreinales que son México y Lima aparecen confrontadas a la capital del virreinato menor que es Buenos Aires, y a la sede imperial de Río de Janeiro en este recorrido.Palabras clave: Ciudades latinoamericanas - Historia urbana - Crónica ciudadana - Géneros urbanos - Utopía latinoamericanaAbstractThis article considers the thinking about cities as space headquarters, an idea nest, a political and social initiative and a cultural manifestation, empha- sizing those discursive productions typical of the urban phenomenon, as the chronicle of the metropolis, the anthropological search that define the cultural strata coexisting in urban headquarters and the police story that restores the linking network that operate in the city perimeters. This latter statement is followed by criminal activities that exploit a set of provisions and urban services such as infrastructure, as Saskia Sassen pointed out.With this objective, we propose a tour through a text corpus that deepen in several urban centers and are not restricted to study their geographical characteristics and buildings, but inscribe them in the set of each nation, in the history of the countries that integrate Latin America (highlighting the tension between city and nation now experienced by Western history) and also in a continental series establishing a hierarchy of cities. The old viceregal capitals, i.e. Mexico and Lima face the minor viceroyalty capital –Buenos Aires– and the imperial headquarters of Rio de Janeiro in this route.Keywords: Latin American cities - Urban history - Citizen chronicle - Urban genres - Latin American utopiaResumo:O objetivo deste artigo é voltar a pensar a cidade como uma sede espa- cial, desencadeador de ideias, iniciativa política e social e manifestações culturais, enfatizando aquelas produções discursivas típicas do fenômeno urbano, como a crônica da metrópole, o reconhecimento antropológico que define os estratos culturais que coexistem na sede urbana e no relato policial que restitui o tramado de ligações que operam no perímetro da cidade. Nesta última formulação integram-se as atividades criminosas que se aproveitam de um conjunto de disposições e serviços urbanos como a infraestrutura, assim como destacou Saskia Sassen.Com este objetivo é proposto percorrer por um corpus de textos que vão parar em diversos núcleos urbanos e não só estarão restritos a estudar suas características geográficas e de construção, mas bem estas se inscrevem no conjunto de cada nação, na história dos países que integram América Latina (destacando a tensão entre a cidade e nação através da história ocidental) e também numa série continental que estabelece uma hierar- quia de cidades. As antigas capitais do vice-reinado colonial: México e Lima são confrontados a capital do vice-reino menor que é Buenos Aires, e a sede imperial do Rio de Janeiro nesta turnê.Palavras-chave: Cidades latino-americanas - História Urbana - Crônica cidadã - Gêneros urbanos - Utopia latino-americana.
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Sakaeda, Kanako, Koji Kurose, Minoru Fukuda, Nanae Sugasaki, Akitoshi Kinoshita, Takashi Kitazaki, Masaaki Fukuda, et al. "Abstract A61: Development of automated immunoassay to detect serum biomarkers predicting response to immune checkpoint inhibitors in NSCLC." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A61. http://dx.doi.org/10.1158/2326-6074.tumimm22-a61.
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Abstract Introduction: Immunotherapy with immune checkpoint inhibitors (ICI) is the standard of care for advanced non-small-cell lung cancer (NSCLC) without driver gene alterations. However, survival benefits with ICI are limited to a small subset of NSCLC patients, and particularly ICI combinations with cytotoxic agents produce serious physical and large financial toxicities. Tumor PD-L1 expression levels/proportion score (TPS) are universally used as predictive biomarkers in ICI monotherapy response and outcomes. However, PD-L1/TPS assays are imperfect because of low analytical validity and reproducibility due to the visual-scoring system by pathologists. Therefore, additional biomarkers are urgently needed to predict ICI therapy response and outcomes. Recently, we reported that serum antibodies (Abs) against NY-ESO-1 and XAGE1 cancer-testis antigens were probably useful biomarkers in the prediction of clinical benefits with anti-PD-1 monotherapy for NSCLC (J Thorac Oncol, 2019). Additionally, we developed a fully automated immunoassay system (HISCLTM) to measure the Abs easily and rapidly (Sakai Y, et al. Clin Chim Acta 2021). In this study, we retrospectively examined whether the Abs measured by HISCLTM predict the clinical benefits with ICI monotherapy for NSCLC.Patients and Methods: Sera were obtained from controls of non-malignant lung diseases (n=75) and healthy subjects (n=100), and advanced NSCLC patients (n=263) to to determine a cutoff value in HISCLTM. In NSCLC patients analyzed here (n=78), sera were obtained before anti-PD-1 monotherapy with nivolumab in second-line or later settings. The serum NY-ESO-1/XAGE1 Abs were measured by HISCLTM, and we examined the relationships between the Abs levels, objective response rate (ORR), progression free survival (PFS), and overall survival (OS) after nivolumab monotherapy.Results: NY-ESO-1/XAGE1 Abs levels in NSCLC patients (n=263) were significantly higher than those in the controls (n=175). A cutoff value was determined as the Abs level of 10 SU/mL, calculated from the Abs values in the controls. The Abs (≥ 10 SU/mL) were detected in 21/78 (27%) of the NSCLC patients treated with nivolumab, and one patient had both NY-ESO-1 and XAGE1 Ab. An ORR was 62%, 16%, and 29% in the Abs-positives, the Abs-negatives, and overall, respectively. The Abs levels in responders were significantly higher than those in non-responders. The NSCLC patients with high-Abs values (≥ 10 SU/mL) had significantly better survivals with nivolumab monotherapy than those with low-Abs (PFS, HR 0.51, 95%CI 0.31-0.83, p < 0.01; OS, HR 0.51, 95%CI 0.31-0.84, p < 0.01). Interestingly, a few NSCLC patients with both high-Abs and driver genes responded well to nivolumab.Conclusions: Serum NY-ESO-1/XAGE1 Abs measured by HISCLTM are potential biomarkers that predict clinical benefits with anti-PD-1 monotherapy for NSCLC, even including driver genes. These findings warrant further biomarker studies using NY-ESO-1/XAGE1 Abs in clinical trial and practice of NSCLC immunotherapy. Citation Format: Kanako Sakaeda, Koji Kurose, Minoru Fukuda, Nanae Sugasaki, Akitoshi Kinoshita, Takashi Kitazaki, Masaaki Fukuda, Takeshi Masuda, Noboru Hattori, Yusuke Atarashi, Yumiko Sakai, Yasuhiro Irino, Mami Yamaki, Toshiyuki Sato, Hiroshi Mukae, Toru Oga, Mikio Oka. Development of automated immunoassay to detect serum biomarkers predicting response to immune checkpoint inhibitors in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A61.
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Hanamura, Toru, Shigehisa Kitano, Hiroshi Kagamu, Makiko Yamashita, Mayako Terao, Banri Tsuda, Takuho Okamura, et al. "Abstract P4-04-09: Systematic analysis of immune cell composition revealed immunological profile of breast cancer microenvironment represented by histologically assessed tumor-infiltrating lymphocyte and PD-L1 expression." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–04–09—P4–04–09. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-04-09.
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Abstract Purpose. The clinical use of immune checkpoint inhibitors for multiple cancers has attracted attention in tumor immunology. Emerging evidence suggests that a better understanding of tumor immunology will lead to the development of new treatment strategies or the effective use of existing therapies. Histologically assessed tumor-infiltrating lymphocytes (hTIL) and programmed cell death 1 ligand 1 (hPD-L1) have been established as prognostic or predictive biomarkers in certain subsets of breast cancer. In addition, researchers have shifted their focus to the various immune cell subsets that make up TILs. However, the complexity of multiple types of immune cells in TIL or PD-L1 expressing cells is not fully understood. In this analysis, the immune cell fraction in breast cancer tissue and blood was evaluated by multicolor flow cytometry (FCM) to analyze the association between them and hTIL and hPD-L1. Methods. Forty-five tumor and 18 blood samples were collected from breast cancer patients. The leukocyte count, proportion of 11 types of immune cell fraction, and PD-L1 expression of each fraction were evaluated by FCM for both tumor and blood samples. The immune cell fractions are classified into the following categories based on the expression of cell surface markers: leukocyte, total T cell (total T), CD4+ T cell (CD4+ T), CD8+ T cell (CD8+T), B cell (B), monocyte/macrophage (Mo/Mϕ), nonclassical monocyte (CD16+Mo), myeloid-derived suppressor cells (MDSC), dendritic cells (DC), myeloid dendritic cells (mDC), natural killer cells (NK), minor NK, and natural killer T cells (NKT). hTIL, and hPD-L1 were evaluated by H-E staining and immunohistochemistry, respectively. Results. The mean density and interquartile range of tumor-infiltrating leukocytes were similar to those in previous report. For the immune cell fraction in the leukocytes of tumor tissue, the main population consisted of CD8+T and CD4+T, which showed a similar trend to that of blood. The proportions of DC, mDC, NK, and minor NK in tumor tissues were positively correlated with those of blood. When the percentage of each immune cell fraction of tumor tissue and that of blood were compared, the proportions of DC, mDC, and minor NK were significantly higher in tumor tissues than those in blood samples, and the proportions of CD4+T and NK were significantly lower in tumor tissue than in blood. No significant association was found between blood immune cell composition and hTIL or hPD-L1. High hTIL levels were associated with high leukocyte infiltration, high proportions of CD4+ T and CD8+ T, and a low proportion of NK and NKT in the tumor tissue. When PD-L1 positive cell percentage of each immune cell fraction was compared between the tumor tissue and blood, PD-L1 positive ratios were significantly higher in tumor tissue than in blood for all lineages except for lymphoid fractions. For tumor tissues, PD-L1 expression was high in Mo/Mϕ, CD16+Mo, MDSC, DC, and mDC. hPD-L1 positivity was associated with PD-L1 expression in Mo/Mϕ, CD16+Mo, DC, and mDC. Conclusion. Comprehensive analysis of the immune cell fractions revealed the immunological profile of breast cancer tissue represented by hTIL or hPD-L1. Our data indicate that hTIL not only reflects the amount of immune cell infiltration but also reflects a state in which acquired immunity is activated relative to innate immunity. Non-B cell antigen-presenting cell fractions such as Mo/Mϕ, CD16+ Mo, MDSC, DC, and mDC were primarily involved in the PD-L1 pathway in breast cancer microenvironments. In addition, hPD-L1 reflects PD-L1 expression in these immune cell fractions. Our data provide a basic understanding of the immune response in the breast cancer microenvironment and contribute to further development of tumor immunology. Citation Format: Toru Hanamura, Shigehisa Kitano, Hiroshi Kagamu, Makiko Yamashita, Mayako Terao, Banri Tsuda, Takuho Okamura, Nobue Kumaki, Katsuto Hozumi, Naoki Harada, Takaiki Iwamoto, Chikako Honda, Sasagu Kurozumi, Naoki Niikura. Systematic analysis of immune cell composition revealed immunological profile of breast cancer microenvironment represented by histologically assessed tumor-infiltrating lymphocyte and PD-L1 expression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-09.
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Joseph, C. "Outbreak of legionnaires’ disease associated with visits to Belgium." Weekly releases (1997–2007) 6, no. 40 (October 3, 2002). http://dx.doi.org/10.2807/esw.06.40.01889-en.
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Five cases of legionnaires’ disease have been reported in British people who all stayed at a hotel in Belgium in the ten days before onset of illness. All have been confirmed as L. pneumophila serogroup 1, one by culture of the organism and four by urinary antigen detection. The first case, who died, was a 63 year old man who became ill on 7 September 2002. He travelled with a small group of ten people, two of whom were reported to have had respiratory symptoms but were negative on testing for legionella infection. Three cases, one male and two female aged between 74 and 84 years were in a party of 46 people on a coach tour to Austria. They became ill between 21 and 24 September and two were hospitalised in France and one in England. The fifth case became ill on the 28 September and is also in hospital in France. This patient (female aged 65 years) was from a third group of 40 British tourists on another Austrian tour. All cases stayed only one night at the hotel in Belgium.
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"Travel associated legionnaires’ disease in Europe in 1999." Eurosurveillance 6, no. 4 (April 1, 2001): 53–60. http://dx.doi.org/10.2807/esm.06.04.00212-en.
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The European Surveillance Scheme for Travel Associated Legionnaires’ Disease was notified of the highest number of cases in travellers in 1999 since the scheme began in 1987. This reflects enhanced surveillance activities and an increase in the use of urinary antigen detection for Legionella pneumophila serogroup 1. The scheme's extensive reporting and investigation activities are complemented in some countries by the activities of tour operators, who have been legally responsible for the health and safety of their clients since the 1996 European Commission’s Package Travel Directive came into force. In recent years, the work conducted by the collaborators has helped establish good surveillance and control in sites used by travellers.
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Lamminsalo, Marko, Timo Karvinen, Astrid Subrizi, Arto Urtti, and Veli-Pekka Ranta. "Extended Pharmacokinetic Model of the Intravitreal Injections of Macromolecules in Rabbits. Part 2: Parameter Estimation Based on Concentration Dynamics in the Vitreous, Retina, and Aqueous Humor." Pharmaceutical Research 37, no. 11 (October 22, 2020). http://dx.doi.org/10.1007/s11095-020-02946-1.
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Abstract Purpose To estimate the diffusion coefficients of an IgG antibody (150 kDa) and its antigen-binding fragment (Fab; 50 kDa) in the neural retina (Dret) and the combined retinal pigment epithelium-choroid (DRPE-cho) with a 3-dimensional (3D) ocular pharmacokinetic (PK) model of the rabbit eye. Methods Vitreous, retina, and aqueous humor concentrations of IgG and Fab after intravitreal injection in rabbits were taken from Gadkar et al. (2015). A least-squares method was used to estimate Dret and DRPE-cho with the 3D finite element model where mass transport was defined with diffusion and convection. Different intraocular pressures (IOP), initial distribution volumes (Vinit), and neural retina/vitreous partition coefficients (Kret/vit) were tested. Sensitivity analysis was performed for the final model. Results With the final IgG model (IOP 10.1 Torr, Vinit 400 μl, Kret/vit 0.5), the estimated Dret and DRPE-cho were 36.8 × 10−9 cm2s−1 and 4.11 × 10−9 cm2s−1, respectively, and 76% of the dose was eliminated via the anterior chamber. Modeling of Fab revealed that a physiological model parameter “aqueous humor formation rate” sets constraints that need to be considered in the parameter estimation. Conclusions This study extends the use of 3D ocular PK models for parameter estimation using simultaneously macromolecule concentrations in three ocular tissues.