Transient immunosuppressive treatment leads to long-term retention of allogeneic myoblasts in hybrid myofibers.

Normal and genetically engineered skeletal muscle cells (myoblasts) show promise as drug delivery vehicles and as therapeutic agents for treating muscle degeneration in muscular dystrophies. A limitation is the immune response of the host to the transplanted cells. Allogeneic myoblasts are rapidly rejected unless immunosuppressants are administered. However, continuous immunosuppression is associated with significant toxic side effects. Here we test whether immunosuppressive treatment, administered only transiently after allogeneic myoblast transplantation, allows the long-term survival of the transplanted cells in mice. Two immunosuppressive treatments with different modes of action were used: (a) cyclosporine A (CSA); and (b) monoclonal antibodies to intracellular adhesion molecule-1 and leukocyte function-associated molecule-1. The use of myoblasts genetically engineered to express beta-galactosidase allowed quantitation of the survival of allogeneic myoblasts at different times after cessation of the immunosuppressive treatments. Without host immunosuppression, allogeneic myoblasts were rejected from all host strains tested, although the relative time course differed as expected for low and high responder strains. The allogeneic myoblasts initially fused with host myofibers, but these hybrid cells were later destroyed by the massive immunological response of the host. However, transient immunosuppressive treatment prevented the hybrid myofiber destruction and led to their long-term retention. Even four months after the cessation of treatment, the hybrid myofibers persisted and no inflammatory infiltrate was present in the tissue. Such long-term survival indicates that transient immunosuppression may greatly increase the utility of myoblast transplantation as a therapeutic approach to the treatment of muscle and nonmuscle disease.

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A high-capacity cell macroencapsulation system supporting the long-term survival of genetically engineered allogeneic cells

Biomaterials ◽

10.1016/j.biomaterials.2013.09.071 ◽

2014 ◽

Vol 35 (2) ◽

pp. 779-791 ◽

Cited By ~ 38

Author(s):

Aurélien Lathuilière ◽

Steffen Cosson ◽

Matthias P. Lutolf ◽

Bernard L. Schneider ◽

Patrick Aebischer

Keyword(s):

High Capacity ◽

Genetically Engineered ◽

Term Survival ◽

Long Term Survival

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Prevention of the initial host immuno-inflammatory response determines the long-term survival of encapsulated myoblasts genetically engineered for erythropoietin delivery

Molecular Therapy ◽

10.1016/s1525-0016(03)00055-8 ◽

2003 ◽

Vol 7 (4) ◽

pp. 506-514 ◽

Cited By ~ 28

Author(s):

Bernard Laurent Schneider ◽

Frank Schwenter ◽

William François Pralong ◽

Patrick Aebischer

Keyword(s):

Inflammatory Response ◽

Genetically Engineered ◽

Term Survival ◽

Long Term Survival

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Immunosuppressive Treatment With mTOR Inhibitors for Malignancies After Liver Transplantation: Long-Term Survival Retrospective Analysis

Transplantation Proceedings ◽

10.1016/j.transproceed.2020.02.058 ◽

2020 ◽

Vol 52 (5) ◽

pp. 1507-1510

Author(s):

Javier Tejedor-Tejada ◽

Carmen Alonso-Martín ◽

Carolina Almohalla-Álvarez ◽

Esteban Fuentes Valenzuela ◽

Rodrigo Nájera Muñoz ◽

...

Keyword(s):

Liver Transplantation ◽

Retrospective Analysis ◽

Immunosuppressive Treatment ◽

Mtor Inhibitors ◽

Term Survival ◽

Long Term Survival

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Effect of anastomotic leaks on long-term survival after oesophagectomy for oesophageal cancer: systematic review and meta-analysis

Diseases of the Esophagus ◽

10.1093/dote/doaa085 ◽

2020 ◽

Author(s):

Rohan R Gujjuri ◽

Sivesh K Kamarajah ◽

Sheraz R Markar

Keyword(s):

Oesophageal Cancer ◽

Early Recognition ◽

Meta Analysis ◽

Immunological Response ◽

Prognostic Impact ◽

Curative Surgery ◽

Term Survival ◽

Long Term Survival ◽

The Impact

Summary Introduction Long-term survival after curative surgery for oesophageal cancer surgery remains poor, and the prognostic impact of anastomotic leak (AL) remains unknown. A meta-analysis was conducted to investigate the impact of AL on long-term survival. Methods A systematic electronic search for articles was performed for studies published between 2001 and 2020 evaluating the long-term oncological impact of AL. Meta-analysis was performed using the DerSimonian-Laird random-effects model to compute hazard ratios and 95% confidence intervals. Results Nineteen studies met the inclusion criteria, yielding a total of 9885 patients. Long-term survival was significantly reduced after AL (HR: 1.79, 95% CI: 1.33–2.43). AL was associated with significantly reduced overall survival in studies within hospital volume Quintile 1 (HR: 1.35, 95% CI: 1.12–1.63) and Quintile 2 (HR: 1.83, 95% CI: 1.35–2.47). However, no significant association was found for studies within Quintile 3 (HR: 2.24, 95% CI: 0.85–5.88), Quintile 4 (HR: 2.59, 95% CI: 0.67–10.07), and Quintile 5 (HR: 1.29, 95% CI: 0.92–1.81). AL was significantly associated with poor long-term survival in patients with associated overall Clavien Dindo Grades 1–5 (HR: 2.17, 95% CI: 1.31–3.59) and severe Clavien Dindo Grades 3–5 (HR: 1.42, 95% CI: 1.14–1.78) complications. Conclusions AL has a negative prognostic impact on long-term survival after restorative resection of oesophageal cancers, particularly in low-volume centers. Future efforts must be focused on strategies to minimize the septic and immunological response to AL with early recognition and treatment thus reducing the impact on long-term survival.

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Transient changes in excitability of rabbit CA3 neurons with a time course appropriate to support memory consolidation

Journal of Neurophysiology ◽

10.1152/jn.1996.76.3.1836 ◽

1996 ◽

Vol 76 (3) ◽

pp. 1836-1849 ◽

Cited By ~ 149

Author(s):

L. T. Thompson ◽

J. R. Moyer ◽

J. F. Disterhoft

Keyword(s):

Memory Consolidation ◽

Time Course ◽

Pyramidal Neurons ◽

Membrane Properties ◽

Resting Potential ◽

Term Retention ◽

Ca3 Pyramidal Neurons ◽

Long Term Retention ◽

Ca3 Neurons

1. The excitability of CA3 pyramidal neurons was assessed with intracellular recordings in hippocampal slices from behaviorally naive rabbits. CA3 pyramidal neurons had large (-13.1 +/- 0.3 mV; mean +/- SE) postburst afterhyperpolarization (AHPs) and exhibited robust spike-frequency adaptation (accommodation) to prolonged (800-ms) depolarizing current injection at resting potentials of -68 mV. AHP and accommodation measures differed in scale but not in kind from those obtained in stable recordings from CA1 pyramidal neurons in the same slices or from the same rabbits, with CA3 neurons having larger longer AHPs but fewer spikes during accommodation. 2. Groups of rabbits were trained in a simple, associative-learning task, trace eye-blink conditioning, which required an intact hippocampus for successful acquisition. Memory consolidation in this task also involves the hippocampus, whereas long-term retention of the learned response does not. The time course and magnitude of learning-specific changes in excitability were assessed in 201 CA3 pyramidal neurons. 3. Learning increased the excitability of CA3 pyramidal neurons soon after acquisition (within 1-24 h). The mean postburst AHP was reduced to approximately half (-6.4 +/- 0.3 mV) the basal amplitude of the AHP observed in naive controls. The area and duration of the postburst AHP similarly were reduced. Approximately half of all pyramidal neurons tested soon after learning exhibited significantly reduced AHPs, whereas none exhibited enhanced AHPs. 4. Trace conditioning also reduced accommodation of CA3 pyramidal neurons 1-24 h after learning. Neurons from successfully trained rabbits fired significantly more action potentials (5.6 +/- 1.5) in response to prolonged depolarization than did neurons from naive controls (4.1 +/- 0.2). The magnitude of the learning-specific change in accommodation was less than that for the AHP. Approximately 45% of neurons tested exhibited significantly reduced accommodation soon after learning. 5. Both learning-specific changes in CA3 increased neuronal excitability. Both changes were highly time dependent. AHPs were reduced maximally 1-24 h after learning, then increased, returning to basal (naive) levels within 7 days and remaining basal thereafter. The decay rate of accommodation to basal levels preceded that of the AHP by several days. 6. Other membrane properties, including action potential characteristics, resting potential, and input resistance, were unchanged by learning. The restriction of the observed changes to two interrelated measures of excitability concurs with earlier reports that learning-specific changes in the mammalian hippocampus are linked to changes in a limited number of membrane conductances. 7. Learning, not long-term memory or performance of the learned behavior, was linked to the excitability changes. Neurons from rabbits that failed to acquire the task after considerable training exhibited no excitability changes. Neurons from pseudoconditioned rabbits were indistinguishable from neurons of behaviorally naive controls. Finally, neurons from rabbits that explicitly demonstrated long-term retention of the conditioned response were indistinguishable from those of naive controls. 8. Behavioral changes persisted for extremely long periods, but the observed changes in hippocampal excitability were transient and greatest soon after learning. Excitability was enhanced for a period of a few days, a period demonstrated in other eyeblink studies to be required for memory consolidation. Because hippocampal excitability then returned to basal levels but memory of the learned task persisted, postconsolidation memory traces (the "engram") must be extrahippocampal.

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Esophageal regeneration following surgical implantation of a tissue engineered esophageal implant in a pediatric model

npj Regenerative Medicine ◽

10.1038/s41536-021-00200-9 ◽

2022 ◽

Vol 7 (1) ◽

Author(s):

Sumati Sundaram ◽

Todd Jensen ◽

Tina Roffidal ◽

Karissa Paquin ◽

Heather Wanczyk ◽

...

Keyword(s):

Survival Time ◽

Tissue Regeneration ◽

Time Course ◽

Ct Imaging ◽

Congenital Defects ◽

Term Survival ◽

Long Term Survival ◽

Time Points ◽

Post Implantation

AbstractDiseases of the esophagus, damage of the esophagus due to injury or congenital defects during fetal esophageal development, i.e., esophageal atresia (EA), typically require surgical intervention to restore esophageal continuity. The development of tissue engineered tubular structures would improve the treatment options for these conditions by providing an alternative that is organ sparing and can be manufactured to fit the exact dimensions of the defect. An autologous tissue engineered Cellspan Esophageal ImplantTM (CEI) was surgically implanted into piglets that underwent surgical resection of the esophagus. Multiple survival time points, post-implantation, were analyzed histologically to understand the tissue architecture and time course of the regeneration process. In addition, we investigated CT imaging as an “in-life” monitoring protocol to assess tissue regeneration. We also utilized a clinically relevant animal management paradigm that was essential for long term survival. Following implantation, CT imaging revealed early tissue deposition and the formation of a contiguous tissue conduit. Endoscopic evaluation at multiple time points revealed complete epithelialization of the lumenal surface by day 90. Histologic evaluation at several necropsy time points, post-implantation, determined the time course of tissue regeneration and demonstrated that the tissue continues to remodel over the course of a 1-year survival time period, resulting in the development of esophageal structural features, including the mucosal epithelium, muscularis mucosae, lamina propria, as well as smooth muscle proliferation/migration initiating the formation of a laminated adventitia. Long term survival (1 year) demonstrated restoration of oral nutrition, normal animal growth and the overall safety of this treatment regimen.

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