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2021 ◽  
Vol 47 (2) ◽  
Author(s):  
Nobuyuki Ishikura ◽  
Masamichi Sugimoto ◽  
Keigo Yorozu ◽  
Mitsue Kurasawa ◽  
Osamu Kondoh
Keyword(s):  

2021 ◽  
Vol 11 (11) ◽  
pp. 1160
Author(s):  
Xin Wu ◽  
Yuhki Yokoyama ◽  
Hidekazu Takahashi ◽  
Shihori Kouda ◽  
Hiroyuki Yamamoto ◽  
...  

In the past few years, we have demonstrated the efficacy of a nanoparticle system, super carbonate apatite (sCA), for the in vivo delivery of siRNA/miRNA. Intravenous injection of sCA loaded with small RNAs results in safe, high tumor delivery in mouse models. To further improve the efficiency of tumor delivery and avoid liver toxicity, we successfully developed an inorganic nanoparticle device (iNaD) via high-frequency ultrasonic pulverization combined with PEG blending during the production of sCA. Compared to sCA loaded with 24 μg of miRNA, systemic administration of iNaD loaded with 0.75 μg of miRNA demonstrated similar delivery efficiency to mouse tumors with little accumulation in the liver. In the mouse therapeutic model, iNaD loaded with 3 μg of the tumor suppressor small RNA MIRTX resulted in an improved anti-tumor effect compared to sCA loaded with 24 μg. Our findings on the bio-distribution and therapeutic effect of iNaD provide new perspectives for future nanomedicine engineering.


Author(s):  
Junyoung Seo ◽  
Jae Do Yoo ◽  
Minseong Kim ◽  
Gayong Shim ◽  
Yu-Kyoung Oh ◽  
...  

AbstractFibrin, one of the components of the extracellular matrix (ECM), acts as a transport barrier within the core of tumors by constricting the blood vessels and forming clots, leading to poor intratumoral distribution of anticancer drugs. Our group previously developed a microplasmin-based thrombolytic ferritin nanocage that efficiently targets and dissolves clots without causing systemic fibrinolysis or disrupting hemostatic clots. We hypothesized that the thrombolytic nanocage-mediated degradation of fibrin clots in the tumor ECM can lead to enhanced intratumoral drug delivery, especially for nanosized anticancer drugs. Fibrin clot deposition worsens after surgery and chemotherapy, further hindering drug delivery. Moreover, the risk of venous thromboembolism (VTE) also increases. Here, we used thrombolytic nanocages with multivalent clot-targeting peptides and fibrin degradation enzymes, such as microplasmin, to dissolve fibrin in the tumor microenvironment and named them fibrinolytic nanocages (FNCs). These FNCs target tumor clots specifically and effectively. FNCs efficiently dissolve fibrin clots inside of the tumor vessels, suggesting that they can mitigate the risk of VTE in cancer patients. Coadministration of FNC and doxorubicin led to improved chemotherapeutic activity in a syngeneic mouse melanoma model. Furthermore, the FNCs increased the distribution of Doxil/doxorubicin nanoparticles within mouse tumors. These results suggest that fibrinolytic cotherapy might help improve the therapeutic efficacy of anticancer nanomedicines. Thus, microplasmin-based fibrinolytic nanocages are promising candidates for this strategy due to their hemostatic safety and ability to home in on the tumor.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Deborah L. Donohoe ◽  
Katherine Dennert ◽  
Rajeev Kumar ◽  
Bonnie P. Freudinger ◽  
Alexander J. Sherman

Abstract Background The ability of 3D printing using plastics and resins that are magnetic resonance imaging (MRI) compatible provides opportunities to tailor design features to specific imaging needs. In this study an MRI compatible cradle was designed to fit the need for repeatable serial images of mice within a mouse specific low field MRI. Methods Several designs were reviewed which resulted in an open style stereotaxic cradle to fit within specific bore tolerances and allow maximum flexibility with interchangeable radiofrequency (RF) coils. CAD drawings were generated, cradle was printed and tested with phantom material and animals. Images were analyzed for quality and optimized using the new cradle. Testing with multiple phantoms was done to affirm that material choice did not create unwanted image artifact and to optimize imaging parameters. Once phantom testing was satisfied, mouse imaging began. Results The 3D printed cradle fit instrument tolerances, accommodated multiple coil configurations and physiological monitoring equipment, and allowed for improved image quality and reproducibility while also reducing overall imaging time and animal safety. Conclusions The generation of a 3D printed stereotaxic cradle was a low-cost option which functioned well for our laboratory.


2021 ◽  
Author(s):  
Jiancai Wang ◽  
Xiang Sun ◽  
Jiayuan Wang ◽  
Kun Zhang ◽  
Yiyi Yuan ◽  
...  

Abstract Background Due to the rapid proliferation, cancer cells have increased anabolic biosynthesis, which requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the catalysis of pyruvate carboxylase (PC) and glutaminase (GLS) respectively. In GLS-suppressed cancer cells, the PC-mediated pathway for anaplerosis is crucial to maintain cell growth and proliferation. Here, we investigated the regulatory role and molecular mechanism of the tumor suppressor NDRG2 in PC and PC-mediated anaplerosis. Methods We first evaluated the correlation between PC and NDRG2 in glioma cell lines and human glioma tissue microarrays. The interaction between PC and NDRG2 was tested by tandem affinity purification-mass spectrometry (TAP-MS) and coimmunoprecipitation (Co-IP). We then detected the effect of NDRG2 on PC-mediated anaplerosis by gas chromatography-mass spectrometry (GC-MS). Preclinical evaluation of NDRG2 alone or combined with a glutaminase inhibitor was conducted in glioma cells and xenograft mouse tumors. Results NDRG2 interacted with PC and induced the degradation of PC in glutamine-deficient glioma cells. NDRG2 also inhibited the activity of PC and PC-mediated anaplerosis. As a result, NDRG2 significantly inhibited the malignant growth and proliferation of glioma cells in combination with a glutamine antagonist. In addition, NDRG2 more significantly inhibited the protein level of PC in IDH1(R132H)-mutant glioma cells than in wild-type glioma cells. Conclusions These findings indicate that the molecular mechanism of NDRG2 inhibits PC-mediated anaplerosis and collaborates with glutamine antagonist to inhibit the malignant proliferation of glioma cells, thus providing a theoretical and experimental basis for targeting anaplerosis in glioma therapy.


2021 ◽  
Author(s):  
Tetsuhiro Harimoto ◽  
Jaeseung Hahn ◽  
Yu-Yu Chen ◽  
Jongwon Im ◽  
Joanna Zhang ◽  
...  

Recent advances in therapeutic modulation of human microbiota have driven new efforts to engineer living microbial medicines using synthetic biology. However, a long-standing challenge for live bacterial therapies is balancing the high dose required to achieve robust efficacy with the potential for sepsis. Here, we developed a genetically encoded microbial encapsulation system with tunable and dynamic expression of surface capsular polysaccharides to enhance therapeutic delivery. Following a synthetic small RNA knockdown screen of the capsular biosynthesis pathway, we constructed synthetic gene circuits that regulate bacterial encapsulation based on sensing the levels of environmental inducer, bacterial density, and blood pH. The induced encapsulation system enabled tunable immunogenicity and survivability of the probiotic Escherichia coli, resulting in increased maximum tolerated dose and enhanced efficacy in murine cancer models. Furthermore, triggering in situ encapsulation was found to increase microbial translocation between mouse tumors, leading to efficacy in distal tumors. The programmable encapsulation system demonstrates a new approach to control microbial therapeutic profiles in vivo using synthetic biology.


2021 ◽  
Author(s):  
Robin Loesch ◽  
Stefano Caruso ◽  
Valerie Paradis ◽  
Cecile Godard ◽  
Angelique Gougelet ◽  
...  

Background and aims: One-third of hepatocellular carcinomas (HCCs) have mutations that activate the β-catenin pathway with mostly CTNNB1 mutations. Mouse models using Adenomatous polyposis coli (Apc) loss-of-functions (LOF) are widely used to mimic β-catenin-dependent tumorigenesis. Considering the low prevalence of APC mutations in human HCCs we aimed to generate hepatic tumors through CTNNB1 exon 3 deletion (βcatΔex3) and to compare them to hepatic tumors with Apc LOF engineered through a frameshift in exon 15 (Apcfs-ex15). Methods: We used hepatic-specific and inducible Cre-lox mouse models as well as a hepatic-specific in vivo CRISPR/Cas9 approach using AAV vectors, to generate Apcfs-ex15 and βcatΔex3 hepatic tumors harboring activation of the β-catenin pathway. Tumors generated by the Cre-lox models were analyzed phenotypically using immunohistochemistry and were selected for transcriptomic analysis using RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (normal tissues (8), HCCs (48) and hepatoblastomas (9)) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immunohistochemistry. Results: Mice with βcatΔex3 alteration in hepatocytes developed liver tumors. Generated tumors were indistinguishable from those arising in Apcfs-ex15 mice. Both Apcfs-ex15 and βcatΔex3 mouse models induced two phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that mouse differentiated tumors are close to human well differentiated CTNNB1-mutated tumors, while undifferentiated ones are closer to human mesenchymal hepatoblastomas, and are activated for YAP signaling. Conclusion: Apcfs-ex15 and βcatΔex3 mouse models similarly induce tumors transcriptionally close to either well differentiated β-Catenin activated human HCCs or mesenchymal hepatoblastomas.


2021 ◽  
pp. 106636
Author(s):  
C. Ankjærgaard ◽  
A.Z. Johansen ◽  
M.M.K. von Staffeldt ◽  
C.E. Andersen ◽  
D.H. Madsen ◽  
...  

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fan Wu ◽  
Fang-Yong Zhang ◽  
Guo-Qian Tan ◽  
Wei-Jia Chen ◽  
Biao Huang ◽  
...  

Abstract Background Our previous studies have reported the down-regulation of EGFL8 correlates to the development and prognosis of colorectal and gastric cancer. The present study is carried out to explore the expression pattern and role of EGFL8 in hepatocellular carcinoma (HCC). Methods and materials EGFL8 expression in 102 cases of HCC tissues matched with adjacent non-tumorous liver tissues, a normal liver cell line and three liver cancer cell lines with different metastatic capacity was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. Moreover, the clinicopathological features and prognosis of HCC patients were correlated with expression of EGFL8. Subsequently, the gain-and loss-of-function experiments were carried out to investigate the biological function of EGFL8 in HCC. We also used N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-(S)- phenylglycine t-butyl ester (DAPT), an inhibitor for Notch signaling pathway, in these experiments to verify the involvement of Notch signaling pathway in the effects of EGFL8. Additionally, a mouse model was established to investigate the effect of EGFL8 on metastasis of HCC cells. The expression of Notch signaling pathway in HCC cells and xenograft mouse tumors were detected by Western blot and immunohistochemistory. Results The expression of EGFL8 was significantly decreased in HCC tissues and cell lines and EGFL8 down-regulation correlated to multiple nodules, vein invasion, high TNM stage and poor prognosis of HCC. Interestingly, the expression levels of EGFL8 in three liver cancer cell lines were negatively associated with their metastatic capacity. In vitro and in vivo experiments indicated that EGFL8 obviously suppressed metastasis and invasion of HCC cells but slightly promoted apoptosis. Meanwhile, the expression of Notch signaling pathway was obviously suppressed in EGFL8 overexpressed HCCLM3 cells and xenograft mouse tumors generated from these cells but markedly elevated in EGFL8 depleted Hep3B cells. Furthermore, the up-regulated expression of Notch signaling pathway and effects induced by EGFL8 knockdown in Hep3B cells could be counteracted by DAPT treatment. Conclusion The down-regulation of EGFL8 was correlated to progression and poor prognosis of HCC and regulates HCC cell migration, invasion and apoptosis through activating the Notch signaling pathway, suggesting EGFL8 as a novel therapeutic target and a potential prognostic marker for HCC.


Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1429
Author(s):  
Tamir Baram ◽  
Nofar Erlichman ◽  
Maya Dadiani ◽  
Nora Balint-Lahat ◽  
Anya Pavlovski ◽  
...  

Triple-negative breast cancer (TNBC) is primarily treated via chemotherapy; in parallel, efforts are made to introduce immunotherapies into TNBC treatment. CD4+ TNFR2+ lymphocytes were reported as Tregs that contribute to tumor progression. However, our published study indicated that TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs) were associated with improved survival in TNBC patient tumors. Based on our analyses of the contents of CD4+ and CD8+ TILs in TNBC patient tumors, in the current study, we determined the impact of chemotherapy on CD4+ and CD8+ TIL subsets in TNBC mouse tumors. We found that chemotherapy led to (1) a reduction in CD4+ TNFR2+ FOXP3+ TILs, indicating that chemotherapy decreased the content of CD4+ TNFR2+ Tregs, and (2) an elevation in CD8+ TNFR2+ and CD8+ TNFR2+ PD-1+ TILs; high levels of these two subsets were significantly associated with reduced tumor growth. In spleens of tumor-bearing mice, chemotherapy down-regulated CD4+ TNFR2+ FOXP3+ cells but the subset of CD8+ TNFR2+ PD-1+ was not present prior to chemotherapy and was not increased by the treatment. Thus, our data suggest that chemotherapy promotes the proportion of protective CD8+ TNFR2+ TILs and that, unlike other cancer types, therapeutic strategies directed against TNFR2 may be detrimental in TNBC.


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