Critical role and potential therapeutic efficacy of interleukin‐37 in the pathogenesis of keloid scarring

2020 ◽  
Vol 19 (7) ◽  
pp. 1805-1806
Author(s):  
Yu Zhao ◽  
Jingpei Shi ◽  
Lechun Lyu
Keyword(s):  
Therapeutic Efficacy ◽  
Critical Role ◽  
Keloid Scarring

Critical Role of CD11a (LFA-1) in Therapeutic Efficacy of Systemically Transferred Antitumor Effector T Cells

1999 ◽  
Vol 192 (2) ◽  
pp. 122-132 ◽  
Author(s):  
Shigehiko Mukai ◽  
Hiroshi Kagamu ◽  
Suyu Shu ◽  
Gregory E. Plautz
Keyword(s):  
T Cells ◽  
Therapeutic Efficacy ◽  
Critical Role ◽  
Effector T Cells ◽  
Antitumor Effector

scholarly journals Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity

2021 ◽  
Vol 9 (5) ◽  
pp. e002155
Author(s):  
Zining Wang ◽  
Feifei Xu ◽  
Jie Hu ◽  
Hongxia Zhang ◽  
Lei Cui ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Therapeutic Efficacy ◽  
Antitumor Immunity ◽  
Critical Role ◽  
T Cell Response

BackgroundDendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy.MethodsIn vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3−/− mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment.ResultsBy screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody.ConclusionsOur findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.

The cancer vaccine therapy using DCs derived from iPS cells (iPSDCs) expressing TAA gene.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 768-768
Author(s):  
Hiromitsu Iwamoto ◽  
Toshiyasu Ojima ◽  
Junya Kitadani ◽  
Hiroaki Tabata ◽  
Keiji Hayata ◽  
...  
Keyword(s):  
Clinical Study ◽  
Cancer Vaccine ◽  
Therapeutic Efficacy ◽  
Antitumor Immunity ◽  
Genetically Modified ◽  
Critical Role ◽  
Ips Cells ◽  
Vaccine Therapy ◽  
Vaccine Strategy ◽  
Cea Gene

768 Background: Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the initiation of anti-tumor immune responses. Many cancer patients have previously been treated by the cancer vaccine therapy using DCs worldwide. We have employed a study of a cancer vaccine therapy using genetically modified DCs expressing tumor-associated antigen (TAA) gene. Clinically DCs are generated from the peripheral blood monocytes of patients. Thus the number of monocytes and potential of them are limited, so they are serious obstacle. Recent studies have revealed that induced pluripotent stem (iPS) cells can be generated from murine fibroblasts. Furthermore, it has been reported that DCs can be successfully derived from murine iPS cells (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of naive DCs, then the above-mentioned problems may be solved. Methods: We have induced iPSDCs from murine iPS cells by 4 steps and examined the efficacy as APCs of iPSDCs compared with naive DCs. We also examined whether a vaccine therapy using genetically modified iPSDCs can induce strong therapeutic antitumor immunity compared with naive DCs. Next, we examined the therapeutic antitumor immunity of iPSDCs expressing CEA gene compared with that of naive DCs in pre-clinical study with CEA transgenic mice. Results: We have clarified that genetically modified iPSDCs have an equal efficacy as APCs and TAA-specific therapeutic antitumor immunity, equivalent to naive DCs. And we also have clarified that genetically modified iPSDCs expressing CEA gene have a TAA-specific therapeutic antitumor immunity. Conclusions: This vaccine strategy using genetically modified iPSDCs has an equal capacity with naive DCs in terms of a therapeutic efficacy. Now, we are engaging another pre-clinical study with human, in an effort to apply in a clinical setting.

scholarly journals Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling

Gut ◽  
2019 ◽  
Vol 69 (6) ◽  
pp. 1053-1063 ◽  
Author(s):  
Pim J Koelink ◽  
Felicia M Bloemendaal ◽  
Bofeng Li ◽  
Liset Westera ◽  
Esther W M Vogels ◽  
...  
Keyword(s):  
T Cell ◽  
Therapeutic Efficacy ◽  
Critical Role ◽  
Transfer Model ◽  
Mouse Bone Marrow ◽  
Dependent Manner ◽  
Cell Transfer ◽  
Cell Type ◽  
T Cell Transfer ◽  
Regulatory Phenotype

ObjectiveMacrophage interleukin (IL)-10 signalling plays a critical role in the maintenance of a regulatory phenotype that prevents the development of IBD. We have previously found that anti-tumour necrosis factor (TNF) monoclonal antibodies act through Fcγ-receptor (FcγR) signalling to promote repolarisation of proinflammatory intestinal macrophages to a CD206+ regulatory phenotype. The role of IL-10 in anti-TNF-induced macrophage repolarisation has not been examined.DesignWe used human peripheral blood monocytes and mouse bone marrow-derived macrophages to study IL-10 production and CD206+ regulatory macrophage differentiation. To determine whether the efficacy of anti-TNF was dependent on IL-10 signalling in vivo and in which cell type, we used the CD4+CD45Rbhigh T-cell transfer model in combination with several genetic mouse models.ResultsAnti-TNF therapy increased macrophage IL-10 production in an FcγR-dependent manner, which caused differentiation of macrophages to a more regulatory CD206+ phenotype in vitro. Pharmacological blockade of IL-10 signalling prevented the induction of these CD206+ regulatory macrophages and diminished the therapeutic efficacy of anti-TNF therapy in the CD4+CD45Rbhigh T-cell transfer model of IBD. Using cell type-specific IL-10 receptor mutant mice, we found that IL-10 signalling in macrophages but not T cells was critical for the induction of CD206+ regulatory macrophages and therapeutic response to anti-TNF.ConclusionThe therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.

scholarly journals Inhibition of ERAD synergizes with FTS to eradicate pancreatic cancer cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rong Du ◽  
Delaney K. Sullivan ◽  
Nancy G. Azizian ◽  
Yuanhui Liu ◽  
Yulin Li
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Therapeutic Efficacy ◽  
Synthetic Lethality ◽  
Critical Role ◽  
Combined Treatment ◽  
Marker Genes ◽  
Genetic Ablation ◽  
Pancreatic Cancer Cells ◽  
A Genome

Abstract Background Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), also known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. FTS has demonstrated limited therapeutic efficacy in PDAC patients despite being well tolerated. Methods To improve the efficacy of FTS in PDAC, we performed a genome-wide CRISPR synthetic lethality screen to identify genetic targets that synergize with FTS treatment. Among the top candidates, multiple genes in the endoplasmic reticulum-associated protein degradation (ERAD) pathway were identified. The role of ERAD inhibition in enhancing the therapeutic efficacy of FTS was further investigated in pancreatic cancer cells using pharmaceutical and genetic approaches. Results In murine and human PDAC cells, FTS induced unfolded protein response (UPR), which was further augmented upon treatment with a chemical inhibitor of ERAD, Eeyarestatin I (EerI). Combined treatment with FTS and EerI significantly upregulated the expression of UPR marker genes and induced apoptosis in pancreatic cancer cells. Furthermore, CRISPR-based genetic ablation of the key ERAD components, HRD1 and SEL1L, sensitized PDAC cells to FTS treatment. Conclusion Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.

scholarly journals BALB/c-hCD3E Transgenic Mice: An Ideal Animal Model for In Vivo Efficacy Study of CD3-Bispecific Antibodies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1048-1048
Author(s):  
Cunxiang Ju ◽  
Mingkun Zhang ◽  
Dongjing Jia ◽  
Jing Tang ◽  
Shuai Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Tumor Cells ◽  
Therapeutic Efficacy ◽  
Critical Role ◽  
Unmet Need ◽  
Regulatory Sequence ◽  
Immune System Activation ◽  
And Function

T cell-mediated immunotherapy is an important strategy for treatment of a variety of tumors.T-cell bispecific antibody (TCB), which binds to a tumor associated antigen (TAA) and human CD3ε (hCD3ε) and directs specific killing of tumor cells carrying the TAA. However, there is still an unmet need for suitable animal models to evaluate the therapeutic efficacy of TCB candidates. Although immune-deficient mice transfused with human PBMCs can be used to evaluate the TCBs, these mice are not fully immune competent and have limitation in studying immune system activation by TCBs. Herewe developed a human CD3ε-transgenic mouse model with BALB/c background (BALB/c-hCD3E) to overcome the limitation. CD3ε plays a critical role in formation and function of the TCR-CD3 complex. However, hCD3ε shares only 47% homology with mouse CD3ε (mCD3ε) in the extracellular domain, indicating that hCD3ε and mCD3ε are not functionally interchangeable. Thus, we established BALB/c-hCD3E mice that carry the human CD3E gene and its entire regulatory sequence and co-express hCD3ε and mCD3ε in over 90% of T cells. BALB/c-hCD3E mice were phenotypically normal and had normal T-, B- and NK-cell populations compared to wild-type BALB/c mice. In addition, splenic T cells from BALB/c-hCD3E mice could be activated by either anti-hCD3 or anti-mCD3 antibodies to produce IFNg, IL2 and TNFa in vitro. Moreover, we knocked out mCD3e in BALB/c-hCD3E mice to generate BALB/c-hCD3E/mCd3e-KO mice that displayed a marked reduction in the number of splenic T cells. BALB/c-hCD3E/mCd3e-KO mice also had reduced percentages and numbers of CD4+ and CD8+T cells. Importantly, anti-mCTLA4 antibodies strongly inhibited the growth of subcutaneously inoculated CT26 tumor cells in BALB/c-hCD3E but not BALB/c-hCD3E/mCd3e-KO mice. Taken together, these findings demonstrate that mCD3ε is indispensable for T-cell development and function in BALB/c-hCD3E transgenic mice and these mice are a novel and valuable model to assessing the therapeutic efficacy of TCBs. Disclosures Ju: GemPharmatech Co., Ltd: Employment. Zhang:GemPharmatech Co., Ltd: Employment. Jia:GemPharmatech Co., Ltd: Employment. Tang:GemPharmatech Co., Ltd: Employment. Li:GemPharmatech Co., Ltd: Employment. Zhao:GemPharmatech Co., Ltd: Employment. Wang:GemPharmatech Co., Ltd: Employment. Gao:GemPharmatech Co., Ltd: Employment.

Dexamethasone Effect on Embryonic Chick Respiratory Epithelium

1982 ◽  
Vol 40 ◽  
pp. 248-249
Author(s):  
M.R. Richter ◽  
R.V. Blystone
Keyword(s):  
Lung Development ◽  
Critical Role ◽  
Respiratory Epithelium ◽  
Chick Embryos ◽  
Embryonic Chick ◽  
White Leghorn ◽  
Lung Maturation ◽  
Synthetic Analogs ◽  
Lung Physiology ◽  
Avian Lung

Dexamethasone and other synthetic analogs of corticosteroids have been employed clinically as enhancers of lung development. The mechanism(s) by which this steroid induction of later lung maturation operates is not clear. This study reports the effect on lung epithelia of dexamethasone administered at different intervals during development. White Leghorn chick embryos were used so as to remove possible maternal and placental influences on the exogenously applied steroid. Avian lung architecture does vary from mammals; however, respiratory surfactant produced by the lung epithelia serves an equally critical role in avian lung physiology.

An atomic resolution study of a carbide phase in platinum

1992 ◽  
Vol 50 (1) ◽  
pp. 20-21
Author(s):  
M.J. Witcomb ◽  
M.A. O'Keefe ◽  
CJ. Echer ◽  
C. Nelson ◽  
J.H. Turner ◽  
...  
Keyword(s):  
Solid Solution ◽  
Carbon Atom ◽  
Carbide Phase ◽  
Structural Changes ◽  
Critical Role ◽  
Alloy System ◽  
Atomic Resolution ◽  
Excess Carbon ◽  
Interstitial Carbon ◽  
Resolution Study

Under normal circumstances, Pt dissolves only a very small amount of interstitial carbon in solid solution. Even so, an appropriate quench/age treatment leads to the formation of stable Pt2C {100} plate precipitates. Excess (quenched-in) vacancies play a critical role in the process by accommodating the volume and structural changes that accompany the transformation. This alloy system exhibits other interesting properties. Due to a large vacancy/carbon atom binding energy, Pt can absorb excess carbon at high temperatures in a carburizing atmosphere. In regions rich in carbon and vacancies, another carbide phase, Pt7C which undergoes an order-disorder reaction was formed. The present study of Pt carburized at 1160°C and aged at 515°C shows that other carbides in the PtxC series can be produced.

Quantitative Model-Based Image Analysis of NuMa Distribution Links Nuclear Organization with Cell Phenotype

2001 ◽  
Vol 7 (S2) ◽  
pp. 578-579
Author(s):  
David W. Knowles ◽  
Sophie A. Lelièvre ◽  
Carlos Ortiz de Solόrzano ◽  
Stephen J. Lockett ◽  
Mina J. Bissell ◽  
...  
Keyword(s):  
Image Analysis ◽  
Mammary Epithelial Cells ◽  
Nuclear Organization ◽  
Critical Role ◽  
Quantitative Model ◽  
Mammary Epithelial ◽  
Cell Phenotype ◽  
Proliferating Cells ◽  
Mitotic Apparatus ◽  
Model Based

The extracellular matrix (ECM) plays a critical role in directing cell behaviour and morphogenesis by regulating gene expression and nuclear organization. Using non-malignant (S1) human mammary epithelial cells (HMECs), it was previously shown that ECM-induced morphogenesis is accompanied by the redistribution of nuclear mitotic apparatus (NuMA) protein from a diffuse pattern in proliferating cells, to a multi-focal pattern as HMECs growth arrested and completed morphogenesis . A process taking 10 to 14 days.To further investigate the link between NuMA distribution and the growth stage of HMECs, we have investigated the distribution of NuMA in non-malignant S1 cells and their malignant, T4, counter-part using a novel model-based image analysis technique. This technique, based on a multi-scale Gaussian blur analysis (Figure 1), quantifies the size of punctate features in an image. Cells were cultured in the presence and absence of a reconstituted basement membrane (rBM) and imaged in 3D using confocal microscopy, for fluorescently labeled monoclonal antibodies to NuMA (fαNuMA) and fluorescently labeled total DNA.

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