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Abstract Background Molybdenum disulfide (MoS2) has excellent physical and chemical properties. Further, chiral MoS2 (CMS) exhibits excellent chiroptical and enantioselective effects, and the enantioselective properties of CMS have been studied for the treatment of neurodegenerative diseases. Intriguingly, left- and right-handed materials have different effects on promoting the differentiation of neural stem cells into neurons. However, the effect of the enantioselectivity of chiral materials on peripheral nerve regeneration remains unclear. Methods In this study, CMS@bacterial cellulose (BC) scaffolds were fabricated using a hydrothermal approach. The CMS@BC films synthesized with L-2-amino-3-phenyl-1-propanol was defined as L-CMS. The CMS@BC films synthesized with D-2-amino-3-phenyl-1-propanol was defined as D-CMS. The biocompatibility of CMS@BC scaffolds and their effect on Schwann cells (SCs) were validated by cellular experiments. In addition, these scaffolds were implanted in rat sciatic nerve defect sites for three months. Results These chiral scaffolds displayed high hydrophilicity, good mechanical properties, and low cytotoxicity. Further, we found that the L-CMS scaffolds were superior to the D-CMS scaffolds in promoting SCs proliferation. After three months, the scaffolds showed good biocompatibility in vivo, and the nerve conducting velocities of the L-CMS and D-CMS scaffolds were 51.2 m/s and 26.8 m/s, respectively. The L-CMS scaffolds showed a better regenerative effect than the D-CMS scaffolds. Similarly, the sciatic nerve function index and effects on the motor and electrophysiological functions were higher for the L-CMS scaffolds than the D-CMS scaffolds. Finally, the axon diameter and myelin sheath thickness of the regenerated nerves were improved in the L-CMS group. Conclusion We found that the CMS@BC can promote peripheral nerve regeneration, and in general, the L-CMS group exhibited superior repair performance. Overall, the findings of this study reveal that CMS@BC can be used as a chiral nanomaterial nerve scaffold for peripheral nerve repair. Graphical Abstract

Tetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in the field of cancer immunology and immunotherapy due to its involvement in the cytotoxic T cell response. Past research has demonstrated that when the availability of BH4 is low, as it is in chronic inflammatory conditions and tumors, electron transfer in the active site of nitric oxide synthase becomes uncoupled from the oxidation of arginine. This results in the production of radical species that are capable of a direct attack on tetrahydrobiopterin, further depleting its local availability. This feedforward loop may act like a molecular switch, reinforcing low tetrahydrobiopterin levels leading to altered NO signaling, restrained immune effector activity, and perpetual vascular inflammation within the tumor microenvironment. In this review, we discuss the evidence for this underappreciated mechanism in different aspects of tumor progression and therapeutic responses. Furthermore, we discuss the preclinical evidence supporting a clinical role for tetrahydrobiopterin supplementation to enhance immunotherapy and radiotherapy for solid tumors and the potential safety concerns.

Conjugate heat transfer between liquid metal and solid is a common phenomenon in a liquid-metal-cooled fast reactor's fuel assembly and heat exchanger, dramatically affecting the reactor’s safety and economy. Therefore, comprehensively studying the sophisticated conjugate heat transfer in a liquid-metal-cooled fast reactor is profound. However, it has been evidenced that the traditional Simple Gradient Diffusion Hypothesis (SGDH), assuming a constant turbulent Prandtl number (Prt, usually 0.85 - 1.0), is inappropriate in the Computational Fluid Dynamics (CFD) simulations of liquid metal. In recent decades, numerous studies have been performed on the four-equation model, which is expected to improve the precision of liquid metal’s CFD simulations but has not been introduced into the conjugate heat transfer calculation between liquid metal and solid. Consequently, a four-equation model, consisting of the Abe k−ε turbulence model and the Manservisi kθ−εθ heat transfer model, is applied to study the conjugate heat transfer concerning liquid metal in the present work. To verify the numerical validity of the four-equation model used in the conjugate heat transfer simulations, we reproduce Johnson’s experiments of the liquid lead-bismuth-cooled turbulent pipe flow using the four-equation model and the traditional SGDH model. The simulation results obtained with different models are compared with the available experimental data, revealing that the relative errors of the local Nusselt number and mean heat transfer coefficient obtained with the four-equation model are considerably reduced compared with the SGDH model. Then, the thermal-hydraulic characteristics of liquid metal turbulent pipe flow obtained with the four-equation model are analyzed. Moreover, the impact of the turbulence model used in the four-equation model on overall simulation performance is investigated. At last, the effectiveness of the four-equation model in the CFD simulations of liquid sodium conjugate heat transfer is assessed. This paper mainly proves that it is feasible to use the four-equation model in the study of liquid metal conjugate heat transfer and provides a reference for the research of conjugate heat transfer in a liquid-metal-cooled fast reactor.

Central nervous system (CNS) trauma, including traumatic brain injury and spinal cord injury, has a high rate of disability and mortality, and effective treatment is currently lacking. Previous studies have revealed that neural inflammation plays a vital role in CNS trauma. As the initial enzyme in neuroinflammation, cytosolic phospholipase A2 (cPLA2) can hydrolyze membranous phosphatides at the sn-2 position in a preferential way to release lysophospholipids and ω3-polyunsaturated fatty acid dominated by arachidonic acid, thereby inducing secondary injuries. Although there is substantial fresh knowledge pertaining to cPLA2, in-depth comprehension of how cPLA2 participates in CNS trauma and the potential methods to ameliorate the clinical results after CNS trauma are still insufficient. The present review summarizes the latest understanding of how cPLA2 participates in CNS trauma, highlighting novel findings pertaining to how cPLA2 activation initiates the potential mechanisms specifically, neuroinflammation, lysosome membrane functions, and autophagy activity, that damage the CNS after trauma. Moreover, we focused on testing a variety of drugs capable of inhibiting cPLA2 or the upstream pathway, and we explored how those agents might be utilized as treatments to improve the results following CNS trauma. This review aimed to effectively understand the mechanism of cPLA2 activation and its role in the pathophysiological processes of CNS trauma and provide clarification and a new referential framework for future research.

Abstract Background Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool of growth factors (GFs) were widely used in local bone repair by its potent pro-regeneration and pro-angiogenesis. However, it is still seldom applied for treating systemic osteopathia due to the lack of a suitable delivery strategy. The non-targeted distribution of GFs might cause tumorigenesis in other organs. Results In this study, PL-derived exosomes (PL-exo) were isolated to enrich the platelet-derived GFs, followed by conjugating with alendronate (ALN) grafted PEGylated phospholipid (DSPE-PEG-ALN) to establish a bone-targeting PL-exo (PL-exo-ALN). The in vitro hydroxyapatite binding affinity and in vivo bone targeting aggregation of PL-exo were significantly enhanced after ALN modification. Besides directly modulating the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs), respectively, PL-exo-ALN also facilitate their coupling under GCs’ stimulation. Additionally, intravenous injection of PL-exo-ALN could successfully rescue GCs induced osteoporosis (GIOP) in vivo. Conclusions PL-exo-ALN may be utilized as a novel nanoplatform for precise infusion of GFs to bone sites and exerts promising therapeutic potential for GIOP. Graphical Abstract

Abstract Background NAFLD has become the most common chronic liver disease worldwide. Human antigen R (HuR), an RNA-binding protein, is an important post-transcriptional regulator. HuR has been reported as a key player in regulating lipid homeostasis in the liver and adipose tissues by using tissue-specific HuR knockout mice. However, the underlying mechanism by which hepatocyte-specific HuR regulates hepatic lipid metabolism under metabolic stress remains unclear and is the focus of this study. Methods Hepatocyte-specific HuR deficient mice (HuRhKO) and age-/gender-matched control mice, as well as long-noncoding RNA H19 knockout mice (H19−/−), were fed a Western Diet plus sugar water (WDSW). Hepatic lipid accumulation, inflammation and fibrosis were examined by histology, RNA transcriptome analysis, qRT–PCR, and Western blot analysis. Bile acid composition was measured using LC–MS/MS. Results Hepatocyte-specific deletion of HuR not only significantly increased hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also markedly induced inflammation by increasing immune cell infiltration and neutrophil activation under metabolic stress. In addition, hepatic deficiency of HuR disrupted bile acid homeostasis and enhanced liver fibrosis. Mechanistically, HuR is a repressor of H19 expression. Analysis of a recently published dataset (GSE143358) identified H19 as the top-upregulated gene in liver-specific HuR knockout mice. Similarly, hepatocyte-specific deficiency of HuR dramatically induced the expression of H19 and sphingosine-1 phosphate receptor 2 (S1PR2), but reduced the expression of sphingosine kinase 2 (SphK2). WDSW-induced hepatic lipid accumulation was alleviated in H19−/− mice. Furthermore, the downregulation of H19 alleviated WDSW-induced NAFLD in HuRhKO mice. Conclusions HuR not only functions as an RNA binding protein to modulate post-transcriptional gene expression but also regulates H19 promoter activity. Hepatic HuR is an important regulator of hepatic lipid metabolism via modulating H19 expression.

The fast refueling of compressed hydrogen has an important influence on the efficiency and safety of the filling process. Precision measurements of the thermodynamic characteristics of hydrogen under the filling process are becoming more important as hydrogen energy is developed and used. One of the key elements of hydrogen fuel cell vehicles is the on-board hydrogen storage cylinder (HSC). Due to the compression of the hydrogen during filling, there could be a fast increase in temperature. The tank's maximum temperature and maximum fueling pressure are both restricted to less than 358.15 K and 125% of the tank's design pressure for safety reasons. This study revealed the hydrogen temperature rise during refueling and developed a theoretical model for computing the temperature rise in the HSC during the high-pressure refueling procedure. The HSC filling procedure was examined using a theoretical approach. Also, the relationship between the refueling procedure and the temperature change of hydrogen in the type IV tank was investigated. The temperature evolution mechanism of various HSCs was explained, and predictions were made for the minimum precooling temperature needed for hydrogen under various filling scenarios. The results of the theoretical analysis gave a theoretical foundation to the present method for controlling the hydrogen temperature of the gas source in the hydrogenation station, which then enables us to determine the optimum amount of energy needed for cooling hydrogen in the hydrogen refueling station.

With the development of the hydrogen fuel automobile industry, higher requirements are put forward for the construction of hydrogen energy infrastructure, the matching of parameters and the control strategy of hydrogen filling rate in the hydrogen charging process of hydrogen refueling stations. At present, the technological difficulty of hydrogen fueling is mainly reflected in the balanced treatment of reducing the temperature rise of hydrogen and shortening the filling time during the fast filling process. Vehicle hydrogen storage cylinder (VHSC) is one of the important components of hydrogen fuel cell vehicles. This study proposed a theoretical model for calculating the temperature rise in the VHSC during the high pressure refueling process, and revealed the hydrogen temperature rise during refueling. A hydrogen temperature rise prediction model was constructed to elucidate the relationship between filling parameters and temperature rise. The filling process of VHSC was analyzed from the theoretical method. The theoretical analysis results were consistent with the simulation and experimental analysis results, which provided a theoretical basis for the current hydrogen temperature control algorithm of the gas source in the hydrogen refueling station, and then reduced the energy consumption required for hydrogen cooling in the hydrogen refueling station.

New potential therapies for inflammatory bowel disease are needed as not all patients respond to or maintain a response to conventional therapies. Here the authors report that mannose supplementation ameliorates experimental colitis in male mice, potentially via effects on intestinal epithelium lysosomal integrity.

This study sought to investigate and evaluate a modified axial translaminar screw fixation for treating odontoid fractures. We performed a retrospective study at Wenzhou Medical University Affiliated Second Hospital between March 2016 and June 2018. We retrospectively collected and analyzed the medical records of 23 cases with odontoid fractures. All patients were identified as type II odontoid fractures without neurological deficiency and serious diseases following the classification of Anderson. The average age, gender ratio, and body mass index (BMI) were 54.3 ± 11.1 years, 12 men to 11 women, and 22.6 ± 2.4 kg/m2, respectively. Patients in this study accepted screw fixation using our modified axial translaminar screw fixation combined with atlas pedicle or lateral mass screw fixation. Within the technique, a small cortical “window” was dug in the middle of the axial contralateral lamina, such that the screws in the lamina were visualized to prevent incorrectly implanting the posterior spinal canal through the visualized “window.” A total of 46 bone screws were accurately inserted into the axial lamina without using fluoroscopy. The length of all translaminar screws ranged between 26 and 30 mm, while the diameter was 3.5 mm. During the follow‐up survey, the visual analog scale (VAS) and neck disability index (NDI) were measured. We provide a simple modification of Wright's elegant technique with the addition of “visualized windows” at the middle of the axial lamina. In all patients, screws were inserted accurately without bony breach and the screw angle was 56.1 ± 3.0°. Mean operative time was 102 ± 28 min with an average blood loss of 50 ± 25 mL. Postoperative hemoglobin and mean length of hospital stay were 12.0 ± 1.4 g/dL and 10.4 ± 3.4 days, respectively. The average follow‐up time of all cases was 14.7 months and no internal fixation displacement, loosening, or breakage was found. All patients with odontoid fractures reported being satisfied with the treatment during the recheck period and good clinical outcomes were observed. At 1, 6, and 12 months, NDI and VAS showed that the symptoms of neck pain and limitations of functional disability improved significantly during follow‐up. Our results suggest that the modified translaminar screw fixation technique can efficiently treat Anderson type II odontoid fracture, followed by the benefits of less soft tissue dissection, simple operation, no fluoroscopy, and accurate placement of screws.

Objective To investigate the prevalence of 11 thoracic vertebrae (TVs), four lumbar vertebrae (LVs) and six LVs among asymptomatic Chinese volunteers, and the influence of spine variations on the global spinal sagittal parameters. Methods A total of 389 asymptomatic Chinese volunteers were recruited. Each subject underwent a full‐spine X‐ray examination with measurement of global spinal sagittal parameters. The radiographs were examined by a spine surgeon and a radiologist to determine the variation in the number of vertebrae. These parameters were used to compare individuals with five LVs to those with 11 TVs, four LVs, and six LVs. Results The study population included 12 individuals (3.1%) with seven cervical vertebrae (C) + 11 thoracic vertebrae (T) + five lumbar vertebrae (L), 8 (2.1%) with 7C + 11T + 6L, 8 (2.1%) with 7C + 12T + 4L, and 15 (3.9%) with 7C + 12T + 6L. Compared to the 7C + 12T + 5L individuals, those with 7C + 11T + 5L had significantly lower C6–T5 Cobb values (P

We have previously demonstrated that scavenger receptor A (SRA) acts as an immunosuppressive regulator of dendritic cell (DC) function in activating antitumor T cells. Here we investigate the potential of inhibiting SRA activity to enhance DC-targeted chaperone vaccines including one that was recently evaluated in melanoma patients. We show that short hairpin RNA-mediated SRA silencing significantly enhances the immunogenicity of DCs that have captured chaperone vaccines designed to target melanoma (i.e., hsp110-gp100) and breast cancer (i.e., hsp110-HER/Neu-ICD). SRA downregulation results in heightened activation of antigen-specific T cells and increased CD8+ T cell-dependent tumor inhibition. Additionally, small interfering RNA (siRNA) complexed with the biodegradable, biocompatible chitosan as a carrier can efficiently reduce SRA expression on CD11c+ DCs in vitro and in vivo. Our proof-of-concept study shows that direct administration of the chitosan-siRNA complex to mice promotes chaperone vaccine-elicited cytotoxic T lymphocyte (CTL) response, culminating in improved eradication of experimental melanoma metastases. Targeting SRA with this chitosan-siRNA regimen combined with the chaperone vaccine also leads to reprogramming of the tumor environment, indicated by elevation of the cytokine genes (i.e., ifng, il12) known to skew Th1-like cellular immunity and increased tumor infiltration by IFN-γ+CD8+ CTLs as well as IL-12+CD11c+ DCs. Given the promising antitumor activity and safety profile of chaperone vaccine in cancer patients, further optimization of the chitosan-siRNA formulation to potentially broaden the immunotherapeutic benefits of chaperone vaccine is warranted.

Abstract Extracted cancer cell membrane carries the antigens of the parent tumor cell. This autologous antigen repertoire presents cancer cell membrane‐derived nanoparticles highly immunogenic to the body's immune system. Cancer cell membrane‐derived nanoparticles antigenically recapitulate the parental cancer cells and can be exploited to induce immune response reactive with tumor‐associated antigens (TAAs). The use of the cancer cell membrane‐derived nanoparticles to deliver immunostimulatory adjuvants facilitates the cross‐presentation of tumor antigens by antigen‐presenting cells and their costimulation, triggering potent antigen‐specific T responses to eliminate established tumors. These nanoparticles can be engineered to carry immunostimulatory signals to facilitate the cross‐presentation of TAAs and the induction of potent antitumor immunity. In this study, cancer cell membrane‐based vesicles (CCMVs) are prepared from B16 melanoma cells and engineered to deliver the immunological agent polyinosinic:polycytidylic acid (poly‐IC). We show that CCMV is preferentially uptaken by bone marrow‐derived dendritic cells (BMDCs) as compared to other cell types (macrophages, fibroblasts). The efficient delivery of poly‐IC to BMDCs results in enhanced antigen cross‐presenting capability of BMDCs and T‐cell activation. Additionally, immunization of mice with poly‐IC‐carrying CCMV elicits a potent antitumor immune response. In conclusion, poly‐IC‐decorated tumor‐derived CCMV may be used as a therapeutic vaccine to potentiate antitumor immunity.

Despite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex interactions between cancer cells and non-transformed cells of the tumor microenvironment. Herein, we report that radiotherapy induces the production of extracellular vesicles by breast cancer cells capable of stimulating tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion. This pro-tumor activity was associated with fibroblast production of the paracrine signaling factor IL-6 and was dependent on the expression of the heparan sulfate proteoglycan CD44v3 on the vesicle surface. Enzymatic removal or pharmaceutical inhibition of its heparan sulfate side chains disrupted this tumor-fibroblast crosstalk. Additionally, we show that the radiation-induced production of CD44v3+ vesicles is effectively silenced by blocking the ESCRT pathway using a soluble pharmacological inhibitor of MDA-9/Syntenin/SDCBP PDZ1 domain activity, PDZ1i. This population of vesicles was also detected in the sera of human patients undergoing radiotherapy, therefore representing a potential biomarker for radiation therapy and providing an opportunity for clinical intervention to improve treatment outcomes.

Abstract Background Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy. Methods We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells. Results We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67− and Ki67low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs. Conclusion Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.

Objectives Occipitocervical fusion (OCF) is an effective treatment for instability of occipitocervical junction (OCJ). The occipital condyle screw serves as a novel surgical technique for occipitocervical fixation. However, the intraoperative procedures for the occipital condyle screw technique have relied on surgeons’ experience, so the pool of surgeons who are able to perform this surgery safely is limited. The present study aims to evaluate the feasibility and safety of the occipital condyle screw technique using human cadavers and to provide image anatomy for clinical application basis. Methods The scientific study comprised 10 fresh‐frozen cadaveric specimens from the anatomy department of Qingdao University. Placement of the occipital condyle screws (3.5 mm diameter and 20.0 mm length) was performed in the 10 fresh‐frozen cadaveric specimens with intact occipitocervical junctions, respectively. Occipitocervical CT was performed for all specimens and the DICOM data was obtained. Occipitocervical CT three‐dimensional (3D) reconstruction was performed for the cadavers. Morphometric analysis was performed on the bilateral occipitocervical junction of 10 cadaveric specimens based on the 3D reconstruction CT images. Detailed morphometric measurements of the 20 occipital condyles screws were conducted including the average length of the screw trajectory, inside and upper tilting angles of screws, distance to the hypoglossal canal, and to the medial wall of occipital condyle. Results Placement of the occipital condyle screws into the 20 occipital condyles of the 10 cadaveric specimens was performed successfully and the trajectory of implantation was satisfactory according to 3D CT reconstruction images, respectively. There was no obvious injury to the spinal cord, nerve root, and vertebral artery. The length of the bilateral screw trajectory was, respectively, 20.96 ± 0.91 mm (left) and 20.59 ± 0.77 mm (right) (t = 1.306, P > 0.05). The upper tilting angle of bilateral screws was, respectively, 11.24° ± 0.74° (left) and 11.11° ± 0.64° (right) (t = 0.681, P > 0.05). The inside tilting angle of bilateral screws was, respectively, 31.00° ± 1.32° (left) and 30.85° ± 1.27° (right) (t = 0.307, P > 0.05). The screw's distance to the bilateral hypoglossal canal was, respectively, 4.84 ± 0.54 mm (left) and 4.70 ± 0.54 mm (right) (t = 0.685, P > 0.05). The screw's distance to the medial wall of the bilateral occipital condyle was, respectively, 5.13 ± 0.77 mm (left) and 5.04 ± 0.71 mm (right) (t = 0.384, P > 0.05). Conclusion The occipital condyle screw technique can serve as a feasible and safe treatment for instability of the occipitocervical junction with meticulous preoperative planning of the screw entry point and direction based on individual differences. Morphometric trajectory analysis is also an effective way to evaluate the surgical procedure.

Scavenger receptor-A (SR-A) is mostly expressed by myeloid cells and has been attributed a variety of biological functions. Here the authors assess SR-A as a biomarker for diagnosis of rheumatoid arthritis (RA) using large-scale training and validation cohorts and show that modulating SR-A levels can alter progression of collagen-induced arthritis in mice.

Abscopal responses in patients and preclinical models following radiation therapy are rare. Here the authors show that, in murine tumor models, reducing adrenergic stress or β2-adrenergic receptor signalling not only improves control of the irradiated tumor but significantly increases abscopal events.

melanoma differentiation associated gene-7 or Interleukin-24 (mda-7, IL-24) displays expansive anti-tumor activity without harming corresponding normal cells/tissues. This anticancer activity has been documented in vitro and in vivo in multiple preclinical animal models, as well as in patients with advanced cancers in a phase I clinical trial. To enhance the therapeutic efficacy of MDA-7 (IL-24), we engineered a designer cytokine (a “Superkine”; IL-24S; referred to as M7S) with enhanced secretion and increased stability to engender improved “bystander” antitumor effects. M7S was engineered in a two-step process by first replacing the endogenous secretory motif with an alternate secretory motif to boost secretion. Among four different signaling peptides, the insulin secretory motif significantly enhanced the secretion of MDA-7 (IL-24) protein and was chosen for M7S. The second modification engineered in M7S was designed to enhance the stability of MDA-7 (IL-24), which was accomplished by replacing lysine at position K122 with arginine. This engineered “M7S Superkine” with increased secretion and stability retained cancer specificity. Compared to parental MDA-7 (IL-24), M7S (IL-24S) was superior in promoting anti-tumor and bystander effects leading to improved outcomes in multiple cancer xenograft models. Additionally, combinatorial therapy using MDA-7 (IL-24) or M7S (IL-24S) with an immune checkpoint inhibitor, anti-PD-L1, dramatically reduced tumor progression in murine B16 melanoma cells. These results portend that M7S (IL-24S) promotes the re-emergence of an immunosuppressive tumor microenvironment, providing a solid rationale for prospective translational applications of this therapeutic designer cytokine.

Purpose: To measure the projection of the most anterior line of the spinal canal on lateral radiographs of the vertebra (C3–L5) and evaluate the efficacy of the safety line (SL) in preventing intraspinal cement leakage in percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP). Materials and Methods: Fifteen adult dry-bone spine specimens were analyzed. The projection of the SL was viewed on lateral radiographs. The distance between the SL and the posterior vertebral body line (PVBL) was measured. Two groups of patients were treated by PKP, and cement injection was stopped either before the PBVL (group 1) or before the SL (group 2) under lateral fluoroscopy. The rate of cement leakage was compared between the two groups. Results: The largest distance between the SL and PVBL was at L1 (5.22 ± 0.62 mm). From L1 to L5, the distance decreased progressively to 1.05 ± 0.64 mm. Similar variation was also observed from L1 to T1 (0.19 ± 0.18 mm). The postoperative computed tomography scan was more sensitive and accurate in detecting intraspinal leakage than radiography in group 1 (p = 0.000); however, there was no significant difference in sensitivity or accuracy between methods in group 2 (p = 0.063). The rate of intraspinal cement leakage was significantly higher in group 1 than group 2 (p = 0.000). Conclusions: The operator should frequently check to ensure that cement injection has stopped upon reaching the SL. Surgeons may benefit from this quantitative anatomical study of PKP and PVP.

Magnetically controlled growing rods have been used to treat early-onset scoliosis for the last 9 years; however, few studies have been published, with only short-term follow-up. The aim of the present study is to systematically review the outcomes of magnetically controlled growing rods in the treatment of early-onset scoliosis with a minimum of 2-year follow-up. Studies were included if patients with early-onset scoliosis (scoliosis diagnosed before 10 years of age) underwent implantation of magnetically controlled growing rods with a minimum of 2-year follow-up. The literature review and data extraction followed the established preferred reporting items for systematic review and meta-analysis guidelines. Data of distraction frequency, number of distractions, distracted length, Cobb angle, kyphosis, T1–T12 length, and T1–S1 length preoperatively, postoperatively, and at final follow-up were collected. Data regarding complications and unplanned reoperations were also extracted. The mean values of these parameters were calculated, or pooled meta-analysis was performed if available. Ten articles were included in this systematic review, with a total of 116 patients and a follow-up period between 23 and 61 months. The mean preoperative Cobb angle and kyphosis angle were 60.1° and 38.0°, respectively, and improved to 35.4° and 26.1° postoperatively. At final follow-up, the Cobb and kyphosis angles were maintained at 36.9° and 36.0°, respectively. The average preoperative T1–T12 and T1–S1 lengths were 180.6 mm and 293.6 mm, respectively, and increased to 198.3 mm and 320.3 mm postoperatively. T1–T12 and T1–S1 lengths were 212.3 mm and 339.3 mm at final follow-up, respectively. The overall rate of patients with complications was 48% (95% confidence interval [CI], 0.38–0.58) and unplanned reoperation 44% (95% CI, 0.33–0.55) after sensitivity analysis. The current evidence from different countries with a minimum of a 2-year follow-up suggests that magnetically controlled growing rods are an effective technique to treat pediatric scoliosis and promote spine growth. However, nearly half of patients still developed complications or required unplanned reoperations.

Abstract Objective To evaluate the conditional survival of patients with chordoma to potentially help physician planning of optimal cancer surveillance and guide better clinical decisions. Methods In total, 1942 patients with chordoma were identified and extracted from Surveillance, Epidemiology, and End Results (SEER) databases (1973–2015). The cumulative survival estimates were used to calculate the conditional survival rate, and the Greenwood formula was used to estimate the 95% CI. In addition, multivariable Cox regression analyses were used to calculate hazard ratios, according to the duration of survival. Results The conditional 5-year disease-specific survival in patients with regional or localized chordoma was relatively stable over time, whereas in patients with distant chordoma, there was a gradual improvement. The conditional 5-year disease-specific survival (DSS) of patients older than 60 years old and patients with a tumor size between 5 and 10 cm improved. Interestingly, for patients with a tumor larger than 10 cm, the conditional 5-year DSS decreased over time. After surviving 5 years, the hazard ratio (HR) of patients older than 60 years old decreased from 1.33 to 1.24, that of patients with a tumor size between 5 and 10 cm decreased from 1.61 to 1.52 and that of patients with distant metastasis decreased from 3.30 to 1.09. However, after surviving 5 years, the HR of patients with a tumor size larger than 10 cm increased from 2.33 to 3.77, that of patients who underwent surgical resection increased from 0.37 to 0.58 and that of patients who received radiation therapy increased from 0.81 to 1.04. Conclusion Age at diagnosis, tumor size and disease stage can influence conditional survival for patients with chordoma. The HR of different factors will change over the survival time. Therefore, understanding the changing risk profile and conditional 5-year DSS of chordoma is critical for accurate clinical treatment guidance.

Background The efficacy of cancer immunotherapy can be limited by the poor immunogenicity of cancer and the immunosuppressive tumor microenvironment (TME). Immunologically programming the TME and creating an immune-inflamed tumor phenotype is critical for improving the immune-responsiveness of cancers. Here, we interrogate the immune modulator Flagrp170, engineered via incorporation of a pathogen-associated molecular pattern (ie, flagellin) into an immunostimulatory chaperone molecule, in transforming poorly immunogenic tumors and establishing a highly immunostimulatory milieu for immune augmentation.Methods Multiple murine cancer models were used to evaluate the immunostimulatory activity, antitumor potency, and potential side effects of Flagrp170 on administration into the tumors using a replication impaired adenovirus. Antibody neutralization and mice deficient in pattern recognition receptors, that is, toll-like receptor 5 (TLR5) and NOD like receptor (NLR) family caspase activation and recruitment domain (CARD) domain-containing protein 4 (NLRC4), both of which can recognize flagellin, were employed to understand the immunological mechanism of action of the Flagrp170.Results Intratumoral delivery of mouse or human version of Flagrp170 resulted in robust inhibition of multiple malignancies including head and neck squamous cell carcinoma and breast cancer, without tissue toxicities. This in situ Flagrp170 treatment induced a set of cytokines in the TME known to support Th1/Tc1-dominant antitumor immunity. Additionally, granulocyte macrophage colony-stimulating factor derived from mobilized CD8+ T cells was involved in the therapeutic activity of Flagrp170. We also made a striking finding that NLRC4, not TLR5, is required for Flagrp170-mediated antitumor immune responses.Conclusion Our results elucidate a novel immune-potentiating activity of Flagrp170 via engaging the innate pattern recognition receptor NLRC4, and support its potential clinical use to reshape cancer immune phenotype for overcoming therapeutic resistance.

Purpose: The purpose of this study was to investigate finite element biomechanical properties of the novel transpedicular transdiscal (TPTD) screw fixation with interbody arthrodesis technique in lumbar spine. Methods: An L4–L5 finite element model was established and validated. Then, two fixation models, TPTD screw system and bilateral pedicle screw system (BPSS), were established on the validated L4–L5 finite element model. The inferior surface of the L5 vertebra was set immobilised, and moment of 7.5 Nm was applied on the L4 vertebra to test the range of motion (ROM) and stress at flexion, extension, lateral bending and axial rotation. Results: The intact model was validated for prediction accuracy by comparing two previously published studies. Both of TPTD and BPSS fixation models displayed decreased motion at L4–L5. The ROMs of six moments of flexion, extension, left lateral bending, right lateral bending, left axial rotation and right axial rotation in TPTD model were 1.92, 2.12, 1.10, 1.11, 0.90 and 0.87°, respectively; in BPSS model, they were 1.48, 0.42, 0.35, 0.38, 0.74 and 0.75°, respectively. The screws' peak stress of above six moments in TPTD model was 182.58, 272.75, 133.01, 137.36, 155.48 and 150.50 MPa, respectively; and in BPSS model, it was 103.16, 129.74, 120.28, 134.62, 180.84 and 169.76 MPa, respectively. Conclusion: Both BPSS and TPTD can provide stable biomechanical properties for lumbar spine. The decreased ROM of flexion, extension and lateral bending was slightly more in BPSS model than in TPTD model, but TPTD model had similar ROM of axial rotation with BPSS model. The screws' peak stress of TPTD screw focused on the L4–L5 intervertebral space region, and more caution should be put at this site for the fatigue breakage. The translational potential of this article: Our finite element study provides the biomechanical properties of novel TPTD screw fixation, and promotes this novel transpedicular transdiscal screw fixation with interbody arthrodesis technique be used clinically. Keywords: Bilateral pedicle screw system, Biomechanics, Finite element, Lumbar arthrodesis, Transpedicular transdiscal screw

Objective: The objective of this study is to use 3D digital lumbar models to investigate and simulate the optimal posterior operative approach for safe decompression and insertion of an interbody cage. Methods: Thirty lumbar spine (L3-S1) computed tomography data are collected for 3D reconstruction. We cut medial half part of the superior facet and define the distance between the margin of the operative side of the spinous process and the medial margin of the cut superior facet as “medial distance (MD)”. Then, we cut the total superior facet and define the distance between the margin of the operative side of the spinous process and the lateral side of the junction of the pedicle and the vertebral body as “extend distance (ED)”. The feasible insertion of the current standard width size (10 mm and 12 mm) interbody cages was assessed by the two aforementioned MD and ED approaches. Besides the ED, we also simulate four other extensive options of lateral upper, lateral lower, vertical upper and lower and transmedian contralateral decompression on 3D digital lumbar model. Results: The MD increased from 13.48 ± 1.28 mm at L3/4 to 18.05 ± 1.43 mm at L5/S1, and the ED increased from 16.64 ± 1.34 mm at L3/4 to 21.12 ± 1.62 mm at L5/S1. To insert a 10-mm-wide cage, 16.7% (left) and 13.3% (right) of MD for L3/4 is not enough, 60.0% (left) and 46.7% (right) of MD for L3/4 is subsafe, 13.3% (left) and 16.7% (right) of MD for L4/5 is subsafe and all others are safe. To insert a 12-mm-wide cage, 76.7% (left) and 60.0% (right) of MD for L3/4 is not enough, 20.0% (left) and 30.0% (right) of MD for L3/4 is subsafe, 13.3%% (left) and 16.7% (right) of MD for L4/5 is not enough, 63.3% (left) and 56.7% (right) of MD for L4/5 is subsafe and 6.7% (left) and 10.0% (right) of MD for L5/S1 is subsafe, whereas 33.3%% (left) and 30.0% (right) of ED for L3/4 is subsafe, 3.3% (left) and 3.3% (right) of ED for L4/5 is subsafe and all others are safe. Besides the ED, on 3D models, four other extensive options could be simulated too and may need to be performed for different special individuals. Conclusion: Our 3D digital image study provides a feasible optimal medial transforaminal lumbar interbody fusion approach with five extensive options on lower lumbar region. It can provide safe lumbar decompression and interbody fusion in most population. In addition, surgeons can choose the different extensive options for special individual conditions. The translational potential of this article: Transforminal lumbar interbody fusion is very common used for lumbar degenerative diseases. The optimal medial transforminal lumbar interbody fusion with five options provide a safe and precise approach for surgeons in treatment of lumbar degenerative diseases. Keywords: 3D images, Anatomic, Lumbar spine, Transforaminal lumbar interbody fusion

Abstract Background An increasing number of studies on spinal morphology in asymptomatic Asian and Western patients have been reported. Variation in spinal anatomy among patients is considered as the cause of wrong-level surgery in up to 40% of cases. The present study examined the rate of presence of 11 thoracic vertebrae and 6 lumbar vertebrae in 293 asymptomatic Chinese adult volunteers. Methods From May 27, 2016, to November 11, 2017, a cohort of 325 asymptomatic Chinese adults meeting the study exclusion criteria was recruited. The radiographs were examined by a spine surgeon and a radiologist to assess the number of thoracic and lumbar vertebrae. Results In total, 293 volunteers were included in this study: 17 (5.8%) had 11 thoracic vertebrae, and 16 (5.5%) had 6 lumbar vertebrae. Among all volunteers, 12 (4.1%) had 7 cervical vertebrae (C), 11 thoracic vertebrae (T), and 5 lumbar vertebrae (L); 5 (1.7%) had 7C, 11T, and 6L; and 11 (3.8%) had 7C, 12T, and 6L. There was no difference between the findings of the spine surgeon and the radiologist. Conclusions For the first time, this study describes the rate of presence of 11 thoracic vertebrae and 6 lumbar vertebrae in 293 asymptomatic Chinese adult volunteers. Variations in the number of thoracic and lumbar vertebrae tend to be ignored by spine surgeons. We encourage spinal surgeons and researchers to be aware of such variations when performing thoracic- and lumbar-level surgery and assessing spinal alignment and parameters.

Abstract Background Thyroid cartilage is an important barrier in anterior cervical approach surgery. The objective of this study is to establish normative values for thyroid cartilage at three planes and to determine their significance on preoperative positioning and intraoperative traction in surgery via the anterior cervical approach. Methods Neck CT scans were collected from 600 healthy adults who did not meet any of the exclusion criteria. Transverse diameters (D1, D2, and D3) of the superior border of the thyroid cartilage (SBTC), inferior border of the thyroid cartilage (IBTC), and the trachea transverse diameters of the inferior border of the cricoid cartilage (IBCC) were measured on a horizontal plane. Results All measured variables had intra-class correlation coefficients (ICCs) of ≥ 0.7. The differences in transverse diameters on the same plane between males and females were significantly different (all p

Abstract Background The objective of this study is to investigate the outcomes and safety of using percutaneous anterior C1/2 transarticular screw fixation as a salvage technique for odontoid fracture if percutaneous odontoid screw fixation fails. Methods Fifteen in 108 odontoid fracture patients (planned to be treated by percutaneous anterior odontoid screw fixation) were failed to introduce satisfactory odontoid screw trajectory. To salvage this problem, we chose the percutaneous anterior C1/2 transarticular screw fixation technique in treatment of these patients. The visual analogue score (VAS) of neck pain and Neck Disability Index (NDI) of all patients were scored at pre-operation, 3 months after operation, and final follow-up. Additional, technique-related complications were recorded and collected. Results Percutaneous C1/2 transarticular screw fixation was performed successfully in all 15 patients whose odontoid screw fixation failed. No technique-related complications (such as nerve injury, spinal cord injury, and esophageal injury) occurred. The VAS of neck pain and NDI score improved significantly (P = 0.000) after operation, and no significant differences were found when compared to 93 non-salvage patients who successfully performed the percutaneous anterior odontoid screw fixation. No screw loose or breakage occurred, all of the odontoid fractures achieve radiographic fusion, bony fusion bridge could be observed at the C1/2 lateral articular facet on 9/15 patients. Conclusions We suggest that percutaneous anterior C1/2 transarticular screw fixation is a good alternative salvage technique if percutaneous odontoid screw fixation failed, and it is a minimally invasive, feasible, and safe technique.

Objective. We sought to evaluate the association between femoral neck (FN) and lumbar spine (LS) bone mineral densities (BMDs) with severity of chronic kidney disease (CKD) and prevalence of osteopenia or osteoporosis (OP) among the CKD group. Methods. Cross-sectional data from 11050 participants aged ≥20 years from the National Health and Nutrition Examination Survey (NHANES) were analyzed. Specifically, Pearson correlation was applied to analyze the relationship between BMD and estimated glomerular filtration rate (eGFR). General linear models (GLMs) were adjusted for potential confounders and used to analyze mean BMD, based on CKD and CKD stages. Results. FN BMD was positively correlated with the eGFR in the total and male CKD, but not in the female CKD population. LS BMD was not significantly associated with eGFR. After controlling for partial correlations, FN T-score was positively correlated with the eGFR in the total at-risk population. According to FN BMD, OP prevalence was positively associated with CKD stage. However, according to LS BMD, there was no significant association between OP and CKD stage. Conclusion. Our results may explain the higher prevalence of hip fracture, relative to that of the spine, among CKD patients and generate meaningful insights to guide care, prevention, and treatment regimens for CKD patients. However, the fact that this was a cross-sectional study may limit the possibility of drawing concrete conclusions. Nevertheless, these findings open up a new frontier for further studies to uncover the higher decrease of FN BMD compared to LS BMD among CKD cases.

Background. Patients with diabetes mellitus are prone to develop osteoporosis, osteomyelitis, or rheumatoid arthritis (RA). Furthermore, the presence of these complications in those with diabetes may lead to higher mortality. The aim of our study was to assess characteristics and mortality of osteoporosis, osteomyelitis, or rheumatoid arthritis in individuals with diabetes. Methods. We analyzed osteoporosis, osteomyelitis, and RA deaths associated with diabetes from 1999–2017 using the CDC WONDER system (CDC WONDER; https://wonder.cdc.gov). We used ICD-10 codes to categorize the underlying and contributing causes of death. Crude mortality rates (CMR) and age-adjusted mortality rates (AAMR) per 1,000,000 person-years were calculated. Results. The AAMR for osteoporosis in the population with diabetes was significantly higher in females (AAMR: 4.17, 95% CI: 4.10–4.24) than in males (AAMR: 1.12, 95% CI: 1.07–1.16). Deaths due to osteoporosis increased gradually from 1999, peaked in 2003 (AAMR: 3.78, 95% CI: 3.55–4.00), and reached a nadir in 2016 (AAMR: 2.32, 95% CI: 2.15–2.48). The AAMR for RA associated with diabetes was slightly higher in females (AAMR: 4.04, 95% CI: 3.98–4.11) than in males (AAMR: 2.45, 95% CI: 2.39–2.51). The mortality rate due to RA increased slightly from 1999 (AAMR: 3.18, 95% CI: 2.97–3.39) to 2017 (AAMR: 3.20, 95% CI: 3.02–3.38). The AAMR for osteomyelitis associated with diabetes was higher in males (AAMR: 4.36, 95% CI: 4.28–4.44) than in females (AAMR: 2.31, 95% CI: 2.26–2.36). From 1999 to 2017, the AAMR from osteomyelitis in this population was 2.63 (95% CI: 2.44–2.82) per 1,000,000 person-years in 1999 and 4.25 (95% CI: 4.05–4.46) per 1,000,000 person-years in 2017. Conclusions. We found an increase in the age-adjusted mortality rates of RA and osteomyelitis and a decrease of osteoporosis associated with diabetes from 1999 to 2017. We suggest that increased attention should therefore be given to these diseases in the population with diabetes, especially in efforts to develop preventative and treatment strategies.

Background: Malignant giant cell tumor of bone (MGCTB) is extremely rare. Currently, population-based prognosis studies are lacking. This study aimed to determine the impact of demographics, tumor characteristics, and treatment on prognosis among patients with MGCTB. Methods: The Surveillance, Epidemiology, and End Results database was used to identify patients with MGCTB from 1984 to 2013. Kaplan-Meier analyses were performed to determine the overall survival (OS). Univariable and multivariable Cox analyses were conducted to identify prognostic factors. Results: There were 250 patients with MGCTB included in our study. The multivariate Cox analysis revealed that age at diagnosis (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 1.07–1.11; P 70 mm (P = 0.015), located in the axial skeleton (P

Mannan binding lectin (MBL), initially known to activate the complement lectin pathway and defend against infection, was recently shown to be potentially involved in the development of several types of cancer; however, its exact role in cancers, especially its effect on tumor microenvironment remain largely unknown. Here, using a murine hepatocellular carcinoma (HCC) model, we showed that MBL was a component of liver microenvironment and MBL-deficient (MBL–/–) mice exhibited an enhanced tumor growth compared with wild-type (WT) mice. This phenomenon was associated with elevation of myeloid derived suppressed cells (MDSCs) in tumor tissue of MBL–/– mice. MBL deficiency also resulted in an increase of activated hepatic stellate cells (HSCs), which showed enhanced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Pharmacological inhibition of COX-2 in vivo partially abrogated the MBL deficiency-promoted tumor growth and MDSC accumulation. Mechanistic studies revealed that MBL could interact directly with HSCs and inhibit HCC-induced HSCs activation via downregulating the extracellular signal-regulated kinase (ERK)/COX-2/PGE2 signaling pathway. Furthermore, MBL-mediated suppression of HCC is validated by administration of MBL-expressing, liver-specific adeno-associated virus (AAV), which significantly inhibited HCC progression in MBL–/– mice. Taken together, these data reveal that MBL may impact on tumor development by shaping the tumor microenvironment via its interaction with the local stromal cells, and also suggests its potential therapeutic use for the treatment of HCC.

Neutrophils are one of the first immune cell types that are recruited to injury and infection site. As a vital component of the immune system, neutrophils are heterogeneous immune cells known to have phagocytic property and function in inflammation. Recent studies revealed that neutrophils play dual roles in tumor initiation, development, and progression. The multifunctional roles of neutrophils in diseases are mainly due to their production of different effector molecules under different conditions. N1 and N2 neutrophils or high density neutrophils (HDNs) and low density neutrophils (LDNs) have been used to distinguish neutrophils subpopulations with pro- vs. anti-tumor activity, respectively. Indeed, N1 and N2 neutrophils also represent immunostimulating and immunosuppressive subsets, respectively, in cancer. The emerging studies support their multifaceted roles in autoimmune diseases. Although such subsets are rarely identified in autoimmune diseases, some unique subsets of neutrophils, including low density granulocytes (LDGs) and CD177+ neutrophils, have been reported. Given the heterogeneity and functional plasticity of neutrophils, it is necessary to understand the phenotypical and functional features of neutrophils in disease status. In this article, we review the multifaceted activates of neutrophils in cancer and autoimmune diseases, which may support new classification of neutrophils to help understand their important functions in immune homeostasis and pathologies.

We reported a technical report of traumatic lower cervical spondylolisthesisca used by bilateral pedicle fracture, without neurological compression. The patient was treated with the minimally invasive technique of percutaneous pedicle screw fixation. Fracture healing and normal cervical motion were confirmed by plain films and physical examinations on the 18-monthpostoperatively. The technique of percutaneous pedicle screw fixation might be an alternative strategy for the treatment of traumatic lower cervical spondylolisthesis with pedicle fracture.

Transpedicular transdiscal screw fixation is an alternative technique used in lumbar spine fixation; however, it requires an accurate screw trajectory. The aim of this study is to design a novel 3D-printed custom drill guide and investigate its accuracy to guide the trajectory of transpedicular transdiscal (TPTD) lumbar screw fixation. Dicom images of thirty lumbar functional segment units (FSU, two segments) of L1–L4 were acquired from the PACS system in our hospital (patients who underwent a CT scan for other abdomen diseases and had normal spine anatomy) and imported into reverse design software for three-dimensional reconstructions. Images were used to print the 3D lumbar models and were imported into CAD software to design an optimal TPTD screw trajectory and a matched custom drill guide. After both the 3D printed FSU models and 3D-printed custom drill guide were prepared, the TPTD screws will be guided with a 3D-printed custom drill guide and introduced into the 3D printed FSU models. No significant statistical difference in screw trajectory angles was observed between the digital model and the 3D-printed model (P > 0.05). Our present study found that, with the help of CAD software, it is feasible to design a TPTD screw custom drill guide that could guide the accurate TPTD screw trajectory on 3D-printed lumbar models.

Objective: Hepatitis E, caused by the hepatitis E virus (HEV), is an important global public health concern. There are conflicting reports in regard to the association of HEV infection and psychiatric disorders. Therefore, we investigated this association in a Chinese population through a case–control seroprevalence study. Methods: A case–control study of 445 psychiatric patients and 445 control subjects was conducted between June 2011 and July 2013 to estimate the seroprevalence and potential risk factors associated with acquiring HEV infection in psychiatric patients in China. Demographic and clinical data and blood samples were collected, and anti-HEV IgG and IgM antibodies were measured by ELISA method. Results: The prevalence of anti-HEV IgG in psychiatric patients (27.19%) was higher than that in healthy controls (19.55%) (p = 0.07). In addition, there were significant differences in seroprevalences of HEV infection according to the type of psychiatric disorder. Sex, age, contact with dogs and cats, and exposure to soil were found to be risk factors for HEV infection. Conclusions: Psychiatric patients have a higher prevalence of HEV infection than control subjects in China. Considering the promotion of public health, psychiatric patients should be considered a specific group of HEV infection.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A) was administered intravenously to wild-type (WT) and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase (ALT) activity, and inhibited production of pro-inflammatory cytokines (e.g. TNF-α, IL-6, IL-17A and IFN-γ). In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism, and could be exploited as a new therapeutic approach for autoimmune hepatitis.

Purpose. To investigate a novel computed method to reconstruct the bilateral digital interarticular channel of atlas and its potential use on the anterior upper cervical screw fixation. Methods. We have used the reverse engineering software (image-processing software and computer-aided design software) to create the approximate and optimal digital interarticular channel of atlas for 60 participants. Angles of channels, diameters of inscribed circles, long and short axes of ellipses were measured and recorded, and gender-specific analysis was also performed. Results. The channels provided sufficient space for one or two screws, and the parameters of channels are described. While the channels of females were smaller than that of males, no significant difference of angles between males and females were observed. Conclusion. Our study demonstrates the radiological features of approximate digital interarticular channels, optimal digital interarticular channels of atlas, and provides the reference trajectory of anterior transarticular screws and anterior occiput-to-axis screws. Additionally, we provide a protocol that can help make a pre-operative plan for accurate placement of anterior transarticular screws and anterior occiput-to-axis screws.

We did a clinical trial to determine whether olfactory mucosa lamina propria (OLP) transplants promote regeneration and functional recovery in chronic human spinal cord injury (SCI). The trial randomized 12 subjects to OLP transplants ( n = 8) or control sham surgery ( n =4). The subjects received magnetic resonance imaging (MRI), electromyography (EMG), urodynamic study (UDS), American Spinal Injury Association impairment scale (AIS), and other functional assessments. OLP-transplanted subjects recovered more motor, sensory, and bladder function compared to sham-operated subjects. At 3 years after OLP transplant, one patient improved from AIS A to C and another recovered from AIS A to B, two recovered more than three segmental sensory levels, two had less spasticity, two had altered H-reflexes and SSEP, two regained bladder and anorectal sensation and had improved bladder compliance on UDS. OLP-treated patients had partial or complete tissue bridges at the injury site compared to cavitary gaps in sham-operated patients. The limited recovery suggests that OLP transplants alone do not have significant benefits but may provide a rationale for larger randomized trials or combination therapies.

BACKGROUND CONTEXT:Animals are commonly used to model the human spine for in vitro and in vivo experiments. Many studies have investigated similarities and differences between animals and humans in the lumbar and thoracic vertebrae. However, a quantitative anatomic comparison of calf, pig, and human cervical spines has not been reported. PURPOSE:To compare fundamental structural similarities and differences in vertebral bodies from the cervical spines of commonly used experimental animal models and humans. STUDY DESIGN:Anatomical morphometric analysis was performed on cervical vertebra specimens harvested from humans and two common large animals (i.e., calves and pigs). METHODS:Multiple morphometric parameters were directly measured from cervical spine specimens of twelve pigs, twelve calves and twelve human adult cadavers. The following anatomical parameters were measured: vertebral body width (VBW), vertebral body depth (VBD), vertebral body height (VBH), spinal canal width (SCW), spinal canal depth (SCD), pedicle width (PW), pedicle depth (PD), pedicle inclination (PI), dens width (DW), dens depth (DD), total vertebral width (TVW), and total vertebral depth (TVD). RESULTS:The atlantoaxial (C1-2) joint in pigs is similar to that in humans and could serve as a human substitute. The pig cervical spine is highly similar to the human cervical spine, except for two large transverse processes in the anterior regions ofC4-C6. The width and depth of the calf odontoid process were larger than those in humans. VBW and VBD of calf cervical vertebrae were larger than those in humans, but the spinal canal was smaller. Calf C7 was relatively similar to human C7, thus, it may be a good substitute. CONCLUSION:Pig cervical vertebrae were more suitable human substitutions than calf cervical vertebrae, especially with respect to C1, C2, and C7. The biomechanical properties of nerve vascular anatomy and various segment functions in pig and calf cervical vertebrae must be considered when selecting an animal model for research on the spine.

To study the morphology of the human spine and new spinal fixation methods, scientists require cadaveric specimens, which are dependent on donation. However, in most countries, the number of people willing to donate their body is low. A 3D printed model could be an alternative method for morphology research, but the accuracy of the morphology of a 3D printed model has not been determined.Forty-five computed tomography (CT) scans of cervical, thoracic and lumbar spines were obtained, and 44 parameters of the cervical spine, 120 parameters of the thoracic spine, and 50 parameters of the lumbar spine were measured. The CT scan data in DICOM format were imported into Mimics software v10.01 for 3D reconstruction, and the data were saved in .STL format and imported to Cura software. After a 3D digital model was formed, it was saved in Gcode format and exported to a 3D printer for printing. After the 3D printed models were obtained, the above-referenced parameters were measured again.Paired t-tests were used to determine the significance, set to P0.800. The other ICC values were 0.600; none were

This paper is devoted to studying the boundary behavior of self-affine sets. We prove that the boundary of an integral self-affine set has Lebesgue measure zero. In addition, we consider the variety of the boundary of a self-affine set when some other contractive maps are added. We show that the complexity of the boundary of the new self-affine set may be the same, more complex, or simpler; any one of the three cases is possible.

Toxocarosis is a widespread zoonosis caused by the ascarid nematodes Toxocara canis and Toxocara cati, which primarily infect dogs and cats, respectively. Most human infections with Toxocara are asymptomatic; however, some infected individuals may develop a serious illness and even death. Nevertheless, epidemiological knowledge regarding the prevalence and risks associated with Toxocara infection is limited in China. Therefore, we performed a cross-sectional pilot study and estimated the seroprevalence of Toxocara infection in humans in Shandong Province, eastern China for the first time, from June 2011 to July 2013, involving clinically healthy individuals, pregnant women and psychiatric patients, aiming to attract public attention to Toxocara infection.Seroprevalence of Toxocara was determined using an enzyme-linked immunosorbent assay based on a cross-sectional study conducted in Qingdao and Weihai, Shandong Province, eastern China. Factors potentially associated with Toxocara infection were identified by logistic regression analysis. The overall Toxocara seroprevalence among the study population (n = 2866) was 12.25%, and a significantly higher seroprevalence in psychiatric patients (16.40%, 73/445) than that in clinically healthy individuals (13.07%, 187/1431) and pregnant women (9.19%, 91/990) was revealed. Univariate analyses suggested that keeping dogs at home (OR = 0.06, 95% CI 0.05-0.08, P

In the title compound, C20H13N5O2, the two pyrazine rings are nearly coplanar with the central pyridine ring, forming dihedral angles of 2.21 (9) and 4.57 (9)°. In contrast, the strong steric hindrance caused by the ortho-carboxyl group on the phenyl ring makes this ring rotate out of the attached pyridine ring plane by 52.60 (9)°. The carboxyl group is twisted from the phenyl ring by 22.6 (1)°. In the crystal, aromatic π–π stacking interactions [centroid–centroid distances = 3.9186 (4) and 3.9794 (5) Å] occur between the antiparallel molecules, generating infinite chains along [100]. O—H...O hydrogen bonds connect the chains, leading to the formation of a two-dimensional supramolecular network parallel to (010). Intermolecular C—H...N hydrogen bonds are also observed.

BACKGROUND: Anterior odontoid screw fixation (AOSF) has been one of the most popular treatments for odontoid fractures. However, the true efficacy of AOSF remains unclear. In this study, we aimed to provide the pooled rates of non-union, reoperation, infection, and approach related complications after AOSF for odontoid fractures. METHODS: We searched studies that discussed complications after AOSF for type II or type III odontoid fractures. A proportion meta-analysis was done and potential sources of heterogeneity were explored by meta-regression analysis. RESULTS: Of 972 references initially identified, 63 were eligible for inclusion. 54 studies provided data regarding non-union. The pooled non-union rate was 10% (95% CI: 7%-3%). 48 citations provided re-operation information with a pooled proportion of 5% (95% CI: 3%-7%). Infection was described in 20 studies with an overall rate of 0.2% (95% CI: 0%-1.2%). The main approach related complication is postoperative dysphagia with a pooled rate of 10% (95% CI: 4%-17%). Proportions for the other approach related complications such as postoperative hoarseness (1.2%, 95% CI: 0%-3.7%), esophageal/retropharyngeal injury (0%, 95% CI: 0%-1.1%), wound hematomas (0.2%, 95% CI: 0%-1.8%), and spinal cord injury (0%, 95% CI: 0%-0.2%) were very low. Significant heterogeneities were detected when we combined the rates of non-union, re-operation, and dysphagia. Multivariate meta-regression analysis showed that old age was significantly predictive of non-union. Subgroup comparisons showed significant higher non-union rates in age ≥ 70 than that in age ≤ 40 and in age 40 to

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) has become one of the most widely used procedures for lumbar spinal disorders. However, it is still unclear whether TLIF with unilateral pedicle screw (PS) fixation is as effective as that with bilateral PS fixation. We performed a meta-analysis of the literatures and aimed to gain a better understanding of whether TLIF with unilateral PS fixation was safe and effective for lumbar diseases. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched Ovid, Springer, and Medline databases for relevant randomized controlled trials (RCTs) that compared the clinical and radiological outcomes of unilateral versus bilateral PS fixation in TLIF. Risk of bias in included studies was assessed using the Cochrane Risk of Bias tool. We generated pooled risk ratios or weighted mean differences across studies. According to our predefined inclusion criteria, seven RCTs with a total of 441 patients were included in this study. Baseline characteristics were similar between the unilateral and bilateral groups. Our meta-analysis showed that no significant difference was detected between the two groups in terms of postoperative clinical function, fusion status, reoperation rate, complication rate, and hospital stay (p>0.05). Pooled estimates revealed that the unilateral group was associated with significantly reduced implant cost, operative time and blood loss (p

BACKGROUND: Dynamic interspinous spacers, such as X-stop, Coflex, DIAM, and Aperius, are widely used for the treatment of lumbar spinal stenosis. However, controversy remains as to whether dynamic interspinous spacer use is superior to traditional decompressive surgery. METHODS: Medline, Embase, Cochrane Library, and the Cochrane Controlled Trials Register were searched during August 2013. A track search was performed on February 27, 2014. Study was included in this review if it was: (1) a randomized controlled trial (RCT) or non-randomized prospective comparison study, (2) comparing the clinical outcomes for interspinous spacer use versus traditional decompressive surgery, (3) in a minimum of 30 patients, (4) with a follow-up duration of at least 12 months. RESULTS: Two RCTs and three non-randomized prospective studies were included, with 204 patients in the interspinous spacer (IS) group and 217 patients in the traditional decompressive surgery (TDS) group. Pooled analysis showed no significant difference between the IS and TDS groups for low back pain (WMD: 1.2; 95% CI: -10.12, 12.53; P = 0.03; I2 = 66%), leg pain (WMD: 7.12; 95% CI: -3.88, 18.12; P = 0.02; I2 = 70%), ODI (WMD: 6.88; 95% CI: -14.92, 28.68; P = 0.03; I2 = 79%), RDQ (WMD: -1.30, 95% CI: -3.07, 0.47; P = 0.00; I2 = 0%), or complications (RR: 1.39; 95% CI: 0.61, 3.14; P = 0.23; I2 = 28%). The TDS group had a significantly lower incidence of reoperation (RR: 3.34; 95% CI: 1.77, 6.31; P = 0.60; I2 = 0%). CONCLUSION: Although patients may obtain some benefits from interspinous spacers implanted through a minimally invasive technique, interspinous spacer use is associated with a higher incidence of reoperation and higher cost. The indications, risks, and benefits of using an interspinous process device should be carefully considered before surgery.

A retrospective clinical study.To evaluate the efficacy and safety of transforaminal decompression and interbody fusion in the treatment of thoracolumbar fracture and dislocation with spinal cord injury.Twenty-six spinal cord injured patients with thoracolumbar fracture and dislocation were treated by transforaminal decompression and interbody fusion. The operation time, intraoperative blood loss, and complications were recorded; the Cobb angle and compressive rate (CR) of the anterior height of two adjacent vertebrae were measured; and the nerve injury was assessed according to sensory scores and motor scores of the American Spinal Injury Association (ASIA) standards for neurological classification of spinal cord injury.The operative time was 250±57 min, and intraoperative blood loss was 440±168 ml. Cerebrospinal leakage was detected and repaired during the operation in two patients. A total of 24 of 26 patients were followed up for more than 2 years. ASIA sensory scores and motor scores were improved significantly at 3 months and 6 months after operation; the Cobb angle and CR of the anterior height of two adjacent vertebrae were corrected and showed a significant difference at post-operation; and the values were maintained at 3 months after operation and the last follow-up.We showed that transforaminal decompression together with interbody fusion is an alternative method to treat thoracolumbar fracture and dislocation.

During the past decade, the dual function of the immune system in tumor inhibition and tumor progression has become appreciated. We have previously reported that neu-specific T cells can induce rejection of neu positive mouse mammary carcinoma (MMC) and also facilitate tumor relapse by inducing neu antigen loss and epithelial to mesenchymal transition (EMT). Here, we sought to determine the mechanism by which CD8+ T cells either eliminate the tumor, or maintain tumor cells in a dormant state and eventually facilitate tumor relapse. We show that tumor cells that express high levels of IFN-γ Rα are eliminated by CD8+ T cells. In contrast, tumor cells that express low levels of IFN-γ Rα do not die but remain dormant and quiescent in the presence of IFN-γ producing CD8+ T cells until they hide themselves from the adaptive immune system by losing the tumor antigen, neu. Relapsed tumor cells show CD44+CD24- phenotype with higher rates of tumorigenesis, in vivo. Acquisition of CD44+CD24- phenotype in relapsed tumors was not solely due to Darwinian selection. Our data suggest that tumor cells control the outcome of tumor immune surveillance through modulation of the expression of IFN-γ Rα.

The advancement of cancer immunotherapy faces barriers which limit its efficacy. These include weak immunogenicity of the tumor, as well as immunosuppressive mechanisms which prevent effective antitumor immune responses. Recent studies suggest that aberrant expression of cancer testis antigens (CTAs) can generate robust antitumor immune responses, which implicates CTAs as potential targets for immunotherapy. However, the heterogeneity of tumor cells in the presence and quantity of CTA expression results in tumor escape from CTA-specific immune responses. Thus, the ability to modulate the tumor cell epigenome to homogenously induce expression of such antigens will likely render the tumor more immunogenic. Additionally, emerging studies suggest that suppression of antitumor immune responses may be overcome by reprogramming innate and adaptive immune cells. Therefore, this paper discusses recent studies which address barriers to successful cancer immunotherapy and proposes a strategy of modulation of tumor-immune cell crosstalk to improve responses in carcinoma patients.