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Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report

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Neural Regeneration Research 2025年第4期20卷 1207-1216页

作者： Pascal J.Goldschmidt-Clermont Aisha Khan George Jimsheleishvili Patricia Graham Adriana Brooks Risset Silvera Alexander J.P.Goldschmidt Damien D.Pearse W.Dalton Dietrich Allan D.Levi James D.Guest Miller School of Medicine University of MiamiMiamiFLUSA Stem Cell Institute Miller School of MedicineUniversity of MiamiMiamiFLUSA The Miami Project to cure Paralysis Miller School of MedicineUniversity of MiamiMiamiFLUSA Alzady International LLC MiamiFLUSA Neurological Surgery Miller School of MedicineUniversity of MiamiMiamiFLUSA

Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular *** amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be ***,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been *** case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such *** 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral *** initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and *** patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron *** confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in *** a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered *** of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or

关键词： allogeneic amyotrophic lateral sclerosis exosomes infusion neuromuscular junction Schwann cell

Animal models of axon regeneration after spinal cord injury

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Neuroscience Bulletin 2013年第4期29卷 436-444页

作者： Do-Hun Lee Jae K. Lee University of Miami School of Medicine Miami Project to Cure Paralysis Department of Neurological Surgery

With advances in genetic and imaging techniques, investigating axon regeneration after spinal cord injury in vivo is becoming more common in the literature. However, there are many issues to consider when using animal models of axon regeneration, including species, strains and injury models. No single particular model suits all types of experiments and each hypothesis being tested requires careful selection of the appropriate animal model. In this review, we describe several commonly-used animal models of axon regeneration in the spinal cord and discuss their advantages and disadvantages.

关键词： pyramidotomy strain differences contusion injury models

Casein kinase signaling in axon regeneration

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Neural Regeneration Research 2016年第2期11卷 210-211页

作者： Nagi G.Ayad Jae K.Lee Vance P.Lemmon The Center for Therapeutic Innovation The Miami Project to Cure Paralysis Department of Psychiatry and Behavioral SciencesUniversity of Miami The Miami Project to cure Paralysis Department of NeurosurgeryUniversity of Miami

Recent studies suggest that cell cycle pathways may contain therapeutic targets important for *** example of this is the finding that the vertebrate cell cycle exploits proteolysis pathways,yet these activities persist in fully differentiated cells that have exited the cell cycle such as *** have known for some time that a ubiquitin ligase.

关键词： APC Casein kinase signaling in axon regeneration

To myelinate or not to myelinate:fine tuning c AMP signaling in Schwann cells to balance cell proliferation and differentiation

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Neural Regeneration Research 2015年第12期10卷 1936-1937页

作者： Paula V.Monje The Miami Project to cure Paralysis and Department of Neurological Surgery University of Miami Miller School of Medicine

cAMP signaling and the control of Schwann cell fate： The ubiquitous second messenger cyclic adenosine monophosphate （cAMP） controls a variety of cellular responses in a cell type-specific and stimulus-de- pendent manner through an elaborate network of signaling intermedi- aries that connect stimulation of cell membrane receptors （typically G protein-coupled receptors, GPCRs） to transcription factor activation. Schwann cells （SCs） are highly responsive to cAMP throughout their lifespan, as extensive research has shown that SC survival, lineage spec- ification, proliferation and differentiation into myelin-forming cells require cAMP signaling.

关键词： AMP cell

Epistaxis in end stage liver disease masquerading as severe upper gastrointestinal hemorrhage

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World Journal of Gastroenterology 2014年第38期20卷 13993-13998页

作者： Marine Camus Dennis M Jensen Jason D Matthews Gordon V Ohning Thomas O Kovacs Rome Jutabha Kevin A Ghassemi Gustavo A Machicado Gareth S Dulai cure Hemostasis Research Group CURE Digestive Diseases Research CenterDavid Geffen School of Medicine at University of California Division of Digestive Diseases at University of California Los AngelesRonald Reagan Medical Center Department of Gastroenterology Lariboisiere Hospital cure Hemostasis Research Group CURE Digestive Diseases Research CenterDavid Geffen School of Medicine at University of CaliforniaLos AngelesLos AngelesCA 90095United States Gastroenterology Division at VA Greater Los Angeles Healthcare System Hunterdon Gastrointestinal Associates

AIM: To describe the prevalence, diagnosis, treatment, and outcomes of end stage liver disease (ESLD) patients with severe epistaxis thought to be severe upper gastrointestinal hemorrhage (UGIH).

关键词： Epistaxis Upper gastrointestinal bleeding End stage liver disease Cirrhosis Nasogastric tube Liver transplantation Digestive bleeding Nasal packing Coagulopathy

Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease

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Neural Regeneration Research 2025年第6期20卷 1644-1664页

作者： Gabriela Seplovich Yazan Bouchi Juan Pablo de Rivero Vaccari Jennifer C.Munoz Pareja Andrew Reisner Laura Blackwell Yehia Mechref Kevin K.Wang J.Adrian Tyndall Binu Tharakan Firas Kobeissy Department of Surgery Morehouse School of MedicineAtlantaGAUSA Department of Neurobiology Center for NeurotraumaMultiomics&Biomarkers(CNMB)Neuroscience InstituteMorehouse School of MedicineAtlantaGAUSA Department of Neurological Surgery and the Miami Project to cure Paralysis University of Miami Miller School of MedicineMiamiFLUSA Division of Pediatric Critical Care Department of PediatricsUniversity of Miami Miller School of MedicineMiamiFLUSA Department of Pediatrics Emory UniversityAtlantaGAUSA Department of Neurosurgery Children’s Healthcare of AtlantaAtlantaGAUSA Department of Chemistry and Biochemistry Texas Tech UniversityLubbockTXUSA Morehouse School of Medicine AtlantaGAUSA

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

关键词： Alzheimer's disease caspase-1 chronic traumatic encephalopathy inflammasomes neurodegeneration neuroinflammation NLRP1 NLRP3 pyroptosis tauopathy traumatic brain injury

What does “Disruptive” mean? Thoughts on the NIH SCI 2020 meeting

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Neural Regeneration Research 2019年第9期14卷 1527-1529页

作者： Vance P.Lemmon The Miami Project to cure Paralysis Department of Neurological SurgeryCenter for Computational Science Miller School of Medicine University of Miami

The SCI 2020 meeting is a wakeup call for the SCI research community. The very large worldwide community of individuals with SCI and their family members are justifiably concerned about the pace of progress. But mismatches between research system realities("where is the innovation", grant durations versus the time it takes to do meaningful chronic studies in animals and people, etc.), clinical trial funding mechanisms, FDA approval processes, and patient needs and expectations will require dramatic changes in strategies and tactics. Those were not addressed at this meeting. If the SCI patient community wants to use its frustration to accelerate the development of specific therapies, itmay want to look at an aggressive top-down approach using a contract research organization model and have all studies done in parallel from the beginning to find robust therapies. Angel investors or foundations in it for the long haul will be needed. Alternatively, the National Center for Advancing Translational Sciences(NCATS) model of funding translational research might work, but rock solid therapeutic targets will be required. This strategy could lead to "disruptions" that could dramatically accelerate the pace of development of novel therapeutics.

关键词： SCI NIH Kennedy Human hope has is

Peaks over Manifold (POM): A Novel Technique to Analyze Extreme Events over Surfaces

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Advances in Pure Mathematics 2022年第1期12卷 48-62页

作者： Gonzalo Perera Angel M. Segura cure Rocha Uruguay

We present a novel method to analyze extreme events of flows over manifolds called Peaks Over Manifold (POM). Here we show that under general and realistic hypotheses, the distribution of affectation measures converges to a Generalized Pareto Distribution (GPD). The method is applicable to floods, ice cover extent, extreme rainfall or marine heatwaves. We present an application to a synthetic data set on tide height and to real ice cover data in Antartica.

关键词： Peaks Over Thresholds (POT) Generalized Pareto Distribution Extreme Events

Advances in the management of infertility in men with spinal cord injury

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Asian Journal of Andrology 2016年第3期18卷 382-390,I0007,I0008页

作者： Emad Ibrahim Nancy L Brackett Charles M Lynne The Miami Project to cure Paralysis University of Miami Miller School of Medicine Miami FL USA Department of Urology University of Miami Miller School of Medicine Miami FL USA.

Couples with a spinal cord injured male partner require assisted ejaculation techniques to collect semen that can then be further used in various assisted reproductive technology methods to achieve a pregnancy. The majority of men sustaining a spinal cord injury regardless of the cause or the level of injury cannot ejaculate during sexual intercourse. Only a small minority can ejaculate by masturbation. Penile vibratory stimulation and electroejaculation are the two most common methods used to retrieve sperm. Other techniques such as prostatic massage and the adjunct application of other medications can be used, but the results are inconsistent. Surgical sperm retrieval should be considered as a last resort if all other methods fail. Special attention must be paid to patients with T6 and rostral levels of injury due to the risk of autonomic dysreflexia resulting from stimulation below the level of injury. Bladder preparation should be performed before stimulation if retrograde ejaculation is anticipated. Erectile dysfunction is ubiquitous in the spinal cord injured population but is usually easily managed and does not pose a barrier to semen retrieval in these men. Semen analysis parameters of men with spinal cord injury are unique for this population regardless of the method of retrieval, generally presenting as normal sperm concentration but abnormally low sperm motility and viability. When sperm retrieval is desired in this population, emphasis should be placed on initially trying the simple methods of penile vibratory stimulation or electroejaculation before resorting to more advanced and invasive surgical procedures.

关键词： assisted reproductive technology ejaculation electroejaculation male infertility paraplegia penile vibratory stimulation semen sperm spinal cord injury surgical sperm retrieval