Methacrylic acid (MAA)‐based biomaterials promote a vascularized host response without the addition of exogenous factors such as cells or growth factors. We presume that materials containing MAA ...favor an alternative foreign body response, rather than the conventional fibrotic response. Here, we characterize selected aspects of the response to two different forms of MAA—a coating, which can be used to prevascularize the subcutaneous tissue for subsequent therapeutic cell delivery or an injectable hydrogel, which can be used to vascularize and deliver cells simultaneously. We show that the MAA‐coating quickly vascularized the subcutaneous space compared to an uncoated silicone tube, and after 14 days of prevascularization, the tissue surrounding the MAA‐coated tube presented fewer immune cells than the uncoated control. We also compared the host response to a MAA‐PEG (polyethylene glycol) hydrogel at day 1, with pancreatic islets in immune‐compromised SCID/bg mice and immune‐competent Balb/c mice. The Balb/c mouse presented a more inflammatory response with increased IFN‐γ production as compared to the SCID/bg. Together with previously published data, this work contributes to a further understanding of tissue responses to a biomaterial in different forms as used for cell delivery.
Objective To determine the long-term safety and outcomes of mesenchymal stem cells (MSCs) for bronchopulmonary dysplasia in premature infants enrolled in a previous phase I clinical trial up to 2 ...years of corrected age (CA). Study design We assessed serious adverse events, somatic growth, and respiratory and neurodevelopmental outcomes at visit 1 (4-6 months of CA), visit 2 (8-12 months of CA), and visit 3 (18-24 months of CA) in a prospective longitudinal follow-up study up to 2 years' CA of infants who received MSCs (MSC group). We compared these data with those from a historical case-matched comparison group. Results One of 9 infants in the MSC group died of Enterobacter cloacae sepsis at 6 months of CA, the remaining 8 infants survived without any transplantation-related adverse outcomes, including tumorigenicity. No infant in the MSC group was discharged with home supplemental oxygen compared with 22% in the comparison group. The average rehospitalization rate in the MSC group was 1.4/patient because of respiratory infections during 2 years of follow-up. The mean body weight of the MSC group at visit 3 was significantly higher compared with that of the comparison group. No infant in the MSC group was diagnosed with cerebral palsy, blindness, or developmental delay; in the comparison group, 1 infant was diagnosed with cerebral palsy and 1 with developmental delay. Conclusions Intratracheal transplantation of MSCs in preterm infants appears to be safe, with no adverse respiratory, growth, and neurodevelopmental effects at 2 years' CA. Trial registration ClinicalTrials.gov : NCT01632475.
Objective To assess the safety and feasibility of allogeneic human umbilical cord blood (hUCB)-derived mesenchymal stem cell (MSC) transplantation in preterm infants. Study design In a phase I ...dose-escalation trial, we assessed the safety and feasibility of a single, intratracheal transplantation of hUCB-derived MSCs in preterm infants at high risk for bronchopulmonary dysplasia (BPD). The first 3 patients were given a low dose (1 × 107 cells/kg) of cells, and the next 6 patients were given a high dose (2 × 107 cells/kg). We compared their adverse outcomes, including BPD severity, with those of historical case-matched comparison group. Results Intratracheal MSC transplantation was performed in 9 preterm infants, with a mean gestational age of 25.3 ± 0.9 weeks and a mean birth weight of 793 ± 127 g, at a mean of 10.4 ± 2.6 days after birth. The treatments were well tolerated, without serious adverse effects or dose-limiting toxicity attributable to the transplantation. Levels of interleukin-6, interleukin-8, matrix metalloproteinase-9, tumor necrosis factor α, and transforming growth factor β1 in tracheal aspirates at day 7 were significantly reduced compared with those at baseline or at day 3 posttransplantation. BPD severity was lower in the transplant recipients, and rates of other adverse outcomes did not differ between the comparison group and transplant recipients. Conclusion Intratracheal transplantation of allogeneic hUCB-derived MSCs in preterm infants is safe and feasible, and warrants a larger and controlled phase II study.
p21-Activated kinase 4 (PAK4), a member of the PAK family, regulates a wide range of cellular functions, including cell adhesion, migration, proliferation, and survival. Dysregulation of its ...expression and activity thus contributes to the development of diverse pathological conditions. PAK4 plays a pivotal role in cancer progression by accelerating the epithelial-mesenchymal transition, invasion, and metastasis. Therefore, PAK4 is regarded as an attractive therapeutic target in diverse types of cancers, prompting the development of PAK4-specific inhibitors as anticancer drugs; however, these drugs have not yet been successful. PAK4 is essential for embryonic brain development and has a neuroprotective function. A long list of PAK4 effectors has been reported. Recently, the transcription factor CREB has emerged as a novel effector of PAK4. This finding has broad implications for the role of PAK4 in health and disease because CREB-mediated transcriptional reprogramming involves a wide range of genes. In this article, we review the PAK4 signaling pathways involved in prostate cancer, Parkinson's disease, and melanogenesis, focusing in particular on the PAK4-CREB axis.
Alzheimer's disease (AD), a main cause of dementia, is the most common neurodegenerative disease that is related to abnormal accumulation of the amyloid β (Aβ) protein. Despite decades of intensive ...research, the mechanisms underlying AD remain elusive, and the only available treatment remains symptomatic. Molecular understanding of the pathogenesis and progression of AD is necessary to develop disease-modifying treatment.
, as the most advanced genetic model, has been used to explore the molecular mechanisms of AD in the last few decades. Here, we introduce
AD models based on human Aβ and summarize the results of their genetic dissection. We also discuss the utility of functional genomics using the
system in the search for AD-associated molecular mechanisms in the post-genomic era.
Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders characterized by ...progressive degeneration of the nervous system. Currently, there is no disease-modifying treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue communication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is thought to be an important underlying mechanism for the advantages. Here, we reviewed studies about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival, neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which there are no adequate treatments nowadays. To date, only a few myokines have been investigated for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore, future studies are needed to discover more myokines and test their effects on NDs.
Objective To determine whether a nonintervention approach for treating hemodynamically significant patent ductus arteriosus (PDA) is associated with decreased mortality and/or morbidity compared with ...a mandatory closure approach in extremely low birth weight infants. Study design We reviewed the medical records of 178 infants of 23-26 weeks' gestational age with PDA, requiring ventilator treatment, and with hemodynamically significant PDA ≥2 mm in size. Mandatory closure was used during period I (July 2009 to December 2011, n = 81), and nonintervention was used during period II (January 2012 to June 2014, n = 97). Results During period I, 64% of infants were first treated with indomethacin, and 82% were ultimately ligated surgically. During period II, no infant was treated with indomethacin and/or ligation. The average postnatal day of PDA closure was day 13 and day 44 during periods I and II, respectively. There was significantly more use of diuretics and fluid restriction during period II compared with period I. There was no difference in mortality or morbidities such as necrotizing enterocolitis or intraventricular hemorrhage. The incidence of bronchopulmonary dysplasia (BPD) and the propensity score adjusted OR of BPD were significantly lower during period II compared with period I. Conclusions Despite longer PDA exposure, nonintervention was associated with significantly less BPD compared with mandatory closure. Additional study is warranted to determine the benefits and risks of non-intervention for the hemodynamically significant PDA in extremely low birth weight infants.
Dendritic cells (DCs) are first responders of the innate immune system that integrate signals from external stimuli to direct context-specific immune responses. Current models suggest that an active ...switch from mitochondrial metabolism to glycolysis accompanies DC activation to support the anabolic requirements of DC function. We show that early glycolytic activation is a common program for both strong and weak stimuli, but that weakly activated DCs lack long-term HIF-1α-dependent glycolytic reprogramming and retain mitochondrial oxidative metabolism. Early induction of glycolysis is associated with activation of AKT, TBK, and mTOR, and sustained activation of these pathways is associated with long-term glycolytic reprogramming. We show that inhibition of glycolysis impaired maintenance of elongated cell shape, DC motility, CCR7 oligomerization, and DC migration to draining lymph nodes. Together, our results indicate that early induction of glycolysis occurs independent of pro-inflammatory phenotype, and that glycolysis supports DC migratory ability regardless of mitochondrial bioenergetics.
Nonvolatile memory characteristics of the ferroelectric field-effect transistors (FeFETs) were investigated by introducing the metal-ferroelectric-metal-insulator-semiconductor (MFMIS) gate-stacks, ...employing Al-doped HfO 2 (Al:HfO 2 ) ferroelectric thin films. The obtained memory window (MW) of the MFMIS FETs increased from 1.0 to 2.8 V by increasing the areal ratios of the metal-insulator-semiconductor (MIS) to the metal-ferroelectric-metal (MFM) (S I /S F ) from 8 to 32. The device with an S I /S F ratio of 16 exhibited a 3-order-of-magnitude on/off memory margin even with a program pulse duration of 500 ns. The long-term data retention was also verified by improving the tolerance against the depolarization field by introducing the MFMIS gate-stacks, which can use fully saturated polarization. The temperature-dependent memory performance and operational reliabilities of the MFMIS-FETs were also investigated at high temperatures to exploit fully the thermal stability of the Al:HfO 2 . The obtained MWs were not markedly degraded for a retention time of 10 4 s from room temperature (RT) to 80 °C.
Multifocal inflammatory lesions featuring destruction of lipid-rich myelin are pathologic hallmarks of multiple sclerosis. Lesion activity is assessed by the extent and composition of myelin uptake ...by myeloid cells present in such lesions. In the inflamed CNS, myeloid cells are comprised of brain-resident microglia, an endogenous cell population, and monocyte-derived macrophages, which infiltrate from the systemic compartment. Using microglia isolated from the adult human brain, we demonstrate that myelin phagocytosis is dependent on the polarization state of the cells. Myelin ingestion is significantly enhanced in cells exposed to TGF-β compared with resting basal conditions and markedly reduced in classically activated polarized cells. Transcriptional analysis indicated that TGF-β-treated microglia closely resembled M0 cells. The tyrosine kinase phagocytic receptor MerTK was one of the most upregulated among a select number of differentially expressed genes in TGF-β-treated microglia. In contrast, MerTK and its known ligands, growth arrest-specific 6 and Protein S, were downregulated in classically activated cells. MerTK expression and myelin phagocytosis were higher in CNS-derived microglia than observed in monocyte-derived macrophages, both basally and under all tested polarization conditions. Specific MerTK inhibitors reduced myelin phagocytosis and the resultant anti-inflammatory biased cytokine responses for both cell types. Defining and modulating the mechanisms that regulate myelin phagocytosis has the potential to impact lesion and disease evolution in multiple sclerosis. Relevant effects would include enhancing myelin clearance, increasing anti-inflammatory molecule production by myeloid cells, and thereby permitting subsequent tissue repair.
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