Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive malignancy with a five year survival rate of <5%. The aberrant expression of extracellular matrix (ECM) in the tumor stroma forms a compact physical barrier, which that leads to insufficient extravasation and penetration of nanosized therapies. To overcome the severe resistance of PDAC to conventional therapies, a sequentially triggered nanoparticle (aptamer/cell-penetrating peptide-camptothecin prodrug, i.e., Apt/CPP-CPTD NPs) with tumor penetration and intelligent drug release profile is designed. An ECM component (tenescin-C) targeting aptamer (GBI-10) is modified onto stroma-permeable cell-penetrating peptide (CPP) for the in vivo CPP camouflage and PDAC-homing. In PDAC stroma, tenascin-C can detach GBI-10 from CPP and exposed CPP can facilitate further PDAC penetration and tumor cell endocytosis. After being endocytosed into PDAC cells, intracellular high redox potential can further trigger controlled chemodrug release. Apt/CPP-CPTD NPs show both deep penetration in vitro 3D PDAC spheroids and in vivo tumor sections. The relatively mild in vitro cytotoxicity and excellent in vivo antitumor efficacy proves the improved PDAC targeting drug delivery and decreased systemic toxicity. The design of ECM-redox sequentially triggered stroma permeable NPs may provide a practical approach for deep penetration of PDAC and enhanced drug delivery efficacy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/advs.201701070

Sequentially Triggered Nanoparticles with Tumor Penetration and Intelligent Drug Release for Pancreatic Cancer Therapy

Re-collapse of cemented vertebrae occasionally occurs after percutaneous augmentation. However, the potential risks still remain unclear. Several articles have reported some possible risk factors which were not consistent or comprehensive. This study aimed to make a retrospective review on patients with osteoporotic vertebral compression fracture (OVCF) after percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) and to further analyse the risk factors for treated vertebral refracture. All patients receiving the PKP/PVP with bilateral approach were retrospectively reviewed from January 2014 to January 2016, among whom 230 patients with single level augmentation (30 in refracture group and 200 in the non-refracture group) were enrolled according to inclusion criteria. The following covariates were reviewed: gender, age, height, weight, body mass index (BMI), bone mineral density (BMD), serum bone turnover markers, surgical parameters including approach, cement volume, anterior height, and Cobb angle restoration. Binary logistic regression analysis was used to determine the relative risk of re-collapse of cemented vertebrae. Regarding the patient data, weight, BMI, and BMD were of statistical significance in refracture group (P < 0.01), among which only low BMD was a risk factor to cemented vertebral re-collapse (P = 0.022, OR = 4.197). In respect of surgical variables, the better restoration of anterior height and Cobb angle was found in refracture group (P < 0.05), both of which might increase the refracture risk but not be risk factors (P = 0.065, OR = 0.891, and P = 0.937, OR = 0.996, respectively). Besides, less injected cement (3.30 ± 0.84 ml vs 4.46 ± 1.10 ml, P = 0.000, OR = 19.433) and PKP (P = 0.007, OR = 13.332) significantly boosted the potential risk of refracture (P < 0.001). Patients with low BMD, or undergoing PKP, or receiving a low volume of injected cement might have a high risk of re-collapse in surgical vertebrae.

Risk factor analysis for re-collapse of cemented vertebrae after percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP)

The incidence of osteosarcoma (OS) is increasing year by year, and the prognosis of patients with advanced OS is extremely poor due to the tendency of recurrence and chemotherapy resistance after surgery. Ferroptosis is a novel form of programmed cell death (PCD) that kills cells through iron-dependent lipid peroxidation. Current studies have shown that ferroptosis is closely related to OS and could reduce chemotherapy resistance to a certain extent, which has great therapeutic potential. In this paper, we review the regulatory mechanism of ferroptosis and its research progress in OS, hoping to provide new help for the clinical treatment of OS.

https://www.frontiersin.org/articles/10.3389/fonc.2022.1031779/pdf

Ferroptosis in osteosarcoma: A promising future

BACKGROUND Intervertebral disc (IVD) degeneration is a common cause of lower back pain, which carries substantial morbidity and economic cost. Omega-3 fatty acids (n-3 FA) are known to reduce inflammatory processes with a relatively benign side effect profile. This study aimed to investigate the effect of n-3 FA supplementation on IVD degeneration. MATERIAL AND METHODS Two non-contiguous lumbar discs of 12 Sprague Dawley rats were needle-punctured to induce disc degeneration. Post-surgery, rats were randomly assigned to either a daily n-3 FA diet (530 mg/kg/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in a 2: 1 ratio, administered in sucrose solution) or control diet (sucrose solution only), which was given for the duration of the study. After 1 month, blood serum arachidonic acid/eicosapentaenoic acid (AA/EPA) ratios were analyzed. After 2 months, micro-MRI (magnetic resonance imaging) analysis and histological staining of disc explants were performed to analyze the IVD. RESULTS A reduction of blood AA/EPA ratios from 40 to 20 was demonstrated after 1 month of daily supplementation with n-3 FA. Micro-MRI analysis showed an injury-induced reduction of IVD hydration, which was attenuated in rats receiving n-3 FA. Histological evaluation demonstrated the destruction of nucleus pulposus tissue in response to needle puncture injury, which was less severe in the n-3 FA diet group. CONCLUSIONS The results of this study suggest that n-3 FA dietary supplementation reduces systemic inflammation by lowering AA/EPA ratios in blood serum and has potential protective effects on the progression of spinal disc degeneration, as demonstrated by reduced needle injury-induced dehydration of intervertebral discs and reduced histological signs of IVD degeneration.

/pdf/omega-3-fatty-acid-supplementation-reduces-intervertebral-4rcdwv0jpn.pdf

Omega-3 Fatty Acid Supplementation Reduces Intervertebral Disc Degeneration

Aim:This review summarized the recent intervertebral disc degeneration (IDD) models and described their advantages and potential disadvantages, aiming to provide an overview for the current condition of IDD model establishment and new ideas for new strategies development of the treatment and prevention of IDD.Methods:The database of PubMed was searched up to May 2021 with the following search terms: nucleus pulposus, annulus fibrosus, cartilage endplate, intervertebral disc(IVD), intervertebral disc degeneration, animal model, organ culture, bioreactor, inflammatory reaction, mechanical stress, pathophysiology, epidemiology. Any IDD model-related articles were collected and summarized.Results:The best IDD model should have the features of repeatability, measurability and controllability. There are a lot of aspects to be considered in the selection of animals. Mice, rats and rabbits are low-cost and easy to access. However, their IVD size and shape are more different from human anatomy than pigs, cattle, sheep and goats. Organ culture models and animal models are two options in model establishment for IDD. The IVD organ culture model can put the studying variables into the controllable system for transitional research. Unlike the animal model, the organ culture model can only be used to evaluate the short-term effects and it is not applicable in simulating the complex process of IDD. Similarly, the animal models induced by different methods also have their advantages and disadvantages. For studying the mechanism of IDD and the corresponding treatment and prevention strategies, the selection of model should be individualized based on the purpose of each study.Conclusions:Various models have different characteristics and scope of application due to their different rationales and methods of construction. Currently, there is no experimental model that can perfectly mimic the degenerative process of human IVD. Personalized selection of appropriate model based on study purpose and experimental designing can enhance the possibility to obtain reliable and real results.

Intervertebral Disc Degeneration Models for Pathophysiology and Regenerative Therapy -Benefits and Limitations.

To evaluate the risk factors correlated with loss of cemented vertebral body height after kyphoplasty in patients with osteoporotic vertebral compression fractures. Thirty-four consecutive patients with single-level osteoporotic vertebral compression fractures who underwent kyphoplasty in the Affiliated Hospital of Jiangsu University between January 2012 and August 2014 were retrospectively analysed. Eight independent variables (age, gender, body mass index, pre-operative T-score in bone mineral density, the volume of polymethylmethacrylate injected, pre-operatively vertebral body height, the restoration of body height and the distance between polymethylmethacrylate and endplate) were assessed. The recompression of body height was the dependent variable. Multivariate linear regression analyses were used to determine the factors associated with recompression of body height. Multiple linear regression analyses indicated that the recompression of cemented vertebral body height was correlated with the distance between polymethylmethacrylate and endplate (P = 0.008, b’ = 0.489). The final multiple linear regression model, which included only the distance between polymethylmethacrylate and endplate, resulted in a formula that accounted for 41.02 % of the recompression of body height. The distance between polymethylmethacrylate and endplate is an important risk factor of recompression of cemented vertebrae after kyphoplasty for patients with osteoporotic vertebral compression fractures.

Risk factors of recompression of cemented vertebrae after kyphoplasty for osteoporotic vertebral compression fractures.

To establish a minimally invasive rat model of lumbar intervertebral disc degeneration (IDD) to better understand the pathophysiology of the human condition. The annulus fibrosus of lumbar level 4-5 (L4-5) and L5-6 discs were punctured by 27-gauge needles using the posterior approach under C-arm fluoroscopic guidance. Magnetic resonance imaging (MRI), histological examination by hematoxylin and eosin (H&E) staining, and reverse transcription polymerase chain reaction (RT-PCR) were performed at baseline and 2, 4, and 8 weeks after disc puncture surgery to determine the degree of degeneration. All sixty discs (thirty rats) were punctured successfully. Only two of thirty rats subjected to the procedure exhibited immediate neurological symptoms. The MRI results indicated a gradual increase in Pfirrmann grade from 4 to 8 weeks post-surgery (P<0.05), and H&E staining demonstrated a parallel increase in histological grade (P<0.05). Expression levels of aggrecan, type II collagen (Col2), and Sox9 mRNAs, which encode disc components, decreased gradually post-surgery. In contrast, mRNA expression of type I collagen (Col1), an indicator of fibrosis, increased (P<0.05). The procedure of annular puncture using a 27-gauge needle under C-arm fluoroscopic guidance had a high success rate. Histological, MRI, and RT-PCR results revealed that the rat model of disc degeneration is a progressive pathological process that is similar to human IDD.

Lumbar intervertebral disc puncture under C-arm fluoroscopy: a new rat model of lumbar intervertebral disc degeneration.

Research on the implications of ferroptosis in tumors has increased rapidly in the last decades. There are evidences that ferroptosis is involved in several aspects of cancer biology, including tumor progression, metastasis, immunomodulation, and therapeutic response. Nonetheless, the interaction between ferroptosis-related lncRNAs (FRLs) and the osteosarcoma immune microenvironment is poorly understood. In this study, a risk model composed of FRLs was developed using univariate and LASSO Cox regression analyses. On the basis of this model, FRL scores were calculated to systematically explore the role of the model in predicting the prognosis and immune characteristics of osteosarcoma patients. Survival analysis showed that osteosarcoma samples with lower FRL-score had better overall survival. After predicting the abundance of immune cells in osteosarcoma microenvironment by single-sample gene-set enrichment analysis (ssGSEA) and ESTIMATE analysis, we found that the FRL-score could distinguish immune function, immune score, stromal score, tumor purity, and tumor infiltration of immune cells in different osteosarcoma patients. In addition, FRL-score was also associated with immune checkpoint gene expression and half-maximal inhibitory concentration of chemotherapeutic agents. Finally, we confirmed that knockdown of RPARP-AS1 suppressed the malignant activity of osteosarcoma cells in vitro experiments. In general, the FRL-based prognostic signature could promote our understanding of the immune microenvironment characteristics of osteosarcoma and guide more effective treatment regimens.

/pdf/comprehensive-analysis-of-a-ferroptosis-related-lncrna-2tnggzoc.pdf

Comprehensive Analysis of a Ferroptosis-Related lncRNA Signature for Predicting Prognosis and Immune Landscape in Osteosarcoma

Cyclin D2 (CCND2) is abnormally overexpressed in many tumor types and has been associated with tumor cell proliferation. Although the important role of miR-1297 is well established, the molecular mechanism between CCND2 and miR-1297 in osteosarcoma (OS) has not been determined. In the present study, we found CCND2 was highly expressed in OS cells, and its downregulation suppressed cell proliferation, resulting in G1 phase cell cycle arrest. In contrast, miR-1297 was lowly expressed in OS compared to normal tissue. Several data platforms predicted that CCND2 was a target of miR-1297, which was validated by a dual-luciferase reporter assay that revealed miR-1297 could bind with CCND2-3'UTR. miR-1297 overexpression greatly inhibited CCND2 protein expression and exerted the same phenotypic effect as CCND2 downregulation in OS cells. Furthermore, miR-1297 inhibition could also be rescued by CCND2. Nude mice injected cells stable overexpressing miR-1297 OS cells showed lower size and tumor weight. Moreover, lower fluorescence activity recorded by in vivo imaging system and bone erosion revealed by microCT in the miR-1297 group demonstrated miR-1297 inhibited OS tumor growth via CCND2. Our findings demonstrated that miR-1297 can inhibit proliferation and tumor growth in OS by directly targeting CCND2, which indicates that miR-1297 may represent a novel therapeutic target for OS.

miR-1297 inhibits osteosarcoma cell proliferation and growth by targeting CCND2.

Phyllanthus emblica (PE), a traditional multiethnic herbal medicine, is commonly applied to treat liver diseases. Our previous study demonstrated that aqueous extract of PE (AEPE) could alleviate carbon tetrachloride (CCl4)-induced liver fibrosis in vivo, but the underlying molecular mechanisms are still unclear. The present study was undertaken to clarify the multitarget mechanisms of PE in treating liver fibrosis by proteomics clues. A CCl4-induced liver fibrosis rat model was established. The anti-liver fibrosis effects of chemical fractions from AEPE were evaluated by serum biochemical indicators and pathological staining. Additionally, tandem mass tag (TMT) - based quantitative proteomics technology was used to detect the hepatic differentially expressed proteins (DEPs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, gene ontology (GO) enrichment and protein-protein interaction (PPI) network were used to perform bioinformatics analysis of DEPs. Western blot analysis was used to verify the key potential targets regulated by the effective fraction of AEPE. The low-molecular-weight fraction of AEPE (LWPE) was determined to be the optimal anti-liver fibrosis active fraction, that could significantly improve ALT, AST, HA, Col IV, PCIII, LN, Hyp levels and reduce the pathological fibrotic lesion of liver tissue in model rats. A total of 195 DEPs were screened after LWPE intervention. GO analysis showed that the DEPs were related mostly to extracellular matrix organization, actin binding, and extracellular exosomes. KEGG pathway analysis showed that DEPs are mainly related to ECM-receptor interactions, focal adhesion and PI3K-Akt signaling pathway. Combined with the GO, KEGG and Western blot results, COL1A2, ITGAV, TLR2, ACE, and PDGFRB may be potential targets for PE treatment of liver fibrosis. In conclusion, LWPE exerts therapeutic effects through multiple pathways and multiple targets regulation in the treatment of liver fibrosis. This study may provide proteomics clues for the continuation of research on liver fibrosis treatment with PE.

/pdf/tandem-mass-tag-based-proteomics-analysis-reveals-the-25lsdqtj.pdf

Tandem mass tag-based proteomics analysis reveals the multitarget mechanisms of Phyllanthus emblica against liver fibrosis

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