Clinical value of Tc-99m MDP SPECT/CT bone imaging for early diagnosis of Relapsing Polychondritis: a report of 5 cases.

BACKGROUND: Relapsing Polychondritis(RP) is a rare rheumatic immune disease. As with most diseases, if intervention is delayed, the patient's prognosis is worse. Currently, the diagnostic criteria used in clinical practice do not include CT, PET/CT, SPECT/CT and other new imaging examinations that have developed rapidly in recent years. However, these examinations have some special manifestations for RP, which can help clinicians diagnose RP earlier and distinguish it from other diseases. CASE PRESENTATION: These five RP patients all had respiratory symptoms such as cough and wheezing as the first symptom, which could not be diagnosed in time according to the previous diagnostic criteria. The clinical data of the five patients are listed in Table 1. The relatively specific manifestations of SPECT/CT examination provided clinicians with very valuable clues to help them advance the diagnosis time. CONCLUSIONS: The application of SPECT/CT bone imaging in early diagnosing RP proves to be effective, enabling clinicians to intervene promptly and enhance the overall well-being and quality of life for individuals affected by this condition.

Causes of recurrence of paediatric inguinal hernia after single-port laparoscopic closure.

PURPOSE: This paper explores the causes of paediatric inguinal hernia (PIH) recurrence after single-port laparoscopic percutaneous extraperitoneal closure (SPLPEC). METHOD: From January 2015 to December 2020, the clinical data of 3480 children with PIHs who underwent SPLPEC were retrospectively reviewed, including 644 children who underwent SPLPEC with a homemade single-hook hernia needle from January 2015 to December 2016 and 2836 children who underwent the SPLPEC with a double-hook hernia needle and hydrodissection from January 2017 to December 2020. There were 39 recurrences (including communicating hydrocele) during the 2-5 years of follow-up. The findings of redo-laparoscopy were recorded and correlated with the revised video of the first operation to analyse the causes of recurrence. RESULT: Thirty-three males and 6 females experienced recurrence, and 8 patients had a unilateral communicating hydrocele. The median time to recurrence was 7.1 months (0-38). There were 20 cases (3.11%) in the single-hook group and 19 cases (0.67%) in the double-hook group. Based on laparoscopic findings, recurrence most probably resulted from multiple factors, including uneven tension of the ligation (10 cases), missing part of the peritoneum (14 cases), loose ligation (8 cases), broken knot (5 cases), and knot reaction (2 cases). All children who underwent repeat SPLPEC were cured by double ligations or reinforcement with medial umbilical ligament. CONCLUSION: The main cause of recurrence is improper ligation. Tension-free and complete PIH ligation are critical to the success of surgery, which requires avoiding the peritoneum skip area and the subcutaneous and muscular tissues. Redo-laparoscopic surgery was suitable for the treatment of recurrent inguinal hernia (RIH). For giant hernias, direct ligation of the internal ring incorporating the medial umbilical ligament (DIRIM) may be needed.

Stimulating thyroglobulin to TSH ratio predict long-term efficacy of 131I therapy in patients with differentiated thyroid cancer after total thyroidectomy: a retrospective study.

OBJECTIVE: This study utilized the stimulated thyroglobulin (sTg) to thyroid stimulating hormone (TSH) ratio to predict the long-term efficacy of 131I therapy in patients with moderate-to-high-risk differentiated thyroid cancer (DTC). METHODS: This study retrospectively analyzed 960 DTC patients with a median follow-up time of 30 months (6-92 months). The median age was 44 years. All patients underwent total thyroidectomy, lymph node dissection, and at least one 131I therapy. Patients were subjected to a final efficacy evaluation according to American Thyroid Association's 2015 guidelines. Patients were grouped according to their TSH levels before the initial 131I therapy and the final efficacy evaluation, and factors influencing TSH levels and final efficacy were analyzed. Construction of nomograms using independent risk factors affecting long-term outcomes. The cut-offs of sTg and sTg/TSH ratios were calculated for different long-term outcomes. Progression-free survival (PFS) of patients was analyzed by making Kaplan-Meier survival according to the cut-offs of sTg and sTg/TSH ratio. RESULTS: TSH (mU/L) levels were more concentrated at 60-90 in females (71.5%) and 30-60 in males (39.0%), while patients with younger age, more lymph node metastases, shorter time interval between surgery and the first 131I therapy, and lower dose of levothyroxine sodium taken prior to the first 131I therapy would have higher TSH levels (All P < 0.05).Patients who are male, have primary tumor involvement of the strap muscles, lymph node metastasis, distant metastasis, and higher sTg and sTg/TSH are more likely to have poor long-term outcomes (All P < 0.05).The cut-offs of sTg and sTg/TSH for long-term efficacy were 7.515 and 0.095. STg, sTg/TSH, tumor size, lymph node metastasis, and distant metastasis were shown to be independent risk factors for long-term efficacy. The mean PFSs were longer for patients who had sTg/TSH ≤ 0.095 and/or sTg≤7.515 ug/L. CONCLUSIONS: For patients with moderate-to-high-risk DTC, when sTg>7.515 ug/L and/or sTg/TSH > 0.095 before the first 131I therapy, patients are more likely to have a poor long-term efficacy after full 131I therapy. This means that this group of patients may require further surgical treatment or targeted drug therapy after 131I therapy.

Clinical characteristics and therapeutic response of differentiated thyroid carcinoma with obesity and diabetes.

BACKGROUND: The effects of obesity and diabetes on the clinical outcomes of differentiated thyroid cancer (DTC) remain unclear. OBJECTIVES: To explore the association between obesity and diabetes with pathological features and therapeutic response of DTC. METHODS: Patients were categorized based on body mass index (BMI) and glycemic status. Compare the correlation between BMI and glycemic status with pathological features and therapeutic response of DTC. To analyze the independent risk factors for the aggressiveness of DTC. RESULTS: The proportion of patients with bilateral tumors was higher in the overweight, obese and diabetes group (P = 0.001, 0.045). The overweight group demonstrated a higher TNM stage (P = 0.004), while the T and TNM stages were higher in the diabetes group (P = 0.032, 0.000). The probability of distant metastasis increases by 37.4% for each unit of BMI increase (odds ratio (OR) = 1.374, CI 95% 1.061-1.778, P < 0.05). The BMI of Biochemical Incomplete Response (BIR) is significantly higher than that of Excellent Response (ER) (P = 0.015), the fasting plasma glucose (FPG) of Structural Incomplete (SIR) was significantly higher than that of ER and BIR (P = 0.030, 0.014). CONCLUSION: Obesity and diabetes have effect on DTC aggressiveness. BMI and FPG have correlation with the therapeutic response of DTC patients.

Higher adjuvant radioactive iodine therapy dosage helps intermediate-risk papillary thyroid carcinoma patients achieve better therapeutic effect.

Objective: This retrospective study aims to evaluate the therapeutic effect of varying dosages of adjuvant radioactive iodine (RAI) therapy on intermediate-risk papillary thyroid carcinoma (PTC) patients. Methods: This retrospective study involved a total of 427 intermediate-risk PTC patients, out of which 202 received a 3.7GBq dosage of RAI, and 225 received a 5.55GBq dosage. The evaluation involved assessing the therapeutic outcomes, number of treatment cycles, and successful remnant ablation rates in both dose groups, six months post-adjuvant RAI therapy. Univariate and multivariate logistic regression analyses were employed to identify factors linked with excellent response (ER). Following this, prognostic nomograms were constructed to provide a visual representation of the prediction models. Calibration curves, the concordance index (C-index), and the receiver operating characteristic (ROC) curve were employed to evaluate the predictive performance of these nomograms. The Hosmer-Lemeshow test was applied to assess the models' goodness-of-fit. Additionally, the clinical utility of the prognostic nomograms was appraised through decision curve analysis (DCA). Results: The high-dose (HD) group exhibited significantly higher proportions of ER, single treatment cycles, and successful remnant ablation rates (p<0.05). Being male, receiving a 3.7GBq dose, having an N1b stage, an sTg level ≥10ng/ml, or an sTg/TSH ratio ≥0.11 were independent risk factors for Non-ER. Two prognostic nomograms, "sTg Nomogram" and "sTg/TSH Nomogram", were established. The ranking of factors contributing to ER, in descending order, included the sTg or sTg/TSH ratio, N stage, therapy dosage, sex, and soft tissue invasion. The "sTg/TSH Nomogram" demonstrated a higher C-index compared to the "sTg Nomogram". The calibration curves indicated excellent calibration for both nomograms. DCA demonstrated that the net benefit of the "sTg/TSH Nomogram" was higher than that of the "sTg Nomogram". Conclusion: Higher initial RAI therapy doses can improve therapeutic efficacy for intermediate-risk PTC patients. The developed nomograms, particularly the "sTg/TSH Nomogram", could assist clinicians in optimal therapeutic decision-making.

Radionuclide 131I-labeled albumin-indocyanine green nanoparticles for synergistic combined radio-photothermal therapy of anaplastic thyroid cancer.

Objectives: Anaplastic thyroid cancer (ATC) cells cannot retain the radionuclide iodine 131 (131I) for treatment due to the inability to uptake iodine. This study investigated the feasibility of combining radionuclides with photothermal agents in the diagnosis and treatment of ATC. Methods: 131I was labeled on human serum albumin (HSA) by the standard chloramine T method. 131I-HSA and indocyanine green (ICG) were non-covalently bound by a simple stirring to obtain 131I-HSA-ICG nanoparticles. Characterizations were performed in vitro. The cytotoxicity and imaging ability were investigated by cell/in vivo experiments. The radio-photothermal therapy efficacy of the nanoparticles was evaluated at the cellular and in vivo levels. Results: The synthesized nanoparticles had a suitable size (25-45 nm) and objective biosafety. Under the irradiation of near-IR light, the photothermal conversion efficiency of the nanoparticles could reach 24.25%. In vivo fluorescence imaging and single-photon emission CT (SPECT)/CT imaging in small animals confirmed that I-HSA-ICG/131I-HSA-ICG nanoparticles could stay in tumor tissues for 4-6 days. Compared with other control groups, 131I-HSA-ICG nanoparticles had the most significant ablation effect on tumor cells under the irradiation of an 808-nm laser. Conclusions: In summary, 131I-HSA-ICG nanoparticles could successfully perform dual-modality imaging and treatment of ATC, which provides a new direction for the future treatment of iodine-refractory thyroid cancer.

New Progress in Basic Research of Macrophages in the Pathogenesis and Treatment of Low Back Pain.

Low back pain (LBP) is quite common in clinical practice, which can lead to long-term bed rest or even disability. It is a worldwide health problem remains to be solved. LBP can be induced or exacerbated by abnormal structure and function of spinal tissue such as intervertebral disc (IVD), dorsal root ganglion (DRG) and muscle; IVD degeneration (IVDD) is considered as the most important among all the pathogenic factors. Inflammation, immune response, mechanical load, and hypoxia etc., can induce LBP by affecting the spinal tissue, among which inflammation and immune response are the key link. Inflammation and immune response play a double-edged sword role in LBP. As the main phagocytic cells in the body, macrophages are closely related to body homeostasis and various diseases. Recent studies have shown that macrophages are the only inflammatory cells that can penetrate the closed nucleus pulposus, expressed in various structures of the IVD, and the number is positively correlated with the degree of IVDD. Moreover, macrophages play a phagocytosis role or regulate the metabolism of DRG and muscle tissues through neuro-immune mechanism, while the imbalance of macrophages polarization will lead to more inflammatory factors to chemotaxis and aggregation, forming an "inflammatory waterfall" effect similar to "positive feedback," which greatly aggravates LBP. Regulation of macrophages migration and polarization, inhibition of inflammation and continuous activation of immune response by molecular biological technology can markedly improve the inflammatory microenvironment, and thus effectively prevent and treat LBP. Studies on macrophages and LBP were mainly focused in the last 3-5 years, attracting more and more scholars' attention. This paper summarizes the new research progress of macrophages in the pathogenesis and treatment of LBP, aiming to provide an important clinical prevention and treatment strategy for LBP.

HSA-MnO2-131I Combined Imaging and Treatment of Anaplastic Thyroid Carcinoma.

Purpose Compelling evidence suggests that nanoparticles (NPs) play a crucial role in cancer therapy. NPs templated with human serum albumin (HSA) has good retention in tumors. Manganese dioxide (MnO2) has been used to enhance the effect of radiotherapy. In this study, synthesized NPs using HSA-MnO2 labeled 131I to perform both imaging and therapy for anaplastic thyroid carcinoma (ATC). Method HSA-MnO2 was synthesized via HSA using a simple biomineralization method, and then labeled with Na131I by the chloramine T method. The cytotoxicity and biosafety of HSA-MnO2 were evaluated by the MTT test. The proliferation-inhibiting effect of HSA-MnO2-131I was evaluated in papillary thyroid cancer cell lines (K1, BCPAP, and KTC) and anaplastic thyroid carcinoma cell lines (Cal62, THJ16T, and ARO). For further translational application in medicine, we established a model of transplantable subcutaneously tumors in BALB\c-nu mice to assess the anti-tumor effect of HSA-MnO2-131I. The imaging effects of NPs were evaluated by MRI and SPECT/CT. Results The MTT test proved that the HSA-MnO2 had low toxicity. HSA-MnO2-131I significantly inhibited the proliferation of PTC and ATC cell lines. In addition, the results unveiled that HSA-MnO2-131I exhibited dual-modality MR/SPECT imaging for thyroid cancer visualization. In particular, HSA-MnO2-131I had an enhanced T1 signal in MR. Using SPECT/CT, we observed that HSA-MnO2-131I had good retention in tumor tissue, which was helpful for the diagnosis and treatment of tumor. In vivo assays indicated that the NPs led to a reduction in radioresistance in the tumor hypoxic microenvironment. Conclusion The nanomaterial had a simple synthesis method, good water solubility and biosafety, and good retention in tumor tissue. Hence, it could be used for SPECT/CT and MR dual mode imaging and therapy with radioiodine of tumor cells. The experimental results provided a feasible solution for combining radiotherapy and dual-model imaging by NPs for cancer diagnosis and treatment.

Analysis of correlation factors influencing the outcome of initial 131I remnant ablative therapy in intermediate- to high-risk patients with papillary thyroid microcarcinoma.

OBJECTIVE: To investigate the factors influencing the outcome of initial 131I remnant ablative therapy in intermediate- to high-risk patients with papillary thyroid microcarcinoma (PTMC). METHODS: We divided 99 patients with PTMC who underwent total thyroidectomy into two groups according to their response to initial 131I remnant ablative therapy: excellent response (ER) and non-ER groups. Clinical and laboratory characteristics were collected and retrospectively analyzed using univariate and multivariate binary logistic regression. Receiver operator characteristic (ROC) curves and diagnostic cutoff values were analyzed to evaluate the predictive value of significant quantitative influencing factors for 131I treatment outcomes. A prognostic nomogram model based on the above independent risk factors was established. RESULTS: Of the 99 eligible patients who accepted the initial 131I treatment following total thyroidectomy, 76 (76.7%) were classified into the ER group and 23 (23.3%) into the non-ER group. The univariate and multivariate analyses showed that extrathyroidal extension [ETE; odds ratio (OR) = 4.769; P = 0.041], preablative thyrotropin (TSH; OR = 0.972; P = 0.017), and stimulated thyroglobulin (sTg; OR = 1.614; P = 0.040) were independent predictors for the therapeutic effect of 131I treatment. Patients with higher sTg (>1.37 ng/ml) and lower TSH (<67.97 mU/l) and ETE tended to have a poor response to initial 131I treatment. The quantification of the therapeutic effect of initial 131I therapy in patients with PTMC using our newly constructed nomogram showed that ETE, preablative sTg, and TSH were contributors to non-ER. CONCLUSION: Intermediate- to high-risk patients with PTMC after total thyroidectomy who had low pretreatment sTg and high preablative TSH levels and negative ETE were more likely to achieve satisfactory response to initial 131I remnant ablative therapy. Our prognostic nomogram is a valuable tool to enable patients and clinical professionals to be better informed about patients' therapeutic response to initial 131I remnant ablative therapy.

Retrospective study of the influence of hypothyroidism on liver function before radioiodine therapy in China: a comparison analysis based on patients with differentiated thyroid cancer.

PURPOSE: The aim of the present study is to investigate the risk factors for hepatic dysfunction before radioiodine therapy in patients with differentiated thyroid cancer (DTC). METHODS: 996 patients (314 men, 682 women; age of 45.07±12.98 years) with postoperative DTC were recruited and divided into two groups including patients with and without hepatic dysfunction. The changes in baseline data and traced liver function levels, together with other metabolic profiles, were compared between the two groups. RESULT: Overall, 31.6% of patients had hepatic dysfunction. Higher aspartate aminotransferase and/or alanine aminotransferase was the most common abnormality (the prevalence rate was 47.5%). The percentages of mild and moderate hepatic dysfunction were 80.0% and 20.0%, respectively. Univariate analyses demonstrated that the most prominent risk factors for hepatic dysfunction (OR=0.324-3.171, p<0.01) were male sex with levothyroxine discontinuation and free triiodothyronine <2.01 pmol/L, free thyroxine (FT4) <4.78 pmol/L, thyroid-stimulating hormone >78.195 µIU/mL, total cholesterol >5.17 mmol/L, triglycerides (TG) >1.71 mmol/L and more than 21 days of thyroid hormone withdrawal. Multivariate analyses demonstrated that for men, FT4 <3.80 pmol/L and TG ≥1.28 mmol/L were the most prominent risk factors. CONCLUSIONS: Patients with minor hepatic dysfunction and ortholiposis are more likely to recover to normal liver function. Patients with moderate hepatic dysfunction should be treated with hepatoprotective drugs. For men, FT4 and TG levels tended to be associated with hepatic dysfunction, and the prognosis of hepatic dysfunction was closely related to the TG level.

Delayed Initial Radioiodine Adjuvant Therapy Does Affect Biochemical Response in Intermediate- to High-Risk Differentiated Thyroid Cancer.

Background: There are no definite recommendations on the optimal time of initiating radioactive iodine (RAI) therapy for differentiated thyroid cancer (DTC) patients in current relevant guidelines. This study aimed to investigate the relationship between the timing of initiating radioiodine adjuvant therapy (RAT) and the clinical outcomes based on dynamic follow-ups and assessments in intermediate- to high-risk DTC patients. Methods: A total of 206 patients with intermediate- to high-risk DTC receiving RAT of 150 mCi were retrospectively reviewed. According to the time interval (TI: between thyroidectomy and initial RAT), the patients were divided into 2 groups: Group 1: TI < 3 months (n=148), and Group 2: TI ≥ 3 months (n=58). The RAT therapy response was evaluated as excellent response (ER), indeterminate response (IDR), biochemical incomplete response (BIR), structural incomplete response (SIR). The univariate and multivariate analyses were conducted to screen out factors associated with incomplete response (IR= BIR+SIR). Finally, the prognostic nomogram was used to explain IR rates as a valuable tool in clinical practice. Results: Response to initial RAT was significantly different between 2 groups during dynamic follow-ups (all P<0.05). Group 2 had significantly lower ER rates (37.9 vs 63.5, 52.0 vs 73.9, 64.4 vs 80.3, all P<0.05, respectively) and higher IR rates (39.7 vs 14.9, 36.0 vs 9.7, 12.2 vs 3.9, all P<0.05, respectively) than group 1 during dynamic follow-ups. By univariate and multivariate analyses, prolonged TI (HR: 6.67, 95%CI: 2.241-19.857, P=0.001), soft tissue invasion (HR: 7.35, 95%CI: 1.624-33.296, P=0.010), higher sTg (HR: 7.21, 95%CI: 1.991-26.075, P=0.003) were manifested to be independent risk factors for IR. The nomogram showed that soft tissue invasion, sTg, and TI were the top 3 contributors to the IR. Conclusions: Early RAT is associated with greater biochemical response but has no impact on SIR. Delayed initial RAT (≥3 months after thyroidectomy) related to IR in intermediate- to high-risk DTC.

Curcumin Modulates the Crosstalk Between Macrophages and Bone Mesenchymal Stem Cells to Ameliorate Osteogenesis.

Bone healing is thought to be influenced by the cross-talk between bone forming and immune cells. In particular, macrophages play a crucial role in the regulation of osteogenesis. Curcumin, the major bioactive polyphenolic ingredient of turmeric, has been shown to regulate inflammatory response and osteogenic activities. However, whether curcumin could regulate macrophage polarization and subsequently influence osteogenesis remain to be elucidated. In this study, the potential immunomodulatory capability of curcumin on inflammatory response and phenotype switch of macrophages and the subsequent impact on osteogenic differentiation of MSCs are investigated. We demonstrated that curcumin exhibited significant anti-inflammatory effect by polarizing the macrophages toward anti-inflammatory phenotype, with increased expression of IL-4, IL-10, and CD206, and decreased expression of IL-1ß, TNF-α, CCR7, and iNOS. In addition, curcumin could improve the osteo-immune microenvironment via promoting osteogenesis-related regenerative cytokine BMP-2 and TGF-ß production. Moreover, the co-cultured test of macrophages and BMSCs showed that curcumin-modulated macrophages conditioned medium could promote osteogenic differentiation of BMSCs with increased gene (ALP, Runx-2, OCN, and OPN) and protein (Runx-2 and OCN) expression levels, enhanced ALP activity, and obvious formation of mineralized nodules. Taken together, with the interaction between curcumin-conditioned macrophage and curcumin-stimulated BMSCs, curcumin could remarkably enhance the osteogenic differentiation of BMSCs in LPS-activated inflammatory macrophage-BMSCs coculture system.

Hsa-miR-557 Inhibits Osteosarcoma Growth Through Targeting KRAS.

Objective: Osteosarcoma is the most common malignancy in the skeletal system; studies showed an important role of miRNAs in tumorigenesis, indicating miRNAs as possible therapeutic molecules. This study found abnormal hsa-miR-557 expression levels in osteosarcoma and tried to explore the potential function and the mechanism. Methods: Differential expression genes of osteosarcoma were analyzed using GSE28423 from the GEO database. Survival analysis of miRNAs was conducted with data obtained from the TARGET-OS database. STRING and miRDIP were used to predict target genes of hsa-miR-557; KRAS was then verified using dual-luciferase reporter assay. Expression of genes was detected by qPCR, and levels of proteins were detected by Western blot. The proliferation ability of cells was detected by CCK-8 and cell cycle analysis. Tumor formation assay in nude mice was used to detect the influence of osteosarcoma by hsa-miR-557 in vivo. Results: Analysis from the GEO and TARGET databases found 12 miRNAs that are significantly related to the osteosarcoma prognosis, 7 downregulated (hsa-miR-140-3p, hsa-miR-564, hsa-miR-765, hsa-miR-1224-5p, hsa-miR-95, hsa-miR-940, and hsa-miR-557) and 5 upregulated (hsa-miR-362-3p, hsa-miR-149, hsa-miR-96, hsa-miR-744, and hsa-miR-769-5p). CCK-8 analysis and cell cycle analysis found that hsa-miR-557 could significantly inhibit the proliferation of osteosarcoma cells. The tumor formation assay in nude mice showed that tumor sizes and weights were inhibited by hsa-miR-557 transfection. Further studies also proved that hsa-miR-557 could target the 3'UTR of KRAS and modulate phosphorylation of downstream proteins. Conclusion: This study showed that hsa-miR-557 could inhibit osteosarcoma growth both in vivo and in vitro, by modulating KRAS expression.

Short-term Efficacy of the Percutaneous Vertebroplasty Using a Curved Versus Straight Vertebroplasty Needle in Osteoporotic Vertebral Compression Fractures.

The purpose of this study was to compare the efficacy of the curved puncture approach with 2 conventional approaches in percutaneous vertebroplasty (PVP) for the treatment of single-level osteoporotic vertebral compression fractures. Ninety-six patients with a single-level thoracolumbar vertebral fracture were surgically treated in the authors' department from February 2016 to February 2018. Patients were randomly divided into 3 groups, including 25 patients who had PVP punctured with a curved vertebroplasty needle (group C), 40 patients with unipedicular PVP with a straight vertebroplasty needle (group U), and 31 patients with bipedicular PVP with a straight vertebroplasty needle (group B). The short-term efficacies of PVP using different vertebroplasty needles were compared. Significant differences were tested preoperatively and postoperatively in vertebral body height variation, visual analog scale score, and Oswestry Disability Index in each of the 3 groups (P<.05). There was no significant difference among the groups in terms of Cobb angle correction and bone cement leakage. Group C and group U were superior to group B in terms of operative time and injected cement volume (P<.05). Twenty-four (96.0%) patients in group C and 29 (93.5%) patients in group B had centered cement distribution without significant differences (P>.05), which was superior to group U (P<.05). Curved puncture PVP achieved a satisfactory clinical outcome for osteoporotic vertebral compression fractures, with the advantages of less operative time, less injected cement volume, and more reasonable cement distribution for stabilization of the affected vertebrae. [Orthopedics. 2021;44(1):e131-e138.].

Surface modified small intestinal submucosa membrane manipulates sequential immunomodulation coupled with enhanced angio- and osteogenesis towards ameliorative guided bone regeneration.

Constructing bioactive guided bone regeneration (GBR) membranes that possess biological multifunctionality is becoming increasingly attractive and promising to meet higher requirements for bone healing. Given the biological responses following implantation, GBR process originates from an early inflammation-driven reaction adjacent to implanted membranes surface. However, to date there is relatively little attention paid to the critical immunoregulatory functions in traditionally designed GBR membranes. Herein, for the first time, we manipulate immunomodulatory properties of the widely-used native small intestinal submucosa (SIS) membrane by incorporating strontium-substituted nanohydroxyapatite coatings and/or IFN-γ to its surface. In vitro results reveal the obtained novel membrane SIS/SrHA/IFN-γ not only promote functions of endothelial cells and osteoblasts directly, but also energetically mediate a sequential M1-M2 macrophages transition to concurrently facilitate angiogenesis and osteogenesis. Moreover, in vivo outcomes of subcutaneous implantation and cranial defects repair further confirm its superior capacity to promote vascularization and in situ bone regeneration than pristine SIS through immunomodulation. These results demonstrate a sequential immunomodulatory strategy renders modified SIS membranes acting as a robust immunomodulator rather than a traditional barrier to significantly ameliorate in vivo GBR outcomes and hence provide important implications that may facilitate concerns on immunomodulatory properties for future GBR developments.

Synergistic Utilization of Necrostatin-1 and Z-VAD-FMK Efficiently Promotes the Survival of Compression-Induced Nucleus Pulposus Cells via Alleviating Mitochondrial Dysfunction.

We recently reported that necroptosis contributed to compression-induced nucleus pulposus (NP) cells death. In the current study, we investigated the regulative effect of necroptosis inhibitor Necrostatin-1 on NP cells apoptosis and autophagy. Necrostatin-1, autophagy inhibitor 3-Methyladenine and apoptosis inhibitor Z-VAD-FMK were employed, and NP cells were exposed to 1.0 MPa compression for 0, 24 and 36 h. Necroptosis-associated molecules were measured by Western blot and RT-PCR. Autophagy and apoptosis levels were evaluated by Western blot and quantified by flow cytometry after monodansylcadaverine and Annexin V-FITC/propidium iodide staining, respectively. The cell viability and cell death were also examined. Furthermore, we measured mitochondrial membrane potential (MMP), mitochondrial permeability transition pore (MPTP) and indices of oxidative stress to assess mitochondrial dysfunction. The results established that Necrostatin-1 blocked NP cells autophagy, and 3-Methyladenine had little influence on NP cells necroptosis. The Necrostatin-1+3-Methyladenine treatment exerted almost the same role as Necrostatin-1 in reducing NP cells death. Necrostatin-1 restrained NP cells apoptosis, while Z-VAD-FMK enhanced NP cells necroptosis. The Necrostatin-1+Z-VAD-FMK treatment provided more prominent role in blocking NP cells death compared with Necrostatin-1, consistent with increased MMP, reduced opening of MPTP and oxidative stress. In summary, the synergistic utilization of Necrostatin-1 and Z-VAD-FMK is a very worthwhile solution in preventing compression-mediated NP cells death, which might be largely attributed to restored mitochondrial function.

A Review of Gene Therapy Delivery Systems for Intervertebral Disc Degeneration.

BACKGROUND: Intervertebral Disc (IVD) degeneration is a major public health concern, and gene therapy seems a promising approach to delay or even reverse IVD degeneration. However, the delivery system used to transfer exogenous genes into intervertebral disc cells remains a challenge. METHODS: The MEDLINE, Web of Science, and Scopus databases were searched for English-language articles related to gene therapy for IVD degeneration articles from 1999 to May 2019. The keywords included "gene therapy" AND "intervertebral disc". The history of the development of different delivery systems was analysed, and the latest developments in viral and non-viral vectors for IVD degeneration treatment were reviewed. RESULTS: Gene therapy delivery systems for IVD degeneration are divided into two broad categories: viral and non-viral vectors. The most commonly used viral vectors are adenovirus, adeno-associated virus (AAV), and lentivirus. Enthusiasm for the use of adenovirus vectors has gradually declined and has been replaced by a preference for lentivirus and AAV vectors. New technologies, such as RNAi and CRISPR, have further enhanced the advantage of viral vectors. Liposomes are the classic non-viral vector, and their successors, polyplex micelles and exosomes, have more potential for use in gene therapy for IVD degeneration. CONCLUSION: Lentivirus and AAV are the conventional viral vectors used in gene therapy for IVD degeneration, and the new technologies RNAi and CRISPR have further enhanced their advantages. Nonviral vectors, such as polyplex micelles and exosomes, are promising gene therapy vectors for IVD degeneration.