Tetrahedral Framework Nucleic Acid-Based Delivery of Astaxanthin Suppresses Chondrocyte Pyroptosis and Modulates Oxidative Stress for the Treatment of Osteoarthritis.

Worldwide, osteoarthritis (OA) is regarded as the most widespread, distressing, and limiting chronic disease that affects degenerative joints. Currently, there is no treatment available to modify the progression of OA. The pathogenesis of OA is significantly linked with oxidative stress and pyroptosis. Astaxanthin (Ast) is a natural ketocarotenoid pigment with potent antioxidant activity and is shown to effectively alleviate cartilage damage in OA. However, its bioavailability is greatly limited due to poor water solubility, high sensitivity to light, temperature, and pH. In this study, Ast-loaded tetrahedral framework nucleic acids (tFNAs) or tFNA/Ast complexes (TAC) for Ast delivery are developed. Compared with free Ast and tFNA alone, TAC exhibits improved drug stability and cellular uptake. Most importantly, TAC effectively protects chondrocytes against oxidative stress-induced pyroptosis while promoting extracellular matrix anabolism by chondrocytes, and ultimately alleviates cartilage damage in a mouse destabilization of the medial meniscus (DMM) model. Thus, TAC holds great promise for the treatment of OA patients.

Pinocembrin alleviates pyroptosis and apoptosis through ROS elimination in random skin flaps via activation of SIRT3.

Random skin flap grafting is the most common skin grafting technique in reconstructive surgery. Despite progress in techniques, the incidence of distal flap necrosis still exceeds 3%, which limits its use in clinical practice. Current methods for treating distal flap necrosis are still lacking. Pinocembrin (Pino) can inhibit reactive oxygen species (ROS) and cell death in a variety of diseases, such as cardiovascular diseases, but the role of Pino in random flaps has not been explored. Therefore, we explore how Pino can enhance flap survival and its specific upstream mechanisms via macroscopic examination, Doppler, immunohistochemistry, and western blot. The results suggested that Pino can enhance the viability of random flaps by inhibiting ROS, pyroptosis and apoptosis. The above effects were reversed by co-administration of Pino with adeno-associated virus-silencing information regulator 2 homolog 3 (SIRT3) shRNA, proving the beneficial effect of Pino on the flaps relied on SIRT3. In addition, we also found that Pino up-regulates SIRT3 expression by activating the AMP-activated protein kinase (AMPK) pathway. This study proved that Pino can improve random flap viability by eliminating ROS, and ROS-induced cell death through the activation of SIRT3, which are triggered by the AMPK/PGC-1α signaling pathway.

Treatment of postoperative non-union with internal fixation loosening of Garden IV femoral neck fracture with teriparatide in a young adult: A case report.

Background: Postoperative non-union of femoral neck fracture often needs secondary operation. We report a case of a postoperative non-union of femoral neck fracture treated with teriparatide. Case presentation: A young male patient with Garden IV femoral neck fracture who showed no obvious signs of healing 3 months after percutaneous hollow nail fixation in which the fracture line was enlarged and the hollow nail was withdrawn. Bone non-union healed after 6 months of continuous subcutaneous injection of teriparatide at a dosage of 20 mg/day after the patient refused a secondary surgery. As far as we know, there have been no relevant reports on this type of fracture yet. Conclusions: Teriparatide is expected to be beneficial in treating young patients with a displaced femoral neck fracture who have difficulty in healing from non-union and who are keen on avoiding secondary surgery.

Tumor-Associated Macrophages Promote Oxaliplatin Resistance via METTL3-Mediated m6A of TRAF5 and Necroptosis in Colorectal Cancer.

As a third-generation platinum drug, oxaliplatin (OX) is widely used as the first-line chemotherapeutic agent in the treatment of colorectal cancer (CRC). CRC cells acquire resistance to chemotherapy and develop resistance, which is a major challenge for the treatment of advanced CRC. Recent studies have suggested that the therapeutic resistance of tumors is affected by the tumor microenvironment (TME). As a critical role among TME, tumor-associated macrophages (TAMs) play an important role. However, their regulatory mechanism underlying the drug resistance in CRC remains largely unknown. In the present study, we found that the density of macrophages infiltrated into the CRC tissues from OX-resistant patients was significantly higher compared with the OX-sensitive patients. Interestingly, both the total N6-methyladenosine (m6A) RNA content and the expression of its critical methyltransferase METTL3 were increased in the CRC tissues from OX-resistant patients compared with the OX-sensitive patients. Furthermore, we demonstrated that the M2-polarized TAMs enabled the OX resistance via the elevation of METTL3-mediated m6A modification in cells. Through whole-genome CRISPR screening and further validation, we found that TRAF5 contributes to the METTL3-triggered OX resistance in CRC cells. This study unveiled that M2-TAMs were important mediators for the acquisition of OX resistance. Furthermore, we provided evidence that targeting of M2-TAMs and METTL3-mediated m6A modification might be a promising adjuvant therapeutic strategy for CRC patients, especially for OX-resistant CRC patients.

Light-Driven Syngas Production over Defective ZnIn2 S4 Nanosheets.

Photocatalytic syngas (CO and H2 ) production with CO2 as gas source not only ameliorates greenhouse effect, but also produces valuable chemical feedstocks. However, traditional photocatalytic systems require noble metal or suffers from low yield. Here, we demonstrate that S vacancies ZnIn2 S4 (VS -ZnIn2 S4 ) nanosheets are an ideal photocatalyst to drive CO2 reduction into syngas. It is found that building S vacancies can endow ZnIn2 S4 with stronger photoabsorption, efficient electron-hole separation, and larger CO2 adsorption, finally promoting both hydrogen evolution reaction (HER) and CO2 reduction reaction (CO2 RR). The syngas yield of CO and H2 is therefore significantly increased. In contrast to pristine ZnIn2 S4 , the syngas yield over VS -ZnIn2 S4 can be improved by roughly ≈4.73 times and the CO/H2 ratio is modified from 1:4.18 to 1:1. Total amount of syngas after 12 h photocatalysis is as high as 63.20 mmol g-1 without use of any noble metals, which is even higher than those of traditional noble metal-based catalysts in the reported literatures. This work demonstrates the critical role of S vacancies in mediating catalytic activity and selectivity, and highlights the attractive ability of defective ZnIn2 S4 for light-driven syngas production.

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy.

Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the heat shock protein 90 (Hsp90) chaperone family, protects cells against oxidative stress and maintains mitochondrial integrity. To date, numerous studies have focused on understanding the relationship between aberrant TRAP1 expression and tumorigenesis. Mitochondrial TRAP1 is a key regulatory factor involved in metabolic reprogramming in tumor cells that favors the metabolic switch of tumor cells toward the Warburg phenotype. In addition, TRAP1 is involved in dual regulation of the mitochondrial apoptotic pathway and exerts an antiapoptotic effect on tumor cells. Furthermore, TRAP1 is involved in many cellular pathways by disrupting the cell cycle, increasing cell motility, and promoting tumor cell invasion and metastasis. Thus, TRAP1 is a very important therapeutic target, and treatment with TRAP1 inhibitors combined with chemotherapeutic agents may become a new therapeutic strategy for cancer. This review discusses the molecular mechanisms by which TRAP1 regulates tumor progression, considers its role in apoptosis, and summarizes recent advances in the development of selective, targeted TRAP1 and Hsp90 inhibitors.

Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes.

OBJECTIVE: Iguratimod, a novel disease-modifying anti-rheumatic drug for the treatment of rheumatoid arthritis, has been approved in China and Japan. Here, we aimed to find whether iguratimod can inhibit the aggressive behavior and promote apoptosis of rheumatoid fibroblast-like synoviocytes (RA-FLSs). METHODS: The proliferation of RA-FLSs was assessed by 5-ethynyl-2'-deoxyuridine test and Cell Counting Kit-8. Migration and invasion were determined by the wound test and a transwell assay. Apoptosis was tested by flow cytometry. The mRNA expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines in RA-FLSs were measured by quantitative PCR and ELISA. To gain insight into the molecular signaling mechanisms, we determined the effect of iguratimod on the activation of mitogen-activated protein kinases (MAPK) signaling pathways by the cellular thermal shift assay (CETSA) and western blot. RESULTS: Iguratimod treatment significantly reduced the proliferation, migration, and invasive capacities of RA-FLSs in a dose-dependent manner in vitro. MMP-1, MMP-3, MMP-9, Interleukin-6 (IL-6), and monocyte chemoattractant protein-1 mRNA and protein levels were all decreased after treatment with iguratimod. Furthermore, tumor necrosis factor-alpha- (TNF-α-) induced expression of phosphorylated c-Jun N-terminal kinases (JNK) and P38 MAPK were inhibited by iguratimod. Additionally, iguratimod promoted the apoptosis of RA-FLSs. Most importantly, iguratimod was shown to directly interact with JNK and P38 protein by CETSA assay. Moreover, activating transcription factor 2 (ATF-2), a substrate of both JNK and P38, was suppressed by iguratimod. CONCLUSIONS: Our findings suggested that the therapeutic effects of iguratimod on RA might be, in part, due to targeting the aggressive behavior and apoptosis of RA-FLSs.

A potential novel therapy for FGFR1-amplified pancreatic cancer with bone metastasis, screened by next-generation sequencing and a patient-derived xenograft model.

Effective therapies are limited for pancreatic cancer, particularly for those with distant tumour metastases. Therefore, more individualised drug screening is urgently required. Next-generation sequencing (NGS) is a powerful tool to investigate the genomic landscape of patients and the mechanism of drug response, which may provide a broader vision for potential clinical drug screening. Patient-derived xenograft (PDX) models may have a significant advantage in predicting clinical treatment response. In our previous study, a PDX of pancreatic cancer bone metastasis was established, and NGS was conducted to investigate the molecular information. In the present study, these data were further analysed and fibroblast growth factor receptor 1 (FGFR1) amplification was identified in a panel of 416 cancer-associated genes. Thus, AZD4547, an inhibitor against FGFR, was selected as a potential therapy, and was evaluated using the PDX model. AZD4547 was shown to exhibit antitumor activity by reducing the expression of FGFR1 and its targets. The present study also demonstrated the high potential of the novel NGS/PDX-based drug screening platform to improve individualised cancer treatment.

Individualized drug screening based on next generation sequencing and patient derived xenograft model for pancreatic cancer with bone metastasis.

The efficacy of traditional chemoradiotherapies for pancreatic cancer remains limited, and no effective targeted therapies or screening tests are currently available. Therefore more individualized drug screening is warranted for the clinical treatment of pancreatic cancer. A patient­derived xenograft (PDX) model of pancreatic cancer bone metastasis was established, and next­generation sequencing (NGS) was used to investigate the molecular characteristics of the cancer and screen for potential drugs. Immunohistochemical analysis was performed to validate that the PDX retained the molecular characteristics from the patient. Using NGS technology, 13 pancreatic­cancer­associated polymorphisms/mutations were identified out of 416 genes sequenced. Based on the sequencing results and associated literatures, AZD6244, a highly selective inhibitor against mitogen­activated protein kinase kinase 1 (MEK1), was chosen as a potential therapy. AZD6244, a highly selective MEK1 inhibitor, was evaluated as effective for the pancreatic cancer PDX model, and thus may provide potential efficacy in the clinical treatment of the patient with pancreatic cancer investigated in the present study. The feasibility of the novel NGS­PDX based drug­screening pattern was demonstrated, and has a potential to improve individua-lized treatment for cancer.

Systematic comparison of biologically active foreign ions-codoped calcium phosphate microparticles on osteogenic differentiation in rat osteoporotic and normal mesenchymal stem cells.

Osteoporosis is a disease characterized by structural deterioration of bone tissue, leading to skeletal fragility with increased fracture risk. Calcium phosphates (CaPs) are widely used in bone tissue engineering strategies as they have similarities to bone apatite except for the absence of trace elements (TEs) in the CaPs. Bioactive glasses (BGs) have also been used successfully in clinic for craniomaxillofacial and dental applications during the last two decades due to their excellent potential for bonding with bone and inducing osteoblastic differentiation. In this study, we evaluated the osteogenic effects of the ionic dissolution products of the quaternary Si-Sr-Zn-Mg-codoped CaP (TEs-CaP) or 45S5 Bioglass® (45S5 BG), both as mixtures and separately, on rat bone marrow-derived mesenchymal stem cells (rOMSCs & rMSCs) from osteoporotic and normal animals, using an MTT test and Alizarin Red S staining. The materials enhanced cell proliferation and osteogenic differentiation, especially the combination of the BG and TEs-CaP. Analysis by quantitative PCR and ELISA indicated that the expression of osteogenic-specific genes and proteins were elevated. These investigations suggest that the TEs-CaP and 45S5 BG operate synergistically to create an extracellular environment that promotes proliferation and terminal osteogenic differentiation of both osteoporotic and normal rMSCs.

Adipose-Derived Stem Cells Suppress Inflammation Induced by IL-1ß through Down-Regulation of P2X7R Mediated by miR-373 in Chondrocytes of Osteoarthritis.

Adipose-derived stem cells (ADSCs) were previously considered to have an anti-inflammatory effect, and Interleukin-1ß (IL-1ß) was found to be a pro-inflammatory factor in chondrocytes, but the mechanism underlying ADSCs and IL-1ß is unclear. In this study, we investigate whether P2X7 receptor (P2X7R) signalling, regulated by microRNA 373 (miR-373), was involved in the ADSCs and IL-1ß mediated inflammation in osteoarthritis (OA). Chondrocytes were collected from 20 OA patients and 20 control participants, and ADSCs were collected from patients who had undergone abdominal surgery. The typical surface molecules of ASDCs were detected by flow cytometry. The level of nitric oxide (NO) was determined by Griess reagent. Concentrations of prostaglandin E2 (PGE2), interleukin 6 (IL-6), matrix metallopeptidase 3 (MMP-3) were detected by enzyme-linked immunosorbent assay (ELISA). The expressions of IL-6, MMP-3, miR-373 and P2X7R were determined by real-time polymerase chain reaction (PCR), and Western blot was used to detect the protein expression of P2X7R. The typical potential characters of ADSCs were verified. In chondrocytes or OA tissues, the miR-373 expression level was decreased, but the P2X7R expression was increased. IL-1ß stimulation increased the level of inflammatory factors in OA chondrocytes, and ADSCs co-cultured with IL-1ß-stimulated chondrocytes decreased the inflammation. OA chondrocytes transfected with the miR-373 inhibitor increased the inflammation level. The miR-373 mimic suppressed the inflammation by targeting P2X7R and regulated its expression, while its effect was reversed by overexpression of P2X7R. IL-1ß induced inflammation in OA chondrocytes, while ADSCs seemed to inhibit the expression of P2X7R that was regulated by miR-373 and involved in the anti-inflammatory process in OA.

Genetic heterogeneity in hepatocellular carcinoma and paired bone metastasis revealed by next-generation sequencing.

Although bone involvement is reported as uncommon in hepatocellular carcinoma (HCC), its incidence has significantly increased in the last decade due to the longer survival of HCC patients related to recent progresses made both in the diagnosis and treatment of the disease. A better understanding of the pathogenic mechanisms underlying the spread of bone metastases in HCC is important. The primary tumor and its corresponding metastases are different at the molecular marker expression or gene status levels and that these differences may affect the clinical outcome of anticancer therapy, particularly in molecularly targeted therapies for the treatment of cancer. No study has investigated the genetic heterogeneity between HCC and paired bone metastasis. In this study, we investigated the genetic heterogeneity in HCC and paired metastasis using a next generation sequencing (NGS) platform to illustrate the molecularly targeted therapy related genes mutations.

Fungal spondylodiscitis in a patient recovered from H7N9 virus infection: a case study and a literature review of the differences between Candida and Aspergillus spondylodiscitis.

To report a rare case of fungal spondylodiscitis in a patient recovered from H7N9 virus infection and perform a literature review of the different characteristics of Candida and Aspergillus spondylodiscitis, we reviewed cases of spondylodiscitis caused by Candida and Aspergillus species. Data, including patients' information, pathogenic species, treatment strategy, outcomes, and relapses, were collected and summarized. The characteristics of Candida and Aspergillus spondylodiscitis were compared to see if any differences in clinical features, management, or consequences could be detected. The subject of the case study was first misdiagnosed as having a vertebral tumor, and then, following open biopsy, was diagnosed as having fungal spondylodiscitis. The patient made a good recovery following radical debridement. Seventy-seven additional cases of Candida spondylodiscitis and 94 cases of Aspergillus spondylodiscitis were identified in the literature. Patients with Candida spondylodiscitis tended to have a better outcome than patients with Aspergillus spondylodiscitis (cure rate 92.3% vs. 70.2%). Candida was found more frequently (47.8%) than Aspergillus (26.7%) in blood cultures, while neurological deficits were observed more often in patients with Aspergillus spondylodiscitis (43.6% vs. 25.6%). Candida spinal infections were more often treated by radical debridement (60.5% vs. 39.6%). Patients with Candida spondylodiscitis have better outcomes, which may be associated with prompt recognition, radical surgical debridement, and azoles therapy. A good outcome can be expected in fungal spondylodiscitis with appropriate operations and anti-fungal drugs.

The Use of Lumbar Spine Magnetic Resonance Imaging in Eastern China: Appropriateness and Related Factors.

Back pain is common and costly. While a general scene of back pain related practice in China remains unknown, there are signs of excessive use of lumbar spine magnetic resonance (MR). We retrospectively studied 3107 lumbar spine MRIs in Eastern China to investigate the appropriateness of lumbar spine MR use. Simple back pain is the most common chief complaint for ordering a lumbar MR study. Only 41.3% of lumbar spine MR studies identified some findings that may have potential clinical significance. Normal lumbar spine is the most common diagnosis (32.7%), followed by lumbar disc bulging and lumbar disc herniation. Walk difficulties, back injury and referred leg pain as chief complaints were associated with greater chance of detecting potentially clinically positive lumbar MR image findings, as compare with simple back pain. There was no difference in positive rates among orthopedic surgeon and specialists of other disciplines. Lumbar spine MR imaging was generally overused in Eastern China by various specialists, particularly at health assessment centers. For appropriate use of lumbar spine MR, orthopedic surgeons are no better than physicians of other disciplines. Professional training and clinical guidelines are needed to facilitate evidence-based back pain practice in China.

Perineural invasion: a potential reason of hepatocellular carcinoma bone metastasis.

The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. Perineural invasion (PNI) is the only interaction between cancer cells and nerves studied to date. It is a symbiotic relationship between cancer cells and nerves that result in growth advantage for both. The potential association between HCC bone metastases and PNI is unknown. In this study, we investigate the nerve density in HCC and paired bone metastases to reveal the potential association of HCC bone metastases and PNI. The nerve density was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) hepatocellular carcinoma (HCC) and paired bone metastases tissues from 13 HCC patients with synchronous or metachronous bone metastases that underwent surgical resection. FFPE specimens of HCC bone metastases tissues express higher perineural density than HCC tissues, pointing to a potential role of the PNI in bone metastases from HCC. This is the first description of the potential association of PNI and HCC bone metastases.

FRZB up-regulated in hepatocellular carcinoma bone metastasis.

The clinical relevance of frizzled-related protein (FRZB) in hepatocellular carcinoma (HCC) bone metastasis remains uncertain. The aim of this study was to assess the clinical relationship of FRZB in patients with HCC bone metastasis after surgical resection. FRZB expression was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) HCC and paired bone metastasis tissues from 13 patients that underwent surgical resection. The clinical characteristics of 13 HCC patients with synchronous or metachronous bone metastasis received surgery were retrospectively reviewed. We found that FRZB was positive in 9 HCC tissues (69.2%) and in 11 paired bone metastatic tissues (84.6%) among these 13 paired samples. The expression of FRZB in the bone metastases was noticeably higher than that in the paired HCC tissues. The expression of FRZB was up-regulated in 10 (76.9%) paired bone metastases tissues. FRZB expression was up-regulated in HCC bone metastasis tissue, which suggested that FRZB might play a key role in the HCC bone metastasis.

Minimally invasive midvastus versus standard parapatellar approach in total knee arthroplasty: a meta-analysis of randomized controlled trials.

OBJECTIVE: Minimally invasive midvastus approach (mini-midvastus) has been widely used in total knee arthroplasty (TKA). However, the clinical effects still remains controversial. This meta-analysis was based on randomized controlled trials (RCTs) aiming to quantitatively analyze the clinical efficacy of mini-midvastus versus standard parapatellar approach in TKA. METHODS: This meta-analysis was performed according to the PRISMA guidelines. A literature search for the eligible RCTs was carried out in the databases of PubMed, the Cochrane library, EMBASE and Web of Science. Two independent reviewers independently completed the study selection, data extraction, and the assessment of methodological quality. Meta-analysis was conducted by the RevMan 5.2 software. RESULTS: A total of 18 RCTs (937 patients with 1093 TKAs) published from 2007 to 2013 were included. The meta-analysis suggested that the mini-midvastus approach significantly improved knee range of motion (ROM) and decreased visual analog score (VAS) at postoperative 1-2 weeks (p<0.05), and there were no statistical differences in terms of knee society score (KSS) (6 weeks to 1 year), VAS (6 weeks to 6 months), ROM (6 weeks to 6 months), lateral retinacular release, blood loss, straight leg raise, hospital stay and postoperative complications between the mini-midvastus and standard parapatellar approach (p>0.05). However, the operative time was significantly longer when performing the mini-midvastus group than the parapartellar approach (p<0.05). CONCLUSION: This meta-analysis found that compared with the standard parapatellar approach, the mini-midvastus approach had early advantages in the VAS and ROM, but had the disadvantage in the operative time. LEVEL OF EVIDENCE: Therapeutic study Level I.

Polymeric immunoglobulin receptor expression is correlated with poor prognosis in patients with osteosarcoma.

The prognosis of patients with osteosarcoma with distant metastasis and local recurrence remains poor. Increased expression of polymeric immunoglobulin receptor (pIgR) in tumor tissue has been detected in various types of cancer. However, the clinical significance of pIgR in osteosarcoma has yet to be elucidated. The present study aimed to investigate the prognostic value of pIgR in patients with osteosarcoma following surgical resection. pIgR expression was assessed using quantitative polymerase chain reaction analysis in cryopreserved osteosarcoma tissues from 22 patients, as well as using immunohistochemistry in paraffin-embedded osteosarcoma tissues from 136 patients. The association between pIgR expression, clinicopathological factors and long-term prognosis was retrospectively examined in these 136 patients. The prognostic significance of negative or positive pIgR expression in osteosarcoma was assessed using Kaplan-Meier survival analysis and log-rank tests. Univariate analysis indicated that patients with positive pIgR osteosarcoma tissue expression had a significantly worse overall survival (OS) compared with patients with negative pIgR osteosarcoma expression. Multivariate analysis revealed that positive pIgR expression in osteosarcoma tissues was an independent prognostic factor for OS following surgical resection (P<0.001). Furthermore, positive pIgR expression was significantly associated with poor prognosis in patients with osteosarcoma. These findings indicate that pIgR may be a novel predictor for poor prognosis in patients with osteosarcoma following surgical resection.