The associations between dysregulation of human blood metabolites and lung cancer risk: evidence from genetic data.

BACKGROUND: Metabolic dysregulation is recognized as a significant hallmark of cancer progression. Although numerous studies have linked specific metabolic pathways to cancer incidence, the causal relationship between blood metabolites and lung cancer risk remains unclear. METHODS: Genomic data from 29,266 lung cancer patients and 56,450 control individuals from the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) were utilized, and findings were replicated using additional data from the FinnGen consortium. The analysis focused on the associations between 486 blood metabolites and the susceptibility to overall lung cancer and its three major clinical subtypes. Various Mendelian randomization methods, including inverse-variance weighting, weighted median estimation, and MR-Egger regression, were employed to ensure the robustness of our findings. RESULTS: A total of 19 blood metabolites were identified with significant associations with lung cancer risk. Specifically, oleate (OR per SD = 2.56, 95% CI: 1.51 to 4.36), 1-arachidonoylglyceropholine (OR = 1.79, 95% CI: 1.22 to 2.65), and arachidonate (OR = 1.67, 95% CI: 1.16 to 2.40) were associated with a higher risk of lung cancer. Conversely, 1-linoleoylglycerophosphoethanolamine (OR = 0.57, 95% CI: 0.40 to 0.82), ADpSGEGDFXAEGGGVR, a fibrinogen cleavage peptide (OR = 0.60, 95% CI: 0.47 to 0.77), and isovalerylcarnitine (OR = 0.62, 95% CI: 0.49 to 0.78) were associated with a lower risk of lung cancer. Notably, isoleucine (OR = 9.64, 95% CI: 2.55 to 36.38) was associated with a significantly higher risk of lung squamous cell cancer, while acetyl phosphate (OR = 0.11, 95% CI: 0.01 to 0.89) was associated with a significantly lower risk of small cell lung cancer. CONCLUSION: This study reveals the complex relationships between specific blood metabolites and lung cancer risk, highlighting their potential as biomarkers for lung cancer prevention, screening, and treatment. The findings not only deepen our understanding of the metabolic mechanisms of lung cancer but also provide new insights for future treatment strategies.

Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer.

Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour's metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine's conversion to polyamines, which exerts their potent ferroptosis-promoting property in an H2O2-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal--iron overload--through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-H2O2 positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the "spread" of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.

IL6-STAT3-C/EBPß-IL6 positive feedback loop in tumor-associated macrophages promotes the EMT and metastasis of lung adenocarcinoma.

BACKGROUND: Lung cancer is one of the most common tumors in the world, and metastasis is one of the major causes of tumor-related death in lung cancer patients. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are frequently associated with tumor metastasis in human cancers. However, the regulatory mechanisms of TAMs in lung cancer metastasis remain unclear. METHODS: Single-cell sequencing analysis of lung cancer and normal tissues from public databases and from 14 patients who underwent surgery at Zhongshan Hospital was performed. In vitro co-culture experiments were performed to evaluate the effects of TAMs on lung cancer migration and invasion. Changes in the expression of IL-6, STAT3, C/EBPΒ, and EMT pathway were verified using RT-qPCR, western blotting, and immunofluorescence. Dual luciferase reporter assays and ChIP were used to reveal potential regulatory sites on the transcription factor sets. In addition, the effects of TAMs on lung cancer progression and metastasis were confirmed by in vivo models. RESULTS: TAM infiltration is associated with tumor progression and poor prognosis. IL-6 secreted by TAMs can activate the JAK2/STAT3 pathway through autocrine secretion, and STAT3 acts as a transcription factor to activate the expression of C/EBPß, which further promotes the transcription and expression of IL-6, forming positive feedback loops for IL6-STAT3-C/EBPß-IL6 in TAMs. IL-6 secreted by TAMs promotes lung cancer progression and metastasis in vivo and in vitro by activating the EMT pathway, which can be attenuated by the use of JAK2/STAT3 pathway inhibitors or IL-6 monoclonal antibodies. CONCLUSIONS: Our data suggest that TAMs promote IL-6 expression by forming an IL6-STAT3-C/EBPß-IL6 positive feedback loop. Released IL-6 can induce the EMT pathway in lung cancer to enhance migration, invasion, and metastasis. The use of IL-6-neutralizing antibody can partially counteract the promotion of LUAD by TAMs. A novel mechanism of macrophage-promoted tumor progression was revealed, and the IL6-STAT3-C/EBPß-IL6 signaling cascade may be a potential therapeutic target against lung cancer.

Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma.

EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical success in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and then gain resistance. We identify transcription factor ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumors. ZNF263 overexpression improves the initial response of cells and delays the formation of persister cells with osimertinib treatment. We further show that ZNF263 binds and recruits DNMT1 to the EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 interacts with nuclear EGFR, impairing the EGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also makes tumor cells with wild-type EGFR expression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or adeno-associated virus (AAV)-mediated ZNF263 overexpression synergistically suppresses tumor growth and regrowth with osimertinib treatment in xenograft animal models. These findings suggest that enhancing ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.

Glutathione degradable manganese-doped polydopamine nanoparticles for photothermal therapy and cGAS-STING activated immunotherapy of lung tumor.

Photothermal therapy (PTT), which utilizes nanomaterials to harvest laser energy and convert it into heat to ablate tumor cells, has been rapidly developed for lung tumor treatment, but most of the PTT-related nanomaterials are not degradable, and the immune response associated with PTT is unclear, which leads to unsatisfactory results of the actual PTT. Herein, we rationally designed and prepared a manganese ion-doped polydopamine nanomaterial (MnPDA) for immune-activated PTT with high efficiency. Firstly, MnPDA exhibited 57.2% photothermal conversion efficiency to accomplish high-efficiency PTT, and secondly, MnPDA can be stimulated by glutathione (GSH) to the release of Mn2+, and it can produce ·OH in a Fenton-like reaction with the overexpressed H2O2 and stimulate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. These two synergistically can effectively remove lung tumor cells that have not been ablated by PTT, resulting in an 86.7% tumor suppression rate under laser irradiation of MnPDA in vivo, and further significantly activated the downstream immune response, as evidenced by an increased ratio of cytotoxic T cells to immunosuppressive Treg cells. Conclusively, the GSH degradable MnPDA nanoparticles can be used for photothermal therapy and cGAS-STING-activated immunotherapy of lung tumors, which provides a new idea and strategy for the future treatment of lung tumors.

MAFF confers vulnerability to cisplatin-based and ionizing radiation treatments by modulating ferroptosis and cell cycle progression in lung adenocarcinoma.

AIMS: Lung cancer is the leading cause of cancer mortality and lung adenocarcinoma (LUAD) accounts for more than half of all lung cancer cases. Tumor elimination is mostly hindered by drug resistance and the mechanisms remain to be explored in LUAD. METHODS: CRISPR screens in cell and murine models and single-cell RNA sequencing were conducted, which identified MAF bZIP transcription factor F (MAFF) as a critical factor regulating tumor growth and treatment resistance in LUAD. RNA and ChIP sequencing analyses were performed for transcriptional target expression and specific binding sites of MAFF. Functions of MAFF in inhibiting tumor growth and promoting cisplatin or irradiation efficacy were investigated using cellular and xenograft models. RESULTS: Patients with lung adenocarcinoma and reduced MAFF expression had worse clinical outcomes. MAFF inhibited tumor cell proliferation by regulating the expression of SLC7A11, CDK6, and CDKN2C, promoting ferroptosis and preventing cell cycle progression from G1 to S. MAFF also conferred tumor cells vulnerable to cisplatin-based or ionizing radiation treatments. MAFF reduction was a final event in the acquisition of cisplatin resistance of LUAD cells. The intracellular cAMP/PKA/CREB1 pathway upregulated MAFF in response to cisplatin-based or ionizing radiation treatments. CONCLUSIONS: MAFF suppresses tumor growth, and pharmacological agonists targeting MAFF may improve cisplatin or irradiation therapies for lung adenocarcinoma patients.

Strong Electron Transfer in Covalently Integrating Cu(I)-Organic Frameworks Enabling Effective Radionuclide Capture.

Rational construction of strong electron-transfer materials remains a challenging task. Herein, we show a design rule for the construction of strong electron-transfer materials through covalently integrating electron-donoring Cu(I) clusters and electron-withdrawing triazine monomers together. As expected, Cu-CTF-1 (Cu(I)-triazine framework) was found to enable strong electron transfer up to 0.46|e| from each Cu(I) metal center to each adjacent triazine fragment. This finally leads to good spatial separation in both photogenerated electron-hole pairs and function units for photocatalytic uranium reduction under ambience and no sacrificial agent and to good charge separation of [I+][I5-] for I2 immobilization under extremely rigorous conditions. The results have not only opened up a structural design principle to access electron-transfer materials but also solved several challenging tasks in the field of radionuclide capture and CTFs.

Tetrandrine downregulates TRPV2 expression to ameliorate myocardial ischemia/reperfusion injury in rats via regulation of cardiomyocyte apoptosis, calcium homeostasis and mitochondrial function.

Our previous study has indicated that tetrandrine (TET) can target miR-202-5p to repress the activation of transient receptor potential vanilloid type 2 (TRPV2), eventually ameliorating the progression of myocardial ischemia/reperfusion injury (MI/RI). This study is aimed to further ascertain the detailed mechanisms between TET and TRPV2 in MI/RI pathogenesis. Here, a myocardial I/R injury rat model and a hypoxia-reoxygenation (H/R) model in rat myocardial cell line (H9C2 cells) were established. We reported that pronounced upregulation of TRPV2 was observed in I/R rats and H/R-induced H9C2 cells. Silencing of TRPV2 could improve cardiac function and myocardial injury, reduced infarction size, and promoted cardiomyocyte proliferation in I/R rats. In I/R rats or H/R-induced H9C2 cells, cardiomyocyte apoptosis was inhibited by knocking-down TRPV2. Meanwhile, the silenced TRPV2 or TET treatment ameliorated the damaged mitochondrial structure, mitigated ROS generation, restored the impaired ΔΨM, inhibited mPTP opening and alleviated Ca2+ overload in H/R-induced H9C2 cells. The results obtained from the overexpression of TRPV2 were contrary to those depicted above. Moreover, TET could downregulate TRPV2 expression, while the overexpression of TRPV2 could reverse the above protective effects of TET in H/R-induced H9C2 cells. The results indicated that TET may function as a TRPV2 blocking agent, thereby attenuating the progression of MI/RI through modulation of cardiomyocyte apoptosis, calcium homeostasis and mitochondrial function. These findings offer a theoretical foundation for potential clinical application of TET therapy in patients with MI/RI.

Bone Healing and Clinical Outcome Following Medial Opening-wedge High Tibial Osteotomy Using Wedge-Shaped Cancellous Allograft.

OBJECTIVE: Medial opening-wedge high tibial osteotomy (MOWHTO) is considered to be an effective treatment for symptomatic knee osteoarthritis (KOA) of isolated the medial compartment with varus alignment of the lower extremity. However, the choice of material to fill the void remains controversial. This study aims to evaluate the bone union of the osteotomy gap using a novel wedge-shaped cancellous allograft after MOWHTO and its effect on clinical outcomes. METHODS: All patients who underwent MOWHTO using a novel wedge-shaped cancellous allograft combined with TomoFix locking compression plate (LCP) fixation between January 2016 and July 2020 were enrolled. The radiographic parameters including hip-knee-ankle angle (HKAA), medial proximal tibial angle (MPTA), femorotibial angle (FTA) and posterior tibial slope angle (PTSA) were measured between pre-operative and post-operative radiographs. Knee Society score (KSS) and range of motion (ROM) were assessed preoperatively and at last follow-up. Patients included in this study were divided into two groups according to the correction angle: small correction group (< 10°; SC group) and large correction group (≥ 10°; LC group). The modified Radiographic Union score for tibial fractures (mRUST) was used to assess the difference in bone healing between the two groups at 1, 3, 6, and 12 months postoperatively and at the final follow-up. A paired student's t test was conducted for comparison of differences of the relevant data pre-operatively and post-operatively. RESULTS: A total of 82 patients (88 knees) were included in this study. The HKAA, MPTA, FTA and PTSA increased from -6.4° ± 3.0°, 85.1° ± 2.6°, 180.1° ± 3.2° and 7.7° ± 4.4° preoperatively to 1.2° ± 4.3° (p < 0.001), 94.4° ± 3.3° (p < 0.001), 171.0° ± 2.8° and 11.8° ± 5.8° (p < 0.001) immediately postoperatively, respectively. However, no significant statistic difference was found in above-mentioned parameters at last follow-up compared to immediate postoperative data (p > 0.05). All patients in this study achieved good bone healing at the final follow-up and no significant differences in mRUST scores were seen between the SC group and LC group. The KSS-Knee score and KSS-Function score improved significantly from 55.4 ± 3.7 and 63.3 ± 4.6 preoperatively to 86.4 ± 2.8 (p < 0.001) and 89.6 ± 2.9 (p < 0.001) at last follow-up, respectively. Nevertheless, there was no significant difference in ROM between pre-operation and last follow-up (p > 0.05). CONCLUSION: For MOWHTO, the wedge-shaped cancellous allograft was a reliable choice for providing good bone healing and clinical outcomes.

Targeting TAM-secreted S100A9 effectively enhances the tumor-suppressive effect of metformin in treating lung adenocarcinoma.

Metformin's effect on tumor treatment was complex, because it significantly reduced cancer cell proliferation in vitro, but made no difference in prognosis in several clinical cohorts. Our transcriptome sequencing results revealed that tumor-associated macrophage (TAM) infiltration significantly increased in active lung adenocarcinoma (LUAD) patients with long-term metformin use. We further identified that the tumor suppressive effect of metformin was more significant in mice after the depletion of macrophages, suggesting that TAMs might play an important role in metformin's effects in LUAD. Combining 10X Genomics single-cell sequencing of tumor samples, transcriptome sequencing of metformin-treated TAMs, and the ChIP-Seq data of the Encode database, we identified and validated that metformin significantly increased the expression and secretion of S100A9 of TAMs through AMPK-CEBP/ß pathway. For the downstream, S100A9 binds to RAGE receptors on the surface of LUAD cells, and then activates the NF-κB pathway to promote EMT and progression of LUAD, counteracting the inhibitory effect of metformin on LUAD cells. In cell-derived xenograft models (CDX) and patient-derived xenograft models (PDX) models, our results showed that neutralizing antibodies targeting TAM-secreted S100A9 effectively enhanced the tumor suppressive effect of metformin in treating LUAD. Our results will enable us to better comprehend the complex role of metformin in LUAD, and advance its clinical application in cancer treatment.

Optimization of limonin invertase production by scaling up Aspergillus tubingensis UA13 fermentation to a 5-l scale.

The enzymatic approach is a highly effective and the major scientific method to eliminating bitter components in citrus-derived products nowadays. Microbial production of limonin invertase stands out due to its pivotal role in the removal of the bitter substance, limonin. The optimization of fermentation parameters and the study of scale-up fermentation are imperative for product commercialization. In this study, we focused on optimizing stirring speed, fermentation temperature, and initial pH to enhance the growth and limonin invertase production by the Aspergillus tabin strain UA13 in a 5-l stirred-tank bioreactor. Our results revealed the following optimal parameters are: a stirring speed of 300 rpm, a fermentation temperature of 35°C and a pH 5.0. Under these optimized conditions, the limonin invertase activity reached its peak at 63.38 U ml-1, representing a 1.67-fold increase compared to the unoptimized conditions (38.10 U ml-1), while also reducing the fermentation duration by 12 h. Furthermore, our research demonstrated that limonin invertase effectively hydrolyze limonin in grapefruit juice, reducing its content from 13.28 to 2.14 µg ml-1, as determined by HPLC, resulting in a 6.21-fold reduction of the bitter substance.

Comparison of joint awareness after total knee arthroplasty, medial unicompartmental knee arthroplasty, and high tibial osteotomy: a retrospective study.

INTRODUCTION: This study aimed to compare the Forgotten Joint Score-12(FJS) outcomes and the minimum clinically important difference (MCID) of the FJS after high tibial osteotomy (HTO), unicompartmental knee arthroplasty (UKA), and total knee arthroplasty (TKA) with short-term follow-up (at least 2 years). Another objective of the study is to investigate the factors influencing FJS. It is hypothesized that there are differences in FJS outcomes among the three procedures. METHODS: Patients who underwent HTO, UKA, and TKA from January 2016 to December 2020 and were followed up for a minimum of 2 years were included in the study. The FJS were analyses from a cohort of people who submitted data to two years. The preoperative and postoperative clinical outcomes were compared and evaluated the patient-related factor. The FJS scores were predicted using multiple linear regression analysis. Additionally, Patient's Joint Perception (PJP) questions were used as anchors to determine the achievement of the forgotten joint, and FJS MCID were calculated using the receiver operating characteristic curve (ROC). RESULTS: Three hundred eighty-nine patients were included in the final study, and there were 111 patients in HTO groups,128patients in UKA groups, and 150 patients in TKA groups. The mean follow-up was 47.0 months. There was a significant difference in the total FJS, between the HTO, UKA, and TKA groups (FJS:59.38 ± 7.25, 66.69 ± 7.44 and 56.90 ± 6.85, p < 0.001. We found the MCID of the FJS of HTO, UKA, and TKA were 63.54, 69.79, and 61.45, respectively. In multiple linear regression, younger age, and higher FS were significant predictors of better FJS. CONCLUSION: Medial UKA demonstrated lower patient awareness in comparison to HTO and TKA, as assessed by the FJS. Younger age and higher FS were identified as significant predictors of improved FJS, providing valuable guidance for surgical decision-making.

ATF3 affects myocardial fibrosis remodeling after myocardial infarction by regulating autophagy and its mechanism of action.

BACKGROUND & OBJECTIVE: Myocardial fibrosis remodeling is a key event in the development of heart anomalousness and dysfunction after myocardial infarction (MI). The purpose of this study was to explore the effect of activating transcription factor 3 (ATF3) on myocardial fibrosis remodeling after MI and its underlying mechanism, so as to provide a theoretical basis for the clinical development of new strategies for MI treatment. METHODS: MI mouse formers were structured by hypodesmus of the left anterior descending (LAD) arteria coronaria of mice, and primary cardiac fibroblasts (CFs) were separated and cultivated to investigate the effect of ATF3 on myocardial fibrosis after MI and its mechanism. RESULTS: Increased collagen content and autophagic flux were found in the left ventricle (LV) tissues of MI mice as shown by Sirius red staining and Western blotting (WB) analysis. Meanwhile, immunofluorescence staining and WB analysis showed that ATF3 was raised in response to MI damage. After remedy with angiotensin II (AngII), the activity and differentiation of CFs were significantly raised, the expression of collagens was increased, and the level of autophagy was notably increased. Furthermore, AngII stimulation remarkably raised the expression of ATF3. Interestingly, knockdown of ATF3 in AngII-CFs reversed the above changes. In addition, after intervention with 3-methyladenine (3-MA), an autophagy restrainer, the activity and differentiation of AngII-CFs, as well as the relative collagen levels and autophagic flux were reduced. However, up-regulation of ATF3 protein expression partially reversed the effect of 3-MA on AngII-CFs. CONCLUSION: ATF3 can regulate the proliferation of CFs and collagen production by affecting autophagy, thus affecting myocardial fibrosis remodeling after MI.

What is the difference in proprioception between single condylar arthroplasty and high tibial osteotomy? a comparative study on both knees of the same patient.

OBJECTIVE: This study aims to investigate the efficacy and outcomes of different surgical procedures, namely unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO), for the treatment of bilateral medial compartment knee osteoarthritis in the same patient. The joint awareness and function of these two surgical methods were evaluated. METHODS: A total of 15 patients with bilateral medial compartment knee osteoarthritis who underwent either UKA or HTO between 2012 and 2020 were included in the study. Patient data, including age, gender, body mass index and length of hospital stay, were collected. Pre- and post-operative measurements were conducted, including tibiofemoral angle, tibial plateau posterior inclination angle, proximal tibial medial angle, distance from mechanical axis to knee joint center, hip-knee-ankle angle, pre- and post-operative knee joint scores, knee joint range of motion, and FIS-12 scores at 3, 6, 12, and 24 months postoperatively. The latest follow-up was used for evaluating the outcomes of osteoarthritis treatment. Normality of continuous variables was assessed using the Shapiro-Wilk test. Between-group comparisons were performed using the paired sample t-test or Wilcoxon rank-sum test. Repeated measures analysis of variance was utilized to analyze FJS-12 measurements at different time points, and the correlation between FJS-12 and postoperative clinical results was examined using Pearson's correlation coefficient. Statistical significance was set at P < 0.05. RESULTS: Significant differences were observed in FJS between the UKA and HTO groups at 3 and 6 months postoperatively, but no significant difference was found at 1 and 2 years postoperatively. FJS in the UKA group demonstrated a significant increase from 3 to 6 months postoperatively, but no significant difference was observed from 6 to 24 months postoperatively. In contrast, FJS in the HTO group showed a significant increase from 3 to 24 months postoperatively. CONCLUSIONS: Patients who underwent UKA exhibited superior joint awareness compared to those who underwent HTO during the early postoperative period. Furthermore, the rate of joint awareness in UKA patients was faster than in HTO patients.

Quantifying Electrochemical Driving Force for Exsolution in Perovskite Oxides by Designing Graded Oxygen Chemical Potential.

Metal nanoparticles exsolved and anchored at the parent perovskite oxide surfaces can greatly enhance the activity and antisintering stability for high-temperature (electro-) chemical catalytic reactions. While exsolution of nanoparticles triggered by using conventional high-temperature thermal reduction suffers from slow kinetics, using an electrochemical driving force can promote the exsolution rate. However, a quantitative correlation between the applied electrochemical driving force and the spatial density of exsolved nanoparticles remains unknown. In this work, we use a specially designed electrochemical device to induce a spatially graded voltage in a La0.43Ca0.37Ti0.94Ni0.06O3-δ electrode, in order to systematically investigate the effect of electrochemical switching on exsolution. With increasing driving force, which leads to decreasing oxygen chemical potential, the density of nanoparticles was observed to increase dramatically, while the average particle size remained roughly constant. We further identified oxygen vacancy pairs or clusters as the preferential nucleation sites for exsolution. Our work provided a high-throughput platform for the systematic study of exsolution of perovskite oxides targeted for fuel electrode materials with improved electrocatalytic performance and stability.

Finite element analysis of the mechanical strength of a new hip Spacer.

BACKGROUND AND OBJECTIVE: At present, the influence of the internal metallic endoskeleton of Spacer on the biomechanical strength of Spacer remains unclear. The aim of this study was to analyze the mechanical stability of a novel Spacer applying a annular skeleton that mimics the structure of trabecular bone using finite element methods. METHEDS: The femur models of three healthy individuals and skeletonless Spacer, K-Spacer, and AD-Spacer were assembled to create 15 3D models. Finite element analysis was performed in an Ansys Bench2022R1. Biomechanical parameters such as stress and strain of the Spacer, internal skeleton and femur were evaluated under three loads, which were applied with the maximum force borne by the hip joint (2100 N), standing on one leg (700 N), and standing on two legs (350 N). The mechanical properties of the new hip Spacer were evaluated. RESULT: The stresses on the medial and lateral surfaces of the AD-Spacer and K-Spacer were smaller than the stresses in the state without skeletal support. The maximum stresses on the medial and lateral surfaces of the AD-Spacer were smaller than those of the inserted K-Spacer, and the difference gradually increased with the increase of force intensity. When the skeleton diameter was increased from 3 to 4 mm, the stresses in the medial and lateral sides of the AD-Spacer and K-Spacer necks decreased. The stress of both skeletons was concentrated at the neck, but the stress of the annular skeleton was evenly distributed on the medial and lateral sides of the skeleton. The mean stress in the proximal femur was higher in femurs with K-Spacer than in femurs with AD-Spacer. CONCLUSIONS: AD-Spacer has lower stress and higher load-bearing capacity than K-Spacer, and the advantages of AD-Spacer are more obvious under the maximum load state of hip joint.

Retinol Saturase Mediates Retinoid Metabolism to Impair a Ferroptosis Defense System in Cancer Cells.

Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal overload of lipid peroxides in cellular membranes. In recent years, modulating ferroptosis has gained attention as a potential therapeutic approach for tumor suppression. In the current study, retinol saturase (RETSAT) was identified as a significant ferroptosis mediator using a publicly accessible CRISPR/Cas9 screening dataset. RETSAT depletion protected tumor cells from lipid peroxidation and subsequent cell death triggered by various ferroptosis inducers. Furthermore, exogenous supplementation with retinoids, including retinol (the substrate of RETSAT) and its derivatives retinal and retinoic acid, also suppressed ferroptosis, whereas the product of RETSAT, 13, 14-dihydroretinol, failed to do so. As effective radical-trapping antioxidant, retinoids protected the lipid membrane from autoxidation and subsequent fragmentation, thus terminating the cascade of ferroptosis. Pseudotargeted lipidomic analysis identified an association between retinoid regulation of ferroptosis and lipid metabolism. Retinoic acid, but not 13, 14-dihydroretinoic acid, interacted with its nuclear receptor and activated transcription of stearoyl-CoA desaturase, which introduces the first double bond into saturated fatty acid and thus catalyzes the generation of monounsaturated fatty acid, a known ferroptosis suppressor. Therefore, RETSAT promotes ferroptosis by transforming retinol to 13, 14-dihydroretinol, thereby turning a strong anti-ferroptosis regulator into a relatively weak one. SIGNIFICANCE: Retinoids have ferroptosis-protective properties and can be metabolized by RETSAT to promote ferroptosis, suggesting the possibility of targeting retinoid metabolism in cancer as a treatment strategy to trigger ferroptosis.

The Evolution of Mitochondrial Genomes between Two Cymbidium Sister Species: Dozens of Circular Chromosomes and the Maintenance and Deterioration of Genome Synteny.

Plant mitochondrial genomes (mitogenomes) exhibit fluid genome architectures, which could lead to the rapid erosion of genome synteny over a short evolutionary time scale. Among the species-rich orchid family, the leafy Cymbidium lancifolium and leafless Cymbidium macrorhizon are sister species with remarkable differences in morphology and nutritional physiology. Although our understanding of the evolution of mitochondria is incomplete, these sister taxa are ideal for examining this subject. In this study, the complete mitogenomes of C. lancifolium and C. macrorhizon, totaling 704,244 bp and 650,751 bp, respectively, were assembled. In the 2 mitogenomes, 38 protein-coding genes, 18 cis- and 6 trans-spliced introns, and approximately 611 Kb of homologous sequences are identical; overall, they have 99.4% genome-wide similarity. Slight variations in the mitogenomes of C. lancifolium and C. macrorhizon in repeat content (21.0 Kb and 21.6 Kb, respectively) and mitochondrial DNA of plastid origin (MIPT; 38.2 Kb and 37.5 Kb, respectively) were observed. The mitogenome architectures of C. lancifolium and C. macrorhizon are complex and comprise 23 and 22 mini-circular chromosomes, respectively. Pairwise comparisons indicate that the two mitogenomes are largely syntenic, and the disparity in chromosome numbers is likely due to repeat-mediated rearrangements among different chromosomes. Notably, approximately 93.2 Kb C. lancifolium mitochondrial sequences lack any homology in the C. macrorhizon mitogenome, indicating frequent DNA gains and losses, which accounts mainly for the size variation. Our findings provide unique insights into mitogenome evolution in leafy and leafless plants of sister species and shed light on mitogenome dynamics during the transition from mixotrophy to mycoheterotrophy.