Local Non-Affine Deformations and Fiber Kinematics of Elastomeric Electrospun Scaffolds

2007 ◽  
Author(s):  
Todd D. Courtney ◽  
Jun Liao ◽  
William R. Wagner ◽  
Michael S. Sacks
Keyword(s):  
Mechanical Response ◽  
De Novo ◽  
Mechanical Load ◽  
Strain Analysis ◽  
Fiber Network ◽  
Mechanical Responses ◽  
Electrospun Scaffolds ◽  
Global Strain

For most tissue engineering applications that seek to generate tissue de novo, the scaffold is the first step in a series of important developmental considerations. Whether synthetic or natural, scaffolds developed for immediate in vivo use must have mechanical properties comparable to the native tissue for at least the minimum time necessary for the accompanying seeded cells, and eventual cells that migrate in, to lay down an equivalent supporting matrix. Scaffolds developed for the purpose of growing a tissue in vitro, with eventual in vivo use, need not necessarily meet these mechanical requirements. However, to better develop new tissues in bioreactors or in vivo, it is pertinent to understand how the fiber network changes under some regimen of mechanical load, in essence to understand what the cell witnesses within the scaffold. Extending our previous work, which focused on measuring and modeling the mechanical response of electrospun poly ester urethane urea (es-PEUU) scaffolds [1], we investigated the intricate and detailed es-PEUU fiber networks that are created during scaffold synthesis and how these networks change under various levels of strain. Specifically, we focused on several scaffold responses to strain: 1) Characteristics of fiber tortuosity, which when increased can yield delayed onset of scaffold stiffness as well as other varying mechanical responses. 2) Fiber splay, which determines the orientation of the all fibers within the scaffold. 3) Local vs global strain analysis to determine whether the scaffolds follow affine or non-affine deformations. 4) Fiber strain, to investigate how increasing levels of scaffold strain are transmitted to local fibers. 5) Changes in fiber tortuosity and overall fiber directions under strain.

Computational study for suppression of CD25/IL-2 interaction

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Moein Dehbashi ◽  
Zohreh Hojati ◽  
Majid Motovali-bashi ◽  
Mazdak Ganjalikhani-Hakemi ◽  
Akihiro Shimosaka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Progression ◽  
Immune Escape ◽  
De Novo ◽  
Computational Study ◽  
Treg Cells ◽  
Homology Search ◽  
Small Interfering Rnas

AbstractCancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which in silico designed small interfering RNAs (siRNAs), de novo designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a de novo designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further in vitro and in vivo studies.

scholarly journals EXTH-51. ANTI-INVASIVE EFFICACY AND SURVIVAL BENEFIT OF THE YAP-TEAD INHIBITOR VERTEPORFIN IN PRECLINICAL GLIOBLASTOMA MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii98-ii98
Author(s):  
Anne Marie Barrette ◽  
Alexandros Bouras ◽  
German Nudelman ◽  
Zarmeen Mussa ◽  
Elena Zaslavsky ◽  
...  
Keyword(s):  
Survival Benefit ◽  
De Novo ◽  
Epithelial Mesenchymal Transition ◽  
Intraperitoneal Administration ◽  
Standard Of Care ◽  
Tumor Burden ◽  
Mesenchymal Transition ◽  
Protein Levels

Abstract Glioblastoma (GBM) remains an incurable disease, in large part due to its malignant infiltrative spread, and current clinical therapy fails to target the invasive nature of tumor cells in disease progression and recurrence. Here, we use the YAP-TEAD inhibitor Verteporfin to target a convergence point for regulating tumor invasion/metastasis and establish the robust anti-invasive therapeutic efficacy of this FDA-approved drug and its survival benefit across several preclinical glioma models. Using patient-derived GBM cells and orthotopic xenograft models (PDX), we show that Verteporfin treatment disrupts YAP/TAZ-TEAD activity and processes related to cell adhesion, migration and epithelial-mesenchymal transition. In-vitro, Verteporfin impairs tumor migration, invasion and motility dynamics. In-vivo, intraperitoneal administration of Verteporfin in mice with orthotopic PDX tumors shows consistent drug accumulation within the brain and decreased infiltrative tumor burden, across three independent experiments. Interestingly, PDX tumors with impaired invasion after Verteporfin treatment downregulate CDH2 and ITGB1 adhesion protein levels within the tumor microenvironment. Finally, Verteporfin treatment confers survival benefit in two independent PDX models: as monotherapy in de-novo GBM and in combination with standard-of-care chemoradiation in recurrent GBM. These findings indicate potential therapeutic value of this FDA-approved drug if repurposed for GBM patients.

scholarly journals PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Nan Huang ◽  
Chang Xu ◽  
Liang Deng ◽  
Xue Li ◽  
Zhixuan Bian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
De Novo ◽  
Dna Damage Repair ◽  
Histone Deacetylase 1 ◽  
Damage Repair ◽  
Damage Response

AbstractPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

Hippokampale Estrogensynthese und synaptische Plastizität

e-Neuroforum ◽  
2007 ◽  
Vol 13 (4) ◽  
Author(s):  
Lars Fester ◽  
Janine Prange-Kiel ◽  
Gabriele M. Rune
Keyword(s):  
De Novo ◽  
Synaptische Plastizität

ZusammenfassungUnsere Untersuchungen der letzten Jahre haben gezeigt, dass nicht das Ovar die Quelle für Estrogen induzierte synaptische Plastizität im Hippokampus ist, sondern dieses aus dem Hippokampus selber stammt und haben damit einen Paradigmawechsel eingeleitet, der Estrogen als Neuromodulator unabhängig vom Geschlecht identifiziert. Hippokampale Neurone von Ratten beiderlei Geschlechts sind in der Lage, aus Cholesterol Estrogene de novo zu synthetisieren. Diese hippokampale Estrogensynthese ist sowohl für den Erhalt von Spinesynapsen in vivo als auch in vitro essenziell. Die Hemmung der Estrogensynthese zieht einen Synapsenverlust nach sich und Langzeitpotenzierung ist nicht mehr induzierbar. Die Effekte von hippokampalem Estrogen sind auto-/parakriner Natur, die über die bekannten Estrogenrezeptor-Subtypen, ERα und ERβ, vermittelt werden. Die Regulation der hippokampalen Estrogensynthese erfolgt über GnRH und erklärt die Korrelation der Spinesynapsendichte mit dem weiblichen genitalen Zyklus, die für den Hippokampus spezifisch ist.

scholarly journals Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mylène Tajan ◽  
Marc Hennequart ◽  
Eric C. Cheung ◽  
Fabio Zani ◽  
Andreas K. Hock ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
De Novo ◽  
Carbon Availability ◽  
Global Protein Synthesis ◽  
Enhanced Expression ◽  
One Carbon Metabolism ◽  
Amino Acid Depletion ◽  
Pathway Inhibition

AbstractMany tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet.

Lipidated Methotrexate Microbubbles: A Promising Rheumatoid Arthritis Theranostic Medicine Manipulated via Ultrasonic Irradiation

2021 ◽  
Vol 17 (7) ◽  
pp. 1293-1304
Author(s):  
Zhuofei Zhao ◽  
Xiaona Lin ◽  
Lulu Zhang ◽  
Xia Liu ◽  
Qingwen Wang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
De Novo ◽  
Low Ph ◽  
Curative Effect ◽  
Inflammatory Microenvironment ◽  
Raw 264.7 Cell ◽  
Infection Focus ◽  
Raw 264.7 Cell Line

De novo designed lipidated methotrexate was synthesized and self-assembled into microbubbles for targeted rheumatoid arthritis theranostic treatment. Controlled lipidatedmethotrexate delivery was achieved by ultrasound-targetedmicrobubble destruction technique. Methotrexate was dissociated inflammatory microenvironment of synovial cavity, owing to representive low pH and enriched leucocyte esterase. We first manipulated methotrexate controlled release with RAW 264.7 cell line in vitro and further verified with rheumatoid arthritis rabbits in vivo. Results showed that lipidated methotrexate microbubbles precisely affected infection focus and significantly enhanced rheumatoid arthritis curative effect comparing with dissociative methotrexate. This study indicates that lipidated methotrexate microbubbles might be considered as a promising rheumatoid arthritis theranostics medicine.

scholarly journals De novo design of self-assembling helical protein filaments

Science ◽  
2018 ◽  
Vol 362 (6415) ◽  
pp. 705-709 ◽  
Author(s):  
Hao Shen ◽  
Jorge A. Fallas ◽  
Eric Lynch ◽  
William Sheffler ◽  
Bradley Parry ◽  
...  
Keyword(s):  
De Novo ◽  
Computational Design ◽  
Building Blocks ◽  
Repeat Units ◽  
Self Assembling ◽  
Wide Range ◽  
Helical Protein ◽  
Monomeric Proteins

We describe a general computational approach to designing self-assembling helical filaments from monomeric proteins and use this approach to design proteins that assemble into micrometer-scale filaments with a wide range of geometries in vivo and in vitro. Cryo–electron microscopy structures of six designs are close to the computational design models. The filament building blocks are idealized repeat proteins, and thus the diameter of the filaments can be systematically tuned by varying the number of repeat units. The assembly and disassembly of the filaments can be controlled by engineered anchor and capping units built from monomers lacking one of the interaction surfaces. The ability to generate dynamic, highly ordered structures that span micrometers from protein monomers opens up possibilities for the fabrication of new multiscale metamaterials.

In vitro and in vivo analysis of co-electrospun scaffolds made of medical grade poly(ε-caprolactone) and porcine collagen

2008 ◽  
Vol 19 (5) ◽  
pp. 693-707 ◽  
Author(s):  
Z. C. C. Chen ◽  
A. K. Ekaputra ◽  
K. Gauthaman ◽  
P. G. Adaikan ◽  
H. Yu ◽  
...  
Keyword(s):  
Electrospun Scaffolds ◽  
In Vivo Analysis ◽  
Porcine Collagen ◽  
Medical Grade

scholarly journals Biocompatibility Evaluation of Electrospun Scaffolds of Poly (L-Lactide) with Pure and Grafted Hydroxyapatite

2017 ◽  
Vol 58 (4) ◽  
Author(s):  
José Manuel Cornejo-Bravo ◽  
Luis Jesús Villarreal-Gómez ◽  
Ricardo Vera-Graziano ◽  
María Raquel Vega-Ríos ◽  
José Luis Pineda-Camacho ◽  
...  
Keyword(s):  
Bacterial Adhesion ◽  
Neutral Red ◽  
C2c12 Cells ◽  
Surrounding Tissue ◽  
Neutral Red Assay ◽  
Electrospun Scaffolds ◽  
Muscle Tissues ◽  
Hematoxylin Eosin

<p>The objective of this work was to evaluate the biocompatibility of scaffolds of poly(<em>L</em>-lactide) with pure and grafted hydroxyapatite, at various concentrations of reinforcement. The biocompatibility tests were carried out <em>in vivo </em>in Wistar rats by implanting the material into the subcutaneous and muscle tissues from 1 to 14 weeks and evaluating the surrounding tissue stained with hematoxylin-eosin. For <em>in vitro </em>assays, MTT and neutral red assay were used to evaluate any cytotoxicity in Mioblast Muscle C2C12 Cells (ATCC® CRL-1772™) and Bovine Coronary Artery Endothelial Cells (BCAEC); <em>Escherichia coli </em>and <em>Staphylococcus aureus </em>were used to evaluate bacterial adhesion. All variants of scaffolds provoked a mild inflammatory response, without showing necrosis. No evidence of cytotoxicity was presented in cell viability tests and good bacterial cell adhesion was visualized for all of the materials studied.</p>

scholarly journals 905 FASN prevents immunogenicity of irradiated glioblastoma by inhibiting ER stress

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A950-A950
Author(s):  
Mara De Martino ◽  
Camille Daviaud ◽  
Claire Vanpouille-Box
Keyword(s):  
Er Stress ◽  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Immune Escape ◽  
De Novo ◽  
Lipid Synthesis ◽  
Adult Brain ◽  
Immune Recognition

BackgroundGlioblastoma (GBM) is the most aggressive and incurable adult brain tumor. Radiation therapy (RT) is an essential modality for GBM treatment and is recognized to stimulate anti-tumor immunity by inducing immunogenic cell death (ICD) subsequent to endoplasmic reticulum (ER) stress. However, RT also exacerbates potent immunosuppressive mechanisms that facilitate immune evasion. Notably, increased de novo lipid synthesis by the fatty acid synthase (FASN) is emerging as a mechanism of therapy resistance and immune escape. Here, we hypothesize that RT induces FASN to promote GBM survival and evade immune recognition by inhibiting ER stress and ICD.MethodsTo determine if lipid synthesis is altered in response to RT, we first assessed FASN expression by western blot (WB) and lipid accumulation by BODIPY staining in murine (CT2A and GL261) and human (U118) GBM cell lines. Next, FASN expression was blocked in CT2A cells using CRISPR-Cas9 or an inducible shRNA directed against Fasn to evaluate ICD and ER stress markers by ELISA, WB, and electron microscopy. Finally, CT2AshFASN cells or its non-silencing control (CT2AshNS) were orthotopically implanted and FASN knockdown was induced by feeding the mice with doxycycline. The immune contexture was determined by in situ immunofluorescence (n=3/group). Remaining mice were followed for survival (n=7/group).ResultsWe found that in vitro irradiation of GBM cells induces lipid accumulation in a dose-dependent fashion; an effect that is magnified over time lasting at least 6/7 days. Consistent with these findings, FASN expression was upregulated in irradiated GBM cells. Confirming the role of FASN, RT-induced accumulation of lipids was reverted when GBM cells were incubated with a FASN inhibitor. Next, we found that FASN ablation in CT2A cells induces mitochondria disruption and was sufficient to increase the expression of the ER stress makers BIP and CHOP. Along similar lines, shFASN enhances the secretion of the ICD markers HMGB1, IFN-beta and CXCL10 in irradiated CT2A cells. In vivo, CT2AshFASN tumors presented increased infiltration of CD11c+ cells and CD8+ T cells, consistent with prolonged mice survival (56 days vs. 28 days for CT2AshNS). Importantly, 43% of CT2AshFASN-bearing mice remained tumor-free for more than 70 days, while none of the CT2AshNS-bearing mice survived.ConclusionsAltogether, our data suggest that FASN-mediated lipid synthesis is an important mechanism to prevent ER stress, ICD, and anti-tumor immune responses in GBM. While much work remains to be done, our data propose FASN as a novel therapeutic target to overcome immunosuppression and sensitize GBM to immunotherapies.

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