PMAIP1 regulates autophagy in osteoblasts via the AMPK/mTOR pathway in osteoporosis.

Osteoporosis (OP) is a highly prevalent disorder characterized by low bone mass that severely reduces patient quality of life. Although numerous treatments for OP have been introduced in clinic, many have side effects and high costs. Therefore, there is still an unmet need for optimal solutions. Here, raw signal analysis was used to identify potential high-risk factors for OP, and the biological functions and possible mechanisms of action (MOAs) of these factors were explored via gene set enrichment analysis (GSEA). Subsequently, molecular biological experiments were performed to verify and analyze the discovered risk factors in vitro and in vivo. PMAIP1 was identified as a potential risk factor for OP and significantly suppressed autophagy in osteoblasts via the AMPK/mTOR pathway, thereby inhibiting the proliferation and differentiation of osteoblasts. Furthermore, we constructed an ovariectomy (OVX) model of OP in rats and simultaneously applied si-PMAIP1 for in vivo interference. si-PMAIP1 upregulated the expression of LC3B and p-AMPK and downregulated the expression of p-mTOR, and these effects were reversed by the autophagy inhibitor. Micro-CT revealed that, si-PMAIP1 significantly inhibited the development of osteoporosis in OVX model rats, and this therapeutic effect was attenuated by treatment with an autophagy inhibitor. This study explored the role and mechanism of PMAIP1 in OP and demonstrated that PMAIP1 may serve as a novel target for OP treatment.

Case report: Significant response to PD-L1 inhibitor after resistance to PD-1 inhibitor in an advanced alpha-fetoprotein-positive gastric cancer.

Alpha-fetoprotein-positive gastric cancer (AFPGC) is a type of gastric cancer with a high degree of malignancy. The disease is more common in the elderly, with a high prevalence in males and generally atypical clinical manifestations. For advanced patients, the current treatment options are limited and, to date, few cases of advanced AFPGC have been treated successfully with conventional chemotherapy. With the development of molecular biology and immunology, tumor immunotherapy offers more therapeutic options to patients with advanced gastric cancer. This study describes a case of advanced gastric cancer in a young woman with a high blood alpha-fetoprotein (AFP) level (>54,000 ng/mL). The patient showed initial promising results when programmed cell death-1 (PD-1) inhibitor treatment was combined with chemotherapy after systemic chemotherapy failed. When the disease progressed again after 129 days, adjustment of the treatment regimen to Atezolizumab in combination with Irinotecan and Surufatinib capsules achieved partial remission (PR). There were no immune-related pneumonia, myocarditis, or other adverse effects observed. The patient currently has an overall survival of more than 14 months. This case demonstrated that switching from PD-1 inhibitor to programmed cell death-Ligand 1 (PD-L1) inhibitor therapy may overcome potential resistance. It providing a reference for immunotherapy of patients with AFP-positive advanced gastric cancer.

Biomechanics of the unilateral posterosuperior, unipedicular, and bipedicular approaches for treatment by percutaneous vertebroplasty: a comparative study.

Percutaneous vertebroplasty (PVP) via the unilateral posterosuperior approach has achieved good clinical results for the treatment of osteoporotic vertebral compression fractures. This study compared the biomechanical performance of a single vertebral body after PVP by the unilateral posterosuperior, unipedicular, and bipedicular approaches. Twenty-one vertebral bodies from the osteoporotic spine segments (T11-L1) of seven older female cadavers were randomly assigned to the unipedicular (group A), bipedicular (group B), or unilateral posterosuperior approach group (group C). After constructing the fracture compression model, PVP was performed by the different approaches. CT scans showed symmetrical, evenly distributed bone cement in groups B and C and unilaterally distributed cement in group A. The recovery rates of the anterior vertebral body height in groups B and C were significantly higher than those in group A after PVP (P<0.05). The left curvature elastic moduli after PVP were significantly higher in group A than in groups B and C; however, the right curvature moduli in group A were lower than in the other groups (P<0.05). The flexion, extension, and vertical compression elastic moduli were lowest in group B (P<0.05). After PVP, failure strength and stiffness in groups B and C were comparable (P>0.05) and higher than those in group A (P<0.05). PVP through the unilateral posterosuperior approach was superior to the unipedicular approach and comparable to the bipedicular approach based on the biomechanical performance of a single vertebral body. Due to its safety, simplicity, and efficacy, the unilateral posterosuperior approach is recommended for clinical application.

INTS7-ABCD3 Interaction Stimulates the Proliferation and Osteoblastic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Suppressing Oxidative Stress.

Increased adipocyte and decreased osteoblast differentiation, combined with the ectopic proliferation of bone marrow mesenchymal stem cells (BM-MSCs), represent the primary causes of osteoporosis. The dysregulation of numerous intracellular bioactive factors is responsible for the aberrant differentiation and growth of BM-MSCs. In this study, we focused on a new stimulative factor, integrator complex subunit 7 (INTS7), and its cooperative protein ATP-binding cassette subfamily D member 3 (ABCD3)/high-density lipoprotein-binding protein (HDLBP) in mouse BM-MSCs. We aimed to uncover the effects of the INTS7-ABCD3/HDLBP interaction on BM-MSC biological behaviors and the potential mechanism underlying these effects. Functional in vitro experiments showed that the suppression of the INTS7-ABCD3 interaction rather than HDLBP could impair BM-MSC proliferation and induce cell apoptosis. Moreover, Alizarin Red S and Oil Red O staining, respectively, revealed that INTS7 and ABCD3 knockdown but not HDLBP knockdown could decrease osteoblastic differentiation and accelerate the adipogenic differentiation of BM-MSCs. Mechanistically, reactive oxygen species (ROS) and histone γ-H2AX quantities significantly increased, whereas the levels of antioxidants declined due to INTS7 and ABCD3 inhibition in BM-MSCs. These findings indicated that the suppression of oxidative stress could be involved in the INTS7/ABCD3 co-regulatory mechanisms for BM-MSC proliferation and differentiation, identifying new potential candidates for osteoporosis therapy.

The Anatomical and Biomechanical Superiority of Novel Posterior En Bloc Elevation Cervical Laminoplasty.

Objectives. In this study, we performed a novel type of posterior en bloc elevation cervical laminoplasty (PEEL) to keep the integrity of the posterior structure, aiming to reduce axial symptoms complicated by a conventional cervical laminoplasty procedure. Methods. Twelve human cervical cadaveric spines (C2-T1) were sequentially tested in the following order: intact condition, open-door laminoplasty (ODL) through bilateral intermuscular approach (mini-invasive ODL), PEEL, and laminectomy (LN). After bilateral transecting at the junction of lamina and lateral mass through the tubular retraction system, the PEEL procedure symmetrically elevated all the posterior structure which was further stabilized with bone grafts and titanium plates. Computed tomography (CT) scan and biomechanical testing were performed after each condition. Results. Both mini-invasive ODL and PEEL procedures were accomplished with 2 small incisions on each side. Two types of laminoplasties could enlarge the spinal canal significantly both in cross-sectional area and anteroposterior diameter comparing with intact condition. The PEEL procedure demonstrated a significantly higher enlargement rate on a canal area and a symmetrical expansion pattern. Compared with intact condition, mini-invasive ODL performed from C3-C7 demonstrated significantly decreased motion in all testing directions except the flexion range of motion (ROM); the PEEL procedure showed mild and insignificant decrease on ROM in all directions. Laminectomy resulted in a statistically significant increase in all directions except the lateral bending ROM. Conclusions. Posterior en bloc elevation cervical laminoplasty can enlarge the canal more effectively and preserve better ROM after operation than the ODL procedure. Although technically challenging, the PEEL procedure probably would decrease the common complications associated with ODL laminoplasty.

Biomaterial-supported MSC transplantation enhances cell-cell communication for spinal cord injury.

The spinal cord is part of the central nervous system (CNS) and serves to connect the brain to the peripheral nervous system and peripheral tissues. The cell types that primarily comprise the spinal cord are neurons and several categories of glia, including astrocytes, oligodendrocytes, and microglia. Ependymal cells and small populations of endogenous stem cells, such as oligodendrocyte progenitor cells, also reside in the spinal cord. Neurons are interconnected in circuits; those that process cutaneous sensory input are mainly located in the dorsal spinal cord, while those involved in proprioception and motor control are predominately located in the ventral spinal cord. Due to the importance of the spinal cord, neurodegenerative disorders and traumatic injuries affecting the spinal cord will lead to motor deficits and loss of sensory inputs.Spinal cord injury (SCI), resulting in paraplegia and tetraplegia as a result of deleterious interconnected mechanisms encompassed by the primary and secondary injury, represents a heterogeneously behavioral and cognitive deficit that remains incurable. Following SCI, various barriers containing the neuroinflammation, neural tissue defect (neurons, microglia, astrocytes, and oligodendrocytes), cavity formation, loss of neuronal circuitry, and function must be overcame. Notably, the pro-inflammatory and anti-inflammatory effects of cell-cell communication networks play critical roles in homeostatic, driving the pathophysiologic and consequent cognitive outcomes. In the spinal cord, astrocytes, oligodendrocytes, and microglia are involved in not only development but also pathology. Glial cells play dual roles (negative vs. positive effects) in these processes. After SCI, detrimental effects usually dominate and significantly retard functional recovery, and curbing these effects is critical for promoting neurological improvement. Indeed, residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (macrophages and neutrophils), activated by SCI, give rise to full-blown inflammatory cascades. These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit.Given the various multifaceted obstacles in SCI treatment, a combinatorial therapy of cell transplantation and biomaterial implantation may be addressed in detail here. For the sake of preserving damaged tissue integrity and providing physical support and trophic supply for axon regeneration, MSC transplantation has come to the front stage in therapy for SCI with the constant progress of stem cell engineering. MSC transplantation promotes scaffold integration and regenerative growth potential. Integrating into the implanted scaffold, MSCs influence implant integration by improving the healing process. Conversely, biomaterial scaffolds offer MSCs with a sheltered microenvironment from the surrounding pathological changes, in addition to bridging connection spinal cord stump and offering physical and directional support for axonal regeneration. Besides, Biomaterial scaffolds mimic the extracellular matrix to suppress immune responses.Here, we review the advances in combinatorial biomaterial scaffolds and MSC transplantation approach that targets certain aspects of various intercellular communications in the pathologic process following SCI. Finally, the challenges of biomaterial-supported MSC transplantation and its future direction for neuronal regeneration will be presented.

Clinical Efficacy of Different Bone Cement Distribution Patterns in Percutaneous Kyphoplasty: A Retrospective Study.

BACKGROUND: Bone cement distribution patterns in percutaneous kyphoplasty (PKP) is the key factor in keeping the vertebral stabilization and curative effect. However, the same cement volume can result in different bone cement distribution patterns and can thereby lead to different clinical outcomes. Therefore we investigated associations between cement distribution patterns and the occurrence rates of recompression in cemented vertebrae after PKP for patients with osteoporotic vertebral compression fractures (OVCFs). OBJECTIVES: The study focuses attention on the influence of compact and dispersive cement distribution patterns in PKP for patients with OVCFs. STUDY DESIGN: A retrospective cohort study. SETTING: An affiliated people's hospital of a university. METHODS: According to different cement distribution patterns, patients were assigned to 4 groups. The demographic data, radiographic data, and clinical outcomes were compared between the 4 groups. The Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) were evaluated before and 2 days after PKP. Moreover, the relationships between bone cement and clinical outcomes were analyzed. The epidemiologic data, clinical outcomes, and complications of the 4 groups were assessed. Comparisons of the radiologic and clinical results of the 4 groups were made pre- and postoperatively. Anterior height of fractured vertebrae (AH), the kyphotic Cobb angle, and the volumetric cubage index of the fractured vertebrae were measured. RESULTS: A total of 104 subjects were retrospectively analyzed and followed up (median age, 75.01 ± 8.42 years; age range, 56-94 years). The mean procedure duration was 61.26 ± 23.05 minutes (range, 30-140 minutes). The mean follow-up was 12.1 ± 2.2 months (range, 2-15 months). Statistically, there was no significant difference in terms of gender, age, body mass index, and bone mineral density (P > 0.05). The incidence of cement leakage was significantly lower in group A than those in the other groups. The total amount of bone cement injected into 104 cases (104 vertebral bodies in total) was 848.5 mL, and the amount of bone cement injected into a single vertebral body was 7.94 ± 1.38 mL. The amount of bone cement injection in each group was the lowest (6.80 ± 1.66 mL) in group D, followed by (7.94 ± 1.38 mL) group B, and the highest (8.96 ± 1.68 mL) in group A, with a statistically significant difference between the 4 groups (P < 0.05). No serious complications were observed during the follow-up periods. The AH and Cobb angle improved significantly for the 4 groups (P < 0.05). The VAS score decreased from 3.55 ± 0.54, 3.53 ± 0.65, 3.40 ± 0.58, and 3.40 ± 0.66 preoperatively to 0.18 ± 0.39, 0.23 ± 0.41, 0.20 ± 0.40, and 0.15 ± 0.36 at 48 hours postoperatively. The ODI score dropped from 35.65 ± 4.54, 36.45 ± 4.72, 34.12 ± 4.86, and 35.65 ± 4.34 preoperatively to 15.47 ± 1.32, 15.32 ± 1.34, 15.23 ± 1.26, and 15.73 ± 1.17 at 48 hours postoperatively. LIMITATIONS: Our estimation of the vertebral body volume is imprecise. In addition, the number of subjects with OVCFs was small in this retrospective study. The volume of the fractured vertebra was not calculated accurately. CONCLUSIONS: Significant associations between cement distribution patterns and bone cement leakage affected the clinical outcome in patients after PKP. A higher incidence of bone cement leakage was observed in patients with treated vertebrae exhibiting a single-dispersive or single-compact pattern. KEY WORDS: Percutaneous kyphoplasty, osteoporotic vertebral compression fracture, bone cement distribution patterns.

Analysis of Correlation Between Age and Cervical Facet Joint Degeneration and Modic Changes in Patients with Cervical Spondylotic Myelopathy.

BACKGROUND Because facet joints move with the disc, changes in vertebral bodies occur simultaneously with progression of degeneration of cervical facet joints. This study investigated age-related differences in cervical facet joint abnormalities and multi-dimensional characteristics of MCs in patients with cervical spondylotic myelopathy. MATERIAL AND METHODS Forty-five patients underwent both magnetic resonance imaging (MRI) and computed tomography (CT) of the cervical spine. Axial and sagittal parameter changes from C3 to C7, including facet orientation (FO) and facet tropism (FT), and Modic changes (MCs), were evaluated and documented preoperatively, and we also measured the heights and diameters of MCs and performed correlation analysis and established linear regression models. RESULTS The axial facet orientation increased slightly from C3 66.5 (11.4) to C7 89.9 (19). The sagittal facet orientation and facet tropism increased between C3-C4 and C6-C7, but it decreased between C4 to C6. The MCs volume decreased from C3 to C4 and increased from C4 to C7. There was a gradual decrease of FO and FT from C3 to C5 and a gradual increase of these 2 angles from C5 to C7 in all age groups. The lowest values of FO and FT were detected at C5, while the highest values of FO and FT were detected at C7. CONCLUSIONS Age was negatively correlated with the axial, sagittal, and coronal cervical facet orientation, especially at C4/5 level. The FT with respect to the axial and sagittal plane from C5 to C6 increased with age.

Vertebral collapse and polymethylmethacrylate breakage after vertebroplasty: A case report.

RATIONALE: Vertebral augmentation has become the main treatment for osteoporotic vertebral fractures (VFs). In this article, we report a very rare case of vertebral collapse and polymethylmethacrylate (PMMA) breakage after vertebroplasty. We describe the clinical characteristics and revision surgery performed to remove the broken PMMA cement, maintain stability, and corrects the kyphotic deformity, and we analyze the possible causes. PATIENT CONCERNS: A 72-year-old man who suffered back pain underwent first lumbar vertebra (L1) percutaneous vertebroplasty (PVP) due to osteoporosis and a vertebral fracture in May 2013. Postoperatively, the patient's back pain was markedly alleviated. Unfortunately, his lumbar back pain recurred in November 2015. DIAGNOSES: Plain radiographs showed collapse of the L1 vertebral body, breakage of the PMMA cement, and severe kyphosis at the thoracolumbar junction. INTERVENTIONS: The posterior pedicle was internally fixed and an anterior artificial vertebral body implant was placed to maintain stability and correct the kyphotic deformity in a 2-step surgical procedure. OUTCOMES: The back pain was alleviated and the patient returned to daily life for more than two years. LESSONS: This case demonstrates that PVP is not a simple minimally invasive surgery, and significant postsurgical care is necessary. The true cause of this rare phenomenon remains unclear, but the long-term use of steroids, new injuries, and poorly corrected kyphosis after PVP may play a role. Surgeons must be aware of the kinds of complications that may occur, including rare complications such as vertebral lysis.

Relationship between Endplate Defects, Modic Change, Disc Degeneration, and Facet Joint Degeneration in Patients with Low Back Pain.

PURPOSE: The endplate defects (EDs), Modic changes (MCs), disc degeneration (DD), facet orientation (FO), and facet tropism (FT) were demonstrated to be related to the low back pain (LBP). The aim of this study was to investigate possible correlations between them. METHODS: 75 patients were reviewed to evaluate the degenerative change in vertebral bodies (EDs and MCs), intervertebral discs (DD), and facet joint degeneration (FO and FT). All patients were categorized into four groups based on the grade of EDs. Clinical outcomes were evaluated with the visual analog scale (VAS) and Oswestry disability index (ODI) before and after surgery. RESULTS: There was no difference between the four groups in baseline characteristics except for gender and weight. FT is positively correlated with FO. The same rule exists between EDs, the size of MCs II, FO (left) and FO (right), and VAS and ODI. The grade of EDs is positively correlated with the grade of DD. L4-L5 can bear more load than other levels; thus, the grade of EDs is higher than that of other lumbar levels. The preoperative LBP was relieved in all groups in varying degrees. The change of pain and dysfunction is inversely proportional to the grade of EDs in the general trend. CONCLUSION: The relationship between weight, gender, and disc degeneration provided a mechanism by which increasing weight can predispose to DD. Different grades of EDs had different effects on patients with LBP. There was a significant correlation between EDs, MCs II, DD, FT, and FO.