Association between polymorphisms and atopic dermatitis susceptibility: A systematic review and meta-analysis.

AIM: Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease that is closely linked to genetic factors. Previous studies have revealed numerous single nucleotide polymorphisms (SNPs) that been related to susceptibility to AD; however, the results are conflicting. Therefore, a meta-analysis was conducted to assess the associations of these polymorphisms and AD risk. MATERIAL AND METHODS: PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure databases were retrieved to identify eligible studies, with selected polymorphisms being reported in a minimum of three separate studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality. Review Manager 5.3 and STATA 14.0 were used to perform the meta-analysis. RESULTS: After screening, 64 studies involving 13 genes (24 SNPs) were selected for inclusion in the meta-analysis. Nine SNPs were positively correlated with AD susceptibility [filaggrin (FLG) R501X, FLG 2282del4, chromosome 11q13.5 rs7927894, interleukin (IL)-17A rs2275913, IL-18 -137 G/C, Toll-like receptor 2 (TLR2) rs5743708, TLR2 A-16934 T, serine protease inhibitor Kazal type-5 (SPINK5) Asn368Ser, interferon-γ (IFN-γ) T874A] and one was negatively associated with AD susceptibility (IL-4 -1098 T/G). The 14 remaining SNPs were not significantly associated with AD susceptibility. CONCLUSIONS: Nine SNPs that may be risk factors and one SNP that may be a protective factor for AD were identified, providing a reference for AD prediction, prevention, and therapy.

Histone deacetylase 3 inhibition alleviates 2,4-dinitrochlorobenzene-induced atopic dermatitis via epigenetically upregulating Nrf2/HO-1 signaling pathway.

Atopic dermatitis (AD) is a frequent skin disorder that is associated with immune dysfunction and skin inflammation. Histone deacetylase 3 (HDAC3) possesses strong immune and inflammatory modulatory properties in multiple diseases. However, the role and mechanism of HDAC3 in AD remain unknown. Here, we reported that HDAC3 expression was aberrantly upregulated in 2,4-dinitrochlorobenzene (DNCB)-induced lesional AD skin in mice. Inhibition of HDAC3 by RGFP966 protected against DNCB-induced AD, indicated by improved histological damages, relieved inflammatory and immune dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway activity in lesional AD skin was significantly decreased and RGFP966 attenuated the decrease. Inhibition of Nrf2/HO-1 signaling pathway via Nrf2 inhibitor ML385 blunted anti-AD effect of RGFP966 in DNCB-treated mice. Mechanistically, RGFP966 promoted Nrf2 expression and upregulated H3K27ac deposition on the promoter region of Nrf2. Collectively, HDAC3 inhibition protects against AD via epigenetically activating Nrf2 transcription to upregulate Nrf2/HO-1 signaling pathway activity. HDAC3 may act as a promising therapeutic target for the treatment of AD.

Sodium Butyrate Ameliorates Atopic Dermatitis-Induced Inflammation by Inhibiting HDAC3-Mediated STAT1 and NF-κB Pathway.

A topic dermatitis (AD) is a common chronic and recurrent skin disorder. The protective effects of sodium butyrate (NaB), a metabolite of short-chain fatty acid breakdown by the gut microbiota, have been widely reported in numerous inflammatory diseases. However, the effect of NaB treatment alone on AD has not been reported. In the current study, AD was induced in BALB/c mice with 2,4-dinitrochlorobenzene (DNCB) for 28 days with NaB (200 mg/kg) treatment by gavage. NaB attenuated AD-induced skin bleeding, scarring, dryness, abrasions and erosions. In addition, NaB inhibited inflammatory cells infiltration and attenuated the expression of inflammatory cytokines and chemokines. Mechanistically, NaB reduced histone deacetylase 3 (HDAC3) expression and NF-κB p65 nuclear translocation by increasing the lysine acetylation levels of STAT1 and NF-κB p65 in AD. Taken together, our study suggests that NaB inhibits inflammatory mediators and ameliorates AD by inhibiting HDAC3 expression, thereby upregulating STAT1 and NF-κB p65 lysine acetylation levels and reducing NF-κB p65 nuclear translocation. Therefore, this study provides a new theoretical basis for NaB in the treatment of AD.

Uncovering the prominent role of satellite cells in paravertebral muscle development and aging by single-nucleus RNA sequencing.

To uncover the role of satellite cells (SCs) in paravertebral muscle development and aging, we constructed a single-nucleus transcriptomic atlas of mouse paravertebral muscle across seven timepoints spanning the embryo (day 16.5) to old (month 24) stages. Eight cell types, including SCs, fast muscle cells, and slow muscle cells, were identified. An energy metabolism-related gene set, TCA CYCLE IN SENESCENCE, was enriched in SCs. Forty-two skeletal muscle disease-related genes were highly expressed in SCs and exhibited similar expression patterns. Among them, Pdha1 was the core gene in the TCA CYCLE IN SENESCENCE; Pgam2, Sod1, and Suclg1 are transcription factors closely associated with skeletal muscle energy metabolism. Transcription factor enrichment analysis of the 42 genes revealed that Myod1 and Mef2a were also highly expressed in SCs, which regulated Pdha1 expression and were associated with skeletal muscle development. These findings hint that energy metabolism may be pivotal in SCs development and aging. Three ligand-receptor pairs of extracellular matrix (ECM)-receptor interactions, Lamc1-Dag1, Lama2-Dag1, and Hspg2-Dag1, may play a vital role in SCs interactions with slow/fast muscle cells and SCs self-renewal. Finally, we built the first database of a skeletal muscle single-cell transcriptome, the Musculoskeletal Cell Atlas (http://www.mskca.tech), which lists 630,040 skeletal muscle cells and provides interactive visualization, a useful resource for revealing skeletal muscle cellular heterogeneity during development and aging. Our study could provide new targets and ideas for developing drugs to inhibit skeletal muscle aging and treat skeletal muscle diseases.

Activated carbon modified titanium dioxide/bismuth trioxide adsorbent: One-pot synthesis, high removal efficiency of organic pollutants, and good recyclability.

Considerable endeavors have focused on tightly combining adsorption with photocatalysis in designing composite materials for environmental pollution treatment. Recent advances in coupling titanium dioxide/bismuth trioxide (TiO2/Bi2O3) with activated carbon (AC) show significantly enhanced photocatalytic performance but face critical limitations including low adsorption capacity and multi-step synthesis. In this work, we introduce a one-pot synthesis of activated carbon modified TiO2/Bi2O3 composite materials (TiO2/Bi2O3/AC). Thanks to the integrated adsorbent/photocatalyst system, TiO2/Bi2O3/AC shows a drastically enhanced removal efficiency for sulfamethazine (>81%), far beyond the corresponding value of the reported AC/TiO2/Bi2O3 adsorbent (<40%). Notably, the removal rates of other typical pollutants including tetracyclines, methyl orange, and rhodamine B are as high as >98%. Furthermore, TiO2/Bi2O3/AC obtains >80% of its adsorption rate for the fifth cycle after simple photo-regeneration without any other post-treatments. Kinetic analysis and photoelectric characterization are carried out to provide insight into adsorption mechanism. Therefore, this work demonstrates a considerable potential to design and construct other multifunctional adsorbents with advanced performance.

RAGE ablation attenuates glioma progression and enhances tumor immune responses by suppressing galectin-3 expression.

BACKGROUND: Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas. METHODS: As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry. RESULTS: Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade. CONCLUSIONS: We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.

Minimum 3-year experience with vertebral body tethering for treating scoliosis: A systematic review and single-arm meta-analysis.

PURPOSE: Over the past 12 years, vertebral body tethering (VBT) has been gradually promoted for treating scoliosis, but there are few published studies, with only short-term follow-up. This study aimed to systematically review VBT efficacy and safety for treating scoliosis. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched for studies on VBT treatment of scoliosis published up to November 2021. Two researchers independently screened the literature, extracted data, and assessed the risk of bias in included studies. Data on clinical efficacy, unplanned reoperations, and complications were extracted. The meta-analysis was performed with R 4.1.0. RESULTS: Twenty-six studies involving 1045 patients were included in the meta-analysis. The correction rate of major curve immediately post-operation was 46.6% ± 13.8% (16%-69%) and that at final follow-up was 53.2% ± 17.9% (16%-79%). The single-arm meta-analysis results of all included studies showed that VBT was effective in general. The overall clinical success rate was 73.02% (95% confidence interval [CI]: 68.31%-78.05%). The pooled overall unplanned reoperation rate was 8.66% (95% CI: 5.53%-13.31%). The overall incidence rate of complications was 36.8% (95% CI: 23.9%-49.7%). The subgroup analysis based on follow-up time indicated that patients with follow-up time >36 months had increased clinical success rate, unplanned reoperation rate, and incidence rate of complications compared with those with <36 months' follow-up time. The preliminary results showed that after 36 months of follow-up, only 7.17% (95% CI: 4.81%-10.55%) of patients required posterior spinal fusion (PSF) surgery and nearly 93% of patients avoided spinal fusion surgeries. CONCLUSIONS: The current evidence from at least 3-year follow-up in different countries indicates that VBT is an effective surgical approach for treating scoliosis, with 73.88% of patients achieving clinical success. Nevertheless, about one in seven patients (15.8%) required unplanned reoperations, but only 7.17% required PSF. About half (52.17%) of the patients experienced complications. Due to the limitation of the study number and quality, our conclusion may be biased and requires verification by further studies with longer follow-up times.

Animal models for COVID-19: advances, gaps and perspectives.

COVID-19, caused by SARS-CoV-2, is the most consequential pandemic of this century. Since the outbreak in late 2019, animal models have been playing crucial roles in aiding the rapid development of vaccines/drugs for prevention and therapy, as well as understanding the pathogenesis of SARS-CoV-2 infection and immune responses of hosts. However, the current animal models have some deficits and there is an urgent need for novel models to evaluate the virulence of variants of concerns (VOC), antibody-dependent enhancement (ADE), and various comorbidities of COVID-19. This review summarizes the clinical features of COVID-19 in different populations, and the characteristics of the major animal models of SARS-CoV-2, including those naturally susceptible animals, such as non-human primates, Syrian hamster, ferret, minks, poultry, livestock, and mouse models sensitized by genetically modified, AAV/adenoviral transduced, mouse-adapted strain of SARS-CoV-2, and by engraftment of human tissues or cells. Since understanding the host receptors and proteases is essential for designing advanced genetically modified animal models, successful studies on receptors and proteases are also reviewed. Several improved alternatives for future mouse models are proposed, including the reselection of alternative receptor genes or multiple gene combinations, the use of transgenic or knock-in method, and different strains for establishing the next generation of genetically modified mice.

RAGE Inhibitors as Alternatives to Dexamethasone for Managing Cerebral Edema Following Brain Tumor Surgery.

Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood-brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema.

Zinc Influx Restricts Enterovirus D68 Replication.

Enterovirus D68 (EV-D68) is a respiratory viral pathogen that causes severe respiratory diseases and neurologic manifestations. Since the 2014 outbreak, EV-D68 has been reported to cause severe complications worldwide. However, there are currently no approved antiviral agents or vaccines for EV-D68. In this study, we found that zinc ions exerted substantial antiviral activity against EV-D68 infection in vitro. Zinc salt treatment potently suppressed EV-D68 RNA replication, protein synthesis, and infectious virion production and inhibited cytopathic effects without producing significant cytotoxicity at virucidal concentrations (EC50=0.033mM). Zinc chloride (ZnCl2) treatment moderately inhibited EV-D68 attachment. Time-dose analysis of EV-D68 structural protein VP1 synthesis showed stronger suppression of VP1 in the culture medium than that in the cell lysates. Furthermore, a zinc ionophore, pyrrolidine dithiocarbamate, which can transport zinc ions into cells, also enhanced the anti-EV-D68 activity of ZnCl2 treatment. Taken together, our results demonstrated that the enhancement of zinc influx could serve as a powerful strategy for the therapeutic treatment of EV-D68 infections.

Early Restoration of Shank3 Expression in Shank3 Knock-Out Mice Prevents Core ASD-Like Behavioral Phenotypes.

Several genes are associated with increased risk for autism spectrum disorder (ASD), neurodevelopmental disorders that present with repetitive movements and restricted interests along with deficits in social interaction/communication. While genetic alterations associated with ASD are present early in life, ASD-like behaviors are difficult to detect in early infancy. This raises the issue of whether reversal of an ASD-associated genetic alteration early in life can prevent the onset of ASD-like behaviors. Genetic alterations of SHANK3, a well-characterized gene encoding a postsynaptic scaffolding protein, are estimated to contribute to ∼0.5% of ASD and remain one of the more replicated and well-characterized genetic defects in ASD. Here, we investigate whether early genetic reversal of a Shank3 mutation can prevent the onset of ASD-like behaviors in a mouse model. Previously, we have demonstrated that mice deficient in Shank3 display a wide range of behavioral abnormalities such as repetitive grooming, social deficits, anxiety, and motor abnormalities. In this study, we replicate many of these behaviors in Shank3 mutant mice. With early genetic restoration of wild-type (WT) Shank3, we rescue behaviors including repetitive grooming and social, locomotor, and rearing deficits. Our findings support the idea that the underlying mechanisms involving ASD behaviors in mice deficient in Shank3 are susceptible to early genetic correction of Shank3 mutations.

Yishenhuoxue formula regulates TGF-ß/Smad signal transduction to protect rats against Diabetic kidney disease injury.

TGF-ß signal pathway activation is vital in the pathogenesis of DKD. We aim to investigate the role of Yishenhuoxue formula on TGF-ß/Smad signal transduction in DKD rats. 60 male adult Wistar rats were enrolled and randomly allocated into four groups: N group, M group (given STZ 60mg/kg, ip), H group (given Yishenhuoxue formula 1.0g/kg/day, ig) and L group (given Yishenhuoxue formula 0.5g/kg/day, ig). The levels of BW, 24h UV, SCr, UCr, mALB were measured after 8 weeks treatment, while the levels of KW/BW index, CCr and UAER were calculated by relevant formula. The rats' left kidneys were harvested to detect histological changes by PAS staining and right kidneys were harvested to detect the levels of TGF-ß, Smad2/3, phosphorylated Smad 2/3, Smad 7 and CTGF by western blot analysis. We found that Yishenhuoxue formula treatment can protect kidneys from DKD injury, which is illustrated with following criteria: 1) a significant decrement in KW/BW index, 24h UV, SCr, mALB and UAER, while a significant increment in BW, UCr, CCr (p<0.05 vs. M group); 2) minor and segmental changes as slight expansion of the glomerular basement membrane compared with M group; 3) an apparent decrease in levels of TGF-ß1, phosphorylated Smad 2/3 and CTGF, while an apparent increase in levels of Smad 2/3 and Smad7 compared with M group (p<0.05). The studies confirm that Yishenhuoxue formula has strong inhibitory effect on TGF-ß/Smad signal transduction in DKD rats' kidneys by decreasing expression of TGF-ß1, weakening of Smad 2/3 phosphorylation and increasing expression of Smad 7.

Methyl-ß-cyclodextrin inhibits EV-D68 virus entry by perturbing the accumulation of virus particles and ICAM-5 in lipid rafts.

Enterovirus D68 (EV-D68) is a member of the Picornavirus family and a causative agent of respiratory diseases in children. The incidence of EV-D68 infection has increased worldwide in recent years. Thus far, there are no approved antiviral agents or vaccines for EV-D68. Here, we show that methyl-ß-cyclodextrin (MßCD), a common drug that disrupts lipid rafts, specifically inhibits EV-D68 infection without producing significant cytotoxicity at virucidal concentrations. The addition of exogenous cholesterol attenuated the anti-EV-D68 activity of MßCD. MßCD treatment had a weak influence on the attachment of viral particles to the cell membrane but significantly inhibited EV-D68 entry into host cells. We demonstrated that EV-D68 facilitated the translocation of the viral receptor ICAM-5 to membrane rafts in infected cells. The colocalization of viral particles with ICAM-5 in lipid rafts was thoroughly abolished in cells after treatment with MßCD. Finally, we showed that MßCD inhibited the replication of isolated circulating EV-D68 strains. In summary, our results demonstrate that MßCD suppresses EV-D68 replication by perturbing the accumulation of virus particles and ICAM-5 in lipid rafts. This mechanism represents a promising strategy for drug development.

Local and Systemic Immune Dysregulation Alters Glioma Growth in Hyperglycemic Mice.

PURPOSE: Unlike most cancers, no clear epidemiological correlation between diabetes (Db) and malignant glioma progression exists. Because hyperglycemia activates proinflammatory pathways through the receptor for advanced glycation endproducts (RAGE), we hypothesized that Db can also promote malignant glioma progression. EXPERIMENTAL DESIGN: We compared the growth of two phenotypically diverse syngeneic glioma models in control and diabetic mice. Tumor growth and antitumor immune responses were evaluated in orthotopic and heterotopic models and correlated to RAGE and RAGE ligand expression. RESULTS: Irrespective of tumor implantation site, growth of a "classical" glioma model, GL261, increased in hyperglycemic mice and was mediated by upregulation of RAGE and its ligand, HMGB1. However, growth of a "mesenchymal" glioma subtype, K-Luc, depended on tumor implantation site. Whereas heterotopic K-Luc tumors progressed rapidly in Db mice, intracranial K-Luc tumors grew slower. We further showed that hyperglycemia inhibited the innate antitumor inflammatory responses in both models. Although this contributed to the accelerated growth of heterotopic tumors, suppression of tumor inflammatory responses dampened the growth of orthotopic K-Luc gliomas. CONCLUSIONS: Hyperglycemia may enhance glioma growth through promotion of RAGE expression and suppression of antitumor immune responses. However, abrogation of the proinflammatory milieu in tumors may also dampen the growth of inflammatory glioma subtypes in the brains of diabetic mice. This dichotomy in glioma growth response to hyperglycemia may partly explain why conflicting epidemiological studies show both an increased risk and a protective effect of Db in patients with malignant gliomas.

Apparent Genetic Rescue of Adult Shank3 Exon 21 Insertion Mutation Mice Tempered by Appropriate Control Experiments.

SHANK3 (ProSAP2) is among the most common genes mutated in autism spectrum disorders (ASD) and is the causative gene in Phelan-McDermid syndrome (PMS). We performed genetic rescue of Shank3 mutant phenotypes in adult mice expressing a Shank3 exon 21 insertion mutation (Shank3G ). We used a tamoxifen-inducible Cre/loxP system (CreTam ) to revert Shank3G to wild-type (WT) Shank3+/+ We found that tamoxifen treatment in adult Shank3GCreTam+ mice resulted in complete rescue of SHANK3 protein expression in the brain and appeared to rescue synaptic transmission and some behavioral differences compared to Shank3+/+CreTam+ controls. However, follow-up comparisons between vehicle-treated, WT Cre-negative mice (Shank3+/+CreTam- and Shank3+/+CreTam+) demonstrated clear effects of CreTam on baseline synaptic transmission and some behaviors, making apparently positive genetic reversal effects difficult to interpret. Thus, while the CreTam tamoxifen-inducible system is a powerful tool that successfully rescues Shank3 expression in our Shank3G/G reversible mutants, one must exercise caution and use appropriate control comparisons to ensure sound interpretation.

Sagittal Profile Response of Cervical Spine After Posterior Correction in Thoracic and Lumbar Adolescent Idiopathic Scoliosis: Correlation with Thoracic Kyphosis?

OBJECTIVE: To analyze postoperative changes in cervical alignment in patients with adolescent idiopathic scoliosis (AIS) with different curve patterns. METHODS: Radiographic data were retrospectively reviewed in 43 patients with AIS with right thoracic major curve versus 39 with major lumbar curve with a minimum of 2 years' follow-up. Radiographic parameters analyzed in this study included cervical sagittal parameters (cervical lordosis [CL], T1 slope, T1 slope minus C2-C7 lordosis, T1-spine, T1 pelvic angle, and C2-C7 sagittal vertical axis) and spinopelvic sagittal parameters obtained from radiographs. Paired t tests were used for comparison with 0.05 as a statistically significant threshold. RESULTS: At baseline, larger CL (5.69° vs. -5.12°, P = 0.002) and smaller T1 slope minus C2-C7 lordosis (9.26° vs. 17.09°, P = 0.001) was noted in patients with lumbar-curve adolescent idiopathic scoliosis (L-AIS), whereas preoperative thoracic kyphosis (TK) was not different between the 2 groups. When the immediate postoperative sagittal profiles were compared between the 2 groups, larger TK (23.72° vs. 18.86°, P = 0.009) and more obvious CL (7.26° vs. -2.60°, P = 0.001) were noticed in the L-AIS group. During the follow-up, larger TK and CL were still maintained in the L-AIS group. In addition, a significant correlation was found between the improvement of CL and TK restoration in patients with L-AIS (r = -0.473, P = 0.002). CONCLUSIONS: Correlations between the improvement of CL and TK highlight the importance of restoration of patients with normal TK or AIS. Reciprocal changes in cervical alignment may happen if the TK was also simultaneously restored in patients with AIS. For patients with different curve patterns, the cervical sagittal parameters tend to be similar during follow-up.

S100B suppression alters polarization of infiltrating myeloid-derived cells in gliomas and inhibits tumor growth.

S100B, a member of the multigene family of Ca2+-binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-based S100B promoter-driven luciferase reporter assay. Initial screening of 768 compounds in the NIH library identified 36 hits with >85% S100B inhibitory activity. Duloxetine (Dul, an SNRI) was selected for the initial proof-of-concept studies. At low concentrations (1-5 µM) Dul inhibited S100B and CCL2 production in mouse GL261 glioma cells, but had minimal cytotoxic activity in vitro. In vivo, however, Dul (30 mg/kg/14 days) inhibited S100B production, altered the polarization and trafficking of tumor-associated myeloid-derived cells, and inhibited the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of more potent S100B inhibitors for glioma therapy.

Fifteen Years and 2530 Patients: The Evolution of Instrumentation, Surgical Strategies, and Outcomes in Adolescent Idiopathic Scoliosis in a Single Institution.

BACKGROUND: Over the past decade, the surgical treatment of adolescent idiopathic scoliosis (AIS) has established new techniques to reduce curve severity and shifted to include the regular use of pedicle screws. Few studies have focused on this evolving trend in AIS correction surgery. In this study, we investigated how the operative approach, instrumentation, and surgical techniques have changed over the past 15 years and to quantify the related improvements in AIS surgical treatment. METHODS: This is a retrospective review of a prospective AIS registry in a single center. Patient data were reviewed from January 2001 to December 2015. The age and surgical case distribution were recorded for each year. Trends in classification use, instrumentation types, levels of fusion, and surgical approaches were analyzed by year. The major Cobb angles and correction rates were compared between different instrumentations and surgical approaches. RESULTS: A total of 2530 patients with AIS (83.0% female) were included, with a mean age of 15.14 years. Most patients underwent surgery at 14 years of age (473 patients, 18.7%), followed by 15 years of age (468 patients, 18.5%). In our center, the classification of patients with AIS shifted from the King classification to the Lenke classification in 2005. The major baseline Cobb angle of the entire cohort averaged 50.99° and this mean Cobb angle decreased to 14.41° after surgery. The correction rates for the first 3 years (2001-2003) were less than 70%, whereas the correction rates for the rest of the years were all greater than 70%. In addition, significantly higher correction rates were observed in patients with Cobb angles <90° (72.93% vs. 55.61%, P < 0.001). A total of 218 anterior-only surgeries and 109 combined anteroposterior surgeries were performed; the remaining 2205 surgeries were performed with a posterior-only approach. The use of anterior-only and anteroposterior approaches trended to decrease after 2005. The correction rate of anterior-only approaches was significantly greater than posterior-only and anteroposterior approaches (77.86%, 72.51%, and 59.37%, respectively). In patients corrected with a posterior-only approach, the screw-hook hybrid construct was used in 342 patients, whereas the all-pedicle-screw construct was used in 1835 patients. The shift from hybrid to all-screw construct occurred in 2006. In patients with thoracic AIS, the correction rate was significantly higher in the all-screw group (73.26% vs. 67.76%; P < 0.001). CONCLUSIONS: Consistent improvement of major curve correction has been achieved by the spine community over 15 years. After stabilized coronal correction and fewer fusion levels, the next steps in this evolution are the restoration of sagittal profiles, especially the hypokyphosis seen in patients with Lenke 1, the posterior minimally invasive approach, and a fast-track return to activity.

Could pelvic parameters determine optimal postoperative thoracic kyphosis in Lenke type 1 AIS patients?

BACKGROUND: A proper restoration of sagittal alignment is essential in AIS patients, but few studies provided a formula to predict an optimal surgical thoracic kyphosis (TK) gain in adolescent idiopathic scoliosis (AIS) patients. A formula was recently proposed (LL = (PI+TK)/2 + 10) to predict the optimal lumbar lordosis (LL) in adult spinal deformity patients, which has not been validated in adolescents. The aim of this study is to establish a formula with TK and pelvic parameters in normal adolescents and predict an optimal TK with this formula pre- and post-operatively in Lenke 1 AIS patients. METHODS: A total of 60 asymptomatic adolescents were used to validate the proposed formula. The subject was considered to match with the formula, if the difference between the virtual TK and the theoretical TK was less than 10°. Then regression analysis was performed to establish a new formula to predict TK in adolescents. The predictive efficiency of the new formula was also validated in 40 Lenke 1 AIS patients. RESULTS: Of the 60 asymptomatic adolescents, only 26 (43.33%) asymptomatic adolescents matched with the adjusted formula: TK = 2 × (LL-10)-PI. The paired t test revealed a significantly different theoretical TK (tTK) compared to the virtual TK (41.23 ± 18.29° vs. 24.80 ± 8.75°, P < 0.001). Multiple linear regression showed that TK had a relationship with LL, SS and age (R2 = 0.331): TK = - 0.785 × LL-0.843 × SS + 0.858 × age + 3.754. There were 27 (67.50%), 32 (80.00%) and 35 (87.50%) Lenke 1 AIS patients matched this formula preoperatively, postoperatively and at the last follow-up. CONCLUSION: Our results revealed that the predictive formula for sagittal alignment for adults was not applicable in adolescents. This study established a new predictive formula for TK based on asymptomatic adolescents. In Lenke 1 AIS patients, post-op TK in 87.5% of patients matched the predictive value, indicating that the new formula can be considered as a reference when making a surgery strategy.

Immunostimulatory CpG on Carbon Nanotubes Selectively Inhibits Migration of Brain Tumor Cells.

Even when treated with aggressive current therapies, patients with glioblastoma usually survive less than two years and exhibit a high rate of recurrence. CpG is an oligonucleotide that activates the innate immune system via Toll-like receptor 9 (TLR9) activation. Injection of CpG into glioblastoma tumors showed promise as an immunotherapy in mouse models but proved disappointing in human trials. One aspect of glioma that is not addressed by CpG therapy alone is the highly invasive nature of glioma cells, which is associated with resistance to radiation and chemotherapy. Here, we demonstrate that single-walled carbon nanotubes noncovalently functionalized with CpG (SWNT/CpG), which retain the immunostimulatory property of the CpG, selectively inhibit the migration of glioma cells and not macrophages without affecting cell viability or proliferation. SWNT/CpG also selectively decreased NF-κB activation in glioma cells, while activating macrophages by induction of the TLR9/NF-κB pathway, as we have previously reported. The migration inhibition of glioma cells was correlated with selective reduction of intracellular levels of reactive oxygen species (ROS), suggesting that an antioxidant-based mechanism mediates the observed effects. To the best of our knowledge, SWNT/CpG is the first nanomaterial that inhibits the migration of cancer cells while stimulating the immune system.