Differentiation and prognostic stratification of acute myeloid leukemia by serum-based spectroscopy coupling with metabolic fingerprints.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by complex molecular and cytogenetic abnormalities. New approaches to predict the prognosis of AML have increasingly attracted attention. There were 98 non-M3 AML cases and 48 healthy controls were enrolled in the current work. Clinically routine assays for cytogenetic and molecular genetic analyses were performed on the bone marrow samples of patients with AML. Meanwhile, metabolic profiling of these AML subjects was also performed on the serum samples by combining Ag nanoparticle-based surface-enhanced Raman spectroscopy (SERS) with proton nuclear magnetic resonance (NMR) spectroscopy. Although most of the routine biochemical test showed no significant differences between the M0-M2 and M5 groups, the metabolic profiles were significantly different either between AML subtypes or between prognostic risk subgroups. Specific SERS bands were screened to serve as potential markers for AML subtypes. The results demonstrated that the classification models for M0-M2 and M5 shared two bands (i.e., 1328 and 741 cm-1 ), all came from nucleic acid signals. Furthermore, Metabolic profiles provided various differential metabolites responsible for different AML subtypes, and we found altered pathways mainly included energy metabolism like glycolysis, pyruvate metabolism, and metabolisms of nucleic acid bases as well as specific amino acid metabolisms. It is concluded that integration of SERS and NMR provides the rational and could be reliable to reveal AML differentiation, and meanwhile lay the basis for experimental and clinical practice to monitor disease progression and prognostic evaluation.

Superior capsular reconstruction using the long head of the biceps to treat massive rotator cuff tears improves patients shoulder pain, mobility and function.

PURPOSE: Arthroscopic superior capsule reconstruction (SCR) with the long head of the biceps (LHBT) was performed to restore structural stability, force couple balance, and shoulder joint function. This study aimed to evaluate the functional outcomes of SCR using the LHBT over at least 24 months of follow-up. METHOD: This retrospective study included 89 patients with massive rotator cuff tears who underwent SCR using the LHBT, met the inclusion criteria and underwent follow up for at least 24 months. The preoperative and postoperative shoulder range of motion (forward flexion, external rotation, and abduction), acromiohumeral interval (AHI), visual analog scale (VAS) score, American Shoulder and Elbow Surgeons (ASES) score and Constant-Murley score were obtained, and the tear size, and Goutallier and Hamada grades were also investigated. RESULTS: Compared with those measured preoperatively, the range of motion, AHI, and VAS, Constant-Murley, and ASES scores were significantly improved immediately postoperatively (P < 0.001) and at the 6-month, 12-month, and final follow-ups (P < 0.001). At the last follow-up, the postoperative ASES score and Constant-Murley score increased from 42.8 ± 7.6 to 87.4 ± 6.1, and 42.3 ± 8.9 to 84.9 ± 10.7, respectively; with improvements of 51 ± 21.7 in forward flexion, 21.0 ± 8.1 in external rotation, and 58.5 ± 22.5 in abduction. The AHI increased 2.1 ± 0.8 mm and the VAS score significantly changed from 6.0 (5.0, 7.0) to 1.0 (0.0, 1.0), at the final follow-up. Eleven of the 89 patients experienced retears, and one patient needed reoperation. CONCLUSION: In this study with at least 24-months of follow-up, SCR using the LHBT for massive rotator cuff tears could effectively relieve shoulder pain, restore shoulder function and increase shoulder mobility to some extent. LEVEL OF EVIDENCE: IV.

Treatment of comminuted metaphyseal distal femoral fractures with a micromotion-balancing osteosynthesis: an animal study.

BACKGROUND: Locking plates are commonly used in the treatment of comminuted metaphyseal distal femoral fractures. However, locking plates form a strong structure and promote asymmetrical callus formation, which is not conducive for rapid fracture healing and may increase fracture risk. To overcome this, we designed a micromotion-balancing fixation system based on locking plates. METHODS: Six healthy pigs (Bama miniature pigs) were used to establish a model of bilateral comminuted distal femoral fracture (AO/ASIF: 33-C2). Standard drilling was performed on one of each pig's hind limbs (control group), whereas eccentric drilling was performed on the other hind limb (experimental group). Both femurs were fixed with a 3-hole locking compression plate using 5-mm-diameter screws. At 12 postoperative weeks, all pigs were euthanized and the femurs with compression plates were radiographically examined. The level of fracture healing and loosening/internal fixation failure were recorded. Bone mineral density, number of trabeculae, trabecular morphology, and calcification precipitations were assessed. RESULTS: All pigs survived, and the fractures healed. No complications related to fracture healing, such as infection and internal fixation failure, were noted. The bone mineral density of the near and far cortical calli, number of the near and far cortical callus trabeculae, and difference in bone mineral density between the near and far cortical calli in the experimental group were significantly higher than those in the control group (p < 0.01). However, the difference in the number of trabeculae between the near and far cortical calli was significantly lower in the experimental group than in the control group (p < 0.01). CONCLUSION: This newly designed system provides stable fixation for comminuted distal femoral fracture, increases the overall strain at the fracture site, and balances the strains at the near and far cortices to achieve uniform callus growth and fracture healing.

LINC00960 affects osteosarcoma treatment and prognosis by regulating the tumor immune microenvironment.

Background: Osteosarcoma (OS), the commonest primary malignant bone tumor, is mainly seen in children and teenagers. LINC00960, a newly discovered long intergenic non-protein coding RNA, has been shown to be important in certain cancers. The objective of this study was to assess LINC00960's prognostic and therapeutic value and analyze its mechanism of action in osteosarcoma. Methods: With the transcriptome information of 85 osteosarcomas from the TARGET database, the Cox regression analyses, K-M curve, and ROC curve, were conducted for survival and prognostic analysis. The functional analysis was conducted using GO, KEGG, GSEA, and GSVA. The ESTIMATE, ssGSEA, MCP-counter, ImmuCellAI algorithms, and immune checkpoint correlation analysis were performed for immune-related analysis. The single-cell RNA sequencing data of 6 osteosarcoma patients was obtained from the Gene Expression Omnibus database. The Tumor Immune Dysfunction and Exclusion algorithm and the "pRRophetic" R package were performed to predict the response to immunotherapy and chemotherapy. Results: LINC00960 overexpression is associated with osteosarcoma metastasis and poor prognosis. Based on the LINC00960 expression, the nomogram prediction model was created, which showed good accuracy and precision to predict the overall survival of osteosarcoma. Single-cell and immune-related analysis showed that LINC00960 is mainly highly expressed in the tumor-exhausted CD8 T cells in osteosarcoma. In osteosarcoma, the expression of LIC00960 was favorably connected with immune checkpoint-related genes and negatively correlated with immune infiltration. TIDE analysis indicated that low LINC00960 expression patients might have a better response to immunotherapy. Drug sensitivity analysis showed that high LINC00960 expression patients might have better responses to Bleomycin and Doxorubicin. Conclusion: LINC00960 has the potential to be a novel biomarker for predicting overall survival in osteosarcoma patients and to guide more individualized treatment and clinical decision-making.

Depression heightened the association of the systemic immune-inflammation index with all-cause mortality among osteoarthritis patient.

BACKGROUND: Systemic immune-inflammatory index (SII) has been recognized as a novel inflammatory indicator in numerous diseases. It remains unknown how SII affects all-cause mortality among patients with osteoarthritis (OA). In this prospective cohort study, we intended to examine the relationship of SII with all-cause mortality among OA populations and assess the interaction between depression and SII. METHODS: Data was collected from National Health and Nutrition Examination Survey (NHANES) in 2005-2018. The National Death Index (NDI) provided vital status records. Multivariable Cox regression analyses with cubic spines were applied to estimate the association between SII and all-cause and CVD mortality. Stratified analysis and interaction tests assessed the interaction of SII and depression on all-cause mortality. RESULTS: In total 3174 OA adults were included. The lowest quartile Q1 (HR:1.44, 95%CI:1.02-2.04) and highest quartile Q4 (HR:1.44, 95%CI:1.02-2.04) of SII presented a higher risk of death compared with those in second quartile Q2 (Ref.) and third quartile Q3 (HR:1.23, 95%CI:0.89-1.68. Restricted cubic splines analysis revealed a U-shaped association of SII with all-cause mortality, the inflection points were 412.93 × 109/L. The interaction test observed a more significant relationship of SII with all-cause mortality in depression patients than in non-depression patients, indicating that depression can modify this association. LIMITATIONS: First, the observational study design failed to make causal inferences. Second, the baseline SII cannot reflect the long-term level of inflammation. Finally, there may be potential bias. CONCLUSION: SII was U-shaped associated with all-cause mortality in OA patients, and this association was significantly heightened by depression.

Identification of 3 key genes as novel diagnostic and therapeutic targets for OA and COVID-19.

Background: Corona Virus Disease 2019 (COVID-19) and Osteoarthritis (OA) are diseases that seriously affect the physical and mental health and life quality of patients, particularly elderly patients. However, the association between COVID-19 and osteoarthritis at the genetic level has not been investigated. This study is intended to analyze the pathogenesis shared by OA and COVID-19 and to identify drugs that could be used to treat SARS-CoV-2-infected OA patients. Methods: The four datasets of OA and COVID-19 (GSE114007, GSE55235, GSE147507, and GSE17111) used for the analysis in this paper were obtained from the GEO database. Common genes of OA and COVID-19 were identified through Weighted Gene Co-Expression Network Analysis (WGCNA) and differential gene expression analysis. The least absolute shrinkage and selection operator (LASSO) algorithm was used to screen key genes, which were analyzed for expression patterns by single-cell analysis. Finally, drug prediction and molecular docking were carried out using the Drug Signatures Database (DSigDB) and AutoDockTools. Results: Firstly, WGCNA identified a total of 26 genes common between OA and COVID-19, and functional analysis of the common genes revealed the common pathological processes and molecular changes between OA and COVID-19 are mainly related to immune dysfunction. In addition, we screened 3 key genes, DDIT3, MAFF, and PNRC1, and uncovered that key genes are possibly involved in the pathogenesis of OA and COVID-19 through high expression in neutrophils. Finally, we established a regulatory network of common genes between OA and COVID-19, and the free energy of binding estimation was used to identify suitable medicines for the treatment of OA patients infected with SARS-CoV-2. Conclusion: In the present study, we succeeded in identifying 3 key genes, DDIT3, MAFF, and PNRC1, which are possibly involved in the development of both OA and COVID-19 and have high diagnostic value for OA and COVID-19. In addition, niclosamide, ciclopirox, and ticlopidine were found to be potentially useful for the treatment of OA patients infected with SARS-CoV-2.

Physical activity modifies the association of the composite dietary antioxidant index with all-cause mortality in the US osteoarthritis population.

Background: It remains unclear how antioxidant intake affects all-cause mortality in osteoarthritis (OA) patients. In this prospective cohort study, we aim to explore the association of the Composite Dietary Antioxidant Index (CDAI) with all-cause mortality and investigate the interaction of physical activity (PA) and CDAI on all-cause mortality in OA populations. Methods: A total of 3,197 adults with OA in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018 were included in this study. Death outcomes were obtained from National Death Index (NDI) records. Multivariable Cox regression analyses with cubic spines were applied to estimate the association of CDAI with all-cause mortality. The interaction between CDAI and PA on all-cause mortality was further assessed in stratified analysis and interaction tests. Results: The hazard ratios for all-cause mortality were 0.95 (0.77-1.17) for Q2, 0.75 (0.59-0.97) for Q3, and 0.71 (0.55-0.92) for Q4 (P for trend <0.001), compared with the lowest quartile of CDAI. A negative linear association was found between CDAI and all-cause mortality. In the stratified analyses, CDAI was negatively associated with all-cause mortality in the insufficient PA group. While in the low and sufficient PA group, there were nonlinear relationships of CDAI with all-cause mortality. Conclusion: A negative linear relationship was observed between CDAI and all-cause mortality in OA patients, and this association was significantly modified by PA. Higher intake of dietary antioxidants might be the interventional objective to reduce the risk of all-cause mortality in the US OA population.

Mitochondrial Dysfunction in Oxidative Stress-Mediated Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is the most common contributor to low back pain (LBP). Recent studies have found that oxidative stress and reactive oxygen species (ROS) play an important role in IVDD. As a by-product of aerobic respiration, ROS is mainly produced in the mitochondria by the electron transport chain and other mitochondrial located proteins. With the excessive accumulation of ROS, mitochondria are also the primary target of ROS attack in disc cells. A disrupted balance between intracellular ROS production and antioxidant capacity will lead to oxidative stress, which is the key contributor to cell apoptosis, cell senescence, excessive autophagy, and mitochondrial dysfunction. As the pivotal ingredient of oxidative stress, mitochondrial dysfunction manifests as imbalanced mitochondrial dynamics and dysregulated mitophagy. Mitochondria can alter their own dynamics through the process of fusion and fission, so that disabled mitochondria can be separated from the mitochondrial pool. Moreover, mitophagy participates by clearing these dysfunctional mitochondria. Abnormality in any of these processes either increases the production or decreases the clearance of ROS, leading to a vicious cycle that results in the death of intervertebral disc cells in large quantities, combined with degradation of the extracellular matrix and overproduction of matrix metalloproteinase. In this review, we explain the changes in mitochondrial morphology and function during oxidative stress-mediated IVDD and highlight the important role of mitochondria in this process. Eventually, we summarize the IVDD therapeutic strategies targeting mitochondrial dysfunction based on current understanding of the role of oxidative stress in IVDD.

A Combined Risk Score Model to Assess Prognostic Value in Patients with Soft Tissue Sarcomas.

A study by Tsvetkov et al. recently published a proposed novel form of copper-induced cell death in Science; however, few studies have looked into the possible mechanism in soft tissue sarcoma (STS). Herein, this study sought to investigate the function of cuproptosis-related genes (CRGs) in the development of tumor-associated immune cells and the prognosis of sarcoma. Herein, this study aimed to explore the role of cuproptosis-related genes (CRGs) in the development, tumor-associated immune cells, and the prognosis of sarcoma. METHODS: The prognostic model was established via the least absolute shrinkage and selection operator (LASSO) algorithm as well as multivariate Cox regression analysis. The stromal scores, immune scores, ESTIMA scores, and tumor purity of sarcoma patients were evaluated by the ESTIMATE algorithm. Functional analyses were performed to investigate the underlying mechanisms of immune cell infiltration and the prognosis of CRGs in sarcoma. RESULTS: Two molecular subgroups with different CRG expression patterns were recognized, which showed that patients with a higher immune score and more active immune status were prone to have better prognostic survival. Moreover, GO and KEGG analyses showed that these differentially expressed CRGs were mainly enriched in metabolic/ions-related signaling pathways, indicating that CRGs may have impacts on the immune cell infiltration and prognosis of sarcoma via regulating the bioprocess of mitochondria and consequently affecting the immune microenvironment. The expression levels of CRGs were closely correlated to the immunity condition and prognostic survival of sarcoma patients. CONCLUSIONS: The interaction between cuproptosis and immunity in sarcoma may provide a novel insight into the study of molecular mechanisms and candidate biomarkers for the prognosis, resulting in effective treatments for sarcoma patients.

Subtype discrimination of acute myeloid leukemia based on plasma SERS technique.

Acute myeloid leukemia (AML) is a common hematologic malignancy. To this day, diagnose of AML and its genetic mutation still rely on invasive and time-consuming methods. In this study, 222 plasma samples were collected to discuss the performance of surface-enhanced Raman spectroscopy (SERS) to discriminate AML subtype acute promyelocytic leukemia and acute monocytic leukemia based on plasma. The Ag nanoparticles-based SERS technique was used to explore the biochemical differences among different AML subtypes. With the help of powerful supervised and unsupervised algorithms, the performance using the whole spectra and band intensities was confirmed to identify different subtypes of AML. The results demonstrated the intensities of several bands and band-intensity ratios were significantly different between groups, thus related to the discrimination of several AML subtypes and control. Combining indexes of band-intensity ratios, the result of multi-indexes ROC has excellent performance in differentiating AML patient with healthy control. Our work demonstrated the great potential of SERS technique as a rapid and micro detection method in clinical laboratory field, it's a new and powerful tool for analyzing human blood plasma.

Effect of Mechanical Strain on Cells Involved in Fracture Healing.

Secondary fracture healing is a complex multi-stage process in which the mechanical environment plays a key role. The use of an appropriate mechanical stimulation such as strain is conducive to tissue formation between fracture ends, thus aiding the healing process. However, if the strain is too large or too small, the biological behavior of the cells involved in bone healing will be affected, resulting in non-union or delayed healing. In this review, we summarize the current state of knowledge regarding the effect of strain on cells that play a role in the fracture-healing process. Overall, the related literature suggests that selection of an adequate strain promotes fracture healing through the stimulation of angiogenesis and osteogenesis, along with inhibition of osteoclast differentiation and bone resorption. However, standardized methods for the application of mechanical stimulation are lacking, and a unified consensus on the mechanism by which strain promotes cell differentiation has not yet been reached. These issues, therefore, deserve further investigation.