NEMF-mediated Listerin-independent mitochondrial translational surveillance by E3 ligase Pirh2 and mitochondrial protease ClpXP.

The ribosome-associated protein quality control (RQC) pathway acts as a translational surveillance mechanism to maintain proteostasis. In mammalian cells, the cytoplasmic RQC pathway involves nuclear export mediator factor (NEMF)-dependent recruitment of the E3 ligase Listerin to ubiquitinate ribosome-stalled nascent polypeptides on the lysine residue for degradation. However, the quality control of ribosome-stalled nuclear-encoded mitochondrial nascent polypeptides remains elusive, as these peptides can be partially imported into mitochondria through translocons, restricting accessibility to the lysine by Listerin. Here, we identify a Listerin-independent organelle-specific mitochondrial RQC pathway that acts on NEMF-mediated carboxy-terminal poly-alanine modification. In the pathway, mitochondrial proteins carrying C-end poly-Ala tails are recognized by the cytosolic E3 ligase Pirh2 and the ClpXP protease in the mitochondria, which coordinately clear ribosome-stalled mitochondrial nascent polypeptides. Defects in this elimination pathway result in NEMF-mediated aggregates and mitochondrial integrity failure, thus providing a potential molecular mechanism of the RQC pathway in mitochondrial-associated human diseases.

C-reactive protein to albumin ratio predict responses to programmed cell death-1 inhibitors in hepatocellular carcinoma patients.

BACKGROUND: Over the years, programmed cell death-1 (PD-1) inhibitors have been routinely used for hepatocellular carcinoma (HCC) treatment and yielded improved survival outcomes. Nonetheless, significant heterogeneity surrounds the outcomes of most studies. Therefore, it is critical to search for biomarkers that predict the efficacy of PD-1 inhibitors in patients with HCC. AIM: To investigate the role of the C-reactive protein to albumin ratio (CAR) in evaluating the efficacy of PD-1 inhibitors for HCC. METHODS: The clinical data of 160 patients with HCC treated with PD-1 inhibitors from January 2018 to November 2022 at the First Affiliated Hospital of Guangxi Medical University were retrospectively analyzed. RESULTS: The optimal cut-off value for CAR based on progression-free survival (PFS) was determined to be 1.20 using x-tile software. Cox proportional risk model was used to determine the factors affecting prognosis. Eastern Cooperative Oncology Group performance status [hazard ratio (HR) = 1.754, 95% confidence interval (95%CI) = 1.045-2.944, P = 0.033], CAR (HR = 2.118, 95%CI = 1.057-4.243, P = 0.034) and tumor number (HR = 2.932, 95%CI = 1.246-6.897, P = 0.014) were independent prognostic factors for overall survival. CAR (HR = 2.730, 95%CI = 1.502-4.961, P = 0.001), tumor number (HR = 1.584, 95%CI = 1.003-2.500, P = 0.048) and neutrophil to lymphocyte ratio (HR = 1.120, 95%CI = 1.022-1.228, P = 0.015) were independent prognostic factors for PFS. Two nomograms were constructed based on independent prognostic factors. The C-index index and calibration plots confirmed that the nomogram is a reliable risk prediction tool. The ROC curve and decision curve analysis confirmed that the nomogram has a good predictive effect as well as a net clinical benefit. CONCLUSION: Overall, we reveal that the CAR is a potential predictor of short- and long-term prognosis in patients with HCC treated with PD-1 inhibitors. If further verified, CAR-based nomogram may increase the number of markers that predict individualized prognosis.

Research progress in cuproptosis in liver cancer. / é“œæ­»äº¡åœ¨è‚ç™Œä¸­çš„ç ”ç©¶è¿›å±•.

Copper, like iron, is an essential trace metal element for human cells. The role of iron overload and ferroptosis has been gradually clarified in tumors, but the role of copper overload and cuproptosis is still being explored. Cuproptosis is a novel mode of cell death, secondary to impaired mitochondrial function induced by copper overload, and characterized by copper-dependent and programmed. The excessive copper leads to protein toxicity stress by binding to sulfhydryl proteins in the tricarboxylic acid (TCA) cycle of mitochondria, disrupting cellular homeostasis and triggering cuproptosis. Copper accumulation has carcinogenic effects on normal cells, dual effects on tumor cells. Liver cancer is one of the most common malignant tumors in China and even globally, with hepatocellular carcinoma (HCC) being the most common histological subtype. Copper exhibits dualism in HCC, as it both contributes to the growth and invasion of HCC cells, and exerts anticancer effects by inducing cuproptosis. Also, cuproptosis-related genes can be the evaluation of immunotherapy effect and the construction of prognostic models. Clarifying the role of copper death in liver cancer can help explore new methods for liver cancer screening, treatment, and prognosis evaluation.

The prognostic value of fibrinogen to albumin ratio in malignant tumor patients: A meta-analysis.

Background: Recent studies have shown that the fibrinogen to albumin ratio (FAR) is closely related to the prognosis of various cancers. The aim of this systematic review and meta-analysis was to investigate the prognostic value of FAR in malignancies based on the available evidence. Method: To systematically search the Cochrane Library, Embase, PubMed, Google Scholar, Baidu scholars, CNKI and VIP databases for relevant studies published before April 1, 2022, and to evaluate the fibrinogen-to-albumin ratio (FAR) and survival of patients with malignant tumors through a meta-analysis relationship between the results. Results. This meta-analysis included 19 eligible studies involving 5926 cancer patients. We found that high FAR was associated with poor overall survival (HR=2.25, 95%CI 1.86-2.74, p<0.001), recurrence-free survival (HR=2.29, 95%CI 1.91-2.76, P<0.001), progression-free survival (HR: 2.10, 95%CI 1.58-2.79, p<0.001), disease-free survival (HR=1.52, 95%CI 1.17-1.96, p=0.001), and time to recurrence (HR: 1.555, 95%CI 1.031-2.346, P=0.035) was significantly correlated. Conclusions: High FAR is significantly associated with poor clinical outcomes in cancer, suggesting that it may be an important predictor of prognosis in patients with malignancies.

Benzoylaconine improves mitochondrial function in oxygen-glucose deprivation and reperfusion-induced cardiomyocyte injury by activation of the AMPK/PGC-1 axis.

Heart failure (HF) has become one of the severe public health problems. The detailed role of mitochondrial function in HF was still unclear. Benzoylaconine (BAC) is a traditional Chinese medicine, but its role in HF still needs to be explored. In this study, oxygen-glucose deprivation and reperfusion (OGD/R) was executed to mimic the injury of H9C2 cells in HF. The viability of H9C2 cells was assessed via MTT assay. OGD/R treatment markedly decreased the viability of H9C2 cells, but BAC treatment evidently increased the viability of OGD/R-treated H9C2 cells. The apoptosis of H9C2 was enhanced by OGD/R treatment but suppressed by BAC treatment. The mitochondrial membrane potential was evaluated via JC-1 assay. BAC improved the mitochondrial function and suppressed oxidative stress in OGD/R-treated H9C2 cells. Moreover, Western blot analysis revealed that the protein expression of p-AMPK and PGC-1α were reduced in OGD/R-treated H9C2 cells, which was reversed by BAC. Rescue assays indicated that AMPK attenuation reversed the BAC-mediated protective effect on OGD/R-treated cardiomyocytes. Moreover, BAC alleviated myocardial injury in vivo. In a word, BAC modulated the mitochondrial function in OGD/R-induced cardiomyocyte injury by activation of the AMPK/PGC-1 axis. The findings might provide support for the application of BAC in the treatment of HF.

Post-traumatic severe ankle valgus and forefoot supination deformities treated by staged surgery using ilizarov technique and limited osteotomy: A case report.

RATIONALE: Post-traumatic ankle valgus deformities are relatively rare. Old post-traumatic ankle deformity compounded by abundant scar contracture tissue formation around the joint is a big challenge for orthopedics. Conventional one-stage corrective osteotomy with internal fixation always results in many knotty postoperative complications, such as soft tissue avascular necrosis, implant-related infections, and distinct lower limb discrepancy. Here, we describe a patient with old post-traumatic severe ankle valgus and forefoot supination deformities and obtained satisfactory clinical results following multi-stage surgery using the Ilizarov technique and limited osteotomy. Even more encouraging, any complications of conventional one-stage surgery were successfully avoided through our treatment regimen. PATIENT CONCERNS: A 24-year-old healthy man had post-traumatic 90-degree hindfoot valgus and forefoot supination deformities of the right foot for more than 10 years. The complicated issue was the vast, poorly vascularized scar contracture tissues tightly adhered to the bones of the lateral malleolus and dorsum pedis. DIAGNOSES: Old post-traumatic severe ankle valgus and forefoot supination deformities and scar contracture of soft tissues of the foot and ankle joint. INTERVENTIONS: In the first stage, Ilizarov external fixation was used to stretch the scar contracture tissue of the lateral malleolus. In the second stage, limited osteotomy of the tibiotalar joint and progressive closure of the osteotomy site were performed. In the third stage, Chopart joint osteotomy and slow forefoot pronation by external frame were performed. OUTCOMES: Our treatment regimen not only guaranteed soft tissue safety, but also avoided infection and obvious lower limb discrepancy. At the 1-year follow-up, the patient acquired aesthetic and functional right foot. LESSONS: Although relatively rare, old post-traumatic severe ankle valgus and forefoot supination deformities can be corrected using Ilizarov external fixation technology combined with limited osteotomy. With a well-designed staged operation scheme, soft tissue avascular necrosis, infection of the wound, obvious lower limb discrepancy, and flap grafting can be avoided.

Open tibia plateau fracture with intra-osseous dislocation of the patella and quadriceps tendon rupture: a case report.

BACKGROUND: Both tibial plateau fractures and extensor apparatus injuries are serious injuries to the knee joint that generally do not occur in the same patient. We report a rare case of open tibial plateau fracture combined with quadriceps tendon rupture and complete displacement of the patella into the tibial plateau fracture. CASE PRESENTATION: The case involved a male who was 19 years old who had been in a motorcycle accident. The patient was admitted to our department with an open tibial plateau fracture 3 h post-injury. X-ray showed a tibial plateau fracture and complete displacement of the patella into the tibial plateau. CT showed an avulsion fracture in the patella and tibial intercondylar eminence. Concomitant quadriceps tendon injury and both anterior and posterior cruciate ligament tibial insertion avulsion fractures were considered. The operative findings of emergency surgery confirmed our preoperative diagnosis. Single-stage quadriceps tendon repair and ORIF for the tibial plateau fracture were performed. Satisfactory restoration of function was acquired at the last follow up. CONCLUSION: The most difficult aspect of this case was the determination of the cause of the intra-osseous dislocation of the patella into the tibial plateau. The most likely mechanism of the injury may be that the patient experienced transient posterior dislocation of the knee during the injury. Rupture of the quadriceps tendon should be considered with posterior dislocation of the knee, and the patella was pushed into the tibial plateau fracture by force after the rupture of the quadriceps tendon.

Perioperative Major Non-neurological Complications in 105 Patients Undergoing Posterior Vertebral Column Resection Procedures for Severe Rigid Deformities.

STUDY DESIGN: Retrospective study. OBJECTIVE: To analyze the perioperative major non-neurological complications (MNNCs) in posterior vertebral column resection (PVCR) procedures for severe rigid deformities and to identify the factors that may increase the risk. SUMMARY OF BACKGROUND DATA: Although surgeons constantly attempted to increase the corrective efficacy and neurological safety after PVCR, there are still significant risks of major and potentially life-threatening complications. METHODS: A total of 105 consecutive patients with severe rigid deformity who underwent 1-stage PVCR at a single center from 2004 to 2013 were reviewed. The demographic data, medical and surgical histories, perioperative and final follow-up radiographical measurements, and prevalence of perioperative MNNCs were reviewed. RESULTS: The mean age of patients at the time of surgery was 18.9 years (range: 10-45 yr). The major curve of scoliosis was 108.9 ± 25.5 preoperatively and 37.2 ± 16.8 at the final follow-up, and segmental kyphosis was from 89.8 ± 31.1 to 30.4 ± 15.3. There were 31 MNNCs in 24 patients: 16 respiratory complications in 13 patients, 9 cardiovascular adverse events in 7 cases, 1 malignant hyperthermia, and 1 optic deficit. There were 3 patients with wound infection, and 1 of them had to undergo partial removal of the implant for infection control. One patient with neurofibromatosis died 1 day after operation. Factors that showed no relationships with an increased prevalence of MNNCs were age, sex, presence of cardiac disease or neural axis malformation, and both sagittal and coronal correction rate. Patients with T6 and upper resected level, undergoing PVCR at the early period, showed a trend toward more MNNCs encountered. Moreover, nonidiopathic deformity, large scoliotic curve greater than 150°, percent predicated forced vital capacity and forced expiratory volume in 1 second (FEV1.0) less than 40%, and estimated blood loss volume more than 5000 mL were identified as risk factors associated with MNNCs. CONCLUSION: Patients who had undergone PVCR experienced expected higher rate of MNNCs, with an overall prevalence of 22.9%. When considering PVCR, it is important to recognize the significantly higher inherent risks and provide appropriate preoperative counseling on the risks and benefits of surgery. LEVEL OF EVIDENCE: 3.

[Experimental study on osteogenic differentiation of adipose-derived stem cells treated with different concentrations of dexamethasone].

OBJECTIVE: Dexamethasone is one of the basic agents which could induce osteogenic differentiation of mesenchymal stem cells. To investigate the optimal concentration of dexamethasone in osteogenic differentiation of adipose-derived stem cells (ADSCs) so as to provide the theoretical basis for further bone tissue engineering researches. METHODS: Five New Zealand rabbits (2-3 kg) of clean grade, aged 3 months and male or female, were obtained. ADSCs were isolated from the subcutaneous adipose tissue of inguinal region, and cultured with collagenase digestion, then were detected and identified by CD44, CD106 immunofluorescence staining and adipogenic differentiation. ADSCs at passage 3 were used and the cell density was adjusted to 1 x 10(5) cells/mL, then the cells were treated with common cultural medium (group A) and osteogenic induced medium containing 0 (group B), 1 x 10(-9) (group C), 1 x 10(-8) (group D), 1 x 10(-7) (group E), 1 x 10(-6) (group F), and 1 x 10(-5) mol/L (group G) dexamethasone, respectively. The cell proliferation and the mRNA expressions of osteocalcin (OC) and core binding factor alpha1 (Cbfalpha1) were detected by MTT and RT-PCR, respectively. The activity of alkaline phosphatase (ALP) was measured, and the percentage of mineral area was calculated. The mineral nodules were also detected by alizarin red staining. RESULTS: ADSCs mostly presented fusiform and polygon shape with positive expression of CD44 and negative expression of CD106. The result of oil red O staining was positive after ADSCs treated with adipogenic induced medium. The result of MTT revealed that the absorbance (A) value declined with the ascending of the concentration of dexamethasone, and there was significant difference in A value between groups D and E at 5 and 7 days after osteogenic induction (P < 0.05). The mRNA expressions of OC and Cbfal reached the peak in groups E and D at 7 days after osteogenic induction, respectively. The activity of ALP and the percentage of mineral area had the maximum value in group D at 14 days, then declined gradually. There was no significant difference in the mRNA expressions of OC and Cbfalpha1, the activity of ALP, and the percentage of mineral area between groups D and E (P > 0.05), but significant differences were found between groups D and E and other groups (P < 0.05). After 14 days, the cells of group G died, and the result of alizarin red staining was positive in groups B, C, D, E, and F. CONCLUSION: When the concentration of dexamethasone in osteogenic medium is 1 x 10(-8) mol/L, it could not only reduce the inhibitive effect on cells proliferation, but also induce osteogenic differentiation of ADSCs more efficiently.