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2021 ◽  
Vol 11 ◽  
Author(s):  
François Lallemand ◽  
Natacha Leroi ◽  
Silvia Blacher ◽  
Mohamed Ali Bahri ◽  
Evelyne Balteau ◽  
...  

PurposeNeoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. Some clinical studies demonstrated that both timing of surgery and RT schedule influence tumor dissemination, and subsequently patient overall survival. Previously, we developed a pre-clinical model demonstrating the impact of NeoRT schedule and timing of surgery on metastatic spreading. We report on the impact of NeoRT on tumor microenvironment by MRI.MethodsAccording to our NeoRT model, MDA-MB 231 cells were implanted in the flank of SCID mice. Tumors were locally irradiated (PXI X-Rad SmART) with 2x5Gy and then surgically removed at different time points after RT. Diffusion-weighted (DW) and Dynamic contrast enhancement (DCE) MRI images were acquired before RT and every 2 days between RT and surgery. IntraVoxel Incoherent Motion (IVIM) analysis was used to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. For DCE-MRI, we performed semi-quantitative analyses.ResultsWith this experimental model, a significant and transient increase of the perfusion factor F [50% of the basal value (n=16, p<0.005)] was observed on day 6 after irradiation as well as a significant increase of the WashinSlope with DCE-MRI at day 6 (n=13, p<0.05). Using immunohistochemistry, a significant increase of perfused vessels was highlighted, corresponding to the increase of perfusion in MRI at this same time point. Moreover, Tumor surgical resection during this peak of vascularization results in an increase of metastasis burden (n=10, p<0.05).ConclusionSignificant differences in perfusion-related parameters (F and WashinSlope) were observed on day 6 in a neoadjuvant radiotherapy model using SCID mice. These modifications are correlated with an increase of perfused vessels in histological analysis and also with an increase of metastasis spreading after the surgical procedure. This experimental observation could potentially result in a way to personalize treatment, by modulating the time of surgery guided on MRI functional data, especially tumor perfusion.


2021 ◽  
Vol 14 (12) ◽  
pp. 1322
Author(s):  
Belinda L. Sun ◽  
Lin Tang ◽  
Xiaoguang Sun ◽  
Alexander N. Garcia ◽  
Sara M. Camp ◽  
...  

Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2078
Author(s):  
Anna Domaszewska-Szostek ◽  
Magdalena Gewartowska ◽  
Marek Stanczyk ◽  
Beata Narowska ◽  
Maria Moscicka-Wesołowska ◽  
...  

Background. Human skin is needed for covering large body areas lost by trauma. The shortcomings of contemporary methods of skin storage are limited preservation time and high immunogenicity if allogeneic. Methods. We investigated whether long-lasting skin preservation in anhydrous sodium chloride (NaCl) may be the source of keratinocytes (KCs) for transplantation. Dehydrated skin fragments were preserved for a time frame from 1 week to 12 months. Then, skin fragments were rehydrated, and KCs were isolated. The viability of KCs was assessed in viability/cytotoxicity test. NaCl-preserved KCs were cultured for 7 days and transplanted to the dorsum of SCID mice. Results. The morphology of NaCl-preserved KCs was unaltered. KCs from all epidermal layers could be identified. All grafts were accepted by the recipients. Transplanted KCs: synthesized keratins 10 and 16 expressed antigens specific for stem cells and transient-amplifying cells, and remained HLA-I-positive. Moreover, they expressed the proliferative marker PCNA. Cells isolated from transplants remained viable and produced enzymes. Conclusions. Transplantation of KCs obtained from human skin and stored in anhydrous NaCl may be considered for the closure of extensive skin wounds. The originality of this method consists of an effective storage procedure and easy preparation of keratinocytes for transplantation.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Federico A. Moretti ◽  
Giuliana Giardino ◽  
Teresa C. H. Attenborough ◽  
Athina Soragia Gkazi ◽  
Ben K. Margetts ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Federico A. Moretti ◽  
Giuliana Giardino ◽  
Teresa C. H. Attenborough ◽  
Athina Soragia Gkazi ◽  
Ben K. Margetts ◽  
...  

AbstractDeficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency.


2021 ◽  
Vol 15 ◽  
Author(s):  
Huiping Li ◽  
Zhongxiao Fu ◽  
Meixin Hu ◽  
Xiu Xu

Neuroimmune interactions have been studied for decades. Several neurodevelopmental disorders have been associated with immune dysfunction. However, the effects of immune system on neuronal function remain unknown. Herein, based on c-Fos protein expression, we characterized the brain areas that are activated after contextual fear conditioning (CFC) training or retrieval in severe combined immune deficiency (SCID) and wild-type mice. Further, we analyzed the interregional correlations of c-Fos activity that are affected by deficiency in adaptive immunity. Results showed significantly lower c-Fos density in learning and memory-associated brain regions of SCID mice after memory retrieval, but not during the CFC training. Moreover, SCID mice exhibited remarkably discordant interregional neuronal activities of learning neuron circuits after CFC training, which could be the cause of inefficient activation of the memory circuit after retrieval. These results provide a new perspective on how adaptive immunity affects neuronal function. Adaptive immune deficiency impairs the coordination of neural activity after training and retrieval, which might be a potential therapeutic target for neurodevelopmental disorders.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Miao Miao ◽  
Henry Masengere ◽  
Guang Yu ◽  
Fengping Shan

Objective. Natural killer (NK) cell-deficient mice are useful models in biomedical research. NOD/SCID mice have been used as a model of this type in research. However, the actual status of NK cells in NOD/SCID mice and CB17/SCID mice in comparison with that in BALB/c mice has not been sufficiently evaluated. Methods. Splenocytes from naïve or poly(I:C)-treated mice were isolated for phenotyping and analysis of cytotoxicity-related molecules and inhibitory receptors; for cytotoxicity assay, purified NK cells were also used. Results. The proportion of splenic NK cells did not differ significantly between NOD/SCID and CB17/SCID mice. The perforin levels in NK cells were similar between the poly(I:C)-treated CB17/SCID and NOD/SCID mice, while the granzyme B and NKG2A/C/E levels in NK cells from NOD/SCID mice were significantly lower than those from CB17/SCID mice. Moreover, the NKG2D and Ly49A levels in NK cells from NOD/SCID mice were higher than those from CB17/SCID. The splenocytes from CB17/SCID mice showed higher cytotoxicity than those from NOD/SCID mice, while the cytotoxicity of purified NK cells basically did not differ between the two strains. After in vitro stimulation with cytokines, the splenocytes from CB17/SCID mice showed higher IFN-γ production than those from NOD/SCID mice; however, NK cells did not. Conclusion. There was no significant difference in the proportion of splenic NK cells between CB17/SCID and NOD/SCID mice, and the function of NK cells was only partially compromised in NOD/SCID mice. Caution should be taken when considering the use of NOD/SCID mice as an NK-deficient model.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4217-4217
Author(s):  
Mo Yang ◽  
Liang Li ◽  
Yi Luo ◽  
Weiqing Su ◽  
Huimin Kong ◽  
...  

Abstract Background: Essential Thrombocythemia (ET) is characterized by persistently elevated platelet counts in the context of a normal red cell mass. However, the molecular mechanism of ET is still under investigation. Our previous studies demonstrated the presence of functional PDGF receptors (PDGFR) on megakaryocytes and their ability to mediate hematopoiesis and megakaryopoiesis (Ye et al, Haematologica, 2010). The role of PDGF-BB on megakaryocytic progenitors (CD41+, CD34+ cells) and its mechanisms on ET will be further studied in this project. Methods: ELISA, CFU assay, immunofluorescence microscope, flow cytometry and NOD/SCID mice were used in this study. Results: Bone marrow plasma levels of PDGF-BB in ET patients (n=18) and normal control (n=10) were tested and found an increased PDGF-BB levels in ET patients (2071.2±124.8 pg/ml), compared with normal control (1382.5±128.3pg/ml) (P=0.002). In vitro experiment, PDGF-BB promoted the ex vivo expansion of human hematopoietic stem (CD34 +) and progenitor (CD41 + CD61 +) cells. More significantly, PDGF enhanced the engraftment of human CD45 + cells and their myeloid subsets (CD33 +, CD14 + cells) in NOD/SCID mice. PDGF-BB stimulated megakaryopoiesis via PDGFR and its signalling. It also showed a direct stimulatory effect of PDGF-BB on c-Fos, GATA-1 and NF-E2 expressions in megakaryocytes. We speculate that these transcription factors might be involved in the signal transduction of PDGF-BB on the regulation of megakaryopoiesis. PDGF-BB also enhanced platelet recovery in mice model with radiation-induced thrombocytopenia. Studies showed that PDGF, like TPO, significantly promoted platelet recovery and the formation of CFU-MK in this irradiated-mouse. An increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis were found in the bone marrow histology sections. In the CHRF apoptotic model, PDGF-BB had a similar anti-apoptotic effect as TPO on megakaryocytes. We also demonstrated that PDGF-BB activated the p -Akt , p-Jak2 and p-Stat3 expression, while addition of imatinib mesylate reduced p-Akt, p-Jak2 and p-Stat3 expression in CHRF cells. Conclusion: Our findings suggested that PDGF-BB is likely to be mediated via PDGF receptors with subsequent activation of the Akt and Jak2/ Stat3 pathways in megakaryopoiesis. These studies provide a possible explanation that PDGF-BB and its signaling may be involved in the molecular mechanism of essential thrombocythemia. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi219-vi219
Author(s):  
Cassandra Verheul ◽  
Federica Fabro ◽  
Ioannis Ntafoulis ◽  
Cecile Beerens ◽  
Youri Hoogstrate ◽  
...  

Abstract INTRODUCTION The search for effective therapies for gliomas is progressively moving towards patient-specific medicine. In order to test patient-tailored therapies, it is vital to develop protocols for reliable establishment of patient-derived glioma cultures. We present a method for reliable culture establishment, with a 95% success rate in 114 consecutive high-grade samples. METHODS Cell cultures were established from either traditionally-resected tumor tissue or ultrasonic surgical aspirator (CUSA) derived tissue fragments, and expanded in serum-free culture, with selection of astrocytic populations if required. Cultures were started from single cells or small tumor fragments of 0.5-3mm (3D). Whole exome and RNA sequencing were carried out with the Illumina Novaseq and HiSeq platforms. Methylation profiling was performed with the Infinium MethylationEPIC array. Cultures and tumors were compared through analysis of single nucleotide polymorphisms and copy number profiles with the Infinium Global Screening Array. Intra-tumoral heterogeneity in cultures was investigated with single-cell transcriptomic sequencing (SORT-seq). We studied tumor-initiating potential by orthotopic injection of cultures in NOD-SCID mice. RESULTS Cultures started from single cells were established from CUSA material more efficiently (92%) than from traditional resection material (70%). 3D-derived cultures had a higher overall efficiency (95% for CUSA, 85% for traditional resection material). We confirmed high concordance in driver mutations, copy number and methylation profiles between tumors and derived cultures. Transcriptomics analysis, comparing tumors and derived cultures, revealed high consistency in gene expression distribution as demonstrated by correlation analysis (r=0.88). Singe-cell RNA-seq shows increased heterogeneity in CUSA derived-cultures, and decreased heterogeneity with passaging over time. Cultures faithfully produce tumors after orthotopic injection in NOD-SCID mice. CONCLUSION We present a highly successful method for the establishment of glioma cultures from patient material, with CUSA-derived cultures revealing greater heterogeneity. Cultures faithfully represent important molecular characteristics of parental tumors and can be used to test potential therapies in vitro.


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