The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death.

Apoptosis, the first regulated form of cell death discovered in mammalian cells, is executed by caspase-3/7, which are dormant in living cells but become activated by upstream caspase-8 or caspase-9 in responding to extracellular cytokines or intracellular stress signals, respectively. The same cell death-inducing cytokines also cause necroptosis when caspase-8 is inhibited, resulting in the activation of receptor-interacting protein kinase 3 (RIPK3), which phosphorylates pseudokinase MLKL to trigger its oligomerization and membrane-disrupting activity. Caspase-1/4/5/11, known as inflammatory caspases, instead induce pyroptosis by cleaving gasdermin D, whose caspase-cleaved N terminus forms pores on the plasma membrane. The membrane protein NINJ1 amplifies the extent of membrane rupture initiated by gasdermin D. Additionally, disturbance of peroxidation of polyunsaturated fatty acid tails of membrane phospholipids triggers ferroptosis, an iron-dependent and caspases-independent necrotic death. This review will discuss how these regulated cell death pathways act individually and interconnectively in particular cell types to carry out specific physiological and pathological functions.

Membrane Damage during Ferroptosis Is Caused by Oxidation of Phospholipids Catalyzed by the Oxidoreductases POR and CYB5R1.

Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.

Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12 Protein Turnover.

The mitochondrial pathway of apoptosis is controlled by the ratio of anti- and pro-apoptotic members of the Bcl-2 family of proteins. The molecular events underlying how a given physiological stimulus changes this ratio to trigger apoptosis remains unclear. We report here that human 17-ß-estradiol (E2) and its related steroid hormones induce apoptosis by binding directly to phosphodiesterase 3A, which in turn recruits and stabilizes an otherwise fast-turnover protein Schlafen 12 (SLFN12). The elevated SLFN12 binds to ribosomes to exclude the recruitment of signal recognition particles (SRPs), thereby blocking the continuous protein translation occurring on the endoplasmic reticulum of E2-treated cells. These proteins include Bcl-2 and Mcl-1, whose ensuing decrease triggers apoptosis. The SLFN12 protein and an apoptosis activation marker were co-localized in syncytiotrophoblast of human placentas, where levels of estrogen-related hormones are high, and dynamic cell turnover by apoptosis is critical for successful implantation and placenta development.

Forearm bone mineral density predicts screw loosening after lumbar fusion similar to lumbar Hounsfield unit value in patients with lumbar spondylolisthesis.

Preoperative bone density assessment is necessary to predict screw loosening. The forearm BMD is a useful predictor of BMD-related complications after lumbar operation. Our results show that the forearm BMD is as effective a predictor of screw loosening as the lumbar average HU value. Measurement of the forearm BMD may be a useful adjunct in predicting screw loosening following lumbar fusion. PURPOSE: To determine the relationship between forearm bone mineral density (BMD) and the risk of pedicle screw loosening in patients with lumbar spondylolisthesis. METHODS: We retrospectively evaluated 270 patients who underwent posterior lumbar interbody fusion for lumbar spondylolisthesis. The patients were divided into two groups on the basis of the with or without loose screws: the loosening group and the non-loosening group. The patient's gender, age, BMI, smoking and diabetes histories, and the operative segment were recorded as the basic information. The Hounsfield unit (HU) value for the BMD of the L1-4 lumbar was measured using computed tomography. The patient's distal one-third of the length of the radius and ulna of the non-dominant forearm was chosen as the site for dual-energy X-ray (DXA) bone density testing. RESULTS: The rate of screw loosening was 13% at a minimum 12 months follow-up. Average forearm BMD (0.461 ± 0.1 vs 0.577 ± 0.1, p < 0.001) and mean HU value (L1-4) (121.1 ± 27.3 vs 155.6 ± 32.2, p < 0.001) were lower in the screw loosening group than those in the non-loosening group. In multivariate logistic regression analysis, the forearm BMD (OR 0.840; 95%CI 0.797-0.886) and HU value (L1-4) (OR 0.952; 95%CI 0.935-0.969) were independent risk factor for screw loosening. The area under the curve (AUC) for the forearm BMD and HU value for prediction of pedicle screw loosening was 0.802 and 0.811. The forearm BMD cut-off for predicting pedicle screw loosening was 0.543 (sensitivity, 0.800; specificity, 0.864). CONCLUSIONS: The forearm BMD was an independent risk factor for loosening of the lumbar pedicle screws. The forearm BMD was a valid predictor of pedicle screw loosening in patients undergoing lumbar fusion, as was the CT HU value.

Simplified S1 vertebral bone quality (vbq) score to assess proximal junctional kyphosis after Lenke 5 adolescent idiopathic scoliosis surgery.

BACKGROUND: Proximal junctional kyphosis (PJK) is a common complication following corrective surgery for adolescent idiopathic scoliosis (AIS) with a Lenke 5 curve. Previous studies have suggested that PJK may be associated with osteopenia, which is prevalent in AIS patients. MRI-based vertebral bone quality (VBQ) scores have been proposed as a valuable tool to assess preoperative bone quality. However, accurately measuring VBQ scores in Lenke 5 AIS patients with a structural lumbar curve can be challenging. Recently, a simplified S1 VBQ score has been proposed as an alternative method when the traditional VBQ score is not applicable. This study aims to evaluate the predictive value of the simplified S1 VBQ score in predicting the occurrence of PJK after corrective surgery for Lenke 5 AIS. METHODS: We conducted a retrospective analysis of patient data to assess the predictive utility of the S1 VBQ score for PJK in Lenke 5 AIS patients. Demographic, radiographic, and surgical data were collected, and S1 VBQ scores were calculated based on preoperative T1-weighted MRI images. Univariate analysis, linear regression, and multivariate logistic regression were performed to identify potential risk factors for PJK and to assess the correlation between other variables and the S1 VBQ score. Receiver operating characteristic analysis and area under the curve values were used to evaluate the predictive efficiency of the S1 VBQ score for PJK. RESULTS: A total of 105 patients (aged 15.50 ± 2.36 years) were included in the analysis, of whom 24 (22.9%) developed PJK. S1 VBQ scores were significantly higher in the PJK group compared to the non-PJK group (2.83 ± 0.44 vs. 2.48 ± 0.30, P < 0.001), and there was a significant positive correlation between the S1 VBQ score and proximal junctional angle (PJA) (r = 0.46, P < 0.0001). Multivariate analysis revealed that the S1 VBQ scores and preoperative thoracic kyphosis (TK) were significant predictors of PJK. CONCLUSION: This study provided evidence that higher S1 VBQ scores were independently associated with PJK occurrence following corrective surgery for Lenke 5 AIS. Preoperative measurement of the S1 VBQ score on MRI may serve as a valuable tool in planning surgical correction for Lenke 5 AIS.

Preoperative geriatric nutritional risk index is useful factor for predicting postoperative delirium among elderly patients with degenerative lumbar diseases.

PURPOSE: It is the first study to evaluate the predictive value of the geriatric nutritional risk index (GNRI) on postoperative delirium (POD) after transforaminal lumber interbody fusion (TLIF) in elderly patients with degenerative lumbar diseases. METHODS: A retrospective study was conducted to assess the outcomes of TLIF surgery in elderly patients with lumbar degenerative disease between the years 2016 and 2022. Delirium was diagnosed by reviewing postoperative medical records during hospitalization, utilizing the Confusion Assessment Method. The geriatric nutritional risk index was calculated using the baseline serum albumin level and body weight. Multivariate logistic regression analysis was employed to identify the association between preoperative GNRI and postoperative delirium (POD). Additionally, a receiver operating characteristic curve was utilized to determine the optimal GNRI cutoff for predicting POD. RESULTS: POD was observed in 50 of the 324 patients. The GNRI was visibly reduced in the delirium group. The mean GNRI was 93.0 ± 9.1 in non-delirium group and 101.2 ± 8.2 in delirium group. On multivariate logistic regression, Risk of POD increases significantly with low GNRI and was an independent factor in predicting POD following TLIF (OR 0.714; 95% CI 0.540-0.944; p = 0.018). On receiver operating characteristic curve, the area under curve (AUC) for GNRI was 0.738 (95% CI 0.660-0.817). The cutoff value for GNRI according to the Youden index was 96.370 (sensitivity: 66.0%, specificity: 70.4%). CONCLUSION: Our study indicated that lower GNRI correlated significantly with POD after TLIF. Performing GNRI evaluation prior to TLIF may be an effective approach of predicting the risk for POD among elderly patients with degenerative lumbar diseases.

Vertebral bone quality score as a novel predictor of proximal junctional kyphosis after thoracic adolescent idiopathic scoliosis surgery.

INTRODUCTION: Proximal junctional kyphosis (PJK) is one of the most common complications after thoracic AIS surgery. Previous studies reported that the etiology of PJK was associated with osteopenia and meanwhile the AIS patients were found osteopenia which could persist into adulthood. Recently, an MRI-based vertebral bone quality score (VBQ) was reported to be a promising tool which can assess preoperative bone quality. OBJECTIVE: This study aims to evaluate the utility of VBQ score in predicting PJK after corrective surgery for thoracic AIS (Lenke 1 and 2). METHODS: We conducted a retrospective study to identify the predictive efficiency of VBQ score for PJK in thoracic AIS patients. Demographic, radiographic parameters, and surgical variables were collected. VBQ score was calculated using preoperative T1-weighted MRI. Univariate analysis, linear regression, and multivariate logistic regression were performed to determine potential risk factors of PJK and correlation between other parameters and VBQ score. Receiver operating characteristic analysis and area under the curve values were utilized to evaluate the predictive efficiency of VBQ score for PJK. RESULTS: A total of 206 patients (aged 14.4 ± 2.3 years) were included, of which 33 (16.0%) developed PJK. VBQ scores were significantly different between the PJK and non-PJK groups (2.8 ± 0.2 vs 2.5 ± 0.2, P < 0.01). A significant positive correlation was found between VBQ score and PJA (R2 = 0.1728, P < 0.01).On multivariate analysis, VBQ score was the only significant predictor of PJK (odds ratio = 2.178, 95% CI = 1.644-2.885, P < 0.001), with a predictive accuracy of 83%. CONCLUSION: Higher VBQ scores were independently associated with PJK occurrence after corrective surgery for thoracic AIS. Preoperative measurement of VBQ score on MRI may serve as a valuable tool in planning thoracic AIS surgery.

MRI-based vertebral bone quality score for predicting cage subsidence by assessing bone mineral density following transforaminal lumbar interbody fusion: a retrospective analysis.

PURPOSE: This is the first study to evaluate the predictive value of the vertebral bone quality (VBQ) score on cage subsidence after transforaminal lumbar interbody fusion (TLIF) in a Chinese population using the spinal quantitative computed tomography (QCT) as the clinical standard. Meanwhile, the accuracy of the MRI-based VBQ score in bone mineral density (BMD) measurement was verified. METHODS: We performed a retrospective study of patients who underwent single-level TLIF from 2015 to 2020 with at least 1 year of follow-up. Cage subsidence was measured using postoperative radiographic images based on cage protrusion through the endplates more than 2 mm. The VBQ score was measured on T1-weighted MRI. The results were subjected to statistical analysis. RESULTS: A total of 283 patients (61.1% of female) were included in the study. The subsidence rate was with 14.1% (n = 40), and the average cage subsidence was 2.3 mm. There was a significant difference in age, sex, VBQ score and spinal QCT between the subsidence group and the no-subsidence group. The multivariable analysis demonstrated that only an increased VBQ score (OR = 2.690, 95% CI 1.312-5.515, p = 0.007) and decreased L1/2 QCT-vBMD (OR = 0.955, 95% CI 0.933-0.977, p < 0.001) were associated with an increased rate of cage subsidence. The VBQ score was found to be moderately correlated with the spinal QCT (r = -0.426, p < 0.001). The VBQ score was shown to significantly predict cage subsidence, with an accuracy of 82.5%. CONCLUSION: Our findings indicate that the MRI-based VBQ score is a significant predictor of cage subsidence and could be used to assess BMD.

Transcription Profiles Reveal the Regulatory Synthesis of Phenols during the Development of Lotus Rhizome (Nelumbo nucifera Gaertn).

Lotus (Nelumbo nucifera Gaertn) is a wetland vegetable famous for its nutritional and medicinal value. Phenolic compounds are secondary metabolites that play important roles in the browning of fresh-cut fruits and vegetables, and chemical constituents are extracted from lotus for medicine due to their high antioxidant activity. Studies have explored in depth the changes in phenolic compounds during browning, while little is known about their synthesis during the formation of lotus rhizome. In this study, transcriptomic analyses of six samples were performed during lotus rhizome formation using a high-throughput tag sequencing technique. About 23 million high-quality reads were generated, and 92.14% of the data was mapped to the reference genome. The samples were divided into two stages, and we identified 23,475 genes in total, 689 of which were involved in the biosynthesis of secondary metabolites. A complex genetic crosstalk-regulated network involved in the biosynthesis of phenolic compounds was found during the development of lotus rhizome, and 25 genes in the phenylpropanoid biosynthesis pathway, 18 genes in the pentose phosphate pathway, and 30 genes in the flavonoid biosynthesis pathway were highly expressed. The expression patterns of key enzymes assigned to the synthesis of phenolic compounds were analyzed. Moreover, several differentially expressed genes required for phenolic compound biosynthesis detected by comparative transcriptomic analysis were verified through qRT-PCR. This work lays a foundation for future studies on the molecular mechanisms of phenolic compound biosynthesis during rhizome formation.

Clues for two-step virion infectivity factor regulation by core binding factor beta.

Lentiviruses threaten human and animal health. Virion infectivity factor (Vif) is essential for the infectivity of most lentiviruses, except for the equine infectious anaemia virus (EIAV). Vif promotes viral infectivity by recruiting a Cullin-based E3 ligase to induce the degradation of a class of host restriction factors, named APOBEC3. Core binding factor beta (CBF-ß) is necessary for several primate lentiviral Vif functions, including HIV-1 Vif. Although much progress has been made in understanding the contribution of CBF-ß to Vif function, the precise mechanism has not yet been fully elucidated. In this study, we found that an interaction with CBF-ß altered the oligomerization and subcellular distribution pattern and increased the stability of two primate lentiviral Vifs, HIV-1 Vif and Macaca simian immunodeficiency virus (SIVmac) Vif. Moreover, using a CBF-ß loss-of-function mutant, we demonstrated that the interaction between CBF-ß and Vif was not sufficient for Vif assistance; a region including F68 in CBF-ß was also required for the stability and function of Vif. For the first time, this study separates the binding and regulating processes of CBF-ß when it is promoting Vif function, which further extends our understanding of the biochemical regulation of Vif by CBF-ß.

Multiple lysines combined in HIV-1 Vif determines the responsiveness to CBF-ß.

The Vif (viral infectivity factor) protein of human immunodeficiency virus type-1 (HIV-1) is critical for HIV-1 infectivity. CBF-ß is required for HIV-1 Vif function, as it increases the steady-state level of the HIV-1 Vif protein to promote host restriction factor APOBEC3 degradation. However, the precise mechanism by which CBF-ß promotes HIV-1 Vif levels remains unclear. In the present study, we provided evidences that CBF-ß promoted steady-state levels of HIV-1 Vif by inhibiting the degradation of HIV-1 Vif through the proteasome pathway. Our results reveal a new mechanism by which a cellular protein supports viral infectivity by inhibiting viral protein degradation.

Core-binding factor subunit beta is not required for non-primate lentiviral Vif-mediated APOBEC3 degradation.

Viral infectivity factor (Vif) is required for lentivirus fitness and pathogenicity, except in equine infectious anemia virus (EIAV). Vif enhances viral infectivity by a Cullin5-Elongin B/C E3 complex to inactivate the host restriction factor APOBEC3. Core-binding factor subunit beta (CBF-ß) is a cell factor that was recently shown to be important for the primate lentiviral Vif function. Non-primate lentiviral Vif also degrades APOBEC3 through the proteasome pathway. However, it is unclear whether CBF-ß is required for the non-primate lentiviral Vif function. In this study, we demonstrated that the Vifs of non-primate lentiviruses, including feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), caprine arthritis encephalitis virus (CAEV), and maedi-visna virus (MVV), do not interact with CBF-ß. In addition, CBF-ß did not promote the stability of FIV, BIV, CAEV, and MVV Vifs. Furthermore, CBF-ß silencing or overexpression did not affect non-primate lentiviral Vif-mediated APOBEC3 degradation. Our results suggest that non-primate lentiviral Vif induces APOBEC3 degradation through a different mechanism than primate lentiviral Vif. Importance: The APOBEC3 protein family members are host restriction factors that block retrovirus replication. Vif, an accessory protein of lentivirus, degrades APOBEC3 to rescue viral infectivity by forming Cullin5-Elongin B/C-based E3 complex. CBF-ß was proved to be a novel regulator of primate lentiviral Vif function. In this study, we found that CBF-ß knockdown or overexpression did not affect FIV Vif's function, which induced polyubiquitination and degradation of APOBEC3 by recruiting the E3 complex in a manner similar to that of HIV-1 Vif. We also showed that other non-primate lentiviral Vifs did not require CBF-ß to degrade APOBEC3. CBF-ß did not interact with non-primate lentiviral Vifs or promote their stability. These results suggest that a different mechanism exists for the Vif-APOBEC interaction and that non-primates are not suitable animal models for exploring pharmacological interventions that disrupt Vif-CBF-ß interaction.

Microanalysis, Pharmacokinetics and Tissue Distribution of Polysaccharide-Protein Complexes from Longan Pulp in Mice.

A high performance size exclusion-fluorescence detection (HPSEC-FD) method combined with fluorescein isothiocyanate (FITC) prelabeling was established for the microanalysis of polysaccharide-protein complexes from longan pulp (LPP). FITC-labeled LPP (LPPF) was fractionated by gel filtration chromatography. The weight-average molecular weight and FITC substitution degree of LPPF were 39.01 kDa and 0.20%, respectively. The HPSEC-FD calibration curves linear over the range of 1-200 µg/mL in mouse plasma, spleen and lung samples with correlation coefficients greater than 0.995. The inter-day and intra-day precisions of the method were not more than 6.9%, and the relative recovery ranged from 93.7% to 106.4%. The concentration-time curve of LPPF in plasma following intravenous (i.v.) administration at 40 mg/kg body weight well fitted to a two-compartment model. LPPF rapidly eliminated from plasma according to the short half-lives (t1/2α=2.23 min, t1/2ß=39.11 min) and mean retention times (MRT0-t=1.15 h, MRT0-∞=1.39 h). After administration over 5 to 360 min, the concentration of LPPF in spleen homogenate decreased from 7.41 to 3.68 µg/mL; the concentration in lung homogenate decreased from 9.08 to 3.40 µg/mL. On the other hand, the increasing concentration of LPPF fraction with low molecular weight in heart homogenate was observed.

Effects of deep frying and baking on the quality attributes, water distribution, and flavor characteristics of duck jerky.

Introduction: The nutritional value of duck meat is well acknowledged due to its low cholesterol and high protein content. Nevertheless, the impacts of deep-frying and baking on its quality characteristics are not extensively documented in literature. Methods: The objective of this study is to examine the effects of deep-frying, pre-boilingdeep-frying, baking, and pre-boiling-baking on the quality attributes, water distribution, microstructure, and flavor characteristics of duck jerky. Results and discussion: The findings revealed that the deep-frying group had better quality attributes than the baking, pre-boiling-deep-frying, and pre-boiling-baking groups. The deepfried duck jerky had a higher a* value (4.25) and a lower b* value (5.87), with a more appropriate texture profile, and had the highest comprehensive impression score (5.84). Moreover, the drying rate was faster, and the intensity of the free water and oil signal was significantly elevated in the deep-frying group. The microstructure results indicated that the muscle fibers in the deep-frying group were closely packed, whereas those in the baking group were relatively loose. Furthermore, the GC-IMS test revealed that the deep-fried duck jerky had a wider range of volatile flavor compounds, including 11 unique compounds that were only found in this particular product.

Evaluation of Pre-Harvest Nutrient Composition and Functional Active Substances in Various Lotus Roots.

This study investigated the impact of variety and harvest time on the visual appearance, nutritional quality, and functional active substances of six lotus root cultivars: "Xinsanwu", "Wuzhi No. 2", "Baiyuzhan", "Huaqilian", "Elian No. 6", and "Elian No. 5". Samples were collected monthly from December 2023 to April 2024. A nutrient analysis revealed a decrease in the water content with a delayed harvest. The total soluble solids and soluble sugar content peaked towards the end and middle-to-late harvest periods, respectively. Starch levels initially increased before declining, while the soluble protein exhibited a triphasic trend with an initial rise, a dip, and a final increase. The vitamin C (Vc) content varied across cultivars. Functional active substances displayed dynamic changes. The total phenolics initially decreased, then increased, before ultimately declining again. The total flavonoid content varied by both cultivar and harvest time. The phenolic acid and flavonoid content mirrored the trends observed for total phenolics and total flavonoids. Gastrodin was the most abundant non-flavonoid compound across all varieties. "Wuzhi No. 2" and "Baiyuzhan" displayed higher levels of functional active substances and starch, while the Elian series and "Xinsanwu" cultivar exhibited a greater content of Vc, soluble sugar, and soluble protein. Specific harvest periods yielded optimal results: "Wuzhi No. 2" (H1 and H5), "Huaqilian" (H2), and "Baiyuzhan" (H3 and H4) demonstrated a high nutrient and functional active substance content. Overall, the lotus roots harvested in period H4 achieved the highest score. Overall, this study provides the foothold for the rapid identification of superior lotus root cultivars and the valorization of lotus root by-products via advanced processing methods. Additionally, it offers valuable insights for market participants and consumers to select optimal varieties and harvest times based on their specific needs.

Comparison of predictive value for cage subsidence between MRI-based endplate bone quality and vertebral bone quality scores following transforaminal lumbar interbody fusion: a retrospective propensity-matched study.

BACKGROUND CONTEXT: Cage subsidence after lumbar fusion can lead to many adverse outcomes. Low bone mineral density (BMD) is a widely recognized risk factor for cage subsidence. Conventional methods can predict and evaluate BMD, but there are many shortcomings. Recently, MRI-based assessment of bone quality in specific parts of the vertebral body has been proposed, including scores for vertebral bone quality (VBQ) and endplate bone quality (EBQ). However, the predictive accuracy of the two scoring systems for cage subsidence after transforaminal lumbar interbody fusion (TLIF) remains unknown. Therefore, we investigated MRI-based VBQ and EBQ scores for assessing bone quality and compared their predictive value for cage subsidence after TLIF. PURPOSE: To compare the predictive value between MRI-based VBQ and EBQ scores for cage subsidence after TLIF. STUDY DESIGN/SETTING: A retrospective case-control study. PATIENTS SAMPLE: Patients with degenerative lumbar diseases underwent single-level TLIF at our medical center between 2014 and 2020, all of whom had preoperative MRIs available. OUTCOMES MEASURES: Cage subsidence, disc height, VBQ score, EBQ score, upper and lower vertebral body bone quality (UL-VBQ) score. METHODS: Data were retrospectively examined for a consecutive sample of 346 patients who underwent TLIF at our medical center between 2014 and 2020. Patients who subsequently experienced cage subsidence or not were matched to each other based on propensity scoring, and the two matched groups (52 patients each) were compared using conditional logistic regression to investigate the association between the potential radiographic factors and cage subsidence. Scores for VBQ and EBQ were assessed for their ability to predict cage subsidence in the matched patients based on the area under the receiver operative characteristic curve (AUC). RESULTS: Among matched patients, those who suffered cage subsidence had significantly higher VBQ score (3.7 vs 3.1, p<.001) and EBQ score (5.0 vs 4.3, p<.001), and regression linked greater risk of subsidence to higher VBQ score (OR 4.557, 95% CI 1.076-19.291, p=.039) and higher EBQ score (OR 5.396, 95% CI 1.158-25.146, p=.032). A cut-off VBQ score of 3.4 predicted the cage subsidence among matched patients with an AUC of 0.799, sensitivity of 84.6%, and specificity of 69.2%. A cut-off EBQ score of 4.7 predicted subsidence with an AUC of 0.829, sensitivity of 76.9%, and specificity of 82.7%. CONCLUSION: Higher VBQ and EBQ scores are associated with a greater risk of cage subsidence following TLIF, and EBQ may perform better because of greater specificity.

TNF and IFNγ-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression.

TNFα and IFNγ (TNF/IFNγ) synergistically induce caspase-8 activation and cancer cell death. However, the mechanism of IFNγ in promoting TNF-initiated caspase-8 activation in cancer cells is poorly understood. Here, we found that in addition to CASP8, CYLD is transcriptionally upregulated by IFNγ-induced transcription factor IRF1. IRF1-mediated CASP8 and CYLD upregulation additively mediates TNF/IFNγ-induced cancer cell death. Clinically, the expression levels of TNF, IFNγ, CYLD, and CASP8 in melanoma tumors are increased in patients responsive to immune checkpoint blockade (ICB) therapy after anti-PD-1 treatment. Accordingly, our genetic screen revealed that ELAVL1 (HuR) is required for TNF/IFNγ-induced caspase-8 activation. Mechanistically, ELAVL1 binds CASP8 mRNA and extends its stability to sustain caspase-8 expression both in IFNγ-stimulated and in basal conditions. Consequently, ELAVL1 determines death receptors-initiated caspase-8-dependent cell death triggered from stimuli including TNF and TRAIL by regulating basal/stimulated caspase-8 levels. As caspase-8 is a master regulator in cell death and inflammation, these results provide valuable clues for tumor immunotherapy and inflammatory diseases.

MRI-based Endplate Bone Quality score independently predicts cage subsidence following transforaminal lumbar interbody fusion.

BACKGROUND CONTEXT: Cage subsidence following transforaminal lumbar interbody fusion (TLIF) has closely correlated with poor vertebral bone quality. Studies have shown better predictive value for cage subsidence by measuring bone density at specific site. However, few studies have been performed to examine the relationship between site-specific MRI bone assessment and cage subsidence in patients who have undergone lumbar interbody fusion. The association between MRI-based assessment of endplate bone quality and cage subsidence after TLIF remains unclear. PURPOSE: To study the predictive value of MRI-based endplate bone quality (EBQ) score for cage subsidence following TLIF, using QCT bone densitometry as a reference standard. STUDY DESIGN/SETTING: A retrospective study. PATIENT SAMPLE: A total of 280 adult patients undergoing single-segment TLIF for degenerative lumbar spine disease from 2010 to 2020 at our institution who had preoperative T1-weighted MRIs. OUTCOME MEASURES: Cage subsidence, disc height, endplate bone quality (EBQ) score, bone mineral density, fusion rate. METHODS: The retrospective study reviewed patients who underwent TLIF at one institution between March 2010 and October 2020. Cage subsidence was measured with postoperative lumbar X-rays based on the cage protrusion through into the superior or inferior end plate or both by more than 2 mm. The EBQ score was measured from preoperative T1-weighted MRI in accordance with the previously reported method. RESULTS: Cage subsidence was observed in 42 of the 280 patients. Bone densitometry with quantitative computed tomography was visibly reduced in the subsidence group. The mean EBQ scores of the lumbar endplate bone was 4.3±0.9 in nonsubsidence and 5.0±0.6 in subsidence. On multivariate logistic regression, the difference between the two groups was remarkable. Risk of cage subsidence increases significantly with higher EBQ scores (odds ratio [OR]=2.063, 95% confidence interval [CI] 1.365-3.120, p=.001) and was an independent factor in predicting subsidence after TLIF. On receiver operating characteristic curve, the AUC for the EBQ score was 0.820 (95% confidence interval [CI]: 0.755-0.844) and the most suitable threshold for the EBQ score was 4.730 (sensitivity: 76.2%, specificity: 83.2%). CONCLUSIONS: Higher EBQ scores measured on preoperative MRI correlated significantly with cage subsidence following TLIF. Performing EBQ assessment prior to TLIF may be a valid method of predicting the risk of postoperative subsidence.

Multiple PDE3A modulators act as molecular glues promoting PDE3A-SLFN12 interaction and induce SLFN12 dephosphorylation and cell death.

The canonical function of phosphodiesterase 3A (PDE3A) is to hydrolyze the phosphodiester bonds in second messenger molecules, such as cyclic AMP (cAMP) and cyclic guanosine monophosphate (cGMP). Recently, a phosphodiesterase-activity-independent role for PDE3A was reported. In this noncanonical function, PDE3A physically interacts with Schlafen 12 (SLFN12) upon treatment of cells with cytotoxic PDE3A modulators. Here, we confirmed that the cytotoxic PDE3A modulators act as molecular glues to initiate the association of PDE3A and SLFN12. The PDE3A-SLFN12 interaction increases the protein stability of SLFN12 located in the cytoplasm, while at the same time also inducing SLFN12 dephosphorylation (including serines 368 and 573). Mutational analysis demonstrates that dephosphorylation is required for cell death induced by cytotoxic PDE3A modulators. Finally, we found that dephosphorylation promoted the rRNA RNase activity of SLFN12 and show that this nucleolytic activity is essential for SLFN12's cell-death-inducing function. Thus, our study deepens the understanding of the biochemical mechanisms underlying SLFN12-mediated cell death.