scholarly journals EXTH-23. MULTIVALENT TARGETED CYTOLYTIC AGENTS FOR GLIOBLASTOMA TREATMENT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii91-ii91
Author(s):  
Puja Sharma ◽  
Denise Herpai ◽  
Callie Roberts ◽  
Izabela Fokt ◽  
Waldemar Priebe ◽  
...  
Keyword(s):  
Cytotoxic Agents ◽  
Convection Enhanced Delivery ◽  
Term Survival ◽  
Pseudomonas Exotoxin A ◽  
Drug Candidates ◽  
Dna Binding Agents ◽  
Anti Tumor Activity

Abstract Glioblastoma (GBM) complexity and heterogeneity requires treatment that addresses those pathobiological features. We have been developing selective cytotoxic agents able to target at the same time several GBM-associated factors. The chosen targets are responsible for the disease progression and/or recurrence as well as for resistance to the existing therapies. As a proof of concept, a Phase I clinical trial of a cytotoxic cocktail targeting IL-13RA2 and EphA2 receptors demonstrated dramatic anti-tumor responses in dogs with spontaneous gliomas that represent the closest translational model to human disease. To this end, we have developed multivalent agents that target four receptors specific to GBM: IL-13RA2, EphA2, EphA3, and EphB2, the combined expression of which covers virtually the whole tumor microenvironment. We have designed a multivalent protein termed QUAD 3.0 that contains an IgG1 scaffold, ephrinA5, which is a ligand for the EphA2, EphA3, and EphB2 receptors, and IL-13.E13K, a mutated version of interleukin 13 (IL-13), which binds preferentially to IL-13RA2. In QUAD 3.0, there is a cysteine at the C-terminal end of the protein to allow site-specific conjugation to cytotoxic cargo. QUAD 3.0 bound effectively to the four receptors in vitro and in vivo. QUAD 3.0 was conjugated to a modified form of Pseudomonas Exotoxin A (PE38QQR) and highly potent DNA binding agents based on modified doxorubicin (WP936, WP1737 and WP1244). All conjugates were highly cytotoxic to established and primary GBM cells with IC50s < 50 nM. We also treated the first dogs with QUAD 3.0-PE38QQR and QUAD 3.0-WP936 at a dose of 1.6 mg/ml using real-time monitored convection-enhanced delivery and observed up to 60% of tumor shrinkage and long-term survival. Thus, multivalent targeted agents demonstrate highly promising anti-tumor activity as single pharmaceutical, off-the-shelf agents. We also expect that our targeted drug candidates produce immune responses against tumors amplifying their cytolytic anti-tumor effect

scholarly journals Monolithic Zirconia: An Update to Current Knowledge. Optical Properties, Wear, and Clinical Performance

2019 ◽  
Vol 7 (3) ◽  
pp. 90 ◽  
Author(s):  
Eleana Kontonasaki ◽  
Athanasios E. Rigos ◽  
Charithea Ilia ◽  
Thomas Istantsos
Keyword(s):  
Clinical Performance ◽  
Current Knowledge ◽  
High Strength ◽  
Wear Properties ◽  
Zirconia Ceramics ◽  
Term Survival ◽  
Monolithic Zirconia

The purpose of this paper was to update the knowledge concerning the wear, translucency, as well as clinical performance of monolithic zirconia ceramics, aiming at highlighting their advantages and weaknesses through data presented in recent literature. New ultra-translucent and multicolor monolithic zirconia ceramics present considerably improved aesthetics and translucency, which, according to the literature reviewed, is similar to those of the more translucent lithium disilicate ceramics. A profound advantage is their high strength at thin geometries preserving their mechanical integrity. Based on the reviewed articles, monolithic zirconia ceramics cause minimal wear of antagonists, especially if appropriately polished, although no evidence still exists regarding the ultra-translucent compositions. Concerning the survival of monolithic zirconia restorations, the present review demonstrates the findings of the existing short-term studies, which reveal promising results after evaluating their performance for up to 5 or 7 years. Although a significant increase in translucency has been achieved, new translucent monolithic zirconia ceramics have to be further evaluated both in vitro and in vivo for their long-term potential to preserve their outstanding properties. Due to limited studies evaluating the wear properties of ultra-translucent material, no sound conclusions can be made, whereas well-designed clinical studies are urgently needed to enlighten issues of prognosis and long-term survival.

scholarly journals Rhesus Theta Defensin 1 Promotes Long Term Survival in Systemic Candidiasis by Host Directed Mechanisms

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Virginia Basso ◽  
Dat Q. Tran ◽  
Justin B. Schaal ◽  
Patti Tran ◽  
Yoshihiro Eriguchi ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Mouse Serum ◽  
Term Survival ◽  
Long Term Survival ◽  
Immunosuppressed Patients ◽  
Time Of Infection

AbstractInvasive candidiasis is an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp., highlighting the urgent need of new antifungal therapies. Rhesus theta (θ) defensin-1 (RTD-1), a natural macrocyclic antimicrobial peptide, was recently shown to be rapidly fungicidal against clinical isolates of MDR C. albicans in vitro. Here we found that RTD-1 was rapidly fungicidal against blastospores of fluconazole/caspofungin resistant C. albicans strains, and was active against established C. albicans biofilms in vitro. In vivo, systemic administration of RTD-1, initiated at the time of infection or 24 h post-infection, promoted long term survival in candidemic mice whether infected with drug-sensitive or MDR strains of C. albicans. RTD-1 induced an early (4 h post treatment) increase in neutrophils in naive and infected mice. In vivo efficacy was associated with fungal clearance, restoration of dysregulated inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-10, and IL-17, and homeostatic reduction in numbers of circulating neutrophils and monocytes. Because these effects occurred using peptide doses that produced maximal plasma concentrations (Cmax) of less than 1% of RTD-1 levels required for in vitro antifungal activity in 50% mouse serum, while inducing a transient neutrophilia, we suggest that RTD-1 mediates its antifungal effects in vivo by host directed mechanisms rather than direct fungicidal activity. Results of this study suggest that θ-defensins represent a new class of host-directed compounds for treatment of disseminated candidiasis.

scholarly journals A Literature Review Study on Atomic Ions Dissolution of Titanium and Its Alloys in Implant Dentistry

Materials ◽  
2019 ◽  
Vol 12 (3) ◽  
pp. 368 ◽  
Author(s):  
Sammy Noumbissi ◽  
Antonio Scarano ◽  
Saurabh Gupta
Keyword(s):  
Dental Implants ◽  
Metal Ion ◽  
Titanium Implants ◽  
In Vitro Studies ◽  
Ion Release ◽  
Term Survival ◽  
Metal Ion Release

This review of literature paper was done in order to conduct a review of the literature and an assessment of the effects of titanium implant corrosion on peri-implant health and success in the oral environment. This paper evaluates and critically reviews the findings of the multiple in-depth in vivo and in vitro studies that are related to corrosion aspects of the titanium and its alloys. A literature survey was conducted by electronic search in Medline and studies that were published between 1940 and August 2018 were selected. The search terms used were types of corrosion, corrosion of titanium implants, titanium corrosion, metal ion release from the titanium implants, fretting and pitting corrosion, implant corrosion, peri implantitis, and corrosion. Both in vivo and in vitro studies were also included in the review. The search and selection resulted in 64 articles. These articles were divided on the basis of their context to different kinds of corrosion related to titanium dental implants. It is evident that metal ions are released from titanium and titanium alloy dental implants as a result of corrosion. Corrosion of implants is multifactorial, including electrical, chemical, and mechanical factors, which have an effect on the peri-implant tissues and microbiota. The literature surveyed showed that corrosion related to titanium and its alloys has an effect on the health of peri-implant soft and hard tissue and the long term survival of metal dental implants. It can be concluded that presence of the long-term corrosion reaction along with continuous corrosion leads to the release of ions into the peri-implant tissue but also to a disintegration of the implant that contribute to material fatigue and even fracture of the abutments and implant body or both. This combined impact of the corrosion, bacterial activity, chemical reactions, and functional stresses are to be looked at as important factors of implant failure. The findings can be used to explore the possible strategies of research to investigate the biological impact of implant materials.

P5990In vivo tracking of long-term survival of xenogeneic porcine mesenchymal stem cells seeded on tissue-engineered heart valve implanted in sheep

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Gyongyosi ◽  
D Lukovic ◽  
N Pavo ◽  
A Gugerell ◽  
J Winkler ◽  
...  
Keyword(s):  
Reporter Gene ◽  
Insertional Mutagenesis ◽  
Term Survival ◽  
Long Term Survival ◽  
Non Invasive ◽  
Pet Ct ◽  
Valve Implantation

Abstract Background Long-term survival of xenogeneic transplanted cells in adults requires strong immunosuppression and/or encapsulation of the cells to achieve peripheral transplant tolerance. Purpose The aim of our project was to seed decellularized tissue engineered heart valves (TEHV) with xenogeneic (porcine) mesenchymal stem cells (pMSCs) transfected transiently (Lipofectamine) with a positron emission tomography (PET)-reporter gene (pMSC-PETr), followed by implantation as pulmonary valve replacement into sheep without immunosuppression. The fate of the seeded pMSC-PETr was tracked via serial in-vivo non-invasive PET-computed tomography (PET-CT). Methods Static cultivation of TEHV scaffold led to successful ingrowth of the pMSC-PETr. For enabling quantitative assessment of viable pMSC-PETr in the TEHV scaffold after in vivo implantation, vials containing 5x104, 2x105, and 4x105 pMSC-PETr were in vitro mixed with the [18F]-FHBG PET tracer for 1 hr, then the non-bound tracer was washed out and vials were in vitro PET-CT imaged, giving reference values. TEHV-pMSC-PETr were then implanted percutaneously into the pulmonary valve position of sheep (n=4) under general anesthesia, while an additional sheep with no valve implantation served as a control. Ten mCi of [18F]-FHBGPET radiotracer was produced for each procedure and serial PET-CT imaging of the sheep was performed at 3 hr, 24 hr, 2 or 3 weeks, and 5 and 6 months after valve implantation. The study followed the Principles of laboratory animal care. Results PET-CT of vials containing increasing number of pMSC-PETr showed dose-dependent tracer uptake in the transfected cells in vitro (Figure). PET-CT images of the sheep 3 hr after implantation of the TEHV-pMSC-PETr showed a clear signal of transfected cells, with a mean estimated number of viable pMSC-PETr of 5.18±1.19x106. No meaningful decrease of the amount of living cells occurred at 24 hr or 2 or 3 weeks. Interestingly, 5- and 6-month follow-up PET-CT images showed clear in vivo and in vitro (after explantation) PET signals of the pMSC-PETr on TEHV, indicating spontaneous stable transfection of the PET reporter plasmid (insertional mutagenesis). Histology confirmed the survival of the pMSC-PETr at 5 and 6-month after xenogeneic transplantation. Merged immunohistochemistry and fluorescence imaging of anti-pig SLA I and anti-sheep MHC I antibodies and PET-reporter gene (HSV1-tk) suggested in vivo inter-species lateral jump gene transfer between pig MSCs and host sheep cells. Figure 1 Conclusions This is the first report on serial non-invasive in vivo tracking of long-term survival of xenogeneic pMSCs-PETr seeded on TEHVs and percutaneously implanted into the pulmonary position of sheep. Long-term follow-up revealed spontaneous stable transfection of the plasmid PET-reporter gene, which suggests the risk of insertional mutagenesis induced by the plasmid (transposon), and PET-reporter gene shuttle from xenogeneic pig MSCs to sheep cells. Acknowledgement/Funding LifeValve EU project (grant number: 242008)

IL15, but Not IL2, Supports Long-Term Survival and Function of Human and Macaque Antigen-Specific CD8+ T Cell Clones.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3237-3237
Author(s):  
Carolina S. Berger ◽  
Michael Jensen ◽  
Stanley R. Riddell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Term Survival ◽  
Long Term Survival ◽  
Cd8 T Cell Memory ◽  
And Function

Abstract The adoptive transfer of antigen-specific CD8+ cytotoxic T lymphocyte (CTL) clones that have been isolated and expanded in vitro is a promising treatment modality for both human malignancies and infections. However, establishing immunity of sufficient magnitude and persistence for sustained efficacy is a limitation of this approach. Recent studies have identified a critical role for cytokine signaling including that mediated by IL15 in the establishment and maintenance of CD8+ T cell memory, suggesting that protocols for generating and transferring antigen-specific T cells might be improved. Interleukin-2 (IL2) is the T cell growth factor that has been widely used in vitro and in vivo for promoting T cell proliferation and persistence, but prolonged exposure of T cells to IL2 can enhance susceptibility to cell death and limit CD8+ memory T cell survival. IL15 is a novel cytokine that shares some activities with IL2 such as the induction of T cell proliferation, but exerts contrasting effects on the homeostasis of CD8+ T cell memory in experimental models. Here, we study the utility of IL15 to enhance the long-term survival and function of human and macaque antigen-specific CD8+ CTL clones in vitro. Human and macaque CD8+ CTL clones reactive against CMV were isolated by limiting dilution, expanded over 14 days in the presence of IL2 or IL15 (1–10 ng/ml), and then rested for >4 weeks in media alone and with IL2 or IL15 at 0.01–10 ng/ml. Surviving T cells were enumerated at intervals, monitored for cell surface phenotype, and assayed for cytotoxicity by chromium release assay. CTL expanded in IL2 or IL15 proliferated equivalently over 14 days with a median of 1100 and 1400 fold increase in number, displayed surface markers consistent with an effector memory phenotype (CD45RA−CD62L−CCR7−CD28−), and showed comparable cytotoxicity (n=4). However, exposure after 14 days to IL15 at doses as little as 0.05-0.1 ng/ml greatly enhanced the survival of the CD8+ CTL as determined by Annexin V staining. By contrast, cells cultured without cytokines or with IL2 declined >80% in number over 3 or 11 days, respectively. Of note, IL15 at higher doses (>0.5 ng/ml), but not IL2, efficiently promoted sustained cell growth illustrated by labeling cells with CFSE. Cells cultured with IL15 displayed 1.5-fold increased expression of antiapoptotic molecules such as Bcl-xL and Bcl-2 over those plated in IL2 (n=4), indicating IL15 mediated its effects at least in part by preventing apoptosis. Of note, the cytotoxicity of CTL rested in IL2 was markedly reduced (>60%, n=3), while the presence of IL15 permitted for sustained CTL function and expansion after restimulation. The responses of human and macaque CTL clones to IL15 were equivalent suggesting in vivo studies of T cell transfer in macaques may be predictive of results in humans. We have constructed retroviral vectors encoding intracytoplasmic truncated macaque CD34 or CD19 genes that could serve as nonimmunogenic selectable marker to track macaque T cells after transfer. Macaque T cells were efficiently transduced to express CD34t and CD19t (>50%), and enriched to high purity by immunomagnetic selection. Studies to examine the safety and utility of IL15 on the survival of adoptively transferred CTL in macaques are in progress. Collectively, our data support that novel cytokines such as IL15 may prove useful to augment the long-term survival and effector function of ex vivo expanded antigen-specific CD8+ CTL clones after transfer.

Short-term injection of antiapoptotic cytokine combinations soon after lethal γ-irradiation promotes survival

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2609-2616 ◽  
Author(s):  
Francis Hérodin ◽  
Philippe Bourin ◽  
Jean-François Mayol ◽  
Jean-Jacques Lataillade ◽  
Michel Drouet
Keyword(s):  
Lethal Dose ◽  
Survival Rates ◽  
Protective Effects ◽  
Γ Irradiation ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Better Than

Recovery from radiation-induced (RI) myelosuppression depends on hematopoietic stem and progenitor cell survival and the active proliferation/differentiation process, which requires early cytokine support. Single cytokine or late-acting growth factor therapy has proved to be inefficient in ensuring reconstitution after severe RI damage. This work was aimed at evaluating the in vivo survival effect of combinations of early-acting cytokines whose antiapoptotic activity has been demonstrated in vitro: stem cell factor (SCF [S]), FMS-like tyrosine kinase 3 ligand (FLT-3 ligand [F]), thrombopoietin (TPO [T]), interleukin-3 (IL-3 [3]), and stromal derived factor-1 (SDF-1). B6D2F1 mice underwent total body irradiation at 8 Gy cesium Cs 137 γ radiation (ie, lethal dose 90% at 30 days) and were treated soon after irradiation, at 2 hours and at 24 hours, with recombinant murine cytokines, each given intraperitoneally at 50 μg/kg per injection. All treatments induced 30-day survival rates significantly higher than control (survival rate, 8.3%). 4F (SFT3) and 5F (4F + SDF-1) were the most efficient combinations (81.2% and 87.5%, respectively), which was better than 3F (SFT, 50%), TPO alone (58.3%), and SDF-1 alone (29.2%) and also better than 4F given at 10 μg/kg per injection (4F10, 45.8%) or as a 50 μg/kg single injection at 2 hours (4Fs, 62.5%). Despite delayed death occurring mainly from day 150 on and possible long-term hematopoiesis impairment, half the 30-day protective effects of 4F and 5F were preserved at 300 days. Our results show that short- and long-term survival after irradiation depends on appropriate multiple cytokine combinations and at optimal concentrations. The proposal is made that an emergency cytokine regimen could be applied to nuclear accident victims as part of longer cytokine treatment, cell therapy, or both.

scholarly journals Inhibition of Kallikrein-related peptidases 7 restrains pancreatic tumor growth through induction of ferroptosis

2021 ◽  
Author(s):  
Yueqing Wang ◽  
Fengyi Xiang ◽  
Hao Deng ◽  
Shuang Leng ◽  
Dengze Zhao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Formation ◽  
Term Survival ◽  
Suicide Substrate ◽  
Substrate Inhibitor ◽  
Novel Drug ◽  
Inhibition Ability

AbstractPancreatic cancer is one of the most aggressive and lethal malignancies with extremely poor prognosis, and KLK7 was considered as a potential therapeutic target. In this study, we analyzed the expression of KLK7 in TCGA and GTEx databases and found that KLK7 had a negative correlation to long-term survival rate (>1.5 years) of pancreatic cancer patients. Compound 42 is a coumarinic derivative, a suicide substrate inhibitor of KLK7, which has been proved to inhibit the proliferation of PANC-1 cells in vitro effectively in our previous study. In this study, we further investigated the inhibition ability of Compound 42 in tumor formation and development in CDX and PDX tumor models of pancreatic cancer subsequently. Besides, we studied the inhibitory mechanism of Compound 42 and the result showed that Compound 42 arrested the pancreatic cancer cell cycle in G0/G1 phase and induced ferroptosis through down-regulation of GPX4 protein level and accumulation of iron ion. Thus, these experiments demonstrate that Compound 42, suppressing pancreatic cancer in vivo, is expected to become a novel drug for pancreatic cancer treatment.

scholarly journals Fructose-a double edged sword for cell death versus differentiation and long-term survival of NSC-34 motor neuron like cells in vitro

2021 ◽  
Author(s):  
Divya Lodha ◽  
Jamuna R. Subramaniam
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Motor Neurons ◽  
Response Regulator ◽  
Nuclear Staining ◽  
Term Survival ◽  
High Fructose

Abstract In various neurological and neurodegenerative diseases (ND), motor neurons (MN) of the spinal cord are affected leading to movement impairments. The ND, Amyotrophic Lateral Sclerosis (ALS), is caused due to MN degeneration. ALS afflicts athletes and other major sports personalities, who generally consume fructose enriched sports drinks. Recently, we have reported that high fructose (F5%) impairs the metabolic activity in the NSC-34, MN cell line and reduces the healthspan of C. elegans. But how fructose impacts the MNs either in vitro or in vivo in the long term is not understood. Here we report, to our surprise, that high fructose (F5%) treatment of NSC-34 leads to differentiation of 1-2% of cells with progressive neurite extension. They could be maintained for 80 days in vitro with 5% CO2 and O2 at 18.8%. On the contrary, 5% fructose significantly reduced cell viability by ~85% and inhibited cell proliferation by Day10. Nuclear staining displayed multiple nuclei in the cells indicative of cytokinesis inhibition which led to the lack of cell proliferation. Further, F5% significantly increased ROS levels (^~34%), the potential cause for reduced viability. In addition, no induction of expression of the master oxidative stress response regulator, the transcription factor, nrf-2, or the downstream effector, sod1, was evident. Despite the adverse effects, in the absence of any, F5% is a potential strategy to maintain at least a small percentage of MNs for a long time, ~45 days in vitro, which also reinforces the Redox-Cell death versus cell survival conundrum.

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