MRG15 aggravates sepsis-related liver injury by promoting PCSK9 synthesis and secretion.

OBJECTIVE: Disorders of lipid oxidation play an important role in organ damage, and lipid metabolites are associated with inflammation and coagulation dysfunction in sepsis. However, the specific molecular mechanism by which lipid metabolism-related proteins regulate sepsis is still unclear. The aim of this study is to investigate the role of mortality factor 4-like protein 1 (MORF4L1, also called MRG15), a hepatic lipid metabolism related gene, in sepsis-induced liver injury. METHODS: In the mouse sepsis models established by cecal ligation and puncture (CLP) and lipopolysaccharide (LPS), the impact of pretreatment with the MRG15 inhibitor argatroban on sepsis-related liver injury was investigated. In the LPS-induced hepatocyte sepsis cell model, the effects of MRG15 overexpression or knockdown on hepatic inflammation and lipid metabolism were studied. Additionally, in a co-culture system of hepatocytes and macrophages, the influence of MRG15 knockdown in hepatocytes on the synthesis and secretion of inflammation-related protein PCSK9 as well as its effect on macrophage activation were examined. RESULTS: Studies have shown that MRG15 expression was increased in septicemia mice and positively correlated with lipid metabolism and inflammation. However, knockdown of MRG15 ameliorates sepsis-induced hepatocyte injury. Increased MRG15 in LPS-stimulated hepatocytes promotes PCSK9 synthesis and secretion, which induces macrophage M1 polarization and exacerbates the inflammatory response. Agatroban, an inhibitor of MRG15, ameliorates sepsis-induced liver injury in mice by inhibiting MRG15-induced lipid metabolism disorders and inflammatory responses. CONCLUSIONS: In sepsis, increased MRG15 expression in hepatocytes leads to disturbed hepatic lipid metabolism and induces macrophage M1 polarization by secreting PCSK9, ultimately exacerbating liver injury.

Investigating Research Hotspots of Combat-related Spinal Injuries: A 30-year Bibliometric Analysis Study.

INTRODUCTION: Spinal cord injuries often lead to significant motor and sensory deficits, as well as autonomic dysfunction. Compared with normal spinal injuries, combat-related spinal injuries (CRSIs) are usually more complex and challenging to treat because of multiple traumas, firing-line treatments, and arduous initial treatments on a battlefield. Yet numerous issues remain unresolved about clinical treatment and scientific research. The enhancement of CRSI diagnosis and treatment quality by military surgeons and nurses is imperative. The objective of this study is to identify the frontiers, hotspots, and trends among recent research, summarize the development process of clinical trials, and visualize them systematically. MATERIALS AND METHODS: We collected publications from CRSI based on the Core Collection of Web of Science for 30 years from January 1, 1993 to May 1, 2023.Visualizations of the knowledge maps were produced using VOSviewer and CiteSpace software. We examined annual trends of publications and distribution patterns, the number of publications, as well as the research hotspots. RESULTS: Among 201 documents, it was found that there was a stable upward trend in publications. There were 2 rapid growth stages during the 30 years. Among all countries, the USA contributed the most publications, along with the highest influence and the most international cooperation. Military Medicine was the journal of the maximum publications, whereas the Spine journal was the most influential one. Keyword co-occurrence analysis and trend topics analysis revealed that these articles focused 5 distinct categories for CRSI. CONCLUSIONS: As the first bibliometric study focused on CRSI, we demonstrated the evolution of the field and provided future research directions. We summarized the hotspots and 5 clusters published. This would serve as a useful guide for clinicians and scientists regarding CRSI global impacts.

Efficacy of computer-assisted robotic based clinical training program for spinal oncology education on pedicle screw placement.

Pedicle screw placement (PSP) is the fundamental surgical technique that requires high accuracy for novice orthopedists studying spinal oncology education. Therefore, we set forth to establish a computer-assisted robotic navigation training program for novice spinal oncology education. Novice orthopedists were involved in this study to evaluate the feasibility and safety of the computer-assisted robotic navigation (CARN) training program. In this research, trainees were randomly taught by the CARN training program and the traditional training program. We prospectively collected the clinical data of patients with spinal tumors from 1st May 2021 to 1st March 2022. The ability of PSP was evaluated by cumulative sum (CUSUM) analysis, learning curve, and accuracy of pedicle screws. The patients included in both groups had similar baseline characteristics. In the CUSUM analysis of the learning curve for accurate PSP, the turning point in the CARN group was lower than that in the traditional group (70th vs. 92nd pedicle screw). The LC-CUSUM test indicated competency for PSP at the 121st pedicle screw in the CARN group and the 138th pedicle screw in the traditional group. The accuracy of PSP was also significantly higher in the CARN group than in the traditional group (88.17% and 79.55%, P = 0.03 < 0.05). Furthermore, no major complications occurred in either group. We first described CARN in spinal oncology education and indicated the CARN training program as a novel, efficient and safe training program for surgeons.

Efficacy and safety of COVID-19 vaccines for patients with spinal tumors receiving denosumab treatment: An initial real-clinical experience study.

Background: Even if COVID-19 vaccine has gradually been adopted in the world, information of side effects and crosstalk in patients with spinal tumors is absent due to the exclusion from clinical research. In this research, we aimed to investigate the efficacy and safety for the patients with spinal tumors treated by denosumab. Methods: In this retrospective research, 400 patients under treatment of denosumab against spinal tumors in real-clinical experience were grouped into two cohorts according to the treatment of COVID-19 vaccine. And linked hospital data, serum samples and unsolicited related adverse events had been collected from January 22nd 2021 to June 1st 2021 respectively. Results: 233 patients of all participants who received regular treatment of denosumab were vaccinated by mRNA or inactivated vaccine. Patients of metastatic disease and primary osseous spinal tumor showed similar distribution in both two groups. Over the study period, within 176 patients tested the status of serologic response of vaccine, 88(81.48%) and 41(87.23%) individuals injected one or two inactivated vaccines had effective antibody against SARS-CoV-2 infections. As 21 patients (85.71%) treated by mRNA vaccine did. Considering of the safety of vaccine, most common systemic adverse events were nausea or vomiting (45 events vs 23events). Interestingly, fewer participants in the vaccine group were statistically recorded in local adverse events than in the placebo group (16 events vs 33 events). Conclusions: Our initial real-clinical experience suggests that COVID-19 vaccines are likely safe and effective in in patients with spinal tumors receiving denosumab treatment.

Robot and working tube-assisted invasion-controlled surgery for spinal metastases.

Objective: This study aims to highlight the use of robots in surgery and that of tube-assisted minimally invasive surgery for spinal metastases, as well as elaborate on the concept of invasion-controlled surgery (ICS). Summary of background: Many patients with spinal metastasis cancer cannot afford serious complications when undergoing traditional open surgery because of their poor physical condition. Robots and minimally invasive technology have been introduced into the field of spine surgery and they have shown significant advantages. Methods: Six patients who underwent robot and working tube-assisted ICS for spinal metastases. Relevant demographic, medical, surgical, and postoperative data were collected from medical records and analyzed. Results: Mean operative time was 3.8 h and the mean length of the surgical incision was 4.9 cm. The mean estimated blood loss was 400 ml. The mean bedtime and hospital length of stay were 3.2 days and 6.5 days, respectively. No obvious complications were reported during treatment. The mean accuracy of screw placement was 98%. The mean time for further system treatment after surgery was 5.8 days. All patients experienced significant pain relief. The mean preoperative visual analog scale (VAS) was 7.83 points. The mean VAS at 1 day, 1 week, and 1 month after surgery were 2.83, 1.83, and 1.17 points, respectively. Frankel grade was improved in five of six patients. One patient preoperatively with Frankel grade D was the same postoperatively. Conclusion: The concept of ICS is suitable for patients with spinal metastases. Robot and working tube-assisted ICS for spinal metastases is one of the safest and most effective treatment methods.

Combination of Bone-Modifying Agents with Immunotarget Therapy for Hepatocellular Carcinoma with Bone Metastases.

Due to limited investigations about efficacy of tyrosine kinase inhibitors (TKIs) plus immune-checkpoint inhibitors (ICIs) versus TKIs alone, and effects of durations of bone modifying agents (BMAs) on the survival of patients with hepatocellular carcinoma (HCC) and bone metastases (BoM), we aim to compare the efficacy of TKIs both alone and in combination with ICIs, as well as comparing long-term and no or perioperative use of BMAs for patients with HCC and BoM. Patients with pathologically confirmed HCC and BoM were included in the study. They were stratified into the TKIs group and the TKIs + ICIs group, and the perioperative and the long-term use of BMAs group. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were calculated to assess the response to these regimes. The cumulative risk of initial skeletal-related events (SREs) was used to evaluate treatment efficacy for bone lesions. A total of 21 (33.9%) patients received TKIs (Sorafenib or Lenvatinib) alone and 41 (66.1%) received TKIs + ICIs. The combination group showed higher ORR than monotherapy group (1/21, 4.7% vs. 9/41, 22.0%; p = 0.1432); Additionally, the TKIs + ICIs group offered improved OS (18 months vs. 31 months; p = 0.015) and PFS (10 months vs. 23 months; p = 0.014), while this survival benefits were more profound in virus-infected patients than those non-infected. Prolonged OS (33 months vs. 16 months; p = 0.0048) and PFS (33 months vs. 11 months; p = 0.0027) were observed in patients with long-term use of BMAs compared with no or perioperative use of BMAs. The TKIs + ICIs combination and long-term adjuvant of BMAs may offer a survival advantage for HCC patients with BoM without severe adverse events, which requires further validations.

Roles of the RANKL-RANK Axis in Immunity-Implications for Pathogenesis and Treatment of Bone Metastasis.

A substantial amount patients with cancer will develop bone metastases, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. Despite advancements in systemic therapies for advanced cancer, survival remains poor for those with bone metastases. The interaction between bone cells and the immune system contributes to a better understanding of the role that the immune system plays in the bone metastasis of cancer. The immune and bone systems share various molecules, including transcription factors, signaling molecules, and membrane receptors, which can stimulate the differentiation and activation of bone-resorbing osteoclasts. The process of cancer metastasis to bone, which deregulates bone turnover and results in bone loss and skeletal-related events (SREs), is also controlled by primary cancer-related factors that modulate the intratumoral microenvironment as well as cellular immune process. The nuclear factor kappa B ligand (RANKL) and the receptor activator of nuclear factor kappa B (RANK) are key regulators of osteoclast development, bone metabolism, lymph node development, and T-cell/dendritic cell communication. RANKL is an osteoclastogenic cytokine that links the bone and the immune system. In this review, we highlight the role of RANKL and RANK in the immune microenvironment and bone metastases and review data on the role of the regulatory mechanism of immunity in bone metastases, which could be verified through clinical efficacy of RANKL inhibitors for cancer patients with bone metastases. With the discovery of the specific role of RANK signaling in osteoclastogenesis, the humanized monoclonal antibody against RANKL, such as denosumab, was available to prevent bone loss, SREs, and bone metastases, providing a unique opportunity to target RANKL/RANK as a future strategy to prevent bone metastases.

Clinical study of intramedullary nailing fixation for the treatment of Danis-Weber B in lateral malleolus fracture.

OBJECTIVE: To compare the clinical effects between anatomical locking plates and interlocking intramedullary nails in patients with Danis-Weber B lateral malleolus fractures. METHODS: This retrospective study enrolled patients with Danis-Weber B fractures of the lateral malleolus. All the operations were completed by the same group of surgeons. The reduction effect, operation time, intraoperative blood loss, hospital stay, fracture healing time and ankle functional outcomes (Olerud-Molander Ankle Score [OMAS]) were compared. Postoperative complications, including incision infections, fixation discomfort and internal fixation loosening, were also compared. RESULTS: This study enrolled 73 patients that were treated with either an anatomical locking plate (locking plate group; n = 37) or an interlocking intramedullary nail (intramedullary nail group; n = 36). There was no significant difference between the two groups in terms of reduction effect, hospital stay and OMAS. The intramedullary nail group had significantly lower operation time, intraoperative blood loss and fracture healing time compared with the locking plate group. Postoperative complications in the intramedullary nail group were significantly lower compared with the locking plate group. CONCLUSION: Using intramedullary nails resulted in more satisfactory functional outcomes compared with using locking plates in patients with Danis-Weber B fractures of the lateral malleolus.

Synthesis and Anti-HCV Activities of 18ß-Glycyrrhetinic Acid Derivatives and Their In-Silico ADMET Analysis.

BACKGROUND: Licorice is widely used as a hepatoprotective herb for thousands of years in Traditional Chinese Medicine, and its main chemical constituent glycyrrhizin (GL) is used as a treatment for chronic hepatitis in Japan for over 20 years. 18ß-Glycyrrhetinic acid (GA) is the main active metabolite of GL. OBJECTIVE: Series of GA derivatives were designed and synthesized, and their anti-HCV activities were screened to investigate the structure-activity relationship (SAR). Besides, their in-silico ADMET properties were analyzed to search for a promising lead compound for further identification of anti-HCV terpenoid candidates. METHODS: GA derivatives were synthesized via reactions of oxidation, oxime, rearrangement, esterification and acylation. In vitro anti-HCV activity of derivatives was tested on the HCV cell culture (HCVcc) system. In-silico ADMET properties analysis was performed via "pkCSM" and "SwissADME" platforms. RESULTS: Eighteen GA derivatives were synthesized, and their structures were confirmed by MS and NMR spectrums. All compounds exhibited superior HCV inhibitory activity to that of GA. Compound 2 possessed the most potent anti-HCV activity with an IC50 value of 0.79 µM, which is nearly 58 times potent than SA (a previously reported potent anti-HCV terpenoids) and >200 times than GA. SAR revealed that the introduction of 3-oxo, short-chain (C1-C3) aliphatic alcohols or cyclic aliphatic amines is conducive to improving anti-HCV activity. In-silico ADMET prediction demonstrated most of the potent compounds possessed favorable ADMET properties. CONCLUSION: Structural modification of GA at 3-position and 30-position is an effective approach to searching for potent anti-HCV agents. Compound 2, with the most potent anti-HCV activity and favorable in-silico ADMET properties, is a promising lead compound for further identification of anti-HCV terpenoid candidates.

The Importance of the Deep Deltoid Ligament Repair in Treating Supination-External Rotation Stage IV Ankle Fracture: A Comparative Retrospective Cohort Study.

BACKGROUND: The necessity of the deep deltoid ligament repair in the treatment of supination-external rotation (SER) ankle stage IV fracture with deltoid ligament rupture is highly debated. We conducted this retrospective research aimed at exploring the curative effect of the deep deltoid ligament repair in treating SER fracture. METHODS: Sixty-three patients with closed SER stage IV fractures received open reduction and internal fixation (ORIF), using either deep deltoid ligament repair (the DDLR group, 31 patients) or nondeep deltoid ligament repair (the NDDLR group, 32 patients). The radiographic parameters examined include the talocrural angle (TA), fibular length (FL), tibiomedial malleolar angle (TMMA), medial clear space (MCS), and tibiofibular clear space (TFCS). The functional performance parameters examined in the study were visual analog scale (VAS) pain score, American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot scales, and range of motion of bilateral ankles (RMBA). Complications, including bone nonunion, infection, and fragment displacement, were also recorded and compared. RESULTS: Similar basic characteristics were found in both cohorts. All patients completed follow-up ranging from 12 to 22 months (mean time: 12.41 ± 4.21 months). The DDLR group had significantly reduced VAS score (p < 0.05), with markedly increased RMBA (p < 0.05) compared to the NDDLR group. The two cohorts showed similar follow-up performance at 3 months (p > 0.05), 6 months (p > 0.05), and 12 months (p > 0.05), in terms of parameters including TA, FL, TMMA, MCS, TCS, and AOFAS ankle-hindfoot scales. CONCLUSION: Although similar radiographic performances were achieved in both cohorts, the DDLR group displayed enhanced functional outcome postsurgery, indicating that DDLR may be a better potential for the treatment of SER stage IV fracture with deltoid ligament rupture.