Comprehensive multi-omics integration uncovers mitochondrial gene signatures for prognosis and personalized therapy in lung adenocarcinoma.

The therapeutic efficacy of lung adenocarcinoma (LUAD), the most prevalent histological subtype of primary lung cancer, remains inadequate, with accurate prognostic assessment posing significant challenges. This study sought to elucidate the prognostic significance of mitochondrial-related genes in LUAD through an integrative multi-omics approach, aimed at developing personalized therapeutic strategies. Utilizing transcriptomic and single-cell RNA sequencing (scRNA-seq) data, alongside clinical information from publicly available databases, we first applied dimensionality reduction and clustering techniques to the LUAD single-cell dataset, focusing on the subclassification of fibroblasts, epithelial cells, and T cells. Mitochondrial-related prognostic genes were subsequently identified using TCGA-LUAD data, and LUAD cases were stratified into distinct molecular subtypes through consensus clustering, allowing for the exploration of gene expression profiles and clinical feature distributions across subtypes. By leveraging an ensemble of machine learning algorithms, we developed an Artificial Intelligence-Derived Prognostic Signature (AIDPS) model based on mitochondrial-related genes and validated its prognostic accuracy across multiple independent datasets. The AIDPS model demonstrated robust predictive power for LUAD patient outcomes, revealing significant differences in responses to immunotherapy and chemotherapy, as well as survival outcomes between risk groups. Furthermore, we conducted comprehensive analyses of tumor mutation burden (TMB), immune microenvironment characteristics, and genome-wide association study (GWAS) data, providing additional insights into the mechanistic roles of mitochondrial-related genes in LUAD pathogenesis. This study not only offers a novel approach to improving prognostic assessments in LUAD but also establishes a strong foundation for the development of personalized therapeutic interventions.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

Psychotic symptoms in Chinese adolescent patients with major depressive disorder: prevalence and related endocrine clinical factors.

OBJECTIVE: Major depressive disorder (MDD) is often accompanied by psychotic symptoms. However, few studies have examined the relationship between psychotic symptoms and endocrine factors in adolescent patients with MDD. Therefore, this study aimed to investigate the prevalence and related endocrine clinical factors of psychotic symptoms in Chinese adolescent patients with MDD. METHODS: In total, 601 patients (aged 12-18) with MDD were recruited. The Patient Health Questionnaire - 9 items (PHQ - 9) was utilized for assessing depressive symptoms. Psychotic symptoms were assessed through clinical interviews. Prolactin (PRL), thyroid-stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), and free thyroxine (FT4) were also measured. RESULTS: The incidence of psychotic symptoms in adolescent patients with MDD was 22.6%. The findings demonstrated that age, self-harming behavior, PHQ-9 score, FT4, and normalized PRL were independently associated with psychotic symptoms in patients with MDD (All p < 0.05). CONCLUSIONS: PRL and FT4 levels are more likely to be abnormally elevated in major depressive adolescents with psychotic symptoms. Prolactin and thyroid hormones in patients with MDD should be paid more attention.

Combination of Polygonatum Rhizoma and Scutellaria baicalensis triggers apoptosis through downregulation of PON3-induced mitochondrial damage and endoplasmic reticulum stress in A549 cells.

OBJECTIVE: Scutellaria baicalensis (SB) and Polygonatum Rhizoma (PR), two traditional Chinese medicines, are both known to suppress cancer. However, the mechanism and effect of combined treatment of them for lung cancer are rarely known. Investigating the combined effect of SB and PR (hereafter referred to as SP) in potential mechanism of lung cancer is required. This study was to evaluate the inhibitory effects of SP on A549 cell growth and to explore the underlying molecular mechanisms. METHODS: According to the theory of Chinese medicine and network pharmacology, in the in vivo experiment, a mouse model of carcinoma in situ was constructed, and lung carcinoma in situ tissues were collected for proteomics analysis, hematoxylin-eosin staining, and CK19 immunohistochemistry. In the in vitro experiment, lung cancer A549 cells at logarithmic growth stage were taken, and the inhibitory effect of SP on the proliferation of A549 cells was detected by CCK8 method. The expression of PON3 was detected by quantitative polymerase chain reaction and western blot. In addition, the effect of SP on the induction of apoptosis in A549 cells and the changes of membrane potential and reactive oxygen species (ROS) content were detected by flow cytometry. The changes of PON3 content in endoplasmic reticulum (ER) are observed by laser confocal microscopy, whereas the effects of SP on the expression of apoptosis-related proteins and ER stress-related proteins in A549 cells were examined by western blot. RESULT: By searching the Traditional Chinese Medicines of Systems Pharmacology (TCMSP) (https://www.tcmspe.com/index.php) database and SymMap database, the respective target genes of PR and SB were mapped into protein network interactions, and using Venn diagrams to show 38 genes in common between PR and SB and lung cancer, SP was found to play a role in the treatment of lung cancer. In vivo experiments showed that in a lung carcinoma in situ model, lung tumor tissue was significantly lower in the SP group compared with the control group, and PON3 was shown to be downregulated by lung tissue proteomics analysis. The combination of SP was able to inhibit the proliferation of A549 cells in a concentration-dependent manner (p < .0001). The expression levels of apoptosis-related proteins and ER stress proteins were significantly increased and the expression levels of PON3 and anti-apoptosis-related proteins were decreased in A549 cells. At the same time, knockdown of PON3 could inhibit tumor cell proliferation (p < .0001). The combination of different concentrations of SP significantly induced apoptosis in A549 cells (p < .05; p < .0001), increased ROS content (p < .01), and damaged mitochondrial membrane potential of A549 cells (p < .05; p < .0001), and significantly increased the expression levels of apoptosis-related proteins and ER stress proteins in lung cancer A549 cells. CONCLUSION: SP inhibits proliferation of lung cancer A549 cells by downregulating PON3-induced apoptosis in the mitochondrial and ER pathways.

Effect of DHCR7 for the co-occurrence of hypercholesterolemia and vitamin D deficiency in type 2 diabetes: Perspective of health prevention.

Type 2 diabetes mellitus (T2DM) is a complex disease caused by multiple factors, which are often accompanied by the disorder of glucose and lipid metabolism and the lack of vitamin D.Over the years, researchers have conducted numerous studies into the pathogenesis and prevention strategies of diabetes. In this study, diabetic SD rats were randomly divided into type 2 diabetes group, vitamin D intervention group, 7-dehydrocholesterole reductase (DHCR7) inhibitor intervention group, simvastatin intervention group, and naive control group. Before and 12 weeks after intervention, liver tissue was extracted to isolate hepatocytes. Compared with naive control group, in the type 2 diabetic group without interference, the expression of DHCR7 increased, the level of 25(OH)D3 decreased, the level of cholesterol increased. In the primary cultured naive and type 2 diabetic hepatocytes, the expression of genes related to lipid metabolism and vitamin D metabolism were differently regulated in each of the 5 treatment groups. Overall, DHCR7 is an indicator for type 2 diabetic glycolipid metabolism disorder and vitamin D deficiency. Targeting DHCR7 will help with T2DM therapy.The management model of comprehensive health intervention can timely discover the disease problems of diabetes patients and high-risk groups and reduce the incidence of diabetes.

Heterogeneity of non-suicidal self-injury behavior in adolescents with depression: latent class analysis.

BACKGROUND: Non-suicidal self-injury (NSSI) by adolescent patients with depression has become a serious public health problem. This cross-sectional study aims to identify subgroups of adolescents based on NSSI and explore the factors related to these subgroups. METHODS: The study recruited 326 in- and out-patient adolescents (263 girls and 63 boys) aged 12 to 18 years (mean = 14.7, SD = 1.6) who had self-injured in the past year. Latent class indicators included 12 NSSI variables, as well as suicidal ideation. Logistic regression examined associations between identified classes and related factors. RESULTS: In this study, two distinct subgroups were identified: a "high suicidal ideation NSSI group" (n = 129, 39.6%) and a "low suicidal ideation NSSI group" (n = 197, 60.4%). Depression (OR = 1.10; 95% CI, 1.05-1.16), female (OR = 2.01; 95% CI, 1.09-3.69), left-behind experience (OR = 2.08; 95% CI, 1.17-3.71), single-parent family (OR = 1.84; 95% CI, 1.11-3.04) and peer victimization (OR = 1.04; 95% CI, 1.02-1.05) increases the probability of belonging to the "high suicidal ideation NSSI group". A high level of perceived social support (OR = 0.99; 95% CI, 0.97-0.99) was a protective factor towards NSSI. CONCLUSIONS: This study identifies two subgroups of NSSI and the factors associated with each subgroup. The early identification of high-risk groups for major NSSI in adolescents diagnosed with depression is possible due to the identification of correlating factors. Different treatment plans can be developed for different subtypes of NSSI to improve the effectiveness of prevention and intervention, promoting the healthy physical and mental development of adolescents with depression.

Childhood trauma, peer victimization, and non-suicidal self-injury among Chinese adolescents: a latent variable mediation analysis.

BACKGROUND: Childhood and peer experiences can influence adolescents' perceptions of interpersonal relationships, which can, in turn, influence their emotional states and behavior patterns. Non-suicidal self-injury (NSSI) is now a common problem behavior among adolescents. The present study examined the role of childhood trauma and peer victimization in adolescents' NSSI. METHODS: A cross-sectional survey was conducted among 1783 adolescents (1464 girls and 318 boys) in the psychiatric outpatient clinics or wards of 14 psychiatric hospitals or general hospitals in nine provinces in China. Data were collected using the Multidimensional Peer Victimization Scale (MPVS), Short-form Childhood Trauma Questionnaire(CTQ-SF), and Functional Assessment of Self-Mutilation (FASM). Structural equation modeling (SEM) with latent variables was used to demonstrate the mediating role of peer victimization in the association between childhoodtrauma and NSSI. RESULTS: The SEM analysis demonstrated that peer victimization plays a partial mediating role in the relationship between childhood trauma and NSSI. In addition, several covariates (such as age, gender, education level, and place of residence) effectively regulated the relationship between peer victimization and NSSI. CONCLUSION: In future studies of NSSI among Chinese adolescents, attention should be paid to the roles of childhood trauma and peer bullying; there is a temporal sequence between these two variables and, to some extent, childhood trauma can have an impact on bullying during adolescence which, in turn, influences NSSI behavior.

Cognitive impairment and factors influencing depression in adolescents with suicidal and self-injury behaviors: a cross-sectional study.

BACKGROUND: Non-suicidal self-injury (NSSI) and suicide attempts (SAs) by adolescent patients with depression have become serious public health problems. There is still insufficient research evidence on the effects of NSSI and SAs on neurocognitive functioning in adolescents. Cognitive function alterations may be associated with SAs and self-injury. NSSI and SAs have different influencing factors. METHODS: Participants were recruited from outpatient clinics and included 142 adolescent patients with depression (12-18 years old). This cohort included the SAs group (n = 52), NSSI group (n = 65), and depression without SAs/NSSI control group (n = 25). All participants underwent a clinical interview and neuropsychological assessment for group comparisons, and post-hoc tests were performed. Finally, partial correlation analysis was used to explore factors related to changes in cognitive function. RESULTS: The SAs group performed significantly worse than the control group in executive function and working memory. The depression score was directly proportional to the executive function of the SAs group, whereas cognitive functioning in the NSSI group was associated with borderline traits and rumination. CONCLUSIONS: These findings suggest that impairment of executive function and working memory may be a common pattern in adolescent depressed patients with SAs. However, borderline traits and rumination may be indicative of NSSI but not SAs.

Investigating efficacy of "microbiota modulation of the gut-lung Axis" combined with chemotherapy in patients with advanced NSCLC: study protocol for a multicenter, prospective, double blind, placebo controlled, randomized trial.

BACKGROUND: Most NSCLCs metastasised out of the lungs at the time of diagnosis and cannot be surgically removed . Cytotoxic chemotherapy drugs have become the main treatment in recent decades, especially in patients with NSCLC without EGFR, ALK, and ROS gene mutations. The prognosis of lung cancer is poor, and the overall 5-year survival rate is only 9-13%. Therefore the treatment of advanced NSCLC remains a significant medical need. Recent studies have shown a significant relationship between the gut-lung axis microecology and malignant tumors. Intestinal probiotics are likely to play a role in inhibiting tumorigenesis through "intestinal-pulmonary axis microecological regulation". This study will seek to investigate the efficacy of "Microbiota modulation of the Gut-Lung Axis" combined with chemotherapy in patients with advanced NSCLC. METHODS: The research is a multicenter, prospective, double blind, placebo controlled, randomized trial. Based on the theoretical basis of "intestinal and lung axis microecological adjustment", combined with traditional platinum-containing two-drug chemotherapy, the efficacy of the new therapy on patients with advanced NSCLC was observed. Collect the basic information of the patient, and study the effect of platinum-based combined chemotherapy on the diversity of intestinal flora in patients with lung cancer after receiving chemotherapy treatment, feces before and after chemotherapy, and the status and extent of adverse reactions during chemotherapy . A total of 180 subjects were included, divided into a control group (platinum-containing dual-drug chemotherapy) and an intervention group (platinum-containing dual-drug chemotherapy combined with Bifico), and were randomly assigned to the group 1:1. DISCUSSION: As a result, intestinal-pulmonary microecological balance could become a new target for the treatment of lung cancer. This study explores the combination of intestinal microecological regulation and chemotherapy to provide new treatment strategies and basis for lung cancer patients. It can help prolong the survival time of lung cancer patients and improve the quality of life, thereby generating huge economic and social benefits. The results can be promoted and applied to units engaged in the treatment of lung cancer. TRIAL REGISTRATION NUMBER: NCT03642548, date: August 22, 2018, the first version protocol. The URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT03642548?term=NCT03642548&draw=2&rank=1 .

Inflammatory cytokines, complement factor H and anhedonia in drug-naïve major depressive disorder.

OBJECTIVE: Anhedonia is a core symptom of major depressive disorder (MDD) and often associated with poor prognosis. The main objective of the present study was to explore the relationship between complement factor H (CFH), inflammatory cytokines and anhedonia in drug-naïve MDD patients. METHODS: A total of 215 participants (61 MDD patients with anhedonia, 78 MDD patients without anhedonia, and 76 control subjects) were included. Severity of depression and levels of anhedonia were evaluated by Hamilton Rating Scale for Depression-17 (HAMD-17) and SHAPS (Snaith-Hamilton Pleasure Scale). Plasma levels of CFH, interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α) were measured. RESULTS: The plasma levels of CFH, IL-10 and TNF-α were higher in drug-naïve MDD patients than control subjects. Compared to MDD patients without anhedonia, patients with anhedonia showed higher levels of CFH and IL-6. The stepwise regression analysis revealed that IL-10, TNF-α, as well as IL-10 × TNF-α were associated with depressive symptoms measured by HAMD-17 in drug-naïve MDD patients, while only CFH levels were identified as a mediator factor for the severity of anhedonia in the patients. CONCLUSION: MDD patients with anhedonia showed different inflammatory characteristics compared to patients without anhedonia. Our results provide novel evidence suggesting that increased plasma CFH levels may be a potential biomarker of anhedonia of subtyping MDD.

Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis.

Recently, the morbidity and mortality from lung cancer have continued to increase. Mitochondrial dysfunction plays a key role in apoptosis, proliferation, and the bioenergetic reprogramming of cancer cells, especially for energy metabolism. Herein, we investigated the ability of melatonin (MLT) to influence lung cancer growth and explored the association between mitochondrial functions and the progression of lung tumors. The deacetylase, sirtuin 3 (Sirt3), is a pivotal player in maintenance of mitochondrial function, among participating in ATP production by regulating the acetylone and pyruvate dehydrogenase complex (PDH). We initially found that MLT inhibited lung cancer growth in the Lewis mouse model. Similarly, we observed that MLT inhibited the proliferation of lung cancer cells (A549, PC9, and LLC cells), and the underlying mechanism of MLT was related to reprogramming cancer cell metabolism, accompanied by a shift from cytosolic aerobic glycolysis to oxidative phosphorylation (OXPHOS). These changes were accompanied by higher ATP production, an elevated ATP production-coupled oxygen consumption rate (QCR), higher ROS levels, higher mito-ROS levels, and lower lactic acid secretion. Additionally, we observed that MLT improved mitochondrial membrane potential and the activities of complexes Ⅰ and Ⅳ in the electron transport chain. Importantly, we also found and verified that the foregoing changes resulted from activation of Sirt3 and PDH. As a result of these changes, MLT significantly enhanced mitochondrial energy metabolism to reverse the Warburg effect via increasing PDH activity with stimulation of Sirt3. Collectively, these findings suggest the potential use of melatonin as an anti-lung cancer therapy and provide a mechanistic basis for this proposal.

Sustained static stress-induced chondrocyte apoptosis in the rat cervical vertebral growth plate and its signal transduction mechanisms.

Apoptosis of the vertebral growth plate chondrocytes plays an important role in the pathogenesis of intervertebral disk degeneration. In this paper, we have successfully established an experimental model induced by static stress and provided a useful method to study the mechanisms of chondrocyte apoptosis.A sustained static load of C0.2 MPa over at least 12 h was observed to induce chondrocyte apoptosis, up-regulation of bax and caspase-3 expression, and down-regulation of bcl-2 expression.

Sustained static stress-induced chondrocyte apoptosis in the rat cervical vertebral growth plate and its signal transduction mechanisms.

Apoptosis of the vertebral growth plate chondrocytes plays an important role in the pathogenesis of intervertebral disk degeneration. In this paper, we have successfully established an experimental model induced by static stress and provided a useful method to study the mechanisms of chondrocyte apoptosis. A sustained static load of ≥0.2 MPa over at least 12 h was observed to induce chondrocyte apoptosis, up-regulation of bax and caspase-3 expression, and down-regulation of bcl-2 expression.

Validation for the effect of intra-exposure patient motion on the assessment of radiostereometric implant migration in a tibial component phantom study.

BACKGROUND: An increasing number of radiostereometry (RSA) research studies have long-term follow-up implant migration outcomes, which show ascending curves of implant migration with occasionally decreasing migration. After scrutinizing images and RSA scenes related to the alternating curves, we suppose that intra-exposure patient motion may contribute to that. The main purposes of this in vitro study were 1) to identify whether the patient motion in different directions could result in the inaccurate assessment of implant migration, and 2) to figure out which direction(s) accounted for the alternating curves. HYPOTHESIS: It was hypothesized that the assessments of implant migration would be less precise and accurate than they could be when patient motion occurred, and such motion would contribute to the alternating curves of radiostereometric implant migration. MATERIALS AND METHODS: A customized phantom, assembled with a tibial component, was designed for simulating intra-exposure patient motion during follow-up RSA examinations. Two different Roentgen tubes were used as the current standard of radiology departments. Radiographs were acquired in a uniplanar technical arrangement. Two defined protocols were conducted: one is to simulate implant migration outcomes at post-op, the early stage (6months), and the later stage (2 to 10years) ; during the later stage, the other is to mimic patient motion by phantom motion in the medial-lateral (x), distal-proximal (y), and anterior-posterior (z) axes. RESULTS: Phantom motion could result in the inaccurate assessment of implant migration, and translations along the medial-lateral (x) axis were the most influenced by patient motion. Motion along the medial-lateral (x) axis could account for the curves with decreasing migration. DISCUSSION: Our assessments of implant migration may be less precise and accurate than they could be when intra-exposure patient motion occurs. We probably neglect the importance of 100% simultaneous exposures, and the influence of patient motion on RSA accuracy and data reliability, due to the difficulty in detecting patient (micro)motion. Electronically synchronized exposures of two paired Roentgen tubes are 100% simultaneous for image acquisition, and they are thus highly recommended for the assessment of implant migration in RSA. TYPE OF STUDY AND LEVEL OF PROOF: not applicable.

Unveiling the STAT3-ACC1 axis: a key driver of lipid metabolism and tumor progression in non-small cell lung cancer.

Background and Objective: Lung cancer is a prevalent global malignancy, and investigating the metabolic reprogramming of tumor cells has significant therapeutic implications. This study aims to explore the molecular mechanism driving the progression of non-small cell lung cancer (NSCLC), with a specific emphasis on the STAT3-ACC1-FAS axis involved in fatty acid synthesis. Methods: The levels of Signal transducer and activator of transcription 3 (STAT3) and acetyl-CoA carboxylase 1 (ACC1) were determined in mouse NSCLC specimens and cell lines using Western blot and qPCR methods. Various assays such as CCK-8, colony formation, EDU, wound-healing, and transwell migration were employed to assess cancer cell proliferation, migration, and invasion. Additionally, a nude mouse xenograft model was utilized for in vivo tumor growth analysis. The interaction between STAT3 and ACC1 was examined through chromatin immunoprecipitation and dual-luciferase assays. Results: The study observed upregulation of STAT3 and ACC1 in NSCLC tissues. Notably, the suppression of STAT3 and ACC1 inhibited the in vitro progression and lipid synthesis of NSCLC cells. Furthermore, STAT3 enhanced lipid synthesis by upregulating ACC1 expression. Mechanistic assays revealed that this process occurred through direct activation of ACC1 transcription by STAT3. STAT3 played a vital role in regulating lipid metabolism and supporting NSCLC progression. Conclusion: The findings of this study underscore the significance of the STAT3-ACC1-FAS axis in NSCLC. The activation of ACC1 through STAT3-mediated transcription serves as a crucial mechanism for stimulating the progression of NSCLC tumors and promoting lipid synthesis. Consequently, targeting the STAT3-ACC1 axis may present a promising avenue for the diagnosis and treatment of NSCLC patients.

Glutathione inhibits lung cancer development by reducing interleukin-6 expression and reversing the Warburg effect.

Reduced glutathione (GSH) is widely used as an antioxidant in clinical practice, but whether GSH affects the development of early lung cancer remains unclear. Herein, we investigated the mechanism underlying the anticancer effect of GSH in patients with pulmonary nodules. Thirty patients with pulmonary nodules were treated with GSH intravenously for 10 days at a dose of 1.8 g/d, followed by oral administration of the drug at a dose of 0.4 g three times daily for 6 months. The results showed that GSH treatment promoted nodule absorption and reduced the IL-6 level in the peripheral blood of the patients. GSH reduced IL-6 expression in inflammatory BEAS-2B and lung cancer cells and inhibited the proliferation of lung cancer cell lines in vitro. In addition, GSH reduced IL-6 expression by decreasing ROS via down-regulating PI3K/AKT/FoxO pathways. Finally, GSH reversed the Warburg effect, restored mitochondrial function, and reduced the IL-6 expression via PI3K/AKT/FoxO pathways. The in vivo experiment confirmed that GSH inhibited lung cancer growth, improved mitochondrial function, and reduced the IL-6 expression by regulating key enzymes via the PI3K/AKT/FoxO pathway. In conclusion, we uncovered that GSH exerts an unprecedentedly potent anti-cancer effect to prevent the transformation of lung nodules to lung cancer by improving the mitochondrial function and suppressing inflammation via PI3K/AKT/FoxO pathway. This investigation innovatively positions GSH as a potentially safe and efficacious old drug with new uses, inhibiting inflammation and early lung cancer. The use of the drug offers a promising preventive strategy when administered during the early stages of lung cancer.

Thyroid hormone enhances efficacy of cisplatin in lung cancer patients via down-regulating GLUT1 expression and reversing the Warburg effect.

Cisplatin (CDDP) is a standard non-small cell lung cancer (NSCLC) chemotherapy, but its efficacy is hampered by resistance, partly due to the Warburg effect. This study investigates how thyroid hormones enhance the Warburg effect, increasing sensitivity to cisplatin in lung cancer. Clinical data from advanced NSCLC patients were analyzed based on thyroid hormone levels, categorizing patients into high and low groups. Cellular experiments involved Control, 10uM CDDP, 10uM CDDP + 0.1uM T3, and 10uM CDDP + 0.1uM T4 categories. Parameters were measured in A549 and PC9 lung cancer cells, including proliferation, apoptosis, mitochondrial membrane potential, ROS production, glycolysis enzyme activity, lactic acid level, and ATP content. Gene and protein expressions were assessed using qPCR and Western Blot. Analysis revealed higher FT3 levels correlated with prolonged progression-free survival before chemotherapy (median PFS: high FT3 group = 12.67 months, low FT3 group = 7.03 months, p = 0.01). Cellular experiments demonstrated that thyroid hormones increase lung cancer cell sensitivity to cisplatin, inhibiting proliferation and enhancing efficacy. The mechanism involves thyroid hormones and cisplatin jointly down-regulating MSI1/AKT/GLUT1 expression, reducing lactic acid and glycolysis. This Warburg effect reversal boosts ATP levels, elevates ROS, and decreases MMP, enhancing cisplatin effectiveness in A549 and PC9 cells. In conclusion, elevated free T3 levels in advanced NSCLC patients correlate with prolonged progression-free survival under cisplatin chemotherapy. Cellular experiments reveal that thyroid hormones enhance lung cancer cell sensitivity to cisplatin by reversing the Warburg effect, providing a mechanistic basis for improved therapeutic outcomes.

Apoptosis of endplate chondrocytes in post-laminectomy cervical kyphotic deformity. An in vivo animal model in sheep.

PURPOSE: The present study was performed to establish an animal model of cervical kyphosis after laminectomy (C2-C5), and to determine the role of endplate chondrocytes apoptosis in cervical kyphosis after laminectomy. METHODS: Twenty-four 3-month-old sheep were randomly divided into two groups: the laminectomy group (n = 12), and the control group (n = 12). The cervical spine alignment was evaluated on a lateral cervical spine X-ray using Harrison's posterior tangent method before surgery and at follow-up. Cartilaginous endplate chondrocyte apoptosis was confirmed using transmission electron microscopy and terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick-end labelling. RESULTS: The mean preoperative cervical curvature (C2-5) in the surgery group was -15.8°. The cervical curvature was 19.1° at 3 months post-operation and decreased to 20.2° at the final follow-up postoperatively. The cervical curvature was significantly decreased in the laminectomy group compared with the control group at the last follow-up (P < 0.001), which was a direct indication of kyphotic change. The incidence of apoptotic cells in the surgery group was significantly higher at the 3- and 6-month follow-up than the incidence in the control group. CONCLUSIONS: The frequency of endplate chondrocyte apoptosis in the laminectomy group was significantly higher than in the control group, indicating that chondrocyte apoptosis may play a pivotal role in the progress of post-laminectomy cervical kyphosis.

Lipid metabolism disorder promotes the development of intervertebral disc degeneration.

Lipid metabolism is a complex process that maintains the normal physiological function of the human body. The disorder of lipid metabolism has been implicated in various human diseases, such as cardiovascular diseases and bone diseases. Intervertebral disc degeneration (IDD), an age-related degenerative disease in the musculoskeletal system, is characterized by high morbidity, high treatment cost, and chronic recurrence. Lipid metabolism disorder may promote the pathogenesis of IDD, and the potential mechanisms are complex. Leptin, resistin, nicotinamide phosphoribosyltransferase (NAMPT), fatty acids, and cholesterol may promote the pathogenesis of IDD, while lipocalin, adiponectin, and progranulin (PGRN) exhibit protective activity against IDD development. Lipid metabolism disorder contributes to extracellular matrix (ECM) degradation, cell apoptosis, and cartilage calcification in the intervertebral discs (IVDs) by activating inflammatory responses, endoplasmic reticulum (ER) stress, and oxidative stress and inhibiting autophagy. Several lines of agents have been developed to target lipid metabolism disorder. Inhibition of lipid metabolism disorder may be an effective strategy for the therapeutic management of IDD. However, an in-depth understanding of the molecular mechanism of lipid metabolism disorder in promoting IDD development is still needed.

Nomogram predicting overall survival of stage IIIB non-small-cell lung cancer patients based on the SEER database.

PURPOSE: We aimed to evaluate the prognostic value of stage IIIB non-small-cell (NSCLC) lung cancer patients and to construct a nomogram to effectively predict their overall survival (OS). METHODS: In total, 4323 patients with stage IIIB NSCLC diagnosed between 1975 and 2018 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Multiple prognostic factors were combined to construct a nomogram for predicting OS of patients with stage IIIB NSCLC. The discrimination and calibration of the nomogram were evaluated by C-indexes and calibration curves. The nomogram was evaluated for predictive ability using receiver operating characteristic (ROC) curves, decision curve analysis curve (DCA), and clinical impact curve (CIC). RESULTS: The nomogram was built on data of 4323 patients with stage IIIB NSCLC and consisted of the following prognostic factors: age, race, sex, primary labeled, pathology, T stage, whether to receive surgery, whether to receive radiotherapy, and whether to receive chemotherapy. The C-index in the training and validation sets for the nomogram was 0.672 (95% CI: 0.661-0.683) and 0.675 (95% CI: 0.656-0.694), respectively. According to scores of the nomogram, patients in the complete set, validation set, and training set were classified into two risk groups, low risk and high risk. CONCLUSIONS: We developed the first validated nomogram to estimate the OS of patients with stage IIIB NSCLC. The nomogram was based on nine prognostic factors and provided an individualized risk estimate of 3-year and 5-year OS survival in patients with stage IIIB NSCLC.