Development of a predictive nomogram for 28-day mortality risk in non-traumatic or post-traumatic subarachnoid hemorrhage patients.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is associated with high rates of mortality and permanent disability. At present, there are few definite clinical tools to predict prognosis in SAH patients. The current study aims to develop and assess a predictive nomogram model for estimating the 28-day mortality risk in both non-traumatic or post-traumatic SAH patients. METHODS: The MIMIC-III database was searched to select patients with SAH based on ICD-9 codes. Patients were separated into non-traumatic and post-traumatic SAH groups. Using LASSO regression analysis, we identified independent risk factors associated with 28-day mortality and incorporated them into nomogram models. The performance of each nomogram was assessed by calculating various metrics, including the area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). RESULTS: The study included 999 patients with SAH, with 631 in the non-traumatic group and 368 in the post-traumatic group. Logistic regression analysis revealed critical independent risk factors for 28-day mortality in non-traumatic SAH patients, including gender, age, glucose, platelet, sodium, BUN, WBC, PTT, urine output, SpO2, and heart rate and age, glucose, PTT, urine output, and body temperature for post-traumatic SAH patients. The prognostic nomograms outperformed the commonly used SAPSII and APSIII systems, as evidenced by superior AUC, NRI, IDI, and DCA results. CONCLUSION: The study identified independent risk factors associated with the 28-day mortality risk and developed predictive nomogram models for both non-traumatic and post-traumatic SAH patients. The nomogram holds promise in guiding prognosis improvement strategies for patients with SAH.

Inhibition of spastin impairs motor function recovery after spinal cord injury.

Promoting axonal regeneration is an effective strategy for recovery from traumatic spinal cord injury (SCI). Spastin, a microtubule-severing protein, modulates axonal outgrowth and branch formation by regulating microtubule dynamics. However, the exact role of spastin during recovery from SCI remains unknown. Therefore, we utilized a hemisection injury model of the mouse spinal cord and explored the effect of spastin using a spastin inhibitor, spastazoline. Results showed that spastazoline significantly suppressed the microtubule-severing activity of spastin in COS-7 cells and inhibited the promoting effect of spastin on neurite outgrowth in primarily cultured hippocampal neurons. The protein expression level of spastin was significantly upregulated in the injured spinal cord. Injured mice showed impaired motor functions, which included increased toe-off angle and foot fault steps and decreased stride length and Basso mouse scale score. Notably, these motor function impairments were aggravated by the application of spastazoline. Inhibition of spastin exacerbated neurogenesis impairment, as demonstrated by neuronal nuclei antigen staining, the inflammatory response, as shown by Iba-1 and GFAP staining, and axonal regeneration impairment, as shown by 5-hydroxytryptamine staining. Furthermore, mass spectrometry analysis revealed that the inhibition of spastin resulted in numerous dysregulated differentially expressed proteins that were closely associated with vesicle organization and transport. Taken together, our data suggest that spastin is critical for recovery from SCI and may be a potential target for the treatment of SCI.

Fabrication and in vivo osteogenesis of biomimetic poly(propylene carbonate) scaffold with nanofibrous chitosan network in macropores for bone tissue engineering.

A biomimetic poly(propylene carbonate) (PPC) porous scaffold with nanofibrous chitosan network within macropores (PPC/CSNFs) for bone tissue engineering was fabricated by a dual solid-liquid phase separation technique. PPC scaffold with interconnected solid pore wall structure was prepared by the first phase separation, which showed a high porosity of 91.9% and a good compressive modulus of 14.2 ± 0.56 MPa, respectively. By the second phase separation, nanofibrous chitosan of 50-500 nm in diameter was formed in the macropores with little influence on the pore structure and the mechanical properties of PPC scaffold. The nanofibrous chitosan content was calculated to be 9.78% by elemental analysis. After incubation in SBF for 14 days, more apatite crystals were deposited on the pore surface as well as the nanofibrous chitosan surface of PPC/CSNFs scaffold compared with PPC scaffold. The in vitro culture of bone mesenchymal stem cells showed that PPC/CSNFs scaffold exhibited a better cell viability than PPC scaffold. After implantation in rabbits for 16 weeks, the defect was entirely repaired by PPC/CSNFs scaffold, as opposed to the incomplete healing for PPC scaffold. It indicated that PPC/CSNFs scaffold showed a faster in vivo osteogenesis rate than PPC scaffold. Hereby, PPC/CSNFs scaffold will be a potential candidate for bone tissue engineering.

A Novel Nomogram for Predicting Morbidity Risk in Patients with Secondary Malignant Neoplasm of Bone and Bone Marrow: An Analysis Based on the Large MIMIC-III Clinical Database.

Objective: Bone and bone marrow are the third most frequent sites of metastases from many cancers and are associated with low survival and high morbidity rates. Currently, there are no effective bedside tools to predict the morbidity risk of these patients in general intensive care units (ICUs). The main objective of this study was to establish and validate a nomogram to predict the morbidity risk of patients with bone and bone marrow metastases. Methods: Data on patients with bone and bone marrow metastases were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The patients were divided into training and validation cohorts. The data were analyzed using univariate and multivariate Cox regression methods. Factors significantly and independently prognostic of survival were used to construct a nomogram predicting 30-day morbidity. The nomogram was validated by various methods, including Harrell's concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, integrated discrimination improvement (IDI), net reclassification index (NRI), and decision curve analysis (DCA). Results: The study included 610 patients in the training cohort and 262 in the validation cohort. Multivariate Cox regression analysis showed that temperature, SpO2, Sequential Organ Failure Assessment (SOFA) score, Oxford Acute Severity of Illness Score (OASIS), comorbidities with coagulopathy, white blood cell count, heart rate, and respiratory rate were independent predictors of patient survival. The resulting nomogram had good discriminative ability, as shown by high AUCs, and was well calibrated, as demonstrated by calibration curves. Improvements in NRI and IDI values suggested that the nomogram was superior to the SOFA scoring system. DCA curves revealed that the nomogram showed good value in clinical applications. Conclusion: This prognostic nomogram, based on demographic and laboratory parameters, was predictive of the 30-day morbidity rate in patients with secondary malignant neoplasms of the bone and bone marrow, suggesting its applicability in clinical practice.

Surface modification of titanium with antibacterial porous N-halamine coating to prevent peri-implant infection.

Peri-implant infection remains one of the greatest threats to orthopedics. The construction of bone implants with good antibacterial and osteogenic properties is beneficial for reducing the risk of implant-related infections and healing bone defects. In this study, N-halamine coating (namely N-Cl) was grafted onto alkali-heat treated titanium (Ti) using polydopamine to endow Ti-based orthopedic implants with strong bactericidal activity. Surface characterization revealed that the N-Cl coating has porous structure loaded with active chlorine (Cl+). The N-Cl coating also provided micro/nano-structured Ti surfaces with excellent antibacterial ability via transformation between N-H and N-Cl, and approximately 100% disinfection was achieved. Furthermore, the as-prepared N-Cl coating exhibited good biocompatibility and osteogenesis abilityin vitro. These results indicate that applying N-Cl coatings on Ti could prevent and treat peri-implant infections.

Single-Cell RNA Sequencing Reveals Transcriptional Changes in the Cartilage of Subchondral Insufficiency Fracture of the Knee.

Purpose: Subchondral insufficiency fracture of the knee (SIFK) is a common cause of knee joint pain that mainly afflicts the elderly. Until now, how a sudden insufficiency fracture of subchondral bone affects the transcriptomic profiles of cartilage in SIFK and OA patients are largely unknown. Methods: Single-cell RNA sequencing (scRNA-seq) was used to identify various cell subsets and evaluate transcriptomic differences in cartilage of SIFK and OA patients. In addition, the above findings were confirmed by histological evaluation and immunohistochemical (IHC) staining. Results: We found that the transcriptomic profiles of cartilage in the SIFK patient was completely different from those of normal and OA patients. Accordingly, several novel cell clusters with activation of hypoxia and endochondral ossification signaling were identified in the SIFK cartilage. Chondrocyte trajectories analysis and IHC staining revealed that transcription factors including TCF4 were found to be highly up-regulated during the occurrence of SIFK, which might drive the reactive formation of cartilage and fibrous tissue and the activation of endochondral ossification. Conclusion: This is the first report to elucidate the transcriptomic alterations and distinct cell type subpopulations in the cartilage of SIFK and OA by the use of scRNA-seq, which provides a new insight in the understanding of the initiation and progression of SIFK.

Combination BET Family Protein and HDAC Inhibition Synergistically Elicits Chondrosarcoma Cell Apoptosis Through RAD51-Related DNA Damage Repair.

BACKGROUND: Chondrosarcoma is the second-most common type of bone tumor and has inherent resistance to conventional chemotherapy. Present study aimed to explore the therapeutic effect and specific mechanism(s) of combination BET family protein and HDAC inhibition in chondrosarcoma. METHODS: Two chondrosarcoma cells were treated with BET family protein inhibitor (JQ1) and histone deacetylase inhibitors (HDACIs) (vorinostat/SAHA or panobinostat/PANO) separately or in combination; then, the cell viability was determined by Cell Counting Kit-8 (CCK-8) assay, and the combination index (CI) was calculated by the Chou method; cell proliferation was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) incorporation and colony formation assay; cell apoptosis and reactive oxygen species (ROS) level were determined by flow cytometry; protein expressions of caspase-3, Bcl-XL, Bcl-2, γ-H2AX, and RAD51 were examined by Immunoblotting; DNA damage was determined by comet assay; RAD51 and γ-H2AX foci were observed by immunofluorescence. RESULTS: Combined treatment with JQ1 and SAHA or PANO synergistically suppressed the growth and colony formation ability of the chondrosarcoma cells. Combined BET and HDAC inhibition also significantly elevated the ROS level, followed by the activation of cleaved-caspase-3, and the downregulation of Bcl-2 and Bcl-XL. Mechanistically, combination treatment with JQ1 and SAHA caused numerous DNA double-strand breaks (DSBs), as evidenced by the comet assay. The increase in γ-H2AX expression and foci formation also consistently indicated the accumulation of DNA damage upon cotreatment with JQ1 and SAHA. Furthermore, RAD51, a key protein of homologous recombination (HR) DNA repair, was found to be profoundly suppressed. In contrast, ectopic expression of RAD51 partially rescued SW 1353 cell apoptosis by inhibiting the expression of cleaved-caspase-3. CONCLUSION: Taken together, our results disclose that BET and HDAC inhibition synergistically inhibit cell growth and induce cell apoptosis through a mechanism that involves the suppression of RAD51-related HR DNA repair in chondrosarcoma cells.

Bax Targeted by miR-29a Regulates Chondrocyte Apoptosis in Osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative joint disease, where chondrocyte apoptosis is responsible for cartilage degeneration. Bax is a well-known proapoptotic protein of the Bcl-2 family, involved in a large number of physiological and pathological processes. However, the regulation mechanisms of Bax underlying chondrocyte apoptosis in OA remain unknown. In the present study, we determined the role of Bax in human OA and chondrocyte apoptosis. The results showed that Bax was upregulated in chondrocytes from the articular cartilage of OA patients and in cultured chondrocyte-like ATDC5 cells treated by IL-1ß. Bax was identified to be the direct target of miR-29a by luciferase reporter assay and by western blotting. Inhibition of miR-29a by the mimics protested and overexpression by miR-29a inhibitors aggravated ATDC5 apoptosis induced by IL-1ß. These data reveal that miR-29a/Bax axis plays an important role in regulating chondrocyte apoptosis and suggest that targeting the proapoptotic protein Bax and increasing expression levels of miR-29a emerge as potential approach for protection against the development of OA.

Up-regulated MiR-27-3p promotes the G1-S phase transition by targeting inhibitor of growth family member 5 in osteosarcoma.

OBJECTIVE: MicroRNAs (miRNAs) play an essential role in regulating malignant progression of tumour cells by inhibiting translation or stability of messenger RNA. However, the expression pattern and regulatory mechanism of miR-27-3p in osteosarcoma remains unclear. METHODS: We examined the expression of miR-27-3p in 5 osteosarcoma cell lines compared with that in 2 normal osteocyte cell lines. Osteosarcoma cells U-2OS and MG-63 were transduced to up-regulate or down-regulate the expression of miR-27-3p. The 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide, or MTT, assay, colony formation assays, BrdUrd labelling, immunofluorescence, anchorage-independent growth ability assay and flow cytometry analysis were used to test the effect of miR-27-3p. Luciferase assays were added to verify the direct relationship between miR-27-3p and the predicted target gene inhibitor of growth family member 5 (ING5). RESULTS: The expression of miR-27-3p was significantly increased in examined osteosarcoma cell lines compared with that in normal osteocyte cell lines. Up-regulation of miR-27-3p significantly accelerated osteosarcoma cell growth via promoting G1-S transition. In addition, the opposite result was observed in miR-27-3p-down-regulated cells. Up-regulation of ING5 significantly attenuated the miR-27-3p-induced proliferation in osteosarcoma cells. CONCLUSIONS: These data suggested that miR-27-3p could promote the G1-S phase transition that leads to proliferation by down-regulating the expression of ING5 in osteosarcoma.