Challenges in advancing Schwann cell transplantation for spinal cord injury repair.

Background Aims: In this article we aimed to provide an expert synthesis of the current status of Schwann cell (SC)therapeutics and potential steps to increase their clinical utility.

Methods: We provide an expert synthesis based on preclinical, clinical and manufacturing experience.

Results: Schwann cells (SCs) are essential for peripheral nerve regeneration and are of interest in supporting axonal repair after spinal cord injury (SCI).

Non-invasive Transcutaneous Spinal Cord Stimulation Programming Recommendations for the Treatment of Upper Extremity Impairment in Tetraplegia.

Objectives: This study analyzes the stimulation parameters implemented during two successful trials that used non-invasive transcutaneous spinal cord stimulation (tSCS) to effectively improve upper extremity function after chronic spinal cord injury (SCI). It proposes a framework to guide stimulation programming decisions for the successful translation of these techniques into the clinic.

Materials And Methods: Programming data from 60 participants who completed the Up-LIFT trial and from 17 participants who subsequently completed the LIFT Home trial were analyzed.

Targeted Therapy Modulates the Secretome of Cancer-Associated Fibroblasts to Induce Resistance in HER2-Positive Breast Cancer.

The combination of trastuzumab plus pertuzumab plus docetaxel as a first-line therapy in patients with HER2-positive metastatic breast cancer has provided significant clinical benefits compared to trastuzumab plus docetaxel alone. However, despite the therapeutic success of existing therapies targeting HER2, tumours invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance, so that specific therapeutic strategies can be developed to provide improved efficacy.

The Interdisciplinary Stem Cell Institute's Use of Food and Drug Administration-Expanded Access Guidelines to Provide Experimental Cell Therapy to Patients With Rare Serious Diseases.

The U.S. Food and Drug Administration (FDA) provides guidance for expanded access to experimental therapies, which in turn plays an important role in the Twenty-first Century Cures Act mandate to advance cell-based therapy.

Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury.

A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery.

Deep brain stimulation of midbrain locomotor circuits in the freely moving pig.

Background: Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been studied as a therapeutic target in rodent models of stroke, parkinsonism, and spinal cord injury. Clinical DBS trials have targeted the closely related pedunculopontine nucleus in patients with Parkinson's disease as a therapy for gait dysfunction, with mixed reported outcomes. Recent studies suggest that optimizing the MLR target could improve its effectiveness.

Neurophysiological Changes in the First Year After Cell Transplantation in Sub-acute Complete Paraplegia.

Neurophysiological testing can provide quantitative information about motor, sensory, and autonomic system connectivity following spinal cord injury (SCI). The clinical examination may be insufficiently sensitive and specific to reveal evolving changes in neural circuits after severe injury. Neurophysiologic data may provide otherwise imperceptible circuit information that has rarely been acquired in biologics clinical trials in SCI.

Population Averaged Stereotaxic T2w MRI Brain Template for the Adult Yucatan Micropig.

Population averaged brain templates are an essential tool for imaging-based neuroscience research, providing investigators with information about the expected size and morphology of brain structures and the spatial relationships between them, within a demographic cross-section. This allows for a standardized comparison of neuroimaging data between subjects and provides neuroimaging software with a probabilistic framework upon which further processing and analysis can be based. Many different templates have been created to represent specific study populations and made publicly available for human and animal research.

Hypoxia compensates cell cycle arrest with progenitor differentiation during angiogenesis.

Angiogenesis, the main mechanism that allows vascular expansion for tissue regeneration or disease progression, is often triggered by an imbalance between oxygen consumption and demand. Here, by analyzing changes in the transcriptomic profile of endothelial cells (ECs) under hypoxia we uncovered that the repression of cell cycle entry and DNA replication stand as central responses in the early adaptation of ECs to low oxygen tension. Accordingly, hypoxia imposed a restriction in S-phase in ECs that is mediated by Hypoxia-Inducible Factors.

Dichotomous Locomotor Recoveries Are Predicted by Acute Changes in Segmental Blood Flow after Thoracic Spinal Contusion Injuries in Pigs.

Neuroimaging facilitates the translation of animal pre-clinical research to human application. The large porcine spinal cord is useful for testing invasive interventions. Ideally, the safety and efficacy of a delayed intervention is tested in pigs that have recovered sufficiently after spinal cord injury (SCI) to allow either deterioration or improvement of function to be detected.

Internal decompression of the acutely contused spinal cord: Differential effects of irrigation only versus biodegradable scaffold implantation.

Severe spinal cord injury leads to hemorrhage, edema and elevated tissue pressures that propagate ischemia. Liquefactive necrosis of damaged tissue eventually results in chronic cavities due to a wound healing process lacking adhesive contractile cells. Biomaterials can potently influence wound healing responses.

Method and Apparatus for the Automated Delivery of Continuous Neural Stem Cell Trails Into the Spinal Cord of Small and Large Animals.

Background: Immature neurons can extend processes after transplantation in adult animals. Neuronal relays can form between injected neural stem cells (NSCs) and surviving neurons, possibly improving recovery after spinal cord injury (SCI). Cell delivery methods of single or multiple bolus injections of concentrated cell suspensions thus far tested in preclinical and clinical experiments are suboptimal for new tract formation.

Clinical and Neurophysiological Changes after Targeted Intrathecal Injections of Bone Marrow Stem Cells in a C3 Tetraplegic Subject.

High-level quadriplegia is a devastating condition with limited treatment options. Bone marrow derived stem cells (BMSCs) are reported to have immunomodulatory and neurotrophic effects in spinal cord injury (SCI). We report a subject with complete C2 SCI who received three anatomically targeted intrathecal infusions of BMSCs under a single-patient expanded access investigational new drug (IND).

Intraspinal Delivery of Schwann Cells for Spinal Cord Injury.

Cell transplant-mediated tissue repair of the damaged spinal cord is being tested in several clinical trials. The current candidates are neural stem cells, stromal cells, and autologous Schwann cells (aSC). Due to their peripheral origin and limited penetration of astrocytic regions, aSC are transplanted intralesionally as compared to neural stem cells that are transplanted into intact spinal cord.

Characterization of Motor and Somatosensory Evoked Potentials in the Yucatan Micropig Using Transcranial and Epidural Stimulation.

Yucatan micropigs have brain and spinal cord dimensions similar to humans and are useful for certain spinal cord injury (SCI) translational studies. Micropigs are readily trained in behavioral tasks, allowing consistent testing of locomotor loss and recovery. However, there has been little description of their motor and sensory pathway neurophysiology.

Clinical translation of autologous Schwann cell transplantation for the treatment of spinal cord injury.

Purpose Of Review: To describe the current status of testing Schwann cell transplantation as a therapy for human spinal cord injury (SCI).

Recent Findings: Transplanted Schwann cells have reparative effects in the damaged spinal cord. A few clinical studies have reported that Schwann cell transplantation appears safe.

Accuracy of definitive casts using 4 implant-level impression techniques in a scenario of multi-implant system with different implant angulations and subgingival alignment levels.

Purpose: To evaluate the effect of various implant-level impression techniques on the accuracy of definitive casts for a multiple internal connection implant system with different implant angulations and subgingival depths.

Material And Methods: Six tapered Screw-Vent implants were placed in a reference model with different angles (0, 15, and 30 degrees) and subgingival positions (0, 1, and 3 mm). Twenty medium-consistency polyether impressions of this model were made with 4 techniques (n = 5 per group): (1) indirect technique, (2) unsplinted direct technique, (3) acrylic resin-splinted direct technique, and (4) metal-splinted direct technique.

Association of alleles at polymorphic sites in the Osteopontin encoding gene in young type 1 diabetic patients.

The Osteopontin (OPN) encoding gene, SPP1, can be considered as a candidate for genetic susceptibility to type 1 diabetes (T1D) because of its known function in immune response and inflammation. This work aimed to evaluate the role of SPP1 gene in susceptibility to T1D. Patients (238: 130 male, 108 female) and unaffected adult control individuals (137: 68 males and 69 females) have been genotyped for three variants in the SPP1 gene: -156 (G/GG) and -66 (T/G) in the promoter and a biallelic ins/del variant (TG/TGTG) at +245 in the first intron.

Differing activation status and immune effector molecule expression profiles of neonatal and maternal lymphocytes in an African population.

Higher susceptibility of newborns to infections has been attributed to the hypo-responsiveness of their cellular immune system. Here we compared the activation status and expression of cytokines and cytotoxic molecules of cord versus maternal peripheral blood mononuclear cells in an African population. Human leucocyte antigen-DR was expressed on a lower percentage of cord compared to maternal gammadelta and CD3(+) T cells.

Mutational screening of the CYP26A1 gene in patients with caudal regression syndrome.

Background: The retinoic acid (RA)-catabolizing enzyme Cyp26a1 plays an important role in protecting tailbud tissues from inappropriate exposure to RA. Cyp26a1-null animals exhibit caudal agenesis and spina bifida, imperforate anus, agenesis of the caudal portions of the digestive and urogenital tracts, and malformed lumbosacral skeletal elements. This phenotype closely resembles the most severe form of caudal agenesis in humans.

Activation status of cord blood gamma delta T cells reflects in utero exposure to Plasmodium falciparum antigen.

Background: Placental Plasmodium falciparum infection modulates neonatal cell-mediated immune responses and is associated with increased susceptibility of infants to malaria.

Methods: By flow-cytometric analysis of maternal peripheral and cord blood samples collected at delivery, we measured and compared the activation status and proinflammatory cytokine activity of T cells from women segregated into groups according to malaria status.

Results: Stimulation with phorbol myristate acetate/ionomycin resulted in the highest percentages of tumor necrosis factor-alpha- and interferon-gamma-positive gamma delta T cells in peripheral blood samples and in corresponding cord blood samples from those treated for malaria during pregnancy.