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Abstract Cell death regulation is essential for tissue homeostasis and its dysregulation often underlies cancer development. Understanding the different pathways of cell death can provide novel therapeutic strategies for battling cancer. This review explores several key cell death mechanisms of apoptosis, necroptosis, autophagic cell death, ferroptosis, and pyroptosis. The research gap addressed involves a thorough analysis of how these cell death pathways can be precisely targeted for cancer therapy, considering tumor heterogeneity and adaptation. It delves into genetic and epigenetic factors and signaling cascades like the phosphatidylinositol 3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK) pathways, which are critical for the regulation of cell death. Additionally, the interaction of the microenvironment with tumor cells, and particularly the influence of hypoxia, nutrient deprivation, and immune cellular interactions, are explored. Emphasizing therapeutic strategies, this review highlights emerging modulators and inducers such as B cell lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics, tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL), chloroquine, and innovative approaches to induce ferroptosis and pyroptosis. This review provides insights into cancer therapy's future direction, focusing on multifaceted approaches to influence cell death pathways and circumvent drug resistance. This examination of evolving strategies underlines the considerable clinical potential and the continuous necessity for in‐depth exploration within this scientific domain.

Acute Liver Injury (ALI), a highly prevalent liver disease in the last two decades, but there is still no effective treatment for it. As a member of Tibetan medicine, Swertia chirayita is commonly used for treating liver-related diseases, while the behavior of S. chirayita in CCl4-induced ALI is deficient. In this work, the chemical constituents of S. chirayita were identified using a UPLC-Q-Exactive Orbitrap MS method. And the potential targets of the active compound of S. chirayita in CCl4-induced ALI have been explored on the basis of bioinformatics analysis and ALI model. The findings revealed that a total of 49 compounds have been identified in S. chirayita, and 10 have been absorbed into blood as prototypes. Network pharmacology and molecular docking studies have shown that S. chirayita has a multi-component, multi-target profile for the treatment of CCl4-induced ALI. Biochemical indicators testing demonstrated that Swertiamarine (STW) improved the levels of AST, ALT, MDA, SOD, TNF-α and IL-6 in CCl4-induced ALI mouse model. Additionally, H&E staining indicated that STW significantly improved cellular necrosis, inflammatory infiltration, and other forms of pathological liver damage in mice. Meanwhile, quantitative reverse transcription PCR (qRT-PCR) showed that STW could ameliorate CCl4-induced ALI by regulate the expression of EGFR, CASP3, STAT3 and other targets. In conclusion, as one of the active compounds of S. chirayita, STW could alleviate ALI by modulating the expression of biochemical indicators, liver pathological indicators and critical targets. This will provide a theoretical basis for the further research and development of the S. chirayita.

Amidst a global rise in lung cancer occurrences, conventional therapies continue to pose substantial side effects and possess notable toxicities while lacking specificity. Counteracting this, the incorporation of nanomedicines can notably enhance drug delivery at tumor sites, extend a drug’s half-life and mitigate inadvertent toxic and adverse impacts on healthy tissues, substantially influencing lung cancer’s early detection and targeted therapy. Numerous studies signal that while the nano-characteristics of lung cancer nanomedicines play a pivotal role, further interplay with immune, photothermal, and genetic factors exist. This review posits that the progression towards multimodal combination therapies could potentially establish an efficacious platform for multimodal targeted lung cancer treatments. Current nanomedicines split into active and passive targeting. Active therapies focus on a single target, often with unsatisfactory results. Yet, developing combination systems targeting multiple sites could chart new paths in lung cancer therapy. Conversely, low drug delivery rates limit passive therapies. Utilizing the EPR effect to bind specific ligands on nanoparticles to tumor cell receptors might create a new regime combining active-passive targeting, potentially elevating the nanomedicines’ concentration at target sites. This review collates recent advancements through the lens of nanomedicine’s attributes for lung cancer therapeutics, the novel carrier classifications, targeted therapeutic modalities and their mechanisms, proposing that the emergence of multi-target nanocomposite therapeutics, combined active-passive targeting therapies and multimodal combined treatments will pioneer novel approaches and tools for future lung cancer clinical therapies.

Aconitum pendulum, a member of the Aconitum genus within the Ranunculaceae family, is known for its remarkable anti-inflammatory, anti-tumor, and analgesic properties. However, the application of Aconitum pendulum in traditional medicine is often restricted by its inherent toxicity, necessitating specific processing methods to ensure safe usage. Tibetan medicine utilizes distinctive processing techniques such as the barley wine, Hezitang, and zanba frying systems to render the herb safe for medicinal use. Despite the known pharmacological importance, scant research exists on how these processing methods affect the phytochemical profile of Aconitum pendulum, indicating a necessity for comparative analysis of the resulting concoctions. In this study, we employed 1H nuclear magnetic resonance (1H NMR) spectroscopy and ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS) to explore the metabolomic variations among different processed products of Aconitum pendulum. Multivariate data analysis techniques, including pattern recognition, allowed us to investigate the intricacies of the compound profiles. To discover signature chemical markers that can differentiate the various processed products, we conducted paired t-tests and generated heat maps highlighting the detected differences. Our integrated analysis of the 1H NMR and UPLC-Q-TOF-MS data revealed distinct chemical signatures unique to each method of Aconitum pendulum processing. By employing chemometric analysis with variable importance in projection (VIP) scores greater than 1.0, and coupled with the statistical rigor of paired t-tests (P

Introduction: Hepatocellular carcinoma (HCC) is responsible for approximately 90% of liver malignancies and is the third most common cause of cancer-related mortality worldwide. However, the role of anoikis, a programmed cell death mechanism crucial for maintaining tissue equilibrium, is not yet fully understood in the context of HCC.Methods: Our study aimed to investigate the expression of 10 anoikis-related genes (ARGs) in HCC, including BIRC5, SFN, UBE2C, SPP1, E2F1, etc., and their significance in the disease.Results: Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we discovered that these ARGs are involved in important processes such as tissue homeostasis, ion transport, cell cycle regulation, and viral infection pathways. Furthermore, we found a significant correlation between the prognostic value of five ARGs and immune cell infiltrates. Analysis of clinical datasets revealed a strong association between BIRC5 expression and HCC pathological progression, including pathological stage, T stage, overall survival (OS), and race. By constructing a competing endogenous RNA (ceRNA) network and using molecular docking, we identified ten bioactive compounds from traditional Chinese medicine (TCM) that could potentially modulate BIRC5. Subsequent in vitro experiments confirmed the influence of platycodin D, one of the identified compounds, on key elements within the ceRNA network.Discussion: In conclusion, our study presents a novel framework for an anoikis-centered prognostic model and an immune-involved ceRNA network in HCC, revealing potential regulatory targets. These insights contribute to our understanding of HCC pathology and may lead to improved therapeutic interventions.

Coriolopsis trogii and Cerrena unicolor were investigated for laccase production in submerged fermentation with different nutrient medium containing metal ions and lignocellulosic materials. The maximum laccase activity of C. trogii Han751 was 8584.44 ± 98.45 U/L and was obtained from nutrient medium 7. However, the maximum laccase activity of C. unicolor Han 849 was 16144.26 ± 635.30 U/L from nutrient medium 9. Thus, the capacity of secreting laccase of C. unicolor Han 849 was superior to that of C. trogii Han751. Different fungal species have different medium components suitable for laccase production. The content of CuSO4·5H2O and MnSO4 in nutrient medium with the concentration of 0.25 g/L and 0.151 g/L, respectively, was more beneficial to C. trogii Han751 secreting laccase. However, the vital components of nutrient medium that contribute to the laccase activity of C. unicolor Han 849 were corncob, glucose, and CuSO4·5H2O, with the corresponding concentrations of 1 g/flask, 5 g/L, and 0.25 g/L, respectively. The results will contribute to the development of new methods to produce low-cost laccase.

Abstract Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer.

Laccase activity secreted by Pleurotus eryngii Han 1787 and Lentinus edodes Han 1788 grown on six types of agroindustrial wastes was investigated. Maximum laccase activity of P. eryngii Han 1787 on Ulmus pumila, Juniperus formosana, Pinus tabuliformis, cottonseed shell, corncob, and leaf of corncob was nearly 5.77-fold, 2.37-fold, 2.78-fold, 2.81-fold, 11.53-fold, and 6.73-fold higher than that of L. edodes Han1788 on corresponding agroindustrial wastes. In general, the capacity of secreting laccase of P. eryngii Han 1787 was superior to that of L. edodes Han 1788. Furthermore, laccase activity of P. eryngii Han 1787 on the leaf of corncob, the corncob, Ulmus pumila, and Juniperus formosana was relatively stable during the whole fermentation process. Different fungi showed different preferences in different agroindustrial wastes to secret laccase on whole fermentation stage. The presence of leaf of corncob was useful for improving laccase activity of P. eryngii Han 1787, while L. edodes Han 1788 was more preferred to produce laccase along with the presence of Juniperus formosana. These results were preliminary conducive in laying the foundation for increasing industrial laccase-producing strains and producing low-cost laccase.

B-cell acute lymphocytic leukemia (B-ALL), a common blood cancer in children, leads to high mortality. Cyclin-dependent kinase 9 inhibitor (CDK9i) effectively attenuates acute myeloid leukemia and chronic lymphoblastic leukemia by inducing apoptosis and inhibiting cell proliferation. However, the effect of CDK9i on B-ALL cells and the underlying mechanisms remain unclear. In this study, we showed that CDK9i induced the apoptosis of B-ALL cells in vitro by activating the apoptotic pathways. In addition, CDK9i restrained the glycolytic metabolism of B-ALL cells, and CDK9i-induced apoptosis was enhanced by co-treatment with glycolysis inhibitors. Furthermore, CDK9i restained the glycolysis of B-ALL cell lines by markedly downregulating the expression of glucose transporter type 1 (GLUT1) and the key rate-limiting enzymes of glycolysis, such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Moreover, cell apoptosis was rescued in B-ALL cells with over-expressed c-Myc after treatment with CDK9i, which is involved in the enhancement of glycolytic metabolism. In summary, our findings suggest that CDK9 inhibitors induce the apoptosis of B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, thus providing a new strategy for the treatment of B-ALL.

Purpose The Shanghai Preconception Cohort (SPCC) was initially established to investigate the associations of parental periconceptional nutritional factors with congenital heart disease (CHD) but has further analysed child growth and development and paediatric diseases.Participants Preparing-for-pregnancy couples who presented at Shanghai preconception examination clinics and early-pregnancy women before 14 gestational weeks were enrolled to comprise the periconceptional baseline study population. General characteristics, routine clinical data and consumption of diet supplements, such as folic acid and multivitamins, were collected. Blood samples were obtained at preconception and early, middle and late gestations using standard procedures. Multiple nutritional factors, including folate, homocysteine, vitamin A, vitamin D, vitamin E and metals, in the blood samples of participants selected using a case–control design were examined. Genomic DNA was extracted.Findings to date The baseline population included 8045 preconception couples, 3054 single women and 15 615 early-pregnancy women. Data from 12 402 births were collected, and follow-up of the cohort for other outcomes is ongoing. Currently, 151 cases of CHD were identified after birth. The pilot analysis in a small subgroup showed that approximately 20.0% of preconception women and 44.9% of early-pregnancy women had red blood cell (RBC) folate levels that met the international recommendation for preventing neural tube defects.Future plans Once a sufficient number of CHD cases are achieved, we will investigate the quantitative association of preconception RBC folate levels with CHD using a nested case–control design. The SPCC will be followed up for 18 years to investigate extensive outcomes of growth, development, obesity, and common and rare diseases during childhood and adolescence according to our plan. Blood nutritional factors will be examined in participants selected for specific aims. The SPCC will also allow for prospective cohort studies on extensive research questions.Trial registration number NCT 02737644

To understand the prevalence of functional constipation in pregnant women and to analyze the impact of its risk factors.We searched hospital databases for women who were 37-41 weeks pregnant (1698 cases) from July 2012 to January 2014 in four hospitals in Shanghai. We reviewed factors including general data, living and eating habits, psychological history, past history of defecation in the 6 months before pregnancy and defecation after pregnancy. Data were analyzed using SPSS software.Pregnant women who were more than 35 years old, with a pre-pregnancy body mass index >24, who were highly educated and employed in a sedentary occupation, showed a higher prevalence of functional constipation. Multivariate logistic regression analysis indicated that the prevalence of functional constipation among pregnant women was related to age, pre-pregnancy body mass index, diet, exercise, occupation, psychological factors, threatened abortion in early pregnancy and constipation history.The prevalence rate of functional constipation in pregnant women was significantly higher than in the general population.

Laccase activity secreted by Pleurotus eryngii Han 1787 and Lentinus edodes Han 1788 grown on six types of agroindustrial wastes was investigated. Maximum laccase activity of P. eryngii Han 1787 on Ulmus pumila, Juniperus formosana, Pinus tabuliformis, cottonseed shell, corncob, and leaf of corncob was nearly 5.77-fold, 2.37-fold, 2.78-fold, 2.81-fold, 11.53-fold, and 6.73-fold higher than that of L. edodes Han1788 on corresponding agroindustrial wastes. In general, the capacity of secreting laccase of P. eryngii Han 1787 was superior to that of L. edodes Han 1788. Furthermore, laccase activity of P. eryngii Han 1787 on the leaf of corncob, the corncob, Ulmus pumila, and Juniperus formosana was relatively stable during the whole fermentation process. Different fungi showed different preferences in different agroindustrial wastes to secret laccase on whole fermentation stage. The presence of leaf of corncob was useful for improving laccase activity of P. eryngii Han 1787, while L. edodes Han 1788 was more preferred to produce laccase along with the presence of Juniperus formosana. These results were preliminary conducive in laying the foundation for increasing industrial laccaseproducing strains and producing low-cost laccase. [ABSTRACT FROM AUTHOR]

Two-dimensional (2D) ion crystals may represent a promising path to scale up qubit numbers for ion trap quantum information processing. However, to realize universal quantum computing in this system, individually addressed high-fidelity two-qubit entangling gates still remain challenging due to the inevitable micromotion of ions in a 2D crystal as well as the technical difficulty in 2D addressing. Here we demonstrate two-qubit entangling gates between any ion pairs in a 2D crystal of four ions. We use symmetrically placed crossed acousto-optic deflectors (AODs) to drive Raman transitions and achieve an addressing crosstalk error below 0.1%. We design and demonstrate a gate sequence by alternatingly addressing two target ions, making it compatible with any single-ion addressing techniques without crosstalk from multiple addressing beams. We further examine the gate performance versus the micromotion amplitude of the ions and show that its effect can be compensated by a recalibration of the laser intensity without degrading the gate fidelity. Our work paves the way for ion trap quantum computing with hundreds to thousands of qubits on a 2D ion crystal., (© 2024. The Author(s).)

Background: Recent studies show that ribosomal protein S21 (RPS21) plays a role in the development and progression of various malignancies. However, the biological value of RPS21 in hepatocellular carcinoma (HCC) and its association with immunotherapy remain unknown., Methods: Here, we examined the differential expression of RPS21 between HCC and normal liver tissues, using the TCGA, ICGC and GEO databases, followed by verification by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in LO2, SMMC7721, HepG2, and MHCC-97H cell lines. Kaplan-Meier and Cox regression analyses were applied to investigate how RPS21 expression influenced overall survival, and a nomogram was established to predict prognosis among HCC patients. We further analyzed how RPS21 expression was related to tumor immune microenvironment, immunotherapy efficiency, and genomic alterations, and investigated potential underlying mechanisms., Results: RPS21 upregulation was observed in HCC tissues and cell lines, compared to normal controls. Survival analysis revealed that RPS21 overexpression was significantly associated with poor clinical outcomes (all p < 0.05). Functional enrichment analyses indicated that differentially expressed genes relative to RPS21 expression were mainly involved in tumor response, proliferation, and metabolism. Additionally, RPS21 expression was positively correlated with the infiltration of activated CD4 + T cells and tumor mutational burden (all p < 0.05). Moreover, RPS21 was co-expressed with immune-related genes and immune checkpoint genes. Analyses of drug sensitivity predict that HCC patients with low RPS21 expression were more sensitive to targeted immunotherapy., Conclusions: The present results suggested that RPS21 might be a promising prognostic marker and a potential immunotherapy target for patients with HCC., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests in this study., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

A large qubit capacity and an individual readout capability are two crucial requirements for large-scale quantum computing and simulation 1 . As one of the leading physical platforms for quantum information processing, the ion trap has achieved a quantum simulation of tens of ions with site-resolved readout in a one-dimensional Paul trap 2-4 and of hundreds of ions with global observables in a two-dimensional (2D) Penning trap 5,6 . However, integrating these two features into a single system is still very challenging. Here we report the stable trapping of 512 ions in a 2D Wigner crystal and the sideband cooling of their transverse motion. We demonstrate the quantum simulation of long-range quantum Ising models with tunable coupling strengths and patterns, with or without frustration, using 300 ions. Enabled by the site resolution in the single-shot measurement, we observe rich spatial correlation patterns in the quasi-adiabatically prepared ground states, which allows us to verify quantum simulation results by comparing the measured two-spin correlations with the calculated collective phonon modes and with classical simulated annealing. We further probe the quench dynamics of the Ising model in a transverse field to demonstrate quantum sampling tasks. Our work paves the way for simulating classically intractable quantum dynamics and for running noisy intermediate-scale quantum algorithms 7,8 using 2D ion trap quantum simulators., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Rationale: Obesity affects 40% of U.S. adults, is associated with a proinflammatory state, and presents a significant risk factor for the development of severe coronavirus disease (COVID-19). To date, there is limited information on how obesity might affect immune cell responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objectives: To determine the impact of obesity on respiratory tract immunity in COVID-19 across the human lifespan. Methods: We analyzed single-cell transcriptomes from BAL in three ventilated adult cohorts with ( n  = 24) or without ( n  = 9) COVID-19 from nasal immune cells in children with ( n  = 14) or without ( n  = 19) COVID-19, and from peripheral blood mononuclear cells in an independent adult COVID-19 cohort ( n  = 42), comparing obese and nonobese subjects. Measurements and Main Results: Surprisingly, we found that obese adult subjects had attenuated lung immune or inflammatory responses in SARS-CoV-2 infection, with decreased expression of IFN-α, IFN-γ, and TNF-α (tumor necrosis factor α) response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Peripheral blood immune cells in an independent adult cohort showed a similar but less marked reduction in type-I IFN and IFNγ response genes, as well as decreased serum IFNα, in obese patients with SARS-CoV-2. Nasal immune cells from obese children with COVID-19 also showed reduced enrichment of IFN-α and IFN-γ response genes. Conclusions: These findings show blunted tissue immune responses in obese patients with COVID-19, with implications for treatment stratification, supporting the specific application of inhaled recombinant type-I IFNs in this vulnerable subset.

Introduction: Bladder exstrophy-epispadias complex (BEEC) comprises a spectrum of anterior midline congenital malformations, involving the lower urinary tract. BEEC is usually sporadic, but families with more than one affected member have been reported, and a twin concordance study supported a genetic contribution to pathogenesis. Moreover, diverse chromosomal aberrations have been reported in a small subset of individuals with BEEC. The commonest are 22q11.2 microduplications, identified in approximately 3% of BEEC index cases., Objectives: We aimed to refine the chromosome 22q11.2 locus, and to determine whether the encompassed genes are expressed in normal developing and mature human urinary bladders., Results: Using DNA from an individual with CBE, the 22q11.2 duplicated locus was refined by identification of a maternally inherited 314 kb duplication (chr22:21,147,293-21,461,017), as depicted in this image. Moreover, the eight protein coding genes within the locus were found to be expressed during normal developing and mature bladders. To determine whether duplications in any of these individual genes were associated with CBE, we undertook copy number analyses in 115 individuals with CBE without duplications of the whole locus. No duplications of individual genes were found., Discussion: The current study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes are expressed in human bladders both during antenatal development and postnatally. Nevertheless, the precise biological explanation as to why duplication of the phenocritical region of 22q11 confers increased susceptibility to BEEC remains to be determined. The fact that individuals with CBE without duplications of the whole locus also lacked duplication of any of the individual genes suggests that in individuals with BEEC and duplication of the 22q11.2 locus altered dosage of more than one gene may be important in BEEC etiology., Conclusions: The study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes within this locus are expressed in human bladders., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

There is an increasing appreciation that many innate and adaptive immune cell subsets permanently reside within non-lymphoid organs, playing a critical role in tissue homeostasis and defense. The best characterized are macrophages and tissue-resident T lymphocytes that work in concert with organ structural cells to generate appropriate immune responses and are functionally shaped by organ-specific environmental cues. The interaction of tissue epithelial, endothelial and stromal cells is also required to attract, differentiate, polarize and maintain organ immune cells in their tissue niche. All of these processes require dynamic regulation of cellular transcriptional programmes, with epigenetic mechanisms playing a critical role, including DNA methylation and post-translational histone modifications. A failure to appropriately regulate immune cell transcription inevitably results in inadequate or inappropriate immune responses and organ pathology. Here, with a focus on the mammalian kidney, an organ which generates differing regional environmental cues (including hypersalinity and hypoxia) due to its physiological functions, we will review the basic concepts of tissue immunity, discuss the technologies available to profile epigenetic modifications in tissue immune cells, including those that enable single-cell profiling, and consider how these mechanisms influence the development, phenotype, activation and function of different tissue immune cell subsets, as well as the immunological function of structural cells., (© 2021 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.)

Iliac bone specimens of 49 normal Chinese subjects were studied. A series of bone histomorphometric parameters were analysed, including mean trabecular width, trabecular bone volume, mean trabecular plate thickness, mean trabecular plate density and mean trabecular plate spacing. The data suggest that there are close correlations of these parameters with aging. The correlations are very significant between mean trabecular width and trabecular bone volume and mean trabecular plate thickness.