Journal articles: 'Targeting Mice'

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Gogos, Joseph A., and Maria Karayiorgou. "?Targeting? schizophrenia in mice." American Journal of Medical Genetics 105, no. 1 (2001): 50–52. http://dx.doi.org/10.1002/1096-8628(20010108)105:1<50::aid-ajmg1058>3.0.co;2-5.

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Kuhn, R., F. Schwenk, M. Aguet, and K. Rajewsky. "Inducible gene targeting in mice." Science 269, no. 5229 (September 8, 1995): 1427–29. http://dx.doi.org/10.1126/science.7660125.

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Gao, Jiangang, Xudong Wu, and Jian Zuo. "Targeting hearing genes in mice." Molecular Brain Research 132, no. 2 (December 2004): 192–207. http://dx.doi.org/10.1016/j.molbrainres.2004.06.035.

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Bléry, Mathieu, Manel Mrabet-Kraiem, Ariane Morel, Florence Lhospice, Delphine Bregeon, Cécile Bonnafous, Laurent Gauthier, et al. "Targeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control." Open Research Europe 1 (October 27, 2021): 107. http://dx.doi.org/10.12688/openreseurope.13314.2.

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Background: MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention. Methods: We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules. Results: The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro. However, it showed insufficient efficiency against solid tumors in vivo, which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice. Conclusions: These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.

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Bléry, Mathieu, Manel Mrabet-Kraiem, Ariane Morel, Florence Lhospice, Delphine Bregeon, Cécile Bonnafous, Laurent Gauthier, et al. "Targeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control." Open Research Europe 1 (September 13, 2021): 107. http://dx.doi.org/10.12688/openreseurope.13314.1.

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Background: MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention. Methods: We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules. Results: The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro. However, it showed insufficient efficiency against solid tumors in vivo, which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice. Conclusions: These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.

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Chen, Szu-Tah, Shin-Huei Fu, Samuel Hsu, Yu-Yao Huang, and Brend Ray-Sea Hsu. "Synergistic Effect of Hyperglycemia and Suppression on Adult Mouse Islet Beta Cell Replication." International Journal of Endocrinology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/417390.

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The complementary role of hyperglycemia and suppression on islet beta cell regeneration was investigated in a syngeneic mouse model. gene silencing was performed by infecting islets of C57BL/6 with shRNA lentiviral particles. At 54 hours after viral infection, protein content in cultured targeting islets was 22% of that in freshly isolated islets. Six days after transplantation to diabetic mice, targeting islet graft had considerably more cells with Ki67-staining nuclei than nontargeting islets. The mice in the targeting-islet group had a significantly shorter duration of temporary hyperglycaemia than mice in the non-targeting-islet group. The long-termex vivobeneficial effect of silencing on graft function was also indicated by the significantly higher cumulative cure rate for diabetes in mice receiving 200 targeting islets than that in mice receiving 200 non-targeting islets. Our data suggest that hyperglycemia and persistent suppression have a synergistic effect on islet beta cell replication in adult mice.

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Nakamura, K., C. Fan, G. Liu, S. Gupta, J. He, S. Dou, A. Kubo, M. Rusckowski, and D. J. Hnatowich. "Evidence of Antisense Tumor Targeting in Mice." Bioconjugate Chemistry 15, no. 6 (November 2004): 1475–80. http://dx.doi.org/10.1021/bc0499073.

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Wu, Lawren C., and Heleen Scheerens. "Targeting IgE production in mice and humans." Current Opinion in Immunology 31 (December 2014): 8–15. http://dx.doi.org/10.1016/j.coi.2014.08.001.

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Collison, Joanna. "Targeting Bcl-2 prevents nephritis in mice." Nature Reviews Rheumatology 12, no. 7 (May 26, 2016): 376. http://dx.doi.org/10.1038/nrrheum.2016.90.

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M. Gordon, Erlinda, Seiya Liu, Sant P. Chawla, and Frederick L. Hall. "Polypeptidic Taxol-Tropins: Targeting paclitaxel to the tumor microenvironment." Cancer Research and Cellular Therapeutics 5, no. 3 (July 26, 2021): 01–11. http://dx.doi.org/10.31579/2640-1053/089.

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Background and Rationale: Although PTX is widely used as a single chemotherapeutic agent and in various combination regimens, its clinical utility is hindered by acquired drug resistance and serious dose-limiting side effects that result from the ungoverned biodistribution of the taxane. Hypothesis: Conceptually, the precision, validity, and efficiency of paclitaxel delivery to tumor compartments might be substantially improved by “actively targeting” the exposed collagenous (XC-) proteins presented within the tumor microenvironment (TME)—XC-proteins physically exposed by the pathologic biochemical processes of tumor invasion, reactive stroma formation, and neo-angiogenesis. Objective: An adaptive bioengineering approach aims to apply pathotropic tumor-targeting functionality to paclitaxel (PTX), a powerful cytotoxic taxane which exhibits anti-tubulin / anti-mitotic / anti-cancer activities against a broad range of solid tumors. Materials and Methods: Synthetic peptide XC-targeting probes (< 40 aa) and polypeptide aptamers (40 to 53 aa), 85 - 99% purity, were prepared by 9-fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis, purified by high performance liquid chromatography (HPLC), and verified by mass spectrometry and amino acid analysis, and the XC-targeting probes were FITC-labeled. Analysis of fluorescence in XC-binding assays was visualized with an Ultra Bright Blue Light trans-illuminator equipped with an amber filter; photo-documentation was provided by a Leica V-Lux 1 digital camera; and comparative fluorescence was quantified using a Quantus benchtop fluorimeter (Promega). The tumor-targeting properties of Taxol-Tropins were tested in vitro by Taxol-aptamer binding assays and collagen-agarose binding assays and the bioactivities of PTX bound non-covalently toTaxol-Tropin aptamers were tested on XC-agarose beads. Further, the tumor targeting property of the Taxol-Tropin aptamers was tested in vivo in a murine model of metastatic cancer. Results: Here we report on the first actively targeted delivery of paclitaxel utilizing bifunctional polypeptide targeting onco-aptamers, called Taxol-Tropins, which: (i) bind PTX upon simple mixing with suitably high affinities and; (ii) bind exposed XC-proteins, thereby promoting enhanced partitioning and drug delivery into the TME. The bifunctional peptide sequence-optimized Taxol-Tropins bound tightly non-covalently to PTX and also exhibited high affinity and selectivity for XC-agarose beads in vitro. Importantly, the cytotoxic bioactivity of the Taxol-Tropin-bound-PTX molecule was well preserved in cellulo, as was demonstrated by cytocidal activity observed in MDA-MB-231 breast cancer cell cultures. Tumor-targeted PTX delivery by Taxol-Tropin onco-aptamers in vivo was modeled by subcutaneous xenografts of human pancreatic cancer in nude mice: where intense fluorescence of the PTX probe was observed in tumors of mice injected with the Taxol-Tropin-bound-PTX within minutes after intravenous injection, but not in untreated mice or mice treated with non-targeted PTX probe. Conclusions: These results demonstrate the feasibility of pro-actively targeting PTX, a clinically important small molecule, using Taxol-Tropins: synthetic polypeptide onco-aptamers, revealing optimized drug binding sequences and structural modifications pertinent to further clinical development of the tumor-targeting platform which may indeed shift the Therapeutic Index of PTX to one of greater clinical efficacy at lower drug doses.

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Kalim, Khalid W., Jun-Qi Yang, Mark Wunderlich, Vishnu Modur, Phuong Nguyen, Yuan Li, Ting Wen, et al. "Targeting of Cdc42 GTPase in regulatory T cells unleashes antitumor T-cell immunity." Journal for ImmunoTherapy of Cancer 10, no. 11 (November 2022): e004806. http://dx.doi.org/10.1136/jitc-2022-004806.

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BackgroundCancer immunotherapy has taken center stage in cancer treatment. However, the current immunotherapies only benefit a small proportion of patients with cancer, necessitating better understanding of the mechanisms of tumor immune evasion and improved cancer immunotherapy strategies. Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T-cell function. In the tumor microenvironment, Treg cells are used by tumor cells to counteract effector T cell-mediated tumor suppression. Targeting Treg cells may thus unleash the antitumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T-cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit patients with cancer.MethodsTreg cells from Treg cell-specific heterozygous Cdc42 knockout mice, C57BL/6 mice treated with a Cdc42 inhibitor CASIN, and control mice were examined for their homeostasis and stability by flow cytometry. The autoimmune responses in Treg cell-specific heterozygous Cdc42 knockout mice, CASIN-treated C57BL/6 mice, and control mice were assessed by H&E staining and ELISA. Antitumor T-cell immunity in Treg cell-specific heterozygous Cdc42 knockout mice, CASIN-treated C57BL/6 mice, humanized NSGS mice, and control mice was assessed by challenging the mice with MC38 mouse colon cancer cells, KPC mouse pancreatic cancer cells, or HCT116 human colon cancer cells.ResultsTreg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 with CASIN does not affect Treg cell numbers but induces Treg cell instability, leading to antitumor T-cell immunity without detectable autoimmune reactions. Cdc42 targeting causes an additive effect on immune checkpoint inhibitor anti-programmed cell death protein-1 antibody-induced T-cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell instability and unleashes antitumor T-cell immunity through carbonic anhydrase I-mediated pH changes.ConclusionsRational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

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Deng, Zhongbin, Shenghui Chu, Rui Sun, Xuemei Gu, and Liang Chen. "Targeting shingolipids inhibits alcohol-induced liver disease." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 75.21. http://dx.doi.org/10.4049/jimmunol.204.supp.75.21.

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Abstract Chronic alcohol consumption is accompanied by intestinal inflammation. However, little is known about how alterations to the intestinal immune system and sphingolipids contribute to pathogenesis of alcoholic liver disease (ALD). We used WT mice, RORγt-deficient mice and sphingosine kinase-deficient mice in a chronic-binge ethanol feeding model. Targeted lipidomics assessed the sphingolipids in gut and liver samples. Ethanol-fed and control mice were treated by SK1 inhibitor. Gut immune cell populations, the amounts of sphingolipids, and the level of liver injury were examined. We found that alcohol intake induces an increase in Th17 cells in the gut. Increased Th17 cells were due to upregulation of SK1 activity and Rorc activation. The pathogenic role of S1P/S1PR1 signaling in ALD was attributable to the migration and activation of Th17 cells. Importantly, deletion of SK1 markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. In conclusion, our findings suggest that S1P signaling was crucial in the pathogenesis of alcoholic liver disease in a Th17 cell dependent manner.

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Melicoff, Ernestina, Shakeel M. Thakurdas, Tanya Siddiqi, Jayasimha Murthy, Leticia Sansores-Garcia, and Roberto Adachi. "Mast Cell-Specific Gene Targeting." Blood 106, no. 11 (November 16, 2005): 3876. http://dx.doi.org/10.1182/blood.v106.11.3876.3876.

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Abstract For years mast cell (MC) studies have relied on MC lines or bone marrow-derived MC. Regular knockout mice have some disadvantages such as early lethality and developmental defects. Also, the phenotype in MCs from these animals could not be a primary defect but secondary to other cell lines affected by the mutation. The Cre/loxP system allows us to target genetic deletions to specific tissues or cells. Cre, a recombinase from bacteriophage P1, recognizes a DNA sequence motif of 34 bases (loxP). If a DNA segment is flanked by two loxP sites in the same orientation, Cre excises that segment activating or silencing a gene. Many genes have been “floxed” (flanked by two loxP sites), but no MC-specific Cre mouse has been created. We are using promoter regions of MC-specific proteins to drive expression of Cre-recombinase. We produced transgenic mice using the promoter for human alpha-subunit and murine beta-subunit of the high-affinity receptor for IgE (hFcεRIα and mFcεRIβ), both expressed in MCs and basophils. We also used the promoter of the murine mast cell protease mMCP-5, a member of a family of cargo proteins expressed only in MCs. For even more controlled expression, we knocked-in Cre cDNA into the mMCP-5, mMCP-6 and Ras guanine releasing protein 4 (RasGRP4) loci, all of them proteins expressed exclusively in MCs, while knocking-out the respective gene. Heterozygotes will express Cre only in MCs, and homozygotes for mMCP-5, mMCP-6 or RasGRP4 deletions will be regular knockouts that will allow us to study the role of these proteins in mast cells. These three transgenic and three knock-out/knock-in lines have been created and are being crossed with reporter mice. We decided to use a double reporter mouse, the Bgeo/GFP (Jackson Laboratory). This mouse has “floxed” lacZ that is constitutively expressed under the control of the CMV enhancer/chicken actin promoter, and when crossed with our Cre recombinase-expressing mouse, lacZ is excised and enhanced green fluorescent protein (EGFP) is expressed in cells expressing Cre. EGFP can be easily detected in MCs from peritoneal lavage by flow-cytometry, using antibodies against c-kit (CD117) and FcεRI to label the MCs. Results of this screening will be presented at the meeting. After documenting the presence of functional Cre-recombinase in our reporter mice, we will cross them with our “floxed” mice to obtain conditional mast cell-specific knockouts.

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Kerr, Bethany A. "A trojan horse targeting bone metastasis." Science Translational Medicine 11, no. 512 (October 2, 2019): eaaz3715. http://dx.doi.org/10.1126/scitranslmed.aaz3715.

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Sung, Young Hoon, In-Jeoung Baek, Duk Hyoung Kim, Jisun Jeon, Jaehoon Lee, Kyunghee Lee, Daewon Jeong, Jin-Soo Kim, and Han-Woong Lee. "Knockout mice created by TALEN-mediated gene targeting." Nature Biotechnology 31, no. 1 (January 2013): 23–24. http://dx.doi.org/10.1038/nbt.2477.

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Bordon, Yvonne. "Targeting VCAM1 rejuvenates the brain in aged mice." Nature Reviews Immunology 19, no. 7 (May 24, 2019): 415. http://dx.doi.org/10.1038/s41577-019-0183-y.

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Alla Katsnelson, special to C&EN. "Polymer shrinks tumors in mice by targeting cysteines." C&EN Global Enterprise 100, no. 40 (November 14, 2022): 5. http://dx.doi.org/10.1021/cen-10040-scicon3.

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Becher, Burkhard, Ari Waisman, and Li-Fan Lu. "Conditional Gene-Targeting in Mice: Problems and Solutions." Immunity 48, no. 5 (May 2018): 835–36. http://dx.doi.org/10.1016/j.immuni.2018.05.002.

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Koop, Anja Christina, Nina Doreen Thiele, David Steins, Erik Michaëlsson, Malte Wehmeyer, Ludger Scheja, Babett Steglich, et al. "Therapeutic Targeting of Myeloperoxidase Attenuates NASH in Mice." Hepatology Communications 4, no. 10 (July 29, 2020): 1441–58. http://dx.doi.org/10.1002/hep4.1566.

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Du, Meng, Xiaojing Wang, Lin Yuan, Bing Liu, Xiaoxiang Mao, Dandan Huang, Liu Yang, et al. "Targeting NFATc4 attenuates non-alcoholic steatohepatitis in mice." Journal of Hepatology 73, no. 6 (December 2020): 1333–46. http://dx.doi.org/10.1016/j.jhep.2020.07.030.

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Luna, Jesus, Steven Grossenbacher, Ian Sturgill, Erik Ames, Sean Judge, Lyes Bouzid, Morgan Darrow, William Murphy, and Robert Canter. "Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells." Cancers 11, no. 1 (January 14, 2019): 85. http://dx.doi.org/10.3390/cancers11010085.

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Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients.

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Small, Donna M., Ryan R. Brown, Declan F. Doherty, Anthony Abladey, Zhe Zhou-Suckow, Rebecca J. Delaney, Lauren Kerrigan, et al. "Targeting of cathepsin S reduces cystic fibrosis-like lung disease." European Respiratory Journal 53, no. 3 (January 17, 2019): 1801523. http://dx.doi.org/10.1183/13993003.01523-2018.

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Cathepsin S (CatS) is upregulated in the lungs of patients with cystic fibrosis (CF). However, its role in CF lung disease pathogenesis remains unclear.In this study, β-epithelial Na+ channel-overexpressing transgenic (βENaC-Tg) mice, a model of CF-like lung disease, were crossed with CatS null (CatS−/−) mice or treated with the CatS inhibitor VBY-999.Levels of active CatS were elevated in the lungs of βENaC-Tg mice compared with wild-type (WT) littermates. CatS−/−βENaC-Tg mice exhibited decreased pulmonary inflammation, mucus obstruction and structural lung damage compared with βENaC-Tg mice. Pharmacological inhibition of CatS resulted in a significant decrease in pulmonary inflammation, lung damage and mucus plugging in the lungs of βENaC-Tg mice. In addition, instillation of CatS into the lungs of WT mice resulted in inflammation, lung remodelling and upregulation of mucin expression. Inhibition of the CatS target, protease-activated receptor 2 (PAR2), in βENaC-Tg mice resulted in a reduction in airway inflammation and mucin expression, indicating a role for this receptor in CatS-induced lung pathology.Our data indicate an important role for CatS in the pathogenesis of CF-like lung disease mediated in part by PAR2 and highlight CatS as a therapeutic target.

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Alme, Angela, Liana Senaldi, Adam Waickman, Paul Zarek, and Jonathan Powell. "Targeting A2aR as a means of enhancing anti-tumor vaccines. (131.3)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 131.3. http://dx.doi.org/10.4049/jimmunol.184.supp.131.3.

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Abstract Adenosine, acting via the A2A adenosine receptor (A2aR), is emerging as an important inhibitor of immune function. Indeed, the tumor microenvironment contains relatively high levels of adenosine suggesting that tumor-derived adenosine is one mechanism by which cancers evade immune destruction. To better understand this potential mechanism of tumor immune evasion we challenged A2aR null mice with EL-4 lymphoma. In this model the A2aR null mice routinely rejected their tumors while Wildtype (Wt) mice succumb to tumor-induced death. Interestingly, while both Wt and A2aR null mice were able to reject low doses of tumor, when such mice were rechallenged with lethal doses of tumor, the A2aR mice were greatly protected compared to Wt controls. Such findings suggest that blocking the A2aR might greatly enhance the anti-tumor memory response. As such Wt and A2aR null mice were vaccinated with a whole cell GM-CSF secreting vaccine (GVAX) and challenged with B16 melanoma cells. In these experiments metastasis was markedly decreased in the untreated A2aR null mice when compared with untreated wt mice. Further, while the vaccine led to decreased metastasis in the Wt mice, the vaccine virtually eliminated lung metastasis in the A2aR null mice. Finally, pharmacologic blockade of the A2aR receptor in tumor-bearing mice promoted an increase in tumor antigen specific immunity. Overall, our data suggests that pharmacologic A2aR blockade can enhance the efficacy of tumor immunotherapy.

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Lau, Sai Ping, Nadine van Montfoort, Priscilla Kinderman, Melanie Lukkes, Jasper Dumas, Menno van Nimwegen, Dana Mustafa, et al. "Effect of targeting CD40 for DC vaccination in pancreatic adenocarcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15783-e15783. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15783.

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e15783 Background: Although immunotherapy yields striking results in various malignancies, results in pancreatic cancer have been disappointing. Both a highly immunosuppressive tumor microenvironment and a dense desmoplastic stroma have been found to prohibit proper T-cell infiltration in these tumors, thereby preventing immunotherapy efficacy. We hypothesize that a rational and translational multistep approach is needed to sensitize pancreatic cancer to immunotherapy. In an aggressive murine pancreatic ductal adenocarcinoma model, we assessed the effectiveness of dendritic cell (DC) vaccination in combination with αCD40 treatment, as these treatments are known to induce effector T cells and degrade stroma, respectively. Methods: Immune competent C57BL/6 mice were inoculated subcutaneously with pancreatic tumor cells (KPC3). Mice with established tumors were vaccinated with tumor-loaded monocyte derived DCs and consequently treated with αCD40 agonistic antibodies. Tumor sizes were monitored over time. Immune responses were determined by flow cytometry of cells in peripheral blood, spleen and tumor. NanoString Technologies were applied on tumor samples. Results: A significant delay in tumor growth was found in the combination therapy arm compared to untreated mice and mice treated with DCs or αCD40 alone. Monotherapy had no effect on tumor growth. Survival of mice treated with the combination therapy was also improved compared to untreated mice or mice treated with monotherapy (P < 0.001). Interim blood analysis showed significant increases in frequencies of activated and proliferating T cells in treated animals and those cells also displayed an effector memory phenotype. This was more pronounced for CD4 T cells in mice treated with DCs while αCD40 therapy induced a confined response in CD8 T cells. Increased frequencies of tumor infiltrating lymphocytes were found in all treated mice compared to untreated mice. mRNA expression analysis indicated less exhausted phenotype of intratumoral lymphoid cells in mice treated with DCs and αCD40 compared to monotherapy DCs or αCD40. Conclusions: These results demonstrate the potency of this novel form of combination immunotherapy and reveals a mechanistic insight into the requirements of effective immunotherapy in pancreatic cancer.

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Ablooglu, Ararat J., Jian Kang, Brian G. Petrich, Mark H. Ginsberg, and Sanford J. Shattil. "Antithrombotic effects of targeting αIIbβ3 signaling in platelets." Blood 113, no. 15 (April 9, 2009): 3585–92. http://dx.doi.org/10.1182/blood-2008-09-180687.

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Abstract αIIbβ3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a “β3(Δ760-762)” knockin mouse was generated that lacked the 3 C-terminal β3 residues (arginine-glycine-threonine [RGT]) necessary for αIIbβ3 interaction with c-Src, but retained β3 residues necessary for talin-dependent fibrinogen binding. β3(Δ760-762) mice were compared with wild-type β3+/+ littermates, β3+/− heterozygotes, and knockin mice where β3 RGT was replaced by β1 C-terminal cysteine-glycine-lysine (EGK) to potentially enable signaling by Src kinases other than c-Src. Whereas β3+/+, β3+/− and β3/β1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, β3(Δ760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including β3 (Tyr747). Unlike control mice, β3(Δ760-762) mice were protected from carotid artery thrombosis after vessel injury with FeCl3. Some β3(Δ760-762) mice exhibited prolonged tail bleeding times; however, none demonstrated spontaneous bleeding, excess bleeding after surgery, fecal blood loss, or anemia. Fibrinogen binding to β3(Δ760-762) platelets was normal in response to saturating concentrations of protease-activated receptor 4 or glycoprotein VI agonists, but responses to adenosine diphosphate were impaired. Thus, deletion of β3 RGT disrupts c-Src–mediated αIIbβ3 signaling and confers protection from arterial thrombosis. Consequently, targeting αIIbβ3 signaling may represent a feasible antithrombotic strategy.

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Nowakowski, Adam, Sonia Alonso-Martín, Elena Arias-Salgado, Darío Fernández, MariPaz Vilar, Matilde Ayuso, and Roberto Parrilla. "Megakaryocyte gene targeting mediated by restricted expression of recombinase Cre." Thrombosis and Haemostasis 105, no. 01 (2011): 138–44. http://dx.doi.org/10.1160/th10-06-0378.

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SummaryThe availability of mice with tissue-specific expression of recombinase Cre is the limiting step for a successful gene targeting by the Cre-LoxP methodology. This work aimed at generating transgenic mice with restricted expression of recombinase Cre in megakaryocytes and platelets, driven by the promoter of the αIIb gene (mαIIb-cre). Mice oocytes were microinjected with a 4.1 Kb construct comprising a 2.7 Kb promoter fragment of the glycoprotein αIIb gene, linked to the CrecDNA and followed by the polyA tail of the SV40. We found four mice with positive DNA genotype and three probable sites of genomic integration of the transgene. Only two of the founders showed presence of Cre-mRNA and production of Cre protein, restricted to megakaryocytes. The activity of Cre in mediating gene targeting was assessed by crossing mαIIb-cre mice to Cre-reporter mice (ROSA26-lacZ). The activity of β-galactosidase, detected only in megakaryocytes, was sufficient to generate intense staining of X-Gal in hepatic haematopoietic islands of 14.5 dpc fetuses, in bone marrow megakaryocytes and platelets from adult mice as well as in vitro cultured megakaryocytes differentiated from bone marrow hematopoietic stem cells. Moreover, the recombinase activity was sufficient to produce the specific gene targeting of a floxed CD40L allele in megakaryocytes. The mαIIb-cre transgenic mice with restricted production of Cre in megakaryocytes, offers a selective, alternative, new tool for the genetic analysis of platelet pathophysiology.

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Vang, Derek, Lucile Vincent, Katherine NH Johnson, Nurulaim Zaveri, and Kalpna Gupta. "Targeting Nociceptin Receptor to Treat Pain in Sickle Cell Disease." Blood 120, no. 21 (November 16, 2012): 373. http://dx.doi.org/10.1182/blood.v120.21.373.373.

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Abstract Abstract 373 Morphine and its congeners remain a sub-optimal approach to treat pain in sickle cell disease (SCD) due to side effects, risk of addiction, and development of tolerance. To avoid these liabilities associated with use of morphine and mu opioid receptor (MOR) agonist analgesics, we examined the ability of nociceptin receptor (NOPR) ligands to treat pain in SCD. The NOPR and its endogenous ligand nociceptin/orphanin FQ (N/OFQ) belonging to the opioid receptor (OR) and opioid family respectively, are involved in nociceptive signaling. Small molecule NOPR agonists are non-addicting, while providing analgesia in acute and chronic pain models. We used AT-200 ([1-(1-cyclooctylpiperidin-4-yl)-indolin-2-one), which has high binding affinity and agonist efficacy at NOPR and low efficacy, partial agonist activity at MOR, to treat chronic and hypoxia/reoxygenation (H/R)-evoked pain, in sickle HbSS-BERK and control HbAA-BERK mice, expressing sickle and normal human hemoglobin, respectively. AT-200 was injected subcutaneously at a dose of 10 mg/Kg. Equal number of mice were treated with vehicle in parallel. Pain behaviors were analyzed over a period of time in the following paradigms [i] under normoxia after a single dose of AT-200, [ii] after injecting AT-200 following the incitement of H/R, and [iii] AT-200 given everyday for 7 days. For comparison, we used 20 mg/Kg morphine treatment following H/R. Pain measures that were characterized included deep tissue pain by grip force measurement, cutaneous hyperalgesia by mechanical sensitivity to von Frey filaments and thermal sensitivity to heat and cold as described by us for sickle mice (Kohli et al., Blood 2010). Blood flow and dorsal skin temperature were measured using laser doppler velocimetry and infrared thermography, respectively. The measure of mechanical threshold and suprathreshold to a 1.0 g von Frey fiber showed a significant reduction in mechanical sensitivity even 24h after AT-200 treatment as compared to vehicle under normoxia (p<0.05 for threshold and p<0.005 for suprathreshold) in sickle mice. H/R evoked a persistent increase in mechanical hyperalgesia in sickle mice up to 24h and in control mice up to 4h, and both were ameliorated by AT-200. Morphine reduced mechanical hyperalgesia following H/R in sickle mice up to 4h but not 24h and its effect was significantly less than that of AT-200. H/R-incitement increased deep pain for 24h in sickle mice and for 30 min in control mice and AT-200 ameliorated both. Interestingly, morphine significantly blocked deep pain at 30 min following H/R (p<0.005), but remained ineffective thereafter in sickle mice. Since deep pain appears is a characteristic feature of vasoocclusive pain in sickle mice as compared to cutaneous pain, it is likely that AT-200 acts as a superior analgesic with a long-lasting effect to treat sickle-specific vasoocclusive pain, compared to morphine. Heat and cold sensitivity were persistently elevated in sickle mice up to 24h post-H/R but returned to baseline (before H/R) in control mice. Both, AT-200 and morphine inhibited the H/R-induced thermal sensitivity up to 24h, in sickle mice, but the effect of AT-200 was significantly more remarkable than morphine. Blood flow and skin temperature increased significantly following H/R in sickle mice (p<0.05 for both vs baseline before H/R) and were significantly reduced by AT-200 and morphine equally, suggesting that both drugs have a similar acute effect on vascular physiology and inflammation in sickle mice. The enhanced analgesic effectiveness of AT-200 compared to morphine, in sickle mice could be due to a ∼2-fold increase in NOPR expression in the dorsal root ganglion of sickle mice compared to control, observed by qPCR in this study. Chronic pain conditions, including pain in sickle mice, are characterized by reduced MOR expression peripherally and in the spinal cord. However, spinal NOPR expression by qPCR did not show a significant difference between sickle and control mice. AT-200 was effective in treating chronic cutaneous, deep tissue and thermal hyperalgesia even after 7 days of continuous treatment without causing tolerance. Thus, AT-200 provided an analgesic effect in chronic pain and that evoked by H/R, without the development of analgesic tolerance in sickle mice. Targeting NOPR appears to be a promising strategy warranting further development of novel NOPR agonists to treat pain in SCD. Disclosures: No relevant conflicts of interest to declare.

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Hu, Jinqi, Guanbin Gao, Meng He, Qiang Yin, Xiaobing Gao, Haixing Xu, and Taolei Sun. "Optimal route of gold nanoclusters administration in mice targeting Parkinson’s disease." Nanomedicine 15, no. 6 (March 2020): 563–80. http://dx.doi.org/10.2217/nnm-2019-0268.

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Aim: To explore the optimal route of gold nanoclusters (AuNCs) administration in mice targeting Parkinson’s disease. Materials & methods: Assessing the pharmacokinetic and bioavailability of AuNCs in mice administrated following intravenous, intraperitoneal, gavage and intranasal injection. Investigating the biodistribution of AuNCs in mice by atomic absorption spectrometry and transmission electron microscope. Toxicity assessments of AuNCs were carried out both in cells and in mice. Results: Administration of AuNCs via intraperitoneal injection showed the greatest bioavailability and the longest residence in brain. AuNCs could penetrate blood–brain barrier and be excreted mainly through kidney. No obvious toxicity of AuNCs found in cells and in mice. Conclusion: The optimal route of AuNCs administration in mice targeting Parkinson’s disease is intraperitoneal administration.

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Chen, X., W. Li, H. Yoshida, S. Tsuchida, H. Nishimura, F. Takemoto, S. Okubo, A. Fogo, T. Matsusaka, and I. Ichikawa. "Targeting deletion of angiotensin type 1B receptor gene in the mouse." American Journal of Physiology-Renal Physiology 272, no. 3 (March 1, 1997): F299—F304. http://dx.doi.org/10.1152/ajprenal.1997.272.3.f299.

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We null mutated the mouse angiotensin type 1B (AT1B) receptor gene (Agtr1b) by gene targeting. To identify the specific cell types carrying high Agtr1b gene transcriptional activities, the AT1B coding exon was replaced with a reporter gene, lacZ. In 6- to 8-wk-old Agtr1b -/- mice, high AT1B transcriptional activity was observed in adrenal zona glomerulosa cells and the testis, including mature and immature spermatic cells, whereas low activity was detected homogeneously in anterior pituitary cells and choroidal plexus vessel walls. A similar pattern was observed in Agtr1b +/- mice with less intensity. Microscopically, the anterior pituitary, heart, adrenal, zona glomerulosa, kidney, and the testis of Agtr1b -/- mice were intact and were indistinguishable from those of Agtr1b +/+ mice. Systemic blood pressure was comparable in Agtr1b -/- and Agtr1b +/+ mice. Moreover, plasma aldosterone level was comparable between the two mouse groups. No compensatory enhancement of AT1A mRNA was found in the kidney and adrenal gland of Agtr1b -/- mice. The observed absence of the abnormal phenotypes in Agtr1b -/- mice, which have been described for homozygous angiotensinogen null mutant mice, indicates that 1) AT1A receptors can take over the role of AT1B receptors in Agtr1b -/- mice or 2) functionally significant non-AT1, non-AT2 receptor(s) may exist for the action of angiotensin.

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Mukherjee, Sandip, Jake Haubner, and Anutosh Chakraborty. "Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases." Molecules 25, no. 6 (March 19, 2020): 1403. http://dx.doi.org/10.3390/molecules25061403.

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In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.

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Nakagawa, Masahiro Marshall, Aruna Kode, Sanil J. Manavalan, Govind Bhagat, Julie Teruya-Feldstein, Azra Raza, Ellin Berman, and Stavroula Kousteni. "Targeting the Osteoblast in Myelodysplasia and Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 2551. http://dx.doi.org/10.1182/blood.v126.23.2551.2551.

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Abstract It has previously been shown that an activating mutation in β-catenin in osteoblasts leads to the development of myelodysplasia (MDS) with rapid progression to AML in mice through upregulation of Jagged1 expression in osteoblasts and subsequent activation of Notch signaling in hematopoietic cells. The disease is cell autonomous, because it can be transferred to healthy, lethally irradiated recipients. Moreover, the AML phenotype is associated with clonal evolution at the cytogenetic level since common clonal abnormalities are detected in leukemic blasts from all leukemic mice examined. Revealing the relevance of these observations to human disease, activated β-catenin/Notch signaling was identified in 30% of patients with MDS or AML arising from previous MDS. In the current study we examined the efficacy of a monoclonal mouse anti-human Jagged1 ab (JAG1 ab) as a therapeutic agent for osteoblast-induced MDS/AML. JAG1 ab, which recognizes EGF2/EGF4 domains of human, mouse and rat JAG-1, efficiently bound to them with an EC50 ≤ 0.066 nM (11ng/ml) and dose dependently inhibited Jagged-1 induced Notch signaling with an IC50 ≤ 6nM (1ug/ml) in a Notch reporter assay. Single administration pharmacokinetic (PK) analysis in mice for 3 mg/kg BW showed maximum blood concentration (6.26 µg/ml) in 24 hr, and a terminal half-life of 36 hrs. Organ dysfunction or toxicity was not observed at concentrations as high as 30 mg/kg BW for 5 weeks. The efficacy of weekly subcutaneous administration of 3 mg/kg BW was examined in the AML model of activated β-catenin in osteoblasts (Ctnnb1CAosb mice). Administration of JAG1 ab atpost natal day 8, a time at which MDS/AML has fully developed, prevented anemia, neutrophilia and lymphocytopenia of Ctnnb1CAosb mice. Infiltration of blood with leukemia blasts was reversed within 2 weeks following JAG1 ab administration (2 doses). JAG1 ab reversed the increase in the LSK+/CD150+/CD48- subset of long term repopulating HSC progenitors, the leukemia initiating population in Ctnnb1CAosb mice. The percentage of mature myeloid population (CD11b+/Gr1+) increased in the JAG1 ab treated mice suggesting that blocking Jagged-1 signaling promotes myeloid maturation. Indeed, JAG ab abolished myeloid block as shown by the decrease in the ckit+/CD11b+/Gr1 cells that define immature myeloid progenitors. Dysplastic features seen in the marrow, spleen and liver of Ctnnb1CAosb mice were absent in JAG ab-treated animals and normal trilineage hematopoiesis was established. As a result, JAG1 ab prevented lethality of Ctnnb1CAosb mice and progressively increased body weight for a period of at least 12 weeks, the entire time that the treatment was maintained. Upon termination of the treatments, blast infiltration in the blood appeared within 5 weeks with subsequent development of full blown AML phenotype leading to lethality within 23 weeks. These results suggest that blocking Jagged-1 signaling between osteoblasts and HSCs efficiently treats osteoblast-induced MDS/AML in mice and may have a therapeutic application in patients with MDS and MDS transformed to AML. Disclosures No relevant conflicts of interest to declare.

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Park, Joo Young, Martin Darvas, and Warren Ladiges. "Targeting IGF1R signaling for brain aging and Alzheimer’s disease." Aging Pathobiology and Therapeutics 4, no. 4 (December 29, 2022): 129–31. http://dx.doi.org/10.31491/apt.2022.12.103.

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The role of IGF1R signaling in the brain and its relationship to aging and neurological dysfunction is controversial. Because it was shown that low IGF1R activity consistently improved myocardial bioenergetics and function in hearts from aging mice, but not hearts from young mice, it was of interest to investigate this relationship in brain aging. We used CRISPR technology to develop a mouse model with targeted replacement of mouse IGF1R with the equivalent of the human R407H (IGF1RR407H) variant enriched in centenarians with a reduction in IGF1R protein activity. Middle-aged mice show improved cognitive performance thus possibly modeling IGF1R signaling in the aging brain, similar to what was reported in the aging heart. Because Alzheimer’s disease (AD) is an age-related disease, specific IGF1RR407H pathways could be therapeutic targets in mice with AAV vector-based AD as well as for overall brain aging. Keywords: IGF1R signaling, IGF1RR407H variant, brain aging, cognition, Alzheimer’s disease

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Wang, Honglin, and Jinlin Liu. "Targeting Tumor-Expressing CCR6 Inhibits Colorectal Cancer Progression in Mice (127.44)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 127.44. http://dx.doi.org/10.4049/jimmunol.188.supp.127.44.

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Abstract Background: CCR6/CCL20 expressed by colorectal cancer (CRC) cells. Although their interactions may play an essential role in proliferation and migration of CRC, the in vivo evidence is lacking. Methods: Expression of CCR6/CCL20 was evaluated in 130 primary tumor specimens from CRC patients. Mouse models was established by the injection of CMT93 transfected with luciferase in CCR6-/- mice, or by crossing CCR6-/- mice with APCmin/+ mice. Intratumor injection of anti-CCR6 was performed in CCR6-/- mice grafted luciferase-labeled CMT93. Luciferase intensity of CMT93 was monitored using the IVIS Imaging System. Intestinal tumor development in APCmin/+ mice was studied with a dissecting microscope. Migration of CMT-93 treated with anti-CCR6 was investigated by the Real-Time Cell Analyzer. Results: In contrast to paratumor tissues, CCR6/CCL20 predominantly expressed by tumor cells in CRC patients of all tumor stages. CCR6/CCL20 was consistently identified in CMT-93. Injection of anti-CCR6, significantly inhibited the growth of CRC in CCR6-/- mice. Knock-out of CCR6 resulted in a decrease in numbers and size of intestinal adenomas in APCmin/+ mice. Anti-CCR6 treatment markedly inhibited the migration of CMT-93 in vitro. Conclusion: The CCR6/CCL20 interaction plays an essential role in proliferation and migration of colorectal cancer cells via the autocrine mechanism in mice, and selectively targeting tumor-expressing CCR6 may harbor a novel therapeutic strategy for human CRC.

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McKallip, Robert, Christy Bridges, Gabriela Law, and Jingping Sun. "Targeting CD44 in SEB-induced acute respiratory distress syndrome (54.13)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 54.13. http://dx.doi.org/10.4049/jimmunol.188.supp.54.13.

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Abstract Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In the current study we investigated the role of CD44 in ALI/ARDS. Intranasal exposure of CD44 wild type (CD44 WT) mice to SEB led to a significant increase in the expression of CD44 on lung mononuclear cells. CD44 knockout (CD44 KO) mice developed significantly reduced SEB-induced ALI/ARDS, compared to similarly treated CD44 WT mice. Deletion of CD44 did not have a significant effect on lymphocyte activation, apoptosis or inflammatory cytokine production. However, mononuclear cell migration to the lungs of SEB-exposed CD44 KO mice was significantly reduced when compared to mononuclear infiltration in the lungs of SEB-exposed CD44 WT mice. Mechanistically, deletion of CD44 led to reduced ability of SEB-exposed spleen cells to bind to lung epithelial cells. Finally, treatment of SEB-exposed mice with anti-CD44 mAbs led to a significant reduction in vascular permeability, prevented inflammatory cells infiltration in the lungs and reduced the ability of SEB-exposed splenocytes to adhere to epithelial cells. Together, these results demonstrate an important role of CD44 in SEB-induced lung injury and suggest the possibility of targeting CD44 for the treatment of SEB-induced ALI/ARDS.

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Dhanesha, Nirav, Manasa K. Nayak, Prakash Doddapattar, Manish Jain, Gagan D. Flora, Shigeyuki Kon, and Anil K. Chauhan. "Targeting myeloid-cell specific integrin α9β1 inhibits arterial thrombosis in mice." Blood 135, no. 11 (March 12, 2020): 857–61. http://dx.doi.org/10.1182/blood.2019002846.

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Abstract Evidence suggests that neutrophils contribute to thrombosis via several mechanisms, including neutrophil extracellular traps (NETs) formation. Integrin α9β1 is highly expressed on neutrophils when compared with monocytes. It undergoes affinity upregulation on neutrophil activation, and stabilizes adhesion to the activated endothelium. The role of integrin α9 in arterial thrombosis remains unexplored. We generated novel myeloid cell-specific integrin α9−/− mice (α9fl/flLysMCre+) to study the role of integrin α9 in arterial thrombosis. α9fl/fl littermates were used as controls. We report that α9fl/flLysMCre+ mice were less susceptible to arterial thrombosis in ferric chloride (FeCl3) and laser injury-induced thrombosis models with unaltered hemostasis. Neutrophil elastase-positive cells were significantly reduced in α9fl/flLysMCre+ mice concomitant with reduction in neutrophil count, myeloperoxidase levels, and red blood cells in the FeCl3 injury-induced carotid thrombus. The percentage of cells releasing NETs was significantly reduced in α9fl/flLysMCre+ mouse neutrophils stimulated with thrombin-activated platelets. Furthermore, we found a significant decrease in neutrophil-mediated platelet aggregation and cathepsin-G secretion in α9fl/flLysMCre+ mice. Transfusion of α9fl/fl neutrophils in α9fl/flLysMCre+ mice restored thrombosis similar to α9fl/fl mice. Treatment of wild-type mice with anti-integrin α9 antibody inhibited arterial thrombosis. This study identifies the potential role of integrin α9 in modulating arterial thrombosis.

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Welling, Mick M., Nikolas Duszenko, Danny M. van Willigen, Wiep Klaas Smits, Tessa Buckle, Meta Roestenberg, and Fijs W. B. van Leeuwen. "Cyclodextrin/Adamantane-Mediated Targeting of Inoculated Bacteria in Mice." Bioconjugate Chemistry 32, no. 3 (February 23, 2021): 607–14. http://dx.doi.org/10.1021/acs.bioconjchem.1c00061.

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37

Tawfeeq, Amer Talib Tawfeeq, Husam Al-Deen Mohammed Kadhim Kadhim, Nahi Yusif Yseen Yseen, Saba K. Kalil Kalil, Teaba H. Jafar Jafar, Aseel F. Ghedan Ghedan, and Rasha A. Hussein Hussein. "Targeting Mice Mammary Adenocarcenoma Cells with Zinc Oxide Nanoparticles." Journal of Biotechnology Research Center 9, no. 2 (June 1, 2015): 14–20. http://dx.doi.org/10.24126/jobrc.2015.9.2.426.

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The cytotoxic effect of zinc oxide nanoparticles against mice mammary adenocarcenoma cells wascarried out in vitro. The used nanoparticles were synthesized by pulsed laser ablation in liquidmethods; the used liquid was deionized water. Colloidal suspension of zinc oxide nanoparticles wassynthesized by Q-switched Nd: YAG pulse laser device (1064 nm) laser energy was 600 mJ and pulseduration was 10 nanosecond. High purity metallic zinc plate was submerged in 10 ml deionizedwater in 50 ml glass baker and ablated with 1000 pulse at room temperature. The nanospecificitiesof the synthesized nanoparticle colloidal were characterized with UV-Vis scanningspectrophotometer. Atomic force microscope was used to determine the particle size distribution andparticles shape. The ZnO crestless formation was characterized by X-ray diffraction.Mice mammary adenocarcenoma cells was treated with 25, 50, 100 ppm of ZnO nanoparticles.Results indicated a significant toxicity of the ZnO nanoparticles toward cancer cells, this toxicitycorrelated directly with ZnO nanoparticles elevated concentrations. These result need to be furtherinvestigated and the molecular mechanism of ZnO nanoparticles effect should be more clarify.

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Lassègue, Bernard, Sandeep Kumar, Rohan Mandavilli, Keke Wang, Michelle Tsai, Dong-Won Kang, Catherine Demos, et al. "Characterization of Poldip2 knockout mice: Avoiding incorrect gene targeting." PLOS ONE 16, no. 12 (December 20, 2021): e0247261. http://dx.doi.org/10.1371/journal.pone.0247261.

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POLDIP2 is a multifunctional protein whose roles are only partially understood. Our laboratory previously reported physiological studies performed using a mouse gene trap model, which suffered from three limitations: perinatal lethality in homozygotes, constitutive Poldip2 inactivation and inadvertent downregulation of the adjacent Tmem199 gene. To overcome these limitations, we developed a new conditional floxed Poldip2 model. The first part of the present study shows that our initial floxed mice were affected by an unexpected mutation, which was not readily detected by Southern blotting and traditional PCR. It consisted of a 305 kb duplication around Poldip2 with retention of the wild type allele and could be traced back to the original targeted ES cell clone. We offer simple suggestions to rapidly detect similar accidents, which may affect genome editing using both traditional and CRISPR-based methods. In the second part of the present study, correctly targeted floxed Poldip2 mice were generated and used to produce a new constitutive knockout line by crossing with a Cre deleter. In contrast to the gene trap model, many homozygous knockout mice were viable, in spite of having no POLDIP2 expression. To further characterize the effects of Poldip2 ablation in the vasculature, RNA-seq and RT-qPCR experiments were performed in constitutive knockout arteries. Results show that POLDIP2 inactivation affects multiple cellular processes and provide new opportunities for future in-depth study of its functions.

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Wen, Min, Shin Jung, Kyung-Sub Moon, Shen Nan Jiang, Song-Yuan Li, and Jung-Joon Min. "Targeting Orthotopic Glioma in Mice with Genetically EngineeredSalmonella typhimurium." Journal of Korean Neurosurgical Society 55, no. 3 (2014): 131. http://dx.doi.org/10.3340/jkns.2014.55.3.131.

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FENG, SHU, NATALIA V. BOGATCHEVA, APARNA A. KAMAT, and ALEXANDER I. AGOULNIK. "Genetic Targeting of Relaxin and Insl3 Signaling in Mice." Annals of the New York Academy of Sciences 1041, no. 1 (May 2005): 82–90. http://dx.doi.org/10.1196/annals.1282.012.

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Doetschman, Thomas, and Mohamad Azhar. "Cardiac-Specific Inducible and Conditional Gene Targeting in Mice." Circulation Research 110, no. 11 (May 25, 2012): 1498–512. http://dx.doi.org/10.1161/circresaha.112.265066.

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Sidaway, Peter. "Targeting connexin-43 reduces progression of CKD in mice." Nature Reviews Nephrology 10, no. 8 (June 10, 2014): 424. http://dx.doi.org/10.1038/nrneph.2014.101.

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Kim, Yongsub, Seung-A. Cheong, Jong Geol Lee, Sang-Wook Lee, Myeong Sup Lee, In-Jeoung Baek, and Young Hoon Sung. "Generation of knockout mice by Cpf1-mediated gene targeting." Nature Biotechnology 34, no. 8 (June 6, 2016): 808–10. http://dx.doi.org/10.1038/nbt.3614.

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Xue, Xingkui, Nancy K. Pech, W. Christopher Shelley, Edward F. Srour, Mervin C. Yoder, and Mary C. Dinauer. "Antibody targeting KIT as pretransplantation conditioning in immunocompetent mice." Blood 116, no. 24 (December 9, 2010): 5419–22. http://dx.doi.org/10.1182/blood-2010-07-295949.

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Abstract Inherited hematologic defects that lack an in vivo selective advantage following gene correction may benefit from effective yet minimally toxic cytoreduction of endogenous hematopoietic stem cells (HSCs) prior to transplantation of gene-modified HSCs. We studied the efficacy of administering a novel sequential treatment of parenteral ACK2, an antibody that blocks KIT, followed by low-dose irradiation (LD-IR) for conditioning of wild-type and X-linked chronic granulomatous disease (X-CGD) mice. In wild-type mice, combining ACK2 and LD-IR profoundly decreased endogenous competitive long-term HSC repopulating activity, and permitted efficient and durable donor-derived HSC engraftment after congenic transplantation. ACK2 alone was ineffective. The combination of ACK2 and LD-IR was also effective conditioning in X-CGD mice for engraftment of X-CGD donor HSCs transduced ex vivo with a lentiviral vector. We conclude that combining ACK2 with LD-IR is a promising approach to effectively deplete endogenous HSCs and facilitate engraftment of transplanted donor HSCs.

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Schwenk, F., P. O. Angrand, R. Kühn, A. F. Stewart, and K. Rajewsky. "Ligand inducible, B cell-specific gene targeting in mice." Immunology Letters 56 (May 1997): 93. http://dx.doi.org/10.1016/s0165-2478(97)85365-5.

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Schwenk, F. "Ligand inducible, B cell-specific gene targeting in mice." Immunology Letters 56, no. 1-3 (May 1997): 93. http://dx.doi.org/10.1016/s0165-2478(97)87203-3.

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Sood, Rashmi, and Hartmut Weiler. "Embryogenesis and gene targeting of coagulation factors in mice." Best Practice & Research Clinical Haematology 16, no. 2 (June 2003): 169–81. http://dx.doi.org/10.1016/s1521-6926(02)00092-0.

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Bianco, Robert A., Henry L. Keen, Julie L. Lavoie, and Curt D. Sigmund. "Untraditional methods for targeting the kidney in transgenic mice." American Journal of Physiology-Renal Physiology 285, no. 6 (December 2003): F1027—F1033. http://dx.doi.org/10.1152/ajprenal.00207.2003.

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With the completion of the human genome project and the sequencing of many genomes of experimental models, there is a pressing need to determine the physiological relevance of newly identified genes. Gene-targeting approaches have become an important tool in our arsenal to dissect the significance of genes expressed in many tissues. A wealth of experimental models has been made to assess the role of gene expression in renal function and development. The development of new and informative models is presently limited by the anatomic complexity of the kidney and the lack of cell-specific promoters to target the numerous diverse cell types in that organ. Because of this, new approaches may have to be developed. In this review, we will discuss several untraditional methods to target gene expression to the kidney. These approaches should provide some additional tricks and tools to help in developing additional informative models for studying renal physiology.

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Liao, Li-Shang, Ming-Wei Zhang, Ying-Jiang Gu, and Xiao-Chuan Sun. "Targeting CCL20 inhibits subarachnoid hemorrhage-related neuroinflammation in mice." Aging 12, no. 14 (June 21, 2020): 14849–62. http://dx.doi.org/10.18632/aging.103548.

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Song, Erwei, Sang-Kyung Lee, Jie Wang, Nedim Ince, Nengtai Ouyang, Jun Min, Jisheng Chen, Premlata Shankar, and Judy Lieberman. "RNA interference targeting Fas protects mice from fulminant hepatitis." Nature Medicine 9, no. 3 (February 10, 2003): 347–51. http://dx.doi.org/10.1038/nm828.

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Journal articles on the topic 'Targeting Mice'

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