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Immunomodulatory oligonucleotide IMT504:Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

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World Journal of Stem Cells 2017年第3期9卷 45-67页

作者： Jorge Zorzopulos Steven M Opal Andrés Hernando-Insúa Juan M Rodriguez Fernanda Elías Juan Fló Ricardo A lópez Norma A Chasseing Victoria A lux-lantos Maria F Coronel Raul Franco Alejandro D Montaner david l horn Immunotech S.A. Ciudad de Buenos Aires C1440FFXArgentina Infectious Disease Division Memorial Hospital of Rhode Island and Alpert Medical SchoolProvidenceRI 02905United States Fundación Pablo Cassara Ciudad Autonoma de Buenos Aires C1440FFXArgentina Instituto de Biología y Medicina Experimental(IBYME-CONICET) Ciudad Autónoma de Buenos Aires C1428ADNArgentina Instituto de Ciencia y Tecnolog'DR.Cesar Milstein” Fundación Pablo CassaráCiudad Autonoma de Buenos Aires C1440FFXArgentina david horn llC DoylestownPA 18902United States

The immune responses of humans and animals to insults(i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged proinflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell(MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.

关键词： Immunohomeostasis Immunoprotection Immunoregeneration Inflammation Mesenchymal stem cells IMT504

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IMT504: A New and Potent Adjuvant for Rabies Vaccines Permitting Significant Dose Sparing

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World Journal of Vaccines 2012年第4期2卷 182-188页

作者： Alejandro D. Montaner Analia De Nichilo Juan M. Rodriguez Andres Hernando-Insua Juan Fló Ricardo A. lopez Verónica Sierra Claudio Paolazzi Oscar larghi david l. horn Jorge Zorzopulos Fernanda Elias david horn LLC Doylestown PA USA. Immunotech S.A. Buenos Aires Argentina Instituto de Investigaciones Biomédicas Fundación Pablo Cassará Buenos Aires Argentina Instituto San Jorge Bagó Buenos Aires Argentina Instituto San Jorge Bagó Buenos Aires Argentina. nstituto de Investigaciones Biomédicas Fundación Pablo Cassará Buenos Aires Argentina

Background: Rabies virus infection causes encephalitis, which is almost always fatal. Vaccination can be extremely effective at preventing disease but is prohibitively costly. Vaccine formulations allowing dose-sparing and fewer inoculations with faster antibody response would be extremely desirable. IMT504, an immunostimulatory non-CpG oligo-deoxynucleotide, is a highly potent vaccine adjuvant. Methods: Human and rat antibody measurements, and rat chal-lenge studies were performed. Results: In rats, highly effective immune responses with IMT504 were observed even after diluting vaccine up to 1/625. In highly lethal, live intracerebral rabies challenge studies, protection occurred even with extremely dilute vaccine plus IMT504. In humans, antibody titers developed faster and were significantly higher with IMT504-adjuvanted diluted vaccine vs non-adjuvanted vaccine (full strength or diluted). All five administered IMT504-adjuvanted diluted vaccine reached protective antibodies (≥0.5 IU/ml) after the second injection. After the third injection, individuals receiving IMT504-adjuvanted diluted vaccine reached levels approximately 10 times higher than controls (M ± SEM: 31.0 ± 10.9 vs 3.40 ± 0.99 IU/ml). Conclusions: These data suggest that IMT504 may allow fewer inoculations, highly significant dose-sparing of vaccine, rapid antibody production and protection from rabies. Extensive clinical studies are necessary to confirm if the use of IMT504 will permit significantly greater access to highly effective life-saving rabies vaccines.

关键词： IMT504 Adjuvant Rabies Vaccine Human Animal

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Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

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Neural Regeneration Research 2025年第6期20卷 1789-1800页

作者： Carina Hromada Patrick Heimel Markus Kerbl lászlóGál Sylvia Nürnberger Barbara Schaedl James Ferguson Nicole Swiadek Xavier Monforte Johannes C.Heinzel Antal Nógrádi Andreas H.Teuschl-Woller david Hercher Department life Science Engineering University of Applied Sciences Technikum WienViennaAustria Austrian Cluster for Tissue Regeneration ViennaAustria ludwig Boltzmann Institute for Traumatology The Research Center in Cooperation with AUVAViennaAustria University Clinic of Dentistry Medical University of ViennaViennaAustria Department of Plastic Reconstructive and Aesthetic SurgeryLandesklinikum Wiener Neustadt2700 Wiener NeustadtAustria Department of Anatomy Histology and EmbryologyAlbert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary Medical University of Vienna Department of Orthopedics and Trauma SurgeryDevision of Trauma SurgeryViennaAustria Department of Hand- PlasticReconstructive and Burn SurgeryBG Unfallklinik TuebingenUniversity of TuebingenTuebingenGermany

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk^(+) tNGCs with the tubes without holes(silk^(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk^(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk^(+) group was found compared with autologous nerve transplants and silk^(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk^(–) tNGCs at 7 weeks postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk^(+) tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimizatio

关键词： axon regeneration blood vessel functional recovery macroporous nerve lesion peripheral nerve repair sciatic nerve silk-based nerve guidance conduit vascularization

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Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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Neural Regeneration Research 2025年第5期20卷 1324-1335页

作者： Hassan Saad Bachar El Baba Ali Tfaily Firas Kobeissy Juanmarco Gutierrez Gonzalez Daniel Refai Gerald R.Rodts Christian Mustroph david Gimbel Jonathan Grossberg Daniel l.Barrow Matthew F.Gary Ali M.Alawieh Department of Neurosurgery Emory University School of MedicineAtlantaGAUSA Department of Neurology Yale UniversityNew HavenCTUSA Center for Neurotrauma Multiomics&Biomarkers(CNMB)Morehouse School of MedicineAtlantaGAUSA

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this *** the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing *** this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the *** study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular *** effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord *** this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human *** review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

关键词： complement neuroinflammation neuroplasticity regeneration spinal cord injury targeted therapy

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Ipsilateral femur and tibia fractures in pediatric patients:A systematic review

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World Journal of Orthopedics 2017年第8期8卷 638-643页

作者： Jason B Anari Alexander l Neuwirth B david horn Keith D Baldwin Department of Orthopaedic Surgery University of Pennsylvania Children’s Hospital of Philadelphia

AIM To better understand how pediatric floating knee injuries are managed after the wide spread use of new orthopaedic *** We searched EMBASE, COCHRANE and MEDlINE computerized literature databases from the earliest date available in the databases to February 2017 using the following search term including variants and pleural counterparts: Pediatric floating knee. All studies were thoroughly reviewed by multiple authors. Reference lists from all articles were scrutinized to identify any additional studies of interest. A final database of individual patients was assembled from the literature. Univariate and multivariate statistical tests were applied to the assembled database to assess differences in *** The English language literature contains series with a total of 97 pediatric patients who sustained floating knee injuries. Patients averaged 9.3 years of age and were mostly male(73). Approximately 25% of the fractures were open injuries, more tibia(27) than femur(10). Over 75% of the fractures of both the tibia and the femur involved the diaphysis. More than half(52) of the patients were treated non-operatively for both fractures. As a sequela of the injury 32(33%) patients were left with a limb length discrepancy, 24(25%) patients had lengthening of the injured limb at follow up, while 8(8%) had shortening of the affected limb. Infection developed in 9 patients and 3 had premature physeal closure. Younger patients were more likely to be treated non-operatively(P lly significant shorter hospital length of stays(P = 0.001).CONClUSION Given the predominance of non-operative managementin published studies, the available literature is not clinically relevant since the popularization of internal fixation for pediatric long-bone

关键词： Pediatrics Femur Tibia Fracture Floating knee

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TOPOlOGY AND CASCADING lINE OUTAGES IN POWER GRIDS

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Journal of Systems Science and Systems Engineering 2007年第2期16卷 202-221页

作者： david l. PEPYNE University of Massachusetts Amherst MA USA

Motivated by the small world network research of Watts ＆ Strogatz, this paper studies relationships between topology and cascading line outages in electric power grids. Cascading line outages are a type of cascading collapse that can occur in power grids when the transmission network is congested. It is characterized by a self-sustaining sequence of line outages followed by grid breakup, which generally leads to widespread blackout. The main findings of this work are twofold： On one hand, the work suggests that topologies with more disorder in their interconnection topology tend to be robust with respect to cascading line outages in the sense of being able to support greater generation and demand levels than more regularly interconnected topologies. On the other hand, the work suggests that topologies with more disorder tend to be more fragile in that should a cascade get started, they tend to break apart after fewer outages than more regularly interconnected topologies. Thus, as has been observed in other complex networks, there appears to be a tradeoff between robustness and fragility. These results were established using synthetically generated power grid topologies and verified using the IEEE 57 bus and 188 bus power grid test cases.

关键词： Power grid blackout cascading line failure complex networks robust yet fragile

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OPTIMAl INVERSE lQG CONTROl FOR CERTAIN ODE AND PDE STATIONARY PROCESSES

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Journal of Systems Science & Complexity 2010年第3期23卷 584-599页

作者： david l.RUSSEll Department of Mathematics Virginia Tech

Following work carried out earlier on linear-quadratic optimal control for linear finitedimensional stationary systems we report,in this article,on extension of some of those results to certaininfinite dimensional systems;in particular a class of PDE systems of elliptic *** systems arestudied in the now familiar framework developed by *** and ***,specialized to asubclass of such systems important in a variety of *** an extended example this paperstudies an optimal redistribution problem in a groundwater flow system governed by Darcy's equation,presenting both analytic and computational work related to such problems.

关键词： Elliptic PDE linear feedback control stationary system.

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Dislocation Creep Accommodated by Grain Boundary Sliding in Dunite

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Journal of Earth Science 2010年第5期21卷 541-554页

作者： Yonghong Zhao david l Kohlstedt School of Earth and Space Sciences Peking University Department of Geology and Geophysics University of Minnesota

To investigate the role of grain boundary sliding during dislocation creep of dunite, a series of deformation experiments were carried out under anhydrous conditions on fine-grained （-15 μm） samples synthesized from powdered San Carlos olivine and powdered San Carlos olivine＋1.5 vol.% MORB. Triaxial compressive creep tests were conducted at a temperature of 1 473 K and confining pressures of 200 and 400 MPa using a high-resolution, gas-medium deformation apparatus. Each sample was deformed at several levels of differential stress between 100 and 250 MPa to yield strain rates in the range of 10^-6 to 10^-4 s^-1. Under these conditions, the dominant creep mechanism involves the motion of dislocations, largely on the easy slip system （010）[100], accommodated by grain boundary sliding （gbs）. This grain size-sensitive creep regime is characterized by a stress exponent of n=3.4±0.2 and a grain size exponent of p=2.0±0.2. The activation volume for this gbs-accommodated dislocation creep regime is V＊=（26±3）×10^-6 m2·mol^-1. Comparison of our flow law for gbs-accommodated dislocation creep with those for diffusion creep and for dislocation creep reveals that the present flow law is important for the flow of mantle rocks with grain sizes of 〈100μm at differential stresses 〉20 MPa. Hence, gbs-accommodated dislocation creep is likely to be an important deformation mechanism in deep-rooted, highly localized shear zones in the lithospheric upper mantle.

关键词： grain boundary sliding creep olivine flow law.

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Zinc deficiency in patients with chronic pancreatitis

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World Journal of Gastroenterology 2019年第5期25卷 600-607页

作者： Miroslav Vujasinovic AleksANDra Hedstr?m Patrick Maisonneuve Roberto Valente Henrik von horn J-Matthias l?hr Stephan l Haas Department for Digestive Diseases Karolinska University Hospital Division of Epidemiology and Biostatistics IEO European Institute of Oncology IRCCS Department for Digestive Diseases Sapienza University of Rome Division of Clinical Chemistry Department of Molecular Medicine and Surgery Karolinska Institutet Karolinska University Hospital Department of Clinical Science Intervention and Technology (CLINTEC)Karolinska Institute

BACKGROUND Zinc is a key element in numerous proteins and plays an important role in essential cell functions such as defense against free radicals and DNA damage repair. Chronic pancreatitis(CP) is a chronic inflammation with progressive fibrosis of pancreas ultimately resulting in pancreatic exocrine insufficiency(PEI),which is associated with malnutrition. Studies analyzing zinc levels in patients with CP are sparse and lead to conflicting *** To investigate serum zinc levels in patients with CP of various *** Between October 2015 and March 2018, patients with a diagnosis of CP were identified and recruited from the Pancreatic Outpatient Clinic at the Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Etiology of CP was determined according to the MANNHEIM classification system into the following etiological subcategories:alcohol consumption, nicotine consumption, hereditary factors, efferent pancreatic duct factors and immunological factors. Pancreatic exocrine function was defined as normal(fecal elastase 1 > 200 μg/g), mildly reduced(100-200μg/g) and severely reduced(fecal elastase 1 lTS A total of 150 patients were included in the analysis. Zinc deficiency(l/l) was present in 39(26.0%) of patients: 22 females and 17 males. In the group of patients with zinc deficiency, 76.7% of patients had an exocrine pancreatic insufficiency(FE-1 lder age was significantly associated with low zinc levels. Following a univariate analysis, patients aged 60-69 and patients ≥ 70 years of age had a significantly higher prevalence of zinc deficiencies compared to patients 0.002]. Smoking and number of packyears were additionally associated with low zinc levels. The risk of zinc deficiency in current smokers and smokers with ≥ 20 pack-years was approximately three times higher

关键词： Zinc Pancreas Pancreatic exocrine insufficiency Chronic pancreatitis Malnutrition

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MEMS-in-the-lens architecture for a miniature high-NA laser scanning microscope

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light(Science & Applications) 2019年第1期8卷 665-675页

作者： Tianbo liu Milind Rajadhyaksha david l.Dickensheets Electrical and Computer Engineering Department Montana State UniversityBozemanMT 59715USA Dermatology Department Memorial Sloan Kettering Cancer CenterNew YorkNY 10022USA

laser scanning microscopes can be miniaturized for in vivo imaging by substituting optical microelectromechanical system(MEMS)devices in place of larger *** emergence of multifunctional active optical devices can support further miniaturization beyond direct component replacement because those active devices enable diffraction-limited performance using simpler optical system *** this paper,we propose a catadioptric microscope objective lens that features an integrated MEMS device for performing biaxial scanning,axial focus adjustment,and control of spherical *** MEMS-in-the-lens architecture incorporates a reflective MEMS scanner between a low-numerical-aperture back lens group and an aplanatic hyperhemisphere front refractive element to support high-numerical-aperture *** implemented this new optical system using a recently developed hybrid polymer/silicon MEMS three-dimensional scan mirror that features an annular aperture that allows it to be coaxially aligned within the objective lens without the need for a beam *** optical performance of the active catadioptric system is simulated and imaging of hard targets and human cheek cells is demonstrated with a confocal microscope that is based on the new objective lens design.

关键词： scanning scanner mirror

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